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

早期阿尔茨海默病功能连接变化的神经生理学基础

基本信息

项目摘要

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.
抽象的 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, 例如认知障碍和记忆缺陷。在 AD 早期,认知正常且积极的个体 淀粉样蛋白-β(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 的这种超连接阶段表明存在一种前驱病理学,可能 被用作临床症状出现之前的早期生物标志物。尽管大脑发生了这些变化 网络连接已被充分记录,但人们对潜在的神经病理学知之甚少。我寻求 测试β淀粉样蛋白引起的兴奋性神经元活动的局部增加是否驱动全脑过度兴奋 公元早期观察到的连通性。我将使用多模态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动的影响(微观),区域神经元回路 AD 小鼠模型中的(介观)和区域间网络连接(宏观)。我的建议 包括以下三个目标: 目标 1:确定β淀粉样蛋白的急性暴露对神经元、 谷氨酸盐和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 积累对 AD 幼年小鼠模型神经元、谷氨酸和网络活动的影响,以及 Aim 3:通过平移磁共振测量确定总谷氨酸浓度如何变化 光谱学,与突触谷氨酸活性随疾病进展的变化有关。在一起,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 广告。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,这项工作紧密结合了我对神经影像学和神经病学的临床兴趣。此外 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师科学家。

项目成果

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Christopher Gregory Cover其他文献

Christopher Gregory Cover的其他文献

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{{ truncateString('Christopher Gregory Cover', 18)}}的其他基金

Neurophysiological Basis for Functional Connectivity Changes in Early Alzheimer’s Disease
早期阿尔茨海默病功能连接变化的神经生理学基础
  • 批准号:
    10710379
  • 财政年份:
    2022
  • 资助金额:
    $ 4.8万
  • 项目类别:

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