The aging brain: Imaging genetics of brain structure and function

这项Roo计划的科学目标是调查特定候选基因的多态，这些基因可能 与认知、功能和结构大脑完整性指数作为中间表型相关 (内表型)痴呆症。内表型策略的假设是基因在 大脑的水平比复杂的行为更直接，并会在风险携带者中表现出关联 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 5个候选基因(APOE、SORL1、BDNF、COMT和Kibra)的变异，都与已知的 痴呆症或认知障碍，并检查候选基因变异之间的关系 和认知任务，允许跨物种比较和探索额叶(反转学习， 元素辨别)或内侧(虚拟水迷宫、横纹)叶功能； 检查脑活动模式(fMRI；默认模式网络)中的基因型差异，以及(3)检查 基因-行为关系的可能机制通过形态(MRI图像和 DTI)和生化(IH MRSI)内含型，采用多模式磁共振成像方法。这将是 通过分析从以下位置收集的DNA、认知和多模式成像数据来完成 大约150名中年、非痴呆症、健康、无痴呆症家族史的成年人。建议 实验将在几个不同的调查层面上提供一致的证据，这些证据也可以 与动物文献中的发现进行交叉比较。对认知缺陷和大脑的洞察 在中年成年人出现任何临床症状之前的变化，这些症状相对 与年轻人和老年人相比，都没有被充分研究。这些发现将使我们更好地理解 用于治疗的致病基因和靶向途径，这可能导致可能的额外治疗 战略。这些研究将为未来的ROI提供遗传、生物学、临床和行为背景 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.