In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease
In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease
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DOI：
10.1212/wnl.0000000000009249
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发表时间：
2020-03
期刊：
影响因子：
9.9
通讯作者：
T. Terada;T. Obi;T. Bunai;T. Matsudaira;E. Yoshikawa;I. Ando;M. Futatsubashi;H. Tsukada;Y. Ouchi
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文献类型：
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作者：
T. Terada;T. Obi;T. Bunai;T. Matsudaira;E. Yoshikawa;I. Ando;M. Futatsubashi;H. Tsukada;Y. Ouchi
目的阿尔茨海默病（Alzheimer disease，AD）患者脑内糖酵解相关的糖代谢和电子传递链相关的线粒体活性可能存在区域性差异。为了测试关于AD病理生理学的这一假设，我们用与MC-I结合的新型PET探针[18 F]2-叔丁基-4-氯-5-2H-哒嗪-3-酮（[18 F]BCPP-EF）测量了线粒体复合物-I（MC-I）的可用性，并将[18 F]BCPP-EF摄取与活体AD脑中的18 F-氟脱氧葡萄糖（[18 F]FDG）摄取进行了比较。方法采用动脉血定量测定10例正常人（NC）的[18 F]BCPP-EF的总分布容积（VT），并观察VT是否可以替代标准摄取值相对于总计数（SUVRg）。18例NC和14例不同NC分别接受了[18 F]BCPP-EF或[18 F]FDG PET。其次，32例AD患者进行了半定量扫描与双PET示踪剂。对MC-I活性（[18 F]BCPP-EF）和葡萄糖代谢（[18 F]FDG）水平进行了参与者间和参与者内比较。结果[18 F]BCPP-EF VT与[18 F]BCPP-EF SUVRg呈正相关，表明SUVRg足以用于半定量评价。AD患者海马旁的[18 F]BCPP-EF SUVRg显著较低，但[18 F]FDG SUVRg无显著性差异，突出了内侧颞叶皮质氧化代谢衰竭的显著性。在早期AD中，在除海马旁以外的几个脑区中观察到[18 F]BCPP-EF SUVRg和[18 F]FDG SUVRg之间的强正相关性。结论AD早期存在海马旁线粒体功能障碍。线粒体相关的能量衰竭可能先于糖酵解相关的代谢减退，在AD中具有病理证实的早期神经变性的区域。
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 (VT) of [18F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether VT 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 VT 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.