Exploring mitochondrial blood-based and genetic markers in older adults with mild cognitive impairment and remitted major depressive disorder.

IF 5.8 1区 医学 Q1 PSYCHIATRY Translational Psychiatry Pub Date : 2024-10-29 DOI:10.1038/s41398-024-03155-9
Jaehyoung Choi, Erika L Beroncal, Timofei Chernega, Heather J Brooks, James L Kennedy, Corinne E Fisher, Alastair J Flint, Nathan Herrmann, Krista L Lanctôt, Linda Mah, Benoit H Mulsant, Bruce G Pollock, Tarek K Rajji, Ana C Andreazza
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Abstract

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 χ2 = 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 (χ2 = 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.

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探索轻度认知障碍和重度抑郁症缓解期老年人的线粒体血液和遗传标记。
轻度认知功能障碍(MCI)是衰老的一个前驱阶段,有可能发展为阿尔茨海默病和相关痴呆症(ADRD),同时出现重度抑郁障碍(MDD)会加速病情发展。人们普遍认为 ADRD 和其他神经退行性疾病中存在代谢和线粒体异常,而线粒体功能障碍可能与 MCI 和 MDD 的病因病理有关。因此,有必要对 MCI、MDD 以及同时患有这两种疾病的患者的线粒体标记物进行调查。研究共纳入了 332 名老年参与者:其中 168 人患有 MCI,108 人患有 MCI 加缓解型 MDD(rMDD),56 人患有 rMDD 但未患有 MCI。我们测量了血浆循环线粒体 DNA(ccf-mtDNA)、乳酸盐和提取的核线粒体编码(NMt)单核苷酸变异(SNVs)(n = 312)。对诊断、临床和心脏代谢变量的ccf-mtDNA和乳酸盐水平进行了非参数统计检验。对 NMt-SNV 进行了二元序列核关联检验(SKAT-O)和负荷检验,并对年龄、种族、性别、II 型糖尿病和 APOE 基因型进行了调整。在 MCI 中观察到较低的乳酸水平(KW χ2 = 14.8,P = 0.0024),更具体地说,在 MCI 和 rMDD 之间发现了较低的血浆乳酸,而在 MCI+rMDD 和 MCI 之间没有发现显著差异,这表明 MCI 有可能是乳酸水平较低的原因。在 APOE-ε4 携带者中观察到较高水平的 ccf-mtDNA (χ2 = 5.04,P = 0.05)。只有 MCI 组(P = 0.043)和 MCI+rMDD 组(P = 0.023)存在这种关系。没有观察到核编码线粒体基因与 MCI 或 MDD 有明显关系。研究结果表明,MCI 和 MCI+rMDD 患者血浆乳酸水平下降,与 ccf-mtDNA 呈反相关,此外,APOE-ε4 还能进一步增加认知障碍患者的 ccf-mtDNA。这些发现有助于加深对MCI和MDD中线粒体标记物的理解,值得进一步研究,以探索线粒体异常在MCI发生和发展中的确切作用。
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来源期刊
CiteScore
11.50
自引率
2.90%
发文量
484
审稿时长
23 weeks
期刊介绍: Psychiatry has suffered tremendously by the limited translational pipeline. Nobel laureate Julius Axelrod''s discovery in 1961 of monoamine reuptake by pre-synaptic neurons still forms the basis of contemporary antidepressant treatment. There is a grievous gap between the explosion of knowledge in neuroscience and conceptually novel treatments for our patients. Translational Psychiatry bridges this gap by fostering and highlighting the pathway from discovery to clinical applications, healthcare and global health. We view translation broadly as the full spectrum of work that marks the pathway from discovery to global health, inclusive. The steps of translation that are within the scope of Translational Psychiatry include (i) fundamental discovery, (ii) bench to bedside, (iii) bedside to clinical applications (clinical trials), (iv) translation to policy and health care guidelines, (v) assessment of health policy and usage, and (vi) global health. All areas of medical research, including — but not restricted to — molecular biology, genetics, pharmacology, imaging and epidemiology are welcome as they contribute to enhance the field of translational psychiatry.
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