ORCID Profile
0000-0003-2785-333X
Current Organisation
University of Sheffield
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Publisher: Royal College of Psychiatrists
Date: 07-10-2020
DOI: 10.1192/BJP.2019.193
Abstract: Depression is a leading cause of disability, with older people particularly susceptible to poor outcomes. To investigate whether the prevalence of depression and antidepressant use have changed across two decades in older people. The Cognitive Function and Ageing Studies (CFAS I and CFAS II) are two English population-based cohort studies of older people aged ≥65 years, with baseline measurements for each cohort conducted two decades apart (between 1990 and 1993 and between 2008 and 2011). Depression was assessed by the Geriatric Mental State examination and diagnosed with the Automated Geriatric Examination for Computer-Assisted Taxonomy algorithm. In CFAS I, 7635 people aged ≥65 years were interviewed, of whom 1457 were diagnostically assessed. In CFAS II, 7762 people were interviewed and diagnostically assessed. Age-standardised depression prevalence in CFAS II was 6.8% (95% CI 6.3–7.5%), representing a non-significant decline from CFAS I (risk ratio 0.82, 95% CI 0.64–1.07, P = 0.14). At the time of CFAS II, 10.7% of the population (95% CI 10.0–11.5%) were taking antidepressant medication, more than twice that of CFAS I (risk ratio 2.79, 95% CI 1.96–3.97, P 0.0001). Among care home residents, depression prevalence was unchanged, but the use of antidepressants increased from 7.4% (95% CI 3.8–13.8%) to 29.2% (95% CI 22.6–36.7%). A substantial increase in the proportion of the population reporting taking antidepressant medication is seen across two decades for people aged ≥65 years. However there was no evidence for a change in age-specific prevalence of depression.
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.NEUROBIOLAGING.2011.04.013
Abstract: Astrocytes contribute to a variety of functions in the brain, including homeostasis, synapse formation, plasticity, and metabolism. Astrocyte dysfunction may disrupt their normal role, including neuronal support, thereby contributing to neurodegenerative pathologies, including Alzheimer's disease (AD). To understand the role of astrocytes in the pathogenesis of age-related disorders, we isolated astrocytes by laser capture microdissection, using glial fibrillary acidic protein (GFAP) as a marker, and characterized the astrocyte transcriptome at different Braak neurofibrillary tangle stages in postmortem temporal cortex s les derived from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) cohort, using microarray analysis. The largest number of significant, differentially expressed genes were identified when the expression profile of astrocytes from isocortical stages of neurofibrillary tangle pathology (Braak stages V-VI) were compared with entorhinal stages (Braak stages I-II). Dysregulation of genes associated with the actin cytoskeleton, proliferation, apoptosis, and ubiquitin-mediated proteolysis occurred at low Braak stages, while altered regulation of intracellular signaling pathways, including insulin, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways were primarily associated with high levels of Alzheimer-type pathology, and occurred at lower Braak stages in in iduals with the APOEε4 allele. Our findings implicate astrocyte dysfunction in the pathogenesis of neurodegenerative pathology in the aging brain, and provide a basis for future candidate studies based on specific pathways.
Publisher: Wiley
Date: 02-05-2021
DOI: 10.1111/NAN.12716
Abstract: Application of advanced molecular pathology in rare tumours is hindered by low s le numbers, access to specialised expertise/technologies and tissue/assay QC and rapid reporting requirements. We assessed the feasibility of co‐ordinated real‐time centralised pathology review (CPR), encompassing molecular diagnostics and contemporary genomics (RNA‐seq/DNA methylation‐array). This nationwide trial in medulloblastoma ( UK diagnoses/year) introduced a national reference centre (NRC) and assessed its performance and reporting to World Health Organisation standards. Paired frozen/formalin‐fixed, paraffin‐embedded tumour material were co‐submitted from 135 patients (16 referral centres). Complete CPR diagnostics were successful for 88% (120/135). Inadequate s ling was the most common cause of failure biomaterials were typically suitable for methylation‐array (129/135, 94%), but frozen tissues commonly fell below RNA‐seq QC requirements (53/135, 39%). Late reporting was most often due to delayed submission. CPR assigned or altered histological variant (vs local diagnosis) for 40/135 tumours (30%). Benchmarking/QC of specific biomarker assays impacted test results fluorescent in‐situ hybridisation most accurately identified high‐risk MYC / MYCN lification (20/135, 15%), while combined methods ( CTNNB1 /chr6 status, methylation‐array subgrouping) best defined favourable‐risk WNT tumours (14/135 10%). Engagement of a specialist pathologist panel was essential for consensus assessment of histological variants and immunohistochemistry. Overall, CPR altered clinical risk‐status for 29% of patients. National real‐time CPR is feasible, delivering robust diagnostics to WHO criteria and assignment of clinical risk‐status, significantly altering clinical management. Recommendations and experience from our study are applicable to advanced molecular diagnostics systems, both local and centralised, across rare tumour types, enabling their application in biomarker‐driven routine diagnostics and clinical/research studies.
