ORCID Profile
0000-0001-8467-7286
Current Organisations
Lund University
,
Region Skåne Hälso- och sjukvård
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Publisher: Elsevier BV
Date: 04-2019
Publisher: Oxford University Press (OUP)
Date: 02-11-2016
DOI: 10.1093/BRAIN/AWW261
Publisher: Oxford University Press (OUP)
Date: 22-03-2017
DOI: 10.1093/BRAIN/AWX055
Publisher: Wiley
Date: 22-03-2022
DOI: 10.1111/EJN.15640
Abstract: People diagnosed with Parkinson's disease (PD) can experience significant neuropsychiatric symptoms, including cognitive impairment and dementia, the neuroanatomical substrates of which are not fully characterised. Symptoms associated with cognitive impairment and dementia in PD may relate to direct structural changes to the corpus callosum via primary white matter pathology or as a secondary outcome due to the degeneration of cortical regions. Using magnetic resonance imaging, the corpus callosum can be investigated at the midsagittal plane, where it converges to a contiguous mass and is not intertwined with other tracts. The objective of this project was thus twofold: First, we investigated possible changes in the thickness of the midsagittal callosum and cortex in patients with PD with varying levels of cognitive impairment and secondly, we investigated the relationship between the thickness of the midsagittal corpus callosum and the thickness of the cortex. Study participants included cognitively unimpaired PD participants ( n = 35), PD participants with mild cognitive impairment ( n = 22), PD participants with dementia ( n = 17) and healthy controls ( n = 27). We found thinning of the callosum in PD‐related dementia compared with PD‐related mild cognitive impairment and cognitively unimpaired PD participants. Regression analyses found thickness of the left medial orbitofrontal cortex to be positively correlated with thickness of the anterior callosum in PD‐related mild cognitive impairment. This study suggests that a midsagittal thickness model can uncover changes to the corpus callosum in PD‐related dementia, which occur in line with changes to the cortex in this advanced disease stage.
Publisher: Radiological Society of North America (RSNA)
Date: 12-2019
Publisher: Cold Spring Harbor Laboratory
Date: 16-07-2019
DOI: 10.1101/19002147
Abstract: Mild cognitive impairment in Parkinson disease places a high burden on patients and is likely a precursor to Parkinson disease-related dementia. Studying the functional connectivity and morphology of subcortical structures within basal ganglia-thalamocortical circuits may uncover neuroimaging biomarkers of cognitive dysfunction in PD. We used an atlas-based seed region-of-interest approach to investigate resting-state functional connectivity of important sub isions of the caudate nucleus, putamen and thalamus, between controls (n = 33), cognitively unimpaired Parkinson disease subjects (n = 33), Parkinson disease subjects with mild cognitive impairment (n = 22) and Parkinson disease subjects with dementia (n = 17). We then investigated how the morphology of the caudate, putamen and thalamus structures and differed between groups. Results indicate that cognitively unimpaired Parkinson disease subjects, compared to controls, display increased functional connectivity of the dorsal caudate, anterior putamen and mediodorsal thalamic sub isions with areas across the frontal lobe, as well as reduced functional connectivity of the dorsal caudate with posterior cortical and cerebellar regions. Compared to cognitively unimpaired subjects, Parkinson disease subjects with mild cognitive impairment demonstrated reduced functional connectivity of the mediodorsal thalamus with midline nodes within the executive-control network. Compared to subjects with mild cognitive impairment, subjects with dementia demonstrated reduced functional connectivity of the mediodorsal thalamus with the posterior cingulate cortex, a key node within the default-mode network. Extensive volumetric and surface-based deflation was found in Parkinson disease subjects with dementia. Our research demonstrates how functional connectivity of the caudate, putamen and thalamus are implicated in the pathophysiology of cognitive impairment and dementia in Parkinson disease, with mild cognitive impairment and dementia in Parkinson disease associated with a breakdown in functional connectivity of the mediodorsal thalamus with para- and posterior cingulate regions of the brain.
