@article{886aab028401442395fc6f1619dc7ee3,
title = "Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET",
abstract = "It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition (18F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. Highlights: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.",
keywords = "Alzheimer's disease, amyloid, biomarker, cognition, cortical atrophy, glucose metabolism, neurodegeneration, small vessel disease, vascular, white matter disease, white matter hyperintensities",
author = "{for the Medical Imaging Trial Network of Canada (MITNEC) and Alzheimer's Disease Neuroimaging Initiative (ADNI)} and Julie Ottoy and Miracle Ozzoude and Katherine Zukotynski and Sabrina Adamo and Christopher Scott and Vincent Gaudet and Joel Ramirez and Walter Swardfager and Hugo Cogo-Moreira and Benjamin Lam and Aparna Bhan and Parisa Mojiri and Kang, {Min Su} and Rabin, {Jennifer S.} and Alex Kiss and Stephen Strother and Christian Bocti and Michael Borrie and Howard Chertkow and Richard Frayne and Robin Hsiung and Laforce, {Robert Jr} and Noseworthy, {Michael D.} and Prato, {Frank S.} and Sahlas, {Demetrios J.} and Smith, {Eric E.} and Kuo, {Phillip H.} and Vesna Sossi and Alexander Thiel and Soucy, {Jean Paul} and Tardif, {Jean Claude} and Black, {Sandra E.} and Maged Goubran",
note = "Funding Information: Dr. Black has received in kind support for PET ligands from GE Healthcare and Eli Lilly Avid. She has received personal fees for educational talks from Biogen and for advisory committees from Biogen and Hoffmann La Roche. She is a Principal Investigator or Sub Investigator for clinical trials with funding to the institution only for the following companies: Hoffmann La Roche, Biogen Eisai, Eli Lilly, UCB Biopharma SRL, Novo Nordisk, and Alector Inc. Dr. Tardif reports research grants from Amarin, AstraZeneca, Ceapro, DalCor Pharmaceuticals, Esperion, Ionis, Novartis, Pfizer, RegenXBio, and Sanofi; honoraria from AstraZeneca, DalCor Pharmaceuticals, HLS Pharmaceuticals, and Pendopharm; minor equity interest from DalCor Pharmaceuticals; and authorship of patents on pharmacogenomics‐guided CETP inhibition, use of colchicine after myocardial infarction, and use of colchicine for coronavirus infection (Dr. Tardif waived his rights in the colchicine patents). Dr. Bocti reports an investment in IMEKA. Dr. Noseworthy is the CEO/director and cofounder of TBIfinder Inc. Dr. Kuo is an employee of Invicro. He is a consultant and/or speaker for Amgen, Bayer, Chimerix, Eisai, Fusion Pharma, General Electric Healthcare, Invicro, Novartis, and UroToday. He is a recipient of research grants from Blue Earth Diagnostics, and General Electric Healthcare. Dr. Strother is a shareholder and senior scientific consultant for ADMdx, Inc., which receives NIH funding, and this work was partially supported by research grants from Canadian Institutes of Health Research (CIHR), and the Ontario Brain Institute in Canada. Dr. Smith consulted for Eli Lilly and for the Data Safety Monitoring Board for the U.S. NIH. Dr. Borrie is the Medical Director for the Aging Brain and Memory Clinic, an investigator with the Cognitive Clinical Research Group (CCRG), Past President of the Consortium for Canadian Centres for Clinical Cognitive Research (C5R). He is the platform lead for the Comprehensive Assessment of Neurodegeneration and Aging (COMPASS‐ND) observational study of the Canadian Collaboration on Neurodegeneration in Aging (CCNA). Since 1995 the CCRG has been a leading Canadian research site conducting randomized controlled trials of new potential treatments for Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease. Author disclosures are available in the supporting information. Funding Information: We would like to express our deepest gratitude toward all the participants and caregivers for their support and participation in this study. We are grateful for the support of the Medical Imaging Trial Network of Canada (MITNEC; https://clinicaltrials.gov/ct2/show/NCT02330510?term=mitnec+sandra+black &rank=1) Grant #NCT02330510, and to Eli Lilly & Company for providing the 18F‐florbetapir ligand. In addition, part of the data collection and sharing for this project was funded by ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research provided some funding to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This study was funded by the Canadian Institute for Health Research (CIHR) MOP Grant #13129, CIHR Foundation grant #159910, the L.C Campbell Foundation, and the SEB Centre for Brain Resilience and Recovery. JO is supported by the Alzheimer's Association fellowship (AARF‐21‐848556). MG is supported by Gerald Heffernan foundation, the Donald Stuss Young Investigator innovation award, and CIHR Grant #PJT178059. Publisher Copyright: {\textcopyright} 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2023",
month = apr,
doi = "10.1002/alz.12750",
language = "English (US)",
volume = "19",
pages = "1503--1517",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "4",
}