ORCID Profile
0000-0003-0422-8398
Current Organisation
University of Sydney
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Gene Expression (incl. Microarray and other genome-wide approaches) | Central Nervous System | Neurogenetics | Biochemistry and Cell Biology | Psychology | Learning, Memory, Cognition And Language | Sensory Processes, Perception And Performance | Genetics | Neurosciences | Cellular Nervous System | Diagnostic Applications | Central Nervous System | Systems Biology
Nervous system and disorders | Mental health | Health related to ageing | Expanding Knowledge in the Biological Sciences | Inherited diseases (incl. gene therapy) | Diagnostic methods |
Publisher: Springer Science and Business Media LLC
Date: 07-2011
DOI: 10.1007/S00401-011-0852-9
Abstract: Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.
Publisher: Springer Science and Business Media LLC
Date: 13-01-2012
Abstract: The A53T mutation in the α-synuclein gene causes autosomal-dominant Lewy body Parkinson's disease (PD). Cultured cell models have linked this mutation to increased cell macroautophagy, although evidence of enhanced macroautophagy in patients with this mutation has not been assessed. To determine whether macroautophagy is increased by the A53T α-synuclein gene mutation in PD patients and cell models. Formalin-fixed paraffin-embedded 10 μm-thick tissue sections from the substantia nigra and anterior cingulate cortex of two PD patients with the A53T α-synuclein gene mutation were compared with four sporadic PD cases and four controls obtained from the Sydney Brain Bank. Lewy bodies were isolated from frontal cortex of a case with late stage PD (recruited from South Australian Brain Bank). Immunohistochemistry was performed for α-synuclein and the macroautophagy markers autophagy-specific gene (ATG) 5, ATG6/Beclin1 and ATG8/LC3. SH-SY5Y cells were transfected with wild type or A53T mutant α-synuclein plasmids and observable changes in macroautophagy marker protein levels assessed using Western blotting. α-Synuclein immunoreactive neurites and dots were more numerous in patients with A53T mutations compared with late stage sporadic PD patients, and perinuclear cytoplasmic α-synuclein aggregates were observed in the α-synuclein A53T gene transfected SH-SY5Y cells compared to wild type transfections. All PD patients (with or without A53T mutations) had increased immunohistochemical evidence for macroautophagy compared with controls, and the levels of the ATG5 complex were equally increased in wild type and A53T α-synuclein gene transfected cells compared to controls. Despite increased α-synuclein accumulation with A53T mutations, macroautophagy is not increased above that observed in sporadic patients with PD or in cells transfected with wild type α-synuclein, suggesting that mutated α-synuclein protein is not removed by macroautophagy.
Publisher: Oxford University Press (OUP)
Date: 05-2007
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.NEUROBIOLAGING.2005.03.011
Abstract: Multiple degenerative hallmarks characterize Alzheimer's disease: insoluble protein deposition, neuronal loss and cortical atrophy. Atrophy begins in the medial temporal lobe and becomes global by end stage. In a small proportion of cases, these tissue changes are caused by mutations in three known genes. These cases are affected earlier in life and have more abundant protein deposition, which may indicate greater tissue atrophy and degeneration. This issue remains unresolved. Grey matter atrophy in different cortical regions was determined in genetic cases of Alzheimer's disease (N = 13) and compared to sporadic cases (N = 13) and non-diseased controls (N = 23). Genetic mutations were found to influence the degree and regional pattern of atrophy. The majority of cases had greater medial temporal atrophy than sporadic disease, suggesting that abnormalities affecting Abeta metabolism selectively increase hippoc al degeneration. Cases with mutations in presenilin-1 demonstrated additional increased frontotemporal atrophy. This effect may be due to the influence of presenilin-1 on tau phosphorylation and metabolism. These differences may explain the earlier onset ages in these different forms of Alzheimer's disease.
Publisher: Oxford University Press (OUP)
Date: 07-2000
Abstract: Whilst many reports mention neurofibrillary tangle pathology in the thalamus in progressive supranuclear palsy, there has been little detailed regional analysis of the distribution and density of thalamic pathology in this disease or in other parkinsonian syndromes. The caudal intralaminar thalamic nuclei are the major thalamic regulators of the caudate nucleus and putamen, areas known to be dysfunctional in progressive supranuclear palsy and Parkinson's disease. We investigated whether these thalamic nuclei degenerate in patients with these disorders compared with age-matched, neurologically normal controls. Neurofibrillary tangle and Lewy body pathology was assessed and unbiased optical disector methods were used to quantify total neuronal number. Despite different thalamic pathology, there was a dramatic reduction in the total neuronal number in the caudal intralaminar nuclei in both progressive supranuclear palsy and Parkinson's disease (40-55% loss). In contrast, there was no loss of volume or total neuronal number in the limbic thalamic nuclei in either disease group, indicating selective degeneration of the caudal intralaminar nuclei. In Parkinson's disease, Lewy bodies were found in these regions, while in progressive supranuclear palsy abundant intracellular neurofibrillary tangles and glial tangles concentrated in the caudal intralaminar nuclei. However, tangle formation accounted for only a small proportion of cell loss (</=10%) in the thalamus in progressive supranuclear palsy. These findings have several implications. The caudal intralaminar thalamus appears to be one of three basal ganglia sites commonly affected in both progressive supranuclear palsy and Parkinson's disease. These sites are the dopaminergic substantia nigra, the cholinergic pedunculopontine tegmental nucleus and, from our results, the glutamatergic caudal intralaminar thalamus. In both diseases these sites contain characteristic but different pathologies, indicating disease-specific mechanisms of neurodegeneration. Interestingly, the proportion of remaining neurons affected by these pathologies is low. This may indicate additional (possibly common) cellular mechanisms responsible for the degeneration in these regions. Both the dopaminergic nigra and the glutamatergic caudal intralaminar thalamus are the major regulators of basal ganglia function via the caudate nucleus and putamen. The pedunculopontine tegmental nucleus has major projections to both of these regulators. These findings indicate that dysregulation of two neurotransmitter systems within the basal ganglia may underlie common parkinsonian symptoms in these disorders. For patients with Parkinson's disease, this loss of glutamate regulation may help explain some problems with dopamine replacement therapies, particularly over time. For patients with progressive supranuclear palsy, more widespread degeneration of basal ganglia structures would contribute to poor treatment outcomes.
Publisher: Public Library of Science (PLoS)
Date: 23-06-2016
Publisher: Elsevier BV
Date: 05-1987
DOI: 10.1016/0165-0173(87)90011-7
Abstract: The VTA contains the A10 group of DA containing neurons. These neurons have been grouped into nuclei to be found on the floor of the midbrain tegmentum--Npn, Nif, Npbp and Nln rostralis and caudalis. The VTA is traversed by many blood vessels and nerve fibers. Close to its poorly defined borders are found DA (A8, A9, A11) and 5-HT containing neurons (B8). Efferent projections of the VTA can be ided into 5 subsystems. The mesorhombencephalic projects to other monoaminergic nuclei, the cerebellum and a fine projection descends to other tegmental nuclei as far as the inferior olive. Fibers to the spinal cord have not been demonstrated. The mesodiencephalic path projects to several thalamic and hypothalamic nuclei and possibly the median eminence. Functionally important ex les are the anterior hypothalamic-preoptic area, N. medialis dorsalis and reuniens thalami. These two subsystems are largely non-dopaminergic. A minor mesostriatal projection is overshadowed by the large mesolimbic projection to the accumbens, tuberculum olfactorium, septum lateralis and n. interstitialis stria terminalis. There are also mesolimbic connections with several amygdaloid nuclei (especially centralis and basolateralis), the olfactory nuclei and entorhinal cortex. A minor projection to the hippoc us has been detected. The mesocortical pathway projects to sensory (e.g. visual), motor, limbic (e.g. retrosplenial) and polysensory association cortices (e.g. prefrontal). Prefrontal, orbitofrontal (insular) and cingulate cortices receive the most marked innervation from the VTA. A more widespread presence of DA in other cortices of rodents becomes progressively more evident in carnivores and primates. Most but not all projections are unilateral. Some neurons project to more than one area in mesodiencephalic, limbic and cortical systems. The majority of these fibers ascend in the MFB. Most areas receiving a projection from the VTA (DA or non-DA) project back to the VTA. The septohippoc al complex in particular and the limbic system in general provide quantitatively much less feedback than other areas. The role of the VTA as a mediator of dialogue with the frontostriatal and limbic/extrapyramidal system is discussed under the theme of circuit systems. The large convergence of afferents to certain VTA projection areas (prefrontal, entorhinal cortices, lateral septum, central amygdala, habenula and accumbens) is discussed under the theme of convergence systems.(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Wiley
Date: 16-03-2016
Publisher: Elsevier BV
Date: 12-2017
Publisher: Wiley
Date: 25-02-2016
DOI: 10.1002/MDS.26529
Abstract: We aimed to determine if peripheral or central inflammatory cytokines are altered in healthy subjects carrying a leucine-rich repeat kinase 2 (LRRK2) G2019S mutation, and thus genetically at risk of Parkinson's disease (PD). We also aimed to identify differences in inflammatory cytokines between LRRK2 G2019S-associated and idiopathic PD once the disease manifests. Participants were genetically screened and phenotyped, and biological s les were collected and stored by the Michael J. Fox Foundation LRRK2 Cohort Consortium. Serum s les and matching clinical data were obtained from 71 asymptomatic LRRK2 G2019S mutation carriers (CSF n = 25), 75 neurologically normal controls (CSF n = 22), 75 idiopathic PD patients (CSF n = 29), and 76 PD patients with a LRRK2 G2019S mutation (CSF n = 20). Inflammatory cytokines were measured using multiplex enzyme-linked immunosorbent assays. Serum levels of interleukin 1 beta could discriminate asymptomatic LRRK2 G2019S mutation carriers from controls, with a high inflammatory subgroup of carriers identified. This subgroup was significantly higher in a number of PD-implicated pro-inflammatory cytokines. Once PD had manifest, LRRK2 G2019S patients were discriminated from idiopathic PD by higher serum platelet-derived growth factor, and higher CSF vascular endothelial growth factor and interleukin 8. The results suggest that peripheral inflammation is higher in a percentage of subjects carrying the LRRK2 G2019S mutation. Replication and longitudinal follow-up is required to determine whether the increased peripheral cytokines can predict clinical PD. Importantly, these biological changes were observed prior to the clinical manifestations thought to herald PD. © 2016 International Parkinson and Movement Disorder Society.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2012
Publisher: Wiley
Date: 02-12-2016
DOI: 10.1002/MDS.26892
Abstract: Leucine rich repeat kinase 2 (LRRK2) is a promising target for the treatment of Parkinson's disease however, little is known about the expression of LRRK2 in human brain and if/how LRRK2 protein levels are altered in Parkinson's disease. We measured the protein levels of LRRK2 as well as its phosphorylation on serines 910, 935, and 973 in the postmortem brain tissue of Parkinson's disease patients and aged controls with and without Lewy bodies. LRRK2 and its phosphorylation were measured by immunoblot in brain regions differentially affected in Parkinson's disease (n = 30) as well as subjects with Lewy bodies restricted to the periphery and lower brain stem (n = 25) and matched controls without pathology (n = 25). LRRK2 levels were increased in cases with restricted Lewy bodies, with a 30% increase measured in the substantia nigra. In clinical Parkinson's disease, levels of LRRK2 negatively correlated to disease duration and were comparable with controls. LRRK2 phosphorylation, however, particularly at serine 935, was reduced with clinical Parkinson's disease with a 36% reduction measured in the substantia nigra. Our data show that LRRK2 phosphorylation is reduced with clinical PD, whereas LRRK2 expression is increased in early potential prodromal stages. These results contribute to a better understanding of the role of LRRK2 in idiopathic Parkinson's disease and may aid efforts aimed at therapeutically targeting the LRRK2 protein. © 2016 International Parkinson and Movement Disorder Society.
Publisher: Wiley
Date: 10-2011
DOI: 10.1111/J.1741-6612.2011.00534.X
Abstract: To examine the concordance rates of common medical conditions and neurocognitive performance in monozygotic (MZ) and dizygotic (DZ) older twins. Twins aged ≥ 65 years and living in the three Eastern states of Australia were recruited through the Australian Twin Registry and underwent detailed neuropsychological and medical assessment. Assessments were conducted on 113 MZ and 96 DZ twin pairs, with a mean age of 70.5 years. MZ twins were more concordant than DZ twins for hypertension and asthma. MZ twins had higher correlations than DZ twins on most neuropsychological tests, with the exception of some tests related to processing speed. The concordance rate for mild cognitive impairment or dementia was 76.2% in MZ twins and 42.9% in DZ twins, a non-significant difference. Except for some aspects of processing speed, most cognitive functions in older in iduals show significant heritability. The heritability of neurocognitive disorders is, however, low.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2010
Publisher: Wiley
Date: 12-1997
DOI: 10.1111/J.1365-2990.1997.TB01326.X
Abstract: The primary site of pathology in Huntington's disease (HD) is the caudate nucleus. However, cortical changes are also commonly reported. While many researchers have studied pathology in the frontal lobe, little attention has been paid to posterior cortical regions. The aim of this study is to examine pathology in the parietal lobe in patients with HD as it has specific projections to the caudate nucleus. Post-mortem brain tissue was obtained from HD patients with both a positive family history and clinicopathological diagnosis (n = 6 Vonsattel grades 2-4) as well as from neurologically normal controls (n = 6). The angular gyrus of the parietal lobe was s led and cellular quantification of SMI-32 immunohistochemically detected pyramidal neurons performed. Cortical blocks were sectioned at 50 microns on a cryostat and stained immunohistochemically using antigen retrieval methods and peroxidase visualization. HD subjects had noticeable histological changes including smaller neurons and a disruption of cortical laminar pattern. Quantification using a point counting method to find the areal fraction of immunoreactive neurons revealed a severe loss of pyramidal neurons in the angular gyrus of HD subjects compared with controls (reduced on average to 55% of mean control values, P = 0.038 using the Mann-Whitney U-test). This striking cortical pathology suggests that HD may preferentially target posterior cortical regions, particularly the angular gyrus which has a significant projection to the caudate nucleus in primates.
Publisher: Springer Science and Business Media LLC
Date: 07-1995
DOI: 10.1007/BF00294461
Publisher: Springer Science and Business Media LLC
Date: 11-1992
DOI: 10.1007/BF00227741
Abstract: With sliding actin-filament motility assays, filament velocity should be independent of changes in the level of actomyosin activation under unloaded conditions. Using a simple modification of the motility assay to measure relative changes in isometric force (activation), we determined that isometric force increased 200-fold with thiophosphorylation of the myosin regulatory light chain, and that with thiophosphorylated myosin, isometric force was further increased by the addition of saturating smooth-muscle tropomyosin (100%) or tropomyosin plus calponin (500%), and decreased with the addition of saturating caldesmon (-100%). Under "reducing conditions," filament velocity (2.0 microns/s) was constant for mixtures of dephosphorylated and thiophosphorylated myosin containing > 5% thiophosphorylated myosin, and was unaffected by the addition of saturating concentrations of tropomyosin or caldesmon. In contrast, "standard assay conditions" were found to be nonreducing. With fully thiophosphorylated smooth-muscle myosin, saturating smooth-muscle tropomyosin increased velocity to 150% of control, and caldesmon halted all filament motion with fully dephosphorylated myosin (< 0.002 mol/mol) filaments only moved when tropomyosin or tropomyosin plus calponin was added. Taken together, these observations suggest that under "standard conditions" a mechanical load is present that is eliminated by "reducing conditions." Filament velocity was insensitive to changes in cross-bridge density, under all conditions, suggesting that noncycling cross-bridges, generated by photochemical oxidation of myosin, is a likely source of mechanical loading.
Publisher: Elsevier BV
Date: 08-2004
Publisher: Springer Science and Business Media LLC
Date: 31-05-2021
DOI: 10.1038/S41380-021-01149-3
Abstract: Neural stem cells in the human subependymal zone (SEZ) generate neuronal progenitor cells that can differentiate and integrate as inhibitory interneurons into cortical and subcortical brain regions yet the extent of adult neurogenesis remains unexplored in schizophrenia and bipolar disorder. We verified the existence of neurogenesis across the lifespan by chartering transcriptional alterations (2 days-103 years, n = 70) and identifying cells indicative of different stages of neurogenesis in the human SEZ. Expression of most neural stem and neuronal progenitor cell markers decreased during the first postnatal years and remained stable from childhood into ageing. We next discovered reduced neural stem and neuronal progenitor cell marker expression in the adult SEZ in schizophrenia and bipolar disorder compared to controls (n = 29-32 per group). RNA sequencing identified increased expression of the macrophage marker CD163 as the most significant molecular change in schizophrenia. CD163
Publisher: Wiley
Date: 30-12-2018
DOI: 10.1002/MDS.27601
Abstract: Leucine-rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine-rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine-rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine-rich repeat kinase 2 inhibitor clinical trials. Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated ex vivo with a leucine-rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine-rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme-linked immunosorbent assay. Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine-rich repeat kinase 2 inhibitor treatment. Leucine-rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine-rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine-rich repeat kinase 2 levels. Immune-cell levels of leucine-rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels. Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine-rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine-rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine-rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine-rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society.
Publisher: Oxford University Press (OUP)
Date: 27-06-2014
DOI: 10.1093/HMG/DDU334
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 2002
DOI: 10.1002/MDS.1261
Abstract: This is the second neuropathological report detailing bilateral electrodes targeting the subthalamic nucleus (STN) in idiopathic Parkinson's disease (PD). The patient presented with unilateral tremor-dominant parkinsonism. Bilateral STN stimulation was carried out 7 years later due to significant disease progression and severe motor fluctuations. The patient exhibited bilateral improvements in rigidity and bradykinesia both intraoperatively and postoperatively. The patient died 2 months later from aspiration pneumonia. Neuropathological examination confirmed both the diagnosis of PD and the electrode placements. The tip of the left electrode was located medially and posteriorly in the left STN and the tip of the right electrode entered the base of the thalamus/zona incerta immediately above the right STN. Tissue changes associated with the subthalamic electrode tracts included mild cell loss, astrogliosis, and some tissue vacuolation. Our postmortem analysis indicates little tissue damage associated with STN stimulation for PD.
Publisher: Elsevier BV
Date: 05-2014
DOI: 10.1016/J.PNEUROBIO.2014.01.004
Abstract: Visual hallucinations are common across a number of disorders but to date, a unifying pathophysiology underlying these phenomena has not been described. In this manuscript, we combine insights from neuropathological, neuropsychological and neuroimaging studies to propose a testable common neural mechanism for visual hallucinations. We propose that 'simple' visual hallucinations arise from disturbances within regions responsible for the primary processing of visual information, however with no further modulation of perceptual content by attention. In contrast, 'complex' visual hallucinations reflect dysfunction within and between the Attentional Control Networks, leading to the inappropriate interpretation of ambiguous percepts. The incorrect information perceived by hallucinators is often differentially interpreted depending on the time-course and the neuroarchitecture underlying the interpretation. Disorders with 'complex' hallucinations without retained insight are proposed to be associated with a reduction in the activity within the Dorsal Attention Network. The review concludes by showing that a variety of pathological processes can ultimately manifest in any of these three categories, depending on the precise location of the impairment.
Publisher: BMJ
Date: 12-05-2016
Publisher: American Medical Association (AMA)
Date: 11-04-2011
Publisher: Oxford University Press (OUP)
Date: 04-2007
Publisher: Wiley
Date: 10-2015
DOI: 10.1002/MDS.26424
Abstract: This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.
Publisher: Cold Spring Harbor Laboratory
Date: 09-11-2022
DOI: 10.1101/2022.11.08.515615
Abstract: Intracellular inclusions accompanying neurodegeneration are histopathologically and ultrastructurally heterogeneous but the significance of this heterogeneity is unclear. iPSC models, while promising for disease modeling, do not form inclusions in a reasonable timeframe and suffer from limited tractability. Here, we developed an iPSC toolbox utilizing piggyBac-based or targeted transgenes to rapidly induce CNS cells with concomitant expression of aggregation-prone proteins. This system is amenable to screening and longitudinal tracking at single-cell and single-inclusion resolution. For proof-of-principle, cortical neuron α-synuclein “inclusionopathy” models were engineered to form inclusions through exogenous seeding or α-synuclein mutation. These models recapitulated known fibril- and lipid-rich inclusion subtypes, uncovering dynamic interactions between them, and refined the classification of inclusions in postmortem brain. Genetic-modifier and protein-interaction screens pinpointed proteins like RhoA whose sequestration into specific inclusion subtypes is likely to be toxic. This iPSC platform should enhance our understanding of proteinaceous pathologies in neurodegeneration and facilitate therapeutics development.
Publisher: Wiley
Date: 03-2001
DOI: 10.1002/MDS.1053
Abstract: We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause.
Publisher: Elsevier BV
Date: 2007
Publisher: Oxford University Press (OUP)
Date: 2000
Abstract: The specific neural substrate underlying the amnesia in alcoholic Korsakoff's psychosis is poorly defined because of the considerable brain damage found in many non-amnesic alcoholics, particularly those with Wernicke's encephalopathy. Using operational criteria to identify alcoholics with and without Korsakoff's psychosis, we have shown that many of the cortical and subcortical regions involved in the encoding and retrieval of episodic memory are either unaffected (hippoc us) or damaged to the same extent (prefrontal cortex and the cholinergic basal forebrain) in both amnesic and non-amnesic alcoholics. In the present study we analysed the diencephalic regions involved in episodic memory to determine the neural substrate for the amnesia observed in alcoholic Korsakoff's psychosis. The number of neurons in spaced serial sections containing the hypothalamic mamillary nuclei and the anterior and mediodorsal thalamic nuclei was estimated using unbiased stereological techniques. Neurodegeneration of the hypothalamic mamillary nuclei and the mediodorsal thalamic nuclei was substantial in both non-amnesic and amnesic alcoholics with Wernicke's encephalopathy. However, neuronal loss in the anterior thalamic nuclei was found consistently only in alcoholic Korsakoff's psychosis. This is the first demonstration of a differentiating lesion in alcoholic Korsakoff's psychosis and supports previous evidence that degeneration of thalamic relays are important in this memory disorder.
Publisher: Wiley
Date: 10-2015
DOI: 10.1002/MDS.26431
Abstract: This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease-modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an in idual's risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available.
Publisher: Wiley
Date: 26-09-2016
DOI: 10.1002/MDS.26796
Publisher: Springer Science and Business Media LLC
Date: 15-06-2019
DOI: 10.1007/S00401-019-02035-7
Abstract: The frontotemporal tauopathies all deposit abnormal tau protein aggregates, but often of only certain isoforms and in distinguishing pathologies of five main types (neuronal Pick bodies, neurofibrillary tangles, astrocytic plaques, tufted astrocytes, globular glial inclusions and argyrophilic grains). In those with isoform specific tau aggregates glial pathologies are substantial, even though there is limited evidence that these cells normally produce tau protein. This review will assess the differentiating features and clinicopathological correlations of the frontotemporal tauopathies, the genetic predisposition for these different pathologies, their neuroanatomical selectivity, current observations on how they spread through the brain, and any potential contributing cellular and molecular changes. The findings show that erse clinical phenotypes relate most to the brain region degenerating rather than the type of pathology involved, that different regions on the MAPT gene and novel risk genes are associated with specific tau pathologies, that the 4-repeat glial tauopathies do not follow in idual patterns of spreading as identified for neuronal pathologies, and that genetic and pathological data indicate that neuroinflammatory mechanisms are involved. Each pathological frontotemporal tauopathy subtype with their distinct pathological features differ substantially in the cell type affected, morphology, biochemical and anatomical distribution of inclusions, a fundamental concept central to future success in understanding the disease mechanisms required for developing therapeutic interventions. Tau directed therapies targeting genetic mechanisms, tau aggregation and pathological spread are being trialled, although biomarkers that differentiate these diseases are required. Suggested areas of future research to address the regional and cellular vulnerabilities in frontotemporal tauopathies are discussed.
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/BRAIN/AWV115
Publisher: Oxford University Press (OUP)
Date: 11-09-2015
DOI: 10.1093/BRAIN/AWU268
Publisher: Elsevier BV
Date: 1990
Publisher: Springer Science and Business Media LLC
Date: 09-1996
DOI: 10.1007/BF02237959
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2008
DOI: 10.1212/01.WNL.0000319691.50117.54
Abstract: White matter hyperintensities (WMH) are commonly seen on neuroimaging scans, but their underlying histopathologic substrate is unclear. The aim of this work was to establish the pathologic correlates of WMH in unselected elderly cases using two study designs. To avoid potential bias from comparisons of different anatomic regions, study 1 compared, region-by-region, the severity of WMH determined in vivo with measures of each of the major white matter (WM) components. Study 2 compared the histopathology of WMH with normal WM. Study 1: The periventricular and deep WM regions of three lobes in 23 brains with in vivo MRI scans were investigated using histologic and immunohistochemical stains. The severity of each pathologic measure was correlated with WMH severity determined using the Scheltens scale. Study 2: Lesioned and nonlesioned areas identified by postmortem MRI in the frontal WM of 20 brains were examined histologically and immunohistochemically. No single pathologic variable correlated with the severity of WMH however, a multiple stepwise regression analysis revealed that vascular integrity predicted total Scheltens score (beta = -0.53, p = 0.01). Comparison of lesioned and nonlesioned areas demonstrated that vascular integrity was reduced in WMH [t(18) = 3.79, p = 0.001]. Blood-brain barrier integrity was also found to be reduced in WMH [t(5) = -5.31, p = 0.003]. White matter hyperintensities (WMH) involve a loss of vascular integrity, confirming the vascular origin of these lesions. This damage to the vasculature may in turn impair blood-brain barrier integrity and be one mechanism by which WMH evolve.
Publisher: Wiley
Date: 02-10-2012
DOI: 10.1002/MDS.25202
Publisher: Cambridge University Press (CUP)
Date: 12-2009
Abstract: The Older Australian Twins Study (OATS) was recently initiated to investigate genetic and environmental factors and their associations and interactions in healthy brain ageing and ageing-related neurocognitive disorders. The study extends the classic MZ-DZ design to include one or two equivalently aged siblings for each twin pair and utilizes the rich resources of the Australian Twin Registry. The study has a number of distinguishing features including comprehensive psychiatric, neuropsychological, cardiovascular, metabolic, and neuroimaging assessments, a longitudinal design and links with a brain donor program. The study measures many behavioral and environmental factors, but in particular lifetime physical and mental activity, physical and psychological trauma, loss of parent early in life, later losses and life events, early-life socioeconomic environment, alcohol and drug use, occupational exposure, and nutrition. It also includes comprehensive cardiovascular assessment, blood biochemistry, genetics and proteomics. The socio-demographic and health data on the first 172 pairs of twins participating in this study are presented. Prevalence of mild cognitive impairment is 12.8% and of dementia 1.5% in the s le. The target s le size is 1000, with at least 400 pairs of twins aged 65–90 years. The cohort will be assessed every two years, with in-depth assessments being repeated. OATS offers an excellent opportunity for collaboration with other similar studies as well as researchers who share the same interests.
Publisher: BMJ
Date: 04-06-2014
Publisher: Informa UK Limited
Date: 2003
DOI: 10.1080/13576500244000175
Abstract: We present histological data from 21 post-mortem, adult human cases that indicate the neocortex on the left planum temporale (secondary auditory cortex) is thinner but longer than that on the right side. The volumes of the left and right regions are approximately equal. Thus, the left planum temporale cortex is long and thin and the right short and thick. The present data fit excellently with previous studies of the volume, surface area, cytoarchitectonics, and neuronal structures of these areas. From these studies we suggest that the hemispheric differences arise from a so-called "balloon model" of cortical development. In this the cortex is extended and stretched by white matter growth. The stretching is greater on the left side, leaving greater distances between neuronal columns and more tangentially (to the pial surface) oriented dendrites on that side. This difference in fine structure can result in more independent activity of in idual columns on the left, and could be an anatomical factor in the usual dominance of the left hemisphere for speech perception (Seldon, 1982, 1985).
Publisher: Frontiers Media SA
Date: 24-06-2014
Publisher: Oxford University Press (OUP)
Date: 24-02-2022
Abstract: Frontotemporal dementia refers to a group of neurodegenerative disorders characterized by behaviour and language alterations and focal brain atrophy. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by loss of motor neurons resulting in muscle wasting and paralysis. Frontotemporal dementia and amyotrophic lateral sclerosis are considered to exist on a disease spectrum given substantial overlap of genetic and molecular signatures. The predominant genetic abnormality in both frontotemporal dementia and amyotrophic lateral sclerosis is an expanded hexanucleotide repeat sequence in the C9orf72 gene. In terms of brain pathology, abnormal aggregates of TAR-DNA-binding protein-43 are predominantly present in frontotemporal dementia and amyotrophic lateral sclerosis patients. Currently, sensitive and specific diagnostic and disease surveillance biomarkers are lacking for both diseases. This has impeded the capacity to monitor disease progression during life and the development of targeted drug therapies for the two diseases. The purpose of this review is to examine the status of current biofluid biomarker discovery and development in frontotemporal dementia and amyotrophic lateral sclerosis. The major pathogenic proteins implicated in different frontotemporal dementia and amyotrophic lateral sclerosis molecular subtypes and proteins associated with neurodegeneration and the immune system will be discussed. Furthermore, the use of mass spectrometry-based proteomics as an emerging tool to identify new biomarkers in frontotemporal dementia and amyotrophic lateral sclerosis will be summarized.
Publisher: Wiley
Date: 04-09-2015
DOI: 10.1002/MDS.26421
Abstract: Parkinson's disease is a progressive neurodegenerative disorder with multiple factors contributing to increasing severity of pathology in specific brain regions. The Braak hypothesis of Lewy pathology progression in Parkinson's disease proposes a systematic spread of α-synuclein that can be staged, with the later stages correlating with clinical aspects of the disease. The spread of pathology through the different stages suggests progression, a theory that has proven correct from evidence of pathology in healthy neurons grafted into the brains of patients with Parkinson's disease. Progression of pathology occurs on a number of levels, within a cell, between nearby cells, and then over longer distances throughout the brain, and evidence using prion proteins suggests two dissociable mechanisms-intracellular toxicity versus a nontoxic infectious mechanism for propagation. In Parkinson's disease, intracellular changes associated with mitochondria and lysosome dysfunction appear important for α-synuclein propagation, with high stress conditions favoring mitochondrial cell death mechanisms. Functional neurons appear necessary for propagation. Unconventional exocytosis releases α-synuclein under stress conditions, and endocytic uptake occurs in nearby cells. This cell-to-cell transmission of α-synuclein has been recapitulated in both cell culture and animal models, but the timeframe of transmission is considerably shorter than that observed in transplanted neurons. The time course of Lewy pathology formation in patients is consistent with the long time course observed in grafted neurons, and the restricted neuronal loss in Parkinson's disease is potentially important for the propagation of α-synuclein through relatively intact circuits.
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0306-4522(91)90043-N
Abstract: The distribution, morphology and number of serotonin-, catecholamine- and substance P-containing neurons in the human dorsal raphe nucleus were studied. Parallel series of sections were prepared from 10 human brainstems obtained at autopsy from patients without neurological disease aged between 42 and 88 years. The neurons were identified using immunohistochemistry with antibodies raised against phenylalanine hydroxylase (tryptophan hydroxylase-containing, serotonin neurons), tyrosine hydroxylase (catecholamine neurons) and substance P. A reference series of Nissl-stained sections was also prepared and data published separately were used to delineate the subnuclear isions of the dorsal raphe nucleus and to establish the total number of neurons in each subnucleus. The following principal findings emerged. (1) Serotonin-synthesizing neurons are present in all regions of the dorsal raphe nucleus and their total number is 165,000 +/- 34,000. The same types of neurons as those seen in Nissl material characterize each of the five subnuclei (caudal, dorsal, ventral, ventrolateral and interfascicular). (2) Substance P-containing neurons mostly occupy the rostral part of the nucleus and their number is 74,600 +/- 17,600. (3) Catecholamine cells are only found in the rostral part of the dorsal raphe nucleus and their number is 5600 +/- 3400. (4) In the ventral and interfascicular subnuclei the combined number of serotonin-synthesizing and substance P-containing neurons exceeds the total number of Nissl-stained neurons suggesting that serotonin and substance P co-exist in a substantial part of the cell population of the dorsal raphe nucleus. This is further supported by the highly similar morphology and size of these neurons. It is concluded that there are demonstrable chemical differences between the various subregions of the human dorsal raphe nucleus. These differences are in harmony with the results of hodological studies in animals, which have demonstrated differential projection pathways emerging from this nucleus.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2016
DOI: 10.1038/SREP31391
Abstract: Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson’s disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson’s disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson’s disease patients. Peripheral mononuclear cells from idiopathic Parkinson’s disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson’s disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson’s disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting.
Publisher: Wiley
Date: 08-11-1990
Abstract: Serial 50 microns Nissl-stained sections through the midbrain and pontine central gray of four adult humans (mean age 56 years, mean postmortem delay 3 hours) were analysed and the subnuclei of the dorsal raphe nucleus (DR) delineated on the basis of neuronal morphology and density. Five subnuclei were apparent: the interfascicular, ventral, ventrolateral, dorsal, and caudal. The area of each subnucleus was measured in sections selected at regular intervals throughout the length of the DR. The number of neurons was counted and their density within each subnucleus calculated. The dorsal subnucleus was the largest and contained the majority of neurons but had the lowest neuronal density. The ventrolateral subnucleus had the highest density of neurons. A total of 235,000 +/- 15,000 neurons (average of 1,200 +/- 200 neurons per section) were found within a volume of 71.3 +/- 4.5 mm3 of DR with a mean neuronal density of 3,300 +/- 200 neurons/mm3. Morphometric and morphological analysis of DR neurons revealed four distinct neuron types: round, ovoid, fusiform, and triangular. These types of neurons characterized particular subnuclei. The location and boundaries of the subnuclei of the human dorsal raphe are presented in the form of an atlas. The sub isions described are similar to that described in other mammals. On the basis of this information the location of particular projection neurons within the human dorsal raphe can be predicted and the effects of disease on this nucleus may be forecast.
Publisher: Springer Science and Business Media LLC
Date: 07-01-2022
DOI: 10.1038/S41598-021-03976-4
Abstract: The generation of new neurons within the mammalian forebrain continues throughout life within two main neurogenic niches, the subgranular zone (SGZ) of the hippoc al dentate gyrus, and the subependymal zone (SEZ) lining the lateral ventricles. Though the SEZ is the largest neurogenic niche in the adult human forebrain, our understanding of the mechanisms regulating neurogenesis from development through aging within this region remains limited. This is especially pertinent given that neurogenesis declines dramatically over the postnatal lifespan. Here, we performed transcriptomic profiling on the SEZ from human post-mortem tissue from eight different life-stages ranging from neonates (average age ~ 2 months old) to aged adults (average age ~ 86 years old). We identified transcripts with concomitant profiles across these decades of life and focused on three of the most distinct profiles, namely (1) genes whose expression declined sharply after birth, (2) genes whose expression increased steadily with age, and (3) genes whose expression increased sharply in old age in the SEZ. Critically, these profiles identified neuroinflammation as becoming more prevalent with advancing age within the SEZ and occurring with time courses, one gradual (starting in mid-life) and one sharper (starting in old age).
Publisher: Wiley
Date: 04-10-2013
DOI: 10.1002/MDS.25693
Publisher: Springer Science and Business Media LLC
Date: 27-02-2020
DOI: 10.1038/S41598-020-60457-W
Abstract: Blood serum is enriched in lipids and has provided a platform to understand the pathogenesis of a number of human diseases with improved diagnosis and development of biomarkers. Understanding lipid changes in neurodegenerative diseases is particularly important because of the fact that lipids make up % of brain tissues. Frontotemporal dementia (FTD) is a common cause of early onset dementia, characterized by brain atrophy in the frontal and temporal regions, concomitant loss of lipids and dyslipidemia. However, little is known about the link between dyslipidemia and FTD pathophysiology. Here, we utilized an innovative approach – lipidomics based on mass spectrometry – to investigate three key aspects of FTD pathophysiology – mitochondrial dysfunction, inflammation, and oxidative stress. We analyzed the lipids that are intrinsically linked to neurodegeneration in serum collected from FTD patients and controls. We found that cardiolipin, acylcarnitine, lysophosphatidylcholine, platelet-activating factor, o-acyl-ω-hydroxy fatty acid and acrolein were specifically altered in FTD with strong correlation between the lipids, signifying pathophysiological changes in FTD. The lipid changes were verified by measurement of the common disease markers (e.g. ATP, cytokine, calcium) using conventional assays. When put together, these results support the use of lipidomics technology to detect pathophysiological changes in FTD.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2015
Abstract: The neural substrates of visual hallucinations remain an enigma, due primarily to the difficulties associated with directly interrogating the brain during hallucinatory episodes. To delineate the functional patterns of brain network activity and connectivity underlying visual hallucinations in Parkinson’s disease. In this study, we combined functional magnetic resonance imaging (MRI) with a behavioral task capable of eliciting visual misperceptions, a confirmed surrogate for visual hallucinations, in 35 patients with idiopathic Parkinson’s disease. We then applied an independent component analysis to extract time series information for large-scale neuronal networks that have been previously implicated in the pathophysiology of visual hallucinations. These data were subjected to a task-based functional connectivity analysis, thus providing the first objective description of the neural activity and connectivity during visual hallucinations in patients with Parkinson’s disease. Correct performance of the task was associated with increased activity in primary visual regions however, during visual misperceptions, this same visual network became actively coupled with the default mode network (DMN). Further, the frequency of misperception errors on the task was positively correlated with the strength of connectivity between these two systems, as well as with decreased activity in the dorsal attention network (DAN), and with impaired connectivity between the DAN and the DMNs, and ventral attention networks. Finally, each of the network abnormalities identified in our analysis were significantly correlated with two independent clinical measures of hallucination severity. Together, these results provide evidence that visual hallucinations are due to increased engagement of the DMN with the primary visual system, and emphasize the role of dysfunctional engagement of attentional networks in the pathophysiology of hallucinations.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.NEUROBIOLAGING.2022.01.001
Abstract: Recent models of hallucinations in Lewy body disorders implicate dysfunction in 'higher order' thalamic regions involved in perceptual integration and cognitive processing. However, the degree of pathology and degeneration in these regions has not been assessed. We sought to assess atrophy, neuronal size, and neuronal numbers in the Mediodorsal (MDn) and Anterior Principal (APn) nuclei of the thalamus across Lewy body disorders comparing between patients with and without hallucinations. Postmortem tissue was acquired from 24 patients with Lewy body disease and 10 age-matched controls and analyzed using standard stereological and quantitative neuropathological techniques. Atrophy in MDn was significantly greater in patients with well-formed visual hallucinations and did not correlate significantly with neuronal size or number. Atrophy in APn was seen across all Lewy body disorders but was not significantly associated with hallucinations. α-synuclein immunoreactivity was found to be low in both the APn and MDn across all groups. These results suggest that MDn atrophy may be a marker of hallucinations and plays a role in their pathophysiology.
Publisher: Oxford University Press (OUP)
Date: 23-07-2013
DOI: 10.1093/BRAIN/AWT192
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CORTEX.2021.12.014
Abstract: The GGGGCC hexanucleotide repeat expansion in the non-coding region of the chromosome 9 open reading frame 72 gene (C9orf72) is the most common genetic cause of familial frontotemporal dementia (FTD). This study aims to clarify the patterns of cerebellar atrophy in FTD patients with and without a C9orf72 repeat expansion compared with healthy controls and determine whether associations between cerebellar atrophy and cognition differ between patient groups. Thirty C9orf72 repeat expansion-positive FTD patients, 30 C9orf72 repeat expansion-negative FTD patients, and 30 age-, sex-, and education-matched healthy controls underwent brain MRI and cognitive assessments. Patient groups were matched for clinical diagnosis, disease duration, general cognition, and disease severity. Compared with controls, the C9orf72 positive group showed cerebellar changes bilaterally involving the lobules V, VI, Crus I, Crus II, VIIb, VIIIa, left VIIIb, and right lobules I-IV. All these changes were localised within the regions affected in the C9orf72 negative group. No significant differences were found between patient groups. Correlation analyses with a liberal threshold found the cerebellar integrity to be associated with attention, language, and executive function in the C9orf72 positive group. In the C9orf72 negative group, these associations included attention, working memory, language, episodic memory, and executive function. This study clarifies the impact of C9orf72 repeat expansion on cerebellar integrity in FTD. The findings reveal overlapping patterns of cerebellar atrophy in C9orf72 positive and negative groups. The associations with cognitive functions suggest that the type of pathology linked with cerebellar atrophy is another relevant variable to consider in future studies.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2014
DOI: 10.1007/S00415-014-7474-9
Abstract: Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the "strength" of family history in FTD, Alzheimer's disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1-3 was regarded as a "strong" family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls 2.3 %, P < 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD.
Publisher: Wiley
Date: 03-01-2018
DOI: 10.1111/NAN.12455
Abstract: The past decade has seen a surge in studies identifying mixed pathologies in elderly populations. Importantly however, few studies have focussed on mixed pathology in Frontotemporal Lobar Degeneration (FTLD), particularly in younger cases. The present study examined concomitant pathological neuronal inclusions of TDP-43, hyperphosphorylated tau and α-synuclein protein in the anterior cingulate, hippoc us and entorhinal cortex in young (≤65 years at death) vs. elderly (≥80 years at death) cases with pathologically confirmed FTLD (n = 52) or Alzheimer's disease (AD) (n = 47). Our results demonstrate the presence of additional neuronal pathologies not associated with the primary pathological diagnosis in a similar proportion of young and elderly FTLD cases, indicating that disease drivers rather than age are the major risk factors for multiple neuronal pathologies in FTLD. When only sporadic FTLD cases were considered, the proportion of cases with multiple neuronal pathologies across FTLD age cohorts remained similar, indicating that multiple neuronal pathologies in young FTLD cases is not driven by known genetic mutations. In contrast to these findings in FTLD, a significantly greater proportion of elderly compared to young AD cases demonstrated multiple neuronal pathologies, corroborating literature. In summary, the present study reports for the first time that age is not a major risk factor for multiple neuronal pathologies in FTLD. These findings have significant implications for the development of protein-specific biomarkers and treatments for FTLD, and underscore the need for further research to identify the disease factors involved in driving multiple neuronal pathologies in FTLD.
Publisher: Wiley
Date: 22-01-2007
DOI: 10.1111/J.1365-2990.2006.00816.X
Abstract: We have previously described a novel 'inflammatory plaque' in the cortex of early onset Alzheimer's disease (EOAD) cases with presenilin 1 mutations (PS1). These plaques are associated with a significant inflammatory infiltrate consisting of reactive microglia and astrocytes. We speculated that these inflammatory plaques might be responsible for the more severe disease process seen in EOAD. In the present study using the superior frontal cortex, 63 EOAD cases with mutations in PS1, presenilin 2 (PS2) and amyloid precursor protein (APP) were categorized as either having inflammatory plaques (13 cases, two APP and 11 PS1) or not. To determine the impact on cell loss, seven EOAD cases with inflammatory plaques (EOIP) and seven EOAD cases without (EONIP) were selected and neuronal cell counts performed. These were compared with neuronal counts taken from the same cortical region of seven control and six sporadic AD cases. Cases with EOAD had significantly less neurones per field compared with sporadic AD and control cases (EOAD = 19.5 +/- 0.8 neurones/field, spAD = 23.7 +/- 1.2 neurones/field, controls = 30.37 +/- 1.2 neurones/field). However, no significant difference in the number of neurones per field was seen in EOAD cases with or without inflammatory plaque pathology (EOIP = 19.2 +/- 1.4, EONIP = 19.7 +/- 0.8). These data demonstrate that EOAD cases exhibit greater neuronal cell loss in the superior frontal cortex than sporadic AD and that this effect is independent of the presence or absence of inflammatory plaque pathology.
Publisher: Wiley
Date: 02-05-2015
DOI: 10.1111/NAN.12216
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-09-2015
Publisher: Elsevier BV
Date: 02-2016
Publisher: Portland Press Ltd.
Date: 19-09-2012
DOI: 10.1042/BST20120119
Abstract: Missense mutations in LRRK2 (leucine-rich repeat kinase 2) contribute significantly to autosomal dominant PD (Parkinson's disease). Genome-wide association studies have suggested further that mutations in LRRK2 comprise a risk factor for sporadic PD. How LRRK2 contributes to PD, however, is largely unknown. Recent work has shown that LRRK2 is highly expressed in tissue and circulating immune cells and is suggestive of a potential role for LRRK2 in innate immunity. These studies and their potential implications for PD are discussed in the present paper.
Publisher: Elsevier BV
Date: 05-1997
DOI: 10.1016/S0304-3940(97)00294-2
Abstract: There have been two detailed neuropathological reports of families with a valine to isoleucine substitution at position 717 of the amyloid precursor protein gene. Surprisingly, in one of these families substantial Lewy body formation occurred in addition to Alzheimer's disease, prompting the speculation that such a genetic mutation may predispose to both Lewy body and plaque formation. This report describes the neuropathology of an additional family with the same genetic mutation. Of two affected members who have come to autopsy, one had brainstem Lewy bodies. Some of these Lewy bodies had peripheral halos immunoreactive for beta-amyloid. These findings suggest a greater than chance link between genetic mutations for Alzheimer's disease and Lewy body formation.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.NEUROBIOLAGING.2009.02.006
Abstract: Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE peptides are biologically active and may be produced in the brain. It is unclear if apoE proteolysis is dependent on isoform or AD status and this was addressed here. Hippoc us, frontal cortex, occipital lobe and cerebellum s les were homogenized into fractions that were soluble in Tris-buffered saline (TBS), Triton X-100 or guanidine hydrochloride and analysed for apoE fragmentation by Western blotting. Approximately 20% of apoE3 was detected as fragments and this was predominantly as a 25 kDa peptide in TBS-soluble fractions. The concentration of TBS-soluble apoE fragments was two- to three-fold higher in apoE3 compared to apoE4 subjects. This difference was observed in all areas of the brain examined and was not related to AD status. Cathepsin-D treatment generated apoE fragments that were very similar to those detected in brain, however, no apoE isoform-specific differences in susceptibility to cathepsin-D proteolysis were detected. This indicates that proteolytic processing of apoE to form soluble fragments in the human brain is dependent on apoE isoform but not AD status.