Publisher: Springer Science and Business Media LLC
Date: 11-2022
DOI: 10.1038/S41591-022-02049-X
Abstract: A major unanswered question in the dementia field is whether cognitively unimpaired in iduals who harbor both Alzheimer’s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study ( n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired in iduals who were amyloid PET-positive (A + ) and tau PET-positive (T + ) in the medial temporal lobe (A + T MTL + ) and/or in the temporal neocortex (A + T NEO-T + ) and compared them with A + T − and A − T − groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A + T NEO-T + (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A + T MTL + (HR = 14.6, 95% CI = 8.1–26.4) and A + T − (HR = 2.4, 95% CI = 1.4–4.3) groups versus the A − T − (reference) group. Both A + T MTL + (HR = 6.0, 95% CI = 3.4–10.6) and A + T NEO-T + (HR = 7.9, 95% CI = 4.7–13.5) groups also showed faster clinical progression to mild cognitive impairment than the A + T − group. Linear mixed-effect models indicated that the A + T NEO-T + ( β = −0.056 ± 0.005, T = −11.55, P 0.001), A + T MTL + ( β = −0.024 ± 0.005, T = −4.72, P 0.001) and A + T − ( β = −0.008 ± 0.002, T = −3.46, P 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A − T − (reference) group (all P 0.001). Both A + T NEO-T + ( P 0.001) and A + T MTL + ( P = 0.002) groups also progressed faster than the A + T − group. In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired in iduals and is therefore of high clinical relevance.
Publisher: Cold Spring Harbor Laboratory
Date: 07-04-2021
DOI: 10.1101/2021.04.01.21254789
Abstract: Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 in iduals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 in iduals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
Publisher: Wiley
Date: 18-09-2012
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2022
DOI: 10.1101/2022.05.23.22275241
Abstract: A major unanswered question in the dementia field is whether cognitively unimpaired in iduals who harbor both Alzheimer’s disease (AD) neuropathological hallmarks (i.e., amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multi-center amyloid and tau PET study (n=1325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired in iduals who were amyloid PET-positive (A+) and tau PET positive (T+) in the medial temporal lobe (A+T MTL +) and/or in the neocortex (A+T NEO +) and compared them with A+T- and A-T-groups. Cox proportional hazard models showed a substantially increased risk for progression to mild cognitive impairment in the A+T NEO + (Hazard ratio [HR]=19.2[95% confidence interval: 10.9-33.7]), A+T MTL + (HR=14.6[8.1-26.4) and A+T-(HR=2.4[1.4-4.3]) groups vs the A-T-(reference) group. Linear mixed effect models indicated that the A+T NEO + (β=-0.056±0.005, T=-11.55, p .001), A+T MTL + (β=-0.024±0.005, T=-4.72, p .001) and A+T-(β=-0.008±0.002, T=-3.46, p .001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T-(reference) group (all p .001). Evidence of advanced AD pathological changes provided by amyloid and tau PET is strongly associated with short-term (i.e., 3-5 years) cognitive decline in cognitively unimpaired in iduals and is therefore of high clinical relevance.
Publisher: Elsevier BV
Date: 03-2021
DOI: 10.1016/J.PNEUROBIO.2020.101904
Abstract: It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, β-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aβ
Publisher: Wiley
Date: 10-03-2014
DOI: 10.1111/APHA.12247
Abstract: Adipose tissue has an important function in total energy homeostasis, and its dysregulation may contribute to lifestyle-related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between in iduals with or without a family history of type 2 diabetes. The 6-month supervised exercise intervention was conducted in 47 healthy men (age 37.8 ± 4.3 years, BMI 28.5 ± 3.6 kg m(-2) ) with a previous low level of physical activity. RNA was analysed using GeneChip Human Gene 1.0 ST arrays (Affymetrix) before and after the exercise. We identified 2,560 significant transcripts differentially expressed before vs. after exercise with a false discovery rate (FDR) < 0.1%, including genes encoding the respiratory chain, histone subunits, small nucleolar RNAs and ribosomal proteins. Additionally, pathways enriched in response to exercise include the ribosome, oxidative phosphorylation, proteasome and many metabolic pathways, whereas the WNT and MAPK signalling pathways were down-regulated (FDR < 5%) after exercise. There were no significant differences in mRNA expression between in iduals with or without a family history of type 2 diabetes. Exercise increased the expression of genes involved in oxidative phosphorylation, which is the opposite of what has been seen in adipose tissue from elderly or obese in iduals with low physical fitness, and our study thereby demonstrates a mechanism for the beneficial effect of exercise.
