In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease
- 14 April 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 94 (15), E1592-E1604
- https://doi.org/10.1212/WNL.0000000000009249
Abstract
Objective In vivo glycolysis-related glucose metabolism and electron transport chain-related mitochondrial activity may be different regionally in the brains of patients with Alzheimer disease (AD). To test this hypothesis regarding AD pathophysiology, we measured the availability of mitochondrial complex-I (MC-I) with the novel PET probe [F-18]2-tert- butyl-4-chloro-5-2H- pyridazin-3-one ([F-18]BCPP-EF), which binds to MC-I, and compared [F-18]BCPP-EF uptake with F-18-fluorodeoxyglucose ([F-18]FDG) uptake in the living AD brain. Methods First, the total distribution volume (V-T) of [F-18]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether V-T could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [F-18]BCPP-EF or [F-18]FDG, respectively. Second, 32 patients with AD were scanned semiquantitatively with double PET tracers. Interparticipant and intraparticipant comparisons of the levels of MC-I activity ([F-18]BCPP-EF) and glucose metabolism ([F-18]FDG) were performed. Results The [F-18]BCPP-EF V-T was positively correlated with the [F-18]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [F-18]BCPP-EF SUVRg, but not the [F-18]FDG SUVRg, was significantly lower in the parahippocampus in patients with AD, highlighting the prominence of oxidative metabolic failure in the medial temporal cortex. Robust positive correlations between the [F-18]BCPP-EF SUVRg and [F-18]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD. Conclusions Mitochondrial dysfunction in the parahippocampus was shown in early-stage AD. Mitochondria-related energy failure may precede glycolysis-related hypometabolism in regions with pathologically confirmed early neurodegeneration in AD.This publication has 41 references indexed in Scilit:
- Brain Imaging in Alzheimer DiseaseCold Spring Harbor Perspectives in Medicine, 2012
- Neuropathological Alterations in Alzheimer DiseaseCold Spring Harbor Perspectives in Medicine, 2011
- Autoimmunity in Amyotrophic Lateral Sclerosis: Past and PresentNeurology Research International, 2011
- fMRI language dominance and FDG-PET hypometabolismNeurology, 2011
- Pittsburgh Compound B (11C-PIB) and Fluorodeoxyglucose (18 F-FDG) PET in Patients With Alzheimer Disease, Mild Cognitive Impairment, and Healthy ControlsJournal of Geriatric Psychiatry and Neurology, 2010
- Oxidative Metabolism in Cultured Rat Astroglia: Effects of Reducing the Glucose Concentration in the Culture Medium and of D-Aspartate or Potassium StimulationJournal of Cerebral Blood Flow & Metabolism, 2005
- Spatial and temporal relationships between plaques and tangles in Alzheimer-pathologyNeurobiology of Aging, 2004
- Posterior cingulate cortex in Alzheimer's diseaseThe Lancet, 1994
- Alzheimer's Disease: The Amyloid Cascade HypothesisScience, 1992
- A New Clinical Scale for the Staging of DementiaThe British Journal of Psychiatry, 1982