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1007/BF03033774
Publisher: Wiley
Date: 06-2000
Publisher: Wiley
Date: 26-06-2019
DOI: 10.1002/MDS.27780
Abstract: Although motor abnormalities have been flagged as potentially the most sensitive and specific clinical features for predicting the future progression to Parkinson's disease, little work has been done to characterize gait and balance impairments in idiopathic rapid eye movement sleep behavior disorder (iRBD). The objective of this study was to quantitatively determine any static balance as well as gait impairments across the 5 independent domains of gait in polysomnography-confirmed iRBD patients using normal, fast-paced, and dual-task walking conditions. A total of 38 participants (24 iRBD, 14 healthy controls) completed the following 5 different walking trials across a pressure sensor carpet: (1) normal pace, (2) fast pace, (3) while counting backward from 100 by 1s, (4) while naming as many animals as possible, (5) while subtracting 7s from 100. Although no gait differences were found between the groups during normal walking, there were significant differences between groups under the fast-paced and dual-task gait conditions. Specifically, in response to the dual tasking, healthy controls widened their step width without changing step width variability, whereas iRBD patients did not widen their step width but, rather, significantly increased their step width variability. Similarly, changes between the groups were observed during fast-paced walking wherein the iRBD patients demonstrated greater step length asymmetry when compared with controls. This study demonstrates that iRBD patients have subtle gait impairments, which likely reflect early progressive degeneration in brainstem regions that regulate both REM sleep and gait coordination. Such gait assessments may be useful as a diagnostic preclinical screening tool for future fulminant gait abnormalities for trials of disease-preventive agents. © 2019 International Parkinson and Movement Disorder Society.
Publisher: Oxford University Press (OUP)
Date: 10-2009
Publisher: Wiley
Date: 03-11-2019
DOI: 10.1111/NAN.12583
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.NEUROSCIENCE.2012.02.037
Abstract: Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB-TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by different alternative transcripts. In this study, we assessed if expression of the three main TrkB alternative transcripts, TrkB-TK+, TrkB-TK-, and TrkB-Shc are altered in AD. Using a cohort of control and AD brains (n=29), we surveyed the hippoc us, temporal cortex, occipital cortex, and cerebellum and found specific increases in TrkB-Shc, a neuron-specific transcript, in the AD hippoc us. No significant changes were detected in TrkB-TK+ and TrkB-TK- transcript levels in AD in any brain region examined. Corresponding changes in truncated TrkB protein levels were found in the hippoc us, although a significant increase in the temporal cortex was also observed. Our findings suggested that neuron-specific changes in TrkB may be occurring in AD thus, we determined whether TrkB-Shc expression could be modulated by amyloid beta 1-42 (Aβ(42)). We found increased TrkB-Shc mRNA levels in differentiated SHSY5Y neuronal cell-lines exposed to fibril-containing Aβ(42) preparations. When we assessed the cellular impact of increased TrkB-Shc, we found co-localization between TrkB-Shc and TrkB-TK+. Interestingly, TrkB-Shc overexpression selectively attenuated BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is increased in vulnerable neurons and linked to abnormal phosphorylation of cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc expression in AD may function as a compensatory response in neurons in AD to promote survival.
Publisher: Elsevier BV
Date: 05-2004
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1007/BF03033777
Publisher: Proceedings of the National Academy of Sciences
Date: 31-08-2015
Abstract: Prions are proteins that assume alternate shapes that become self-propagating, and while some prions perform normal physiological functions, others cause disease. Prions were discovered while studying the cause of rare neurodegenerative diseases of animals and humans called scrapie and Creutzfeldt–Jakob disease, respectively. We report here the discovery of α-synuclein prions that cause a more common neurodegenerative disease in humans called multiple system atrophy (MSA). In contrast to MSA, brain extracts from Parkinson’s disease (PD) patients were not transmissible to genetically engineered cells or mice, although much evidence argues that PD is also caused by α-synuclein, suggesting that this strain (or variant) is different from those that cause MSA.
Publisher: American Chemical Society (ACS)
Date: 12-01-2022
Publisher: Springer Science and Business Media LLC
Date: 22-01-2013
Publisher: Wiley
Date: 22-03-2004
DOI: 10.1002/AJMG.B.30014
Abstract: Until recently, cortical Lewy body disease (CLB) was considered essentially the same as dementia with Lewy bodies (DLB). It is now known patients with Parkinson's disease (PD) with a later-onset dementia (PD-dementia) have the same pattern and extent of cortical Lewy body pathology. Inheritance patterns of CLB have not been evaluated previously. To identify genetic influence on CLB, all cases with this pathology need to be considered. We selected 180 cases meeting clinical and/or pathological criteria for DLB or PD (+/-dementia) from two patient groups: a PD and PD-dementia brain donor program, and a case-control study of Alzheimer's disease (AD). Cases meeting NINCDS-ADRDA criteria for probable AD were excluded and non-demented PD cases used as a comparison group. A detailed family history was taken analyzing onset and progression of dementia and PD phenotypes and a family tree constructed. The frequency of a positive family history of dementia and/or PD and risk of developing CLB in relatives was calculated. Fifty-five percent of dementia and 52% of PD cohorts did not have relatives with clinical disease. There was no increased frequency of familial disease in the CLB cohort compared with PD. However, in half the CLB families, rather than a dominant dementia, the clinical presentation varied (dementia and/or PD). Unlike PD, there was an increased risk of dementia if CLB was present in a parent ( approximately 20% risk) compared with another family member ( approximately 5% risk), suggesting CLB is more likely than PD to occur in a pattern consistent with autosomal dominant inheritance.
Publisher: Springer International Publishing
Date: 2014
Publisher: SAGE Publications
Date: 1992
DOI: 10.1177/088307389200700108
Abstract: Little neuropathology has been documented in sudden infant death syndrome (SIDS) infants. Two hypotheses predict abnormalities in the hypoglossal nucleus and dorsal motor nucleus of the vagus: first, that upper airways are obstructed as a result of abnormal innervation (principally the hypoglossal nerve), and second, that they are obstructed as a result of abnormal cardiorespiratory control (the vagus nerve). A quantitative morphometric analysis was carried out to test these hypotheses in SIDS infants and controls (who died in accidents). The following nuclei dimensions were analyzed length, volume, density, and estimated total cell number. In addition, cell size was analyzed. There were no differences in the anatomical distribution, site, or number of neurons between the groups. The most significant difference between the SIDS and control infants was the neuronal size: control infants had significantly larger neurons. In many other variables, there were trends suggesting a difference between the groups: the volume occupied by the neuronal populations was smaller in the SIDS infants, and therefore the neuronal density was increased. These values suggest differences in the development of these nuclei between SIDS and control infants. ( J Child Neurol 1992 :44-49).
Publisher: Elsevier BV
Date: 03-2014
Publisher: Elsevier BV
Date: 07-1992
Publisher: Wiley
Date: 08-2012
DOI: 10.1002/MDS.25104
Abstract: Patients with advanced Parkinson's disease (PD) commonly suffer with significant executive dysfunction and concomitant visual hallucinations. Although the underlying pathophysiology remains poorly understood, numerous studies have highlighted the strong association between these neuropsychiatric features, suggesting common neural pathways. Although previous neuroimaging studies have identified widespread volume loss across a number of cortical regions, to date, no studies have utilized proton magnetic resonance spectroscopy to provide insights into how neurometabolic changes may relate to such symptoms. Twenty patients with PD and 20 healthy controls underwent spectroscopy to determine the N-acetyl aspartate/creatine (NAA/Cr) ratio, which reflects the degree of neuronal integrity in neurodegenerative diseases. Voxels were obtained from the anterior cingulate cortex (ACC), an area critical for a wide range of executive mechanisms as well as from a control volume in the posterior cingulate cortex (PCC). Compared to controls, patients with PD had lower NAA/Cr ratios in the ACC. In turn, lower NAA/Cr ratios significantly correlated with poorer executive function on tasks of attentional set-shifting and response inhibition, as well as more-severe psychotic symptoms and poorer performance on the Bistable Percept Paradigm, a neuropsychological probe of visual hallucinations. NAA/Cr ratios were significantly lower in hallucinators, compared to nonhallucinators, within the ACC, but did not differ in the PCC. These results suggest that loss of neuronal integrity within the ACC plays an important role in the pathophysiology underlying executive functioning and visual hallucinations in PD. © 2012 Movement Disorder Society.
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/978-3-319-57193-5_2
Abstract: Alzheimer's disease is the most common form of dementia accounting for 50-60% of all dementia cases. This chapter briefly reviews the history of Alzheimer's disease and provides an overview of the clinical syndromes associated with Alzheimer pathology and their associated neuroimaging findings. This chapter also reviews the neuropathology and genetics of Alzheimer's disease and concludes by discussing current work undertaken to identify suitable in vivo biomarkers for the disease.
Publisher: Wiley
Date: 12-05-2015
DOI: 10.1111/NEUP.12205
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.NEUROBIOLAGING.2015.10.017
Abstract: Primary progressive aphasia (PPA) comprises a heterogeneous group of neurodegenerative conditions that can be classified in three cliniconeuroanatomic syndromes. Limited information exists, however, about patterns of neuropathologic spreading and microscopic changes underpinning each syndrome. We performed an analysis of a longitudinal in vivo cohort and a postmortem PPA cohort to investigate neurodegeneration over time and to quantify microscopic changes in key language brain areas. The longitudinal analyses demonstrated distinctive patterns of topological extension of brain atrophy. Although semantic variant (sv-PPA) showed an eccentric pattern, nonfluent and/or agrammatic (nfv-PPA) and logopenic (lv-PPA) variants showed additional multifocal extension. The quantitative pathology showed that sv-PPA had neuronal loss and thinning in BA 38, whereas nfv-PPA showed thinning in BA 44/45 and evidence of microscopic involvement in BA 40/22. Although lv-PPA showed neuronal loss focused on BA 40/22, imaging results demonstrated widespread left-sided brain atrophy. These analyses provide an account of the pathologic process whereby each variant has stereotypical patterns of brain atrophy extension, which is largely determined by the specific pathologic type.
Publisher: Wiley
Date: 26-04-2021
DOI: 10.1002/MDS.28615
Abstract: Pathology in the noradrenergic A6 locus coeruleus has not been compared with more rostral dopaminergic A9 substantia nigra and A10 ventral tegmental area, and cholinergic Ch4 basal nucleus and Ch1/2 septal regions in the same cases of Parkinson's disease (PD). To determine whether there is a gradient of caudal to rostral cell loss in PD. Postmortem brains were collected from longitudinally followed donors with PD (n = 14) and aged‐matched healthy donors (n = 13), six with restricted brainstem Lewy pathology (RLP), fixed in formalin and serial tissue slabs processed for cell and pathological quantitation. Noradrenergic A6 neurons were assessed and compared with previously published midbrain and basal forebrain data. From these data, regression estimates of pathological onset and progression were determined. Restricted Lewy pathology (RLP) cases had high pathological variability but no significant reduction in neurons. Pathology containing A6 neuron loss started at PD diagnosis and progressed faster (2.4% p.a) than the loss of dopaminergic A9 neurons (2% loss p.a.). Cases with dementia had significantly more pathology in noradrenergic and cholinergic neurons, had greater noradrenergic A6 neuron loss (29% more, progressing at 3.2% p.a.), and a selective loss of lateral A10 nonmelanized dopamine‐producing neurons (starting a decade following diagnosis). These findings show that in the same Parkinson's disease cases cell loss in these neurotransmitter systems does not follow a strict caudal to rostral trajectory and suggests symptom onset may relate to substantial pathology in the noradrenergic A6 locus coeruleus neurons in people with reduced dopamine‐producing A9 substantia nigra neurons. © 2021 International Parkinson and Movement Disorder Society
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000328165
Abstract: i Background/Aims: /i To evaluate the utility of the Addenbrooke’s Cognitive Examination-Revised (ACE-R) as a screening tool for mild cognitive impairment in Parkinson’s disease (PD-MCI). i Methods: /i PD patients underwent comprehensive neuropsychological and neurological evaluations and ACE-R assessment. i Results: /i The ACE-R was superior to the Mini-Mental State Exam (MMSE) in detecting PD-MCI, with a cutoff score of ≤93 offering a sensitivity of 61% and a specificity of 64%. The utility of the ACE-R in detecting PD-MCI is largely influenced by the fluency sub-domain score, and has optimal discriminability when utilized in patients with lower levels of education (≤12 years of formal schooling). i Conclusion: /i The ACE-R must be used cautiously as a screening tool for PD-MCI, with results being most influenced by its fluency sub-domain score and patient education levels.
Publisher: Elsevier BV
Date: 03-2016
DOI: 10.1016/J.PARKRELDIS.2015.12.018
Abstract: It is well known that α-synuclein (SNCA) and microtubule associated protein (MAPT) genes predispose in iduals to develop Parkinson's disease (PD). However, whether these genes contribute to differences in the variable progression observed in PD is obscure. This study aims to evaluate the association of common variants in SNCA (rs11931074, rs894278) and MAPT (rs242557_H1c haplotype, rs3744456) genes with the severity and duration of motor and cognitive performance. 296 Chinese patients with PD were recruited from Shanghai Ruijin Hospital. Motor performance was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS-III) and Hoehn &Yahar (H&Y) stages and cognitive performance using the Mini-Mental Status Examination (MMSE). Genetic associations were analysed using general linear modelling for severity and Cox regression analysis for duration to motor (UPDRS-III≥36 or H&Y ≥ 3, average duration 13 years) and cognitive (MMSE 0.05). Our findings add further data showing that common variants in SNCA and MAPT genes contribute to variability in progression of PD, with SNCA variants associating with motor progression while MAPT variants associated with clinical severity.
Publisher: S. Karger AG
Date: 2004
DOI: 10.1159/000077161
Abstract: The pattern and degree of brain atrophy in frontotemporal dementia (FTD) has the potential for use as an aid in the diagnosis of this disorder and its differentiation from other neurodegenerative diseases. However, before this can occur, the sequence and progression of atrophy needs to be fully elucidated. Recently, we have described a four-point scheme for staging the severity of degeneration in FTD, which correlates with both duration of disease and severity of dementia [Broe M., et al.: Neurology 2003 :1005–1011]. When volumetric analysis is performed in post-mortem-confirmed cases of FTD, atrophy of all lobes is present by stage 2 and then progresses with successive stages. Within each lobe, there is variation in the degree of atrophy between different functionally discreet brain regions with some regions showing marked atrophy and others showing little. Much of the frontal lobe, the amygdala and hippoc us are severely atrophic by stage 2, suggesting that they are some of the earliest areas affected in FTD.
Publisher: American Chemical Society (ACS)
Date: 12-09-2006
DOI: 10.1021/AC060294S
Abstract: Formalin is a routine fixative facilitating tissue preservation and histopathology. Proteomic techniques require freshly frozen specimens, which are often difficult to procure, and methods facilitating proteomic analysis of archival formalin-fixed brain tissue are lacking. We employed antigen-epitope-retrieval principles to facilitate proteomic analysis of brain tissue that had been fixed and stored in formalin for 3-7 years. Twenty-micrometer-thick cryopreserved OCT-embedded sections from inferior temporal cortex of human (7 years in formalin) or mouse brain specimens (3 years in formalin) were hematoxylin-/eosin-stained. Approximately 16-64-mm2 areas of the tissue sections were manually scraped off slides, or approximately 2 mm2 of human brain cortex was captured off membrane-coated slides using laser microdissection. Tissue was treated using various pH and temperature conditions prior to trypsin digestion and nano-LC-MS/MS. The largest number of proteins were retrieved by solubilization at pH 9 at 95 degrees C for 1 h treatments at pH 4 or 6 at 25 or 65 degrees C were generally ineffective. Three-year formalin-fixed murine tissue did not yield more proteins compared to human tissue. Use of formalin-fixed tissue for proteomics is an invaluable tool for medical research. The combination of proteomics and microdissection enables selective enrichment and identification of novel, unique, or abundant proteins that may be important in pathogenesis.
Publisher: American Medical Association (AMA)
Date: 12-2015
DOI: 10.1001/JAMANEUROL.2015.2061
Abstract: A gap in the literature exists regarding progression in behavioral variant frontotemporal dementia (BVFTD). Guidance is needed concerning markers that will enable clinicians to discriminate FTD more effectively from phenocopies and to identify factors that determine progression and thereby prognosis. To observe longitudinal outcomes and progression in probable and possible BVFTD in accordance with international diagnostic criteria and to identify features that may aid clinicians to prognosticate better in cases of possible BVFTD. Longitudinal cohort study performed in a specialist tertiary FTD research clinic. Fifty-eight consecutive patients were followed up longitudinally from January 1, 2008, through December 31, 2013, and classified as having possible, probable, or definite BVFTD at presentation and latest review. Final follow-up was completed on December 31, 2013, and data were analyzed from January 1 to August 1, 2014. Clinical, pathological, genetic, neuropsychological, and neuroimaging data were analyzed to categorize patients, to compare differences between groups with changed and unchanged diagnoses, to determine rates of progression in BVFTD, and to identify prognostic features in possible BVFTD. At presentation, 38 of the 58 patients fulfilled criteria for probable BVFTD of these, 36 continued to satisfy probable criteria or underwent conversion to definite criteria over time. The remaining 20 patients satisfied possible criteria only, and 11 of these patients changed categories over time to probable or definite BVFTD and showed progression on cognitive and functional measures (termed changed status). Of these 11 patients, 8 (73%) carried the C9orf72 expansion. A positive family history, memory impairment, and clinical abnormalities at presentation were key features of progression (P < .05). A continuum of neuropsychological scores, progression rates, and atrophy severity emerged across patients in probable, possible, changed status, and nonchanged status groups patients with probable BVFTD exhibited the most severe abnormalities. Behavioral variant FTD shows variable progression over time. Clinicians can use a detailed neurologic and cognitive assessment to identify key predictive features of progression when faced with possible BVFTD, whereas a diagnosis of probable BVFTD is accurate in a clinical setting.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.JOCN.2006.10.009
Abstract: In many cases of sporadic frontotemporal dementia (FTD) and in FTD caused by tau mutations (FTDP-17) there is disruption of the normal splicing of tau leading to the aberrant expression of tau isoforms and neurodegeneration. This suggests a central role for tau in the pathogenesis of FTD. However, more than half the cases of sporadic FTD show no tau deposition. We question whether altered expression is also involved in the pathogenesis of tau-negative FTD. Real-time polymerase chain reaction was used to investigate tau isoform expression in tau-negative FTD and age-matched controls. There were no differences in total tau mRNA or 4R versus 3R isoform expression. Our study suggests that perturbed tau mRNA expression is unlikely to be involved in the pathogenesis of tau-negative FTD.
Publisher: American Chemical Society (ACS)
Date: 04-08-2021
Publisher: Wiley
Date: 30-05-2015
DOI: 10.1111/NAN.12233
Abstract: Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2. Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings. In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NEUBIOREV.2017.01.004
Abstract: Frontotemporal dementia (FTD) is the second most common cause of young onset dementia. It is increasingly recognized that there is a clinical continuum between FTD and amyotrophic lateral sclerosis (ALS). At a clinical, pathological and genetic level there is much heterogeneity in FTD, meaning that our understanding of this condition, pathophysiology and development of treatments has been limited. A number of mouse models focusing predominantly on recapitulating neuropathological and molecular changes of disease have been developed, with most transgenic lines expressing a single specific protein or genetic mutation. Together with the species-typical presentation of functional deficits, this makes the direct translation of results from these models to humans difficult. However, understanding the phenotypical presentations in mice and how they relate to clinical symptomology in humans is essential for advancing translation. Here we review current mouse models in FTD and compare their phenotype to the clinical presentation in patients.
Publisher: Wiley
Date: 26-09-2012
DOI: 10.1002/MDS.25112
Abstract: Few studies have examined the relationship between cerebrovascular disease, vascular risk factors, and Parkinson's disease (PD), although 1 study found small-vessel disease (SVD) to be the main subtype of cerebrovascular disease. In this study we compared the extent and topography of SVD and assessed associated vascular risk factors in autopsy-proven PD cases and community-dwelling controls. Seventy-seven PD and 32 control brains from the Sydney Brain Bank were assessed microscopically by a single examiner blinded to the diagnosis. SVD was assessed by grading perivascular pallor, gliosis, hyaline thickening, and enlargement of perivascular spaces in the white matter underlying the superior frontal and primary motor cortices, basal ganglia, and white matter tracts. A history of vascular risk factors (hypertension, heart disease, diabetes, and cigarette smoking) was obtained. Groups were compared using stepwise multiple regression analysis. There was significantly greater frontal pallor (P = .004) and widening of perivascular spaces in the globus pallidus interna (P = .007) in controls compared with PD. Hyaline thickening and widening of perivascular spaces in the frontal white matter, hyaline thickening in the motor white matter, and widening of perivascular spaces in the caudate nucleus were more common in the control group, but did not reach significance. The prevalence of vascular risk factors and SVD pathology was significantly lower in autopsy-proven PD compared with controls (P = .03) living in the same community. The results of this study support the need for further research in this area.
Publisher: Wiley
Date: 13-12-2010
DOI: 10.1002/MDS.23295
Abstract: To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson's syndrome (PSP-RS), and PSP parkinsonism (PSP-P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition. We compared 24 pathologically confirmed PSP cases (17 PSP-RS and 7 PSP-P) with 22 controls from a Sydney brain donor program. Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point-counting technique, and tau-immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified. Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated. Cortical atrophy was more severe in PSP-RS than PSP-P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP-RS. As expected, more severe frontal lobe tau pathology differentiated PSP-RS from PSP-P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms. Our study shows that thalamocortical atrophy is a defining feature of PSP-RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature. Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP-RS that requires further investigation.
Publisher: Wiley
Date: 11-1995
Publisher: Oxford University Press (OUP)
Date: 23-07-2015
DOI: 10.1093/BRAIN/AWV151
Publisher: Wiley
Date: 09-1993
Abstract: The basal nucleus of Meynert, incorporating the Ch4 group of cholinergic neurons, was examined in six patients with no signs of neurological abnormalities. The ages of the patients ranged from 20 to 80 years. Despite a number of descriptions of these neurons, few age-related studies have been dedicated to the analysis of the entire anteroposterior extent of the nucleus. Staining with cresyl violet and acetylcholinesterase histochemistry, alone or in combination, was used to identify the cytoarchitectural organization of the Ch4. Computer-assisted morphometry was used for three-dimensional visualization and quantitation. The three-dimensional computer reconstructions revealed a continuous ribbon of neurons with a highly variable density. Four distinct subregions could be clearly identified in all cases by their cytoarchitecture and cellular morphology, although these subgroups were different to those previously described. There were no quantitative differences between the hemispheres in volume, density or cell number of the Ch4, although equivalent levels varied in area and density. The measures were similar in all cases with the exception of the case aged 80 years old. The data demonstrate in idual variability in three dimensions and confirm previous studies that found only a mild decline of the Ch4 in old age.
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.BRAINRESBULL.2008.08.014
Abstract: Although the intralaminar thalamus is a target of alpha-synuclein pathology in Parkinson's disease, the degree of neuronal loss in Lewy body diseases has not been assessed. We have used unbiased stereological techniques to quantify neuronal loss in intralaminar thalamic nuclei concentrating alpha-synuclein pathology (the anterodorsal, cucullar, parataenial, paraventricular, central medial, central lateral and centre-median arafascicular complex) in different clinical forms of Lewy body disease (Parkinson's disease with and without dementia, and dementia with Lewy bodies, N=21) compared with controls (N=5). Associations were performed in the Lewy body cases between intralaminar cell loss and the main diagnostic clinical (parkinsonism, dementia, fluctuation in consciousness, and visual hallucinations) and pathological (Braak stage of Parkinson's disease) features of these diseases, as well as between cell loss and the scaled severity of the alpha-synuclein deposition within the intralaminar thalamus. As expected, significant alpha-synuclein accumulation occurred in the intralaminar thalamus in the cases with Lewy body disease. Pathology concentrated anteriorly and in the central lateral and paraventricular nuclei was related to the Braak stage of Parkinson's disease, ageing, and the presence of dementia. Across all types of Lewy body cases there was substantial atrophy and neuronal loss in the central lateral, cucullar and parataenial nuclei, and neuronal loss without atrophy in the centre-median arafascicular complex. Cases with visual hallucinations showed a greater degree of atrophy of the cucullar nucleus, possibly due to amygdala denervation. The significant degeneration demonstrated in the intralaminar thalamus is likely to contribute to the movement and cognitive dysfunction observed in Lewy body disorders.
Publisher: Wiley
Date: 17-01-2019
DOI: 10.1002/MDS.27556
Abstract: Spread of α-synuclein pathology from the peripheral to central nervous system may be an important etiological factor in Parkinson's disease, although there are some unanswered questions about its correlation with neuronal loss. Experimental evidence has highlighted the gastrointestinal tract as a potential starting point for aggregated α-synuclein, with the vagus nerve acting as a "highway" by which pathology may be transmitted to the lower brain stem. This review begins by highlighting the key studies demonstrating that α-synuclein pathology has the ability to spread from certain sites in the gastrointestinal tract to the brain (and vice versa). We go on to assess the recent epidemiological studies that have shown that vagotomy and appendectomy may have the potential to reduce the risk of developing Parkinson's disease. Finally, we discuss the factors in the gastrointestinal tract (such as dysbiosis of the gut microbiota, infection, and inflammation) that may trigger α-synuclein aggregation in the first place, as well as other potential mechanisms underlying the distribution of α-synuclein pathology in the brain. © 2019 International Parkinson and Movement Disorder Society.
Publisher: Wiley
Date: 02-06-2015
DOI: 10.1111/NAN.12236
Publisher: Future Medicine Ltd
Date: 05-2013
DOI: 10.2217/FNL.13.9
Abstract: LRRK2 is currently considered to be a potential therapeutic target for the treatment of Parkinson’s disease. A number of pathological mutations, the majority of which lie in the dual catalytic domains of LRRK2, segregate with Parkinson’s disease in an autosomal-dominant fashion. The most common mutation, G2019S, results in an increase in the kinase activity of LRRK2 and much work has, therefore, gone into the development of potent and specific inhibitors of LRRK2 kinase activity. A number of LRRK2 kinase inhibitors have now been employed in the search for the physiological function of LRRK2 and the targets of LRRK2 kinase activity.
Publisher: Cold Spring Harbor Laboratory
Date: 02-08-2018
DOI: 10.1101/382994
Abstract: Parkinson’s disease is primarily characterised by diminished dopaminergic function, however the impact of these impairments on large-scale brain dynamics remains unclear. It has been difficult to disentangle the direct effects of Parkinson’s disease from compensatory changes that reconfigure the functional signature of the whole brain network. To examine the causal role of dopamine depletion in network-level topology, we investigated time-varying network structure in 37 in iduals with idiopathic Parkinson’s disease, both ‘On’ and ‘Off’ dopamine replacement therapy, along with 50 age-matched, healthy control subjects using resting-state functional MRI. By tracking dynamic network-level topology, we found that the Parkinson’s disease ‘Off’ state was associated with greater network-level integration than in the ‘On’ state. The extent of integration in the ‘Off’ state inversely correlated with motor symptom severity, suggesting that a shift toward a more integrated network topology may be a compensatory mechanism associated with preserved motor function in the dopamine depleted ‘Off’ state. Furthermore, we were able to demonstrate that measures of both cognitive and brain reserve (i.e., premorbid intelligence and whole brain grey matter volume) had a positive relationship with the relative increase in network integration observed in the dopaminergic ‘Off’ state. This suggests that each of these factors plays an important role in promoting network integration in the dopaminergic ‘Off’ state. Our findings provide a mechanistic basis for understanding the PD ‘Off’ state and provide a further conceptual link with network-level reconfiguration. Together, our results highlight the mechanisms responsible for pathological and compensatory change in Parkinson’s disease.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0306-4522(95)00577-3
Abstract: The chronic consumption of alcohol significantly reduces the number of vasopressin-producing neurons in the rat supraoptic nucleus [Maderia et al. (1993) Neourscience 56, 657-672] suggesting this region is particularly vulnerable to alcohol neurotoxicity. As hypothalamic vasopressin producing neurons are necessary for fluid homeostasis, it is important to assess if similar changes occur in humans. We analysed arginine vasopressin-immunoreactive neurons in the magnocellular hypothalamic nuclei of ten chronic alcoholic men (consuming > 80 g of ethanol per day) and four age- and sex-matched controls (consuming < 10g of ethanol per day). Brains were collected at autopsy and fixed in formalin. Serial 50 mu m-thick-sections of the hypothalamus were stained and assessed. The volume of the paraventricular and supraoptic nuclei and number of neurons were estimated using Cavalieri's principle and the optical dissector technique. The volume of these nuclei significantly correlated with the number of neurons and the number of vasopressin-immunoreactive neurons, and these measures significantly correlated with the maximum daily intake of alcohol. There was a loss of neurons at consumption levels greater than 100 g of ethanol per day, principally affecting the supraoptic nucleus although neuron loss also occurred in the paraventricular nucleus in cases with long histories of alcohol consumption. These results indicate that chronic alcohol consumption is toxic to hypothalamic vasopressin-producing neurons in a concentration- and time-dependent manner. As these magnocellular neurons are osmo-receptive, neuronal loss may result in fluid imbalances.
Publisher: American Chemical Society (ACS)
Date: 21-04-2005
DOI: 10.1021/BI0504052
Abstract: Apolipoprotein-E (apoE) plays an important role in neuronal lipid transport and is thought to stabilize microtubules by preventing tau hyperphosphorylation. ApoE is also associated with insoluble amyloid detected in Alzheimer disease brain lesions. The apoE C-terminal shares several physicochemical features with alpha-synuclein, another neuronal apolipoprotein-like protein. Alpha-synuclein is phosphorylated by protein kinase CK2 (CK2) at an atypical PSD/E motif in vivo and in vitro. We identified a similar PSD/E motif in apoE and therefore investigated its potential phosphorylation by CK2 in vitro. When a [(32)P]-labeling approach was used, CK2 readily phosphorylated purified human apoE as well as recombinant forms of human apoE3 and apoE4. Using liquid chromatography mass spectrometry techniques, we mapped the major apoE CK2 phosphorylation site to Ser296 within the apoE PSD/E motif. We also found that apoE potently activated CK2 as demonstrated by increased CK2beta subunit autophosphorylation and by increased phosphorylation of tau when the latter was added to the kinase reaction mixtures. Other proteins such as apolipoprotein A-I and albumin did not effectively activate CK2. The phosphorylation of apoE by CK2 as well as the activation of CK2 by apoE may be relevant in vivo where apoE, CK2, and tau are co-localized with additional CK2 targets on neuronal microtubules.
Publisher: Wiley
Date: 22-10-1986
Abstract: The five component nuclei of the ventromedial mesencephalic tegmentum (VMT) were studied on Nissl stained serial sections of the brain stem of rat, cat, monkey (Macaca nemestrina) and human. Models of the VMT nuclei were constructed to compare their size, shape and disposition across species. For each nucleus in each species the following were calculated: the volume, the number of neurons, the size distribution of neurons, the mean soma size and the packing density of neurons. The morphology of the cells in the different nuclei is also described. The parabrachial pigmented nucleus (PBP) forms, on average, 51% of the VMT volume and cell number. The paranigral nucleus (PN) and the central linear nucleus (LC) formed 19% and 14% of the VMT volume and cell number respectively. The relatively small, but compact interfascicular nucleus (IF) was on average 9% of the VMT volume and cell number and the rostral linear nucleus (LR) formed its remaining 7%. However, in different species the relative prominence varies between species. Thus PBP is the largest of the VMT nuclei in the monkey, PN is particularly well developed in the human, IF contains a particularly large number of cells in the rat, and LR and LC are strongly developed in the cat. This study presents a cytoarchitectonic description of the five nuclei in each species. The distinctive cytoarchitectonic appearance of each nucleus suggests that their functions may differ. This possibility, which is strengthened by evidence that the projections of the VMT nuclei are differential, may need to be considered in the interpretation of the results of experimental investigations using stimulation and/or lesion experiments in the VMT region and in the interpretation of pathological findings in the human brain.
Publisher: Springer Science and Business Media LLC
Date: 22-12-2013
Publisher: Springer Science and Business Media LLC
Date: 07-05-2011
DOI: 10.1007/S12031-011-9528-0
Abstract: We developed a staging scheme for assessing pathology in frontotemporal lobar degeneration (FTLD), which relates to atrophy and accounts for the large variability seen at postmortem (Broe et al. 2003 :1005-11). Atrophy of the temporal lobe has the most linear relationship to disease stage. We review how this simple staging technique has been applied in clinical settings, where it is the best predictor of survival and discriminates semantic dementia and behavioural phenocopies. Patients with clinical presentations of motor neuron disease or progressive supranuclear palsy have significantly lower disease stages than other FTLD syndromes. We also review the pathologies relating to disease stage. There is no significant difference in the overall distribution of stages between the different pathological subtypes of FTLD, indicating a similar underlying disease process. The cellular variables relating independently to increasing disease stage are (1) increasing neuronal loss, astrocytosis and microvacuolation, and (2) increasing glial apoptosis. Of note, the degree of protein deposition does not relate to disease stage.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1998
DOI: 10.1097/00001756-199810050-00034
Abstract: Mutations in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) cases. We identified three missense mutations in the coding sequence of the PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's disease was confirmed in one pedigree by autopsy. Mutation analysis of PCR products lified from genomic DNA templates of affected in iduals showed two novel mutations resulting in Ser169Leu and Pro436Gln and one known mutation resulting in Glu318Gly. The two new mutations are located within predicted transmembrane domains three (TM-3) and seven (TM-7), and are associated with a very early age of onset which is consistent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported previously in a separate pedigree with this mutation.
Publisher: American Chemical Society (ACS)
Date: 21-12-2020
DOI: 10.26434/CHEMRXIV.13415918.V1
Abstract: We developed a methodological workflow combining size exclusion chromatography, native isoelectric focusing, and high sensitivity X-ray-based metal detection within electrophoresis gels to analyze the metal content of single proteins purified from minimal amounts ( mg) of post-mortem human brain and spinal cord tissue. An important metalloprotein in the human central nervous system is copper-zinc superoxide dismutase (SOD1), an antioxidant enzyme linked to the aetiology of both amyotrophic lateral sclerosis and Parkinson’s disease. Abnormal SOD1 metallation is suspected to play a role in the pathogenic aggregation of SOD1 in both disorders, although data describing SOD1 metal occupancy in human tissues has not previously been reported. Validating our novel approach we demonstrated step-by-step metal preservation, preserved SOD1 activity, and substantial enrichment of SOD1 protein vs confounding metalloproteins. We found Cu and Zn were bound to SOD1 in a ratio of 1.12 ± 0.28 in human central nervous system tissues from healthy in iduals, a ratio close to the expected value of 1. Our methodological workflow can be adapted to study a range of metalloproteins from human tissues and other sources.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2020
DOI: 10.1186/S13195-020-00587-5
Abstract: The Centiloid scale was developed to standardise the results of beta-amyloid (Aβ) PET. We aimed to determine the Centiloid unit (CL) thresholds for CERAD sparse and moderate-density neuritic plaques, Alzheimer’s disease neuropathologic change (ADNC) score of intermediate or high probability of Alzheimer’s Disease (AD), final clinicopathological diagnosis of AD, and expert visual read of a positive Aβ PET scan. Aβ PET results in CL for 49 subjects were compared with post-mortem findings, visual read, and final clinicopathological diagnosis. The Youden Index was used to determine the optimal CL thresholds from receiver operator characteristic (ROC) curves. A threshold of 20.1 CL (21.3 CL when corrected for time to death, AUC 0.97) yielded highest accuracy in detecting moderate or frequent plaque density while 10 CL was optimal for excluding neuritic plaque. The threshold for ADNC intermediate or high likelihood AD was 49.4 CL (AUC 0.98). Those cases with a final clinicopathological diagnosis of AD yielded a median CL result of 87.7 (IQR ± 42.2) with 94% 45 CL. Positive visual read agreed highly with results 26 CL. Centiloid values 10 accurately reflected the absence of any neuritic plaque and 20 CL indicated the presence of at least moderate plaque density, but approximately 50 CL or more best confirmed both neuropathological and clinicopathological diagnosis of Alzheimer’s disease.
Publisher: Oxford University Press (OUP)
Date: 21-08-2023
DOI: 10.1093/JNEN/NLAD052
Publisher: Elsevier BV
Date: 02-1990
Publisher: Elsevier BV
Date: 06-1996
Abstract: Stain sensitivity is a key factor in estimating the frequency of plaques and neurofibrillary tangles in Alzheimer's disease (AD), making it essential that the sensitivity and selectivity of detection methods for identifying these lesions is maximized. Several new, improved techniques have recently been described, although these methods have not been compared quantitatively with those techniques currently recommended for use in standardized diagnostic protocols. In the present study, eight different stains were examined for their selectivity and sensitivity in detecting plaques and tangles in serial tissue sections from AD and control brains. Techniques compared were immunohistochemistry for tau and beta-amyloid, thioflavin S, nickel peroxidase method, and four silver impregnation techniques (Gallyas silver iodide, C bell-Switzer-Martin, Garvey's modified Bielschowsky and methenamine silver methods). Among these eight staining techniques, the nickel peroxidase proved the most reliable method for the demonstration of the histopathological lesions of AD. This method labels all morphological types of plaques and tangles within a single tissue section, and provides several advantages for the analysis of lesion progression and distribution.
Publisher: Oxford University Press (OUP)
Date: 20-01-2016
DOI: 10.1093/BRAIN/AWV399
Abstract: Pathophysiological and atrophic changes in the cerebellum are documented in Parkinson's disease. Without compensatory activity, such abnormalities could potentially have more widespread effects on both motor and non-motor symptoms. We examined how atrophic change in the cerebellum impacts functional connectivity patterns within the cerebellum and between cerebellar-cortical networks in 42 patients with Parkinson's disease and 29 control subjects. Voxel-based morphometry confirmed grey matter loss across the motor and cognitive cerebellar territories in the patient cohort. The extent of cerebellar atrophy correlated with decreased resting-state connectivity between the cerebellum and large-scale cortical networks, including the sensorimotor, dorsal attention and default networks, but with increased connectivity between the cerebellum and frontoparietal networks. The severity of patients' motor impairment was predicted by a combination of cerebellar atrophy and decreased cerebellar-sensorimotor connectivity. These findings demonstrate that cerebellar atrophy is related to both increases and decreases in cerebellar-cortical connectivity in Parkinson's disease, identifying potential cerebellar driven functional changes associated with sensorimotor deficits. A post hoc analysis exploring the effect of atrophy in the subthalamic nucleus, a cerebellar input source, confirmed that a significant negative relationship between grey matter volume and intrinsic cerebellar connectivity seen in controls was absent in the patients. This suggests that the modulatory relationship of the subthalamic nucleus on intracerebellar connectivity is lost in Parkinson's disease, which may contribute to pathological activation within the cerebellum. The results confirm significant changes in cerebellar network activity in Parkinson's disease and reveal that such changes occur in association with atrophy of the cerebellum.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2013
Publisher: Oxford University Press (OUP)
Date: 24-07-2014
DOI: 10.1093/BRAIN/AWU193
Abstract: The neuropathological substrate of dementia in patients with Parkinson's disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinson's disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinson's disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippoc al cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippoc us of six demented and five non-demented patients with Parkinson's disease and five age-matched control in iduals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippoc us and frontal cortex of eight demented and eight non-demented patients with Parkinson's disease, as well as in the same areas of eight age-matched controls. All patients with Parkinson's disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinson's disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippoc al cholinergic activity was consistently reduced in all patients with Parkinson's disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinson's disease dementia were differentiated by a significant reduction in hippoc al cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippoc us. Overall, these results point to increasing α-synuclein deposition and hippoc al dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinson's disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinson's disease.
Publisher: S. Karger AG
Date: 2003
DOI: 10.1159/000072800
Abstract: i Background: /i Spatial function has been suggested to be disproportionately worse in people with dementia with Lewy bodies (DLB) than other dementia groups, and poor performance on the Mini-Mental State Examination pentagon copying (PC) task has been proposed as adequate for assessing this. We aimed to establish the prevalence of poor PC in the non-demented elderly determine the validity of the use of PC as a spatial function test, and determine if poor PC is more common in DLB than non-DLB dementias. i Methods: /i In a population-based s le of 299 participants, 126 were rated as being cognitively normal (clinical rating scale [CDR] = 0), 95 mildly cognitively impaired (CDR = 0.5), and 78 met criteria for dementia, 19 of whom met criteria for probable DLB (pDLB) and 25 with none of the core features of DLB (non-DLB). The accuracy of PC performance was determined across CDR groups, and the relationship of PC to performance on a broad range of cognitive tests was evaluated. The dementia groups were compared cross-sectionally to determine differences in PC and other cognitive test performance, as well as 3 and 6 years earlier to determine cognitive differences at initial stages of cognitive decline. i Results: /i Poor PC was common in the non-demented elderly (39% CDR = 0 43% CDR = 0.5). In this non-demented group, PC was selectively related to tests of spatial function. Poor PC was not significantly different in the pDLB and non-DLB groups at any assessment time, however it became more prevalent as dementia severity increased. Memory function and verbal fluency were more impaired in the pDLB group in the early stages of the disorder. i Comment: /i PC appears to be a good measure of spatial function in the elderly. However, in contrast to other findings of poor spatial skills in DLB when dementia is in the mild to moderate stages, poor PC performance has not been shown to be a good early marker of DLB and its clinical correlates are yet to be determined.
Publisher: Elsevier BV
Date: 02-2000
DOI: 10.1016/S0024-3205(00)00442-2
Abstract: The use of neuroleptic drugs to treat schizophrenia is almost invariably associated with extrapyramidal movement disorders. One of these disorders, tar e dyskinesia (TD), can persist long after neuroleptic withdrawal suggesting that permanent neurological damage is produced. However, there appears to be no convincing pathology of TD and its pathogenesis remains unknown. Findings that neuroleptics interfere with normal mitochondrial function and produce mitochondrial ultrastructural changes in the basal ganglia of patients and animals suggest that mitochondrial dysfunction plays a role in TD. We have established a model for persistent TD in baboons that appears to involve compromised mitochondrial function. In this study, we evaluated two animals treated for 41 weeks with a derivative of haloperidol and two treated with vehicle only. Treatment was then withdrawn and the animals observed for a further 17-18 weeks. Treated animals developed abnormal orofacial signs that were consistent with TD. These symptoms persisted during the drug-free period. The animals were euthanased, the brains perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate and putamen prepared for electron microscopy. Regardless of whether mitochondria were located in neural soma, excitatory terminals, glia or in non-somal neuropil there was no consistent difference either in size or number between treated and control animals. Thus, even if mitochondria in striatal neurons undergo ultrastructural alterations during neuroleptic therapy, these changes do not persist after drug withdrawal.
Publisher: Wiley
Date: 23-04-2012
DOI: 10.1002/MDS.25005
Abstract: Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold P < 0.001) and DST genes (log(2) 2.3-fold P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.NEULET.2006.12.051
Abstract: Mutations in the parkin gene are the major cause of autosomal recessive early-onset forms of Parkinson's disease (PD). As reduced parkin expression might also affect the clinical course of idiopathic PD we investigated the effect of a low expressing allele in the parkin promoter region on the age at disease onset (AAO). Patients with PD (n=175) fulfilling standard diagnostic criteria were recruited by experienced neurologists at two movement disorders clinics in Sydney and Brisbane, Australia. DNA was extracted from whole blood and the -258 T/G polymorphism genotyped using PCR/RFLP. AAO effects were analysed using univariate ANOVA, binomial logistic regression modelling and Kaplan-Meier survival analysis. Subjects with the GG genotype (n=10, mean AAO=46.2+/-11.5 (S.D.) years) had a significantly lower mean AAO compared to the common TT genotype (n=104, mean AAO=56.1+/-12.7, p=0.02). There was no difference in mean AAO between the TT and TG in iduals (n=61, mean AAO=55.3+/-11.6). Stratifying the s le by median AAO (55 years) revealed that the GG genotype was over-represented in the early-onset group (n=9, OR=18.6, 95% CI=1.41-245.3, p=0.03). We speculate that reduced expression of normal parkin protein may result in an early manifestation of PD symptoms.
Publisher: Elsevier BV
Date: 12-1992
DOI: 10.1016/0006-8993(92)90164-5
Abstract: The loss of noradrenergic locus coeruleus neurons has been identified as the possible critical lesion inducing amnesia in alcoholic patients with the Wernicke-Korsakoff syndrome. The present study aims to test this hypothesis by quantifying the number of pigmented locus coeruleus neurons in 4 alcoholics with the Wernicke-Korsakoff syndrome, 5 alcoholics with Wernicke's encephalopathy alone but no amnesia, and 1 alcoholic and 5 age-matched controls with no neurological disorders. Apart from an increased vascularity in the locus coeruleus of alcoholics, no significant differences in the number, morphology or distribution of pigmented locus coeruleus neurons was noted between any of the groups analysed. There was a significant correlation between the number of locus coeruleus neurons and brain weight. These data demonstrate that neither alcohol neurotoxicity nor thiamine deficiency result in a reduction in the number of pigmented cells in the locus coeruleus and refute the hypothesis that locus coeruleus cell loss is critical for the amnesia in the Wernicke-Korsakoff syndrome.
Publisher: Springer Science and Business Media LLC
Date: 09-1993
DOI: 10.1007/BF00996930
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 27-11-2022
Publisher: Cambridge University Press (CUP)
Date: 08-2009
DOI: 10.1017/S1041610209009454
Abstract: Background: The clinical presentations in dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) overlap considerably with that of Alzheimer's disease (AD) despite different pathological processes. Autopsy studies have also shown that multiple brain pathology occurs frequently, even in cases with a single clinical diagnosis. We aimed to determine the frequency of clinical diagnosis of FTD and DLB and the underlying pathology in a well-characterized cohort of patients with a clinical diagnosis of probable or possible AD. Methods: We conducted a retrospective analysis of 170 AD patients (probable AD = 83 possible AD = 87) originally enrolled in a case-control study, 27 with postmortem examination, to establish the number of cases meeting probable diagnosis for FTD and DLB, using a checklist of features compiled from their consensus criteria. Results: 23/83 probable AD cases and 32/87 possible AD cases met probable criteria for another dementia, more commonly DLB than FTD. AD pathology was present in 8/15 probable AD and 8/12 possible AD cases coming to autopsy. DLB pathology was seen in four cases and FTD pathology in eight cases. In the AD cases reaching clinical diagnosis for a second dementia syndrome and coming to autopsy, a minority showed non-AD pathology only. Conclusions: Presence of core clinical features of non-AD dementia syndromes is common in AD. Concordance between clinical and pathological diagnoses of dementia remains variable. We propose that repeat clinical examinations and structural neuroimaging will improve diagnostic accuracy. In addition, clinical diagnostic criteria for the main dementia syndromes require refinement.
Publisher: Wiley
Date: 25-08-2018
DOI: 10.1002/MDS.27431
Abstract: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease (PD). Although recent validation studies suggest high accuracy, one unmet need is for highly specific criteria for clinical trials in early/de novo PD. The objective of this study was to generate and test a PD diagnostic criteria termed "clinically established early PD." We modified the Movement Disorder Society criteria to increase specificity for early PD by removing all disease duration components and changing red flags to absolute exclusions. We then estimated the sensitivity/specificity of clinically established early PD criteria in patients with disease duration <5 years, selected from a 626-patient validation study. After documentation of parkinsonism, 18 in idual exclusion criteria are assessed that preclude the diagnosis of "clinically established early PD." Among 212 PD and 152 non-PD patients, the estimated specificity was 95.4%, with 69.8% sensitivity. We describe high-specificity criteria for de novo PD, which are freely available for use in clinical trials. © 2018 International Parkinson and Movement Disorder Society.
