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.
Neurology. 2020 Apr 14;94(15):e1592-e1604. doi: 10.1212/WNL.0000000000009249. Epub 2020 Mar 5.
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 [F]2-tert- butyl-4-chloro-5-2H- pyridazin-3-one ([F]BCPP-EF), which binds to MC-I, and compared [F]BCPP-EF uptake with F-fluorodeoxyglucose ([F]FDG) uptake in the living AD brain.
First, the total distribution volume (V) of [F]BCPP-EF from 10 normal controls (NCs) was quantified using arterial blood samples and then tested to observe whether V could substitute for the standard uptake value relative to the global count (SUVRg). Eighteen NCs and 14 different NCs underwent PET with [F]BCPP-EF or [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 ([F]BCPP-EF) and glucose metabolism ([F]FDG) were performed.
The [F]BCPP-EF V was positively correlated with the [F]BCPP-EF SUVRg, indicating that the use of the SUVRg was sufficient for semiquantitative evaluation. The [F]BCPP-EF SUVRg, but not the [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 [F]BCPP-EF SUVRg and [F]FDG SUVRg were observed in several brain regions, except the parahippocampus, in early-stage AD.
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.
阿尔茨海默病（AD）患者大脑的糖代谢与电子传递链相关的线粒体活性可能存在区域性差异。为了验证 AD 病理生理学方面的这一假说，我们采用新型正电子发射断层扫描（PET）探针[F]2-叔丁基-4-氯-5-2H-哒嗪-3-酮（[F]BCPP-EF）来测量与线粒体复合物 I（MC-I）相关的葡萄糖代谢，并用该探针来评估 AD 患者活体大脑中 MC-I 的活性，并与 F-氟脱氧葡萄糖（[F]FDG）摄取进行了比较。
首先，通过动脉血样对 10 例正常对照者（NC）的[F]BCPP-EF 总分布容积（V）进行了定量，并对其进行了检测，以观察 V 是否可以替代相对于全脑计数的标准摄取值（SUVRg）。18 例 NC 及 14 例不同的 NC 分别接受[F]BCPP-EF 或[F]FDG 的 PET 检查。其次，32 例 AD 患者进行了双示踪剂正电子发射断层扫描。对 MC-I 活性（[F]BCPP-EF）和葡萄糖代谢（[F]FDG）水平进行了组间和组内比较。
[F]BCPP-EF 的 V 与[F]BCPP-EF 的 SUVRg 呈正相关，这表明 SUVRg 足以进行半定量评估。与 NC 相比，AD 患者的旁海马区[F]BCPP-EF 的 SUVRg 显著降低，突出了内侧颞叶皮质氧化代谢衰竭的重要性。在早期 AD 患者中，除了旁海马区外，[F]BCPP-EF 的 SUVRg 与[F]FDG 的 SUVRg 之间存在显著的正相关。
在早期 AD 中，旁海马区出现了线粒体功能障碍。在 AD 中，有病理证实存在早期神经退行性变的区域中，与糖代谢相关的代谢低下可能先于与线粒体相关的能量衰竭。
