In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease

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 [¹⁸F]2-tert- butyl-4-chloro-5–2H- pyridazin-3-one ([¹⁸F]BCPP-EF), which binds to MC-I, and compared [¹⁸F]BCPP-EF uptake with ¹⁸F-fluorodeoxyglucose ([¹⁸F]FDG) uptake in the living AD brain. Methods First, the total distribution volume (V_T) of [¹⁸F]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 [¹⁸F]BCPP-EF or [¹⁸F]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 ([¹⁸F]BCPP-EF) and glucose metabolism ([¹⁸F]FDG) were performed. Results The [¹⁸F]BCPP-EF V_T was positively correlated with the [¹⁸F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [¹⁸F]BCPP-EF SUVRg, but not the [¹⁸F]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 [¹⁸F]BCPP-EF SUVRg and [¹⁸F]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.