In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease
Tatsuhiro Terada, Tomokazu Obi, Tomoyasu Bunai, Takashi Matsudaira, Etsuji Yoshikawa, Ichiro Ando, Masami Futatsubashi, Hideo Tsukada, Yasuomi Ouchi
Abstract
<h3>Objective</h3> 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 [<sup>18</sup>F]2-tert- butyl-4-chloro-5–2H- pyridazin-3-one ([<sup>18</sup>F]BCPP-EF), which binds to MC-I, and compared [<sup>18</sup>F]BCPP-EF uptake with <sup>18</sup>F-fluorodeoxyglucose ([<sup>18</sup>F]FDG) uptake in the living AD brain. <h3>Methods</h3> First, the total distribution volume (V<sub>T</sub>) of [<sup>18</sup>F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether V<sub>T</sub> could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [<sup>18</sup>F]BCPP-EF or [<sup>18</sup>F]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 ([<sup>18</sup>F]BCPP-EF) and glucose metabolism ([<sup>18</sup>F]FDG) were performed. <h3>Results</h3> The [<sup>18</sup>F]BCPP-EF V<sub>T</sub> was positively correlated with the [<sup>18</sup>F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [<sup>18</sup>F]BCPP-EF SUVRg, but not the [<sup>18</sup>F]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 [<sup>18</sup>F]BCPP-EF SUVRg and [<sup>18</sup>F]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD. <h3>Conclusions</h3> 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.