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缓临床症状的出现至关重要， 比如认知障碍和记忆缺陷。在AD早期，积极的认知正常的人 对于AD的预测生物标志物-淀粉样蛋白-β，在大脑连接能力下降之前，显示出一过性的增加 大脑连通性和认知能力。AD的这种高连接性阶段提示一种前驱病理，可能 在临床症状出现之前被用作早期生物标记物。尽管大脑中的这些变化 网络连通性已经被很好地记录下来，但对潜在的神经病理知之甚少。我想要 测试淀粉样蛋白-β引起的局部兴奋性神经元活动增加是否会导致全脑兴奋. 在AD早期观察到连通性。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(微观)、区域神经元回路的影响 (中观)和区域间网络连通性(宏观)，在AD小鼠模型中。我的建议 包括以下三个目的：目的1：确定急性暴露淀粉样蛋白-β对神经元的影响， 谷氨酸，以及正常皮质中的网络活动，目标2：确定慢性、进行性的影响 淀粉样蛋白-β在阿尔茨海默病幼鼠模型神经元、谷氨酸和网络活动上的积聚 3：通过翻译核磁共振测量，确定总谷氨酸浓度如何变化 光谱，与突触谷氨酸活性随疾病进展而变化有关。加在一起，这些 实验可以确定早期观察到的连接性变化的神经生理学基础 广告。这项研究的数据可能会为有患AD风险的患者引入新的治疗策略。 此外，这项工作紧密结合了我对神经成像和神经学的临床兴趣。除了……之外 严格的导师指导研究培训，这项建议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内科科学家。

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.