Publisher: Wiley
Date: 05-2020
DOI: 10.1002/MDS.28039
Publisher: Springer Science and Business Media LLC
Date: 12-04-2021
DOI: 10.1007/S00259-021-05311-5
Abstract: [ 18 F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. A total of 2770 [ 18 F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [ 18 F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD). Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region. Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2022
Publisher: Elsevier BV
Date: 06-2021
Publisher: BMJ
Date: 10-11-2022
Abstract: A putative role for iron in driving Alzheimer’s disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aβ 42 /t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF s les from BioFINDER (n=1239 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aβ 42 /t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%–40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.
Publisher: Society of Nuclear Medicine
Date: 20-10-2016
DOI: 10.2967/JNUMED.116.174508
Abstract: Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of
Publisher: Springer Science and Business Media LLC
Date: 29-04-2021
Publisher: American Medical Association (AMA)
Date: 09-2019
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2021
DOI: 10.1101/2021.08.03.21261494
Abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis -instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.PSCYCHRESNS.2018.03.004
Abstract: We sought to investigate morphological and resting state functional connectivity changes to the striatal nuclei in Parkinson disease (PD) and examine whether changes were associated with measures of clinical function. Striatal nuclei were manually segmented on 3T-T1 weighted MRI scans of 74 PD participants and 27 control subjects, quantitatively analysed for volume, shape and also functional connectivity using functional MRI data. Bilateral caudate nuclei and putamen volumes were significantly reduced in the PD cohort compared to controls. When looking at left and right hemispheres, the PD cohort had significantly smaller left caudate nucleus and right putamen volumes compared to controls. A significant correlation was found between greater atrophy of the caudate nucleus and poorer cognitive function, and between greater atrophy of the putamen and more severe motor symptoms. Resting-state functional MRI analysis revealed altered functional connectivity of the striatal structures in the PD group. This research demonstrates that PD involves atrophic changes to the caudate nucleus and putamen that are linked to clinical dysfunction. Our work reveals important information about a key structure-function relationship in the brain and provides support for caudate nucleus and putamen atrophy as neuroimaging biomeasures in PD.
Publisher: Wiley
Date: 02-2022
DOI: 10.1002/ALZ.12549
Abstract: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total‐tau (t‐tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt‐Jakob registry (Creutzfeldt‐Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t‐tau in most real‐life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
Publisher: Cold Spring Harbor Laboratory
Date: 15-07-2019
DOI: 10.1101/19002139
Abstract: Parkinson’s disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD ( n = 32) compared to Controls ( n = 20). To investigate functional connectivity of the thalamus we sub ided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor sub isions of the thalamus and the supplementary motor area, and between prefrontal thalamic sub isions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of sub isions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.
Publisher: Wiley
Date: 08-02-2022
DOI: 10.1002/MDS.28958
Abstract: Neuroinflammation is implicated in the pathophysiology of Parkinson's disease (PD) and related conditions, yet prior clinical biomarker data report mixed findings. The aim was to measure a panel of neuroinflammatory acute phase response (APR) proteins in the cerebrospinal fluid (CSF) of participants with PD and related disorders. Eleven APR proteins were measured in the CSF of 867 participants from the BioFINDER cohort who were healthy (612) or had a diagnosis of PD (155), multiple system atrophy (MSA) (26), progressive supranuclear palsy (PSP) (22), dementia with Lewy bodies (DLB) (23), or Parkinson's disease with dementia (PDD) (29). CSF APR proteins were mostly unchanged in PD, with only haptoglobin and α1‐antitrypsin significantly elevated compared to controls. These proteins were variably increased in the other disorders. Certain protein components yielded unique signatures according to diagnosis: ferritin and transthyretin were selectively elevated in MSA and discriminated these patients from all others. Haptoglobin was selectively increased in PSP, discriminating this disease from MSA when used in combination with ferritin and transthyretin. This panel of proteins did not correlate well with severity of motor impairment in any disease category, but several (particularly ceruloplasmin and ferritin) were associated with memory performance (Mini‐Mental State Examination) in patients with DLB and PDD. These findings provide new insights into inflammatory changes in PD and related disorders while also introducing biomarkers of potential clinical diagnostic utility. © 2022 International Parkinson and Movement Disorder Society
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000381857
Abstract: b i Background/Aims: /i /b Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. b i Methods: /i /b The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of ‘definite', ‘very likely', ‘probable', or ‘possible' PD. b i Results: /i /b A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. b i Conclusions: /i /b This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-07-2019
