权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10534529
负责人：
Christopher Gregory Cover
金额：
$ 4.8万
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/10534529
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 Translations United States Wild Type Mouse Work Yang abeta accumulation awake base calcium indicator career clinical development clinically relevant early detection biomarkers 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 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.

摘要