Publisher: Springer Science and Business Media LLC
Date: 19-10-2017
Publisher: Springer Science and Business Media LLC
Date: 22-03-2006
DOI: 10.1007/S00401-006-0048-X
Abstract: The pathological distinctions between the various clinical and pathological manifestations of frontotemporal lobar degeneration (FTLD) remain unclear. Using monoclonal antibodies specific for 3- and 4-repeat isoforms of the microtubule associated protein, tau (3R- and 4R-tau), we have performed an immunohistochemical study of the tau pathology present in 14 cases of sporadic forms of FTLD, 12 cases with Pick bodies and two cases without and in 27 cases of familial FTLD associated with 12 different mutations in the tau gene (MAPT), five cases with Pick bodies and 22 cases without. In all 12 cases of sporadic FTLD where Pick bodies were present, these contained only 3R-tau isoforms. Clinically, ten of these cases had frontotemporal dementia and two had progressive apraxia. Only 3R-tau isoforms were present in Pick bodies in those patients with familial FTLD associated with L266V, Q336R, E342V, K369I or G389R MAPT mutations. Patients with familial FTLD associated with exon 10 N279K, N296H or +16 splice site mutations showed tau pathology characterised by neuronal neurofibrillary tangles (NFT) and glial cell tangles that contained only 4R-tau isoforms, as did the NFT in P301L MAPT mutation. With the R406W mutation, NFT contained both 3R- and 4R-tau isoforms. We also observed two patients with sporadic FTLD, but without Pick bodies, in whom the tau pathology comprised only of 4R-tau isoforms. We have therefore shown by immunohistochemistry that different specific tau isoform compositions underlie the various kinds of tau pathology present in sporadic and familial FTLD. The use of such tau isoform specific antibodies may refine pathological criteria underpinning FTLD.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.JCHEMNEU.2016.02.001
Abstract: The pathology of Parkinson's disease (PD) is characterised by the loss of neurons in the substantia nigra parcompacta (A9), which results in the insufficient release of dopamine, and the appearance of motor symptoms. Not all neurons in the A9 subregions degenerate in PD, and the dopaminergic (DA) neurons located in the neighboring ventral tegmental area (A10) are relatively resistant to PD pathogenesis. An increasing number of quantitative studies using human tissue s les of these brain regions have revealed important biological differences. In this review, we first describe current knowledge on the multi-segmental neuromere origin of these DA neurons. We then compare the continued transcription factor and protein expression profile and morphological differences distinguishing subregions within the A9 substantia nigra, and between A9 and A10 DA neurons. We conclude that the expression of three types of factors and proteins contributes to the ersity observed in these DA neurons and potentially to their differential vulnerability to PD. In particular, the specific axonal structure of A9 neurons and the way A9 neurons maintain their DA usage makes them easily exposed to energy deficits, calcium overload and oxidative stress, all contributing to their decreased survival in PD. We highlight knowledge gaps in our understanding of the cellular biomarkers for and their different functions in DA neurons, knowledge which may assist to identify underpinning disease mechansims that could be targeted for the treatment of any subregional dysfunction and loss of these DA neurons.
Publisher: Wiley
Date: 14-05-2013
DOI: 10.1002/MDS.25493
Abstract: Parkinson's disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive in iduals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1-D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-10-2019
DOI: 10.1212/WNL.0000000000008439
Abstract: To assess the amount of phosphorylated and nonphosphorylated TAR DNA-binding protein 43 (TDP-43) in the motor brain regions of cases of amyotrophic lateral sclerosis (ALS) with and without repeat expansions in the ATXN2 or C9ORF72 genes. The 45-kDa phosphorylated form of TDP-43 and 43-kDa nonphosphorylated form of TDP-43 were quantified by immunoblot in postmortem brain tissue from the motor cortex, spinal cord, and cerebellar vermis of 23 cases with ALS with repeat expansions in the ATXN2 or C9ORF72 genes and sporadic disease and 10 controls. Significantly greater levels of phosphorylated TDP-43 were identified in the motor cortex of cases with ALS with C9ORF72 expansions, and significantly greater amounts of phosphorylated TDP-43 were found in the spinal cord of cases with ALS with intermediate ATXN2 expansions. In contrast, however, similar levels of nonphosphorylated TDP-43 were found in all 3 regions between ALS groups. Despite its central role in the pathogenesis of ALS and the emergence of potential targets to modify its aggregation, TDP-43 levels have not been quantified in pathologically confirmed cases with ALS. The present results demonstrating significant differences in phosphorylated but not nonphosphorylated TDP-43 levels suggest that different posttranslational modifications are involved in the generation of greater pathologic TDP-43 levels identified here in our cohort of cases with genetic expansions. These findings are consistent with emerging studies implicating distinct pathomechanisms in the generation of pathologic TDP-43 in cases with ALS with C9ORF72 or ATXN2 expansions and are of relevance to therapeutic research aimed at reducing pathologic TDP-43 in all or a subset of patients with ALS.
Publisher: Elsevier BV
Date: 03-1996
Abstract: We have examined by immunohistochemistry the parvalbumin-containing neurons of the substantia nigra in patients with Parkinson's disease and in age-matched controls. Parvalbumin, a calcium binding protein, is involved in buffering intracellular calcium and in this study was localized within the majority of non-pigmented neurons of the human pars reticulata. Previous studies have shown that the parvalbumin-immunoreactive pars reticulata neurons are GABAergic and project to the motor thalamus and tectum. Their increased output, due to the loss of dopaminergic inhibition in Parkinson's disease, decreases cortical activation via thalamic pathways, causing parkinsonian symptoms. In Parkinson's disease there was a significant loss of parvalbumin-immunoreactivity from these neurons, though there was no evidence of actual cell loss. This loss of parvalbumin-immunoreactivity was detected only in those cases with end-stage Parkinson's disease.
Publisher: Oxford University Press (OUP)
Date: 05-01-2005
DOI: 10.1093/BRAIN/AWH348
Abstract: Early and severe memory impairment is generally held to be an exclusion criterion for the clinical diagnosis of frontotemporal dementia (FTD). However, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, or even present solely with amnesia. A review of severe amnesia at presentation in patients with pathologically proven FTD is therefore warranted. The present study examined the records of all patients in the joint Cambridge-Sydney neuropathological series of patients with dementia and a pathological diagnosis of FTD to identify those for whom memory complaints were dominant at presentation. Eight of 71 patients met these criteria. For two patients, memory loss was the only complaint for one patient, memory loss was accompanied by personality change for two patients, memory loss was accompanied by prominent dysexecutive symptoms and for three patients, memory loss was accompanied by apathy but no other behavioural changes. In seven patients local specialist teams initially diagnosed Alzheimer's disease four patients entered anticholinesterase drug trials. All eight later developed behavioural features: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. In conclusion, severe amnesia at presentation in FTD is commoner than previously thought and the clinical consensus criteria for the diagnosis of FTD may need to be revised. The underlying basis of the memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.
Publisher: Wiley
Date: 23-09-2011
DOI: 10.1002/MDS.23896
Abstract: Visual misperceptions and hallucinations are a major cause of distress in patients with Parkinson's disease (PD), particularly in the advanced stages of the condition. Recent work has provided a framework for understanding the pathogenesis of these symptoms, implicating impairments from the retina to the integration of external information with preformed internal images. In this article, we propose a novel hypothesis that attempts to explain the presence of visual misperceptions and hallucinations in PD through the aberrant coordination of complimentary yet competing neural networks. We propose that hallucinations in PD reflect the relative inability to recruit activation in the dorsal attention network in the presence of an ambiguous percept, leading to overreliance on default mode network processing and salience arising from the ventral attention network. This inability is proposed to stem from improper function across cortical and subcortical structures secondary to the presence of Lewy body pathology. This hypothesis may be empirically tested by the use of targeted cognitive paradigms. In turn, this may assist our understanding of the pathophysiological mechanisms and cognitive processes contributing to visual misperceptions and hallucinations and ultimately may inform more effective treatment strategies for this troubling symptom.
Publisher: Wiley
Date: 02-06-2020
DOI: 10.1002/BRB3.1672
Publisher: Wiley
Date: 2016
DOI: 10.1016/J.DADM.2016.03.006
Abstract: Clinicopathologic correlation in non‐Alzheimer's tauopathies is variable, despite refinement of pathologic diagnostic criteria. In the present study, the clinical and neuroimaging characteristics of globular glial tauopathy (GGT) were examined to determine whether subtyping according to consensus guidelines improves clinicopathologic correlation. Confirmed GGT cases (n = 11) were identified from 181 frontotemporal tauopathy cases. Clinical and neuroimaging details were collected, and cases sub‐typed according to the consensus criteria for GGT diagnosis. Relationships between clinical syndrome and GGT subtype were investigated. In total, 11 patients (seven males, four females, mean age = 67.3 +/− 10.6 years) with GGT were included. Most, but not all, presented with behavioral variant frontotemporal dementia, but none had amyotrophic lateral sclerosis. Subtyping of GGT proved to be difficult and did not improve clinicopathologic correlation. Sub‐classification of GGT pathology may be difficult and did not improve clinicopathologic correlation. Better biomarkers of tau pathology are needed.
Publisher: Oxford University Press (OUP)
Date: 04-2000
Abstract: We examined the topography and degree of cell loss within basal ganglia structures commonly involved in progressive supranuclear palsy in order to identify any relationship between degeneration in these nuclei and gaze palsy. Serial section analyses and unbiased quantitative techniques were applied to brain tissue from six cases with progressive supranuclear palsy (four with gaze palsy and two without) and six controls with no neurological or neuropathological abnormalities. The total number of nucleolated neurons within the substantia nigra pars compacta (SNc) and reticulata (SNr), the subthalamic nucleus, and the internal and external segments of the globus pallidus was determined for all subjects and the data expressed as percentages of control values to compare degeneration across these basal ganglia structures. The density of neurofibrillary tangles was also evaluated within these structures. Despite significant subcortical neurofibrillary tangle formation in all cases, there was considerable variability in the degree of neuronal cell loss in all basal ganglia regions, except the SNc which was consistently affected. There was no correlation between the ranked density of neurofibrillary tangles and the degree of neuronal cell loss in any basal ganglia region. Comparisons between cases with and without gaze palsy revealed a 40% greater decrease in the number of SNr neurons in cases with gaze palsy (75 +/- 8% loss) compared with those without (35 +/- 14% loss). This was the largest difference between these cases. As the SNr projects to the superior colliculus, degeneration of this basal ganglia structure may disrupt eye movements in progressive supranuclear palsy.
Publisher: Elsevier BV
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 03-1995
DOI: 10.1007/BF01991780
Publisher: Springer Science and Business Media LLC
Date: 29-10-2014
Publisher: Wiley
Date: 12-1994
DOI: 10.1111/J.1530-0277.1994.TB01455.X
Abstract: Despite reduced levels of noradrenaline and increased cortical beta-adrenergic receptor binding, there is controversy regarding the effect of chronic alcohol consumption on the noradrenergic neurons of the locus coeruleus (LC). The aim of this study is to investigate the effects of chronic alcohol consumption on the LC in particular, to determine whether or not there is any alteration in the size or number of neurons, or other significant changes in this nucleus. Eight chronic alcoholics without additional medical complications and eight age-matched controls were selected for this study. Immunohistochemistry with antibodies against tyrosine hydroxylase (TH) was used to visualize TH-positive neurons in spaced serial 50-microns sections throughout the length of the LC. These neurons were counted and no correction factors applied. There was no significant loss of TH-positive neurons in the LC of alcoholics compared with controls who had up to 20% variation in the number of neurons between in iduals. This confirms published results from one alcoholic without complications, but contradicts recent findings of a significant neuronal loss in five alcoholics, all with liver pathology. Our analysis suggests that central noradrenergic neurons in alcoholics without significant medical complications are not susceptible to alcohol neurotoxicity.
Publisher: Cold Spring Harbor Laboratory
Date: 09-10-2022
DOI: 10.1101/2022.10.09.511389
Abstract: DNA methylation is a critical molecular mark involved in cellular differentiation and cell-specific processes. Single-cell whole genome DNA methylation profiling methods hold great potential to resolve the DNA methylation profiles of in idual cell-types. Here we present a method that couples single-cell combinatorial indexing (sci) with enzymatic conversion (sciEM) of unmethylated cytosines. The method facilitates single-base resolution DNA methylation profiling of single-cells that is highly correlated with single-cell bisulfite-based workflows (r 2 .99) whilst improving sequencing alignment rates, reducing adapter contamination and over-estimation of DNA methylation levels (CpG and non-CpG). As proof-of-concept we perform sciEM analysis of the temporal lobe, motor cortex, hippoc us and cerebellum of the human brain to resolve single-cell DNA methylation of all major cell-types.
Publisher: Wiley
Date: 22-06-2021
DOI: 10.1002/ACN3.51363
Abstract: The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis‐frontotemporal dementia (ALS‐FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS‐FTD. In a prospective case‐controlled study design, 100 participants were enrolled including ALS ( n = 37, 24% satisfied criteria for ALS‐Plus), ALS‐FTD ( n = 11), bvFTD ( n = 27) and healthy controls ( n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel‐based morphometry analyses determined atrophy patterns in patients experiencing psychosis‐like experiences and other perceptual abnormalities. The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS‐FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer‐based reports (18%) and self‐report measures of psychotic‐like experiences (21%). In an ENTER regression model, social anxiety and ACE‐III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis‐like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. The model for psychosis proneness in ALS‐FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for in idualised patient management.
Publisher: Elsevier BV
Date: 05-2005
DOI: 10.1016/J.JNS.2005.02.003
Abstract: Marked brain atrophy occurs in frontotemporal dementia (FTD) yet substantial variation between cases is seen. Recently, a four-level staging scheme which reflects increasing disease duration, severity of dementia and degree of neurodegeneration was described. In the present study, the extent and magnitude of atrophy in behavioral variant FTD and its relationship to disease duration and pathological subtype was further evaluated by quantifying the volume of 30 anatomically-defined regions. A validated point count technique was applied to 17 patients with FTD (9 Pick's disease, 6 dementia lacking distinctive histology, 2 FTD with motor neuron disease) and 21 controls. Atrophy was seen in all brain regions except the inferior frontal cortex and area 37. As might be expected, increasing severity of atrophy occurred with increasing disease duration and stage however measurable atrophy was more widespread than indicated by the staging scheme. Furthermore, severity of atrophy was not related to pathological subtype. Frontal, limbic and temporal regions appeared to be severely affected early in the disease process with temporal lobe atrophy the best predictor of disease duration. White matter, more posterior regions and the subcortex were affected later in the disease. These findings demonstrate a pattern of selective vulnerability which progresses over time. Furthermore, they demonstrate that although patients with a similar clinical subtype may have differing underlying histopathology, the pattern, severity and progression of brain atrophy is the same. This suggests that the regional pattern of neurodegeneration, rather than the type of histopathology influences the clinical syndrome in FTD.
Publisher: Wiley
Date: 28-11-2005
DOI: 10.1002/ANA.20691
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor symptoms. We identified two functional single nucleotide polymorphisms in the glycogen synthase kinase-3beta gene (GSK3B). A promoter single nucleotide polymorphism (rs334558) is associated with transcriptional strength in vitro in which the T allele has greater activity. An intronic single nucleotide polymorphism (rs6438552) regulates selection of splice acceptor sites in vitro. The T allele is associated with altered splicing in lymphocytes and increased levels of GSK3B transcripts that lack exons 9 and 11 (GSKDeltaexon9+11). Increased levels of GSKDeltaexon9+11 correlated with enhanced phosphorylation of its substrate, Tau. In a comparison of PD and control brains, there was increased in frequency of T allele (rs6438552) and corresponding increase in GSKDeltaexon9+11 and Tau phosphorylation in PD brains. Conditional logistic regression indicated gene-gene interaction between T/T genotype of rs334558 and H1/H1 haplotype of microtubule-associated protein Tau (MAPT) gene (p = 0.009). There was association between a haplotype (T alleles of both GSK3B polymorphisms) and disease risk after stratification by Tau haplotypes ((H1/H2+H2/H2 in iduals: odds ratio, 1.64 p = 0.007 (H1/H1 in iduals: odds ratio, 0.68 p < 0.001). Ours results suggest GSK3B polymorphisms alter transcription and splicing and interact with Tau haplotypes to modify disease risk in PD.
Publisher: BMJ
Date: 09-1997
Abstract: The cholinergic nucleus basalis (Ch4) is an exclusive site of neurofibrillary degeneration in alcoholic patients with Wernicke's encephalopathy. To test the hypothesis that the loss of Ch4 neurons contributes to the memory disorder, Korsakoff's psychosis, commonly seen in Wernicke's encephalopathy. Magnocellular basal forebrain neurons were quantified in alcoholic patients with Wernicke's encephalopathy, both with and without Korsakoff's psychosis, and neurologically asymptomatic alcoholic and non-alcoholic controls. Because amnesic and non-amnesic patients with Wernicke's encephalopathy share common periventricular lesions, both thiamine deficient groups as well as alcoholic patients with no neurological complications were included to determine the lesion specific to memory impairment. Ch4 cell number did not differ significantly between alcoholic and non-alcoholic controls and there was no correlation between cell number and lifetime alcohol intake. However, Ch4 cell number in all groups was significantly correlated with the volume of its major projection target, the cerebral cortex. Ch4 cell number in the non-amnesic Wernicke's encephalopathy group was significantly below controls (24%), with cell number in patients with Korsakoff's psychosis 21% below controls. There was considerable overlap in cell number between groups. On discriminant analysis, there was significantly greater cell loss in three non-amnesic patients with Wernicke's encephalopathy than in some patients with Korsakoff's psychosis. The nonamnesic patient with the greatest cell loss was impaired on attentional tasks. Whereas neurons in the nucleus basalis are at risk in thiamine deficient alcoholic patients, cell loss is minor and does not account for the profound memory disorder.
Publisher: Elsevier BV
Date: 09-1988
DOI: 10.1016/0006-8993(88)90726-3
Abstract: We have studied the distribution of tyrosine hydroxylase-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the adult human hypothalamus. Large numbers of these neurons were seen in these hypothalamic nuclei approximately 40% of all the cells within the SON and PVN were immunoreactive for tyrosine hydroxylase (TH-ir). Most of these cells were magnocellular. Their distribution was compared to that of arginine-vasopressin-immunoreactive (AVP-ir) cells. In the SON a greater proportion of magnocellular TH-ir cells was found caudally compared to AVP-ir cells. In the PVN the magnocellular TH-ir cells were larger in mean diameter compared to AVP-ir cells. In double-immunofluorescence experiments some TH-ir cells contained oxytocin immunoreactivity but none contained AVP-ir. In the adult human a large number of PVN and SON magnocellular cells appear to synthesize a catecholamine. A subclass of these neurons also synthesize oxytocin but most cells are distinct from the classically described neurosecretory neurons.
Publisher: Springer Science and Business Media LLC
Date: 25-11-2017
Publisher: Elsevier BV
Date: 02-2001
Publisher: Elsevier BV
Date: 09-2019
Publisher: Oxford University Press (OUP)
Date: 05-2000
Abstract: Genetic mutations in the tau gene on chromosome 17 are known to cause frontotemporal dementias. We have identified a novel silent mutation (S305S) in the tau gene in a subject without significant atrophy or cellular degeneration of the frontal and temporal cortices. Rather the cellular pathology was characteristic of progressive supranuclear palsy, with neurofibrillary tangles concentrating within the subcortical regions of the basal ganglia. Two affected family members presented with symptoms of dementia and later developed neurological deficits including abnormality of vertical gaze and extrapyramidal signs. The third presented with dystonia of the left arm and dysarthria, and later developed a supranuclear gaze palsy and falls. The mutation is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site. Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the presence of tau containing four microtubule-binding repeats. This study provides direct molecular evidence for a functional mutation that causes progressive supranuclear palsy pathology and demonstrates that mutations in the tau gene are pleiotropic.
Publisher: Wiley
Date: 25-04-2005
DOI: 10.1002/MDS.20497
Abstract: Deep brain stimulation therapy is increasingly gaining acceptance in the management of levodopa-induced dyskinesia and fluctuations in idiopathic Parkinson's disease. It is generally not recommended for the other forms of parkinsonism such as progressive supranuclear palsy or multiple system atrophy where the response to levodopa is usually poor and disease progression more rapid, making any benefit short-lived. Here, we present an autopsy-confirmed case of "minimal-change" multiple system atrophy in whom pallidal stimulation surgery was effective in abolishing severe levodopa-induced dyskinesia.
Publisher: Oxford University Press (OUP)
Date: 13-07-2005
DOI: 10.1093/BRAIN/AWH596
Abstract: Changes in motor cortical activation are associated with the major symptoms observed in both Parkinson's disease and progressive supranuclear palsy (PSP). While research has concentrated on basal ganglia abnormalities as central to these cortical changes, several studies in both disorders have shown pathology in the thalamus and motor cortices. In particular, we recently reported an 88% loss of corticocortical projection neurones in the pre-supplementary motor (pre-SMA) cortex in Parkinson's disease. Further analysis of the degree of neuronal loss and pathology in motor cortices and their thalamocortical relays in Parkinson's disease and PSP is warranted. Six cases with PSP, nine cases with Parkinson's disease and nine controls were selected from a prospectively studied brain donor cohort. alpha-Synuclein, ubiquitin and tau immunohistochemistry were used to identify pathological lesions. Unbiased stereological methods were used to analyse atrophy and neuronal loss in the motor thalamus [ventral anterior, ventrolateral anterior and ventrolateral posterior (VLp) nuclei] and motor cortices (primary motor, dorsolateral premotor and pre-SMA cortices). Analysis of variance and post hoc testing was used to determine differences between groups. In Parkinson's disease, the motor thalamus and motor cortices (apart from the pre-SMA) were preserved containing only rare alpha-synuclein-positive and ubiquitin-positive Lewy bodies. In contrast, patients with PSP had significant atrophy and neuronal loss in VLp (22 and 30%, respectively), pre-SMA (21 and 51%, respectively) and primary motor cortices (33 and 54%, respectively). In the primary motor cortex of PSP cases, neuronal loss was confined to inhibitory interneurones, whereas in the pre-SMA both interneurones (reduced by 26%) and corticocortical projection neurones (reduced by 82%) were affected. Tau-positive neurofibrillary and glial tangles were observed throughout the motor thalamus and motor cortices in PSP. These non-dopaminergic lesions in motor circuits are likely to contribute to the pathogenesis of both PSP and Parkinson's disease. The selective involvement of the VLp and primary motor cortex in PSP implicates these cerebellothalamocortical pathways as differentiating this disease, possibly contributing to the early falls.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2022
DOI: 10.1038/S41572-022-00382-6
Abstract: Multiple system atrophy (MSA) is a rare neurodegenerative disease that is characterized by neuronal loss and gliosis in multiple areas of the central nervous system including striatonigral, olivopontocerebellar and central autonomic structures. Oligodendroglial cytoplasmic inclusions containing misfolded and aggregated α-synuclein are the histopathological hallmark of MSA. A firm clinical diagnosis requires the presence of autonomic dysfunction in combination with parkinsonism that responds poorly to levodopa and/or cerebellar ataxia. Clinical diagnostic accuracy is suboptimal in early disease because of phenotypic overlaps with Parkinson disease or other types of degenerative parkinsonism as well as with other cerebellar disorders. The symptomatic management of MSA requires a complex multimodal approach to compensate for autonomic failure, alleviate parkinsonism and cerebellar ataxia and associated disabilities. None of the available treatments significantly slows the aggressive course of MSA. Despite several failed trials in the past, a robust pipeline of putative disease-modifying agents, along with progress towards early diagnosis and the development of sensitive diagnostic and progression biomarkers for MSA, offer new hope for patients.
Publisher: Frontiers Media SA
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
Publisher: Springer Science and Business Media LLC
Date: 23-05-2010
DOI: 10.1038/NM.2165
Abstract: Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.
Publisher: Wiley
Date: 25-11-2013
DOI: 10.1002/HBM.22420
Publisher: Wiley
Date: 2017
DOI: 10.1002/ANA.24820
Publisher: Wiley
Date: 08-04-1992
Abstract: In order to verify the existence of the ventral and posterodorsal tegmental nuclei and to extend previous findings regarding the dorsal tegmental nucleus in the human brainstem, studies were conducted using cyto- and chemoarchitectonics, and computer reconstruction techniques. Serial sections of five brainstems from adults with no known neurological disorders were stained for Nissl substance, acetylcholinesterase, and substance P. The topography, cytoarchitecture, and acetylcholinesterase reactivity of the tegmental nuclei were presented in a mini-atlas depicting sections cut in transverse and sagittal planes. The dorsal and posterodorsal tegmental nuclei were identified fully within the central grey matter while the ventral tegmental nucleus extended across the medial longitudinal fasciculus into the pontine reticular formation. The dorsal tegmental nucleus featured a cell-poor pericentral part, strongly positive for acetylcholinesterase, and a central part comprised of densely packed small neurons that displayed moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The posterodorsal tegmental nucleus, located in the same transverse plane as the rostral part of the motor nucleus of the trigeminal nerve, was composed of diffusely arranged small to medium neurons with its neuropil displaying moderate acetylcholinesterase reactivity and strong substance P-like immunoreactivity. The ventral tegmental nucleus, identified as a prominent structure in the pontine tegmentum immediately rostral to the genu of the facial nerve, contained predominantly large neurons and displayed intensive acetylcholinesterase reactivity and substance P-like immunoreactivity. These studies showed that the tegmental nuclei, which displayed distinctive cyto- and chemoarchitectonic features, were fully present in adult human brainstem.
Publisher: Springer Science and Business Media LLC
Date: 04-2002
DOI: 10.1007/S00401-001-0477-5
Abstract: Neurofibrillary tangle (NFT) formation in the CA1 region of the hippoc us is one of the early events in the pathogenesis of Alzheimer's disease (AD). As the disease progresses more NFTs form and there is substantial neuron loss. In this study we investigated whether NFT formation accounts for all the CA1 pyramidal neuron loss seen in AD. Using unbiased stereological techniques, we estimated the total number of neurons and the number of intra- and extra-cellular NFTs in the hippoc us of 10 patients with AD and 10 age-matched controls. Marked neuronal loss (approximately 60%) was identified in AD, although NFTs accounted for only a small proportion of this loss (2.2-17.2%, mean 8.1%). Analysis of NFT accumulation with duration of dementia showed a linear relationship, supporting the belief that NFTs progressively accumulate with time.
Publisher: BMJ
Date: 18-02-2011
Abstract: To determine whether neuropsychological measures differ between patients with idiopathic Parkinson's disease (PD) who acquire dementia within 10 years of disease onset versus those who acquire dementia later in the disease course, using data from the longitudinal Sydney Multicentre Study of PD. The Sydney Multicentre Study of PD is a cohort of 149 community-living de novo patients with idiopathic PD studied over a 20-year period. Detailed clinical and neuropsychological tests were administered at baseline and at 3, 5, 10, 15 and 20 years, and the dementia status was assessed at each time point. For the present study, the pattern of longitudinal neuropsychological measures was compared between PD patients with the onset of dementia in the middle (5-10 years, mid-stage PD dementia, N = 20) or late (>10 years, late-stage PD dementia, N = 10) disease stages using analysis of variance and multiple linear regression modelling, and the relationship between age and dementia onset assessed using survival statistics. Mid-stage PD dementia patients were differentiated from late-stage PD dementia patients by having greater deficits in vocabulary skills prior to and at dementia onset. The pattern of cognitive deficits following dementia onset are similar, and there is no difference in the age of dementia onset between the different PD groups. These data suggest that the evolution of dementia within PD occurs at around 70 years of age, regardless of the time of PD onset, and affects cognitive domains in a similar way, although patients with earlier-onset PD have a preserved linguistic ability prior to dementia onset.
Publisher: Elsevier
Date: 2003
Publisher: Elsevier BV
Date: 05-1996
DOI: 10.1016/0304-3940(96)12592-1
Abstract: Glial fibrillary acidic protein (GFAP) is the principal marker for brain astrocytes. The present study aims to examine the variability in GFAP immunohistochemistry in formalin-fixed human brain. Four commercially-available antisera were tested using standardised protocols in the cerebral cortex of three cases with prominent glial reactions and one control. GFAP immunoreactivity was largely confined to the pial surface and white matter in control cortex, with the number of astrocytic cell bodies and processes as well as intensity of staining markedly increased in damaged cortices. A dramatic difference in the pattern of GFAP staining using different antisera was observed and may account for discrepancies between past studies. This variance has important practical implications for the interpretation of results using GFAP immunohistochemistry in human tissue.
Publisher: Wiley
Date: 1988
Abstract: The raphe nuclei also contained SP-like immunoreactivity (up to 30%) while few monoamine-synthesizing neurons in the lateral and dorsomedial medulla contained SP-like immunoreactivity (approximately 5% of presumed serotonin-, noradrenaline-, and adren- the adult human. The majority of SP-like immunoreactive neurons were found in four main regions: the lateral medulla, the dorsomedial medulla, the spinal trigeminal nucleus, and the raphe nuclei. The morphology of immunoreactive cells varied according to the region in which they were found. In contrast to previous studies, we found large numbers (90,000) of SP-like immunoreactive neurons throughout the adult human medulla oblongata. The distribution of these SP-like immunoreactive neurons appears to be significantly different from those described in the rat and cat. These results were compared to the distributions of monoamine-synthesizing and neuropeptide Y (NPY)-like immunoreactive neurons in the human medulla previously reported (Halliday et al.: Neuroscience, in press, 1988a J. Comp. Neurol., in press, 1988b). Colocalization studies revealed that many presumed serotonin-synthesizing neurons in the raphe nuclei also contained SP-like immunoreactivity (up to 30%) while few monoamine-synthesizing neurons in the lateral and dorsomedial medulla contained SP-like immunoreactivity (approximately 5% of presumed serotonin-, noradrenaline-, and adrenaline-synthesizing neurons). The distributions of SP- and NPY-like immunoreactive neurons were similar, although SP-like immunoreactive neurons were concentrated in the lateral regions of the same structures. We have found that the distributions of monoamine-synthesizing, NPY-, and SP-like immunoreactive neurons significantly overlap, particularly in the lateral medulla of the adult human. There is a large increase in the number of these cells in this region compared to other species, emphasizing the neuroanatomical differences between humans and other species.
Publisher: Wiley
Date: 15-04-2014
DOI: 10.1002/MDS.25857
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1016/J.JNEUROIM.2012.07.015
Abstract: Gene association with HLA suggests involvement of immune mediated mechanisms in the pathogenesis of Parkinson's disease (PD). Only a small number of studies have found differences between circulating leukocyte populations in PD patients compared to controls, with conflicting results. To clarify whether there is a circulating leukocyte PD phenotype, we assessed the numbers of T, B and natural killer cells, and monocytes and found a small reduction (15-25%) in CD4+ T and CD19+ B cells in PD. These findings suggest some compromise in immune cells in PD and have potential implications for immune function and the progression of PD.
Publisher: Wiley
Date: 13-08-2004
DOI: 10.1002/MDS.20286
Abstract: The movement disorders progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) both deposit tau in degenerating neurons and are considered to be tauopathies. The recently developed scheme for staging tissue degeneration in another tauopathy, frontotemporal dementia [Broe et al., Neurology 2003 :1005-1011] was applied to pathologically confirmed PSP (n = 24) and CBD (n = 9) cases and correlated with clinical indices. In contrast to frontotemporal dementia, the majority of PSP cases had limited or no visible atrophy, while the pattern of atrophy in CBD cases conformed to the existing staging scheme (all but one case exhibiting substantial visible tissue atrophy). Despite similar clinical severity and disease duration between groups, there was a marked difference between the PSP and CBD cases in pathological disease stage (chi(2) = 8.86 P = 0.03). The degree of global atrophy in PSP appears to be distinct from other tauopathies, while CBD fits the same pattern as other pathological forms of frontotemporal dementia.
Publisher: MDPI AG
Date: 22-11-2022
Abstract: Dementia with Lewy bodies (DLB) is an insidious neurodegenerative disease characterised by a precipitous decline in cognition, sleep disturbances, motor impairment and psychiatric features. Recently, criteria for prodromal DLB (pDLB) including clinical features and biomarkers have been put forward to aid the classification and research of this ambiguous cohort of patients. Researchers can use these criteria to classify patients with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) as either possible (either one core clinical feature or one biomarker are present) or probable pDLB (at least two core clinical features, or one core clinical feature and at least one biomarker present). However, as isolated REM sleep behaviour disorder (iRBD) confirmed with polysomnography (PSG) can be included as both a clinical and a biomarker feature, potentially reducing the specificity of these diagnostic criteria. To address this issue, the current study classified a cohort of 47 PSG-confirmed iRBD patients as probable prodromal DLB only in the presence of an additional core feature or if there was an additional non-PSG biomarker. Thirteen iRBD patients demonstrated MCI (iRBD-MCI). In the iRBD-MCI group, one presented with parkinsonism and was thus classified as probable pDLB, whilst the remaining 12 were classified as only possible pDLB. All patients performed three tasks designed to measure attentional deficits, visual hallucinations and visuospatial impairment. Patients also attended clinical follow-ups to monitor for transition to DLB or another synucleinopathy. Findings indicated that the only patient categorised by virtue of having two core clinical features as probable pDLB transitioned over 28 months to a diagnosis of DLB. The performance of this probable pDLB patient was also ranked second-highest for their hallucinatory behaviours and had comparatively lower visuospatial accuracy. These findings highlight the need for more stringent diagnostic research criteria for pDLB, given that only one of the 13 patients who would have satisfied the current guidelines for probable pDLB transitioned to DLB after two years and was indeed the patient with two orthogonal core clinical features.
Publisher: Public Library of Science (PLoS)
Date: 29-08-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-07-2016
Publisher: Elsevier BV
Date: 08-2007
DOI: 10.1016/J.NBD.2007.04.014
Abstract: Mutations in parkin are a common cause of early-onset autosomal recessive Parkinson's disease. Parkin Co-Regulated Gene (PACRG) is a novel gene that was discovered because of its close genetic proximity to parkin and the two genes were subsequently demonstrated to be regulated by a bi-directional promoter. However the role of PACRG has not been well characterized and the distribution of the protein in both normal and diseased brain is not known. Here, we report that like parkin, PACRG is regulated by the ubiquitin-proteasomal system. Immunohistochemistry identified PACRG in astrocytes throughout the brain and in pigmented noradrenergic neurons of the locus coeruleus. PACRG was also detected in Lewy bodies and glial cytoplasmic inclusions in patients with Parkinson's disease and Multiple System Atrophy, respectively. Together, these results demonstrate that PACRG is regulated by the ubiquitin-proteasomal system and may play a role in the pathogenesis of Parkinson's disease.
Publisher: Elsevier
Date: 2004
Publisher: BMJ
Date: 26-09-2014
Publisher: Springer Science and Business Media LLC
Date: 27-11-2015
DOI: 10.1038/NCOMMS9836
Abstract: Alzheimer’s disease (AD) is characterized by synapse loss due to mechanisms that remain poorly understood. We show that the neural cell adhesion molecule 2 (NCAM2) is enriched in synapses in the human hippoc us. This enrichment is abolished in the hippoc us of AD patients and in brains of mice overexpressing the human amyloid-β (Aβ) precursor protein carrying the pathogenic Swedish mutation. Aβ binds to NCAM2 at the cell surface of cultured hippoc al neurons and induces removal of NCAM2 from synapses. In AD hippoc us, cleavage of the membrane proximal external region of NCAM2 is increased and soluble extracellular fragments of NCAM2 (NCAM2-ED) accumulate. Knockdown of NCAM2 expression or incubation with NCAM2-ED induces disassembly of GluR1-containing glutamatergic synapses in cultured hippoc al neurons. Aβ-dependent disassembly of GluR1-containing synapses is inhibited in neurons overexpressing a cleavage-resistant mutant of NCAM2. Our data indicate that Aβ-dependent disruption of NCAM2 functions in AD hippoc us contributes to synapse loss.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-01-2011
Publisher: Elsevier BV
Date: 07-1988
DOI: 10.1016/0306-4522(88)90136-4
Abstract: We have described the distribution of neuropeptide Y-like immunoreactive neurons in the medulla oblongata of the adult human. The majority of neuropeptide Y-like immunoreactive cells were found in four regions of the medulla: the ventrolateral reticular formation, the dorsomedial medulla, the secondary sensory nuclei and the rostral raphe nuclei. The morphology of neuropeptide Y-like immunoreactive cells varied in each of these regions. In the ventrolateral reticular formation, the labelled neurons were round and pigmented caudal to the obex but elongated and non-pigmented rostral to the obex in the dorsomedial medulla, they were triangular and pigmented caudal to but not rostral to the obex in the secondary sensory nuclei, they were multipolar, non-pigmented and significantly smaller than in the other areas in the rostral raphe nuclei, they were bipolar and non-pigmented. Colocalization studies revealed that many neuropeptide Y-like immunoreactive cells also synthesize monoamines, consistent with conclusions based on a quantitative comparison of their distributions. Neuropeptide Y-like immunoreactivity was present in about 25% of presumed noradrenaline-synthesizing cells in the caudal ventrolateral medulla (corresponding to the A1 region) about 50% of adrenaline- and 70% of presumed serotonin-synthesizing cells in the rostral ventrolateral medulla (C1 and B2-3 regions) 90-100% of presumed noradrenaline-synthesizing cells in the dorsomedial medulla at and above the obex (A2 region) about 50% of adrenaline-synthesizing cells in the rostral dorsomedial medulla (C2 region) about 5% of presumed serotonin-synthesizing cells in the rostral raphe nuclei (B2-3 region). The largest of these groups was the presumed serotonin-synthesizing cells that contained neuropeptide Y-like immunoreactivity in the rostral ventrolateral medulla. This is the first report of such a cell group in the medulla of any mammal, and emphasizes the neuroanatomical differences between humans and other species.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/526277
Abstract: Ageing is the major risk factor for Alzheimer’s disease (AD), a condition involving brain hypoxia. The majority of early onset familial AD (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for AD occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfAD pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.
Publisher: Oxford University Press (OUP)
Date: 13-09-2004
DOI: 10.1093/BRAIN/AWH250
Publisher: Wiley
Date: 07-2017
DOI: 10.1111/EJN.13623
Abstract: Neurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n = 26-35, 41 days to 43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into ageing (n = 50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.
Publisher: Oxford University Press (OUP)
Date: 07-08-2010
DOI: 10.1093/BRAIN/AWQ186
Publisher: Wiley
Date: 20-05-2008
DOI: 10.1002/AJMG.B.30633
Abstract: Idiopathic Parkinson's disease is a common movement disorder characterized by a loss of dopaminergic neurons in the substantia nigra. Its pathogenesis is postulated to involve complex interactions between genetic susceptibility and environmental exposures. The IGF2-INS-TH gene cluster on the telomeric end of human chromosome 11 is a gene rich region expressing several proteins important for dopamine neuron homeostasis. We used a haplotyping approach to determine whether common genetic variation in the IGF2-INS-TH cluster influences the risk of idiopathic Parkinson's disease in a Caucasian case-control group recruited from Brisbane, Australia. Three tagging polymorphisms, the SNPs, rs680 and rs689 and the microsatellite, HUMTH01, were genotyped in 215 cases and 215 age- and gender-matched controls. Eight common haplotypes accounted for 91% of the genetic variation in our control group and one haplotype, IGF2-INS-TH*6, was significantly under-represented among the cases with idiopathic Parkinson's disease (OR = 0.42, 95% CI = 0.25-0.72, P-value = 0.001). Analysis of the in idual polymorphisms showed that the IGF2-rs680 alternate 'A' allele accounted for the majority of the protective effect. Our findings suggest that common genetic variants in the IGF2-INS-TH cluster modify susceptibility to idiopathic Parkinson's disease.
Publisher: Wiley
Date: 05-2011
DOI: 10.1002/MDS.23669
Abstract: The identification of the widespread deposition of fibrillized α-synuclein in Lewy bodies and Lewy neurites in the brains of patients with Parkinson's disease in 1997 has had a profound impact on how the disease is now conceptualized. The previous focus on the loss of the dopaminergic nigrostriatal system, the concept of subcortical dementia, and the idea that Parkinson's disease was dominated by motor impairment have all given way to research assessing more erse brain regions, clinical symptoms, and phenotypes. It is now recognized that Parkinson's disease is more than just a loss of midbrain dopaminergic neurons in association with Lewy bodies. There are now several theories on how the disease develops and progresses currently being validated in a variety of studies, although many of these theories have yet to incorporate the phenotypic clinical and pathological changes associated with age. A particularly exciting new area of research involves the cell-to-cell transmission of pathogenic proteins. The recent consensus definition of Parkinson's disease dementia will allow its pathologic substrates to be determined. These advances have progressed to a stage where the preclinical stages of Parkinson's disease and its specific signs and symptoms are being predicted and tested clinically. Such strategies herald a future wave of preventive strategies for Parkinson's disease and its clinical symptoms.
Publisher: Wiley
Date: 27-02-2002
DOI: 10.1002/CNE.10165
Abstract: This study compares the basal ganglia of rats, marmosets, macaques, baboons, and humans. It uses established protocols to estimate the volume and number of neurons within the output nuclei (internal globus pallidus, IGP and nondopaminergic substantia nigra, SNND), two internal relay and modulating nuclei (subthalamic nucleus, STh and external globus pallidus, EGP), and a modulator of the striatum (dopaminergic substantia nigra, SND). Nuclear boundaries were defined by using immunohistochemistry for striatal afferents. Total numbers of Nissl-stained and parvalbumin-immunoreactive neurons were calculated by using the fractionator technique. Comparisons between species were standardized relative to brain mass (rats < marmosets < macaques < baboons < humans). The EGP consistently had more neurons relative to the IGP, STh, and SND, which had similar neuronal numbers within each species. The SNND had proportionally more neurons in rats than in primates (especially humans). The distribution of SND neurons varied substantially between rats and primates (very few ventrally located neurons in rats) with humans containing fewer SND neurons than other primates. The reduction in SND neurons in humans suggests less dopaminergic regulation of the basal ganglia system compared with other species. The consistency in the number of IGP neurons across all species, combined with the reduction in SNND neurons in humans, suggests a greater emphasis on output pathways through the IGP and that there are proportionally more STh and EGP neurons in humans.
Publisher: Wiley
Date: 17-02-2009
DOI: 10.1002/MDS.22214
Abstract: Recent whole genome association studies provided little evidence that polymorphisms at the familial Parkinsonism loci influence the risk for Parkinson's disease (PD). However, these studies are not designed to detect the types of subtle effects that common variants may impose. Here, we use an alternative targeted candidate gene approach to examine common variation in 11 genes related to familial Parkinsonism. PD cases (n = 331) and unaffected control subjects (n = 296) were recruited from three specialist movement disorder clinics in Brisbane, Australia and the Australian Electoral Roll. Common genetic variables (76 SNPs and 1 STR) were assessed in all subjects and haplotype, genotype, and allele associations explored. Modest associations (uncorrected P < 0.05) were observed for common variants around SNCA, UCHL1, MAPT, and LRRK2 although none were of sufficient magnitude to survive strict statistical corrections for multiple comparisons. No associations were seen for PRKN, PINK1, GBA, ATP13A2, HTRA2, NR4A2, and DJ1. Our findings suggest that common genetic variables of selected PD-related loci contribute modestly to PD risk in Australians.
Publisher: BMJ
Date: 1997
DOI: 10.1136/JNNP.62.1.51
Abstract: To establish better operational criteria for the diagnosis of Wernicke's encephalopathy. Current criteria for diagnosing Wernicke's encephalopathy require the presence of three clinical signs (oculomotor abnormalities, cerebellar dysfunction, and an altered mental state), although it has often been reported that most patients do not fulfil all these criteria. The clinical histories of 28 alcoholics with neurological and neuropsychological assessments and definitive neuropathological diagnoses were examined to determine clinical signs for use in a screening schedule. Operational criteria were then proposed for differentiating patients with Wernicke's encephalopathy alone or in combination with Korsakoff's psychosis or hepatic encephalopathy. The new criteria for Wernicke's encephalopathy require two of the following four signs (1) dietary deficiencies, (2) oculomotor abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment. Reproducibility and validity testing of these criteria were performed on 106 alcoholics screened from a large necropsy s le. Despite rater variability with regard to specific symptoms, within and between rater reliability for diagnostic classification using the criteria retrospectively on patient records was 100% for three independent raters. Validity testing showed that Wernicke's encephalopathy was underrecognized only when occurring with hepatic encephalopathy (50% sensitivity). By contrast with current criteria, the proposed operational criteria show that the antemortem identification of Wernicke's encephalopathy can be achieved with a high degree of specificity.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.NBD.2015.08.024
Abstract: The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2021
Publisher: Elsevier BV
Date: 09-2019
Publisher: Wiley
Date: 11-03-2014
DOI: 10.1002/MDS.25844
Publisher: Wiley
Date: 30-10-2013
DOI: 10.1002/MDS.25729
Abstract: Genetic studies have provided increasing evidence that ceramide homeostasis plays a role in neurodegenerative diseases including Parkinson’s disease (PD). It is known that the relative amounts of different ceramide molecular species, as defined by their fatty acyl chain length, regulate ceramide function in lipid membranes and in signaling pathways. In the present study we used a comprehensive sphingolipidomic case-control approach to determine the effects of PD on ceramide composition in postmortem brain tissue from the anterior cingulate cortex (a region with significant PD pathology) and the occipital cortex (spared in PD), also assessing mRNA expression of the major ceramide synthase genes that regulate ceramide acyl chain composition in the same tissue using quantitative PCR. In PD anterior cingulate cortex but not occipital cortex, total ceramide and sphingomyelin levels were reduced from control levels by 53% (P < 0.001) and 42% (P < 0.001), respectively. Of the 13 ceramide and 15 sphingomyelin molecular lipid species identified and quantified, there was a significant shift in the ceramide acyl chain composition toward shorter acyl chain length in the PD anterior cingulate cortex. This PD-associated change in ceramide acyl chain composition was accompanied by an upregulation of ceramide synthase-1 gene expression, which we consider may represent a response to reduced ceramide levels. These data suggest a significant shift in ceramide function in lipid membranes and signaling pathways occurs in regions with PD pathology. Identifying the regulatory mechanisms precipitating this change may provide novel targets for future therapeutics.
