Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Research Institute, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l'Ouest-de-l'Île-de-Montréal, Montreal, QC, Canada.
Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Eur J Neurol. 2022 May;29(5):1324-1334. doi: 10.1111/ene.15246. Epub 2022 Jan 22.
Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET).
Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [ F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [ C]Pittsburgh Compound-B (PiB) and [ F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models.
[ F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [ F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [ F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden.
In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [ F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.
阿尔茨海默病（AD）大脑中的线粒体代谢异常已被描述。然而，AD 病理生理学与关键线粒体过程之间的关系仍不清楚。本研究的目的是使用正电子发射断层扫描（PET）研究轻度 AD 患者的线粒体复合物 I 功能障碍是否与淀粉样蛋白聚集或葡萄糖代谢和脑萎缩有关。
有临床痴呆评定量表（CDR）为 0.5 或 1 的淀粉样蛋白和 tau 阳性症状性 AD 患者（N=30；平均年龄±标准差：71.8±7.6 岁）接受磁共振成像和 PET 扫描，使用[ F]2-叔丁基-4-氯-5-2H-哒嗪-3-酮（BCPP-EF）、[ C]匹兹堡化合物-B（PiB）和[ F]氟脱氧葡萄糖（FDG）分别评估脑萎缩、线粒体复合物 I 功能障碍、淀粉样蛋白沉积和葡萄糖代谢。采用基于体素的回归模型评估这些生物标志物与灰质体积之间的局部皮质关联。
[ F]BCPP-EF 标准化摄取值比值（SUVR）与广泛脑区的[ F]FDG SUVR 呈正相关，而与灰质体积的相关性仅限于海马旁回。[ F]BCPP-EF SUVR 的降低与特定领域的认知表现有关。我们没有观察到线粒体功能障碍与淀粉样蛋白负担之间的区域关联。
在有症状的病例中，尽管线粒体复合物 I 减少与广泛的下游神经退行性过程（如代谢低下、萎缩和认知下降）有关，但与淀粉样蛋白无关联。这里提供的数据支持[ F]BCPP-EF 作为研究 AD 中线粒体功能障碍的一种极好的成像工具。
