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

多巴胺在健康老年人阿尔茨海默氏病病理认知弹性中的作用

基本信息

批准号：
10678125
负责人：
Jourdan Parent
金额：
$ 3.38万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2025-07-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678125
关键词：
Acceleration Acute Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Alzheimer’s disease biomarker Amyloid beta-Protein Animal Model Anterior Attention Berry Boston Brain Cognition Cognitive Cognitive aging Cohort Studies Communication Compensation Development Disease Dopamine Elderly Faculty Functional Magnetic Resonance Imaging General Hospitals Genes Goals Hippocampus Human Impaired cognition Individual Intervention Link Maintenance Massachusetts Measures Medial Memory Memory impairment Mentors Mentorship Metabolic Methods Midbrain structure Monitor Motivation Neurofibrillary Tangles Neuromodulator Neurons Neuropsychology Neurotransmitters Parkinson Disease Pathologic Pathology Pattern Performance Population Positron-Emission Tomography Predisposition Prefrontal Cortex Prevalence Prevention Research Process Proxy Qualifying Research Research Support Rest Rodent Model Role Sampling Senile Plaques Signal Transduction Site Structure System Testing Therapeutic Traction Training Universities Up-Regulation Work Youth age effect age related blood oxygen level dependent brain tissue career cingulate cortex cognitive function cognitive performance cognitive reserve cognitive testing college dopamine system experience healthy aging human subject in vivo innovation insight interest multimodal neuroimaging neural neuroimaging neuroimaging marker neuromechanism neuropathology neuroregulation preservation resilience statistics tomography young adult

项目摘要

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.

项目概要阿尔茨海默病 (AD) 的特点是 β-淀粉样蛋白和 tau 神经病理学，这与破坏有关量化体内病理学的人类神经成像方法取得了进展。揭示了 AD 治疗的一个有希望的目标，即认知储备，即某些能力鉴于我们提出的研究，个体的认知能力优于预期。检查大脑多巴胺在维持最佳认知功能和大脑年轻模式中的作用尽管存在病理现象，但成功维持多巴胺功能可以预防病理现象。当多巴胺直接输入海马体并支持最佳记忆时，认知发生相关改变可以使用以下方法评估人类海马 AD 相关病理的功能影响。测量局部功能连接性（即区域同质性）的新兴功能磁共振成像分析方法。啮齿动物模型和人类记忆表现和病理负担的敏感预测因子，并且正在获得进展作为功能性神经影像生物标志物的牵引力也受到局部功能连接的影响。多巴胺等神经调节系统可能支持衰老过程中的代偿性变化，并且可能具有 AD 中 AD 相关病理积累与多巴胺相互作用的程度。神经调节剂影响局部功能连接和记忆的功能尚不清楚。研究将通过评估老年人样本中记忆、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 相关病理学 (tau) 和多巴胺合成能力，以及局部 AD 易受影响区域的功能连接将通过静息态功能磁共振成像进行测量，以及拟议的研究将通过标准的神经心理学评估来测量记忆力。多巴胺合成能力与 tau 病理学之间的相互作用，以检验升高的假设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，从而目标 1 将确定年龄和 tau 病理学对局部功能的影响目标 2 将研究多巴胺合成能力的相互作用。该提案独特地整合了老年人局部功能连接和记忆的 AD 病理学。人类受试者中与 AD 相关的研究和多巴胺机制，可能支持 AD 治疗工作。完成本研究将实现申请人的培训目标，包括 (1) 多模式培训神经影像，(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总医院拥有卓越的师资力量和 Anne Berry 博士（发起人）和 Elizabeth Kensinger 博士（共同发起人）经验丰富。导师并专注于认知衰老、功能磁共振成像、正电子断层扫描和记忆系统。将成功提高申请人成功从事老龄化和 AD 职业的资格，多巴胺和记忆系统。