Publisher: Wiley
Date: 10-08-2018
DOI: 10.1002/GLIA.23465
Abstract: Oxidative stress and oxidative DNA damage are early features of mild cognitive impairment and Alzheimer's disease (AD), occurring before the formation of classical AD neuropathology, and resulting from an imbalance between pro- and anti-oxidants. Astrocytes play a major neuroprotective role, producing high levels of anti-oxidants including metallothionein-I and -II (MT-I/II). In the present study we characterized the immunoreactive profile of MT-I/II in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) aging population-representative neuropathology cohort, and examined H
Publisher: Wiley
Date: 09-2020
DOI: 10.1111/NAN.12656
Abstract: Biomarker‐driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub‐classify iMB, and proffer strategies for personalized, risk‐adapted therapies. We characterized the iMB molecular landscape, including second‐generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). iMB Grp3 (42%) and iMB SHH (40%) subgroups predominated. iMB Grp3 harboured second‐generation subtypes II/III/IV. Subtype II strongly associated with large‐cell/anaplastic pathology (LCA 23%) and MYC lification (19%), defining a very‐high‐risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies novel approaches are urgently required. Subtype VII (predominant within iMB Grp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI‐based therapies randomized‐controlled trials of upfront radiation‐sparing and/or second‐line radiotherapy should be considered. Seventy‐five per cent of iMB SHH showed DN/MBEN histopathology in discovery and validation cohorts ( P 0.0001) central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non‐DN/MBEN pathology was associated significantly with worse outcomes within iMB SHH . iMB SHH harboured two distinct subtypes (iMB SHH‐I/II ). Within the discriminated favourable‐risk iMB SHH DN/MBEN patient group, iMB SHH‐II had significantly better progression‐free survival than iMB SHH‐I , offering opportunities for risk‐adapted stratification of upfront therapies. Both iMB SHH‐I and iMB SHH‐II showed notable rescue rates (56% combined post‐relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup‐dependent survival models highlight opportunities for biomarker‐directed therapies.
Publisher: Wiley
Date: 18-01-2021
DOI: 10.1002/JCSM.12660
Abstract: Poor performance in the 5‐chair stand test (5‐CST) indicates reduced lower limb muscle strength. The 5‐CST has been recommended for use in the initial assessment of sarcopenia, the accelerated loss of muscle strength and mass. In order to facilitate the use of the 5‐CST in sarcopenia assessment, our aims were to (i) describe the prevalence and factors associated with poor performance in the 5‐CST, (ii) examine the relationship between the 5‐CST and gait speed, and (iii) propose a protocol for using the 5‐CST. The population‐based study Cognitive Function and Ageing Study II recruited people aged 65 years and over from defined geographical localities in Cambridgeshire, Newcastle, and Nottingham. The study collected data for assessment of functional ability during home visits, including the 5‐CST and gait speed. We used multinomial logistic regression to assess the associations between factors including the SARC‐F questionnaire and the category of 5‐CST performance: fast ( s), intermediate (12–15 s), slow ( s), or unable, with slow/unable classed as poor performance. We reviewed previous studies on the protocol used to carry out the 5‐CST. A total of 7190 participants aged 65+ from the three erse localities of Cognitive Function and Ageing Study II were included (54.1% female). The proportion of those with poor performance in the 5‐CST increased with age, from 34.3% at age 65–69 to 89.7% at age 90+. Factors independently associated with poor performance included positive responses to the SARC‐F questionnaire, physical inactivity, depression, impaired cognition, and multimorbidity (all P 0.005). Most people with poor performance also had slow gait speed (57.8%) or were unable to complete the gait speed test (18.4%). We found variation in the 5‐CST protocol used, for ex le, timing until a participant stood up for the fifth time or until they sat down afterwards. Poor performance in the 5‐CST is increasingly common with age and is associated with a cluster of other factors that characterize risk for poor ageing such as physical inactivity, impaired cognition, and multimorbidity. We recommend a low threshold for performing the 5‐CST in clinical settings and provide a protocol for its use.
