Fascicle- and Glucose-Specific Deterioration in White Matter Energy Supply in Alzheimer’s Disease

Article type: Research Article

Authors: Roy, Maggie^{a; b; *} | Rheault, François^d | Croteau, Etienne^{e; f} | Castellano, Christian-Alexandre^a | Fortier, Mélanie^a | St-Pierre, Valérie^a | Houde, Jean-Christophe^d | Turcotte, Éric E.^{e; f; g; h} | Bocti, Christian^{a; c} | Fulop, Tamas^{a; c} | Cunnane, Stephen C.^{a; b; c; 1} | Descoteaux, Maxime^{d; 1}

Affiliations: [a] Research Center on Aging, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada | [b] Department of Pharmacology and Physiology, Université de Sherbrooke, Sherbrooke, QC, Canada | [c] Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada | [d] Department of Computer Science, Université de Sherbrooke, Sherbrooke, QC, Canada | [e] CR-CHUS, CIUSSS de l’Estrie – CHUS, Sherbrooke, QC, Canada | [f] Sherbrooke Molecular Imaging Center, Université de Sherbrooke, Sherbrooke, QC, Canada | [g] Department of Nuclear Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada | [h] Department of Radiobiology, Université de Sherbrooke, Sherbrooke, QC, Canada

Correspondence: [*] Correspondence to: Maggie Roy, PhD, Research Center on Aging, 1036 Belvedere South, Sherbrooke (QC) J1H 4C4, Canada. Tel.: +1 819 780 2220; E-mail: [email protected].

Note: [1] These authors are co-senior authors on this work.

Abstract: Background:White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer’s disease (AD), glucose and ketones, the brain’s two main fuels, are rarely quantified in white matter in AD. Objective:Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14). Methods:Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. Results:The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (–22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. Conclusion:To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

Keywords: Alzheimer’s disease, diffusion MRI, FDG, ketones, PET, white matter

DOI: 10.3233/JAD-200213

Journal: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 863-881, 2020