There is accumulating evidence that mitochondrial dysfunction is associated with the contribution of diabetes to Alzheimer disease (AD) progression. Neuronal mitochondrial proteins are found in plasma neuronal-derived exosomes (NDEs) at levels that reflect those in brain neurons. Here, we tested the performance of mitochondrial proteins in plasma NDEs to predict cognitive decline and brain injury in participants with diabetes. The study participants with type 2 diabetes mellitus (T2DM) included 41 cognitively normal control subjects, 97 individuals with mild cognitive impairment (MCI) (68 individuals with stable MCI; 29 individuals with progressive MCI), and 36 patients with AD dementia. Plasma neuroexosomal proteins were measured by ELISA kits. Spearman correlation was used to test associations between plasma neuroexosomal mitochondrial proteins and other core biomarkers of AD. Diagnostic accuracy for progressive MCI and AD was obtained for mitochondrial proteins using receiver operating characteristic curve analyses. The associations of mitochondrial proteins with the conversion from MCI to AD were assessed by Cox proportional hazard regression analysis. Plasma levels of neuroexosomal NADH ubiquinone oxidoreductase core subunit S3 (NDUFS3) and succinate dehydrogenase complex subunit B (SDHB) were significantly lower in patients with T2DM with AD dementia and progressive MCI than in cognitively normal subjects (P < 0.001 for both groups). We also found that plasma neuroexosomal NDUFS3 and SDHB levels were lower in progressive MCI subjects than in stable MCI subjects. Both plasma neuroexosomal NDUFS3 and SDHB offer diagnostic utility for AD. Low plasma neuroexosomal SDHB levels significantly predicted conversion from MCI to AD. In addition, low mitochondrial protein levels were associated with the rate of hippocampal and gray matter atrophy and reduced AD signature cortical thickness in progressive MCI over the follow-up period. These data suggest that both plasma neuroexosomal NDUFS3 and SDHB are already increased at the early clinical stage of AD, and indicate the promise of plasma neuroexosomal mitochondrial proteins as diagnostic and prognostic biomarkers for the earliest symptomatic stage of AD in participants with diabetes.

中文翻译：

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血液神经外泌体线粒体蛋白可预测糖尿病中的阿尔茨海默病

越来越多的证据表明线粒体功能障碍与糖尿病对阿尔茨海默病 (AD) 进展的影响有关。神经元线粒体蛋白存在于血浆神经元衍生的外泌体 (NDE) 中，其水平反映了脑神经元中的水平。在这里，我们测试了血浆 NDE 中线粒体蛋白的性能，以预测糖尿病参与者的认知能力下降和脑损伤。患有 2 型糖尿病 (T2DM) 的研究参与者包括 41 名认知正常的对照受试者、97 名轻度认知障碍 (MCI) 个体（68 名患有稳定 MCI 的个体；29 名患有进行性 MCI 的个体）和 36 名患有 AD 痴呆症的患者。通过ELISA试剂盒测量血浆神经外泌体蛋白。Spearman 相关性用于测试血浆神经外泌体线粒体蛋白与 AD 的其他核心生物标志物之间的关联。使用接受者操作特征曲线分析获得了线粒体蛋白进行性 MCI 和 AD 的诊断准确性。通过 Cox 比例风险回归分析评估线粒体蛋白与从 MCI 到 AD 的转换的关联。与认知正常的受试者相比，患有 AD 痴呆和进行性 MCI 的 T2DM 患者的血浆神经外泌体 NADH 泛醌氧化还原酶核心亚基 S3 (NDUFS3) 和琥珀酸脱氢酶复合亚基 B (SDHB) 水平显着低于认知正常受试者（P < 0.001）。我们还发现，进行性 MCI 受试者的血浆神经外泌体 NDUFS3 和 SDHB 水平低于稳定的 MCI 受试者。血浆神经外泌体 NDUFS3 和 SDHB 都为 AD 提供诊断效用。低血浆神经外泌体 SDHB 水平显着预测从 MCI 到 AD 的转化。此外，低线粒体蛋白水平与随访期间进行性 MCI 中海马和灰质萎缩率和 AD 特征皮层厚度降低有关。这些数据表明血浆神经外泌体 NDUFS3 和 SDHB 在 AD 的早期临床阶段已经增加，并表明血浆神经外泌体线粒体蛋白有望作为糖尿病参与者 AD 最早症状阶段的诊断和预后生物标志物。低线粒体蛋白水平与随访期间进行性 MCI 中海马和灰质萎缩率以及 AD 特征皮层厚度降低有关。这些数据表明血浆神经外泌体 NDUFS3 和 SDHB 在 AD 的早期临床阶段已经增加，并表明血浆神经外泌体线粒体蛋白有望作为糖尿病参与者 AD 最早症状阶段的诊断和预后生物标志物。低线粒体蛋白水平与随访期间进行性 MCI 中海马和灰质萎缩率以及 AD 特征皮层厚度降低有关。这些数据表明血浆神经外泌体 NDUFS3 和 SDHB 在 AD 的早期临床阶段已经增加，并表明血浆神经外泌体线粒体蛋白有望作为糖尿病参与者 AD 最早症状阶段的诊断和预后生物标志物。