ARTICLE In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease Tatsuhiro Terada, MD, PhD, Tomokazu Obi, MD, PhD, Tomoyasu Bunai, MD, Takashi Matsudaira, MD, Etsuji Yoshikawa, BA, Ichiro Ando, BA, Masami Futatsubashi, BA, Hideo Tsukada, PhD, and Yasuomi Ouchi, MD, PhD Neurology ® 2020;94:1-13. doi:10.1212/WNL.0000000000009249 Correspondence Dr. Ouchi ouchi@hama-med.ac.jp Abstract Objective In vivo glycolysis-related glucose metabolism and electron transport chain-related mitochon- drial 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 mito- chondrial complex-I (MC-I) with the novel PET probe [ 18 F]2-tert- butyl-4-chloro-5–2H- pyridazin-3-one ([ 18 F]BCPP-EF), which binds to MC-I, and compared [ 18 F]BCPP-EF uptake with 18 F-fluorodeoxyglucose ([ 18 F]FDG) uptake in the living AD brain. Methods First, the total distribution volume (V T ) of [ 18 F]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 [ 18 F]BCPP-EF or [ 18 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 ([ 18 F]BCPP-EF) and glucose metabolism ([ 18 F]FDG) were performed. Results The [ 18 F]BCPP-EF V T was positively correlated with the [ 18 F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [ 18 F]BCPP-EF SUVRg, but not the [ 18 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 [ 18 F]BCPP-EF SUVRg and [ 18 F] 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. RELATED ARTICLE Editorial Mitochondria in Alzheimer brains: A PET project shows complex changes Page XXX From the Department of Biofunctional Imaging (T.T., T.B., T.M., Y.O.), Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine; Department of Neurology (T.T., T.O., T.M.), Shizuoka Institute of Epilepsy and Neurological Disorders; and Central Research Laboratory (E.Y., I.A., M.F., H.T.), Hamamatsu Photonics KK; and Hamamatsu PET Imaging Center (I.A., M.F.), Hamamatsu Medical Photonics Foundation, Japan. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Copyright © 2020 American Academy of Neurology 1 Copyright © 2020 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Published Ahead of Print on March 5, 2020 as 10.1212/WNL.0000000000009249