Neurophysiological Basis for Functional Connectivity Changes in Early Alzheimer’s Disease

摘要 阿尔茨海默病（AD）的早期诊断和治疗对于延迟临床症状的发作至关重要， 如认知障碍和记忆缺陷。在AD早期，认知正常的人谁是积极的 对于淀粉样蛋白-β，一种AD的预测生物标志物，在大脑连接性下降之前表现出短暂的增加。 大脑连接和认知。AD的这种超连通性阶段表明可能存在前驱病理学， 在临床症状发作之前，可将其用作早期生物标志物。虽然大脑中的这些变化 网络连接已经被很好地记录，但对潜在的神经病理学知之甚少。我寻求 测试淀粉样蛋白-β引起的兴奋性神经元活动的局部增加是否会驱动全脑的超 在早期AD中观察到的连通性。我将使用多模式成像方法来确定淀粉样蛋白的影响- β对神经元和谷氨酸活性的神经元（显微镜），区域神经元回路的规模 （介观）和区域间网络连接（宏观）。我的提议 包括以下三个目的：目的1：确定急性暴露的淀粉样蛋白-β对神经元的影响， 目的2：确定慢性、进行性和慢性脑缺血对大脑皮层的影响。 β-淀粉样蛋白蓄积对年轻AD小鼠模型中神经元、谷氨酸和网络活动的影响， 3：确定总谷氨酸浓度如何变化，通过平移磁共振测量 光谱，与突触谷氨酸活性随疾病进展的变化有关。所有这些 实验可以确定早期观察到的连接变化的神经生理学基础， AD.这项研究的数据可以为有AD风险的患者引入新的治疗策略。 此外，这项工作密切结合了我在神经影像学和神经病学的临床兴趣。除了 严格的指导研究培训，该提案包括临床经验和专业发展 这将有助于我成长为一名独立的医学科学家。

Abstract Early diagnosis and treatment of Alzheimer’s disease (AD) are critical for delaying the onset of clinical symptoms, such as cognitive impairments and memory deficits. Early in AD, cognitively normal individuals who are positive for amyloid-β, a predictive biomarker of AD, exhibit a transient increase in brain connectivity prior to a decline in brain connectivity and cognition. This hyper-connectivity phase of AD suggests a prodromal pathology that may be exploited as an early biomarker prior to the onset of clinical symptoms. Though these changes in brain network connectivity have been well documented, little is known about the underlying neuropathology. I seek to test whether localized increases in excitatory neuronal activity caused by amyloid-β drive the brain-wide hyper- connectivity observed in early AD. I will use a multimodal imaging approach to determine the impact of amyloid- β on neuronal and glutamate activity on the scale of the neuron (microscopic), regional neuronal circuit (mesoscopic), and inter-regional network connectivity (macroscopic) in mouse models of AD. My proposal comprises the following three aims: Aim 1: Determine the impact of acute exposure of amyloid-β on neuronal, glutamate, and network activity in the normal cortex, Aim 2: Determine the impact of chronic, progressive amyloid-β accumulation on neuronal, glutamate, and network activity in a young mouse model of AD, and Aim 3: Determine how total glutamate concentration changes, measured by translational magnetic resonance spectroscopy, relate to synaptic glutamate activity changes with disease progression. Together, these experiments could determine the neurophysiological underpinnings of the connectivity changes observed in early AD. Data from this study could introduce novel treatment strategies for patients at risk of developing AD. Furthermore, this work closely integrates my clinical interest in neuroimaging and neurology. In addition to rigorous mentored research training, this proposal includes clinical experience and professional development that will facilitate my growth into an independent physician-scientist.