| 1. |
- Knopman, David S., et al.
(författare)
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The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease : Perspectives from the Research Roundtable
- 2018
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:4, s. 563-575
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Forskningsöversikt (refereegranskat)abstract
- The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the “A, T, N System” (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.
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| 2. |
- Mielke, Michelle M, et al.
(författare)
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Comparison of variables associated with cerebrospinal fluid neurofilament, total-tau, and neurogranin.
- 2019
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 15:11, s. 1437-1447
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Tidskriftsartikel (refereegranskat)abstract
- Three cerebrospinal fluid (CSF) markers of neurodegeneration (N) (neurofilament light [NfL], total-tau [T-tau], and neurogranin [Ng]) have been proposed under the AT(N) scheme of the National Institute on Aging-Alzheimer's Association Research Framework.We examined, in a community-based population (N = 777, aged 50-95) (1) what variables were associated with each of the CSF (N) markers, and (2) whether the variables associated with each marker differed by increased brain amyloid. CSF T-tau was measured with an automated electrochemiluminescence Elecsys immunoassay; NfL and Ng were measured with in-house enzyme-linked immunosorbent assays.Multiple variables were differentially associated with CSF NfL and T-tau levels, but not Ng. Most associations were attenuated after adjustment for age and sex. T-tau had the strongest association with cognition in the presence of amyloidosis, followed by Ng. Variables associations with NfL did not differ by amyloid status.Understanding factors that influence CSF (N) markers will assist in the interpretation and utility of these markers in clinical practice.
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| 3. |
- Poulakis, Konstantinos, et al.
(författare)
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Fully bayesian longitudinal unsupervised learning for the assessment and visualization of AD heterogeneity and progression
- 2020
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Ingår i: Aging. - : IMPACT JOURNALS LLC. - 1945-4589 .- 1945-4589. ; 12:13, s. 12622-12647
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Tidskriftsartikel (refereegranskat)abstract
- Tau pathology and brain atrophy are the closest correlate of cognitive decline in Alzheimer's disease (AD). Understanding heterogeneity and longitudinal progression of atrophy during the disease course will play a key role in understanding AD pathogenesis. We propose a framework for longitudinal clustering that simultaneously: 1) incorporates whole brain data, 2) leverages unequal visits per individual, 3) compares clusters with a control group, 4) allows for study confounding effects, 5) provides cluster visualization, 6) measures clustering uncertainty. We used amyloid-beta positive AD and negative healthy subjects, three longitudinal structural magnetic resonance imaging scans (cortical thickness and subcortical volume) over two years. We found three distinct longitudinal AD brain atrophy patterns: one typical diffuse pattern (n=34, 47.2%), and two atypical patterns: minimal atrophy (n=23 31.9%) and hippocampal sparing (n=9, 12.5%). We also identified outliers (n=3, 4.2%) and observations with uncertain classification (n=3, 4.2%). The clusters differed not only in regional distributions of atrophy at baseline, but also longitudinal atrophy progression, age at AD onset, and cognitive decline. A framework for the longitudinal assessment of variability in cohorts with several neuroimaging measures was successfully developed. We believe this framework may aid in disentangling distinct subtypes of AD from disease staging.
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| 4. |
- Seto, Mabel, et al.
(författare)
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Exploring common genetic contributors to neuroprotection from amyloid pathology.
- 2022
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Ingår i: Brain communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical Alzheimer's disease describes some individuals who harbour Alzheimer's pathologies but are asymptomatic. For this study, we hypothesized that genetic variation may help protect some individuals from Alzheimer's-related neurodegeneration. We therefore conducted a genome-wide association study using 5 891 064 common variants to assess whether genetic variation modifies the association between baseline beta-amyloid, as measured by both cerebrospinal fluid and positron emission tomography, and neurodegeneration defined using MRI measures of hippocampal volume. We combined and jointly analysed genotype, biomarker and neuroimaging data from non-Hispanic white individuals who were enrolled in four longitudinal ageing studies (n = 1065). Using regression models, we examined the interaction between common genetic variants (Minor Allele Frequency >0.01), including APOE-ɛ4 and APOE-ɛ2, and baseline cerebrospinal levels of amyloid (CSF Aβ42) on baseline hippocampal volume and the longitudinal rate of hippocampal atrophy. For targeted replication of top findings, we analysed an independent dataset (n = 808) where amyloid burden was assessed by Pittsburgh Compound B ([11C]-PiB) positron emission tomography. In this study, we found that APOE-ɛ4 modified the association between baseline CSF Aβ42 and hippocampal volume such that APOE-ɛ4 carriers showed more rapid atrophy, particularly in the presence of enhanced amyloidosis. We also identified a novel locus on chromosome 3 that interacted with baseline CSF Aβ42. Minor allele carriers of rs62263260, an expression quantitative trait locus for the SEMA5B gene (P = 1.46 × 10-8; 3:122675327) had more rapid neurodegeneration when amyloid burden was high and slower neurodegeneration when amyloid was low. The rs62263260 × amyloid interaction on longitudinal change in hippocampal volume was replicated in an independent dataset (P = 0.0112) where amyloid burden was assessed by positron emission tomography. In addition to supporting the established interaction between APOE and amyloid on neurodegeneration, our study identifies a novel locus that modifies the association between beta-amyloid and hippocampal atrophy. Annotation results may implicate SEMA5B, a gene involved in synaptic pruning and axonal guidance, as a high-quality candidate for functional confirmation and future mechanistic analysis.
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