Mitochondrial complex I abnormalities is associated with tau and clinical symptoms in mild Alzheimer’s disease

• Published in: Molecular neurodegeneration Vol. 16; no. 1; pp. 28 - 12
• Main Authors: Terada, Tatsuhiro, Therriault, Joseph, Kang, Min Su Peter, Savard, Melissa, Pascoal, Tharick Ali, Lussier, Firoza, Tissot, Cecile, Wang, Yi-Ting, Benedet, Andrea, Matsudaira, Takashi, Bunai, Tomoyasu, Obi, Tomokazu, Tsukada, Hideo, Ouchi, Yasuomi, Rosa-Neto, Pedro
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 26.04.2021; BioMed Central; BMC
• Subjects: [18F]BCPP-EF; Advertising executives; Age; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimer’s disease (AD); Aminopyridines - pharmacokinetics; Amyloid; Aniline Compounds - pharmacokinetics; Autopsy; Benzothiazoles - pharmacokinetics; Brain cancer; Brain Chemistry; Brain injury; Carbon Radioisotopes; Cerebrovascular disease; Data processing; Dementia; Dementia disorders; Electron transport; Electron transport chain; Electron Transport Complex I - analysis; Entorhinal Cortex - chemistry; Entorhinal Cortex - diagnostic imaging; Female; Fluorine Radioisotopes; Humans; Hydrocephalus; Image processing; Magnetic Resonance Imaging; Male; Memory; Mental Status and Dementia Tests; Middle Aged; Mitochondria; NADH-ubiquinone oxidoreductase; Neurodegenerative diseases; Neuroimaging; Oxidative stress; Pathogenesis; Pathology; PET; PET imaging; Positron emission tomography; Pyridazines - pharmacokinetics; Pyridines - pharmacokinetics; Radiopharmaceuticals - pharmacokinetics; Severity of Illness Index; Symptom Assessment; Tau; Tau protein; tau Proteins - analysis; Thiazoles - pharmacokinetics; Traumatic brain injury; Japan; [18F]BCPP-EF; Tau; Mitochondria; Amyloid; Alzheimer’s disease (AD); PET
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-021-00448-1

Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer's disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [ F]BCPP-EF. Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [ F]BCPP-EF mitochondrial function, [ C]PBB3 for tau deposition, and [ C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. The [ F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [ C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [ F]BCPP-EF SUVR and [ C]PBB3 BP (R = 0.2679, p = 0.04), but not [ C] PiB SUVR. Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [ C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.