Lower Brain ¹⁸F-Fluorodeoxyglucose Uptake But Normal ¹¹C-Acetoacetate Metabolism in Mild Alzheimer's Disease Dementia

Article type: Research Article

Authors: Castellano, Christian-Alexandre^{a; b; *} | Nugent, Scott^{a; b} | Paquet, Nancy^c | Tremblay, Sébastien^d | Bocti, Christian^{a; c} | Lacombe, Guy^{a; e} | Imbeault, Hélène^a | Turcotte, Éric^{c; d} | Fulop, Tamas^{a; e} | Cunnane, Stephen C.^{a; e}

Affiliations: [a] Research Center on Aging, Health and Social Sciences Center, Geriatrics Institute, Sherbrooke, QC, Canada | [b] Department Physiology and Biophysics, Université de Sherbrooke, Sherbrooke, QC, Canada | [c] Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, QC, Canada | [d] Sherbrooke Molecular Imaging Center, Université de Sherbrooke, Sherbrooke, QC, Canada | [e] Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada

Correspondence: [*] Correspondence to: Christian-Alexandre Castellano, Research Center on Aging, 1036 Belvedere South, Sherbrooke, QC, J1H 4C4, Canada. Tel.: +1 819 780 2220; Fax: +1 819 829 7141; E-mail: [email protected].

Abstract: Background:The cerebral metabolic rate of glucose (CMRg) is lower in specific brain regions in Alzheimer's disease (AD). The ketones, acetoacetate and β-hydroxybutyrate, are the brain's main alternative energy substrates to glucose. Objective:To gain insight into brain fuel metabolism in mild AD dementia by determining whether the regional CMR and the rate constant of acetoacetate (CMRa and Ka, respectively) reflect the same metabolic deficit reported for cerebral glucose uptake (CMRg and Kg). Methods:Mild AD dementia (Mild AD; n = 10, age 76 y) patients were compared with gender- and age-matched cognitively normal older adults (Controls; n = 29, age 75 y) using a PET/MRI protocol and analyzed with both ROI- and voxel-based methods. Results:ROI-based analysis showed 13% lower global CMRg in the gray matter of mild AD dementia versus Controls (34.2 ± 5.0 versus 38.3 ± 4.7 μmol/100 g/min, respectively; p = 0.015), with CMRg and Kg in the parietal cortex, posterior cingulate, and thalamus being the most affected (p ≤ 0.022). Neither global nor regional CMRa or Ka differed between the two groups (all p ≥ 0.188). Voxel-based analysis showed a similar metabolic pattern to ROI-based analysis with seven clusters of significantly lower CMRg in the mild AD dementia group (uncorrected p ≤ 0.005) but with no difference in CMRa. Conclusion:Regional brain energy substrate hypometabolism in mild AD dementia may be specific to impaired glucose uptake and/or utilization. This suggests a potential avenue for compensating brain energy deficit in AD dementia with ketones.

Keywords: Acetoacetate, Alzheimer's disease, β-hydroxybutyrate, cerebral metabolic rate, energy metabolism, glucose, ketones

DOI: 10.3233/JAD-141074

Journal: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1343-1353, 2015