Publisher: Wiley
Date: 10-12-1984
Abstract: We have studied the normal ultrastructure of the ventral mesencephalic tegmentum (VMT) in the cat, particularly the morphology and distribution of presynaptic terminals and the types of synaptic junctions. The following subnuclei of the region were examined: n. linearis rostralis (LR), n. paranigralis (PN), and n. interfascicularis (IF). The qualitative and quantitative data revealed significant ultrastructural differences between these subnuclei. Each subnucleus had a characteristic dendritic structure. In LR the dendrites were nonspinous and cylindrical and had presynaptic terminals randomly distributed over their surface. In PN we observed varicose dendrites with spines the presynaptic terminals formed clusters on the narrow segments of the dendrites and around the spines. Dendrodendritic synapses were also observed in this nucleus. In IF, there was an internal ision regarding dendritic structure: in the rostral part of the nucleus there were cylindrical dendrites while in the caudal part irregularly shaped dendrites bearing long spines were found. In IF and LR some of the cylindrical dendrites were seen to be in direct contact with the basal lamina of blood vessels. Four types of presynaptic terminals were distinguished by the morphology of their vesicles, and the proportion of each type in the total terminal population was determined. On this basis the compositions of the presynaptic terminal population in the three subnuclei were found to be very similar. Most terminals contained clear, round vesicles (62.6%), or both clear and dense-cored vesicles (35.1%). Few terminals were seen with dense-cored vesicles only (1.4%) or with pleomorphic vesicles (0.9%). The majority of synapses in the VMT were found to have symmetrical densities. LR had twice as many asymmetrical synapses as the other two subnuclei. Eighty percent of the terminals formed synapses with dendrites, although axosomatic and axoaxonic synapses were also seen. The density of the terminals was significantly different for each subnucleus: 191/1,000 micrometers 2 in IF, 120/1,000 micrometers 2 in PN, and 81/1,000 micrometers 2 in LR. These data indicate that while the subnuclei of the VMT receive morphologically similar afferents, each has a unique way of processing the information provided by them, through a different internal circuitry.
Publisher: Wiley
Date: 13-06-2013
DOI: 10.1002/HBM.22321
Publisher: Springer Science and Business Media LLC
Date: 03-1995
DOI: 10.1007/BF01991785
Publisher: Wiley
Date: 27-12-2005
DOI: 10.1002/ANA.20366
Abstract: Presenilin-1 (PS-1) mutations can cause Pick's disease without evidence of Alzheimer's disease (AD). We describe a family with a PS-1 M146L mutation and both Pick bodies and AD. Sarkosyl-insoluble hyperphosphorylated tau showed three bands consistent with AD, although dephosphorylation showed primarily three-repeat isoforms. M146L mutant PS-1 may predispose to both Pick's disease and AD by affecting multiple intracellular pathways involving tau phosphorylation and amyloid metabolism.
Publisher: Wiley
Date: 15-07-1988
Abstract: We have employed immunohistochemical and morphometric procedures to study the distribution of monoamine-synthesizing neurons in the medulla oblongata of the adult human, utilizing antibodies to tyrosine hydroxylase (TH), phenylethanolamine N-methyltransferase (PNMT), and phenylalanine hydroxylase (PH8). In the human brain, the antigen with which PH8 reacts occurs within neurons that presumably synthesize serotonin (Haan et al., '87). Neurons containing these antigens were mapped and counted in successive coronal sections with the aid of a computer-assisted procedure. The results indicate that monoamine-synthesizing neurons are distributed in the human brain in patterns broadly similar to those described for other species. TH-immunoreactive cells extended caudorostrally for approximately 32 mm commencing at the spinomedullary junction and ending 8 mm caudal to the pontomedullary junction. In coronal sections these TH-immunoreactive neurons were seen in the lateral medulla dorsal to the inferior olive extending in a continuous band to the dorsomedial medulla. Above the obex the majority of these cells apparently synthesize adrenaline since many PNMT-immunoreactive cells were also found in this region. There were few or no PNMT-immunoreactive cells caudal to the obex, indicating that the TH-immunoreactive cells in this region synthesize either noradrenaline or dopamine. Approximately 65% of these TH-immunoreactive neurons contained melanin pigment, whereas few or no PNMT-immunoreactive cells contained melanin pigment. PH8-immunoreactive cells extended throughout the rostrocaudal extent of the medulla oblongata (approximately 40 mm). In coronal sections the majority were found in the medullary raphe nuclei. However, many cells throughout the rostrocaudal extent of the medulla were found laterally intermingled with catecholamine-synthesizing neurons. Occasional neurons in the lateral medulla appeared to contain both PH8- and TH-immunoreactivity.
Publisher: Elsevier BV
Date: 12-2002
DOI: 10.1016/S0301-0082(02)00127-2
Abstract: The symptoms of Parkinson's disease (PD) were first described nearly two centuries ago and its characteristic pathology identified nearly a century ago, yet its pathogenesis is still poorly understood. Parkinson's disease is the most prevalent neurodegenerative movement disorder and research into its pathogenesis recently accelerated following the identification of a number of causal genetic mutations. The mutant gene products all cause dysfunction of the ubiquitin-proteosome system, identifying protein modification and degradation as critical for pathogenesis. Modified non-degraded intracellular proteins accumulate in certain neuronal populations in all forms of the disease. However, neuronal degeneration is more highly selective and associates with substantial activation of microglia, the inflammatory cells of the brain. We review the current change in thinking regarding the role of microglia in the brain in the context of Parkinson's disease and animal models of the disease. Comparison of the cellular tissue changes across a number of animal models using erse stimuli to mimic Parkinson's disease reveals a consistent pattern implicating microglia as the effector for the selective degeneration of dopaminergic neurons. While previous reviews have concentrated on the intracellular neuronal changes in Parkinson's disease, we highlight the cell to cell interactions and immune regulation critical for neuronal homeostasis and survival in Parkinson's disease.
Publisher: Elsevier BV
Date: 07-1999
Abstract: Our structural studies of the substantia nigra in parkinsonian patients identified previously unsuspected changes in the pars reticulata, suggesting significant dysfunction in this basal ganglia output. There have been few similar structural studies of the other major basal ganglia output, the internal segment of the globus pallidus. This is despite significant evidence that this basal ganglia region is crucially important for generating parkinsonian symptoms. In fact current surgical interventions target this region in Parkinson's disease. The cellular anatomy of the internal globus pallidus was compared among five controls, six patients with Parkinson's disease, and five patients with progressive supranuclear palsy. Neurons and pathological structures were quantified using the unbiased fractionator method. Only cases with progressive supranuclear palsy had detectable pathology within the internal globus pallidus in the form of tau-positive neuronal and glial tangles and substantial neurodegeneration. Cases with Parkinson's disease had a significant reduction in the proportion of neurons containing parvalbumin but were without significant neurodegeneration, consistent with dysfunction of both basal ganglia output nuclei in advanced parkinsonism. Surgical ablation of the internal globus pallidus for Parkinson's disease appears at odds with the significant neurodegeneration in the similarly akinetic and rigid patients with progressive supranuclear palsy. The results are discussed in association with current hypotheses of basal ganglia function and recent experimentation in patients undergoing pallidotomy for hyperkinetic disorders.
Publisher: Oxford University Press (OUP)
Date: 03-2002
DOI: 10.1093/BRAIN/AWF082
Abstract: Regional brain volumes were measured in 21 patients with progressive supranuclear palsy (PSP), 17 patients with Parkinson's disease and 23 controls using 3D MRI-based volumetry. Cortical, subcortical and ventricular volume measures were correlated with global indices of motor disability and cognitive disturbance. All MRI measures, including hippoc al volume, were preserved in Parkinson's disease. Patients with PSP could be distinguished from both Parkinson's disease and controls by whole brain volume loss, ventricular dilatation and disproportionate atrophy of the frontal cortex. Caudate nucleus volume loss additionally differentiated PSP from controls, but was modest in severity and proportionate to whole brain volume loss. The present study identifies disease-specific differences in the topography of brain atrophy between PSP and Parkinson's disease, and has potential implications for the in vivo radiological differentiation of these two disorders. In PSP, the variance in frontal grey matter volume related to measures of behavioural disturbance, confirming the use of behavioural tests for ante-mortem case differentiation and suggesting that intrinsic cortical deficits contribute to these clinical disturbances.
Publisher: Wiley
Date: 02-2005
DOI: 10.1111/J.1471-4159.2004.02975.X
Abstract: Neuromelanin is a dark brown pigment present at high concentrations in dopaminergic neurones of the human substantia nigra (SN). Early electron microscopic examinations of neuromelanin fine structure revealed a significant neutral lipid component however, the identity of this lipid has remained unknown. Here we show that the lipid component of neuromelanin pigment derived from human SN is the polyisoprenoid dolichol. Established methods were used to isolate the pigment from the SN of 32 brains and the lipid fraction was recovered in high purity and yield. Using reversed-phase HPLC, atmospheric pressure chemical ionization mass spectrometry, and 1H- and 13C-NMR techniques, we showed that the neuromelanin dolichol contained 17-23 isoprenoid units. Dolichol accounted for 14% of the mass of neuromelanin pigment low levels of other hydrophobic compounds were detected (e.g. ubiquinone-10, alpha-tocopherol and cholesterol together accounted for < 0.5% of the neuromelanin lipid mass). This is the first time that dolichol has been identified in such a physiological setting and significantly advances our understanding of neuromelanin pigment structure and biosynthetic pathways. Furthermore, these studies identify a potential novel role for the isoprenoid pathway in the regulation of neuromelanin function and neurodegeneration within the SN.
Publisher: Wiley
Date: 2020
DOI: 10.1002/MDS.27939
Publisher: Wiley
Date: 21-01-2011
DOI: 10.1002/MDS.23336
Abstract: There have been no previous studies assessing the severity of regional atrophy, cell loss and lesion densities between the overlapping conditions of Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) and relating these pathologies to different clinical features. Clinical indices and basal ganglia, brainstem, and cerebellar pathology from 43 longitudinally studied cases (PD = 8, PSP = 15, MSA = 12, controls = 8) were compared. A point-counting method was used to evaluate subregional volumes, and α-synuclein and phospho-tau immunohistochemistry was used to assess pathological inclusions and stage disease severity. Logistic regression analyses were used to identify pathological associations with clinical features. All PD, PSP, and MSA cases had severe degeneration of the substantia nigra. Clinical features correlated with tissue loss and the severity of inclusion pathologies. Levodopa responsiveness and a lack of resting tremor was associated with preservation of pallidal volume, the presence of gait ataxia was associated with atrophy of the putamen, and the parkinsonian-plus phenotype with early falls and supranuclear vertical gaze abnormalities had more substantial midbrain atrophy and greater inclusion pathology in the caudate nucleus. This is the first study to compare the severity of regional pathologies across parkinsonian conditions. The data show that tissue loss and inclusion densities in certain regions correlate with clinical indices, with regional volume changes likely to be the best indicator of clinical progression of disease.
Publisher: SAGE Publications
Date: 02-1997
DOI: 10.3109/00048679709073796
Abstract: Objective:To describe the rationale for investigating the dopaminergic system in patients with melancholia by applying molecular biological (notably, in situ hybridisation) and histopathological techniques in postmortem brain tissue. Method:Relevant advances in the functional neuroanatomy of frontostriatal circuits, as well as insights from clinical neuroimaging studies in primary and secondary depressive disorders, are presented. These are integrated with developments in the pharmacological and molecular characteristics of dopamine receptor subtypes and recognition of their selective anatomical distribution. Results:Converging data from the basic and clinical neurosciences suggest that the pathophysiology of depressive disorders characterised by psychomotor phenomena, such as melancholia, may involve dysregulation of dopaminergic mechanisms within complex frontostriatal circuits. Conclusions:The key feature of in situ hybridisation is its capacity to test for variations in the functional components of designated biochemical systems within highly specific anatomical regions. We utilise this approach, in combination with relevant histopathological techniques, to test the structural and functional integrity of the dopaminergic system within key fronto-striatal circuits in patients who had exhibited psychomotor phenomena. The same approach can also be used to study the integrity of other relevant biochemical systems, such as the serotoninergic and noradrenergic systems, in patients with other mood disorders.
Publisher: Wiley
Date: 2011
DOI: 10.1002/MDS.23455
Abstract: Glia are traditionally known as support cells for neurons, and their role in neurodegeneration has been largely considered secondary to neuronal dysfunction. We review newer concepts on glial function and assess glial changes in Parkinson's disease (PD) at the time of disease initiation when α-synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident. Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become nonreactive and accumulate α-synuclein. Experimental evidence has shown that astrocytic α-synuclein deposition initiates the noncell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Although there is still controversy on the role microglia play in neurodegeneration, there is evidence that microglia are activated early in PD and possibly assist with the clearance of extracellular α-synuclein at this time. Microglia transform to phagocytes and target neurons as the disease progresses but appear to become dysfunctional with increasing amounts of ingested debris. Only nonmyelinating oligodendroglial cells are affected in PD, and only late in the disease process. Glial cells are responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and α-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD.
Publisher: American Medical Association (AMA)
Date: 06-2000
DOI: 10.1001/ARCHNEUR.57.6.831
Abstract: There has been no analysis of brain tissue from longitudinally observed, cognitively tested patients to validate whether anti-inflammatory medications protect against the pathological changes of Alzheimer disease. To investigate the role of anti-inflammatory medications in alleviating the pathological features of Alzheimer disease. A 5-year postmortem tissue collection was performed after a case-control study of Alzheimer disease (approximately 90 [30%] of patients died during follow-up, of whom consent for autopsy was obtained in 44 [50%]). Cases were selected on the basis of (1) adequate clinical histories of nonsteroidal anti-inflammatory drug usage, (2) no neuropathological findings other than Alzheimer disease, and (3) no generalized sepsis at death. Variables analyzed included neuropsychological test scores and amount of tissue inflammation and Alzheimer-type pathological changes. Two-way analysis of variance was used to determine whether drug usage significantly affected these variables. The Centre for Education and Research on Ageing and the Prince of Wales Medical Research Institute, Sydney, Australia. Twelve patients with Alzheimer disease (5 taking anti-inflammatory drugs) and 10 nondemented controls (3 taking anti-inflammatory drugs) were selected (50% of available s le). Of the patients with Alzheimer disease, anti-inflammatory drug users performed better on neuropsychological test scores than did nonusers. However, there were no significant differences in the amount of inflammatory glia, plaques, or tangles in either diagnostic group. Long-term anti-inflammatory medications in patients with Alzheimer disease enhanced cognitive performance but did not alleviate the progression of the pathological changes. Arch Neurol. 2000.
Publisher: Wiley
Date: 28-09-2010
DOI: 10.1111/J.1471-4159.2010.06992.X
Abstract: Neurogenesis, the birth of new neurons, continues throughout adulthood in the human subventricular zone (SVZ) and hippoc us. It is not known how levels of putative proliferation-regulating factors change with age in human adult neurogenic areas. The current project employed ELISAs to investigate changes in levels of putative proliferation-regulating factors in the healthy human SVZ and dentate gyrus throughout the adult lifespan (18-104 years). Levels of brain-derived neurotrophic factor, basic fibroblast growth factor and interleukin (IL)-1β were significantly higher in the hippoc us than in the SVZ and levels of glial-derived neurotrophic factor and transforming growth factor-α were significantly higher in the SVZ (p < 0.005), suggesting that factors with predominant influences on neurogenesis differ between the two human adult neurogenic areas. Hippoc al levels of transforming growth factor-β1 strongly increased with age (n = 9, p < 0.01), whereas hippoc al and SVZ levels of brain-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, glial-derived neurotrophic factor, heparin-binding epidermal growth factor, insulin-like growth factor-1, IL-1β, IL-6 and transforming growth factor-α did not change significantly with age in the SVZ or hippoc us. These findings suggest regulation of the adult neurogenic environment in the human brain may differ over time from that in other species.
Publisher: Elsevier BV
Date: 12-2009
Publisher: Wiley
Date: 03-2000
DOI: 10.1002/1531-8249(200003)47:3<345::AID-ANA10>3.0.CO;2-V
Publisher: Elsevier BV
Date: 07-1999
DOI: 10.1016/S0301-0082(98)00091-4
Abstract: Brain atrophy in alcoholics has been identified using both radiological and pathological techniques. However the magnitude and topography of the atrophy, and the factors which contribute to it, are unclear. This review compares the results of imaging and pathological studies in alcoholics examining variables which may contribute to any discrepancies. We conclude that significant brain damage does occur as a result of alcohol abuse per se, that the damage is regionally specific with the frontal lobes being particularly affected, and that both grey matter and white matter components are damaged.
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/0306-4522(94)00483-L
Abstract: A controversy exists in the literature as to whether neurons containing the calcium binding protein calbindin-D28k are located within the human substantia nigra. The point of variance between reports, however, is not the anatomical distribution of these neurons, but rather the delineation of the dorsal border of the substantia nigra. It has been suggested that the dense substance P striatonigral innervation delimits the substantia nigra in the human. The aim of the present study is to re-examine the distribution of calbindin-D28k-positive neurons throughout the substantia nigra using substance P to delimit its borders. Although a few calbindin-D28k-positive neurons were found in the medial cell group of the substantia nigra, the vast majority of positive neurons were located in the adjacent A8 and A10 dopaminergic cell groups. This anatomical location of calbindin-D28k-positive neurons is consistent with previous reports, though our results indicate that when the striatonigral projection is used to define the substantia nigra, calbindin-D28k is not a notable feature of these neurons. This questions the neuroprotective role of this protein in Parkinson's disease.
Publisher: Oxford University Press (OUP)
Date: 09-01-2014
DOI: 10.1093/HMG/DDT674
Publisher: Wiley
Date: 11-2002
DOI: 10.1002/MDS.10258
Abstract: The nonprimary motor cortices have not previously been studied in Parkinson's disease, despite the selective pattern of dysfunction observed in these regions. In particular, the pre-supplementary motor region is consistently underactive, with successful treatments correlating with increased excitatory drive to nonprimary motor regions. This finding could suggest a primary cortical abnormality in the pre-supplementary motor area (pre-SMA) in Parkinson's disease. We analysed and compared neuronal number in the pre-SMA and dorsolateral premotor cortical regions in 5 cases of Parkinson's disease and 5 controls. For each cortical region, the total neuronal number as well as the estimated numbers of subpopulations of interneurons and pyramidal neurons was quantified using previously published unbiased techniques. The results showed a significant loss of cortico-cortical projecting pyramidal neurons in the pre-SMA with no loss of other pyramidal neurons or interneurons either in this region or in the dorsolateral premotor region. These findings indicate a highly selective loss of pyramidal cells in the pre-SMA in Parkinson's disease, consistent with previous imaging findings in this disease. Our results implicate the degeneration of the premotor projection from the pre-SMA, along with dopaminergic basal ganglia dysfunction, in the pathogenesis of Parkinson's disease.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.NEUROIMAGE.2006.10.010
Abstract: Transcranial sonography reveals an increase in echogenicity in the substantia nigra of patients with idiopathic Parkinson's disease. Marked hyperechogenicity has also been described in 9% of the healthy population and is associated with subtle clinical or functional neuroimaging findings suggestive of changes in nigrostriatal function. It has therefore been hypothesised that a hyperechogenic substantia nigra represents an early stage of nigral degeneration or a predisposition for Parkinson's disease. In the present study, we correlated sonographic findings with motor and cognitive deficits in a group of healthy, very elderly subjects. Marked and moderately increased substantia nigra echogenicity was present in 25% and 21% of our healthy, very elderly subjects, respectively, and correlated strongly with the presence of extrapyramidal symptoms in the absence of cognitive deficits. The high incidence of substantia nigra hyperechogenicity measured in our very elderly subjects compared with previous TCS studies suggests that the prevalence of this feature increases with age and is consistent with the higher prevalence of Parkinson's disease in advanced age, as well as the increased frequency of extrapyramidal symptoms. Our results indicate that this simple technique can be used to identify and quantify brain changes associated with subtle motor dysfunction in the very elderly.
Publisher: Wiley
Date: 11-11-2005
DOI: 10.1111/J.1532-5415.2005.00532.X
Abstract: To identify the clinical correlates of functional incapacity in the community living "old-old." Cross-sectional. Community-based. One hundred six nondemented people aged 80 to 94. Participants were medically and cognitively assessed, underwent magnetic resonance imaging scanning (MRI), and were interviewed regarding their functional status: activities of daily living (ADLs), instrumental ADLs (IADLs), and the complex IADL functions of reading, hobbies, and socializing. Dependency in IADLs, but not ADLs, was present. After controlling for age, sex, and education, extrapyramidal (EP) signs were significantly associated with two of the three IADLs, with EP signs comprising a composite score of 10 EP signs (e.g., resting tremor) and a 5-meter timed walk. Cognitive test performance on a range of tests was also associated with functional status. A hierarchical model confirmed the association between the EP signs and cognitive test performance and functional scores, but no "pattern" of cognitive association emerged. Hippoc al volume was associated with socializing. This study has shown that many nondemented very old people living in the community are losing capacity to perform IADL functions and that areas of incapacity are associated with the presence of EP signs and impaired cognition. These results highlight the need for health workers to include an assessment of EP and cognitive status in their evaluation of older persons living in the community, even in the context of a lack of dementia diagnosis. Furthermore, it signifies the need to directly evaluate IADL function to identify need for intervention and support if required. This group of old-old in iduals may now be considered the "survivors" of their cohort, and early detection of the difficulties they are experiencing will enable clinicians to respond appropriately, thus providing them a higher quality of life for their years to come.
Publisher: Springer Science and Business Media LLC
Date: 28-03-2022
DOI: 10.1038/S41531-022-00297-9
Abstract: Leucine-rich-repeat kinase 2 (LRRK2), a potential therapeutic target for the treatment of Parkinson’s disease (PD), is highly expressed in monocytes and macrophages and may play a role in the regulation of inflammatory pathways. To determine how LRRK2 protein levels and/or its activity modulate inflammatory cytokine/chemokine levels in human immune cells, isogenic human induced pluripotent stem cells (iPSC) with the LRRK2-activating G2019S mutation, wild-type LRRK2, and iPSC deficient in LRRK2 were differentiated to monocytes and macrophages and stimulated with inflammatory toll-like receptor (TLR) agonists in the presence and absence of LRRK2 kinase inhibitors. The effect of LRRK2 inhibitors and the effect of increasing LRRK2 levels with interferon gamma on TLR-stimulated cytokines were also assessed in primary peripheral blood-derived monocytes. Monocytes and macrophages with the LRRK2 G2019S mutation had significantly higher levels of cytokines and chemokines in tissue culture media following stimulation with TLR agonists compared to isogenic controls. Knockout of LRRK2 impaired phagocytosis but did not significantly affect TLR-mediated cytokine levels. Interferon gamma significantly increased the levels of LRRK2 and phosphorylation of its downstream Rab10 substrate, and potentiated TLR-mediated cytokine levels. LRRK2 kinase inhibitors did not have a major effect on TLR-stimulated cytokine levels. Results suggest that the LRRK2 G2019S mutation may potentiate inflammation following activation of TLRs. However, this was not dependent on LRRK2 kinase activity. Indeed, LRRK2 kinase inhibitors had little effect on TLR-mediated inflammation under the conditions employed in this study.
Publisher: Cambridge University Press (CUP)
Date: 12-2005
DOI: 10.1017/S0140525X05310132
Abstract: There is little to refute in Collerton et al.'s argument that recurrent complex visual hallucinations involve multiple physiological mechanisms, and the target article's proposed PAD model implicitly incorporates this concept, advancing the field. The novel concept in this model is the intrusion of hallucinatory proto-objects into relatively preserved scenes. The weakness of the model is the lack of physiological detail for this mechanism.
Publisher: Wiley
Date: 16-08-2012
DOI: 10.1111/J.1471-4159.2012.07873.X
Abstract: Previously, we reported elevated levels of the neuron-specific tropomyosin receptor kinase B (TrkB) transcript, TrkB- sarc homology containing (Shc) in the hippoc us of Alzheimer's disease (AD) brains. In this study, we determined how TrkB-Shc transcripts are increased in AD. Utilizing a TrkB minigene transiently transfected into SHSY5Y cells, we found increased exon 19 inclusion in TrkB minigene transcripts (to generate TrkB-Shc) following cellular exposure to amyloid beta 1-42 (Αβ(42)). As this suggested altered TrkB pre-mRNA splicing in AD, we conducted an in silico screening for putative splice regulatory protein-binding sites in the intron/exon splice regulatory regions of exons 18 and 19 of the TrkB gene and then assessed their gene expression profiles using a microarray database of control/AD post-mortem human hippoc al brain tissue. We found significant changes in serine/arginine protein 20 (Srp20) gene expression in AD cases and confirmed this using a second cohort of control/AD. In vitro, we found increased Srp20 mRNA levels in SHSY5Y cells treated with Αβ(42) fibrils. Moreover, Srp20 over-expression was found to increase exon 19 inclusion in TrkB minigene transcripts and ratio of endogenous TrkB-Shc:TrkB-TK+ mRNA expression. Conversely, Srp20 expression knockdown produced the opposite effects. Our findings suggest that dysregulation of factors regulating TrkB pre-mRNA splicing may contribute to gene expression changes that occur in AD.
Publisher: Wiley
Date: 12-2006
Abstract: Alzheimer's disease (AD) is characterized by Abeta peptide-containing plaques and tau-containing neurofibrillary tangles (NFTs). Both pathologies have been combined by crossing Abeta plaque-forming APP mutant mice with NFT-forming P301L tau mutant mice or by stereotaxically injecting beta-amyloid peptide 1-42 (Abeta42) into brains of P301L tau mutant mice. In cell culture, Abeta42 induces filamentous tau aggregates. To understand which processes are disrupted by Abeta42 in the presence of tau aggregates, we applied comparative proteomics to Abeta42-treated P301L tau-expressing neuroblastoma cells and the amygdala of P301L tau transgenic mice stereotaxically injected with Abeta42. Remarkably, a significant fraction of proteins altered in both systems belonged to the same functional categories, i.e. stress response and metabolism. We also identified model-specific effects of Abeta42 treatment such as differences in cell signaling proteins in the cellular model and of cytoskeletal and synapse associated proteins in the amygdala. By Western blotting (WB) and immunohistochemistry (IHC), we were able to show that 72% of the tested candidates were altered in human AD brain with a major emphasis on stress-related unfolded protein responsive candidates. These data highlight these processes as potentially important initiators in the Abeta42-mediated pathogenic cascade in AD and further support the role of unfolded proteins in the course of AD.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2017
DOI: 10.1038/NRDP.2017.13
Abstract: Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.
Publisher: Oxford University Press (OUP)
Date: 02-1997
DOI: 10.1097/00005072-199702000-00003
Abstract: The subthalamus has become a promising target for the neurosurgical treatment of parkinsonian symptoms. We have used unbiased counting techniques to quantify the neuronal populations of the subthalamic nucleus in patients with idiopathic Parkinson's disease and progressive supranuclear palsy. In addition, the type of calcium binding proteins contained within these subthalamic neurons was established using immunohistochemistry. Most of the 550,000 subthalamic neurons contain either parvalbumin or calretinin calcium binding proteins, and patients with idiopathic Parkinson's disease sustained no damage to this nucleus. This is consistent with current theories of basal ganglia circuitry, which postulate that overstimulation of this excitatory nucleus contributes to the inhibition of the motor thalamus via the activation of inhibitory relays. In contrast, we found that there was substantial cell loss in the subthalamus in progressive supranuclear palsy (45 to 85% neuronal reduction) and that both cell types were equally affected. Extracellular neurofibrillary tangles as well as tau-positive glia were observed in the subthalamus of these cases. As the patients with Parkinson's disease and progressive supranuclear palsy all had overlapping parkinsonian symptoms, the loss of subthalamic stimulation within the basal ganglia of progressive supranuclear palsy cases is puzzling, unless their parkinsonian symptoms were generated by an alternate mechanism.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 09-2004
DOI: 10.1007/S00415-004-0489-X
Abstract: Tau gene mutations with insoluble Tau neuropathology have been identified in pedigrees with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), are also characterised by insoluble Tau neuropathology. This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases. Sixty-four in iduals with clinical features consistent with FTD and other tauopathies were referred over a three year period. There was neuropathological confirmation of disease in 30%. In iduals were screened for mutations in the coding region and flanking intronic regions of the tau gene by direct sequencing of PCR products. Four confirmed tau gene mutations were identified representing 6.3 % for the total affected proband cohort. Tau gene mutations were found in three of twelve (25%) of the cases with a family history of dominantly inherited frontotemporal dementia, but in only one of 25 cases without a family history (4 %). Although tauopathies have been considered to result from genetic defects, screening for tau gene mutations in sporadic cases is not likely to identify pathogenic mutations.
Publisher: Elsevier BV
Date: 2017
DOI: 10.1016/J.NBD.2016.09.008
Abstract: Gene transfer is a promising drug delivery method of advanced therapeutic entities for Parkinson's disease. One advantage over conventional therapies, such as peripheral delivery of the dopamine pre-cursor l-DOPA, is site-specific expression of proteins with regenerative, disease-modifying and potentially neuroprotective capacity. Several clinical trials have been performed to test the capacity of glial-cell line derived neurotrophic factor and neurturin to rescue degenerating dopaminergic neurons in the substantia nigra and their axon terminals in the striatum by delivery of these neurotrophic factors either as purified protein or by means of viral vector mediated gene delivery to the brain. Although gene therapy approaches tested so far have been shown to be safe, none met their primary endpoints in phase II clinical trials designed and powered to test the efficacy of the intervention. Within the scope of this review we aim to describe the state-of-the-art in the field, how different technical parameters were translated from pre-clinical studies in non-human primates to clinical trials, and what these trials taught us regarding important factors that may pave the way to the success of gene therapy for the treatment of Parkinson's disease.
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.NEUROBIOLAGING.2005.02.015
Abstract: Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. The age-related development and regulation of neuromelanin within these dopamine neurons has not been previously described. Optical density and area measurements of unstained neuromelanin in ventral substantia nigra neurons from 29 people spanning the ages of 24 weeks to 95 years old, demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-04-2019
DOI: 10.1212/WNL.0000000000007530
Abstract: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features. All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined. MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in progranulin (n = 2) or an abnormal repeat expansion in C9orf72 (n = 1). All FTLD-tau cases with coexisting LBD were sporadic. The H1H1 MAPT haplotype was found in all cases that could be genotyped (n = 6 of 9). Seven cases presented with a predominant dementia disorder, 3 of which developed parkinsonism. Two cases presented with a movement disorder and developed dementia in their disease course. The age at symptom onset (62 ± 11 years) and disease duration (8 ± 5 years) in FTLD cases with coexisting LBD did not differ from pure FTLD or pure LBD cases in the brain bank. Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.
Publisher: Elsevier BV
Date: 10-2007
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.PARKRELDIS.2006.01.002
Abstract: Assessment of a series of 279 cases with Lewy body disease revealed 14 families having a family history consistent with autosomal dominant inheritance, eight of these with dominant Parkinsonism and six with dominant dementia. Analysis of the age at onset and genetic features in these families revealed significant anticipation only in a subset of parkinsonian families, with no pathological alleles for spinocerebellar ataxias or the common alpha-synuclein or LRRK2 point mutations.
Publisher: Wiley
Date: 02-09-2005
DOI: 10.1111/J.1365-2990.2005.00667.X
Abstract: Inflammation, in the form of reactive astrocytes and microglia, is thought to play an important role in Alzheimer's disease (AD) pathogenesis where it correlates with brain atrophy and disease severity. The Abeta protein, which comprises senile plaques, is thought to be responsible for initiating this inflammatory response. Despite having a more aggressive disease process and greater Abeta deposition, few studies have investigated inflammation in early onset AD cases with mutations in the presenilin-1 (PS-1) gene. In fact, many researchers place importance on a variant plaque pathology in PS-1 cases, known as cotton wool plaques, which lack significant inflammatory infiltrate. We investigated the association between inflammation and plaque pathology in PS-1 AD. Classic cored, cotton wool and diffuse Abeta plaques were observed in all cases. PS-1 cases also exhibited a novel plaque pathology with a significantly greater inflammatory response in the form of reactive microglia and astrocytes. These 'inflammatory plaques' consisted of a dense cresyl violet-, silver-, and thioflavin S-positive, but Abeta-, tau-, apolipoprotein E (ApoE)-, non-Abeta component of Alzheimer's disease amyloid (NAC)- and PS-1-negative core. These findings indicate potent stimulator(s) of inflammation that are not typical of the Abeta that accumulates in the pathological hallmarks of sporadic AD. Identification of this substance may be important for the development of future therapeutic strategies.
Publisher: Wiley
Date: 02-05-2015
DOI: 10.1111/NAN.12195
Publisher: The Company of Biologists
Date: 2013
DOI: 10.1242/DMM.011460
Abstract: Frontotemporal dementia (FTD) is associated with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). Together, this group of disorders constitutes a major cause of young-onset dementia. One of the three clinical variants of FTD is progressive nonfluent aphasia (PNFA), which is focused on in this study. The steroid hormone progesterone (PROG) is known to have an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum s les (39 FTD, 91 controls), low serum PROG was associated with FTD overall. In subgroup analysis, low PROG levels were significantly associated with FTD-MND and CBS, but not with PSP or PNFA. PROG levels of & pg/ml were significantly correlated with lower disease severity (frontotemporal dementia rating scale) for in iduals with CBS. In the human neuroblastoma SK-N-MC cell line, exogenous PROG (9300-93,000 pg/ml) had a significant effect on overall Tau and nuclear TDP-43 levels, reducing total Tau levels by ~1.5-fold and increasing nuclear TDP-43 by 1.7- to 2.0-fold. Finally, elevation of plasma PROG to a mean concentration of 5870 pg/ml in an Ala315Thr (A315T) TARDBP transgenic mouse model significantly reduced the rate of loss of locomotor control in PROG-treated, compared with placebo, mice. The PROG treatment did not significantly increase survival of the mice, which might be due to the limitation of the transgenic mouse to accurately model TDP-43-mediated neurodegeneration. Together, our clinical, cellular and animal data provide strong evidence that PROG could be a valid therapy for specific related disorders of FTD.
Publisher: Oxford University Press (OUP)
Date: 13-05-2022
Abstract: Many genetic risk factors for Parkinson’s disease have lipid-related functions and lipid-modulating drugs such as statins may be protective against Parkinson’s disease. Moreover, the hallmark Parkinson’s disease pathological protein, α-synuclein, has lipid membrane function and pathways dysregulated in Parkinson’s disease such as the endosome–lysosome system and synaptic signalling rely heavily on lipid dynamics. Despite the potential role for lipids in Parkinson’s disease, most research to date has been protein-centric, with large-scale, untargeted serum and CSF lipidomic comparisons between genetic and idiopathic Parkinson’s disease and neurotypical controls limited. In particular, the extent to which lipid dysregulation occurs in mutation carriers of one of the most common Parkinson’s disease risk genes, LRRK2, is unclear. Further, the functional lipid pathways potentially dysregulated in idiopathic and LRRK2 mutation Parkinson’s disease are underexplored. To better determine the extent of lipid dysregulation in Parkinson’s disease, untargeted high-performance liquid chromatography–tandem mass spectrometry was performed on serum (n = 221) and CSF (n = 88) obtained from a multi-ethnic population from the Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium. The cohort consisted of controls, asymptomatic LRRK2 G2019S carriers, LRRK2 G2019S carriers with Parkinson’s disease and Parkinson’s disease patients without a LRRK2 mutation. Age and sex were adjusted for in analyses where appropriate. Approximately 1000 serum lipid species per participant were analysed. The main serum lipids that distinguished both Parkinson’s disease patients and LRRK2 mutation carriers from controls included species of ceramide, triacylglycerol, sphingomyelin, acylcarnitine, phosphatidylcholine and lysophosphatidylethanolamine. Significant alterations in sphingolipids and glycerolipids were also reflected in Parkinson’s disease and LRRK2 mutation carrier CSF, although no correlations were observed between lipids identified in both serum and CSF. Pathway analysis of altered lipid species indicated that sphingolipid metabolism, insulin signalling and mitochondrial function were the major metabolic pathways dysregulated in Parkinson’s disease. Importantly, these pathways were also found to be dysregulated in serum s les from a second Parkinson’s disease cohort (n = 315). Results from this study demonstrate that dysregulated lipids in Parkinson’s disease generally, and in LRRK2 mutation carriers, are from functionally and metabolically related pathways. These findings provide new insight into the extent of lipid dysfunction in Parkinson’s disease and therapeutics manipulating these pathways may be beneficial for Parkinson’s disease patients. Moreover, serum lipid profiles may be novel biomarkers for both genetic and idiopathic Parkinson’s disease.
Publisher: Elsevier BV
Date: 2004
DOI: 10.1016/S1474-4422(03)00619-7
Abstract: Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2015
Publisher: Wiley
Date: 12-06-2009
DOI: 10.1002/MDS.22481
Abstract: The recent knowledge that 10 years after transplantation surviving human fetal neurons adopt the histopathology of Parkinson's disease suggests that Lewy body formation takes a decade to achieve. To determine whether similar histopathology occurs in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-primate models over a similar timeframe, the brains of two adult monkeys made parkinsonian in their youth with intermittent injections of MPTP were studied. Despite substantial nigral degeneration and increased alpha-synuclein immunoreactivity within surviving neurons, there was no evidence of Lewy body formation. This suggests that MPTP-induced oxidative stress and inflammation per se are not sufficient for Lewy body formation, or Lewy bodies are human specific.
Publisher: Oxford University Press (OUP)
Date: 28-01-2014
DOI: 10.1093/BRAIN/AWT367
Publisher: Elsevier BV
Date: 07-1999
Abstract: Tar e dyskinesia (TD) is relatively common among psychiatric patients on maintenance therapy with typical neuroleptics and persists in more than 20% even after withdrawal of the medication. Such persistence suggests an underlying pathology due to neurotoxicity. We present evidence for such a neurotoxic mechanism in a baboon model of TD. Four baboons were treated chronically with the dehydration product of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HPTP), which is metabolized, similarly to haloperidol, to two neurotoxic pyridinium species. The animals developed orofacial dyskinesia which persisted after HPTP was ceased. Serial sections of the entire brain from the four treated animals and four vehicle-treated controls revealed volume loss in the basal forebrain and hypothalamus. Histological evaluation demonstrated a reduction in the density of magnocellular neurons in the anterior region of the nucleus basalis of Meynert (NbM). We speculate that the loss of these NbM neurons may be associated with the persistent orofacial dyskinesia observed in the HPTP-treated animals. These findings may contribute to a better understanding of neuroleptic-induced TD.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/S0967-5868(96)90083-1
Abstract: We have quantified midbrain cell loss in idiopathic Parkinson's disease (PD) compared with controls six patients had PD with onset before 70 years, five patients had late onset PD (>70 years) and nine patients had diffuse Lewy body disease. The pattern of cell loss in these last two groups has not been previously described. No age associated neuronal loss was seen in controls. There was cell loss and reduced area of the pars compacta in all cases but no difference in the pattern of cell loss, which was predominantly ventral. The amount of cell loss in the dorsolateral cluster correlated with the duration of Parkinsonian symptoms, while greater cell loss in the dorsomedial cluster correlated with the presence of tremor and the absence of early dementia. These results suggest that the topography of midbrain pathology does not assist in differentiating these overlapping syndromes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-06-2017
DOI: 10.1212/WNL.0000000000004058
Abstract: The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123 iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.
Publisher: Wiley
Date: 11-12-2009
DOI: 10.1002/MDS.22389
Abstract: MtDNA haplogroups J and K have been associated with a decreased risk of developing Parkinson's disease (PD). To confirm this finding, we compared the distribution of mtDNA haplogroups J and K in a large s le of Australian patients with PD (n = 890) to population-based controls (n = 3,491). We assigned subjects to haplogroups J or K using standard PCR/RFLP techniques. Of the 890 subjects with PD, 10.6% were haplogroup J (95% CI 8.6-12.8, n = 94) and 7.1% were haplogroup K (95% CI 5.5-8.9, n = 63). In our controls, 10.2% belonged to haplogroup J (95% CI 9.2-11.2, n = 356), and 7.8% were in haplogroup K (95% CI 6.9-8.7, n = 272). There was no significant difference in the prevalence of mtDNA haplogroup J or K in PD patients compared to population-based controls. Our findings indicate that mtDNA haplogroups J and K are not associated with a lower risk of PD.
Publisher: Wiley
Date: 1996
DOI: 10.1002/(SICI)1096-9861(19960101)364:1<121::AID-CNE11>3.0.CO;2-1
Abstract: In bacteria stop codons are recognized by one of two class I release factors (RF1) recognizing TAG, RF2 recognizing TGA, and TAA being recognized by both. Variation across bacteria in the relative abundance of RF1 and RF2 is thus hypothesized to select for different TGA/TAG usage. This has been supported by correlations between TAG:TGA ratios and RF1:RF2 ratios across multiple bacterial species, potentially also explaining why TAG usage is approximately constant despite extensive variation in GC content. It is, however, possible that stop codon trends are determined by other forces and that RF ratios adapt to stop codon usage, rather than vice versa. Here, we determine which direction of the causal arrow is the more parsimonious. Our results support the notion that RF1/RF2 ratios become adapted to stop codon usage as the same trends, notably the anomalous TAG behavior, are seen in contexts where RF1:RF2 ratios cannot be, or are unlikely to be, causative, that is, at 3'untranslated sites never used for translation termination, in intragenomic analyses, and across archaeal species (that possess only one RF1). We conclude that specifics of RF biology are unlikely to fully explain TGA/TAG relative usage. We discuss why the causal relationships for the evolution of synonymous stop codon usage might be different from those affecting synonymous sense codon usage, noting that transitions between TGA and TAG require two-point mutations one of which is likely to be deleterious.
Publisher: Wiley
Date: 10-08-2009
DOI: 10.1111/J.1471-4159.2009.06233.X
Abstract: Postmortem human brain tissue is widely used in neuroscience research, but use of tissue originating from different brain bank centers is considered inaccurate because of possible heterogeneity in s le quality. There is thus a need for well-characterized markers to assess the quality of postmortem brain tissue. Toward this aim, we determined tryptophan (TRP) concentrations, phosphofructokinase-1 and glutamate decarboxylase activities in 119 brain tissue s les. These neurochemical parameters were tested in s les from autopsied in iduals, including control and pathological cases provided by 10 different brain bank centers. Parameters were assessed for correlation with agonal state, postmortem interval, age and gender, brain region, preservation and freezing methods, storage conditions and storage time, RNA integrity, and tissue pH value. TRP concentrations were elevated significantly (p = 0.045) with increased postmortem interval which might indicate increased protein degradation. Therefore, TRP concentration might be one useful and convenient marker for estimating the quality of human postmortem brain tissue.
Publisher: Elsevier
Date: 2007
Publisher: American Medical Association (AMA)
Date: 06-2000
DOI: 10.1001/ARCHNEUR.57.6.817
Abstract: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. A medical research institute in Sydney, Australia. Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive s le. Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.
Publisher: Wiley
Date: 10-11-2017
DOI: 10.1002/MDS.26869
Publisher: Springer Science and Business Media LLC
Date: 05-08-2022
DOI: 10.1007/S11064-022-03700-2
Abstract: Astrocytes are a major class of glial cell in the central nervous system that have a erse range of types and functions thought to be based on their anatomical location, morphology and cellular properties. Recent studies highlight that astrocyte dysfunction contributes to the pathogenesis of neurological conditions. However, few studies have described the pattern, distribution and density of astrocytes in the adult human cortex. This study mapped the distribution and density of astrocytes immunolabelled with a range of cytoskeletal and membrane markers in the human frontal cortex. Distinct and overlapping astrocyte populations were determined. The frontal cortex from ten normal control cases (75 ± 9 years) was immunostained with glial fibrillary acidic protein (GFAP), aldehyde dehydrogenase-1 L1 (ALDH1L1), connexin-43 (Cx43), aquaporin-4 (AQP4), and glutamate transporter 1 (GLT-1). All markers labelled populations of astrocytes in the grey and white matter, separate cortical layers, subpial and perivascular regions. All markers were informative for labelling different cellular properties and cellular compartments of astrocytes. ALDH1L1 labelled the largest population of astrocytes, and Cx43-immunopositive astrocytes were found in all cortical layers. AQP4 and GLT-1 labelled distal astrocytic process and end-feet in the same population of astrocytes (98% of GLT-1-immunopositive astrocytes contained AQP4). In contrast, GFAP, the most widely used marker, predominantly labelled astrocytes in superficial cortical layers. This study highlights the ersity of astrocytes in the human cortex, providing a reference map of the distribution of distinct and overlapping astrocyte populations which can be used for comparative purposes in various disease, inflammatory and injury states involving astrocytes.
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1365-2990.1995.TB01065.X
Abstract: Magnocellular neurons in the cholinergic nucleus basalis appear to be vulnerable in a variety of pathological conditions, including chronic alcoholism. While neurofibrillary degeneration of these neurons has been noted in a number of disorders characterized by dementia, the mechanism of cell death in thiamine-deficient chronic alcoholics has not been identified. In the present post-mortem investigation, multiple brain regions of seven thiamine-deficient chronic alcoholics, three neurologically asymptomatic chronic alcoholics and seven non-alcoholic age matched controls were screened for neurofibrillary pathology using both tau-immunohistochemistry and a modified Bielschowsky silver stain. In chronic alcoholics with thiamine deficiency, neurofibrillary pathology was found in the nucleus basalis, but not any other brain region. Neurofibrillary tangles were not seen in age-matched controls and were infrequent in alcoholics without neuropathological signs of thiamine-deficiency. Neurofibrillary tangles were most numerous in those cases with cell loss in the nucleus basalis. These findings suggest that neurodegeneration of the nucleus basalis in chronic alcoholics proceeds through the formation of neurofibrillary tangles.
Publisher: Oxford University Press (OUP)
Date: 05-05-2022
Abstract: Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.
Publisher: Oxford University Press (OUP)
Date: 04-07-2022
DOI: 10.1093/BRAINCOMMS/FCAC189
Abstract: Chronic traumatic encephalopathy neuropathologic change can only be definitively diagnosed post-mortem. It has been associated with repetitive mild neurotrauma sustained in amateur and professional contact, collision and combat sports, although it has also been documented in people with a single severe traumatic brain injury and in some people with no known history of brain injury. The characteristic neuropathology is an accumulation of perivascular neuronal and astrocytic phosphorylated tau in the depths of the cortical sulci. The tau-immunopositive neurons and astrocytes that are considered pathognomonic for chronic traumatic encephalopathy are morphologically indistinguishable from Alzheimer-related neurofibrillary tangles and ageing-related tau astrogliopathy, respectively, although they are found in different spatial distributions throughout the cortex. The Sydney Brain Bank collection consists of neurodegenerative diseases and neurologically normal controls. We screened 636 of these cases for chronic traumatic encephalopathy neuropathologic change. A subset of 109 cases had a known history of traumatic brain injury. Three cortical regions were screened for the presence of neuronal and astrocytic phosphorylated tau according to the current 2021 National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering consensus criteria for chronic traumatic encephalopathy. Five cases (0.79%) showed pathological evidence of chronic traumatic encephalopathy and three of these had a history of traumatic brain injury. Three cases had coexisting Alzheimer’s and/or Lewy body disease pathology meeting criteria for neurodegenerative disease. Another eight cases almost met criteria for chronic traumatic encephalopathy neuropathological change except for an absence of neuronal tau or a strict perivascular arrangement. Ageing-related tau astrogliopathy was found in all eight cases as a coexisting neuropathology. Traumatic brain injury was associated with increased odds ratio [1.79, confidence interval 1.18–2.72] of having a higher neurofibrillary tangle stage and phosphorylated TAR DNA binding protein 43 (OR 2.48, confidence interval 1.35–4.54). Our study shows a very low rate of chronic traumatic encephalopathy neuropathological change in brains with or without neurodegenerative disease from the Sydney Brain Bank. Our evidence suggests that isolated traumatic brain injury in the general population is unlikely to cause chronic traumatic encephalopathy neuropathologic change but may be associated with increased brain ageing.