DOI: 10.1212/WNL.0000000000007831
Abstract: To determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)–related decline. In 1,120 cognitively unimpaired in iduals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore s le size as a function of treatment effect. Cognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline however, these findings were all cohort-specific. Despite design differences across the cohorts, with large s le sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures. A preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%–50% delays clinically relevant impairment by 3 years—a potentially meaningful treatment effect. However, assuming a 40%–50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required s le size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2023
Publisher: Springer Science and Business Media LLC
Date: 06-04-2022
DOI: 10.1038/S41586-022-04554-Y
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify in idual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future s le of MRI data ( www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the ersity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of in iduals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of in idual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
Publisher: SAGE Publications
Date: 17-11-2022
DOI: 10.1177/00048674211058684
Abstract: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of erse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for ex le with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2] parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
Publisher: Wiley
Date: 31-07-2019
Publisher: Cold Spring Harbor Laboratory
Date: 10-06-2021
DOI: 10.1101/2021.06.08.447489
Abstract: Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify in idual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here, we built an interactive resource to benchmark brain morphology, www.brainchart.io , derived from any current or future s le of magnetic resonance imaging (MRI) data. With the goal of basing these reference charts on the largest and most inclusive dataset available, we aggregated 123,984 MRI scans from 101,457 participants aged from 115 days post-conception through 100 postnatal years, across more than 100 primary research studies. Cerebrum tissue volumes and other global or regional MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 showed high stability of in idual centile scores over longitudinal assessments and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared to non-centiled MRI phenotypes, and provided a standardised measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In sum, brain charts are an essential first step towards robust quantification of in idual deviations from normative trajectories in multiple, commonly-used neuroimaging phenotypes. Our collaborative study proves the principle that brain charts are achievable on a global scale over the entire lifespan, and applicable to analysis of erse developmental and clinical effects on human brain structure. Furthermore, we provide open resources to support future advances towards adoption of brain charts as standards for quantitative benchmarking of typical or atypical brain MRI scans.
Publisher: Wiley
Date: 11-2018
DOI: 10.1002/ANA.25333
Publisher: Oxford University Press (OUP)
Date: 20-11-2018
DOI: 10.1093/IJE/DYY230
Abstract: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson’s disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. A total of 715 incident PD cases were ascertained in a cohort of 220 494 in iduals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose–response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking years were 0.84 [95% confidence interval (CI) 0.67–1.07], 20–29 years 0.73 (95% CI 0.56–0.96) and years 0.54 (95% CI 0.43–0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose–response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49–0.99) ruled out the effect of unmeasured confounding. These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CLINBIOCHEM.2019.05.006
Abstract: Alzheimer's disease (AD) biomarkers, such as cerebrospinal fluid (CSF) amyloid-β (1-42 Aβ42), can provide high diagnostic accuracy. Several immunoassays are available for Aβ42 quantitation, but standardisation across assays remains an issue. We compared the Elecsys® β-Amyloid (1-42) CSF assay with three assays and two liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Three method comparison studies evaluated the correlation between the Elecsys® β-Amyloid (1-42) CSF assay versus: INNOTEST® β-AMYLOID(1-42) (860 s les) and the Roche Diagnostics-developed LC-MS/MS method (250 s les) INNO-BIA AlzBio3 and the University of Pennsylvania (UPenn)-developed LC-MS/MS method (250 s les) and ADx-EUROIMMUN Beta-Amyloid (1-42) enzyme-linked immunosorbent assay (ELISA) (49 s les). High correlation was demonstrated between Elecsys® β-Amyloid (1-42) CSF and comparator assays: INNOTEST® β-AMYLOID(1-42) (Spearman's ρ, 0.954) INNO-BIA AlzBio3 (Spearman's ρ, 0.864) ADx-EUROIMMUN Beta-Amyloid (1-42) ELISA (Pearson's r, 0.925). Elecsys® assay and LC-MS/MS measurements were highly correlated: Pearson's r, 0.949 (Roche Diagnostics-developed method) and 0.943 (UPenn-developed method). Findings from this multicentre evaluation further support use of the Elecsys® β-Amyloid (1-42) CSF assay to aid AD diagnosis. CSF-based certified reference materials should improve agreement across assays and mass spectrometry-based methods, which is essential to establish a global uniform CSF Aβ42 cut-off to detect amyloid pathology.
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No related grants have been discovered for Oskar Hansson.