Publisher: Massachusetts Medical Society
Date: 28-05-2009
Publisher: Springer Science and Business Media LLC
Date: 08-02-2016
Publisher: MDPI AG
Date: 25-10-2020
DOI: 10.3390/IJMS21217924
Abstract: White matter lesions (WML) are a common feature of the ageing brain associated with cognitive impairment. The gene expression profiles of periventricular lesions (PVL, n = 7) and radiologically-normal-appearing (control) periventricular white matter cases (n = 11) obtained from the Cognitive Function and Ageing Study (CFAS) neuropathology cohort were interrogated using microarray analysis and NanoString to identify novel mechanisms potentially underlying their formation. Histological characterisation of control white matter cases identified a subgroup (n = 4) which contained high levels of MHC-II immunoreactive microglia, and were classified as “pre-lesional.” Microarray analysis identified 2256 significantly differentially-expressed genes (p ≤ 0.05, FC ≥ 1.2) in PVL compared to non-lesional control white matter (1378 upregulated and 878 downregulated) 2649 significantly differentially-expressed genes in “pre-lesional” cases compared to PVL (1390 upregulated and 1259 downregulated) and 2398 significantly differentially-expressed genes in “pre-lesional” versus non-lesional control cases (1527 upregulated and 871 downregulated). Whilst histological evaluation of a single marker (MHC-II) implicates immune-activated microglia in lesion pathology, transcriptomic analysis indicates significant downregulation of a number of activated microglial markers and suggests established PVL are part of a continuous spectrum of white matter injury. The gene expression profile of “pre-lesional” periventricular white matter suggests upregulation of several signalling pathways may be a neuroprotective response to prevent the pathogenesis of PVL.
Publisher: Oxford University Press (OUP)
Date: 07-08-2020
DOI: 10.1093/JNEN/NLAA064
Abstract: Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aβ phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p & 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer’s neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer’s.
Publisher: Springer Science and Business Media LLC
Date: 19-04-2016
DOI: 10.1038/NCOMMS11398
Abstract: Dramatic global increases in future numbers of people with dementia have been predicted. No multicentre population-based study powered to detect changes over time has reported dementia incidence. MRC Cognitive Function and Ageing Study (CFAS) undertook baseline interviews in populations aged 65+ years in England and Wales (1989–1994). Three areas (CFAS I) were selected for new s ling two decades later (2008–2011) with same geographical boundaries, s ling and approach methods (CFAS II). At 2 years CFAS I interviewed 5,156 (76% response) with 5,288 interviewed in CFAS II (74% response). Here we report a 20% drop in incidence (95% CI: 0–40%), driven by a reduction in men across all ages above 65. In the UK we estimate 209,600 new dementia cases per year. This study was uniquely designed to test for differences across geography and time. A reduction of age-specific incidence means that the numbers of people estimated to develop dementia in any year has remained relatively stable.
Publisher: Wiley
Date: 13-03-2014
DOI: 10.1111/NAN.12062
Publisher: Wiley
Date: 28-10-2016
DOI: 10.1111/NAN.12363
Abstract: Microinfarcts, small ischaemic foci common in ageing brain, are associated with dementia and gait dysfunction. We determined their relationship with dementia, mobility and cerebrovascular disease in an older population‐representative brain donor cohort. These data on microinfarcts were evaluated in relation to pathological assessments of clinically significant cerebral small vessel disease ( SVD ). Microinfarcts were assessed in the MRC Cognitive Function and Ageing Study (n = 331). Nine brain areas were staged according to the number of areas affected. 36% of brains showed at least 1 microinfarct. Higher cortical microinfarct stage was associated with dementia at death ( OR 1.41, 95% CI 1.02 1.96, P = 0.038), whilst cortical and subcortical microinfarct stages were associated with impaired mobility ( OR 1.36, 95% CI 1.05–1.74 P 0.018) and falls ( OR 1.96, 95% CI 1.11–3.43 P = 0.02). Adding data on microinfarcts to a definition of SVD , based on white matter lesions ( WML s), lacunes and significant arteriosclerosis, were assessed by comparing area under ROC curve ( AUC ) with and without microinfarcts. SVD was significantly related to dementia status with or without inclusion of microinfarcts. Modelling potential pathological definitions of SVD to predict dementia or impaired mobility indicated optimal prediction using combined assessment of WML s, lacunes and microinfarcts. Cortical (dementia) and subcortical microinfarcts (impaired mobility) are related to erse clinical outcomes. Optimal pathological assessment of significant SVD in brain ageing is achieved based on WML s, lacunes and microinfarcts and may not require subjective assessment of the extent and severity of arteriosclerosis.