Publisher: Elsevier BV
Date: 10-2003
DOI: 10.1016/S0197-4580(02)00227-0
Abstract: The present study analyses the pattern of atrophy in anatomically discrete brain regions in prospectively-studied pathologically-confirmed patients with Alzheimer's disease (AD) and controls. Standard volumetric measurements were made of the entire cortex sub ided into 23 anatomical regions. Analyses determined regions of significant atrophy in AD and differences between the severity and rates of atrophy. Two levels of severity were found. Atrophy concentrated in medial temporal lobe structures as well as in inferior temporal and superior and middle frontal cortices. The degree of atrophy in these regions related to disease duration, consistent with an early and sustained disease process. The rate of atrophy was significantly greater for the fusiform gyrus. The inferior frontal lobes were entirely spared at all AD stages, while atrophy of other cortical regions was less marked and not related to disease duration, suggesting late involvement. Our findings show that the fusiform gyrus is particularly affected by AD, and suggest two levels of atrophy that correspond with published neurofibrillary tangle (most atrophic) and senile plaque (less atrophic) densities.
Publisher: Bentham Science Publishers Ltd.
Date: 11-2011
DOI: 10.2174/156720511797633232
Abstract: Apolipoprotein E (APOE) ε4 allele and sigma-1 receptor (SIGMAR1) c.5C (Q2P) polymorphisms have been acknowledged as risk factors for developing Alzheimer's disease (AD). However, whether these polymorphisms influence the disease process is unclear. Therefore, two cohorts with a clinical diagnosis of AD were recruited, a postmortem confirmed Australian cohort (82 cases) from the Australian Brain Bank Network, and a Chinese cohort with detailed clinical assessments recruited through an epidemiology study in Shanghai and through the neurology department outpatients clinic of Shanghai Ruijin Hospital (330 cases). SIGMAR1 Q2P and APOE genotyping was performed on all cases. Dementia severity in the Chinese cohort was assessed using MMSE scores, and the stages of senile plaques and neurofibrillary tangles (NFT) assessed in the Australian cohort. Associations between SIGMAR1 Q2P and APOE genotypes and disease severity were assessed using SPSS. Results confirmed that APOE 4 allele associated with increased NFT stages and cognitive decline, with carriers with one APOE ε2 or ε3 allele often having better clinical outcomes compared to carriers with none or two ε2 or ε3 alleles respectively. SIGMAR1 c.5C polymorphism alone did not associate with MMSE score variability in Chinese or with pathological stages in Caucasians. However, the association studies revealed a significant genetic interaction between the APOE ε4 allele and SIGMAR1 2P carriers in both populations, i.e., in APOE non ε4 allele carriers, SIGMAR1 2P variant had increased cognitive dysfunction and more advanced stages of NFT. Our data demonstrate that SIGMAR1 and APOE interact to influence AD severity across ethnic populations.
Publisher: Springer London
Date: 2007
Publisher: Wiley
Date: 04-2010
DOI: 10.1002/ANA.21882
Publisher: Wiley
Date: 27-12-2014
DOI: 10.1002/MDS.25784
Publisher: Springer Science and Business Media LLC
Date: 03-2010
Abstract: A 48 year-old woman presented with an 18 month history of bizarre and complex delusions on a background of social, behavioral and cognitive decline over several years. Her psychosis progressed despite receiving high doses of antipsychotics. The patient's father also had a psychotic episode in his 40s. He subsequently developed motor neuron disease, which caused his death at 68 years of age. Physical examination, neuropsychological testing, nerve conduction studies, brain MRI and transcranial magnetic stimulation. On the basis of the patient's age at onset of the delusions, imaging findings and family history, a diagnosis of frontotemporal dementia (FTD) was favored over a primary psychotic disorder. The ubiquitin-positive and TAR DNA binding protein 43-positive inclusions that were found at autopsy confirmed the diagnosis of FTD. The patient was treated with various antipsychotics at high doses however, her delusions continued to progress. No disease-specific treatments for FTD currently exist.
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG085
Abstract: Frontotemporal dementia is a term used to characterize erse neuropathological conditions that can present with the same clinical phenotype. Five different neuropathologies underlie this disorder. However, consistent frontal and/or temporal neuronal loss and gliosis characterize all cases, the majority having no obvious pathological inclusions. Because neuronal loss and gliosis are consistent features across all cases, the present study aimed to determine the relationship between neuronal loss, gliosis and, for cases with abnormal tau inclusions, intracellular tau deposition. Formalin-fixed brain specimens from sporadic cases with frontotemporal dementia (eight with tau-positive Pick bodies, five with frontotemporal lobar degeneration without inclusions) were compared with those from non-diseased controls (n = 5). Brain specimens were cut into 3 mm coronal slices for evaluation and tissue s les from the superior frontal gyrus were taken for microscopic analysis. Immuno histochemistry for glia-specific proteins (astrocytic glial fibrillary acidic protein and microglial major histocompatibility complex II) and different tau epitopes was performed on 50 microm free-floating sections. Gross patterns of brain atrophy were analysed and upper and lower layer pyramidal neurons and glial cell numbers were quantified. A disease severity scheme was devised using the degree of gross macroscopic frontal and temporal atrophy to establish the relationship between the gliosis and neurodegeneration. In this small s le, the patterns of gross atrophy could be grouped reliably into four stages of severity. These stages were the same across disease groups and correlated with volume- corrected pyramidal neuron densities. In cases with Pick bodies, disease stage also correlated with duration, providing further evidence that these stages represent the progression of degeneration in this limited s le. Whereas there were, on average, many more reactive astrocytes in the cases with Pick bodies than in those with frontotemporal lobar atrophy, there was significant overlap between cases in the degree of astrocytosis. However, a large proportion of the astrocytes in Pick's disease displayed phosphorylated tau immunoreactivity, whereas no tau-positive astrocytes were found in frontotemporal lobar degeneration. The pattern and degree of microglia activation were similar in all the dementia cases analysed, with considerably more activated microglia accumulating in white matter. In this small s le, the abundance of white matter microglia at early disease stages suggests a prominent role for this cell type in the neurodegenerative process. In frontotemporal lobar degeneration, a significant proportion of the activated white matter microglia were tau-2-immunoreactive, suggesting direct involvement in axonal degeneration, possibly via immune processes.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/0165-0270(95)00114-X
Abstract: The physiological characteristics of central neural populations are being increasingly explored in slice preparations. A major challenge of this approach is to correlate the physiological properties of in idual neurones or groups of neurones with their anatomical and chemical properties in order to gain key insights into their functional identities. The present study describes a method for determining the precise topographical position and the immunohistochemical characteristics of neurones in brain slice preparations that are used frequently in electrophysiological investigations. Thick horizontal slices of rat brainstem were re-cut using a method that provided thin sections that were always in the same plane as the parent slice and that were of suitable thickness for immunohistochemistry. Catecholaminergic neurones in these co-planar (horizontal) sections were stained using antisera to tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. To identify in idual catecholamine neurones in the co-planar sections, we constructed a reference atlas of the distribution of catecholamine neurones in the horizontal plane of the rat brain. The combined use of the horizontal atlas and of immunohistochemical techniques in co-planar sections of horizontal slices enables the determination of several key properties: (1) whether a neurone is TH-positive, (2) its precise topographical position and (3) its content of neuropeptides and other immunohistochemical markers. Thus our study offers a readily feasible method for correlative anatomy and immunohistochemistry of physiologically identified catecholaminergic neurones in brain slices.
Publisher: Cold Spring Harbor Laboratory
Date: 12-04-2023
DOI: 10.1101/2023.04.11.536367
Abstract: Parkinso’s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they acumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate PD patients who will benefit from LRRK2-related therapeutics. Peripheral blood-derived cells can be employed to stratify Parkinso’s disease patients most likely to respond to LRRK2-related therapeutics.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.NBD.2015.07.011
Abstract: Frontotemporal lobar degeneration (FTLD) defines a spectrum of heterogeneous neurodegenerative disorders characterized by the progressive deterioration of the frontal and anterior temporal lobes of the brain. FTLD is histopathologically classified according to the presence of neuropathological protein aggregates. Two of the major pathologies, FTLD-TDP and FTLD-FUS, are characterized by the abnormal accumulation in cytoplasmic inclusions of RNA-binding proteins (RBPs) - TDP-43 and FUS/TLS, respectively. That suggests that a crucial common downstream pathway leading to cell death might involve the disruption of RNA-based mechanisms. Long noncoding RNAs have emerged as key regulators in the different layers of gene regulation. Increasing evidence suggests that long non-coding RNAs (lncRNAs) may have pivotal biological functions in the brain and, not surprisingly, they have been implicated with neurodegenerative diseases, like Alzheimer's and Parkinson's diseases. Recent studies report that FTLD/ALS-related proteins TDP-43 and FUS/TLS bind lncRNAs, and that several lncRNAs have binding sites for TDP-43 and/or FUS/TLS. These findings raise important questions about how TDP-43 and FUS/TLS pathologies can affect lncRNA-based mechanisms. One alternative is that TDP-43 and FUS/TLS regulate lncRNA transcription or transcript stability. In fact, it has been demonstrated that lncRNAs are dysregulated upon either depletion or unavailability of functional TDP-43 or FUS/TLS in a range of different models and diseases, including post-mortem s les from subjects with FTLD-TDP. The second alternative is that the binding to TDP-43 or FUS/TLS would enable lncRNAs to perform their cellular function. In this case, the unavailability of these RBPs would disrupt functional properties of lncRNAs, without necessarily altering their cellular levels. It has been experimentally demonstrated that the cellular function of some lncRNAs is strictly dependent on the direct binding to TDP-43 or FUS/TLS.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 19-10-2005
DOI: 10.1212/01.WNL.0000187889.17253.B1
Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each in idual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
Publisher: Society for Neuroscience
Date: 11-10-2017
DOI: 10.1523/JNEUROSCI.1787-16.2017
Abstract: The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD. Dual Perspectives Companion Paper: Prying into the Prion Hypothesis for Parkinson's Disease, by Patrik Brundin and Ronald Melki
Publisher: Wiley
Date: 29-04-2019
DOI: 10.1002/MDS.27701
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-2019
DOI: 10.1126/SCITRANSLMED.AAT8462
Abstract: Cellular assays reveal a decline in Aβ and tau pathological conformers in Alzheimer’s disease brain s les.
Publisher: Oxford University Press (OUP)
Date: 04-2003
DOI: 10.1093/BRAIN/AWG090
Abstract: The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.
Publisher: Wiley
Date: 2004
DOI: 10.1002/ANA.20203
Abstract: The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This study reexamines the relationships between clinical and pathological subtypes of FTD in a large series from two centers (n = 61). Clinical subtypes defined were behavioral variant FTD (n = 26), language variants (semantic dementia, n = 9 and progressive nonfluent aphasia, n = 8), and motor variants (corticobasal degeneration, n = 9 and motor neuron disease, n = 9), although most cases presented with a combination of behavioral and language problems. Unexpectedly, some behavioral cases (n = 5) had marked amnesia at presentation. The pathological subtypes were those with tau-immunopositive inclusions (with Pick bodies, n = 20 or without, n = 11), those with ubiquitin immunopositive inclusions (n = 16), and those lacking distinctive histology (n = 14). Behavioral symptoms and semantic dementia were associated with a range of pathologies. In contrast, other clinical phenotypes had relatively uniform underlying pathologies: motor neuron disease predicted ubiquitinated inclusions, parkinsonism and apraxia predicted corticobasal pathology, and nonfluent aphasia predicted Pick bodies. Therefore, the pathological substrate can be predicted in a significant proportion of FTD patients, which has important implications for studies targeting mechanistic treatments.
Publisher: Oxford University Press (OUP)
Date: 04-1999
Abstract: The aim of this study was to determine the topography and degree of atrophy in speech and language-associated cortical gyri in Alzheimer's disease. The post-mortem brains of 10 patients with pathologically confirmed Alzheimer's disease and 21 neurological and neuropathological controls were sectioned in serial 3 mm coronal slices and grey and white matter volumes were determined for specific cortical gyri. All Alzheimer's disease patients had prospectively documented impairments in verbal and semantic memory with concomitant global decline. The cortical regions of interest included the planum temporale, Heschl's gyri, the anterior superior temporal gyri, the middle and inferior temporal gyri, area 37 at the inferior temporoparietal junction, areas 40 and 39 (supramarginal and angular gyri) and Broca's frontal regions. Although most patients had end-stage disease, the language-associated cortical regions were affected to different degrees, with some regions free of atrophy. These included Broca's regions in the frontal lobe and Heschl's gyri on the superior surface of the temporal lobe. In contrast, the inferior temporal and temporoparietal gyri (area 37) were severely reduced in volume. The phonological processing regions in the superior temporal gyri (the planum temporale) were also atrophic in all Alzheimer's disease patients while the anterior superior temporal gyri were only atrophic in female patients. Such atrophy may underlie the more severe language impairments previously described in females with Alzheimer's disease. The present study is the first to analyse the volumes of language-associated gyri in post-mortem patients with confirmed Alzheimer's disease. The results show that atrophy is not global but site-specific. Atrophied gyri appear to reflect a specific network of language and semantic memory dissolution seen in the clinical features of patients with Alzheimer's disease. Females showed greater atrophy than males in the anterior superior temporal gyri.
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0166-4328(02)00087-6
Abstract: While rotational asymmetry is used as a characteristic behavioural sign of striatal dopamine (DA) loss in unilateral animal models of Parkinson's disease (PD), there is relatively little analysis of how other common behavioural deficits relate to nigrostriatal DA depletion. We analysed the relationships between several deficits induced by unilateral 6-OHDA lesions and striatal neurochemistry, as well as neuronal loss in the dopaminergic substantia nigra (SN). Behaviour was evaluated from before until 6 weeks after surgery and abnormalities appeared in body axis, head position and sensorimotor performance as well as apomorphine-induced rotation. As expected, rotational behaviour correlated with striatal DA loss and not with other striatal neurotransmitters measured. Similar observations were found for sensorimotor deficits ('disengage task'). Both deficits were observed in rats with >70% loss of TH+ nigral neurons and >80% loss of striatal DA. Additional postural abnormalities appeared with mean losses of 87% of nigral DA neurons and 97% striatal DA, consistent with observations in patients with advanced PD. The data show that the repertoire of behavioural abnormalities manifested by hemiparkinsonian rats relate directly to the degree of nigrostriatal DA loss and, therefore, mimic features of PD. Analysis of such behaviours are relevant for chronic therapeutic studies targeting PD.
Publisher: Oxford University Press (OUP)
Date: 11-10-2005
DOI: 10.1093/BRAIN/AWH625
Abstract: The pathogenesis of idiopathic Parkinson's disease is unknown, but nigral degeneration and depigmentation are associated with microglial inflammation and anti-inflammatory medications appear to protect against the disease. The possibility that humoral immunity may play a role in initiating or regulating the inflammation has been suggested by experimental studies triggering dopamine cell death using a variety of transfer strategies and the observation of CD8+ T lymphocytes and complement in the nigra in Parkinson's disease. We analysed the association between degeneration and humoral immune markers in brain tissue of patients with idiopathic (n = 13) or genetic (n = 2 with alpha-synuclein and n = 1 with parkin mutations) Parkinson's disease and controls without neurological disease (n = 12) to determine the humoral immune involvement in Parkinson's disease. Formalin-fixed tissue s les from the substantia nigra and primary visual cortex for comparison were stained for alpha-synuclein, major histocompatibility complex II (HLA), immunoglobulin M (IgM), immunoglobulin G (IgG), IgG subclasses 1-4 and IgG receptors FcgammaR I-III. Antigen retrieval and both single immunoperoxidase and double immunofluorescence procedures were employed to determine the cell types involved and their pattern and semiquantitative densities. Significant dopamine neuron loss occurred in all patients with Parkinson's disease, negatively correlating with disease duration (r = -0.76, P = 0.002). Although all patients had increased inflammatory HLA immunopositive microglia, the degree of inflammation was similar throughout the disease (r = 0.08, P = 0.82). All patients with Parkinson's disease had IgG binding on dopamine neurons but not IgM binding. Lewy bodies were strongly immunolabelled with IgG. A mean 30 +/- 12% of dopamine nigral neurons were immunoreactive for IgG in Parkinson's disease with the proportion of IgG immunopositive neurons negatively correlating with the degree of cell loss in the substantia nigra (r = -0.67, P < 0.0001) and positively correlating with the number of HLA immunopositive microglia (r = 0.51, P = 0.01). Most neuronal IgG was the IgG1 subclass with some IgG3 and less IgG2 also found in the damaged substantia nigra. The high affinity activating IgG receptor, FcgammaRI, was expressed on nearby activated microglia. The low affinity activating IgG receptor, FcgammaRIII was expressed on cells morphologically resembling lymphocytes, whereas immunoreactivity for the inhibitory IgG receptor FcgammaRII was absent in all cases. This pattern of humoral immune reactivity is consistent with an immune activation of microglia leading to the targeting of dopamine nigral neurons for destruction in both idiopathic and genetic cases of Parkinson's disease.
Publisher: Wiley
Date: 04-01-2012
DOI: 10.1002/MDS.24900
Abstract: Visual misperception and hallucinations represent a major problem in advanced PD. The pathophysiological mechanisms underlying these symptoms remain poorly understood, with limited tests for their assessment. A recent hypothesis has suggested that visual misperception and hallucinations may arise from disrupted processing in the attentional networks. To assess and quantify visual misperceptions, we developed the novel bistable percept paradigm (BPP), which consists of a battery of "single" and "hidden" monochromatic images that subjects are required to study until they are satisfied that they have recognized everything that the image may represent. In this experiment, 45 patients and 18 age-matched controls performed the BPP. Using an error score value derived from the control group, 23 patients were identified as having significant deficits on the task. Compared to patients who were unimpaired on the task, this group of patients had significantly higher levels of self-reported hallucinations on the SCales for Outcomes in PArkinson's Disease-Psychiatric Complications and also symptoms of rapid eye movement sleep behavior disorder (RBD). Furthermore, impairment on the BPP was associated with significantly reduced performance on an attentional set-shifting task. Patients with impaired performance on the BPP had higher rates of hallucinations, increased symptoms of RBD, and poorer performance on set shifting, suggesting disrupted processing within the attentional control networks. We propose that the BPP may offer a novel approach for exploring the neural correlates underlying visual hallucinations and misperceptions in PD.
Publisher: American Medical Association (AMA)
Date: 04-2003
Publisher: Springer Science and Business Media LLC
Date: 22-03-2009
DOI: 10.1007/S00401-009-0521-4
Abstract: Mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes cause autosomal dominant familial Alzheimer's disease (AD). PSEN1 and PSEN2 are essential components of the gamma-secretase complex, which cleaves APP to affect Abeta processing. Disruptions in Abeta processing have been hypothesised to be the major cause of AD (the amyloid cascade hypothesis). These genetic cases exhibit all the classic hallmark pathologies of AD including neuritic plaques, neurofibrillary tangles (NFT), tissue atrophy, neuronal loss and inflammation, often in significantly enhanced quantities. In particular, these cases have average greater hippoc al atrophy and NFT, more significant cortical Abeta42 plaque deposition and more substantial inflammation. Enhanced cerebral Abeta40 angiopathy is a feature of many cases, but particularly those with APP mutations where it can be the dominant pathology. Additional frontotemporal neuronal loss in association with increased tau pathology appears unique to PSEN mutations, with mutations in exons 8 and 9 having enlarged cotton wool plaques throughout their cortex. The mechanisms driving these pathological differences in AD are discussed.
Publisher: Wiley
Date: 07-1999
DOI: 10.1002/1531-8257(199907)14:4<626::AID-MDS1012>3.0.CO;2-U
Abstract: Underactivity of the external segment of the globus pallidus is thought to contribute to the generation of parkinsonian hypokinetic symptoms in association with striatal dopaminergic dysfunction and overactivity of the subthalamus. These symptoms can be corrected by neurosurgical techniques aimed at normalizing subthalamic overactivity. The aim of the present study was to compare the amount of neurodegeneration and changes in the calcium-binding protein parvalbumin in the external segment of the globus pallidus in parkinsonian disorders. Cases with progressive supranuclear palsy were compared with cases with Parkinson's disease and control subjects. The number of neurones and neurofibrillary tangles was estimated using unbiased stereologic techniques. The external segment of the globus pallidus in Parkinson's disease was not significantly different from that in control subjects. In contrast, most patients with progressive supranuclear palsy had significant neurodegeneration of the external pallidum, particularly patients with significant degeneration of both the subthalamus and substantia nigra. These results suggest that the parkinsonian symptoms in progressive supranuclear palsy are caused by the degeneration of the external segment of the globus pallidus because such degeneration would increase thalamic inhibition through the basal ganglia output nuclei, particularly in patients with a loss of excitatory drive from the subthalamus.
Publisher: Oxford University Press (OUP)
Date: 20-04-2005
DOI: 10.1093/BRAIN/AWH508
Abstract: Most cerebral imaging studies of patients with progressive supranuclear palsy (PSP) have noted subtle atrophy, although the full extent of atrophy and any correlates to clinical features have not been determined. We used voxel-based morphometry analysis of grey matter, white matter and CSF on MRI brain scans to map the statistical probability of regional tissue atrophy in 21 patients with PSP, 17 patients with Parkinson's disease and 23 controls. PSP and Parkinson's disease cohorts were selected to approximate the mid-stages of their respective disease courses. Where regions of significant tissue atrophy were identified in a disease group relative to controls, the probability of tissue loss within those regions was correlated with global indices of motor disability, and behavioural and cognitive disturbance for that disease group. Minimal regional atrophy was observed in Parkinson's disease. PSP could be distinguished from both controls and Parkinson's disease by symmetrical tissue loss in the frontal cortex (maximal in the orbitofrontal and medial frontal cortices), subcortical nuclei (midbrain, caudate and thalamic) as well as periventricular white matter. For PSP, motor deficits correlated with atrophy of the caudate and motor cingulate, while behavioural changes related to atrophy in the orbitofrontal cortex and midbrain. These data suggest that intrinsic neurodegeneration of specific subcortical nuclei and frontal cortical subregions together contribute to motor and behavioural disturbances in PSP and differentiate this disorder from Parkinson's disease within 2-4 years of symptom onset.
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0165-0270(94)90028-0
Abstract: The aim of this study was to establish methodological variability in the estimation of the total number of neurones using the optical disector. Variations in the 3 dimensions of the disector probe were analysed under uniform s ling conditions in 50-microns-thick frozen sections of the human mediodorsal thalamic nucleus. There was no significant difference between the estimated neuronal number using s les of variable height (fractionator vs. non-fractionator s ling). In addition, different methods of volume calculation (in idual s le vs. an average) did not significantly change the estimated total neuronal number. Large variations in the estimated total neuronal number occurred when the x and y dimensions of the disector probe were altered. In this study, accurate and reproducible estimates were achieved when the disector probe was large enough to have a probability of s ling at least 2 cells per frame. We conclude that the variables in the x-y plane (the disector frame size as well as the s le interval) significantly contribute to differences in the estimated total neuronal number. Several practical measurements to estimate this probability and enhance experimental design are discussed.
Publisher: Wiley
Date: 08-1995
DOI: 10.1111/J.1365-2826.1995.TB00801.X
Abstract: The aim of this study was to assess the number and proportion of vasopressin-producing neurons in the hypothalamic magnocellular nuclei in rats and humans. Accurate and unbiased neuronal counts were estimated using the optical disector method. Arginine vasopressin-containing neurons were immunohistochemically visualized in formalin-fixed tissue sections. The magnocellular neurons were similar in size and morphology in both species. While the human hypothalamus contained significantly more vasopressin-containing neurons compared with the rat (36-fold increase), the proportion of vasopressin-containing neurons between species was similar. In both species, the majority of supraoptic neurons contained vasopressin, however the proportion of vasopressin-containing neurons in the human paraventricular nucleus was double that of the rat (nearly a 100-fold increase in number). These results suggest that the paraventricular nucleus contributes significantly to the release of vasopressin from the posterior pituitary in humans, whereas in rats vasopressin is mainly released by supraoptic neurons.
Publisher: Wiley
Date: 21-04-2022
DOI: 10.1002/MDS.29005
Abstract: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence‐based and consensus‐based methodology. We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Publisher: Wiley
Date: 2001
DOI: 10.1046/J.1440-1681.2001.03398.X
Abstract: 1. Research on the structural basis for schizophrenia was considered a graveyard for neuropathologists, largely because its aetiology has remained obscure. However, there have been several recent major reviews and studies in leading journals on the neuropathology of schizophrenia highlighting the alterations found in the brains of schizophrenic patients. 2. It is clear from the evidence that schizophrenia can no longer be considered a purely functional psychosis with no structural basis. Multiple and possibly widespread neural systems are likely to participate, because diffuse ventricular enlargement and decreased cortical volume are common in schizophrenia. Interestingly, these features do not herald neuronal loss, findings similar to those obtained in alcoholic and aged populations. Impairment in judgement is common to all these subject groups. 3. The frontal and temporal lobes and their thalamic relays appear particularly affected in schizophrenia and there is some evidence for significant asymmetries. These regions are also consistently affected in patients with neurodegenerative cognitive impairment, although patients with schizophrenia can be distinguished by a lack of classical tissue pathology. 4. The cellular phenotypes that must be structurally compromised have yet to be definitively identified and the relationship between any neurochemical and structural abnormality remains unclear. The subtlety of these changes and their diffuse nature have evoked a consistent chorus that schizophrenia is a neurodevelopmental abnormality however, this is hard to prove at a structural level using cross‐sectional post‐mortem analyses.
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C2MT20151H
Abstract: Disturbances in brain copper result in rare and severe neurological disorders and may play a role in the pathogenesis and progression of multiple neurodegenerative diseases. Our current understanding of mammalian brain copper transport is based on model systems outside the central nervous system and no data are available regarding copper transport systems in the human brain. To address this deficit, we quantified regional copper concentrations and examined the distribution and cellular localization of the copper transport proteins Copper transporter 1, Atox1, ATP7A, and ATP7B in multiple regions of the human brain using inductively coupled plasma-mass spectrometry, Western blot and immunohistochemistry. We identified significant relationships between copper transporter levels and brain copper concentrations, supporting a role for these proteins in copper transport in the human brain. Interestingly, the substantia nigra contained twice as much copper than that in other brain regions, suggesting an important role for copper in this brain region. Furthermore, ATP7A levels were significantly greater in the cerebellum, compared with other brain regions, supporting an important role for ATP7A in cerebellar neuronal health. This study provides novel data regarding copper regulation in the human brain, critical to understand the mechanisms by which brain copper levels can be altered, leading to neurological disease.
Publisher: Wiley
Date: 11-06-2012
DOI: 10.1002/CNE.23051
Abstract: G-protein-regulated inward-rectifier potassium channel 2 (GIRK2) is reported to be expressed only within certain dopamine neurons of the substantia nigra (SN), although very limited data are available in humans. We examined the localization of GIRK2 in the SN and adjacent ventral tegmental area (VTA) of humans and mice by using either neuromelanin pigment or immunolabeling with tyrosine hydroxylase (TH) or calbindin. GIRK2 immunoreactivity was found in nearly every human pigmented neuron or mouse TH-immunoreactive neuron in both the SN and VTA, although considerable variability in the intensity of GIRK2 staining was observed. The relative intensity of GIRK2 immunoreactivity in TH-immunoreactive neurons was determined in both species nearly all SN TH-immunoreactive neurons had strong GIRK2 immunoreactivity compared with only 50-60% of VTA neurons. Most paranigral VTA neurons also contained calbindin immunoreactivity, and approximately 25% of these and nearby VTA neurons also had strong GIRK2 immunoreactivity. These data show that high amounts of GIRK2 protein are found in most SN neurons as well as in a proportion of nearby VTA neurons. The single previous human study may have been compromised by the fixation method used and the postmortem delay of their controls, whereas other studies suggesting that GIRK2 is located only in limited neuronal groups within the SN have erroneously included VTA regions as part of the SN. In particular, the dorsal layer of dopamine neurons directly underneath the red nucleus is considered a VTA region in humans but is commonly considered the dorsal tier of the SN in laboratory species.
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S0197-4580(98)00066-9
Abstract: Neurofibrillary tangle staging was compared in the nucleus basalis and cerebral cortex of Alzheimer's disease patients with and without Lewy body disease. In pure Alzheimer's disease, cholinergic nucleus basalis cell number, as determined from counts in serial forebrain sections, was 22-60% of control mean, with the majority of residual cells containing tangles. A comparison between control cell number and the combined number of tangles plus tangle-free neurons in pure Alzheimer's disease suggests that the majority of nucleus basalis neurons were lost through neurofibrillary degeneration. The staging of neurofibrillary degeneration in the nucleus basalis was discordant with cortical changes as some controls had more extensive tangle formation in the nucleus basalis than in the cerebral cortex. Patients having both Alzheimer's disease and Lewy body pathology had few or no tangles in the nucleus basalis despite greater loss of neurons than purely demented patients. The presence of concomitant pathology had a greater effect on nucleus basalis tangle burden than did cortical disease stage, suggesting dichotomous disease processes in the cerebral cortex and forebrain.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.EXPNEUROL.2009.03.002
Abstract: An increasing body of research suggests that a number of immune mechanisms play a role in degenerative pathways in Parkinson's disease (PD). In the current work we investigated a posited humoral immune response in this disorder. Sera from PD patients exhibited a significantly enhanced absorbance response on a novel ELISA for anti-melanin antibodies, compared to sera from age-matched control subjects. The enhanced ELISA absorbance response was specific for catecholamine-based melanins and was unrelated to antiparkinsonian dopaminergic medication. Further, the absorbance response was significantly and negatively correlated with disease duration. These data suggest that a specific humoral anti-melanin antibody response is present in PD and is more active in early disease. While the contribution of this novel immune response to the initiation and progression of this disorder is unclear, this finding supports the hypothesis that specific immune responses occurring in PD may respond to therapeutic interventions in this disorder.
Publisher: BMJ
Date: 12-2004
Publisher: Oxford University Press (OUP)
Date: 04-07-2022
DOI: 10.1093/BRAINCOMMS/FCAC161
Abstract: The Addenbrooke’s Cognitive Examination III is a brief cognitive screening tool that is widely used for the detection and monitoring of dementia. Recent findings suggest that the three variants of primary progressive aphasia can be distinguished based on their distinct profiles on the five subdomain scores of this test. Here, we investigated the utility of the Addenbrooke’s Cognitive Examination III to differentiate the primary progressive aphasia variants based on their item-by-item performance profiles on this test. From these results, we created an interactive primary progressive aphasia Addenbrooke’s Cognitive Examination III calculator which predicts the variant based on a patient’s unique item-by-item profile. Twenty-eight logopenic variant, 25 non-fluent variant and 37 semantic variant primary progressive aphasia patients and 104 healthy controls completed the Addenbrooke’s Cognitive Examination III at first clinical presentation. Multinomial regression analyses were conducted to establish performance profiles among groups, and R Shiny from RStudio was used to create the interactive Addenbrooke’s Cognitive Examination III diagnostic calculator. To verify its accuracy, probability values of the regression model were derived based on a 5-fold cross-validation of cases. The calculator’s accuracy was then verified in an independent s le of 17 logopenic, 19 non-fluent and 13 semantic variant primary progressive aphasia patients and 68 Alzheimer’s disease patients who had completed the Addenbrooke’s Cognitive Examination III (or an older version of this test: Revised) and had in vivo amyloid-PET imaging and/or brain autopsy pathological confirmation. Cross-validation of cases in the calculator model revealed different rates of sensitivity in classifying variants: semantic = 100%, non-fluent = 80.6% and logopenic = 79.9% healthy controls were distinguished from primary progressive aphasia patients with 100% sensitivity. Verification of in vivo amyloid and/or autopsy-confirmed patients showed that the calculator correctly classified 10/13 (77%) semantic variant, 3/19 (16%) non-fluent variant and 4/17 (24%) logopenic variant patients. Importantly, for patients who were not classified, diagnostic probability values mostly pointed toward the correct clinical diagnosis. Furthermore, misclassified diagnoses of the primary progressive aphasia cohort were rare (1/49 2%). Although 22 of the 68 Alzheimer’s disease patients (32%) were misclassified with primary progressive aphasia, 19/22 were misclassified with the logopenic variant (i.e. falling within the same neuropathological entity). The Addenbrooke’s Cognitive Examination III primary progressive aphasia diagnostic calculator demonstrates sound accuracy in differentiating the variants based on an item-by-item Addenbrooke’s Cognitive Examination III profile. This calculator represents a new frontier in using data-driven approaches to differentiate the primary progressive aphasia variants.
Publisher: Springer Science and Business Media LLC
Date: 29-03-2015
DOI: 10.1007/S10048-015-0445-1
Abstract: Pervasive transcription of the genome produces a erse array of functional non-coding RNAs (ncRNAs). One particular class of ncRNAs, long intervening non-coding RNAs (lincRNAs) are thought to play a role in regulating gene expression and may be a major contributor to organism and tissue complexity. The human brain with its heterogeneous cellular make-up is a rich source of lincRNAs however, the functions of the majority of lincRNAs are unknown. Recently, by completing RNA sequencing (RNA-Seq) of the human frontal cortex, we identified linc00320 as being highly expressed in the white matter compared to grey matter in multiple system atrophy (MSA) brain. Here, we further investigate the expression patterns of linc00320 and conclude that it is involved in specific brain regions rather than having involvement in the MSA disease process. We also show that the full-length linc00320 is only expressed in human brain tissue and not in other primates, suggesting that it may be involved in improved functional connectivity for higher human brain cognition.
Publisher: Springer Science and Business Media LLC
Date: 21-09-2012
DOI: 10.1007/S00429-011-0349-2
Abstract: The three main dopamine cell groups of the brain are located in the substantia nigra (A9), ventral tegmental area (A10), and retrorubral field (A8). Several sub isions of these cell groups have been identified in rats and humans but have not been well described in mice, despite the increasing use of mice in neurodegenerative models designed to selectively damage A9 dopamine neurons. The aim of this study was to determine whether typical sub isions of these dopamine cell groups are present in mice. The dopamine neuron groups were analysed in 15 adult C57BL/6J mice by anatomically localising tyrosine hydroxylase (TH), dopamine transporter protein (DAT), calbindin, and the G-protein-activated inward rectifier potassium channel 2 (GIRK2) proteins. Measurements of the labeling intensity, neuronal morphology, and the proportion of neurons double-labeled with TH, DAT, calbindin, or GIRK2 were used to differentiate subregions. Coronal maps were prepared and reconstructed in 3D. The A8 cell group had the largest dopamine neurons. Five subregions of A9 were identified: the reticular part with few dopamine neurons, the larger dorsal and smaller ventral dopamine tiers, and the medial and lateral parts of A9. The latter has groups containing some calbindin-immunoreactive dopamine neurons. The greatest ersity of dopamine cell types was identified in the seven subregions of A10. The main dopamine cell groups in the mouse brain are similar in terms of ersity to those observed in rats and humans. These findings are relevant to models using mice to analyse the selective vulnerability of different types of dopamine neurons.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2019
DOI: 10.1038/S41467-019-13564-W
Abstract: Parkinson’s disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we lified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.
Publisher: MDPI AG
Date: 19-10-2017
Publisher: Cold Spring Harbor Laboratory
Date: 24-04-2023
DOI: 10.1101/2023.04.17.23288471
Abstract: Pick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. We established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies. See funding section
Publisher: Elsevier BV
Date: 08-2016
Publisher: Wiley
Date: 09-04-2021
DOI: 10.1111/NAN.12709
Abstract: To determine the underlying cellular changes and clinical correlates associated with pathology of the hypothalamus in amyotrophic lateral sclerosis (ALS), as hypothalamic atrophy occurs in the preclinical phase of the disease. The hypothalamus was pathologically examined in nine patients with amyotrophic lateral sclerosis in comparison to eight healthy control subjects. The severity of regional atrophy (paraventricular nucleus: PVN, fornix and total hypothalamus) and peptidergic neuronal loss (oxytocin, vasopressin, cocaine‐ and hetamine‐regulating transcript: CART, and orexin) was correlated with changes in eating behaviour, sleep function, cognition, behaviour and disease progression. Tar DNA‐binding protein 43 (TDP‐43) inclusions were present in the hypothalamus of all patients with amyotrophic lateral sclerosis. When compared to controls, there was atrophy of the hypothalamus (average 21% atrophy, p = 0.004), PVN (average 30% atrophy p = 0.014) and a loss of paraventricular oxytocin‐producing neurons (average 49% loss p = 0.02) and lateral hypothalamic orexin‐producing neurons (average 37% loss, significance p = 0.02). Factor analysis identified strong relationships between abnormal eating behaviour, hypothalamic atrophy and loss of orexin‐producing neurons. With increasing disease progression, abnormal sleep behaviour and cognition associated with atrophy of the fornix. Substantial loss of hypothalamic oxytocin‐producing neurons occurs in ALS, with regional atrophy and the loss of orexin neurons relating to abnormal eating behaviour in ALS. Oxytocin‐ and orexin neurons display TDP43 inclusions. Our study points to significant pathology in the hypothalamus that may play a key role in metabolic and pathogenic changes in ALS.
Publisher: Public Library of Science (PLoS)
Date: 28-02-2011
Publisher: Cold Spring Harbor Laboratory
Date: 23-05-2018
DOI: 10.1101/327890
Abstract: DNA methylation is associated with age. The deviation of age predicted from DNA methylation from actual age has been proposed as a biomarker for ageing. However, a better prediction of chronological age implies less opportunity for biological age. Here we used 13,661 s les (from blood and saliva) in the age range of 2 to 104 years from 14 cohorts measured on Illumina HumanMethylation450/EPIC arrays to perform prediction analyses. We show that increasing the s le size achieves a smaller prediction error and higher correlations in test datasets. We demonstrate that smaller prediction errors provide a limit to how much variation in biological ageing can be captured by methylation and provide evidence that age predictors from small s les are prone to confounding by cell composition. Our predictor shows a similar or better performance in non-blood tissues including saliva, endometrium, breast, liver, adipose and muscle, compared with Horvath’s across-tissue age predictor.
Publisher: Wiley
Date: 05-2006
DOI: 10.1002/MDS.20779
Abstract: Major clinical features and global measures were systematically evaluated and compared in progressive supranuclear palsy (PSP) and Parkinson's disease (PD). In addition to gaze palsy and early postural instability in PSP, absence of levodopa-induced dyskinesia, frontalis muscle overactivity, primitive reflexes, visuospatial impairment, and substantial frontal behavioral disturbances differentiated almost all patients with this disorder from PD. For PSP, behavioral changes related to severity of general disability, thereby challenging previous models of relationships between behavior, motor, and cognitive disturbance for this disorder.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2017
DOI: 10.1038/NRN.2016.178
Publisher: Informa UK Limited
Date: 1992
DOI: 10.3109/10520299209110052
Abstract: It has been suggested that the use of avidin-biotin immunohistochemical techniques for antigen detection in neural tissue produces nonspecific background staining. For this reason neural tissue was used to test the quality, sensitivity and specificity of four commercially available antibody detection kits which use avidin or streptavidin binding to biotin. Free-floating, thick-section immunohistochemistry on perfusion fixed rat central nervous system revealed variability among staining kits for all parameters analyzed under the same experimental conditions. The reagents from the Vector 'Elite' kit were the most sensitive and specific, and received the highest overall rating for quality. Most commercial products tested could be used at greater dilutions than those recommended by the manufacturers without compromising specific staining. No staining was evident when the primary and secondary antibodies were omitted. This suggests that nonspecific binding is unlikely to be due to endogenous ligands, charge or hydrophilic reactions between these tertiary complexes and the tissue sections.
Publisher: Elsevier BV
Date: 2014
Publisher: Wiley
Date: 12-11-2010
DOI: 10.1002/ANA.22244
Publisher: Springer Science and Business Media LLC
Date: 25-07-2019
DOI: 10.1038/S41531-019-0086-4
Abstract: The heterogeneous nature of Parkinson’s disease (PD) symptoms and variability in their progression complicates patient treatment and interpretation of clinical trials. Consequently, there is much interest in developing models that can predict PD progression. In this study we have used serum s les from a clinically well characterized longitudinally followed Michael J Fox Foundation cohort of PD patients with and without the common leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. We have measured 27 inflammatory cytokines and chemokines in serum at baseline and after 1 year to investigate cytokine stability. We then used the baseline measurements in conjunction with machine learning models to predict longitudinal clinical outcomes after 2 years follow up. Using the normalized root mean square error (NRMSE) as a measure of performance, the best prediction models were for the motor symptom severity scales, with NRMSE of 0.1123 for the Hoehn and Yahr scale and 0.1193 for the unified Parkinson’s disease rating scale part three (UPDRS III). For each model, the top variables contributing to prediction were identified, with the chemokines macrophage inflammatory protein one alpha (MIP1α), and monocyte chemoattractant protein one (MCP1) making the biggest peripheral contribution to prediction of Hoehn and Yahr and UPDRS III, respectively. These results provide information on the longitudinal assessment of peripheral inflammatory cytokines in PD and give evidence that peripheral cytokines may have utility for aiding prediction of PD progression using machine learning models.
Publisher: Elsevier
Date: 2003
Publisher: Wiley
Date: 29-04-2009
Publisher: Elsevier BV
Date: 02-2005
DOI: 10.1016/J.PNEUROBIO.2005.02.001
Abstract: Neuromelanin (NM) is a dark polymer pigment produced in specific populations of catecholaminergic neurons in the brain. It appears in greatest quantities in the human brain, in lesser amounts in some other non-human primates, but is absent from the brain in many lower species. Interest in this pigment has seen a resurgence in recent years because of a hypothesised link between neuromelanin and the especial vulnerability of neuromelanin-containing neurons to cell death in Parkinson's disease (PD). Little is known regarding the biology of neuromelanin. As neuromelanin appears to have characteristics in common with the better studied peripheral melanin pigments this review compares what is known about neuromelanin with melanins found in other body tissues. Unlike peripheral melanins, which are produced in specialised cells called melanocytes and may be transferred to other cell types, neuromelanin granules are believed to be stored in the cell in which they are produced. Neuromelanin granules display a unique, more heterogeneous appearance compared with peripheral melanins. Unlike melanin, neuromelanin is traditionally thought to result from a non-enzymatic synthesis pathway with no known pathway for neuromelanin catabolism. More recent data, however, is indicative of some regulation of neuromelanin synthesis and turnover. By analogy with peripheral melanins, neuromelanin may function in vivo to attenuate the effects of damaging stimuli. Among several possible mechanisms suggested, the ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms has received particular attention. Recent data from neuromelanin in the Parkinson's disease brain suggests that this proposed function may be compromised, thus rendering pigmented neurons vulnerable to oxidative damage in this disorder.
Publisher: Oxford University Press (OUP)
Date: 1991
Abstract: Substance P immunoreactive (SP+) neurons were analysed quantitatively in serial sections of the mesopontine tegmentum in 6 patients with idiopathic Parkinson's disease and 5 age-matched normal controls. In the tegmentum of the Parkinson's disease brains many SP+ neurons contained swollen, twisted neuronal processes as well as Lewy bodies. There were significant reductions in the total number of SP+ neurons in the pedunculopontine tegmental nucleus (loss 43%), in the laterodorsal tegmental nucleus (loss 28%), in the oral pontine reticular nucleus (loss 41%) and in the median raphe nucleus (loss 76%). It was the large SP+ (greater than 20 microns) neurons that were particularly affected. In our control group we did not document a significant relationship between age at death and number of SP+ neurons in these tegmental nuclei or between age at death and number of pigmented neurons in the locus coeruleus. In contrast, in patients with Parkinson's disease, there was a strong inverse relationship between age at death and numbers of SP+ and pigmented neurons. Our findings suggest an interaction between the pathophysiological mechanisms initiated by Parkinson's disease and other processes related to ageing. Since tegmental SP+ neurons are affected by the primary pathological processes underlying Parkinson's disease as severely as catecholamine-synthesizing neurons are affected, theories of pathogenesis and therapeutic strategies in Parkinson's disease will need to take into account the involvement of these SP+ neurons.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2017
Publisher: Springer Science and Business Media LLC
Date: 13-03-2011
DOI: 10.1007/S00401-011-0815-1
Abstract: Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue s les from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.
Publisher: Hindawi Limited
Date: 2015
DOI: 10.1155/2015/135674
Abstract: Background . α -Synuclein ( SNCA ) and microtubule-associated protein tau ( MAPT ) are the two major genes independently, but not jointly, associated with susceptibility for Parkinson’s disease (PD). The SNCA gene has recently been identified as a major modifier of age of PD onset. Whether MAPT gene synergistically influences age of onset of PD is unknown. Objective . To investigate independent and joint effects of MAPT and SNCA on PD onset age. Methods . 412 patients with PD were recruited from the Australian PD Research Network (123) and the Neurology Department, Ruijin Hospital Affiliated to Shanghai Jiaotong University, China (289). MAPT (rs17650901) tagging H1/H2 haplotype and SNCA (Rep1) were genotyped in the Australian cohort, and MAPT (rs242557, rs3744456) and SNCA (rs11931074, rs894278) were genotyped in the Chinese cohort. SPSS regression analysis was used to test genetic effects on age at onset of PD in each cohort. Results . SNCA polymorphisms associated with the onset age of PD in both populations. MAPT polymorphisms did not enhance such association in either entire cohort. Conclusion . This study suggests that, in both ethnic groups, SNCA gene variants influence the age at onset of PD and α -synuclein plays a key role in the disease course of PD.
Publisher: Elsevier BV
Date: 02-2004
DOI: 10.1016/J.NBD.2003.10.008
Abstract: Mutations in presenilin-1 (PS-1) account for the majority of familial Alzheimer's disease (AD). While increasing Abeta42 is one mechanism whereby PS-1 mutations are thought to exert their pathogenic effect, little is known about the role of tau in PS-1 AD. This study compares staining (AT8 and tau-2), morphology and quantity of tau-immunoreactive cortical plaques in six PS-1 and five sporadic AD cases. The densities of tau-positive plaques differentiated PS-1 from sporadic AD cases. All PS-1 cases demonstrated a greater than 6-fold increase in tau-2-positive plaques. In PS-1 cases with mutations in exons 5 and 6, there was an increase in classical AD plaques containing hyperphosphorylated tau (AT8- and tau 2-positive). However, cases with exon 8 and 9 mutations had numerous cotton wool plaques containing nonhyperphosphorylated tau (tau-2-positive, AT8-negative). These findings suggest that PS-1 mutations increase tau deposition while mutation-specific cellular responses determine phosphorylation events and may influence cell death mechanisms.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.BBADIS.2012.04.007
Abstract: Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-β (Aβ) plaques and tau-containing tangles are its histopathological hallmark lesions. These do not occur at random rather, the neurodegenerative process is stereotyped in that it is initiated in the entorhinal cortex and hippoc al formation. Interestingly, it is the latter brain area where the calcium-sensing enzyme hippocalcin is highly expressed. Because calcium deregulation is a well-established pathomechanism in AD, we aimed to address the putative role of hippocalcin in human AD brain and transgenic mouse models. We found that hippocalcin levels are increased in human AD brain and in Aβ plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in Aβ toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with Aβ and found them to be more susceptible to Aβ toxicity than controls. Likewise, treatment with either thapsigargin or ionomycin, both known to deregulate intracellular calcium levels, caused an increased toxicity in hippoc al neurons from HC KO mice compared to wild-type. We found further that mitochondrial complex I activity increased from 3 to 6months in hippoc al mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. Aβ treatment induced significant toxicity on hippoc al mitochondria from HC KO mice already at 3months of age, while wild-type mitochondria were spared. Our data suggest that hippocalcin has a neuroprotective role in AD, presenting it as a putative biomarker.
