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Widespread cell stress and mitochondrial dysfunction in early Alzheimer’s Disease
medRxiv - Neurology Pub Date : 2021-08-13 , DOI: 10.1101/2021.08.11.21261851
Ashwin V Venkataraman , Ayla Mansur , Gaia Rizzo , Courtney Bishop , Yvonne Lewis , Ece Kocagoncu , Anne Lingford-Hughes , Mickael Huiban , Jan Passchier , James B Rowe , Hideo Tsukada , David J. Brooks , Laurent Martarello , Robert A. Comley , Laigao Chen , Adam J. Schwarz , Richard Hargreaves , Roger N. Gunn , Eugenii A. Rabiner , Paul M Matthews

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic vesicular protein SV2A with [11C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and brain perfusion (CBF) measured with MRI arterial spin labelling. 8 AD patients were followed longitudinally to estimate rates of change with disease progression over 12-18 months. The AD patients showed widespread increases in S1R (≤ 27%) and regional decreases in MC1 (≥ -28%), SV2A (≥ -25%), brain volume (≥ -23%), and CBF (≥ -26%). [18F]BCPP-EF PET MC1 density (≥ -12%) and brain volumes (≥ -5%) were further reduced at follow up in brain regions consistent with the differences between AD patients and controls at baseline. Exploratory analyses showing associations of MC1, SV2A and S1R density with cognitive changes at baseline and longitudinally with AD, but not in controls, suggested a loss of metabolic functional reserve with disease. Our study thus provides novel in vivo evidence for widespread cellular stress and bioenergetic abnormalities in early AD and that they may be clinically meaningful.

中文翻译:

早期阿尔茨海默病中广泛的细胞应激和线粒体功能障碍

细胞应激和氧化磷酸化受损是阿尔茨海默病 (AD) 细胞病理学中突触丢失和神经变性机制的核心。我们使用 [ 11 C]SA4503 PET量化了内质网应激标记物 sigma 1 受体 (S1R) 的体内密度,以及使用 [ 18 F]BCPP-EF 和前体的线粒体复合物 I (MC1) 的密度。-突触小泡蛋白 SV2A 与 [ 11C]UCB-J 在 12 名早期 AD 患者和 16 名认知正常对照中。我们将这些分子测量与使用 MRI 动脉自旋标记测量的区域脑容量和脑灌注 (CBF) 的评估相结合。对 8 名 AD 患者进行纵向随访,以估计 12-18 个月内疾病进展的变化率。AD 患者表现出 S1R (≤ 27%) 的普遍增加和 MC1 (≥ -28%)、SV2A (≥ -25%)、脑容量 (≥ -23%) 和 CBF (≥ -26%) 的区域性减少. [ 18F]BCPP-EF PET MC1 密度(≥ -12%)和脑容量(≥ -5%)在大脑区域的随访中进一步降低,这与 AD 患者和对照组在基线时的差异一致。探索性分析显示 MC1、SV2A 和 S1R 密度与 AD 的基线和纵向认知变化的关联,但在对照组中没有,表明代谢功能储备的丧失与疾病有关。因此,我们的研究为早期 AD 中广泛的细胞应激和生物能异常提供了新的体内证据,并且它们可能具有临床意义。
更新日期:2021-08-16
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