Abstract
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.
Competing Interest Statement
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.
Footnotes
↵** Data used in preparation of this article were obtained, in part, from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
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