Publisher: Wiley
Date: 04-09-2009
DOI: 10.1002/MDS.22747
Abstract: To determine whether variable thalamic degeneration in Parkinson's disease (PD) contributes to less drug responsive clinical features. Formalin-fixed thalami from longitudinally followed patients with PD and early dystonia (N = 6), early falls (N = 5) or no dystonia or falls (N = 6) and age-matched controls without neuropathology (N = 10) were serially sectioned, stained, and analyzed. Neurons in the centromedian parafascicular (CM-Pf) nucleus were quantified using the optical disector method and analysis of variance with post hoc testing used to determine variability in neurodegeneration between groups. Patients with PD were confirmed to have significant neurodegeneration in the CM-Pf complex, with no difference in the degree of neurodegeneration between patients with PD with early falls compared with patients with no history of falls or dystonia. In contrast, patients with PD with early dystonia had significantly less neurodegeneration of the CM but not the Pf than patients without this feature. Preservation of the CM in patients with PD with early dystonia would result in a relative increase in CM activity through the direct basal ganglia pathway and increased primary motor cortex activity. Overall this data provides evidence for pathway-specific neurodegeneration as an underlying feature of the clinical variability observed in patients with PD.
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.EXPNEUROL.2007.07.006
Abstract: This article reviews the current knowledge on alpha-synuclein and its cellular locations in studies using human brain tissue. Alterations in the conformation and distribution of alpha-synuclein are examined in Parkinson's disease and the relationship between clinical symptoms and pathology explored. alpha-Synuclein as a molecular chaperone has several isoforms and is known to have different environment-dependent conformations. Processing methods for studying human brain tissue significantly impact on the conformational type of alpha-synuclein analysed, and antibody species used for the in situ detection of alpha-synuclein give variable results depending on the epitope visualised. Human studies show that alpha-synuclein is not isolated to neurons, but is also found in glia, making the interpretation of studies using brain tissue homogenates less clearly related to neurons. These methodological issues impact significantly on our understanding of the form, location, and therefore function of alpha-synuclein in normal human brain tissue. There are less methodological issues regarding highly aggregated alpha-synuclein found in the major hallmark of Parkinson's disease, the Lewy body. However, it remains unclear whether these alpha-synuclein inclusions are harmful to host neurons or provide protection. Several correlations exist between the clinical symptoms of Parkinson's disease and the distribution of Lewy pathology, the strongest being the association between limbic and cortical Lewy bodies and well-formed visual hallucinations. Further correlation studies in prospectively-followed patients and, perhaps more importantly, controls are required in order to determine normal versus pathologic alpha-synuclein and how to detect such differences in clinical situations.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2016
DOI: 10.1007/S00415-016-8168-2
Abstract: It is increasingly recognized that metabolic factors influenced by eating behavior, may affect disease progression in neurodegeneration. In frontotemporal dementia (FTD), which shares a significant overlap with Amyotrophic lateral sclerosis (ALS), patients are well known to develop changes in eating behavior. Whether patients with pure ALS and those with cognitive and behavioral changes associated with ALS also develop similar changes is not known. The current study aimed to examine caloric intake, eating behavioral changes, body mass index, and using cox regression analyses survival across the spectrum of 118 ALS-FTD patients (29 pure ALS, 12 ALS-plus and 21 ALS-FTD, 56 behavioral variant FTD), compared with 25 control subjects. The current study found contrary to previous assumptions eating changes are not restricted to FTD, but a spectrum of eating behavioral changes occur in ALS, present in those with pure ALS and worsening as patients develop cognitive changes. ALS patients with cognitive impairment exhibited changes in food preference, with caloric intake and BMI increasing with the development of cognitive/behavioral changes. Both pure ALS and those with cognitive impairment demonstrated increased saturated fat intake. Survival analyses over the mean patient follow-up period of 6.9 years indicated that increasing eating behavioral changes were associated with an improved survival (threefold decrease risk of dying). Changes in eating behavior and metabolism occur in ALS in association with increasing cognitive impairment, perhaps exerting a protective survival influence. These changes provide insights into the common neural networks controlling eating and metabolism in FTD and ALS and provide potential targets to modify disease prognosis and progression.
Publisher: Oxford University Press (OUP)
Date: 12-1998
Abstract: Hippoc al size and neuron number are reduced in a number of conditions, including temporal lobe epilepsy and Alzheimer's disease. Furthermore, a decrease with advancing age has also been suggested. The present study examined the entire hippoc al formation of 12 subjects aged from 46 to 85 years and free from neurological disease. The volume of seven subregions (CA1, CA2-3, CA4, dentate gyrus, subiculum, presubiculum and white matter) was determined and the number of neurons estimated in each of these grey matter subregions using the optical dissector technique. There was a significant relationship between CA1 neuron number and cerebrum volume. Multivariate analysis showed the greater contribution to the variance in CA1 neuron number was made by cerebrum volume (69%) rather than age (2%) or sex (1%). The findings of this study show that, in neurologically normal in iduals, brain size is a major determinant of the number of CA1 neurons.
Publisher: Springer Science and Business Media LLC
Date: 09-2010
DOI: 10.1038/NM0910-961A
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-03-2022
Abstract: More than 50 neurological and neuromuscular diseases are caused by short tandem repeat (STR) expansions, with 37 different genes implicated to date. We describe the use of programmable targeted long-read sequencing with Oxford Nanopore’s ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of STR sites, from a list of predetermined candidates. This correctly diagnoses all in iduals in a small cohort ( n = 37) including patients with various neurogenetic diseases ( n = 25). Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing and identifies noncanonical STR motif conformations and internal sequence interruptions. We observe a ersity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of repeat disorders. Last, we show how the inclusion of pharmacogenomic genes as secondary ReadUntil targets can further inform patient care.
Publisher: Springer Science and Business Media LLC
Date: 02-1994
DOI: 10.1007/BF00296188
Publisher: Springer Science and Business Media LLC
Date: 06-11-2015
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0361-9230(98)00128-2
Abstract: The present study evaluates the cytoarchitecture of midbrain dopaminergic regions in baboons using similar methodology to that recently applied to compare humans and rats. This information is relevant for the interpretation of nonhuman primate models of Parkinson's disease (PD). The midbrains of four alpha male baboons were serially sectioned into 10 evenly spaced series of 50 microm sections. Series were stained with either cresyl violet or immunohistochemically reacted for tyrosine hydroxylase, substance P, calbindin-D28k, or parvalbumin. The organization of dopaminergic cell groups and the distribution of proteins within these groups were found to be very similar to that previously described in humans [McRitchie et al., J. Comp. Neurol. 364:121-150 1996]. Dorsal and ventral tiers of the A9 substantia nigra (SN) pars compacta and all isions of the A8 and A10 cell groups were identified revealing a high degree of homology in the arrangement of chemically distinct midbrain neurons between primates. The major difference between the organization of human and baboon midbrain dopaminergic neurons is the anteroposterior extent of the dense cell clusters within the SN pars compacta. In baboons the dorsomedial cell cluster is absent at posterior levels. The ventral tier cell clusters, which are targeted by PD in humans, are restricted to the posterior and ventral regions of the SN pars compacta of the baboon. In humans these cell clusters are found throughout the rostrocaudal extent of the SN. These ventral cell clusters have been previously shown to have reciprocal connections with sensorimotor regions of the putamen.
Publisher: Wiley
Date: 27-05-2013
DOI: 10.1111/CNS.12124
Publisher: Wiley
Date: 18-08-2022
DOI: 10.1111/NAN.12845
Abstract: Over the past decade, considerable efforts have been made to accelerate pathophysiological understanding of fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) with brain banks at the forefront. In addition to exploratory disease mechanisms, brain banks have aided our understanding with regard to clinical diagnosis, genetics and cell biology. Across neurodegenerative disorders, the impact of brain tissue in ALS research has yet to be quantified. This review aims to outline (i) how postmortem tissues from brain banks have influenced our understanding of ALS over the last 15 years, (ii) correlate the location of dedicated brain banks with the geographical prevalence of ALS, (iii) identify the frequency of features reported from postmortem studies and (iv) propose common reporting standards for materials obtained from dedicated brain banks. A systematic review was conducted using PubMed and Web of Science databases using key words. From a total of 1439 articles, 73 articles were included in the final review, following PRISMA guidelines. Following a thematic analysis, articles were categorised into five themes clinico‐pathological (13), genetic (20), transactive response DNA binding protein 43 (TDP‐43) pathology (12), non‐TDP‐43 neuronal pathology (nine) and extraneuronal pathology (19). Research primarily focused on the genetics of ALS, followed by protein pathology. About 63% of the brain banks were in the United States of America and United Kingdom. The location of brain banks overall aligned with the incidence of ALS worldwide with 88% of brain banks situated in Europe and North America. An overwhelming lack of consistency in reporting and replicability was observed, strengthening the need for a standardised reporting system. Overall, postmortem material from brain banks generated substantial new knowledge in areas of genetics and proteomics and supports their ongoing role as an important research tool.
Publisher: Wiley
Date: 04-01-2000
DOI: 10.1046/J.1440-1681.2000.03200.X
Abstract: 1. Of the neurodegenerative diseases that cause dementia, Alzheimer’s disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology. 2. The senile plaques of AD consist primarily of complexes of the β‐amyloid protein. This protein is central to the pathogenesis of the disease. 3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. β‐Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin. 4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti‐inflammatory drugs. Longitudinal studies have shown that the consumption of anti‐inflammatory medications reduces the risk of AD only in younger patients ( 75 years). 5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non‐steroidal anti‐inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD. 6. Cyclo‐oxygenase 2 enzyme is constitutively expressed in neurons and is up‐regulated in degenerative brain regions in AD. Non‐steroidal anti‐inflammatory drugs may reduce this expression. 7. Platelets are a source of β‐amyloid and increased platelet activation and increased circulating β‐amyloid have been identified in AD. Anti‐platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences. 8. Increased levels of luminal β‐amyloid permeabilizes the blood–brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti‐inflammatory medications may alleviate these problems.
Publisher: Wiley
Date: 07-2014
DOI: 10.1002/ANA.24205
Publisher: Elsevier BV
Date: 08-2002
Abstract: Patterns of huntingtin protein aggregation and cortical neuronal loss suggest early involvement of corticostriatal pathways in Huntington's disease. However, theories of pathogenesis of chorea rely on the motor cortices being intact. The motor cortices have not previously been studied at a cellular level in Huntington's disease. We analyzed the neuronal number in the caudate, putamen, and three motor cortical areas in five cases of Huntington's disease and five controls. For each motor cortical region the total neuronal number, number of interneurons, and number of SMI32 immunopositive pyramidal neurons were quantified using previously published techniques and any relationship between cell loss and severity or duration of chorea was examined. The results showed a loss of long projecting SMI32 immunopositive pyramidal neurons in the primary motor cortex with associated morphological changes and suggest a loss of short projecting pyramidal neurons in the premotor cortex. Degeneration in the primary motor cortex correlated with subcortical degeneration. These findings indicate pyramidal cell involvement in Huntington's disease and implicate the degeneration of corticostriatal pathways in the production of chorea.
Publisher: Elsevier BV
Date: 09-1995
DOI: 10.1016/0306-4522(95)00163-D
Abstract: At present there is no consensus concerning the internal organization of the human substantia nigra, despite its pivotal role in neurodegenerative conditions. We have quantitatively analysed the variability in the pattern of clusters of melanin-pigmented neurons in the human substantia nigra using serial section analysis and computer reconstructions. The substantia nigra pars compacta showed a bilaminar organization consisting of the pars medialis and pars lateralis, as well as dorsal and ventral tiers as described previously [D. A. McRitchie et al. (1995) J. comp. Neurol. (in press)]. Both the dorsal and ventral tiers could be further sub ided into three mediolateral cell columns based on position and cell density. The presence and arrangement of these cell clusters was most variable in transverse sections (the plane currently used for diagnostic neuropathology). Quantitative assessment of the topographical pattern of cell loss within single transverse sections of the human substantia nigra should therefore be treated with some caution. In contrast, the full rostrocaudal extent of the cell columns could be seen in horizontal sections. Thus, consistent s les of larger numbers of pigmented neurons per region were found in this section plane, although only two cell columns were found in most sections. Our results show that greater quantitative reliability can be achieved with horizontal sections of the substantia nigra.
Publisher: Informa UK Limited
Date: 2001
Abstract: Frontotemporal dementia (FTD) is usually characterized as a spectrum of relatively slowly progressive disorders with largely focal frontal or temporal presentations. The development of clinical and research criteria for discriminating FTD from Alzheimer's disease has relied, in part, on the relative preservation of episodic memory in FTD. We present a patient with FTD who, in addition to the more typical behavioural and language deficits, had a profound anterograde amnesia at the time of diagnosis. Neuroimaging confirmed atrophy of frontal and temporal lobes bilaterally, most marked in the anterior left temporal region. At post-mortem, non-Alzheimer pathology resulting in devastating cell loss was revealed in the hippoc i, as well as in the frontal and temporal cortex, thus providing neuroanatomical corroboration of the episodic memory deficit. Progression of the disease was extraordinarily rapid, with just 2 years between reported onset and time of death. This case demonstrates that the pattern of FTD may include severe anterograde amnesia as a prominent and early consequence of the disease.
Publisher: Wiley
Date: 04-1991
Abstract: We have employed immunohistochemical and morphometric procedures to study serotonin-synthesizing (PH8-immunoreactive) neurons in the pontine reticular formation of the adult human. PH8-immunoreactive neurons were found in three cytoarchitectural regions: the median raphe nucleus (MnR), oral pontine reticular nucleus (PnO), and supralemniscal region (group B9). On the basis of cell size, morphology, and position, it was possible to distinguish distinct subgroups within the MnR (dorsal, midline, and paramedian cell clusters) and within the PnO (dorsal and central cell clusters), whereas within the B9 there were no distinct cell clusters. We have estimated that there are approximately 125,000 PH8-immunoreactive neurons in the human pontine tegmentum 64,400 in the MnR, 30,700 in PnO and 29,000 in B9. The large numbers of serotonin-synthesizing neurons in the human pontine tegmentum contrasts with their relative paucity in nonprimate species such as rats and cats. Nonhuman primates also have large numbers of pontine serotonergic neurons but the morphology of these neurons and their spatial arrangement is significantly different in humans. These results are discussed with respect to the possible projections and functions of these neurons in humans.
Publisher: Elsevier
Date: 2007
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.NLM.2016.01.007
Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder, a major subset of which is characterized by the accumulation of abnormal forms of the protein tau, leading to impairments in motor functions as well as language and behavioral alterations. Tau58-2/B mice express human tau with the P301S mutation found in familial forms of FTLD in neurons. By assessing three age cohorts of Tau58-2/B mice in a comprehensive behavioral test battery, we found that the tauopathy animals showed age-dependent signs of impulsivity, decreased social exploration and executive dysfunction. The deficit in executive function was first limited to decreased spatial working memory, but with aging this was extended to impaired instrumental short-term memory. Tau pathology was prominent in brain regions underlying these behaviors. Thus, Tau-58-2/B mice recapitulate neurological deficits of the behavioral variant of frontotemporal dementia (bvFTD), presenting them as a suitable model to test therapeutic interventions for the amelioration of this variant.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-02-2019
DOI: 10.1212/WNL.0000000000007146
Abstract: To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort. A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score ≤3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy. ALS was identified in 18% of patients with nfvPPA and 5% of patients with svPPA. PPA-ALS but not PPA was found to have a strong family history. At autopsy, frontotemporal lobar degeneration (FTLD)–TDP was identified in 100% of nfvPPA-ALS cases, 100% of svPPA-ALS cases, 24% of nfvPPA cases, and 78% of svPPA cases. Clinicopathologic assessments revealed a significant association between a strong family history and underlying FTLD-TDP pathology. Pathogenic mutations in known frontotemporal dementia (FTD)/ALS genes were identified in 100% of these familial PPA cases but only 50% of familial PPA-ALS cases, suggesting the involvement of novel genetic variants in this underacknowledged phenotype. The present study identified ALS in 12% of a large cohort of patients with nfvPPA and svPPA, which is comparable to the 10%–15% reported in FTD overall, indicating that a third of patients with FTD-ALS will have a predominant language profile. These findings highlight the importance of assessing for ALS in PPA, particularly since this is the only PPA phenotype in which a perfect clinicopathologic association has been reported in to date.
Publisher: Oxford University Press (OUP)
Date: 03-2020
Abstract: Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A& G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD’s interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0306-4522(91)90313-D
Abstract: Neurons in the ventrolateral medulla oblongata of rats, guinea-pigs and cats that contain tyrosine hydroxylase, dopamine-beta-hydroxylase, phenylethanolamine-N-methyltransferase and neuropeptide Y have been demonstrated immunohistochemically in serial coronal sections of tissue taken from the level of the cervical spinal cord to the level of the facial nucleus. The anatomical distribution of these neurons has been described, quantified and reconstructed in three dimensions to compare the neuron populations between species. In all species, between 50 and 90% of immunoreactive neurons lay rostral to the level of the obex. There were no significant differences in the number and distribution of neurons containing catecholamine-synthesizing enzymes between control animals and those pretreated with colchicine, with two exceptions: all dopamine-beta-hydroxylase neurons were weakly immunoreactive without colchicine pretreatment in cats, and pretreatment with colchicine revealed a small rostral group of tyrosine hydroxylase-positive neurons in guinea-pigs. There were remarkable similarities in the rostrocaudal distributions of neurons containing tyrosine hydroxylase, dopamine-beta-hydroxylase and neuropeptide Y in relation to comparable anatomical landmarks across the species. However, the distributions of neurons containing tyrosine hydroxylase. Phenylethanolamine-N-methyltransferase-positive neurons, while densely stained in rats, were only faintly stained in cats and absent in guinea-pigs the distribution of these neurons was similar to the distribution of neurons containing only tyrosine hydroxylase. The similarity of the distribution of neurons demonstrated using tyrosine hydroxylase, dopamine-beta-hydroxylase and neuropeptide Y immunohistochemistry implies that homologous catecholamine-containing neuron groups do exist in the ventrolateral medulla despite the variation in phenylethanolamine-N-methyltransferase between species. In contrast to the previous classification of neuron groups into A1 and C1 based on the presence or absence of this latter enzyme, the data suggest that a discrete group of tyrosine hydroxylase-immunoreactive neurons, which probably do not contain dopamine-beta-hydroxylase or neuropeptide Y, can be distinguished in the rostral ventrolateral medulla of all species. The absence of detectable dopamine-beta-hydroxylase in this group of neurons suggests that they may not synthesize either adrenaline or noradrenaline.
Publisher: Springer Science and Business Media LLC
Date: 26-07-2021
DOI: 10.1038/S41531-021-00203-9
Abstract: With the advent of the genetic era in Parkinson’s disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein’s varied roles, as they are known today and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.
Publisher: Wiley
Date: 02-1996
DOI: 10.1111/J.1530-0277.1996.TB01045.X
Abstract: Despite the considerable evidence that alcoholics have perturbation of serotonergic function, there is little pathological evidence for alcohol directly affecting the nervous system. The present study aims to assess neuronal loss that occurs as a consequence of alcohol neurotoxicity in the serotonergic dorsal raphe nucleus (DRN). To that end, the brains of eight alcoholics and eight age-matched control cases were carefully screened to eliminate serious liver disease, the sequela of thiamine deficiency, Wernicke-Korsakoff syndrome (WKS), and other pathological abnormalities. Brains were formalin-fixed for 2 weeks, cut, and then immunohistochemically stained using a monoclonal PH8 antibody specific for the rate-limiting enzyme of serotonin synthesis, tryptophan hydroxylase. The morphology of the serotonin-synthesizing neurons and their average size was similar in all cases. However, there was a reduction in the staining intensity of the reaction product in the DRN serotonergic neurons of most alcoholics. Neuronal counts on spaced serial sections revealed that there were an estimated average total of 106,100 +/- 19,500 serotonergic neurons in the DRN of alcoholics and 108,300 +/- 11,800 in the DRN of controls, indicating that in most alcoholics there is no reduction in the number of these neurons. Therefore, the effect of chronic alcohol consumption on the serotonergic system, in the absence of WKS or liver disease, seems to be functional rather than neuropathological.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-10-2014
Publisher: Elsevier BV
Date: 07-1996
DOI: 10.1016/0197-4580(96)00005-X
Abstract: The present study investigated the effect of age on total and regional brain volumes and compared age-associated changes in 20 healthy controls with those observed in 12 patients with Alzheimer's disease (AD). Weights and volumes of the whole brain and cerebrum, as well as the fractional volumes of the frontal, temporal, and parieto-occipital cortices, medial temporal structures, deep brain structures, and white matter were measured. Males had larger and heavier brains than females of comparable age. A small decline in brain volume with age was found (approximately 2 ml per year), but only within the white matter. In comparison, no further loss of white matter occurred in AD however, the cerebral cortex was significantly reduced in volume, with the greatest loss from the medial temporal structures. This loss was related to disease progression greater proportional loss was associated with more rapid decline in older patients. This study suggests that significant brain atrophy is not a consequence of advancing age. In addition, it suggests a regional specificity of damage in AD.
Publisher: Oxford University Press (OUP)
Date: 02-05-2022
DOI: 10.1093/BRAINCOMMS/FCAC120
Abstract: Alzheimer’s disease is a devastating neurodegenerative disease that affects more women than men. The pathomechanism underlying the sex disparity, especially in the brain, is unclear. ABCA7 is one of the strongest susceptibility genes for Alzheimer’s disease. It mediates the transport of lipids across membranes and is associated with pathways related to amyloid-β neuropathology. However, the role of ABCA7 in the regulation of brain lipids is largely unknown. Sex-specific differences in the pathological link between brain lipid dysregulation and amyloid-β are also unknown. Here, we undertook quantitative discovery lipidomics of male and female Abca7 knockout (n = 52) and wild type (n = 35) mouse brain using sophisticated liquid chromatography/mass spectrometry. We identified 61 lipid subclasses in the mouse brain and found sex-specific differences in lipids that were altered with Abca7 deletion. The altered lipids belong to cellular pathways that control cell signalling, sterol metabolism, mitochondrial function and neuroprotection. We also investigated the relationship between lipids and amyloid-β levels in the Abca7 knockout mice and found elevated free cholesterol only in female mice that was significantly correlated with amyloid-β42 levels. In male Abca7 knockout mice, the neuroprotective ganglioside GD1a levels were elevated and inversely correlated with amyloid-β42 levels. Collectively, these results demonstrate that Abca7 deletion leads to sex-specific lipid dysregulation in the brain, providing insight into the underlying sex disparity in the aetiology of Alzheimer’s disease.
Publisher: Oxford University Press (OUP)
Date: 21-12-2023
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.NEUROBIOLAGING.2007.10.015
Abstract: Age-related brain changes are widely documented. Because of differences in measurement methods and case selection, the reported effects of age on regional grey and white matter brain volumes, however, are much more pronounced and widespread in neuroimaging than in postmortem studies. Consequently, the magnitude of the effect that is specific to chronological age remains unresolved. We present postmortem volume measurements for 26 cortical, subcortical and white matter regions, in 24 human brains aged 46-92 years, free of neuropathological abnormalities. Significant age-related loss was observed in anterior and posterior white matter but not in total grey matter volumes. Further analyses on five cortical subregions previously reported to exhibit large age-related loss on MRI yielded negative results. These analyses demonstrate smaller changes with age than those reported in imaging studies. Although this discrepancy between postmortem and imaging studies may partly be explained by the increase in noise of the neuroimaging data with age, our results suggest that healthy brain ageing is a process affecting predominantly white matter not grey matter.
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1093/BRAIN/AWF251
Abstract: The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala sub isions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was sub ided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 ) 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala sub isions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.
Publisher: Wiley
Date: 23-08-2022
DOI: 10.1002/MDS.29164
Abstract: Multiple System Atrophy is a rare neurodegenerative disease with alpha‐synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome‐wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy‐confirmed cases. We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). The most strongly disease‐associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P ‐values below 5 × 10 −6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4‐immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4‐mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Publisher: Wiley
Date: 15-06-2009
DOI: 10.1002/MDS.22513
Publisher: Cold Spring Harbor Laboratory
Date: 12-11-2021
DOI: 10.1101/2021.11.11.21265915
Abstract: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied common genetic variation in only autopsy-confirmed cases (N = 731) and controls (N = 2,898). The most strongly disease-associated markers were rs16859966 on chromosome 3 (P = 8.6 × 10 −7 , odds ratio (OR) = 1.58, [95% confidence interval (CI) = 1.32-1.89]), rs7013955 on chromosome 8 (P = 3.7 × 10 −6 , OR = 1.8 [1.40-2.31]), and rs116607983 on chromosome 4 (P = 4.0 × 10 −6 , OR = 2.93 [1.86-4.63]), all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms with P-values below 5 × 10 −5 . The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4 positive neurons were significantly reduced in patients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Elsevier BV
Date: 03-1997
Abstract: Using unbiased quantitative techniques, we evaluated the effect of Parkinson's disease on the regional size and the number of tyrosine hydroxylase-producing neurons and all neurons in the midbrain A8 and A10 dopaminergic cell groups located adjacent to the substantia nigra. Seven patients with Lewy body Parkinson's disease were evaluated and compared with five controls. Four of the patients with Parkinson's disease had additional neuropathology, and the effect of concomitant pathology on A10 populations was also determined. Degeneration was not observed in the A8 regions of any patient, and only certain A10 nuclei were affected by the disease. The parabrachial pigmented nucleus situated dorsal to the substantial nigra, and the parapeduncular nucleus located rostromedially were significantly reduced by 40-50% in patients with Parkinson's disease. Few differences were found between patients with or without additional pathology, suggesting a similar pathogenic mechanism to that observed in the substantia nigra of these patients. However, patients with additional pathology also had serotonergic cell loss in the caudal linear nucleus. There was a reduction in tyrosine hydroxylase immunoreactivity but no overt neurodegeneration in other A10 regions, suggesting the disease may also influence the production of dopamine in some surviving neurons.
Publisher: Elsevier BV
Date: 06-2004
Publisher: Springer Science and Business Media LLC
Date: 07-01-2020
DOI: 10.1038/S41531-019-0106-4
Abstract: While several studies have investigated the clinical progression of cognitive decline in Parkinson’s disease (PD) patients, there has been a paucity of data on specifically evaluating PD patients with a disease duration of over 20 years. This study retrospectively investigated the frequency of dementia in PD (PDD) patients with a disease duration of over 20 years assessed in research clinics across the UK and Australia. Data from 2327 PD patients meeting the United Kingdom Parkinson’s Disease Society Brain Bank Criteria was pooled. A diagnosis of probable PDD was made according to the Movement Disorder Society Level 1 criteria. Thirty-six participants had a disease duration of at least 20 years. Of the 36 patients, only 7 (19%) were classified as probable PDD. Compared to PD patients without dementia, those with dementia had lower levels of educational attainment and exhibited more severe motor features. Additionally, 34 out of the 36 patients (94%) exhibited a non-tremor dominant phenotype. No significant differences in age, age onset, disease duration, dopaminergic medication use, and sex distribution were observed between PD patients with and without dementia. Findings from the present study suggest that the prevalence of dementia in long-term PD patients may be lower than anticipated and suggest that the trajectory of cognitive decline in PD patients can be different. These findings highlight the need to investigate factors that might affect the outcome of cognitive decline in long-term PD patients, which may lead to the determination of potential modulating factors in the development of dementia in these patients.
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.NEUROSCIENCE.2014.10.028
Abstract: Inflammation has long been associated with the pathogenesis of Parkinson's disease (PD) but the extent to which it is a cause or consequence is sill debated. Over the past decade a number of genes have been implicated in PD. Relatively rare missense mutations in genes such as LRRK2, Parkin, SNCA and PINK1 are causative for familial PD whereas more common variation in genes, including LRRK2, SNCA and GBA, comprise risk factors for sporadic PD. Determining how the function of these genes and the proteins they encode are altered in PD has become a priority, as results will likely provide much needed insights into contributing causes. Accumulating evidence indicates that many of these genes function in pathways that regulate aspects of immunity, particularly inflammation, suggesting close associations between PD and immune homeostasis.
Publisher: Springer Science and Business Media LLC
Date: 05-05-2015
Abstract: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are related neurodegenerative disorders, which are characterized by a rapid decline in cognitive and motor functions, and short survival. Although the clinical and neuropathological characterization of these diseases has progressed--in part--through animal studies of pathogenetic mechanisms, the translation of findings from rodent models to clinical practice has generally not been successful. This article discusses the gap between preclinical animal studies in mice and clinical trials in patients with FTD or ALS. We outline how to better design preclinical studies, and present strategies to improve mouse models to overcome the translational shortfall. This new approach could help identify drugs that are more likely to achieve a therapeutic benefit for patients.
Publisher: Elsevier BV
Date: 10-2005
Publisher: Springer Science and Business Media LLC
Date: 19-01-2006
Publisher: Springer Science and Business Media LLC
Date: 17-02-2022
DOI: 10.1038/S41531-022-00279-X
Abstract: Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson’s disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB ( n = 25) and age-matched controls ( n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.
Publisher: Elsevier BV
Date: 03-1997
Abstract: We have analyzed the neuropathology of the substantia nigra in four cases of progressive supranuclear palsy compared with age-matched controls and patients with Parkinson's disease. Although there are many reports of severe dopaminergic cell loss in progressive supranuclear palsy, the fate of the GABAergic pars reticulata neurones remains unclear. Serial section analysis and fractional counts of pars compacta neurones (identified by their neuromelanin pigment) and pars reticulata neurones (identified using parvalbumin immunohistochemistry) were performed, and the type and distribution of neuropathology were described. Severe neurodegeneration within the dopaminergic pars compacta was seen in all cases of progressive supranuclear palsy and all cases of Parkinson's disease compared with controls. Lewy body pathology was found only in cases of Parkinson's disease, while neurofibrillary tangles were seen only in cases of progressive supranuclear palsy. Tau-positive astrocytes and neuropil threads were occasionally seen in controls and cases of Parkinson's disease (particularly those of advanced age) but were extremely numerous in all cases of progressive supranuclear palsy. There was a similar decrease in parvalbumin immunoreactivity within the pars reticulata in both progressive supranuclear palsy and Parkinson's disease. However, there was a striking 70% reduction in the number of pars reticulata neurones in progressive supranuclear palsy, with no cell loss observed in Parkinson's disease compared with controls. Our results show that both the dopaminergic pars compacta and the GABAergic pars reticulata are significantly damaged in cases of progressive supranuclear palsy. The distribution of neurodegeneration in patients with Parkinson's disease and progressive supranuclear palsy is discussed with respect to the current theories on pathophysiology in basal ganglia circuitry.
Publisher: Public Library of Science (PLoS)
Date: 23-10-2013
Publisher: MDPI AG
Date: 28-06-2019
DOI: 10.3390/IJMS20133161
Abstract: Neuroinflammation is an inflammatory response in the brain and spinal cord, which can involve the activation of microglia and astrocytes. It is a common feature of many central nervous system disorders, including a range of neurodegenerative disorders. An overlap between activated microglia, pro-inflammatory cytokines and translocator protein (TSPO) ligand binding was shown in early animal studies of neurodegeneration. These findings have been translated in clinical studies, where increases in TSPO positron emission tomography (PET) signal occur in disease-relevant areas across a broad spectrum of neurodegenerative diseases. While this supports the use of TSPO PET as a biomarker to monitor response in clinical trials of novel neurodegenerative therapeutics, the clinical utility of current TSPO PET radioligands has been h ered by the lack of high affinity binding to a prevalent form of polymorphic TSPO (A147T) compared to wild type TSPO. This review details recent developments in exploration of ligand-sensitivity to A147T TSPO that have yielded ligands with improved clinical utility. In addition to developing a non-discriminating TSPO ligand, the final frontier of TSPO biomarker research requires developing an understanding of the cellular and functional interpretation of the TSPO PET signal. Recent insights resulting from single cell analysis of microglial phenotypes are reviewed.
Publisher: Elsevier
Date: 2012
Publisher: Wiley
Date: 06-1995
DOI: 10.1111/J.1365-2990.1995.TB01058.X
Abstract: It has been suggested that the defect underlying the sudden infant death syndrome (SIDS) lies in brain stem nuclei involved in cardiac and respiratory function. However, most studies have not used rigorous quantitative techniques to assess brain stem nuclear volumes and neuronal numbers. We have measured the volume, neuronal numbers and position of brain stem nuclei in 11 SIDS and 11 aged-matched control infants. Using serial sagittal sections, nuclei involved in maintaining airway patency (hypoglossal, ambiguus and retroambiguus), heart rate (dorsal vagal) and generation of respiratory rhythm (ambiguus and dorsal vagal) were studied. No significant differences were found in nuclear volume increase with age, total neuronal number or nuclear position between SIDS and control cases. These findings support the hypothesis that the nervous system in SIDS may be normal until the final event that kills these infants.
Publisher: Frontiers Media SA
Date: 02-11-2016
Publisher: Springer Science and Business Media LLC
Date: 26-05-2006
DOI: 10.1007/S00702-006-0451-4
Abstract: Neuromelanin (NM) is different to other melanins in that its ultrastructure includes a lipid component. The objectives of this study were to identify and quantify lipids associated with NM. Quantification of the lipid component associated with the pigment on electron micrographs demonstrated that this component comprises 35% of the NM granule volume in the normal brain. The irregular ultrastructural appearance of the NM granules was quite different to the round regular boundary of melanin granules. Using reversed phase high performance liquid chromatography (HPLC) coupled with atmospheric pressure chemical ionization (APCI) mass spectrometry we demonstrated that the isoprenoid dolichol accounted for approximately 12% of total NM pigment mass. Low levels of other lipids were detectable (cholesterol, ubiquinone-10 and alpha-tocopherol) and account for <0.05% of NM lipid, in contrast to cholesterol accounting for 35% of total brain lipids. Unlike other melanins, a substantial proportion of NM volume is comprised of lipid and the major type of lipid associated with NM granules is the isoprenoid dolichol.
Publisher: Wiley
Date: 29-01-2019
DOI: 10.1111/ENE.13887
Abstract: Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8-year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow-up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (β = 0.46, P < 0.001) was the strongest predictor of progression. Deficits in letter fluency (β = -0.43, P = 0.017) and greater atrophy in the motor cortex (β = 0.51, P = 0.03) were also associated with faster progression. This study provides novel clinical predictors of survival and progression in bvFTD. Our findings are likely to have an impact on prognostication and care planning in this difficult disease.
Publisher: Wiley
Date: 2001
DOI: 10.1002/ANA.67
Publisher: Oxford University Press (OUP)
Date: 12-2020
Abstract: This scientific commentary refers to ‘CD8 T cell nigral infiltration precedes synucleinopathy in early stages of Parkinson’s disease’, by Galiano-Landeira et al. (doi:10.1093/brain/awaa269).
Publisher: Future Medicine Ltd
Date: 10-2015
DOI: 10.2217/NMT.15.37
Publisher: Wiley
Date: 04-07-2023
DOI: 10.1111/NAN.12919
Abstract: Although the orally available brain‐penetrant copper compound CuATSM has demonstrated promising effects in SOD1‐linked mouse models, the impact of CuATSM on disease pathology in patients with amyotrophic lateral sclerosis (ALS) remains unknown. The present study set out to address this deficit by performing the first pilot comparative analysis of ALS pathology in patients that had been administered CuATSM and riluzole [ N = 6 cases composed of ALS‐TDP ( n = 5) and ALS‐SOD1 ( n = 1)] versus riluzole only [ N = 6 cases composed of ALS‐TDP ( n = 4) and ALS‐SOD1 ( n = 2)]. Our results revealed no significant difference in neuron density or TDP‐43 burden in the motor cortex and spinal cord of patients that had received CuATSM compared with patients that had not. In patients that had received CuATSM, p62‐immunoreactive astrocytes were observed in the motor cortex and reduced Iba1 density was found in the spinal cord. However, no significant difference in measures of astrocytic activity and SOD1 immunoreactivity was found with CuATSM treatment. These findings, in this first postmortem investigation of patients with ALS in CuATSM trials, demonstrate that in contrast to that seen in preclinical models of disease, CuATSM does not significantly alleviate neuronal pathology or astrogliosis in patients with ALS.
Publisher: S. Karger AG
Date: 1996
DOI: 10.1159/000106896
Abstract: This study measured brain atrophy in patients with idiopathic Parkinson''s disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopaminergic neurons and absence of Alzheimer''s disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimer''s disease and is likely to be the anatomical substrate for the memory deficits found in each of these patient groups. Frontal lobe atrophy was a feature of both late-onset Parkinson''s disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopaminergic deafferentation, frontal atrophy and dementia.
Publisher: Elsevier BV
Date: 07-1996
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.NEUROBIOLAGING.2014.12.016
Abstract: An increase in DNA content is associated with neuronal degeneration in Alzheimer's disease but has not been evaluated in Lewy body diseases. Using stereological principles, flow cytometry, and standard histopathologic methods, we evaluated the number and DNA content of neurons and all cells and the severity of Lewy and Alzheimer pathologies, in brain regions affected at different stages in Lewy body diseases compared with controls. An increase in neuronal DNA content was observed in all the affected brain regions examined, although this change was related to different pathologies. In the substantia nigra, increased neuronal DNA content related to neuronal loss, whereas in the cortex and hippoc us, increased neuronal DNA content related to Alzheimer pathologies. Of note, increased neuronal DNA content did not relate to the deposition of Lewy bodies in any region examined. These data support the concept that increased DNA content increases neuronal susceptibility to degeneration and Alzheimer pathologies.
Publisher: Wiley
Date: 12-12-2015
Publisher: Elsevier BV
Date: 11-2003
DOI: 10.1016/J.EXPNEUROL.2003.08.006
Abstract: Many dopamine agonists used in the treatment of Parkinson's disease are suggested to be potentially neuroprotective. On the basis of its structure, the dopamine agonist lisuride may share this characteristic. In the current study discrete asymptomatic lesions were produced by the injection of iron-laden neuromelanin into the rat substantia nigra and the animals treated with lisuride to determine the protective potential of this substance. Two treatment regimes were utilised. In the neuroprotective protocol, animals were treated with 0.1 mg.kg(-1) lisuride twice daily 3 days prior to, and 7 days following, the iron lesion. In the neurorescue protocol, the animals received 0.1 mg.kg(-1) lisuride twice daily for 1 week beginning on the fourth day post surgery. Eight weeks post surgery, tyrosine hydroxylase-positive neurons surrounding the injection site (33% of total nigral volume) were counted. Dopamine neuron number in iron-lesioned animals was reduced to 50% of that in vehicle-injected animals. The absence of motoric disturbances or a striatal dopamine deficit in these animals suggests a subclinical dopaminergic lesion. Dopamine neuron number in the quantified area in sham-injected animals receiving lisuride or iron-lesioned animals receiving lisuride in both the neuroprotection and neurorescue groups were not significantly reduced. These results suggest that lisuride can protect neurons against iron-induced cell death and might thus be neuroprotective in Parkinson's disease.
Publisher: Elsevier BV
Date: 1991
DOI: 10.1016/0306-4522(91)90314-E
Abstract: The data in the preceding paper [Halliday G. M. and McLachlan E. M. (1991) Neuroscience 43, 531-550] suggest that some neurons in the rostral ventrolateral medulla contain some catecholamine-synthesizing enzymes but may not produce catecholamines. The present study addresses this question directly by comparing the anatomical location and morphology of these neurons with those revealed by formaldehyde-induced fluorescence. Catecholamine-containing somata of rats and guinea-pigs have been demonstrated following FAGLU-perfusion in normal untreated animals, in animals pretreated with pargyline (a monoamine oxidase inhibitor), and in animals pretreated with colchicine (to block axoplasmic transport). The number and location of fluorescent somata in the ventrolateral medulla have been determined in serial coronal sections of tissue from the cervical spinal cord to the level of the facial nucleus. Catecholamine-fluorescent neurons at different levels of the ventrolateral medulla varied in their topography and sensitivity to pharmacological manipulation. However, the rostrocaudal distributions in rats and guinea-pigs were quantitatively remarkably similar implying that homologous groups of catecholamine-containing neurons exist. Comparison between these distributions and those of somata stained immunohistochemically for catecholamine-synthesizing enzymes and neuropeptide Y [Halliday G. M. and McLachlan E. M. (1991) Neuroscience 43, 531-550] revealed that the majority of fluorescent neurons in both species probably contain dopamine-beta-hydroxylase and neuropeptide Y as well as tyrosine hydroxylase. Those neurons lying just caudal to the facial nucleus immunoreactive for tyrosine hydroxylase and phenylethanolamine-N-methyltransferase but not dopamine-beta-hydroxylase and neuropeptide Y also lack catecholamine fluorescence. This rostral group of somata can be identified immunohistochemically in cats. The size and morphology of catecholamine-fluorescent neurons have been analysed in detail, and compared with the same features of the immunohistochemically stained neurons. Three morphological types of catecholamine-containing neurons could be distinguished in material prepared by both techniques from rats and guinea-pigs, and in immunohistochemical material from cats. Rostral tyrosine hydroxylase-positive neurons, which differed morphologically from these three types, were present in all three species. On the basis of anatomical location, neuronal morphology and chemical characteristics, four groups of tyrosine hydroxylase-immunoreactive neurons have been identified in the ventrolateral medulla of rats, guinea-pigs and cats. Only the caudal three of these four groups appear to synthesize catecholamine, probably noradrenaline. From published data it seems likely that these four groups of tyrosine hydroxylase-positive neurons have distinct projections and functions related to cardiovascular and respiratory control.
Publisher: Oxford University Press (OUP)
Date: 26-12-2022
DOI: 10.1093/BRAINCOMMS/FCAC340
Abstract: Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease characterized by the degeneration of motor neurons and loss of various muscular functions. Dyslipidaemia is prevalent in amyotrophic lateral sclerosis with aberrant changes mainly in cholesterol ester and triglyceride. Despite this, little is known about global lipid changes in amyotrophic lateral sclerosis or in relation to disease progression. The present study incorporated a longitudinal lipidomic analysis of amyotrophic lateral sclerosis serum with a comparison with healthy controls using advanced liquid chromatography-mass spectrometry. The results established that diglyceride, the precursor of triglyceride, was enriched the most, while ceramide was depleted the most in amyotrophic lateral sclerosis compared with controls, with the diglyceride species (18:1/18:1) correlating significantly to neurofilament light levels. The prenol lipid CoQ8 was also decreased in amyotrophic lateral sclerosis and correlated to neurofilament light levels. Most interestingly, the phospholipid phosphatidylethanolamine and its three derivatives decreased with disease progression, in contrast to changes with normal ageing. Unsaturated lipids that are prone to lipid peroxidation were elevated with disease progression with increases in the formation of toxic lipid products. Furthermore, in vitro studies revealed that phosphatidylethanolamine synthesis modulated TARDBP expression in SH-SY5Y neuronal cells. Finally, diglyceride, cholesterol ester and ceramide were identified as potential lipid biomarkers for amyotrophic lateral sclerosis diagnosis and monitoring disease progression. In summary, this study represents a longitudinal lipidomics analysis of amyotrophic lateral sclerosis serum and has provided new insights into multiple pathways of lipid dysregulation in amyotrophic lateral sclerosis.
Publisher: Wiley
Date: 16-04-2021
DOI: 10.1111/ENE.14849
Abstract: Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA‐binding protein (pTDP‐43) inclusions in motor and non‐motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity. All ALS cases held by the New South Wales Brain Bank ( n = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined. Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities. The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.
Publisher: Oxford University Press (OUP)
Date: 10-2021
DOI: 10.1093/BRAINCOMMS/FCAB257
Abstract: The disease syndromes of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant FTD (n = 58) and ALS–FTD (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippoc us, amygdala, thalamus and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-ALS patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the ALS–FTD and behavioural variant FTD groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76–90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in ALS–FTD relative to pure-ALS. In contrast, pure-ALS displayed significantly greater parietal atrophy. Both behavioural variant FTD and ALS–FTD were characterized by volume decrease in the frontal lobes relative to pure-ALS. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in ALS–FTD compared with pure-ALS, and greater left motor cortex and insula atrophy relative to behavioural variant FTD. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the ALS–FTD spectrum, with key structures including the motor cortex and insula. Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NEUROBIOLAGING.2013.09.034
Abstract: Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinson's disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with α-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by α-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder.
Publisher: Springer Science and Business Media LLC
Date: 10-01-2015
Publisher: Springer Science and Business Media LLC
Date: 25-05-2016
DOI: 10.1038/SREP26697
Abstract: MicroRNA-146a is upregulated in the brains of patients with Alzheimer’s disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippoc al delivery of a microRNA-146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippoc al levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis and inhibition of this microRNA could be a viable novel in vivo therapy for AD.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.NBD.2015.04.009
Abstract: α-Synuclein (α-syn), a small protein that has the intrinsic propensity to aggregate, is implicated in several neurodegenerative diseases including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are collectively known as synucleinopathies. Genetic, pathological, biochemical, and animal modeling studies provided compelling evidence that α-syn aggregation plays a key role in the pathogenesis of PD and related synucleinopathies. It is therefore of utmost importance to develop reliable tools that can detect the aggregated forms of α-syn. We describe here the generation and characterization of six novel conformation-specific monoclonal antibodies that recognize specifically α-syn aggregates but not the soluble, monomeric form of the protein. The antibodies described herein did not recognize monomers or fibrils generated from other amyloidogenic proteins including β-syn, γ-syn, β-amyloid, tau protein, islet amyloid polypeptide and ABri. Interestingly, the antibodies did not react to overlapping linear peptides spanning the entire sequence of α-syn, confirming further that they only detect α-syn aggregates. In immunohistochemical studies, the new conformation-specific monoclonal antibodies showed underappreciated small micro-aggregates and very thin neurites in PD and DLB cases that were not observed with generic pan antibodies that recognize linear epitope. Furthermore, employing one of our conformation-specific antibodies in a sandwich based ELISA, we observed an increase in levels of α-syn oligomers in brain lysates from DLB compared to Alzheimer's disease and control s les. Therefore, the conformation-specific antibodies portrayed herein represent useful tools for research, biomarkers development, diagnosis and even immunotherapy for PD and related pathologies.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2014
Publisher: Elsevier
Date: 2013
Publisher: Oxford University Press (OUP)
Date: 02-2002
DOI: 10.1093/BRAIN/AWF033
Abstract: Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippoc al, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippoc us, with early hallucinations relating to higher densities in parahippoc al and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-03-2021
DOI: 10.1212/WNL.0000000000011638
Abstract: To test the hypothesis that white matter hyperintensities (WMH) in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer disease (AD) are associated with disease variables such as disease severity, cortical atrophy, and cognition, we conducted a cross-sectional brain MRI study with volumetric and voxel-wise analyses. A total of 129 patients (64 bvFTD, 65 AD) and 66 controls underwent high-resolution brain MRI and clinical and neuropsychological examination. Genetic screening was conducted in 124 cases (54 bvFTD, 44 AD, 26 controls) and postmortem pathology was available in 18 cases (13 bvFTD, 5 AD). WMH were extracted using an automated segmentation algorithm and analyses of total volumes and spatial distribution were conducted. Group differences in total WMH volume and associations with vascular risk and disease severity were examined. Syndrome-specific voxel-wise associations between WMH, cortical atrophy, and performance across different cognitive domains were assessed. Total WMH volumes were larger in patients with bvFTD than patients with AD and controls. In bvFTD, WMH volumes were associated with disease severity but not vascular risk. Patients with bvFTD and patients with AD showed distinct spatial patterns of WMH that mirrored characteristic patterns of cortical atrophy. Regional WMH load correlated with worse cognitive performance in discrete cognitive domains. WMH-related cognitive impairments were shared between syndromes, with additional associations found in bvFTD. Increased WMH are common in patients with bvFTD and patients with AD. Our findings suggest that WMH are partly independent of vascular pathology and associated with the neurodegenerative process. WMH occur in processes independent of and related to cortical atrophy. Furthermore, increased WMH in different regions contributes to cognitive deficits.