Publisher: MDPI AG
Date: 04-01-2020
DOI: 10.3390/IJMS21010340
Abstract: Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2014
Publisher: Elsevier BV
Date: 07-2017
Publisher: Elsevier BV
Date: 10-2017
Publisher: S. Karger AG
Date: 2012
DOI: 10.1159/000341581
Abstract: Glial tau pathology is seen in certain tauopathies and in ageing. We determined its frequency in ageing mesial temporal lobe and its relationship to other tau pathologies in the MRC-CFAS population-representative neuropathology cohort. Mesial temporal lobe, including hippoc us, amygdala, entorhinal cortex and white matter, was examined using immunohistochemistry with the AT8 antibody to phospho-tau and RD3 and RD4 antibodies to 3R and 4R tau isoforms. Gallyas silver stain was used to detect fibrillar aggregates. Thorn-shaped astrocytes (TSA), positive with AT8, RD4 and Gallyas, were present in 49% of cases. They were particularly prevalent in subpial, periventricular and white matter perivascular locations and were less frequent in grey matter. Coiled bodies were seen in 18.8%. TSA were not related to Braak neurofibrillary tangle or hippoc al tangle pathology stages. TSA in grey matter were associated with coiled bodies (p = 0.011) and argyrophilic grains (p = 0.048), which were identified in 11.5% of cases. They did not correlate with dementia. Astrocyte tau pathology is common in the ageing mesial temporal lobe. Its formation is independent of Alzheimer-type pathology. It is a 4R tauopathy, which may form part of a mesial temporal age-related 4R tauopathy that includes oligodendroglial tau and argyrophilic grains.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2022
Publisher: Cold Spring Harbor Laboratory
Date: 05-05-2022
DOI: 10.1101/2022.04.28.22274107
Abstract: Although a variety of brain lesions may contribute to the pathological diagnosis of dementia, the relationship of these lesions to dementia, how they interact and how to quantify them remain uncertain. Systematically assessing neuropathological measures in relation to the cognitive and functional definitions of dementia may enable the development of better diagnostic systems and treatment targets. The objective of this study is to apply machine learning approaches for feature selection to identify key features of Alzheimer-related pathologies associated with dementia. We applied machine learning techniques for feature ranking and classification as an unbiased comparison of neuropathological features and assessment of their diagnostic performance using a cohort (n=186) from the Cognitive Function and Ageing Study (CFAS). Seven feature ranking methods using different information criteria consistently ranked 22 out of the 34 neuropathology features for importance to dementia classification. Braak neurofibrillary tangle stage, Beta-amyloid and cerebral amyloid angiopathy features were the most highly ranked, although were highly correlated with each other. The best performing dementia classifier using the top eight ranked neuropathology features achieved 79% sensitivity, 69% specificity, and 75% precision. A substantial proportion (40.4%) of dementia cases was consistently misclassified by all seven algorithms and any combination of the 22 ranked features. These results highlight the potential of using machine learning to identify key indices of plaque, tangle and cerebral amyloid angiopathy burdens that may be useful for the classification of dementia.
Publisher: Oxford University Press (OUP)
Date: 07-06-2017
DOI: 10.1093/JNEN/NLX041
Publisher: Wiley
Date: 23-04-2015
DOI: 10.1111/NAN.12202
Publisher: Elsevier BV
Date: 11-2015
Publisher: Wiley
Date: 17-12-2014
DOI: 10.1111/BPA.12219
Publisher: Wiley
Date: 20-11-2014
DOI: 10.1111/BPA.12216
Publisher: Springer Science and Business Media LLC
Date: 10-12-2015
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S40478-019-0858-4
Abstract: Aβ-amyloid deposition is a key feature of Alzheimer’s disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aβ-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aβ phase predicts dementia better than CERAD in a population-representative cohort ( n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aβ in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score ( p 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage ( p 0.001). CAA was not associated with microinfarcts ( p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of in iduals with similar Braak stage but with more Aβ. They also did not have higher hippoc al-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes ( p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aβ pathology, but addition of more than one Aβ measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.
