Voineskos Aristotle N, Lerch Jason P, Felsky Daniel, Shaikh Sajid, Rajji Tarek K, Miranda Dielle, Lobaugh Nancy J, Mulsant Benoit H, Pollock Bruce G, Kennedy James L
Department of Psychiatry, Geriatric Mental Health Program, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada M5T 1R8.
Arch Gen Psychiatry. 2011 Feb;68(2):198-206. doi: 10.1001/archgenpsychiatry.2010.194.
The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder.
To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance.
A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan.
University hospital.
A total of 69 healthy volunteers ranging from 19 to 82 years of age.
The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated.
The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility.
The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD.
脑源性神经营养因子（BDNF）Val66Met（rs6265）多态性可能预测阿尔茨海默病（AD）的风险。然而，BDNF基因与AD的遗传关联研究结果并不一致。影像遗传学策略可能通过表征BDNF基因变异对该疾病中易损的风险结构或神经网络的影响，来阐明其预测AD风险的方式。
通过检查（1）皮质厚度、（2）白质束的分数各向异性（即白质完整性）和（3）情景记忆表现，确定BDNF Val66Met基因变异是否与年龄相互作用，以预测成年期健康志愿者在与AD相关的中间表型模式下的脑和认知指标。
一项横断面研究，对成年期健康个体进行遗传学、高分辨率磁共振成像、扩散张量成像和认知测试。
大学医院。
共69名年龄在19至82岁之间的健康志愿者。
评估BDNF Val66Met基因型、载脂蛋白E基因型、皮质厚度、白质束的微观结构完整性和情景记忆表现。
BDNF Val66Met多态性与年龄相互作用，以预测（1）皮质厚度（主要在内嗅皮质和颞回）、（2）白质束的分数各向异性（主要在连接内侧颞叶的白质束）和（3）情景记忆表现。对于这些发现中的每一项，模式都是相似的：晚年的缬氨酸/缬氨酸个体易患，而在成年早期，甲硫氨酸等位基因携带者易患。
BDNF基因以年龄依赖性方式对与AD最早阶段易损神经回路一致的脑结构和认知功能产生风险。我们的新发现为与AD相关的中间表型中BDNF遗传易感性机制提供了体内的聚合证据。