Publisher: Public Library of Science (PLoS)
Date: 25-01-2013
Publisher: Informa UK Limited
Date: 23-03-2019
Publisher: Wiley
Date: 08-2023
DOI: 10.1111/NAN.12922
Abstract: This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older in iduals. Clinical and neuropathological data were retrieved for 149 autopsy cases years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti‐hypertensive medication usage. Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6–14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aβ progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aβ progression but only in those with moderate to severe white matter SVD. This histopathological study provides further evidence that antihypertensive medication use in older in iduals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aβ propagation through the brain.
Publisher: Informa UK Limited
Date: 06-2012
DOI: 10.1586/ERN.12.47
Abstract: Braak's proposal that, in patients with Parkinson's disease, Lewy bodies and neurites progressively invade the brain through regions connected to autonomic and olfactory centers remains contentious. Confounding factors include the lack of an in vivo marker to examine the progression of Lewy pathology, the retrospective nature or absence of clinical information for many cross-sectional pathological datasets, and for those with limited disease (clinically or neuropathologically), the absence of information concerning additional conditions. Despite these data limitations at this time, the brain pathology for most patients with typical Parkinson's disease can be predicted using Braak's scheme. What this tells us about the pathogenesis of Parkinson's disease will be explored in this review.
Publisher: Wiley
Date: 08-10-2008
DOI: 10.1111/J.1471-4159.2007.05038.X
Abstract: Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected in iduals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected in iduals who present with dementia only, suggesting the existence of a protective factor in some in iduals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.
Publisher: Springer Science and Business Media LLC
Date: 20-08-2009
DOI: 10.1007/S00702-009-0293-Y
Abstract: Frontotemporal lobar degeneration (FTLD) is a common cause of presenile dementia characterised by behavioural and language disturbances. Pick's disease (PiD) is a subtype of FTLD, which presents with intraneuronal inclusions consisting of hyperphosphorylated tau protein aggregates. Although Alzheimer's disease (AD) is also characterised by tau lesions, these are both histologically and biochemically distinct from the tau aggregates found in PiD. What determines the distinct characteristics of these tau lesions is unknown. As phosphorylated, soluble tau has been suggested to be the precursor of tau aggregates, we compared both the level and phosphorylation profile of tau in tissue extracts of AD and PiD brains to determine whether the differences in the tau lesions are reflected by differences in soluble tau. Levels of soluble tau were decreased in AD but not PiD. In addition, soluble tau was phosphorylated to a greater extent in AD than in PiD and displayed a different phosphorylation profile in the two disorders. Consistently, tau kinases were activated to different degrees in AD compared with PiD. Such differences in solubility and phosphorylation may contribute, at least in part, to the formation of distinct tau deposits, but may also have implications for the clinical differences between AD and PiD.
Publisher: Oxford University Press (OUP)
Date: 06-07-2005
DOI: 10.1093/BRAIN/AWH584
Abstract: The distribution and tempo of neuronal loss in Parkinson's disease correlates poorly with the characteristic and more widely spread intracellular changes associated with the disease process (Lewy bodies and Lewy neurites). To determine early intracellular changes in regions where cell loss is most marked (dopaminergic A9 substantia nigra) versus regions with Lewy bodies but where cell loss is limited, we assessed 13 patients with definite Parkinson's disease at various disease stages in comparison with controls. Using immunohistochemistry for alpha-synuclein, we confirmed the concentration of this protein in the soma of normal A9 neurons and in Lewy body pathology in brainstem catecholamine neurons in Parkinson's disease. Analysis of the degree of cell loss in brainstem catecholamine cell groups revealed that only the A9 substantia nigra had consistent significant cell loss early in the disease course with greater A9 cell loss correlating with increasing disease duration. To assess the earliest intracellular changes differentiating neurons more likely to degenerate, pigmented A9 and A10 neurons with and without obvious pathology were targeted, cell size and pigment density measured, and intracellular changes in alpha-synuclein location and lipid components analysed at both the light and electron microscope levels. There were no changes observed in healthy A10 neurons in Parkinson's disease compared with controls. Pigmented A9 neurons in later stages of degeneration with obvious Lewy body formation had a significant reduction in intracellular pigment, as previously described. In contrast, A9 neurons of normal morphological appearance and no characteristic pathology in Parkinson's disease exhibited significantly increased pigment density associated with a concentration of alpha-synuclein to the lipid component of the pigment and a loss of associated cholesterol. These changes in vulnerable but apparently healthy A9 neurons occurred without any change in cell size or in the amount of intracellular pigment compared with controls. The increase in pigment density is consistent with previously reported increases associated with oxidation and iron loading, reactions known to precipitate alpha-synuclein. The selectivity of the changes observed in A9 nigral neurons suggests that these early intracellular changes predispose these neurons to more rapid cell loss in Parkinson's disease. The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. Overall, these changes may trigger a cascade of events leading to larger intracellular aggregates of alpha-synuclein and the dispersement of protective pigment to precipitate cell death in Parkinson's disease.
Publisher: Springer Science and Business Media LLC
Date: 19-07-2019
DOI: 10.1038/S41582-019-0231-Z
Abstract: Frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders with different pathological signatures, genetic variability and complex disease mechanisms, for which no effective treatments exist. Despite advances in understanding the underlying pathology of FTD, sensitive and specific fluid biomarkers for this disease are lacking. As in other types of dementia, mounting evidence suggests that neuroinflammation is involved in the progression of FTD, including cortical inflammation, microglial activation, astrogliosis and differential expression of inflammation-related proteins in the periphery. Furthermore, an overlap between FTD and autoimmune disease has been identified. The most substantial evidence, however, comes from genetic studies, and several FTD-related genes are also implicated in neuroinflammation. This Review discusses specific evidence of neuroinflammatory mechanisms in FTD and describes how advances in our understanding of these mechanisms, in FTD as well as in other neurodegenerative diseases, might facilitate the development and implementation of diagnostic tools and disease-modifying treatments for FTD.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2011
DOI: 10.1007/S00702-011-0641-6
Abstract: Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.
Publisher: Oxford University Press (OUP)
Date: 06-07-2005
DOI: 10.1093/BRAIN/AWH582
Abstract: Semantic dementia is a syndrome of progressive deterioration in semantic memory (knowledge of objects, people, concepts and words). It falls within the clinical spectrum of frontotemporal dementia but its pathology is yet to be studied systematically. This study included 18 consecutive post mortem cases meeting clinical criteria for semantic dementia. Clinic records and diagnostic histopathology were available for all cases structural neuroimaging, neuropsychology and semi-quantitative histopathology/immunohistochemistry data were analysed where possible. The pathological diagnosis in a clear majority of cases was frontotemporal degeneration with ubiquitin inclusions (n = 13). Eleven of these cases had characteristic motor neuron disease-type inclusions in the dentate gyrus and cerebral cortex. Ubiquitin inclusions were found only in the inferior olivary nucleus in the other two, one of which was the only case to show degeneration of motor tracts and also to have shown evidence of motor neuron disease during life. None of the patients had motor symptoms or signs at presentation. A family history of motor neuron disease was documented in one case. Pick body-positive Pick's disease appeared three times. Two cases had Alzheimer's disease and significant coincidental Alzheimer-type pathology was also found in one of the ubiquitin inclusion cases. One of the Alzheimer's disease patients had changes in white matter signal on scanning, whereas all other scans showed cerebral atrophy only. Semi-quantitative assessment of regional neuronal loss found that anterior and inferior temporal regions bore the brunt of disease across all histopathological subtypes, usually on the left side, implicating this region in semantic processing.
Publisher: Oxford University Press (OUP)
Date: 1996
Abstract: A patient with a rapidly developing fluent progressive aphasia was tested prospectively up to the time of death and examined neuropathologically. Severe impairment in accessing semantic skills with substantially intact phonological, syntactic and discourse skills was found. Some social behavioural difficulties were also noted. This case presented a unique opportunity to relate this significant language impairment to the pattern of neurodegeneration, a difficult task in most neuropathological studies of severe end-stage dementia. A detailed neuropathological examination revealed focal atrophy with neuronal loss without neuronal inclusions (Pick bodies, Lewy bodies, neurofibrillary tangles or senile plaques) or neuronal changes (shrinkage or swelling). In addition, spongiform degeneration (confined to layer two of the cortex) and gliosis were detected at atrophic sites. To establish the amount of tissue loss and pathology associated with the focal language deficit, volume analyses were performed and compared with two age- and sex-matched, neurologically normal controls. Both the left and right angular gyri and Brodmann's area 37 showed marked volume reduction compared with controls. The predominant language impairment seen in this case is likely to reflect these marked changes in the posterior parieto-temporal areas. The milder unilateral atrophy was concentrated in the right temporal lobe as well as the right hemisphere homologue of Broca's area. Recent work suggests a relationship between such unilateral changes and the social behavioural difficulties which were noted in this case. The hippoc us and other gyri such as the supramarginal gyrus showed no volume loss compared with controls correlating with the relative preservation of other language skills.
Publisher: SAGE Publications
Date: 22-06-2017
Abstract: To date, only limited research has concurrently investigated the presence of rapid eye movement sleep behavior disorder (RBD) and other features associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB) in people presenting with mild cognitive impairment (MCI). As a first step towards a longitudinal research project, the present study explored the relationships between MCI, RBD, and depression in 108 older adults who presented with subjective memory complaints but were not known to have a neurodegenerative condition. The present study found that RBD was a frequent feature in in iduals with MCI (35%). Furthermore, MCI patients with RBD were more likely to exhibit nonamnestic MCI (89%) rather than an amnestic MCI phenotype (χ
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.NEUROBIOLAGING.2012.07.019
Abstract: Recent studies suggest a variety of factors characterize substantia nigra neurons vulnerable to Parkinson's disease, including the transcription factors pituitary homeobox 3 (Pitx3) and orthodenticle homeobox 2 (Otx2) and the trophic factor receptor deleted in colorectal cancer (DCC), but there is limited information on their expression and localization in adult humans. Pitx3, Otx2, and DCC were immunohistochemically localized in the upper brainstem of adult humans and mice and protein expression assessed using relative intensity measures and online microarray data. Pitx3 was present and highly expressed in most dopamine neurons. Surprisingly, in our elderly subjects no Otx2 immunoreactivity was detected in dopamine neurons, although Otx2 gene expression was found in younger cases. Enhanced DCC gene expression occurred in the substantia nigra, and higher amounts of DCC protein characterized vulnerable ventral nigral dopamine neurons. Our data show that, at the age when Parkinson's disease typically occurs, there are no significant differences in the expression of transcription factors in brainstem dopamine neurons, but those most vulnerable to Parkinson's disease rely more on the trophic factor receptor DCC than other brainstem dopamine neurons.
Publisher: Wiley
Date: 26-01-2013
DOI: 10.1007/S11745-013-3760-Z
Abstract: We have developed a protocol suitable for high-throughput lipidomic analysis of human brain s les. The traditional Folch extraction (using chloroform and glass-glass homogenization) was compared to a high-throughput method combining methyl-tert-butyl ether (MTBE) extraction with mechanical homogenization utilizing ceramic beads. This high-throughput method significantly reduced s le handling time and increased efficiency compared to glass-glass homogenizing. Furthermore, replacing chloroform with MTBE is safer (less carcinogenic/toxic), with lipids dissolving in the upper phase, allowing for easier pipetting and the potential for automation (i.e., robotics). Both methods were applied to the analysis of human occipital cortex. Lipid species (including ceramides, sphingomyelins, choline glycerophospholipids, ethanolamine glycerophospholipids and phosphatidylserines) were analyzed via electrospray ionization mass spectrometry and sterol species were analyzed using gas chromatography mass spectrometry. No differences in lipid species composition were evident when the lipid extraction protocols were compared, indicating that MTBE extraction with mechanical bead homogenization provides an improved method for the lipidomic profiling of human brain tissue.
Publisher: Public Library of Science (PLoS)
Date: 20-08-2013
Publisher: Oxford University Press (OUP)
Date: 04-2021
DOI: 10.1093/BRAINCOMMS/FCAB104
Abstract: Neuropathological observations in neurodegenerative synucleinopathies, including Parkinson disease, implicate a pathological role of α-synuclein accumulation in extranigral sites during the prodromal phase of the disease. In a transgenic mouse model of peripheral-to-central neuroinvasion and propagation of α-synuclein pathology (via hindlimb intramuscular inoculation with exogenous fibrillar α-synuclein: the M83 line, expressing the mutant human Ala53Thr α-synuclein), we studied the development and early-stage progression of α-synuclein pathology in the CNS of non-symptomatic (i.e. freely mobile) mice. By immunohistochemical analyses of phosphroylated α-synuclein on serine residue 129 (p-S129), our data indicate that the incipient stage of pathological α-synuclein propagation could be categorized in distinct phases: (i) initiation phase, whereby α-synuclein fibrillar inoculum induced pathological lesions in pools of premotor and motor neurons of the lumbar spinal cord, as early as 14 days post-inoculation (ii) early central phase, whereby incipient α-synuclein pathology was predominantly detected in the reticular nuclei of the brainstem and (iii) late central phase, characterized by additional sites of lesions in the brain including vestibular nuclei, deep cerebellar nuclei and primary motor cortex, with coincidental emergence of a sensorimotor deficit (mild degree of hindlimb clasping). Intriguingly, we also detected progressive α-synuclein pathology in premotor and motor neurons in the thoracic spinal cord, which does not directly innervate the hindlimb, as well as in the oligodendroglia within the white matter tracts of the CNS during this prodromal phase. Collectively, our data provide crucial insights into the spatiotemporal propagation of α-synuclein pathology in the nervous system of this rodent model of α-synucleinopathy following origin in periphery, and present a neuropathological context for the progression from pre-symptomatic stage to an early deficit in sensorimotor coordination. These findings also hint towards a therapeutic window for targeting the early stages of α-synuclein pathology progression in this model, and potentially facilitate the discovery of mechanisms relevant to α-synuclein proteinopathies. In a rodent model of synucleinopathy, Ferreira et al., delineate the spatiotemporal progression of incipient α-synuclein pathology (of peripheral origin) in the CNS. The authors show early affection of brainstem reticular nuclei in non-paralyzed mice, and pathological white matter lesions in relation to the neuronal pathology.
Publisher: S. Karger AG
Date: 2007
DOI: 10.1159/000100973
Abstract: i Background/Aims: /i The status of imaging findings in the clinical diagnosis of frontotemporal dementia (FTD) remains uncertain while they may be supportive of a diagnosis of frontotemporal dementia, they are not mandatory. Our aim was to assess patterns of lobar atrophy in a large s le of clinically defined, prospectively studied, patients using a magnetic resonance image (MRI) rating scale, to (1) determine whether imaging findings warrant a more prominent position in FTD diagnosis and (2) correlate the extent of lobar atrophy with clinical data. i Methods: /i We adapted a recently devised post mortem rating scale for FTD to rate lobar atrophy on MRI scans. The areas rated included the frontal cortex and both anterior and posterior temporal regions bilaterally. All available brain scans from all patients seen in the Cambridge Dementia Clinic (n = 258) diagnosed as having FTD, together with controls (n = 20), were used to assess the reliability of the method. A subset of these (n = 121) were used for clinico-anatomic analysis. i Results: /i The scale proved quick and reliable (intra-, inter-rater k = 0.80, 0.67). MRI scans were abnormal in the majority of patients (75%), with focal atrophy present in 100% of semantic dementia (SD) patients. By contrast, nearly half (47%) of the patients with clinical behavioural variant FTD had scans within the normal range. Behavioural cases with normal scans generally had fewer cognitive deficits and milder functional impairment than those with abnormal scans, yet displayed a clinically indistinguishable behavioural syndrome. They were not, however, simply at an earlier stage of the disease. i Conclusions: /i MRI findings should form part of the diagnostic criteria for SD the absence of atrophy on MRI in many behavioural cases raises the prospect that the behavioural syndrome of FTD is not specific for patients with a neurodegenerative disease.
Publisher: Elsevier BV
Date: 11-2006
DOI: 10.1016/J.NEUROBIOLAGING.2005.09.033
Abstract: Inflammation, insoluble protein deposition and neuronal cell loss are important features of the Alzheimer's disease (AD) brain. S100B is associated with the neuropathological hallmarks of AD where it is thought to play a role in neuritic pathology. S100A8, S100A9 and S100A12 comprise a new group of inflammation-associated proteins that are constitutively expressed by neutrophils and inducible in numerous inflammatory cells. We investigated expression of S100B, S100A8, S100A9 and S100A12 in brain s les from sporadic and familial (PS-1) AD cases and controls using immunohistochemistry and Western blot analysis. S100B, S100A9 and S100A12, but not S100A8, were consistently associated with the neuropathological hallmarks of AD. Western blot analysis confirmed significant increases in soluble S100A9 in PS-1 AD compared to controls. S100A9 complexes that were resistant to reduction were also evident in brain extracts. A reactive component of a size consistent with hexameric S100A12 was seen in all cases. This study indicates a potential role for pro-inflammatory S100A9 and S100A12 in pathogenesis caused by inflammation and protein complex formation in AD.
Publisher: Elsevier BV
Date: 06-1997
DOI: 10.1016/S0306-4522(97)00083-3
Abstract: There is some controversy in the literature concerning whether chronic alcohol consumption damages the cerebral cortex. While decreased neuronal density in specific cortical regions is well described in chronic alcoholics, a recent study by Badsberg Jensen and Pakkenberg using unbiased stereological methods questions whether neurodegeneration occurs. In order to assess selective neurodegeneration in the cerebral cortex of chronic alcoholics, regional volumes and unbiased estimates of regional neuronal number (including neuronal identification with calcium-binding proteins) were calculated for 14 chronic alcoholics and 21 controls. Cases were carefully screened to exclude any interfering pathologies. Lifetime and maximum daily alcohol consumption was determined, and homogeneous groups were identified (four chronic alcoholics with Wernicke's encephalopathy and Korsakoff's psychosis, four chronic alcoholics with Wernicke's encephalopathy alone, six chronic alcoholics without Wernicke's encephalopathy or Korsakoff's psychosis, and 21 controls). Brain volume analysis revealed that discrete regions were significantly smaller in the chronic alcoholics compared to controls. As previously shown, white matter regions (particularly in the frontal lobe) were the most significantly reduced in volume. Alcoholics with Wernicke's encephalopathy (either alone or in combination with Korsakoff's psychosis) had significantly smaller white matter volumes than controls or alcoholics without these complications. Medial temporal lobe regions and the thalamus were also reduced in volume. Regression analyses revealed that the volume of both the white matter and thalamus negatively correlated with alcohol consumption. Consistent with the interpretation of previous neuronal density studies, selective neuronal loss was found in the superior frontal association cortex of chronic alcoholics, while no loss occurred from the motor cortex. The number of parvalbumin-, calbindin- and calretinin-immunoreactive neurons was found to be unaltered in chronic alcoholics, suggesting that the neurodegeneration is confined to the non-GABAergic pyramidal neurons. As neurodegeneration was observed in all alcoholic groups, damage to the frontal association cortex is not restricted to alcoholics with the amnesia of Korsakoff's psychosis. These results are consistent with the notion that chronic alcohol consumption is associated with selective neuronal vulnerability. The selective frontal neurodegeneration and the frontal focus of white matter atrophy are supported by neuropsychological, regional blood flow, and magnetic resonance imaging studies of frontal lobe dysfunction in chronic alcoholics and may correlate with abnormalities in working memory.
Publisher: Elsevier
Date: 2001
DOI: 10.1016/S0074-7742(01)48016-0
Abstract: A hypothesis has been presented that links many of the identified and putative risk factors for AD and suggests a mechanism for their action. Crawford (1996, 1998) proposes an association between AD and cerebral blood flow (CBF) by citing evidence that many of the factors that are linked with an increased risk of AD also decrease CBF (e.g., old age, depression, underactivity, head trauma). Similarly, it is suggested factors that increase CBF are associated with a decreased risk of AD (e.g., education, exercise, smoking, NSAIDs). Although the authors acknowledge that reduced CBF is not sufficient to cause AD, the reported positive and negative associations provide tantalizing evidence for a common mode of action for many of the equivocal risk factors reported to date. This hypothesis is also consistent with other data that links microvascular damage and impaired blood flow (de la Torre, 1997, 2000) and low education with increased cerebrovascular disease (Del Ser et al., 1999). Gaining a better understanding of the interaction between AD and vascular disease is of great importance. Not only will it provide insights into the pathogenesis of AD, but it may also provide us with a rare opportunity for the treatment and possible prevention of AD. A great many risk factors for vascular disease have been identified and intervention programs have successfully reduced the incidence of heart disease and stroke. The potential exists to provide the same level of success with AD.
Publisher: Wiley
Date: 04-02-2017
DOI: 10.1111/ACEL.12565
Publisher: Springer Science and Business Media LLC
Date: 18-11-2008
DOI: 10.1007/S00401-008-0458-Z
Abstract: Most cases of Alzheimer's disease (AD) are sporadic in nature, although rarer familial AD (FAD) cases have provided important insights into major pathological disease mechanisms. Mutations in the presenilin 1 gene (PS1) are responsible for the majority of FAD cases, causing an earlier age of onset and more rapid progression to end-stage disease than seen in sporadic AD. We have investigated the cytoskeletal alterations in neuritic AD pathology in a cohort of FAD cases in comparison to sporadic AD and pathologically aged cases. Tau-immunoreactive neurofibrillary tangle (NFT) loads were similar between PS1 FAD and sporadic AD cases. Similarly, plaque loads, both beta-amyloid (Abeta) and thioflavine S, in PS1 FAD and sporadic AD cases were not significantly different however, in pathologically aged cases, they were significantly lower than those in PS1 cases, but were not different from sporadic AD cases. The 'cotton wool' plaque characteristic of PS1 cases did not demonstrate a high density of dystrophic neurites compared to other Abeta plaque types, but did demonstrate a localised mass effect on the neuropil. Despite minimal differences in plaque and NFT loads, immunolabelling demonstrated clear phenotypic differences in the NFTs and dystrophic neurites in PS1 FAD cases. Presenilin-1 cases exhibited significantly (P < 0.05) more tau-positive NFTs that were immunolabelled by the antibody SMI312 (anti-phosphorylated NF protein and phosphorylated tau) than sporadic AD cases. Presenilin-1 cases also exhibited numerous ring-like NF-positive and elongated tau-labelled dystrophic neurites, whereas these dystrophic neurite types were only abundant at the very early (pathologically aged cases) or very late stages of sporadic AD progression, respectively. These differences in cytoskeletal pathology in PS1 cases suggest an accelerated rate of neuritic pathology development, potentially due to mutant PS1 influencing multiple pathogenic pathways.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.BBALIP.2010.05.005
Abstract: The Niemann-Pick type C1 (NPC1) protein mediates the trafficking of cholesterol from lysosomes to other organelles. Mutations in the NPC1 gene lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC disease. Several parallels exist between NPC disease and Alzheimer's disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles, and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not been investigated so far. In the present study, we measured NPC1 mRNA and protein expression in three distinct regions of the human brain, and we revealed that NPC1 expression is upregulated at both mRNA and protein levels in the hippoc us and frontal cortex of AD patients compared to control in iduals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippoc us of 12-month-old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 12-month-old wild type mice, whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippoc us indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP or by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippoc us from AD patients compared to control in iduals, and it is therefore possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 21-10-2008
DOI: 10.1007/S00401-008-0446-3
Abstract: Certain genetic defects in LRRK2 and parkin are pathogenic for Parkinson's disease (PD) and both proteins deposit in the characteristic Lewy bodies. LRRK2 is thought to be involved in the early initiation of Lewy bodies. The involvement of LRRK2 and parkin in the similar cellular deposition of fibrillar alpha-synuclein in glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA) has not yet been assessed. To determine whether LRRK2 and parkin may be similarly associated with the abnormal deposition of alpha-synuclein in MSA GCI, paraffin-embedded sections from the basal ganglia of 12 patients with MSA, 4 with PD and 4 controls were immunostained for LRRK2, parkin, alpha-synuclein and oligodendroglial proteins using triple labelling procedures. The severity of neuronal loss was graded and the proportion of abnormally enlarged oligodendroglia containing different combinations of proteins assessed in 80-100 cells per case. Parkin immunoreactivity was observed in only a small proportion of GCI. In contrast, LRRK2 was found in most of the enlarged oligodendroglia in MSA and colocalised with the majority of alpha-synuclein-immunopositive GCI. Degrading myelin sheaths containing LRRK2-immunoreactivity were also observed, showing an association with one of the earliest oligodendroglial abnormalities observed in MSA. The proportion of LRRK2-immunopositive GCI was negatively associated with an increase in neuronal loss and alpha-synuclein-immunopositive dystrophic axons. Our results indicate that an increase in LRRK2 expression occurs early in association with myelin degradation and GCI formation, and that a reduction in LRRK2 expression in oligodendroglia is associated with increased neuronal loss in MSA.
Publisher: Oxford University Press (OUP)
Date: 11-1993
DOI: 10.1097/00005072-199311000-00003
Abstract: There are several lines of evidence to suggest that serotonergic neurons in the brain are detrimentally affected by chronic alcohol consumption. The present study aims to quantify pathological changes in brainstem regions containing serotonergic neurons in chronic alcoholics compared to age-matched non-alcoholic controls. An antibody specific for tryptophan hydroxylase was used to immunohistochemically demonstrate serotonergic neurons in serial sections of postmortem brainstem. The cases analyzed were ided into four groups on the basis of their clinical and pathological presentation chronic alcoholics with Wernicke's encephalopathy, chronic alcoholics with additional Korsakoff's psychosis, non-alcoholic controls, and a single chronic alcoholic without neurological complications. There was an overall reduction in the number of serotonergic neurons in all alcoholic cases when compared with controls. All brainstem regions were affected, but the largest neuronal loss was found in areas of the medullary and caudal pontine reticular formation (reduced by 80-90%). Alcoholics with Korsakoff's psychosis did not differ in the amount or extent of pathology from the other alcoholic cases analyzed. The data indicate that significant numbers of serotonergic neurons degenerate in chronic alcoholics. Such a loss is likely to have significant clinical consequences.
Publisher: Wiley
Date: 04-1990
Publisher: Wiley
Date: 05-09-2016
DOI: 10.1111/JNC.13752
Abstract: Circular RNAs (circRNAs) have been recently identified as a naturally occurring family of widespread and erse endogenous non-coding RNAs that may regulate gene expression in mammals. They are unusually stable RNA molecules with cell type- or developmental stage-specific expression patterns. However, the role of circRNAs in pathology of complex disease is entirely unknown. Here, we report the specific circular transcriptome in the multiple system atrophy (MSA) brain as determined by RNA sequencing. Five circRNAs, namely IQCK, MAP4K3, EFCAB11, DTNA, and MCTP1, were identified and validated as specifically over-expressed in MSA frontal cortex. The expression levels of linear transcripts were not significantly altered and thus did not follow the pattern of their circular counterparts. Further analysis of expression of five MSA-specific circRNAs revealed their over-expression in the white matter of the MSA cortical tissue. Together, this is the first report describing perturbation of circular transcriptome in α-synucleinopathies.
Publisher: Elsevier BV
Date: 2017
Publisher: Elsevier BV
Date: 03-2016
Publisher: Oxford University Press (OUP)
Date: 07-06-2017
DOI: 10.1093/JNEN/NLX041
Publisher: Wiley
Date: 03-12-2002
DOI: 10.1002/ANA.10071
Abstract: Hippoc al volume and neuron number were measured using stereological techniques in pathologically confirmed dementia with Lewy bodies (n = 8), Parkinson's disease only (n = 4), and controls (n = 9). We, and others, have previously shown considerable cell loss in the CA1 and subiculum subregions in Alzheimer's disease. In contrast, these regions were spared in dementia with Lewy bodies where a selective loss of lower presubiculum pyramidal neurons was found. These findings suggest a selective loss of frontally projecting hippoc al neurons in dementia with Lewy bodies versus those projecting to temporal lobe regions in Alzheimer's disease.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2002
DOI: 10.1007/S00401-002-0529-5
Abstract: The aim of this study was to assess the variation between neuropathologists in the diagnosis of common dementia syndromes when multiple published protocols are applied. Fourteen out of 18 Australian neuropathologists participated in diagnosing 20 cases (16 cases of dementia, 4 age-matched controls) using consensus diagnostic methods. Diagnostic criteria, clinical synopses and slides from multiple brain regions were sent to participants who were asked for case diagnoses. Diagnostic sensitivity, specificity, predictive value, accuracy and variability were determined using percentage agreement and kappa statistics. Using CERAD criteria, there was a high inter-rater agreement for cases with probable and definite Alzheimer's disease but low agreement for cases with possible Alzheimer's disease. Braak staging and the application of criteria for dementia with Lewy bodies also resulted in high inter-rater agreement. There was poor agreement for the diagnosis of frontotemporal dementia and for identifying small vessel disease. Participants rarely diagnosed more than one disease in any case. To improve efficiency when applying multiple diagnostic criteria, several simplifications were proposed and tested on 5 of the original 20 cases. Inter-rater reliability for the diagnosis of Alzheimer's disease and dementia with Lewy bodies significantly improved. Further development of simple and accurate methods to identify small vessel lesions and diagnose frontotemporal dementia is warranted.
Publisher: Wiley
Date: 10-06-2009
Publisher: Wiley
Date: 28-12-2008
DOI: 10.1002/MDS.21907
Abstract: Progressive supranuclear palsy (PSP) and Parkinson's disease (PD) differ in their response to dopaminergic replacement therapies, despite having a similar degree of neuronal degeneration in the dopaminergic substantia nigra. We observed more widespread dopamine neuron loss in the extranigral A10 midbrain cell groups in PSP compared with PD. These cell groups innervate subcortical and cortical regions and may be required for adequate response to levodopa therapy.
Publisher: Oxford University Press (OUP)
Date: 29-09-2006
DOI: 10.1093/BRAIN/AWL289
Abstract: Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.
Publisher: Wiley
Date: 22-08-2014
DOI: 10.1002/MDS.26004
Abstract: One of the most challenging tasks in neuroscience is to be able to meaningfully connect information across the different levels of investigation, from molecular or structural biology to the resulting behavior and cognition. Visual hallucinations are a frequent occurrence in Parkinson's disease and significantly contribute to the burden of the disease. Because of the widespread pathological processes implicated in visual hallucinations in Parkinson's disease, a final common mechanism that explains their manifestation will require an integrative approach, in which consideration is taken across all complementary levels of analysis. This review considers the leading hypothetical frameworks for visual hallucinations in Parkinson's disease, summarizing the key aspects of each in an attempt to highlight the aspects of the condition that such a unifying hypothesis must explain. These competing hypotheses include implications of dream imagery intrusion, deficits in reality monitoring, and impairments in visual perception and attention.
Publisher: Wiley
Date: 22-08-2014
DOI: 10.1002/MDS.26000
Publisher: Wiley
Date: 07-07-2006
DOI: 10.1111/J.1365-2990.2006.00736.X
Abstract: In order to gain insight into the pathogenesis of frontotemporal lobar degeneration (FTLD), the mean tau load in frontal cortex was compared in 34 patients with frontotemporal dementia linked to chromosome 17 (FTDP-17) with 12 different mutations in the tau gene (MAPT), 11 patients with sporadic FTLD with Pick bodies and 25 patients with early onset Alzheimer's disease (EOAD). Tau load was determined, as percentage of tissue occupied by stained product, by image analysis of immunohistochemically stained sections using the phospho-dependent antibodies AT8, AT100 and AT180. With AT8 and AT180 antibodies, the amount of tau was significantly (P < 0.001 in each instance) less than that in EOAD for both FTDP-17 (8.5% and 10.0% respectively) and sporadic FTLD with Pick bodies (16.1% and 10.0% respectively). With AT100, the amount of tau detected in FTDP-17 was 54% (P < 0.001) of that detected in EOAD, but no tau was detected in sporadic FTLD with Pick bodies using this particular antibody. The amount of insoluble tau deposited within the brain in FTDP-17 did not depend in any systematic way upon where the MAPT mutation was topographically located within the gene, or on the physiological or structural change generated by the mutation, regardless of which anti-tau antibody was used. Not only does the amount of tau deposited in the brain differ between the three disorders, but the pattern of phosphorylation of tau also varies according to disease. These findings raise important questions relating to the role of aggregated tau in neurodegeneration - whether this represents an adaptive response which promotes the survival of neurones, or whether it is a detrimental change that directly, or indirectly, brings about the demize of the affected cell.
Publisher: Oxford University Press (OUP)
Date: 15-10-2019
DOI: 10.1093/BRAIN/AWZ311
Abstract: Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson’s disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.
Publisher: Elsevier BV
Date: 03-1997
DOI: 10.1016/S0306-4522(96)00569-6
Abstract: Cortical atrophy and cell loss in the cholinergic nucleus basalis is a well-established characteristic of Alzheimer's disease however, previous studies not have analysed cholinergic cell loss and cortical atrophy in concert. In autopsy brains from eight patients with Alzheimer's disease and 12 control subjects, the numbers of nucleus basalis neurons were determined from 50-microm serial Nissl-stained sections. Volumes of the cerebrum, cortical gray matter (total, lobar and subregional), white matter and deep gray structures were computed by point counting on black and white photographs of gapless 3-mm coronal slices of formalin-fixed brains. Cell loss in the nucleus basalis was found to range between 89% and 42% in Alzheimer's disease compared with controls. White matter volume was unchanged in absolute terms in Alzheimer's disease patients compared with controls, while cortical volume was significantly reduced. Gray matter atrophy was most prominent in temporal and frontal cortices. A highly significant linear relationship was found between cortical volume and nucleus basalis cell number in controls and Alzheimer's disease patients, with values for both groups on a single regression line. Whole brain and cerebral volumes were also highly correlated to nucleus basalis cell numbers in both groups. A quantitative analysis of plaque and tangle burden in cortical target areas of the nucleus basalis was performed. In contrast to the relationship with cortical volume, nucleus basalis cell number and neurofibrillary tangle number were not significantly correlated to the density of cortical histopathology. These results suggest that the volume of cortical gray matter is coupled to the number of nucleus basalis neurons. Compromised viability of nucleus basalis neurons may precede cortical volume loss as large numbers of neurofibrillary tangles, detected with nickel peroxidase staining, were found in this nucleus in all Alzheimer's disease cases, including those with minimal cell loss.
Publisher: Informa UK Limited
Date: 15-05-2014
DOI: 10.4161/AUTO.29074
Publisher: Springer Science and Business Media LLC
Date: 26-02-2008
Publisher: SAGE Publications
Date: 05-08-2004
Abstract: The diagnosis of Parkinson’s disease with dementia (PDD) or dementia with Lewy bodies (DLB) is based on an arbitary distinction between the time of onset of motor and cognitive symptoms. These syndromes share many neurobiological similarities, but there are also differences. Deposition of beta-amyloid protein is more marked and more closely related to cognitive impairment in DLB than PDD, possibly contributing to dementia at onset. The relatively more severe executive impairment in DLB than PDD may relate to the loss of frontohippoc al projections in DLB. Visual hallucinations and delusions associate with more abundant Lewy body pathology in temporal cortex in DLB. The differential involvement of pathology in the striatum may account for the differences in parkinsonism. Longitudinal studies with neuropathological and neurochemical evaluations will be essential to enable more robust comparisons and determine pathological substrates contributing to the differences in cognitive, motor, and psychiatric symptoms. ( J Geriatr Psychiatry Neurol 2004 17:137-145)
Publisher: Wiley
Date: 25-08-2018
DOI: 10.1002/MDS.27362
Abstract: In 2015, the International Parkinson and Movement Disorder Society published clinical diagnostic criteria for Parkinson's disease. These criteria aimed to codify/reproduce the expert clinical diagnostic process and to help standardize diagnosis in research and clinical settings. Their accuracy compared with expert clinical diagnosis has not been tested. The objectives of this study were to validate the International Parkinson and Movement Disorder Society diagnostic criteria against a gold standard of expert clinical diagnosis, and to compare concordance/accuracy of the International Parkinson and Movement Disorder Society criteria to 1988 United Kingdom Brain Bank criteria. From 8 centers, we recruited 626 parkinsonism patients (434 PD, 192 non-PD). An expert neurologist diagnosed each patient as having PD or non-PD, regardless of International Parkinson and Movement Disorder Society criteria (gold standard, clinical diagnosis). Then a second neurologist evaluated the presence/absence of each in idual item from the International Parkinson and Movement Disorder Society criteria. The overall accuracy/concordance rate, sensitivity, and specificity of the International Parkinson and Movement Disorder Society criteria compared with the expert gold standard were calculated. Of 434 patients diagnosed with PD, 94.5% met the International Parkinson and Movement Disorder Society criteria for probable PD (5.5% false-negative rate). Of 192 non-PD patients, 88.5% were identified as non-PD by the criteria (11.5% false-positive rate). The overall accuracy for probable PD was 92.6%. In addition, 59.3% of PD patients and only 1.6% of non-PD patients met the International Parkinson and Movement Disorder Society criteria for clinically established PD. In comparison, United Kingdom Brain Bank criteria had lower sensitivity (89.2%, P = 0.008), specificity (79.2%, P = 0.018), and overall accuracy (86.4%, P < 0.001). Diagnostic accuracy did not differ according to age or sex. Specificity improved as disease duration increased. The International Parkinson and Movement Disorder Society criteria demonstrated high sensitivity and specificity compared with the gold standard, expert diagnosis, with sensitivity and specificity both higher than United Kingdom Brain Bank criteria. © 2018 International Parkinson and Movement Disorder Society.
Publisher: American Medical Association (AMA)
Date: 11-2006
DOI: 10.1001/ARCHNEUR.63.11.1627
Abstract: To assess the clinical course and prognosis in patients with behavioral-variant frontotemporal dementia (FTD) lacking evidence of brain atrophy on magnetic resonance imaging (MRI). Patients were enrolled into this prospective cohort study over a period of 15 years cognitive status, duration of symptoms, and behavioral indexes were recorded. Brain MRIs were rated using a standardized scale. Regional early-onset dementia clinic. Thirty-one participants diagnosed clinically with behavioral-variant FTD. Intervention Rating of MRIs. Death or institutionalization after a minimum of 3 years' follow-up indicated poor prognosis, while the ability to live independently was regarded as a good prognosis for the purpose of survival (Kaplan-Meier) and discriminant function analysis. Patients with normal or borderline MRI findings (n = 15) showed significantly longer survival to institutionalization or death than those (n = 16) with definite frontotemporal atrophy (mean +/- SE, 9.3 +/- 1.7 years vs 3.0 +/- 0.7 years P<.01). Using groups defined by 3-year outcome (good or bad prognosis), cerebral atrophy predicted poor outcome while age, symptom duration, cognitive performance, behavioral impairment, and overall disability at baseline did not. Patients with FTD with normal MRI results follow a more benign course than cases with atrophy at presentation. The substrate of the behavioral symptoms in such cases may differ from the neurodegenerative pathological features typically associated with FTD.
Publisher: Wiley
Date: 13-05-2010
DOI: 10.1111/J.1365-2990.2010.01067.X
Abstract: To determine the pathological structures associated with macroautophagy in Alzheimer's disease (AD) and any relationship to disease progression. Immunohistochemistry using antibodies to beclin-1, Atg5 and Atg12, early macroautophagy markers and LC3, the mammalian homologue of the later macroautophagy marker Atg8, were localized in formalin-fixed, paraffin-embedded medial temporal lobe sections of AD cases at variable neuritic disease stages. Double immunofluorescence labelling was used to co-localize these macroautophagy markers with Abeta and phospho-tau (AT8) and correlations performed using Spearman rank tests. Atg12 immunoreactivity in AD was either dispersed in the soma and dendrites or concentrated in tau-immunoreactive dystrophic neurites and some neurofibrillary tangles. Fewer Atg12-immunopositive neurones were observed with longer disease durations. Atg12-immunoreactive endothelial cells were found spatially associated with Abeta-positive plaques, with more Atg12-immunoreactive capillary endothelial cells with higher neuritic disease stage. These findings were confirmed by the other autophagy markers beclin-1, Atg5 and LC3. The data confirm that macroautophagy occurs in neurones undergoing neuritic degeneration in AD, identified early macroautophagy markers in capillary endothelial cells in close proximity to Abeta plaques, and found that evidence for macroautophagy changes with disease progression.
Publisher: Springer Science and Business Media LLC
Date: 13-07-2021
Publisher: Public Library of Science (PLoS)
Date: 24-01-2014
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-08-2023
DOI: 10.1126/SCITRANSLMED.ABO1557
Abstract: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region–specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNA DX ) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 ( LRRK2 ) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non–disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient–derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNA DX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.
Publisher: Elsevier BV
Date: 10-1988
DOI: 10.1016/0361-9230(88)90206-7
Abstract: The distribution and morphology of the substance P-like immunoreactive (SP-IR) fibres and terminals in the rat ventromedial mesencephalic tegmentum (VMT) were studied using qualitative and quantitative immunohistochemical methods at light and electron microscopic levels. All five component nuclei of the VMT were examined and the size, number and density of immunoreactive terminals determined. The SP-IR fibres were distributed heterogeneously within the VMT. Under the electron microscope, SP-IR axon terminals contained both clear and dense-cored vesicles and made both symmetrical and asymmetrical synapses. The ultrastructure of the SP-IR terminals appeared to differ between nuclei. Small, clear vesicle terminals made symmetrical synaptic junctions with small calibre dendrites in the paranigral nucleus while large, clear and dense-cored vesicle terminals made asymmetrical junctions with somata and large calibre dendrites in the interfascicular nucleus. Quantitative differences between the VMT nuclei were also seen in the density of SP-IR terminals, the paranigral nucleus contained the highest density and the rostral linear nucleus the lowest. A comparison between the number of SP-IR terminals and the total number of axon terminals in the VMT reveals that the majority of all terminals in the paranigral nucleus were SP-IR, as well as the majority of axosomatic synapses in the interfascicular nucleus. These regional differences in the SP-IR innervation suggest that substance P and related peptides may perform several specific functions within the VMT and therefore have a more variable influence on this region than was previously thought.
Publisher: Elsevier BV
Date: 11-2021
DOI: 10.1016/J.NEUROBIOLAGING.2021.07.004
Abstract: Clinical and pathological heterogeneity is common in patients with frontotemporal lobar degeneration (FTLD) pathology. This investigated clinical or imaging characteristics that differentiate FTLD-TDP from FTLD-tau, FTLD-TDP subtypes from each other, or pathological stages of FTLD-TDP. Initial clinical, neuropsychological and neuroimaging characteristics were compared between pathologically defined FTLD-tau and FTLD-TDP groups. Voxel-based morphometry analyses contrasted grey matter atrophy patterns. Twenty-six FTLD-TDP, 28 FTLD-tau and 78 controls were included. Amyotrophic lateral sclerosis features, when present, were highly specific FTLD-TDP, which displayed greater cortical and subcortical atrophy than FTLD-tau. FTLD-TDP-43 type B had significantly shorter survival than type A. Type A patients were more cognitively impaired than type B, and basal ganglia atrophy appeared to distinguish type A from type B. Age at onset and survival duration were comparable between stages II and IV. In conclusion, Amyotrophic lateral sclerosis features may be useful in distinguishing FTLD-TDP from FTLD-tau. TDP-43 type A and B appear to present with distinct profiles. The relationship between clinical features and pathological staging in FTLD-TDP-43 is complex, and TDP-43 subtyping may have more clinical utility.
Publisher: American Chemical Society (ACS)
Date: 21-12-2020
DOI: 10.26434/CHEMRXIV.13415918
Abstract: We developed a methodological workflow combining size exclusion chromatography, native isoelectric focusing, and high sensitivity X-ray-based metal detection within electrophoresis gels to analyze the metal content of single proteins purified from minimal amounts ( mg) of post-mortem human brain and spinal cord tissue. An important metalloprotein in the human central nervous system is copper-zinc superoxide dismutase (SOD1), an antioxidant enzyme linked to the aetiology of both amyotrophic lateral sclerosis and Parkinson’s disease. Abnormal SOD1 metallation is suspected to play a role in the pathogenic aggregation of SOD1 in both disorders, although data describing SOD1 metal occupancy in human tissues has not previously been reported. Validating our novel approach we demonstrated step-by-step metal preservation, preserved SOD1 activity, and substantial enrichment of SOD1 protein vs confounding metalloproteins. We found Cu and Zn were bound to SOD1 in a ratio of 1.12 ± 0.28 in human central nervous system tissues from healthy in iduals, a ratio close to the expected value of 1. Our methodological workflow can be adapted to study a range of metalloproteins from human tissues and other sources. br
Publisher: Springer Science and Business Media LLC
Date: 07-2021
Publisher: Wiley
Date: 16-05-2017
DOI: 10.1111/ENE.13314
Abstract: To determine the clinical utility of the midbrain-to-pons (M/P) ratio as a clinical biomarker of progressive supranuclear palsy (PSP) in patients with non-fluent primary progressive aphasia syndromes. Patients with PSP, progressive non-fluent aphasia (PNFA) and logopenic progressive aphasia (LPA) were recruited. Patients were diagnosed clinically, but pathological confirmation was available in a proportion of patients. Midbrain and pons areas were measured using Osirix Lite, a free DICOM viewer. The M/P ratio and Magnetic Resonance Parkinsonism Index were calculated and their diagnostic utility compared. A total of 72 participants were included (16 PSP, 18 PNFA, 16 LPA and 22 controls). Patients with PSP had motor features typical of the syndrome. Both the M/P ratio and Magnetic Resonance Parkinsonism Index differed significantly in PSP compared with controls. The M/P ratio was disproportionately reduced in PSP compared with PNFA and LPA (PSP, 0.182 ± 0.043 PNFA, 0.255 ± 0.034 LPA, 0.258 ± 0.033 controls, 0.292 ± 0.031 P < 0.001). An M/P ratio of ≤0.215 produced a positive predictive value of 77.8% for the diagnosis of PSP syndrome. Pathological examination revealed Alzheimer's disease in three cases (all LPA), pathological PSP in two cases (one clinical PSP and one PNFA) and corticobasal degeneration in one case (PNFA). The M/P ratio was ≤0.215 in both pathological cases of PSP. The M/P ratio was disproportionately reduced in PSP, suggesting its potential as a clinical marker of the PSP syndrome. Larger studies of pathologically confirmed cases are needed to establish the M/P ratio as a biomarker of PSP pathology.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2010
DOI: 10.1007/S00401-010-0657-2
Abstract: We have investigated alterations in myelin associated with Abeta plaques, a major pathological hallmark of Alzheimer's disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Abeta pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Abeta plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Abeta plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation.