Publisher: Elsevier BV
Date: 11-2011
DOI: 10.1016/J.NEULET.2011.09.049
Abstract: Impairment of the blood brain barrier (BBB) in human brain ageing and its relationship to Alzheimer-type pathology remains poorly defined. We have investigated the BBB in temporal cortex of brain donations from a population-representative s le of 92 participants from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS), a longitudinal study with a programme of brain donation. BBB alteration was investigated by immunohistochemistry to albumin and fibrinogen and to the tight junction proteins claudin-5, zonula occludens-1 (ZO-1) and occludin. BBB leakage showed wide population-variation and increased with progression of Alzheimer-type pathology, though with considerable overlap between different levels of Alzheimer-type pathology. This was accompanied by increased mean vascular density, but not by down-regulation of tight junction proteins. ZO-1 and occludin were also expressed in glia. Mechanisms leading to BBB leakage in brain ageing remain to be defined, but the population-variation in BBB changes and its early increase in relationship to Alzheimer-type pathology progression suggest that BBB dysfunction contributes to brain ageing.
Publisher: Wiley
Date: 29-10-2013
DOI: 10.1111/NAN.12033
Abstract: Calcium dyshomeostasis is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease. However, much of the previous research has focused on changes in neuronal calcium signalling. In a recent microarray study we identified dysregulation of several key signalling pathways including the Ca(2+) signalling pathway in astrocytes as Alzheimer-type pathology developed. In this study we sought to determine the expression of calpain-10 and calcium/calmodulin-dependent kinase alpha (CamKIIα) in relation to Alzheimer-type pathology in a population-based study. Using post mortem temporal cortex s les derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) ageing brain cohort we examined calpain-10 and CamKIIα gene and protein expression using quantitative polymerase chain reaction and immunohistochemistry. We demonstrate that astrocytic expression of calpain-10 is up-regulated, and CamKIIα down-regulated with increasing Braak stage. Using immunohistochemistry we confirm protein expression of calpain-10 in astrocytes throughout the temporal cortex and demonstrate that calpain-10 immunoreactivity is correlated with both local and global measures of Alzheimer-type pathology. In addition, we identify a subpopulation of calpain-10 immunoreactive interlaminar astrocytes that extend processes deep into the cortex. CamKIIα is predominantly neuronal in localization and is associated with the presence of diffuse plaques in the ageing brain. Dysregulated expression of key calcium signalling molecules occurs with progression of Alzheimer-type pathology in the ageing brain, highlighting the need for further functional studies of astrocytic calcium signalling with respect to disease progression.
Publisher: Wiley
Date: 15-02-2021
DOI: 10.1111/BPA.12928
Abstract: White matter lesions (WML) are common in the ageing brain, often arising in a field effect of diffuse white matter abnormality. Although WML are associated with cerebral small vessel disease (SVD) and Alzheimer’s disease (AD), their cause and pathogenesis remain unclear. The current study tested the hypothesis that different patterns of neuroinflammation are associated with SVD compared to AD neuropathology by assessing the immunoreactive profile of the microglial (CD68, IBA1 and MHC‐II) and astrocyte (GFAP) markers in ageing parietal white matter (PARWM) obtained from the Cognitive Function and Ageing Study (CFAS), an ageing population‐representative neuropathology cohort. Glial responses varied extensively across the PARWM with microglial markers significantly higher in the subventricular region compared to either the middle‐zone (CD68 p = 0.028, IBA1 p 0.001, MHC‐II p 0.001) or subcortical region (CD68 p = 0.002, IBA1 p 0.001, MHC‐II p 0.001). Clasmatodendritic (CD) GFAP + astrocytes significantly increased from the subcortical to the subventricular region ( p 0.001), whilst GFAP + stellate astrocytes significantly decreased ( p 0.001). Cellular reactions could be grouped into two distinct patterns: an immune response associated with MHC‐II/IBA1 expression and CD astrocytes and a more innate response characterised by CD68 expression associated with WML. White matter neuroinflammation showed weak relationships to the measures of SVD, but not to the measures of AD neuropathology. In conclusion, glial responses vary extensively across the PARWM with erse patterns of white matter neuroinflammation. Although these findings support a role for vascular factors in the pathogenesis of age‐related white matter neuroinflammation, additional factors other than SVD and AD pathology may drive this. Understanding the heterogeneity in white matter neuroinflammation will be important for the therapeutic targeting of age‐associated white matter damage.
