The Role of Dopamine in Cognitive Resilience to Alzheimer's Disease Pathology in Healthy Older Adults

项目总结 阿尔茨海默病(AD)以β-淀粉样蛋白和tau神经病理为特征，与神经功能障碍有关 在内存性能方面。量化活体病理的人类神经成像方法的进展 揭示了AD治疗的一个有希望的目标，即认知储备，这是一些人的能力 考虑到他们的病理水平，个体有比预期更好的认知。我们建议的研究 研究了大脑中的多巴胺在维持最佳认知功能和年轻的大脑模式中的作用 尽管有病理性的活动。在衰老过程中成功地维持多巴胺功能可能会预防病理- 当多巴胺直接进入海马体并支持最佳记忆时，认知的相关改变 性能。在人类中，AD相关的海马区病理的功能影响可以用 衡量局部功能连通性(即区域同质性)的新兴功能磁共振分析方法。这是 一个灵敏的预测啮齿动物模型和人类记忆表现和病理负担的指标，并正在获得 作为功能性神经影像生物标记物的牵引。本地功能连接也受到以下因素的影响 神经调节系统，如多巴胺，可能支持衰老的代偿性变化，并可能 AD的应用程序。衰老过程中AD相关病理堆积与多巴胺相互作用的程度 神经调节剂的功能如何影响局部功能连通性和记忆尚不清楚。建议数 研究将通过在老年人样本中评估记忆、正电子之间的关系来填补这一空白 发射断层扫描(PET)测量AD相关病理(Tau)和多巴胺合成能力，以及局部 易患AD地区的功能连接。连接性将使用静息状态功能磁共振进行测量，以及 记忆力将用标准的神经心理学评估来衡量。拟议的研究将检查 多巴胺合成能力和tau病理之间的相互作用以检验这一假说 多巴胺合成能力抵消了病理对记忆和局部功能连接的影响，因此 代表了一种认知储备机制。目标1将确定年龄和tau病理对局部功能的影响 AD易患地区的连接性。目标2将研究多巴胺合成能力的交互作用 以及AD病理对老年人局部功能连接和记忆的影响。该提案独一无二地整合了 与AD相关的研究和人类受试者的多巴胺机制，并可能支持AD的治疗努力。 本研究的完成将实现申请人的培训目标，包括(1)多式联运培训 神经成像，(2)衰老中的记忆系统，(3)统计学，(4)科学交流，(5)指导。 布兰迪斯大学、波士顿学院和马萨诸塞州综合医院提供杰出的教职员工和 神经成像设备。安妮·贝瑞博士(赞助人)和伊丽莎白·肯辛格博士(共同赞助人)经验丰富 指导和专门研究认知老化、功能磁共振成像、正电子发射计算机断层扫描和记忆系统。拟议的项目和培训 将成功提升申请人在老龄化和AD领域成功追求职业生涯的资格， 多巴胺和记忆系统。

PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by β-amyloid and tau neuropathology, which are linked to disruptions in memory performance. Advances in human neuroimaging approaches that quantify pathology in vivo have revealed a promising target for AD therapeutics known as cognitive reserve, which is the capacity for some individuals to have better-than-expected cognition given their level of pathology. Our proposed research examines the role of brain dopamine in maintaining optimal cognitive function and youth-like patterns of brain activity despite pathology. Successful maintenance of dopamine function in aging may protect against pathology- related alterations in cognition as dopamine inputs directly into the hippocampus and supports optimal memory performance. The functional impact of hippocampal AD-related pathology can be assessed in humans using emerging fMRI analysis methods that measure local functional connectivity (i.e. regional homogeneity). This is a sensitive predictor of memory performance and pathology burden in rodent models and humans and is gaining traction as a functional neuroimaging biomarker. Local functional connectivity is also affected by neuromodulator systems like dopamine, which may support compensatory changes in aging and could have applications for AD. The extent to which AD-related pathology accumulation in aging interacts with dopamine neuromodulator functions to affect local functional connectivity and memory is not known. The proposed research will fill this gap by assessing, within an older adult sample, relationships among memory, positron emission tomography (PET) measured AD-related pathology (tau) and dopamine synthesis capacity, and local functional connectivity in AD-vulnerable regions. Connectivity will be measured with resting-state fMRI, and memory will be measured with standard neuropsychological assessment. The proposed research will examine interactions between dopamine synthesis capacity and tau pathology to test the hypothesis that elevated dopamine synthesis capacity counteracts effects of pathology on memory and local functional connectivity, thus representing a cognitive reserve mechanism. Aim 1 will establish age and tau pathology effects on local functional connectivity in AD-vulnerable regions. Aim 2 will investigate interactive effects of dopamine synthesis capacity and AD pathology on local functional connectivity and memory in older adults. This proposal uniquely integrates AD-relevant research and dopamine mechanisms in human subjects and may support AD treatment efforts. Completion of this research will achieve the applicant’s training goals including training in (1) multi-modal neuroimaging, (2) memory systems in aging, (3) statistics (4) scientific communication, and (5) mentorship. Brandeis University, Boston College, and Massachusetts General Hospital provide exceptional faculty and neuroimaging facilities. Dr. Anne Berry (sponsor) and Dr. Elizabeth Kensinger (co-sponsor) are experienced mentors and specialize in cognitive aging, fMRI, PET, and memory systems. The proposed project and training will successfully advance the applicant’s qualifications for successful pursuit of a career in aging and AD, dopamine, and memory systems.