TY - JOUR
T1 - Amyloid-PET of the white matter
T2 - Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease
AU - for the Medical Imaging Trials Network of Canada (MITNEC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI)
AU - Ottoy, Julie
AU - Ozzoude, Miracle
AU - Zukotynski, Katherine
AU - Kang, Min Su
AU - Adamo, Sabrina
AU - Scott, Christopher
AU - Ramirez, Joel
AU - Swardfager, Walter
AU - Lam, Benjamin
AU - Bhan, Aparna
AU - Mojiri, Parisa
AU - Kiss, Alex
AU - Strother, Stephen
AU - Bocti, Christian
AU - Borrie, Michael
AU - Chertkow, Howard
AU - Frayne, Richard
AU - Hsiung, Robin
AU - Laforce, Robert Jr
AU - Noseworthy, Michael D.
AU - Prato, Frank S.
AU - Sahlas, Demetrios J.
AU - Smith, Eric E.
AU - Kuo, Phillip H.
AU - Chad, Jordan A.
AU - Pasternak, Ofer
AU - Sossi, Vesna
AU - Thiel, Alexander
AU - Soucy, Jean Paul
AU - Tardif, Jean Claude
AU - Black, Sandra E.
AU - Goubran, Maged
N1 - Funding Information:
We would like to express our deepest gratitude towards 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 ), and to Eli Lilly & Company for providing the F-florbetapir ligand. 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. 18
Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: 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 partly 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.
Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the Canadian Institute for Health Research (CIHR) MOP Grant #13129, CIHR Foundation grant #159910, CIHR Project Grant #PJT178059, the L.C Campbell Foundation and the SEB Centre for Brain Resilience and Recovery. The work was also supported by the Medical Imaging Trial Network of Canada (MITNEC) Grant #NCT02330510. 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). 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 the Canada Research Chairs program. Acknowledgements
Publisher Copyright:
© The Author(s) 2023.
PY - 2023/6
Y1 - 2023/6
N2 - White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.
AB - White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.
KW - Alzheimer’s disease
KW - amyloid-PET
KW - diffusion MRI
KW - free water
KW - white matter
UR - http://www.scopus.com/inward/record.url?scp=85147529871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85147529871&partnerID=8YFLogxK
U2 - 10.1177/0271678X231152001
DO - 10.1177/0271678X231152001
M3 - Article
C2 - 36695071
AN - SCOPUS:85147529871
SN - 0271-678X
VL - 43
SP - 921
EP - 936
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 6
ER -