Publisher: Public Library of Science (PLoS)
Date: 23-02-2015
Publisher: Wiley
Date: 17-11-2014
DOI: 10.1111/NAN.12156
Abstract: Abnormalities of the brain microvasculature in Alzheimer's disease have led to the vascular hypothesis of the disease, which predicts that vascular changes precede neuronal dysfunction and degeneration. To determine the spectrum of endothelial injury in the elderly and its relation to Alzheimer-type neuropathology we investigated DNA damage in a population-based s le derived from the Medical Research Council Cognitive Function and Ageing Study. We examined endothelial damage in frontal and temporal cortex (n = 97) using immunohistochemistry for γH2AX and DNA-protein kinase (DNA-PKcs). To determine the effects of endothelial DNA damage at the earliest stages of Alzheimer's pathology we further focused our analysis on cases classified as Braak 0-II and examined endothelial senescence using histochemistry for β-galactosidase and the expression of genes related to DNA damage and senescence using quantitative polymerase chain reaction (qPCR). We demonstrated large variation in endothelial DNA damage which was not associated with Alzheimer's neuropathology. Endothelial DNA-PKcs correlated with neuronal and glial DNA-PKcs counts. Focusing our further analysis on Braak 0-II cases, qPCR analysis demonstrated a trend to increased TP53 (P = 0.064) in cases with high compared with low endothelial DNA damage which was supported by immunohistochemical analysis of p53. Endothelial β-galactosidase expression was associated with increased neuronal (P = 0.033) and glial (P = 0.038), but not endothelial DNA-PKcs expression. Damage to brain endothelial cells occurs early in relation to, or independently of, Alzheimer pathology, and parallels that in neurones and glia. Endothelial DNA damage and senescence are a brain ageing process that may contribute to dysfunction of the neurovascular unit in some elderly in iduals.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-LB-201
Abstract: Disease recurrence following multi-modal therapy is the single most adverse event in medulloblastoma (MB). Currently & % of relapsing patients die, accounting for ∼10% of childhood cancer deaths. MB is heterogeneous at diagnosis, comprising four molecular subgroups with distinct clinicopathological and molecular features and outcomes. The relevance of these features at relapse is unknown, making characterisation, modelling and targeted therapy of relapse biology essential to improve outcomes. However, relapsed MBs are not routinely biopsied in clinical practice. We undertook a first comprehensive investigation of the molecular, clinical and pathological features of 29 relapsed MBs and paired tumour s les taken at diagnosis, including the assessment of features with established significance at diagnosis (e.g. chromosome 17 and TP53 pathway status, MYC family (MYC, MYCN) gene lification, polyploidy, CTNNB1 mutation and molecular subgroup status). Molecular subgroup was concordant at diagnosis and relapse, however evidence of alteration of all other features examined was found in relapsed tumours, with the majority of changes (30/44) representing acquired high-risk events. Most notably, MYC family gene lifications and TP53 pathway defects commonly emerged in combination at relapse following conventional multimodal treatment (P=0.02, 7/22, 32%) and predicted rapid progression to death (P=0.016). These observations suggested aberrant activation of MYC family genes synergizes with TP53 inactivation in the genesis of biologically aggressive MB. To investigate any such relationship, we examined Trp53 status in our transgenic mouse model of spontaneously-arising MYCN-driven MB (GTML Glt1-tTA/TRE-MYCN-Luc). Somatic Trp53 mutations were found in 83% of tumors (n=10/12). Direct modelling of this interaction in GTML/Trp53KI/KI mice dramatically enhanced MB formation with 100% penetrance (43/43, median survival 47 days) in GTML/Trp53KI/KI versus 6% (3/50) in GTML P& .0001), faithfully mimicked clinicopathological characteristics of TP53-MYC family gene-associated relapsed human tumors, and validated the essential role of TP53 in potentiating the growth of MYCN-driven MB. Finally, therapeutic inhibition of Aurora-A kinase using MLN8237 in these tumours, and in derived neurospheres in vitro, promoted degradation of MYCN, reduced tumor growth and prolonged survival. In summary, while subgroup status remains stable, MBs display altered molecular, pathological and clinical features at relapse, and the emergence of combined TP53-MYC family gene defects is common following conventional therapy. Their association with rapid demise, coupled with their biological validation as driving and therapeutically exploitable events in a novel mouse MB model, strongly support further investigation and routine biopsy of relapse disease to drive future in idualised therapeutic strategies. Citation Format: Rebecca M. Hill, Sanne Kuijper, Janet Lindsey, Ed C. Schwalbe, Karen Barker, Jessica Boult, Daniel Williamson, Zai Ahmad, Albert Hallsworth, Sarra Ryan, Evon Poon, Simon Robinson, Ruth Ruddle, Florence Raynaud, Louise Howell, Colin Kwok, Abhijit Joshi, Sarah Nicholson, Stephen Crosier, Stephen Wharton, Tom Jacques, Keith Robson, Antony Michalski, Darren Hargrave, Barry Pizer, Simon Bailey, Fredrik J. Swartling, Kevin Petrie, William A. Weiss, Louis Chesler, Steve Clifford. MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2014-LB-201
