Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Centre for Addiction and Mental Health, Toronto, ON, Canada.
Transl Psychiatry. 2024 Oct 29;14(1):457. doi: 10.1038/s41398-024-03155-9.
Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer's disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.
轻度认知障碍 (MCI) 是衰老向可能进展为阿尔茨海默病和相关痴呆 (ADRD) 的前驱阶段，其中重度抑郁症 (MDD) 的共病会加速进展。代谢和线粒体异常在 ADRD 和其他神经退行性疾病中被广泛提出，而可能的线粒体功能障碍与 MCI 和 MDD 的病因发病机制有关。因此，研究 MCI、MDD 以及这两种情况同时存在时的线粒体标志物是有必要的。共有 332 名老年参与者被纳入研究：168 名 MCI 患者，108 名 MCI 合并缓解期 MDD (rMDD) 患者，56 名 rMDD 但无 MCI 患者。我们测量了血浆循环线粒体 DNA (ccf-mtDNA)、乳酸，并提取了核线粒体编码 (NMt) 单核苷酸变异 (SNV)（n=312）。对 ccf-mtDNA 和乳酸水平进行了非参数统计检验，以评估诊断、临床和心脏代谢变量。对 NMt-SNV 进行了二进制序列核关联测试 (SKAT-O) 和负担测试，调整了年龄、种族、性别、2 型糖尿病和 APOE 基因型。在 MCI 中观察到乳酸水平较低（KW χ=14.8，P=0.0024），特别是在 MCI 组和 rMDD 组之间观察到血浆乳酸水平显著降低，而在 MCI+rMDD 组和 MCI 组之间则没有，提示其在 MCI 中发挥作用可能导致乳酸水平降低。在 APOE-ε4 携带者中观察到 ccf-mtDNA 水平升高（χ=5.04，P=0.05）。这种关系仅存在于 MCI 组（P=0.043）和 MCI+rMDD 组（P=0.023）。在 MCI 或 MDD 中未观察到核编码线粒体基因与 MCI 或 MDD 的显著相关性。研究结果表明，MCI 和 MCI+rMDD 患者的血浆乳酸水平降低，与 ccf-mtDNA 呈负相关，此外，APOE-ε4 对认知障碍患者的 ccf-mtDNA 进一步升高有影响。这些发现有助于更深入地了解 MCI 和 MDD 中的线粒体标志物，需要进一步研究来探索线粒体异常在 MCI 发展和进展中的精确作用。
