Journal article
Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease
Annals of neurology, Vol.90(5), pp.751-762
11/01/2021
DOI: 10.1002/ana.26233
PMCID: PMC8841129
PMID: 34617306
Abstract
Objective Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology. Methods Cortical thickness (N) and F-18-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups. Results The summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected. Interpretation These data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021
Details
- Title: Subtitle
- Tau-Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease
- Creators
- Sandhitsu R. Das - University of PennsylvaniaXueying Lyu - University of PennsylvaniaMichael Tran Duong - University of PennsylvaniaLong Xie - University of PennsylvaniaLauren McCollum - University of Tennessee at KnoxvilleRobin Flores - Univ Caen Normandie, INSERM UMRS U1237, Caen, FranceMichael DiCalogero - University of PennsylvaniaDavid J. Irwin - University of PennsylvaniaBradford C. Dickerson - Massachusetts General HospitalIlya M. Nasrallah - University of PennsylvaniaPaul A. Yushkevich - University of PennsylvaniaDavid A. Wolk - University of PennsylvaniaAlzheimer's Disease Neuroimaging Initiative
- Contributors
- HyungSub Shim (Contributor) - University of Iowa, Neurology
- Resource Type
- Journal article
- Publication Details
- Annals of neurology, Vol.90(5), pp.751-762
- DOI
- 10.1002/ana.26233
- PMID
- 34617306
- PMCID
- PMC8841129
- NLM abbreviation
- Ann Neurol
- ISSN
- 0364-5134
- eISSN
- 1531-8249
- Publisher
- Wiley
- Number of pages
- 12
- Grant note
- W81XWH-12-2-0012 / DOD ADNI (Department of Defense) BioClinica, Inc. National Institute of Biomedical Imaging and Bioengineering; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Biomedical Imaging & Bioengineering (NIBIB) Eli Lilly and Company; Eli Lilly Fujirebio Araclon Biotech Cogstate; CogState Limited CereSpir, Inc. GE Healthcare; General Electric Meso Scale Diagnostics, LLC. Northern California Institute for Research and Education Lundbeck; Lundbeck Corporation F. Hoffmann-La Roche Ltd; Hoffmann-La Roche AbbVie EuroImmun NeuroRx Research; Neurotrack Technologies Johnson & Johnson Pharmaceutical Research & Development LLC.; Johnson & Johnson; Johnson & Johnson USA U01 AG024904 / Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Merck Co., Inc.; Merck & Company Lumosity Biogen Piramal Imaging Servier Takeda Pharmaceutical Company; Takeda Pharmaceutical Company Ltd Bristol-Myers Squibb Company; Bristol-Myers Squibb Eisai Inc.; Eisai Co Ltd Alzheimer's Association IXICO Ltd. Pfizer Inc.; Pfizer Janssen Alzheimer Immunotherapy Research & Development, LLC. Transition Therapeutics National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Elan Pharmaceuticals, Inc. Alzheimer's Drug Discovery Foundation Novartis Pharmaceuticals Corporation; Novartis Genentech, Inc.; Roche Holding; Genentech
- Language
- English
- Date published
- 11/01/2021
- Academic Unit
- Neurology; Psychiatry
- Record Identifier
- 9984302211702771
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