The aging brain: Imaging genetics of brain structure and function

这项ROO提案的科学目标是调查特定候选基因的多态性， 与作为中间表型的认知、功能和结构脑完整性指数相关 （endophenotypes）痴呆症。内表型策略的假设是，基因作用于 大脑水平比复杂行为更直接，并会在风险携带者中表现出关联性 等位基因，即使携带者没有表现出临床诊断特征。主要目的是：（1）测量 五个候选基因（APOE，SORL 1，BDNF，COMT和KIBRA）的变异，所有这些基因都与已知的 痴呆或认知障碍，并检查候选基因变异之间的关系， 和认知任务，允许跨物种的比较和探测任何一个正面（逆转学习， 元素辨别）或内侧颞叶（虚拟水迷宫，横向图案）功能;（2） 检查大脑活动模式的基因型差异（fMRI;默认模式网络），以及（3）检查 通过形态学（MRI体积测量和 DTI）和生化（IH MRSI）的脑内型，采用多模态MR成像方法。这将 通过分析DNA，认知和多模态成像数据来完成，这些数据来自 约150名中年、非痴呆、健康成人，无痴呆家族史。提出 实验将提供几个不同层次的调查，也可以是收敛的证据 与动物文献中的结果进行交叉比较。深入了解认知缺陷和大脑 中年人的变化之前，任何临床症状的表现，这已经相对 与年轻人和老年人相比，研究不足。这些发现将有助于我们更好地理解 致病位点和治疗靶向途径，这可能导致可能的额外治疗 战略布局这些研究将为未来的ROI提供遗传学、生物学、临床和行为学背景 旨在识别与年龄相关的认知衰退和痴呆症相关的新基因的应用。

The scientific goal of this ROO proposal is to investigate polymorphisms in specific candidate genes that may be associated with indices of cognitive, functional, and structural brain integrity as intermediate phenotypes (endophenotypes) of dementia. The assumption of the endophenotype strategy is that gene effects at the level of the brain are more direct than the complex behavior, and will show association in carriers of risk alleles even if the carriers show no clinical diagnostic characteristics.The primary aims are to: (1) measure variation in five candidate genes (APOE, SORL1, BDNF, COMT, and KIBRA), all with known involvement in either dementia or cognitive impairment, and examine the relationships between candidate gene variants and cognitive tasks allowing for cross-species comparisons and probing either frontal (reversal learning, elemental discriminations) or medial temporal (virtual water maze, transverse patterning) lobe function; (2) examine genotype differences in brain activaty patterns (fMRI; Default Mode Network), and (3) examine possible mechanisms underlying the gene-behavior relationship through morphological (MRI voumetrics and DTI) and biochemical (IH MRSI) endophentypes, employing a multi-modal MR imaging approach. This will be accomplished through the analyses of DNA , cognitive, and multi-modal imaging data collected from approximately 150 middle-aged, non-demented, healthy adults without family history of dementia. Proposed experiments will provide converging evidence on several different levels of investigation that can also be cross-compared to the findings from animal literature. Insights will be gained into cognitive deficits and brain changes in middle-aged adults prior to any manifestation of clinical symptoms, which have been relatively understudied in comparison to both younger and older adults. The findings will lead to a better understanding of pathogenic loci and target pathways for therapy, which could result in possible additional treatment strategies. These studies will provide a genetic, biological, clinical and behavioral background for future ROI applications aimed at identifying new genes associated with age-related cognitive decline and dementia.