Assessing Diffusion MRI Metrics for Detecting Changes of Synaptic Density in Alzheimer's Disease

评估弥散 MRI 指标以检测阿尔茨海默病突触密度的变化

基本信息

批准号：
10739911
负责人：
SCOTT E SNYDER
金额：
$ 79.03万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739911
关键词：
Address Affect Age Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Animal Model Area Autopsy Autoradiography Axodendritic Synapse Axon Binding Brain Characteristics Clinical Cognitive Dendrites Deposition Development Diffuse Axonal Injury Diffusion Diffusion Magnetic Resonance Imaging Disadvantaged Disease Progression Early Diagnosis Electrophysiology (science)Future Glycoproteins Goals Hippocampus Human Image Imaging Techniques Impaired cognition Individual Ionizing radiation Knowledge Laboratories Learning Ligand Binding Ligands Magnetic Resonance Imaging Measures Memory Memory Loss Modeling Modernization Molecular Monitor Morphology Mus Neurites Neurodegenerative Disorders Outcome Outcome Measure Participant Performance Phase Positron-Emission Tomography Prevention Prognosis Progressive Disease Proxy Radiation exposure Radiopharmaceuticals Reporting Research Resolution Sampling Senile Plaques Signal Transduction Stains Structure Synapses Synaptic Vesicles Synaptic plasticity Techniques Time Tracer United States Validation Verbal Learning behavior test cognitive function cost density diagnostic criteria diagnostic tool human old age (65+)imaging biomarker in vivo mild cognitive impairment mild traumatic brain injury mouse model normal aging novel pre-clinical radiotracer tool white matter

项目摘要

Project Abstract Synaptic structure and function are the keys to several neurodegenerative disorders, including Alzheimer’s disease (AD). Specifically, dysfunctional synapses and dysregulated synaptic plasticity in the hippocampus are responsible for early memory and cognitive decline in AD. Invasive tools, such as electrophysiological or immunohistochemical techniques, have been for decades to study synaptic morphology and density in animal models or human postmortem brain samples. Nevertheless, it has been challenging to study synaptic structure in living humans. The goals of the proposed research are: (1) to characterize the ability of in vivo diffusion MRI techniques to detect alterations of axodendritic synapse density in a mouse model of Alzheimer’s disease and (2) to assess the translational utility of such diffusion metrics for future in vivo human brain studies. A recent milestone in radiopharmaceutical development enables the possibility of studying synaptic vesicle glycoprotein 2A (SV2A) in vivo via PET imaging. PET imaging with the 11C-UCB-J tracer has shown a reduction of SV2A binding in mild cognitive impairment and AD patients. Despite its molecular accuracy, PET imaging suffers from disadvantages including high cost, low spatial resolution, and ionizing radiation exposure. On the other hand, MRI is a safe, non-invasive, and non-irradiating imaging technique that provides at least a 5-fold better spatial resolution. The modern advancement in diffusion MRI provides metrics that reflect neurite density (i.e., axons and dendrites) via compartment modeling of intracellular volume fraction. Using in vivo diffusion compartment-modeling imaging on the human brain, our laboratory demonstrated a significant decrease in intra-neurite volume fraction in white-matter areas consequent to mild traumatic brain injury, normal aging, and mild cognitive decline. We have also demonstrated decreased intra-neurite volume fraction in the human hippocampal subfields associated with poor performance in cognitive and verbal learning assessments across the clinical AD continuum. Cumulatively, our and others’ results in human studies suggest these advanced diffusion metrics are sensitive to brain degenerations and associated with cognitive and memory declines, which are thought to be caused by dysfunctional and dysregulated synapses. Nevertheless, there has not been direct evidence nor detailed characterization connecting these advanced diffusion metrics and synaptic density. The proposed research aims to address this knowledge gap.

项目摘要突触结构和功能是几种神经退行性疾病的关键，包括阿尔茨海默氏症疾病（AD）。特别是在海马中的突触功能失调和合成可塑性失调负责AD的早期记忆和认知能力下降。侵入性工具，例如电生理或免疫组织化学技术已经数十年来研究动物的突触形态和密度模型或人类后脑脑样本。然而，研究突触已受到挑战活着的人类的结构。拟议研究的目标是：（1）表征体内的能力扩散MRI技术以检测阿尔茨海默氏症小鼠模型中轴dendritic突触密度的改变疾病和（2）评估这种扩散指标的转化效用研究。最近的放射性药物发展里程碑可以研究突触囊泡通过PET成像在体内糖蛋白2a（SV2A）。使用11C-UCB-J示踪剂进行宠物成像已显示轻度认知障碍和AD患者中SV2A结合的减少。尽管具有分子精度，但成像遭受弱势群体，包括高成本，低空间分辨率和电离辐射暴露。另一方面，MRI是一种安全，无创和非辐射成像技术，至少提供 5倍更好的空间分辨率。扩散MRI的现代进步提供了反映神经蛋白的指标密度（即轴突和树突）通过细胞内体积分数的隔室建模。使用体内在人脑上扩散室模型成像，我们的实验室表现出重要的在白色物体中减少抑制脑内脑部损伤的区域中的静脉内体积分数，正常衰老和轻度认知下降。我们还证明了静脉内的体积分数减少在人类海马子场中，与认知和言语学习的表现不佳有关整个临床广告连续体的评估。累积地，我们和其他人在人类研究中的结果表明这些高级扩散指标是敏感的脑退化并与认知和记忆下降有关，这被认为是由功能失调和功能失调的突触。但是，尚未有直接证据或详细的证据将这些高级扩散指标和突触密度连接的表征。拟议的研究旨在解决这一知识差距。