Roussotte Florence F, Hua Xue, Narr Katherine L, Small Gary W, Thompson Paul M
Department of Neurology, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
Imaging Genetics Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Biol Psychiatry Cogn Neurosci Neuroimaging. 2017 Apr;2(3):280-288. doi: 10.1016/j.bpsc.2016.09.005.
The C677T functional variant in the methylene-tetrahydrofolate reductase () gene leads to reduced enzymatic activity and elevated blood levels of homocysteine. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression.
Here, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 Alzheimer's patients, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).
We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine mediates the association between genotype and lower medial orbitofrontal volumes, and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B deficiency interacts with the C677T variant in the etiology of hyperhomocysteinemia.
This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and represents a significant advance in our understanding of clinically relevant associations relating to genotype.
亚甲基四氢叶酸还原酶（MTHFR）基因中的C677T功能变异导致酶活性降低和血液中同型半胱氨酸水平升高。高同型半胱氨酸血症与心血管疾病、认知能力下降和晚年抑郁症的发生率较高有关。
在此，对738名个体（年龄：75.5±6.8岁；438名男性/300名女性）的三维磁共振成像数据进行了分析，其中包括173名阿尔茨海默病患者、359名轻度认知障碍受试者和206名健康老年人，这些扫描作为阿尔茨海默病神经成像计划（ADNI）的一部分。
我们发现，在控制年龄、性别和痴呆状态后，该变异与涉及智力和情感功能的脑区局部脑萎缩有关，特别是内侧眶额皮质。内侧眶额皮质参与情绪过程的认知调节，该区域的局部萎缩先前与认知障碍和抑郁症状均有关。在此，我们报告血浆同型半胱氨酸升高介导了MTHFR基因型与内侧眶额体积减小之间的关联，并且这些体积介导了该老年队列中认知能力下降与情绪低落之间的关联。我们还表明，维生素B缺乏在高同型半胱氨酸血症的病因中与C677T变异相互作用。
本研究揭示了血管危险因素、年龄相关的认知能力下降和晚年抑郁症之间的重要关系，并代表了我们对与MTHFR基因型相关的临床相关关联理解上的重大进展。