Publisher: Elsevier BV
Date: 02-2003
Publisher: Springer Science and Business Media LLC
Date: 11-04-2006
DOI: 10.1007/S00702-006-0449-Y
Abstract: Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. Here we describe the age-related development and regulation of neuromelanin within these dopamine neurons. 10 microm sections from formalin-fixed midbrain from 29 people spanning the ages of 24 weeks to 95 years old were either stained with a basic Nissl substance stain (0.5% cresyl violet), or processed unstained. After locating the substantia nigra using the stained sections, digital photos were taken of in idual ventral substantia nigra neurons in the unstained sections, and the cellular area occupied by pigment, and optical density were measured using computer software. These measurements demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.
Publisher: BMJ
Date: 06-2002
Abstract: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippoc al formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippoc al volume and CA1 neurone number. Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippoc al formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippoc al atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2016
Publisher: Wiley
Date: 16-01-2015
DOI: 10.1002/MDS.26141
Abstract: Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α-synuclein-positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone-mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal-associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD-related increases in α-synuclein in autopsy s les from subjects in the early pathological stage of PD (n = 9), compared to age- and postmortem delay-matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α-synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD s les, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α-synuclein, and suggests that dysregulation of CMA-mediated protein degradation occurs before substantial α-synuclein aggregation in PD.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2004
DOI: 10.1007/S00401-004-0917-0
Abstract: Frontotemporal dementia (FTD) is a prevalent neurodegenerative disease of heterogeneous histopathology. Neuropathological subtypes are identified on the basis of the presence or absence of tau- or ubiquitin-positive neuronal inclusions. Our recent work has established four disease stages that are independent of neuropathological subtype and reflect the clinical and degenerative progression observed in FTD. The variability in the extent of neuronal loss, astrogliosis, and microvacuolation are, therefore, more likely to reflect disease stage with potentially predictable differences between cases at early versus late disease stages. Understanding the variability in these parameters may assist in determining the importance of erse disease subtypes in FTD. We examined 21 cases of sporadic, behavioural variant FTD and quantified the progression of histopathological change. The neuropathology of early disease was marked by severe astrogliosis of both the frontal and temporal cortices and neuronal loss, which was more evident in upper cortical layers of the frontal lobe. In late disease, neuronal loss was evident from both layer III and V in frontal and temporal cortices, and particularly the CA1 sector of the hippoc us. In addition, we compared the neuropathology of Pick's disease, dementia lacking distinctive histopathology and FTD with motor neuron disease, and found no difference in these pathological subtypes on the basis of neuronal loss, astrogliosis or microvacuolation. These results show that the earliest cellular changes in FTD occur in glia, and that disease stage rather than FTD subtype determines the pattern and extent of neuronal degeneration.
Publisher: Springer Science and Business Media LLC
Date: 07-02-2014
Publisher: Wiley
Date: 09-2017
DOI: 10.1002/MDS.27115
Publisher: Springer Science and Business Media LLC
Date: 27-08-2015
Abstract: The concept of differing clinical phenotypes within Parkinson’s disease (PD) is well represented in the literature. However, there is no consensus as to whether any particular disease phenotype is associated with an increased risk of mild cognitive impairment (MCI) using the newly proposed Movement Disorders Society diagnostic criteria for this feature. To explore the expression of PD-MCI in relation to the heterogeneity of idiopathic PD. A cluster analysis incorporating a range of specific demographic, clinical and cognitive variables was performed on 209 patients in the early stages of PD (between Hoehn and Yahr stages I–III). Post hoc analyses exploring variables not included in the clustering solution were performed to interrogate the veracity of the subgroups generated. This study identified four distinct PD cohorts: a younger disease-onset subgroup, a tremor dominant subgroup, a non-tremor dominant subgroup, and a subgroup with rapid disease progression. The present study identified a differential expression of PD-MCI across these subgroups, with the highest frequency observed in the non-tremor dominant cluster. The non-tremor dominant subgroup was also associated with a higher prevalence of freezing of gait, hallucinations, daytime somnolence, and rapid eye movement sleep behavior disorder compared with other subgroups. This study confirms the existence of heterogeneity within the early clinical stages of PD and for the first time highlights the differential expression of PD-MCI using the newly defined diagnostic criteria for this feature. An improved understanding of PD-MCI and its clinical relationships may lead to an improved understanding of the pathophysiology underlying heterogeneity in PD.
Publisher: Springer Science and Business Media LLC
Date: 02-09-2022
DOI: 10.1007/S00401-022-02488-3
Abstract: Parkinson’s disease (PD) is a movement disorder characterized by the early loss of nigrostriatal dopaminergic pathways producing significant network changes impacting motor coordination. Recently three motor stages of PD have been proposed (a silent period when nigrostriatal loss begins, a prodromal motor period with subtle focal manifestations, and clinical PD) with evidence that motor cortex abnormalities occur to produce clinical PD[8]. We directly assess structural changes in the primary motor cortex and corticospinal tract using parallel analyses of longitudinal clinical and cross-sectional pathological cohorts thought to represent different stages of PD. 18F-FP-CIT positron emission tomography and subtle motor features identified patients with idiopathic rapid-eye-movement sleep behaviour disorder ( n = 8) that developed prodromal motor signs of PD. Longitudinal diffusion tensor imaging before and after the development of prodromal motor PD showed higher fractional anisotropy in motor cortex and corticospinal tract compared to controls, indicating adaptive structural changes in motor networks in concert with nigrostriatal dopamine loss. Histological analyses of the white matter underlying the motor cortex showed progressive disorientation of axons with segmental replacement of neurofilaments with α-synuclein, enlargement of myelinating oligodendrocytes and increased density of their precursors. There was no loss of neurons in the motor cortex in early or late pathologically confirmed motor PD compared to controls, although there were early cortical increases in neuronal neurofilament light chain and myelin proteins in association with α-synuclein accumulation. Our results collectively provide evidence of a direct impact of PD on primary motor cortex and its output pathways that begins in the prodromal motor stage of PD with structural changes confirmed in early PD. These adaptive structural changes become considerable as the disease advances potentially contributing to motor PD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-08-2012
Publisher: Portland Press Ltd.
Date: 31-05-2013
DOI: 10.1042/BJ20121764
Abstract: Members of the ABCA (ATP-binding cassette subfamily A) family are characterized by their ability to transport lipids across cellular membranes and regulate lipid homoeostasis in the brain and peripheral tissues. ABCA8 is a little-known member of this subfamily that was originally cloned from human brain libraries and has no known function. In an effort to elucidate the role of ABCA8 in the brain we first undertook a comprehensive analysis of its expression in the human brain. ABCA8 was differentially expressed in multiple regions of adult human brains with significantly higher expression in oligodendrocyte-enriched white matter regions compared with grey matter cortical regions. We then assessed the impact of ABCA8 on sphingomyelin production in oligodendrocyte and showed that ABCA8 was able to significantly stimulate both sphingomyelin synthase 1 expression and sphingomyelin production. Furthermore, ABCA8 expression in the prefrontal cortex across the human life span correlated strongly with age-associated myelination, and the myelinating gene p25α was significantly up-regulated with ABCA8. The present study represents the first extensive expression and functional study of ABCA8 in the human brain and the results strongly suggest that ABCA8 regulates lipid metabolism in oligodendrocytes and potentially plays a role in myelin formation and maintenance.
Publisher: Wiley
Date: 16-03-2015
DOI: 10.1002/MDC3.12139
Abstract: People diagnosed with Parkinson's disease (PD) frequently experience visual and non‐visual hallucinations often with comorbid psychosis, however, there is currently no gold standard tool for accurately assessing these symptoms. To address this problem, we designed a novel questionnaire to evaluate the presence of hallucinatory and psychotic symptoms in PD, as well as related symptoms, such as attentional dysfunction and sleep disturbance. We administered the 20‐item Psychosis and Hallucinations Questionnaire (PsycH‐Q) and three common questionnaire measures in a large cohort of 197 patients with idiopathic PD via a postal survey. We established concurrent validity, convergent validity, and internal consistency of the questionnaire and then assessed test‐retest reliability in a subcohort of 44 patients. PsycH‐Q was found to be a valid instrument when analogous items were compared across three other existing tools (Spearman's rho range: 0.34–0.64 P 0.01). PsycH‐Q demonstrated a strong relationship between self‐reported hallucinations and psychosis and symptoms of the broader hallucinatory phenotype (Kendall's tau = 0.41 P 0.01 positive predictive value = 0.97). PsycH‐Q also displayed a high level of internal consistency (Cronbach's alpha = 0.900 range, 0.696–0.923) and reproducibility (intraclass correlation coefficient = 0.928). PsycH‐Q is a simple, valid, self‐completed instrument that reliably identifies hallucinations and psychosis in PD and has the ability to characterize related patterns of attentional and sleep impairments. As such, PsycH‐Q is a highly valuable tool for use in both clinical and research settings.
Publisher: Wiley
Date: 02-1996
Publisher: Elsevier BV
Date: 09-1993
DOI: 10.1016/0304-3940(93)90923-9
Abstract: The topography of parvalbumin-immunoreactive neurons within the ventrolateral medulla of rats was investigated. Parvalbumin is a member of the 'EF-hand' family of Ca-binding proteins and is present in certain cell types within the central nervous system (fast-firing neurons with high metabolic rates). Parvalbumin-immunoreactive neurons were located in discrete rostrocaudal isions of the ambiguus complex corresponding to regions containing respiratory-related neurons. Based on the location of physiologically characterized respiratory-related neurons reported in the literature, parvalbumin immunoreactivity does not appear to distinguish inspiratory- from expiratory-related neurons.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.NEUROBIOLAGING.2008.02.005
Abstract: Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD-MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD-MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD-MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD-MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions.
Publisher: Wiley
Date: 24-04-2008
DOI: 10.1002/MDS.21956
Abstract: After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the erse features of advanced PD that go far beyond a lack of dopamine.
Publisher: Wiley
Date: 12-09-2005
DOI: 10.1111/J.1471-4159.2005.03404.X
Abstract: We investigated the effects of neuromelanin (NM) isolated from the human substantia nigra and synthetic dopamine melanin (DAM) on neuronal and glial cell lines and on primary rat mesencephalic cultures. Lactate dehydrogenase (LDH) activity and lipid peroxidation were significantly increased in SK-N-SH cells by DAM but not by NM. In contrast, iron-saturated NM significantly increased LDH activity in SK-N-SH cells, compared with 100 mg/mL ETDA-treated NM containing a low concentration of bound iron. DAM, but not NM, stimulated hydroxyl radical production and increased SK-N-SH cell death via apoptotic-like mechanisms. Neither DAM nor NM induced any changes in the glial cell line U373. 3H-dopamine uptake in primary rat mesencephalic cultures was significantly reduced in DAM-compared with NM-treated cultures, accompanied by increased cell death via an apoptosis-like mechanism. Interestingly, Fenton-induced cell death was significantly decreased in cultures treated with both Fenton reagent and NM, an effect not seen in cultures treated with Fenton reagent plus DAM. These data are suggestive of a protective role for neuromelanin under conditions of high oxidative load. Our findings provide new evidence for a physiological role for neuromelanin in vivo and highlights the caution with which data based upon model systems should be interpreted.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2008
Abstract: Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND. Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing. Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected in iduals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one in idual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree. Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.
Publisher: Springer Science and Business Media LLC
Date: 09-05-2013
Abstract: ATP13A2 ( PARK9 ) loss of function mutations are a genetic cause of an early-onset form of Parkinson’s disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced ergent results mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies. To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies. In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition. Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.
Publisher: Springer Science and Business Media LLC
Date: 10-2014
Publisher: BMJ
Date: 09-11-2013
Publisher: Wiley
Date: 11-06-2020
DOI: 10.1002/MDS.28114
Publisher: Elsevier BV
Date: 03-2002
Publisher: Cold Spring Harbor Laboratory
Date: 10-2021
DOI: 10.1101/2021.09.27.21263187
Abstract: Short-tandem repeat (STR) expansions are an important class of pathogenic genetic variants. Over forty neurological and neuromuscular diseases are caused by STR expansions, with 37 different genes implicated to date. Here we describe the use of programmable targeted long-read sequencing with Oxford Nanopore’s ReadUntil function for parallel genotyping of all known neuropathogenic STRs in a single, simple assay. Our approach enables accurate, haplotype-resolved assembly and DNA methylation profiling of expanded and non-expanded STR sites. In doing so, the assay correctly diagnoses all in iduals in a cohort of patients ( n = 27) with various neurogenetic diseases, including Huntington’s disease, fragile X syndrome and cerebellar ataxia (CANVAS) and others. Targeted long-read sequencing solves large and complex STR expansions that confound established molecular tests and short-read sequencing, and identifies non-canonical STR motif conformations and internal sequence interruptions. Even in our relatively small cohort, we observe a wide ersity of STR alleles of known and unknown pathogenicity, suggesting that long-read sequencing will redefine the genetic landscape of STR expansion disorders. Finally, we show how the flexible inclusion of pharmacogenomics (PGx) genes as secondary ReadUntil targets can identify clinically actionable PGx genotypes to further inform patient care, at no extra cost. Our study addresses the need for improved techniques for genetic diagnosis of STR expansion disorders and illustrates the broad utility of programmable long-read sequencing for clinical genomics. This study describes the development and validation of a programmable targeted nanopore sequencing assay for parallel genetic diagnosis of all known pathogenic short-tandem repeats (STRs) in a single, simple test.
Publisher: Wiley
Date: 28-10-2010
DOI: 10.1002/ANA.22274
Abstract: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected in iduals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected in iduals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.
Publisher: Wiley
Date: 04-01-2006
DOI: 10.1111/J.1365-2990.2005.00704.X
Abstract: Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.
Publisher: Elsevier BV
Date: 05-1992
DOI: 10.1016/0165-1838(92)90232-6
Abstract: The rostral ventrolateral medulla (RVLM) contains sympathoexcitatory neurons that exert a powerful control over the sympathetic outflow to the cardiovascular system. In the cat there is a concentration of such neurons (but not neurons subserving other functions) within a narrow longitudinal column in the RVLM termed the subretrofacial (SRF) nucleus. Furthermore, it has been suggested that there are subgroups of cells, located at different rostrocaudal levels of the SRF nucleus, that preferentially or exclusively control different vascular beds (e.g. in the kidney and hindlimb). The aim of this study was to map quantitatively the rostrocaudal distribution within the nucleus of different cell types, defined according to morphological and/or chemical criteria, and to correlate this with the regional vasomotor effects (in hindlimb and kidney) evoked by stimulation of SRF cells at the corresponding rostrocaudal levels. SRF cells were highly heterogeneous with respect to both their morphology and chemical properties. They varied greatly in size (equivalent diameter ranging from 10-40 microns) as well as in shape and orientation. An immunohistochemical examination using the avidin-biotin procedure revealed that many SRF cells (estimated 57% of all SRF cells) were immunoreactive for tyrosine hydroxylase (TH, a marker of catecholamine cells). In addition, there were SRF cells immunoreactive for neuropeptide Y (NPY, 11% of total), enkephalin (ENK, 16% of total), and serotonin (5HT, 10% of total), but not for substance P, galanin or somatostatin. Different cell types, defined according to their morphology and/or chemical properties, were unevenly distributed throughout the nucleus. In the most caudal part of the SRF nucleus, virtually all cells were TH-positive, and the large majority (estimated 80%) were NPY-positive, suggesting that many cells at this level contained both TH and NPY. In contrast, in the most rostral part of the SRF nucleus, only 30% of cells were TH-positive, and no NPY-positive cells were observed. Both 5HT- and ENK-positive cells were found throughout the rostrocaudal extent of the nucleus, but predominantly within its rostral part. Furthermore, TH-positive cells in the rostral SRF nucleus were on average significantly larger (mean equivalent diameter 18-43% greater) than TH/NPY-positive cells in the caudal part of the nucleus, but smaller than 5HT- or ENK-positive cells at the same level. Overall, rostral cells (regardless of their chemical type) were larger than caudal cells within the SRF nucleus (mean equivalent diameter 13-28% greater).(ABSTRACT TRUNCATED AT 400 WORDS)
Publisher: Wiley
Date: 2009
Publisher: Elsevier BV
Date: 2005
DOI: 10.1016/J.NEUROSCIENCE.2004.11.043
Abstract: DCC (deleted in colorectal cancer)-the receptor of the netrin-1 neuronal guidance factor-is expressed and is active in the central nervous system (CNS) during development, but is down-regulated during maturation. The substantia nigra contains the highest level of netrin-1 mRNA in the adult rodent brain, and corresponding mRNA for DCC has also been detected in this region but has not been localized to any particular neuron type. In this study, an antibody raised against DCC was used to determine if the protein was expressed by adult dopamine neurons, and identify their distribution and projections. Significant DCC-immunoreactivity was detected in midbrain, where it was localized to ventrally displaced A9 dopamine neurons in the substantia nigra, and ventromedial A10 dopamine neurons predominantly situated in and around the interfascicular nucleus. Strong immunoreactivity was not detected in dopamine neurons found elsewhere, or in non-dopamine-containing neurons in the midbrain. Terminal fields selectively labeled with DCC antibody corresponded to known nigrostriatal projections to the dorsolateral striatal patches and dorsomedial shell of the accumbens, and were also detected in prefrontal cortex, septum, lateral habenular and ventral pallidum. The unique distribution of DCC-immunoreactivity in adult ventral midbrain dopamine neurons suggests that netrin-1/DCC signaling could function in plasticity and remodeling previously identified in dopamine projection pathways. In particular, a recent report that DCC is regulated through the ubiquitin-proteosome system via Siah/Sina proteins, is consistent with a potential involvement in genetic and sporadic forms of Parkinson's disease.
Publisher: Elsevier BV
Date: 06-1999
DOI: 10.1016/S0306-4522(98)90664-9
Abstract: This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.
Publisher: Informa UK Limited
Date: 05-2006
DOI: 10.1080/13554790500502918
Abstract: BVR was 77 years old when he sustained a large posterior cerebral artery territory infarct. Medical, cognitive and functional data collected on four occasions over 10 years initially revealed circumscribed neurological signs, no functional or cognitive deficits. BVR became significantly impaired only after two other strokes, 3 years before death. On brain MRI, the lesions involved large portions of the right occipital and temporal cortices, the right thalamus, and the left cerebellum, as well as thinning of the corpus callosum. Postmortem investigations revealed additional recent vascular lesions in the occipital region. This case study underscores the importance of comprehensive assessment methods combining neurological, neuroimaging and cognitive tools.
Publisher: Public Library of Science (PLoS)
Date: 10-08-2016
Publisher: BMJ
Date: 05-1996
Abstract: To further elucidate the relation between diffuse Lewy body disease and Parkinson's disease. The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer's neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson's disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson's disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson's disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson's disease.
Publisher: Wiley
Date: 1997
DOI: 10.1002/(SICI)1098-1063(1997)7:1<78::AID-HIPO8>3.0.CO;2-3
Abstract: Biofilm infection has been identified as a crucial factor of the pathogenesis of chronic wound, but wound biofilm diagnosis remains as an unmet clinical need. We previously proposed a modified wound blotting technique using Alcian blue staining for biofilm detection that was characterized as being non-invasive, time-saving, non-expansive, and informative for biofilm distribution. In this study, we adapted a novel Alcian blue grading method as the severity of biofilm infection for the wound blotting technique and compared its biofilm detection efficacy with MolecuLight
Publisher: Wiley
Date: 29-01-2004
DOI: 10.1002/MDS.10709
Abstract: A 73-year-old man with Parkinson's disease underwent thalamic stimulation for disabling tremor with excellent results only when stimulation on. Post-mortem neuropathology (7 years postoperatively) revealed 60% cell loss within 0.5 mm of the electrode tip. Tremor improvement was attributable to chronic stimulation, not microthalamotomy.
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.BIOCEL.2006.08.016
Abstract: Virus-induced signaling adaptor (VISA) is essential for host innate immune responses against double-stranded RNA viral infection and viral replication. It is an adaptor that activates the transcription factors nuclear factor kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3) that regulate the expression of type I interferons. The localization of VISA to the outer membrane of mitochondria and the cellular consequences of its activation implicate this protein in the cellular etiology of neurodegenerative disorders.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2008
DOI: 10.1007/S00018-008-7581-9
Abstract: Neuromelanin and lipofuscin are two pigments produced within the human brain that, until recently, were considered inert cellular waste products of little interest to neuroscience. Recent research has increased our understanding of the nature and interactions of these pigments with their cellular environment and suggests that these pigments may, indeed, influence cellular function. The physical appearance and distribution of the pigments within the human brain differ, but both accumulate in the aging brain and the pigments share some structural features. Lipofuscin accumulation has been implicated in postmitotic cell aging, while neuromelanin is suggested to function as an iron-regulatory molecule with possible protective functions within the cells which produce this pigment. This review presents comparative aspects of the biology of neuromelanin and lipofuscin, as well as a discussion of their hypothesized functions in brain and their possible roles in aging and neurodegenerative disease.
Publisher: Springer Science and Business Media LLC
Date: 06-03-2020
DOI: 10.1038/S41467-020-15065-7
Abstract: An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected in iduals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
Publisher: Wiley
Date: 06-1998
DOI: 10.1046/J.1365-2990.1998.00115.X
Abstract: Pathological criteria have recently been developed to differentiate those cases where Lewy bodies contribute to the dementing process. We applied consensus criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all demented) and/or Parkinson's disease (three without dementia) and eight controls. In addition, we applied the criteria to the different cortical layers to determine whether the site of the semiquantification affected the diagnosis. In the parietal lobe, few Lewy bodies were observed, and this region could be excluded. Rare Lewy bodies present in the frontal association cortex in a number of Parkinson's disease cases resulted in their classification as limbic or transitional cases with Lewy bodies. Exclusion of this non-limbic association cortex resulted in many of these cases with rare cortical Lewy bodies being re-classified as having brain stem predominant Lewy bodies, thus improving the diagnostic accuracy of the criteria. Most of these cases were non-demented. No other case was re-classified by excluding these cortical regions from the analysis. Few Lewy bodies were present in cortical layers I and II, and these layers could be excluded from the semiquantitative procedure without change to the overall classification of cases. The occasional presence of possible Lewy bodies in cases with Alzheimer's disease and controls incorrectly classified these cases as having brain stem predominant Lewy body disease, although these cases had no brain stem Lewy bodies. These modifications to the consensus criteria for assessing Lewy body disease (i.e. exclude parietal and frontal lobe, cortical layers I and II, and cases without brain stem Lewy bodies), provide significant time and cost savings for neuropathologists and researchers using this criteria to diagnose and study dementia with Lewy bodies.
Publisher: Elsevier BV
Date: 03-1999
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.BIOPSYCH.2011.07.036
Abstract: An active cognitive lifestyle is linked to diminished dementia risk, but the underlying mechanisms are poorly understood. Potential mechanisms include disease modification, neuroprotection, and compensation. Prospective, population-based brain series provide the rare opportunity to test the plausibility of these mechanisms in humans. Participants came from the United Kingdom Medical Research Council Cognitive Function and Ageing Study, comprising 13,004 in iduals aged over 65 years and followed for 14 years. In study 1, a Cognitive Lifestyle Score (CLS) was computed on all Cognitive Function and Ageing Study subjects to define low, middle, and high groups. By August 2004, 329 in iduals with CLS data had come to autopsy and underwent Consortium to Establish a Registry of Alzheimer's Disease assessment. Study 2 involved more detailed quantitative histology in the hippoc us and Brodmann area 9 in 72 clinically matched in iduals with high and low CLS. CLS groups did not differ on several Alzheimer disease neuropathologic measures however, high CLS men had less cerebrovascular disease after accounting for vascular risk factors, and women had greater brain weight. No group differences were evident in hippoc al neuronal density. In Brodmann area 9, cognitively active in iduals had significantly greater neuronal density, as well as correlated increases in cortical thickness. An active cognitive lifestyle was associated with protection from cerebrovascular disease in men, but there was no evidence for Alzheimer disease modification or hippoc al neuroprotection. Men and women both exhibited neurotrophic changes in the prefrontal lobe linked to cognitive lifestyle, consistent with a compensatory process. Lifespan complex cognitive activity may therefore protect against dementia through multiple biological pathways.
Publisher: Wiley
Date: 13-06-2022
DOI: 10.1002/MDC3.13488
Abstract: Dementia with Lewy bodies (DLB) is a common cause of dementia with poor prognosis and high hospitalization rates. DLB is frequently misdiagnosed, with clinical features that overlap significantly with other diseases including Parkinson's disease (PD). Clinical instruments that discriminate and track the progression of cognitive impairment in DLB are needed. The current study was designed to assess the utility of a mental rotation (MR) task for assessing visuospatial impairments in early DLB. Accuracy of 22 DLB patients, 22 PD patients and 22 age‐matched healthy controls in the MR task were compared at comparing shapes with 0°, 45° and 90° rotations. Healthy controls and PD patients performed at similar levels while the DLB group were significantly impaired. Further, impairment in the visuospatial and executive function measures correlated with MR poor outcomes. These findings support the MR task as an objective measure of visuospatial impairment with the ability to adjust difficulty to suit impairments in a DLB population. This would be a useful tool within clinical trials.
Publisher: Oxford University Press (OUP)
Date: 03-2006
DOI: 10.1093/BRAIN/AWH720
Publisher: Elsevier BV
Date: 12-2009
Publisher: Elsevier BV
Date: 04-1989
DOI: 10.1016/0361-9230(89)90092-0
Abstract: The distribution and morphology of serotonin-like immunoreactive (5HT-IR) nerve cells, fibres and terminals in the rat ventromedial mesencephalic tegmentum (VMT) was studied using qualitative and quantitative immunohistochemical methods at light and electron microscopic levels. All five component nuclei were examined and the size, number and density of immunoreactive neurons and terminals determined. Thirty percent of all neurons in the caudal linear nucleus and 1% in the interfascicular nucleus were immunoreactive for serotonin. Different regions of the VMT had morphologically distinct 5HT-IR fibres and quantitative differences between the VMT nuclei were seen in the density of 5HT-IR terminals. In the lateral VMT, many thick, nonvaricose 5HT-IR fibres were found in the parabrachial pigmented nucleus while many fine, varicose 5HT-IR fibres were found in the paranigral nucleus. Fine, varicose 5HT-IR fibres were also seen in the rostral and caudal linear nuclei. Many 5HT-IR axon profiles formed synapses with small calibre dendrites. 5HT-IR fibres in the interfascicular nucleus were thick with variable sized varicosities at irregular intervals. Few 5HT-IR axon profiles formed synapses in this nucleus. A comparison between the number of 5HT-IR terminals and the total number of axon terminals in the VMT (25) reveals that the majority of all terminals in the paranigral and rostral linear nuclei can be labelled with serotonin. The effect of serotonin on VMT cells is therefore likely to be mediated by different types of 5HT-IR fibres which preferentially innervate particular VMT nuclei.
Publisher: American Medical Association (AMA)
Date: 11-2000
DOI: 10.1001/ARCHNEUR.57.11.1586
Abstract: Anti-inflammatory medications have an inverse association with Alzheimer disease (AD). To examine at what doses this anti-inflammatory drug effect occurs and whether other medications and/or International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses affect the association. Subjects 75 years and older from a random population s le were classified by consensus using International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses. Drug associations with different types of dementia with and without the International Classification of Diseases, Ninth Revision, Clinical Modification diagnoses as well as dosage data were analyzed. The Centre for Education and Research on Aging, Concord Hospital, Concord, Australia. The Sydney Older Persons Study recruited 647 subjects (average age, 81 years). A total of 163 patients were given diagnoses placing them in different dementia categories and were compared with 373 control subjects. Of the patients with dementia, 78 had AD without vascular dementia, 45 had vascular dementia (permissive of other dementia diagnoses), and 40 had other dementia diagnoses (without AD or vascular dementia). Fifty drugs or drug groups were subjected to a 2 (drug used vs drug not used) x 4 (dementia and control groups) chi(2) analysis. Drugs with inverse associations were identified and potential confounders (logistic regression) and dosage data (exact small s le 1-tailed tests) analyzed. As expected, there was an inverse association between nonsteroidal anti-inflammatory drugs and aspirin (and unexpectedly angiotensin-converting enzyme inhibitors) and AD. This association was not observed with vascular dementia or any other diagnoses. Analysis showed no evidence for a dosage effect, ie, responses were equivalent for low and high doses. This study does not support a high-dose anti-inflammatory action of nonsteroidal anti-inflammatory drugs or aspirin in AD. Potential mechanisms for the beneficial effects of these medications are discussed.
Publisher: Wiley
Date: 29-08-2018
DOI: 10.1111/NAN.12514
Abstract: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Quantitative real-time polymerase chain reactions were used to assess levels of SIRT1-3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno-associated viral vectors in mice. We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. We show that SIRT1 expression is increased in HD-affected brain regions and that metabolic pathways are altered in the HD hypothalamus.
Publisher: Wiley
Date: 2010
DOI: 10.1111/J.1749-6632.2009.05118.X
Abstract: To identify the progression of pathology over the entire course of Parkinson's disease, we longitudinally followed a clinical cohort to autopsy and identified three clinicopathological phenotypes that progress at different rates. Typical Parkinson's disease has an initial rapid loss of midbrain dopamine neurons with a slow progression of Lewy body infiltration into the brain (over decades). Dementia intervenes late when Lewy bodies invade the neocortex. Older onset patients (> 70 years old) dement earlier and have much shorter disease durations. Paradoxically, they have far more alpha-synuclein-containing Lewy bodies throughout the brain, and many also have additional age-related plaque pathology. In contrast, dementia with Lewy bodies has the shortest disease course, with substantive amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that two age-related factors influence pathological progression in Parkinson's disease--the age at symptom onset and the degree and type of age-related Alzheimer-type pathology.
Publisher: BMJ
Date: 07-2003
Abstract: Huntington's disease (HD) results from neurodegeneration of the neostriatum. The mutation on chromosome 4 is an expansion in a triplet repeat (CAG)(n) located within the IT15 gene. Only six patients have been reported with clinical features of HD in association with limited neuropathology. Of these, only one has had the diagnosis confirmed by genetic (DNA) testing. We describe a patient with the clinical phenotype and genetically confirmed HD but unexpected limited neuropathology. The patient was seen because of aggressive behaviour and memory problems of two years duration. The differential diagnosis included HD although there was no family history. DNA testing was positive for the HD mutation. Clinical follow up three months later confirmed classic features of HD. Progression of the disease was rapid with death three years later. Neuropathology revealed a largely intact neostriatum with bilateral ischaemic damage and cell loss in the external globus pallidus. Such pathology alone could explain the clinical features of HD. This is only the second report of genetically confirmed clinically manifest HD with little evidence of HD neuropathology. There are several unusual features which could not have been predicted by the clinical picture, in particular the progressive course of bilateral ischaemic changes restricted to the external globus pallidus. The potential to miss other HD cases at post-mortem examination, and the implications of this for family members, are discussed.
Publisher: Springer New York
Date: 2014
Publisher: Elsevier BV
Date: 12-1998
Abstract: The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntington's disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntington's disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntington's disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntington's disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntington's disease.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2010
Abstract: Apolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippoc us from control and AD post-mortem s les were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions. In apoE3 homozygous s les, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD s les were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous s les but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous s les. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain s le homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts. The identification of disulphide-linked apoE dimers in human cortical and hippoc al tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.
Publisher: Elsevier
Date: 2010
Publisher: Wiley
Date: 11-11-2019
DOI: 10.1111/JSR.12939
Abstract: The vast majority of patients with idiopathic rapid eye movement sleep behaviour disorder will develop a neurodegenerative α‐synuclein‐related condition, such as Parkinson’s disease or dementia with Lewy bodies. The pathology underlying dream enactment overlaps anatomically with the brainstem regions that regulate circadian core body temperature. Previously, nocturnal core body temperature regulation has been shown to be impaired in Parkinson’s disease. However, no study to date has investigated nocturnal core body temperature changes in patients with idiopathic rapid eye movement sleep behaviour disorder, which may prove to be an early objective biomarker for α‐synucleinopathies. Ten healthy controls, 15 patients with idiopathic rapid eye movement sleep behaviour disorder, 31 patients with Parkinson’s disease and six patients with dementia with Lewy bodies underwent clinical assessment and nocturnal polysomnography with core body temperature monitoring. A validated cosinor method was utilised for core body temperature analysis. No differences in mesor, nadir or time of nadir were observed between groups. However, when compared with healthy controls, the litude of the nocturnal core body temperature (mesor minus nadir) was significantly reduced in patients with idiopathic rapid eye movement sleep behaviour disorder, Parkinson’s disease with concurrent rapid eye movement sleep behaviour disorder and dementia with Lewy bodies ( p 0.001, p = 0.043 and p = 0.017, respectively). Importantly, this relationship was not seen in those patients with Parkinson’s disease without rapid eye movement sleep behaviour disorder. In addition, there was a significant negative correlation between litude of the core body temperature and self‐reported rapid eye movement sleep behaviour disorder symptoms. Changes in thermoregulatory circadian rhythm may be specifically associated with the pathology underlying rapid eye movement sleep behaviour disorder rather than simply that of α‐synucleinopathy. These findings implicate thermoregulatory dysfunction as a potential early biomarker for development of rapid eye movement sleep behaviour disorder‐associated neurodegeneration, and suggest that subpopulations with differing pathological underpinnings might exist in Parkinson’s disease.
Publisher: MDPI AG
Date: 25-02-2023
Abstract: Multiple system atrophy (MSA) is a debilitating movement disorder with unknown etiology. Patients present characteristic parkinsonism and/or cerebellar dysfunction in the clinical phase, resulting from progressive deterioration in the nigrostriatal and olivopontocerebellar regions. MSA patients have a prodromal phase subsequent to the insidious onset of neuropathology. Therefore, understanding the early pathological events is important in determining the pathogenesis, which will assist with developing disease-modifying therapy. Although the definite diagnosis of MSA relies on the positive post-mortem finding of oligodendroglial inclusions composed of α-synuclein, only recently has MSA been verified as an oligodendrogliopathy with secondary neuronal degeneration. We review up-to-date knowledge of human oligodendrocyte lineage cells and their association with α-synuclein, and discuss the postulated mechanisms of how oligodendrogliopathy develops, oligodendrocyte progenitor cells as the potential origins of the toxic seeds of α-synuclein, and the possible networks through which oligodendrogliopathy induces neuronal loss. Our insights will shed new light on the research directions for future MSA studies.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2013
Publisher: Springer Science and Business Media LLC
Date: 30-01-2008
DOI: 10.1007/S00401-008-0344-8
Abstract: The present study describes the pathological progression of longitudinally followed cases with levodopa-responsive Parkinson's disease who came to autopsy during the Sydney Multicenter Study of Parkinson's disease. Standardised clinical and neuropathological assessments over five epochs of time verified three different clinicopathological groups. A group of younger onset patients with a typical long duration clinical course of Parkinson's disease. This group of cases had Lewy body distributions consistent with the Braak staging of disease. In this group, brainstem Lewy bodies dominate in those surviving to 5 years by 13 years, 50% of cases have a limbic distribution of Lewy bodies and by 18 years, all will have at least this pathological phenotype. Approximately 25% of cases had an early malignant, dementia-dominant syndrome and severe neocortical disease consistent with dementia with Lewy bodies. The last group had an older onset, shorter survival, and a more complex disease course with higher Lewy body loads and a higher proportion with additional neuropathologies. These cases with higher loads of Lewy bodies and shorter survivals suggest that widespread Lewy body pathology either occurs at the onset of clinical disease or rapidly infiltrates the brain. In these cases with shorter survivals, there was more plaque pathology, supporting a more aggressive and linked phenotype. Our data suggest that the selection of similar study cohorts by pathology alone would not be able to differentiate the three different phenotypes identified. The data are also not consistent with a unitary concept of the pathogenesis of Lewy body disease.
Publisher: Wiley
Date: 07-2001
DOI: 10.1002/MDS.1124
Abstract: Six cases with a clinical corticobasal syndrome (progressive asymmetric apraxia and parkinsonism unresponsive to levodopa) and tau pathology were selected from 97 brain donors with parkinsonism. Postmortem volumetric measures of regional brain atrophy (compared with age/sex-matched controls) were correlated with clinical features and the degree of underlying cortical and subcortical histopathology. At death, no significant asymmetry of pathology was detected. All cases had prominent bilateral atrophy of the precentral gyrus (reduced by 22-54%) with other cortical regions variably affected. Subcortical atrophy was less severe and variable. Two cases demonstrated widespread atrophy of basal ganglia structures (44-60% atrophy of the internal globus pallidus) and substantial subcortical pathology consistent with a diagnosis of progressive supranuclear palsy (PSP). The remaining four cases had typical pathology of corticobasal degeneration. In all cases, neuronal loss and gliosis corresponded with subcortical atrophy, while the density of cortical swollen neurons correlated with cortical volume loss. Atrophy of the internal globus pallidus was associated with postural instability, while widespread basal ganglia histopathology was found in cases with gaze palsy. This study confirms the involvement of the precentral gyrus in the corticobasal syndrome and highlights the variable underlying pathology in these patients.
Publisher: Springer Science and Business Media LLC
Date: 06-1993
DOI: 10.1007/BF00996893
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S43856-021-00060-W
Abstract: Behavioral variant frontotemporal dementia (bvFTD) is a common form of younger-onset dementia with a proportion of cases overlapping pathologically and genetically with amyotrophic lateral sclerosis (ALS). Previous studies have identified that the human endogenous retrovirus K (HERV-K) is elevated in ALS serum and is associated with ALS TDP-43 pathology. In contrast, little is known about HERV-K changes in bvFTD. Here, we investigated the possible role of HERV-K in bvFTD. We measured the HERV-K env gene in sporadic bvFTD ( N = 63), sporadic ALS ( N = 89), and control ( N = 21) serum by ddPCR. We also analyzed HERV-K env , by qPCR, and the HERV-K reverse transcriptase protein, by confocal immunofluorescence microscopy, in the disease-affected superior frontal cortex of bvFTD with TDP-43 pathology. Here, we show that HERV-K env levels are significantly elevated ( P = 3.5 × 10 −6 ) in bvFTD compared to control serum, differentiating cases with an AUC value of 0.867. HERV-K env levels are also specifically elevated in the superior frontal cortex of bvFTD with TDP-43 pathology, with the HERV-K reverse transcriptase protein and TDP-43 deposit localized to the neuronal cytoplasm. Furthermore, in a neuronal cell line overexpression of TDP-43 induces HERV-K env transcription. These results suggest that manifestation of HERV-K is associated with bvFTD TDP-43 pathology. Analysis of HERV-K in bvFTD may provide insight into an unrecognized but targetable perturbed pathology.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-05-2023
Abstract: Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.JNS.2016.05.005
Abstract: The hypoglossal nucleus was recently identified as a key brain region in which the presence of TDP-43 pathology could accurately discriminate TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis (ALS). The objective of the present study was to assess the hypoglossal nucleus in behavioral variant frontotemporal dementia (bvFTD), and determine whether TDP-43 in this region is associated with clinical ALS. Twenty-nine cases with neuropathological FTLD-TDP and clinical bvFTD that had not been previously assessed for hypoglossal TDP-43 pathology were included in this study. Of these 29 cases, 41% (n=12) had a dual diagnosis of bvFTD-ALS at presentation, all 100% (n=12) of which demonstrated hypoglossal TDP-43 pathology. Of the 59% (n=17) cohort that presented with pure bvFTD, 35% (n=6) were identified with hypoglossal TDP-43 pathology. Review of the case files of all pure bvFTD cases revealed evidence of possible or probable ALS in 5 of the 6 hypoglossal-positive cases (83%) towards the end of disease, and this was absent from all cases without such pathology. In conclusion, the present study validates grading the presence of TDP-43 in the hypoglossal nucleus for the pathological identification of bvFTD cases with clinical ALS, and extends this to include the identification of cases with possible ALS at end-stage.
Publisher: Springer Science and Business Media LLC
Date: 10-12-2015
Publisher: Springer Science and Business Media LLC
Date: 02-01-2019
Publisher: Wiley
Date: 06-1996
Publisher: Springer Science and Business Media LLC
Date: 05-10-2015
DOI: 10.1007/S00401-015-1486-0
Abstract: The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.
Publisher: Springer Science and Business Media LLC
Date: 18-10-2018
DOI: 10.1038/S41598-018-33921-X
Abstract: Missense mutations in glucocerebrosidase ( GBA1 ) that impair the activity of the encoded lysosomal lipid metabolism enzyme (GCase) are linked to an increased risk of Parkinson’s disease. However, reduced GCase activity is also found in brain tissue from Parkinson’s disease patients without GBA1 mutations, implicating GCase dysfunction in the more common idiopathic form of Parkinson’s disease. GCase is very highly expressed in monocytes, and thus we measured GCase activity in blood s les from recently diagnosed Parkinson’s disease patients. Flow cytometry and immunoblotting assays were used to measure levels of GCase activity and protein in monocytes and lymphocytes from patients with Parkinson’s disease (n = 48) and matched controls (n = 44). Gene sequencing was performed to screen participants for GBA1 missense mutations. In the Parkinson’s disease patients, GCase activity was significantly reduced in monocytes, but not lymphocytes, compared to controls, even when GBA1 mutation carriers were excluded. Monocyte GCase activity correlated with plasma ceramide levels in the Parkinson’s disease patients. Our results add to evidence for GCase dysfunction in idiopathic Parkinson’s disease and warrant further work to determine if monocyte GCase activity associates with Parkinson’s disease progression.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-09-2021
DOI: 10.1212/WNL.0000000000012450
Abstract: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance. One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI). Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE ( p = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points ( p = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points ( p = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable ( p = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD. Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2010
DOI: 10.1007/S00401-010-0742-6
Abstract: Huntington disease (HD) is a fatal neurodegenerative disorder caused by expansion of a CAG repeat in the HD gene. Degeneration concentrating in the basal ganglia has been thought to account for the characteristic psychiatric symptoms, cognitive decline and motor dysfunction. However, the homeostatic control of emotions and metabolism are disturbed early in HD, and focused studies have identified a loss of orexin (hypocretin) neurons in the lateral hypothalamus in HD patients. There has been limited assessment of other hypothalamic cell populations that may be involved. In this study, we quantified the neuropeptide-expressing hypothalamic neurons known to regulate metabolism and emotion in patients with HD compared to healthy controls using unbiased stereological methods. We confirmed the loss of orexin-expressing neurons in HD and revealed substantial differences in the peptide expression of other neuronal populations in the same patients. Both oxytocin- and vasopressin-expressing neurons were decreased by 45 and 24%, respectively, while the number of cocaine- and hetamine-regulated transcript (CART)-expressing neurons was increased by 30%. The increased expression of CART in the hypothalamus is consistent with a previous study showing increased CART levels in cerebrospinal fluid from HD patients. There was no difference in the numbers of neuropeptide Y-expressing neurons. These results show significant and specific alterations in the peptide expression of hypothalamic neurons known to regulate metabolism and emotion. They may be important in the development of psychiatric symptoms and metabolic disturbances in HD, and may provide potential targets for therapeutic interventions.
Publisher: BMJ
Date: 07-2003
Abstract: Olfactory and sleep disturbances are common in Parkinson's disease, and may be early disease indicators. To obtain information about olfactory and sleep deficits preceding the onset of motor symptoms in Parkinson's disease. 38 community dwelling patients with Parkinson's disease (73% response rate) and 32 age matched controls (60% response rate). Using a questionnaire survey, the frequencies, timing, and relations between olfactory and sleep disturbances, drug treatment, mood, and motor deficits in Parkinson's disease were compared with those in age matched controls. Reliability of information was validated by informant interview in 9% of the s le. Interdependency of factors was assessed using Fisher's fourfold table test, and differences between populations were analysed using chi(2) and unpaired t tests. Microsmia was reported by 26 patients (68%) (and only one control), on average within a year of the diagnosis of Parkinson's disease. More patients than controls had excessive daytime somnolence (45% v 6%), restless legs (50% v 19%), and abnormal movements during sleep (34% v 0%), which generally occurred three to five years after diagnosis and were independent of mood disorders and drug treatment. Many patients with Parkinson's disease have microsmia at the onset of motor deficits, but some sleep disorders are a subsequent occurrence.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1007/S00415-011-6205-8
Abstract: In order to determine the relationship between regional neuropathology and severity of clinical features in Richardson's syndrome (PSP-RS), the following hypotheses were tested: (1) executive dysfunction relates to prefrontal pathology (2) language difficulties to pathology in Broca's area and/or the perirhinal cortex and (3) visuospatial impairment to pathology in the supramarginal region. A prospectively studied case series of brain donors at a specialist clinic in Addenbrooke's Hospital Cambridge, UK, were examined. All those fulfilling postmortem criteria for PSP-RS and their last cognitive assessment within 24 months of death (N = 11/25) were included. The degree of regional neuronal loss and neuronal tau deposition across a number of cortical brain regions was performed and compared to 10 age- and sex-matched controls from the Sydney Brain Bank. Stepwise multiple linear regressions were used to determine the neuropathological correlates to cognitive scores and revealed the following. Executive dysfunction, as indexed by letter fluency, related to the degree of tau deposition in the superior frontal gyrus and supramarginal cortices (p < 0.020), language deficits related to neuron loss in the perirhinal gyrus (p < 0.001) and tau deposition in Broca's area (p = 0.020), while visuospatial dysfunction and global cognitive impairment related to tau deposition in the supramarginal gyrus (p < 0.007). The severity of cognitive deficits relate to regional cortical tau deposition in PSP-RS, although language impairment related to neuronal loss in the perirhinal region. Global cognitive dysfunction related most to the severity of tau deposition in the supramarginal gyrus warranting further research on the role of this brain region in PSP-RS.
Start Date: 07-2007
End Date: 01-2011
Amount: $259,067.00
Funder: Australian Research Council
View Funded ActivityStart Date: 04-2022
End Date: 12-2023
Amount: $535,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2010
End Date: 04-2011
Amount: $520,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2005
End Date: 12-2006
Amount: $323,400.00
Funder: Australian Research Council
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