Publisher: Wiley
Date: 15-06-2009
DOI: 10.1111/J.1471-4159.2009.06104.X
Abstract: Mutations in spastin are the most common cause of hereditary spastic paraplegia (HSP) but the mechanisms by which mutant spastin induces disease are not clear. Spastin functions to regulate microtubule organisation, and because of the essential role of microtubules in axonal transport, this has led to the suggestion that defects in axonal transport may underlie at least part of the disease process in HSP. However, as yet there is no direct evidence to support this notion. Here we analysed axonal transport in a novel mouse model of spastin-induced HSP that involves a pathogenic splice site mutation, which leads to a loss of spastin protein. A mutation located within the same splice site has been previously described in HSP. Spastin mice develop gait abnormalities that correlate with phenotypes seen in HSP patients and also axonal swellings containing cytoskeletal proteins, mitochondria and the amyloid precursor protein (APP). Pathological analyses of human HSP cases caused by spastin mutations revealed the presence of similar axonal swellings. To determine whether mutant spastin influenced axonal transport we quantified transport of two cargoes, mitochondria and APP-containing membrane bound organelles, in neurons from mutant spastin and control mice, using time-lapse microscopy. We found that mutant spastin perturbs anterograde transport of both cargoes. In neurons with axonal swellings we found that the mitochondrial axonal transport defects were exacerbated distal to axonal swellings both anterograde and retrograde transport were severely reduced. These results strongly support a direct role for defective axonal transport in the pathogenesis of HSP because of spastin mutation.
Publisher: Springer Science and Business Media LLC
Date: 06-01-2021
DOI: 10.1186/S40478-020-01109-Y
Abstract: Type 2 diabetes mellitus (T2D), characterised by peripheral insulin resistance, is a risk factor for dementia. In addition to its contribution to small and large vessel disease, T2D may directly damage cells of the brain neurovascular unit. In this study, we investigated the transcriptomic changes in cortical neurones, and associated astrocytes and endothelial cells of the neurovascular unit, in the ageing brain. Neurone, astrocyte, and endothelial cell-enriched mRNA, obtained by immuno-laser capture microdissection of temporal cortex (Brodmann area 21/22) from 6 cases with self-reported T2D in the Cognitive Function and Ageing Study neuropathology cohort, and an equal number of age and sex-matched controls, was assessed by microarray analysis. Integrated Molecular Pathway Level Analysis was performed using the Kyoto Encyclopaedia of Genes and Genomes database on significantly differentially expressed genes, defined as P 0.05 and fold-change ± 1.2. Hub genes identified from Weighted Gene Co-expression Network Analysis were validated in neurones using the NanoString nCounter platform. The expression and cellular localisation of proteins encoded by selected candidate genes were confirmed by immunohistochemistry. 912, 2202, and 1227 genes were significantly differentially expressed between cases with self-reported T2D and controls in neurones, astrocytes, and endothelial cells respectively. Changes in cortical neurones included alterations in insulin and other signalling pathways, cell cycle, cellular senescence, inflammatory mediators, and components of the mitochondrial respiratory electron transport chain. Impaired insulin signalling was shared by neurovascular unit cells with, additionally, apoptotic pathway changes in astrocytes and dysregulation of advanced glycation end-product signalling in endothelial cells. Transcriptomic analysis identified changes in key cellular pathways associated with T2D that may contribute to neuronal damage and dysfunction. These effects on brain cells potentially contribute to a diabetic dementia, and may provide novel approaches for therapeutic intervention.
Location: United Kingdom of Great Britain and Northern Ireland
Location: Mexico
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Stephen B Wharton.