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

批准号：
10710379
负责人：
Christopher Gregory Cover
金额：
$ 4.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10710379
关键词：
APP-PS1 Acute Address Affect Age Months Aging Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Animals Basic Science Brain Calcium Characteristics Chronic Clinical Clinical Sciences Cognition Cognitive Concentration measurement Data Dementia Development Disease Disease Progression Dose Early Diagnosis Early Intervention Early treatment Event Exhibits Fluorescence Microscopy Functional disorder Glutamates Glutamine Growth Human Hyperactivity Image Impaired cognition Individual Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Memory impairment Mentors Microscopic Multimodal Imaging Mus Nerve Degeneration Neurodegenerative Disorders Neurology Neurons Neurotransmitters Optics Pathology Patients Phase Physicians Physiological Research Training Risk Rodent Role Scientist Signal Transduction Specificity Spectrum Analysis Symptoms Synapses Technical Expertise Techniques Testing Training United States Wild Type Mouse Work abeta accumulation awake calcium indicator career clinical development clinically relevant early detection biomarkers excitatory neuron excitotoxicity experience experimental study extracellular human imaging human subject imaging approach in vivo in vivo fluorescence interest mouse model neuroimaging neuronal circuitry neuropathology neurophysiology novel optical imaging optical sensor predictive marker response sensor tau Proteins tau-1 translational model treatment strategy two photon microscopy two-photon

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.

抽象的阿尔茨海默氏病（AD）的早期诊断和治疗对于延迟临床症状的发作至关重要，例如认知障碍和记忆缺陷。在广告早期，正常的人是积极的对于AD的预测生物标志物淀粉样蛋白β，在下降之前，大脑连接的瞬时增加大脑连通性和认知。 AD的这个超连接阶段表明一种前瞻性病理可能在临床症状发作之前，可以作为早期生物标志物探索。尽管这些大脑的变化网络连通性已被充分记录，对基本神经病理学知之甚少。我寻求测试由淀粉样蛋白β引起的兴奋性神经元活性的局部增加是否驱动大脑范围在AD早期观察到的连通性。我将使用多模式成像方法来确定淀粉样蛋白的影响 β在神经元和谷氨酸活性上的神经元（微观），区域神经元回路的β上 AD小鼠模型中（介质）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：确定淀粉样蛋白β急性暴露对神经元的影响，正常皮层中的谷氨酸和网络活动，目标2：确定慢性，进行性的影响 AD的年轻小鼠模型中的神经元，谷氨酸和网络活性的淀粉样蛋白-β积累，AIM 3：确定总谷氨酸浓度如何变化，通过翻译的磁共振测量光谱法与突触谷氨酸活性随疾病进展的变化有关。在一起，这些实验可以确定在早期观察到的连通性变化的神经生理基础广告。来自这项研究的数据可能会针对患有AD的风险的患者介绍新的治疗策略。此外，这项工作紧密整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，该建议包括临床经验和专业发展这将促进我成为独立的身体科学家的成长。