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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' 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

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）。具体来说，海马体中的功能失调的突触和失调的突触可塑性 是导致AD早期记忆和认知能力下降的原因。侵入性工具，如电生理或 免疫组织化学技术几十年来一直用于研究动物突触形态和密度 模型或人类死后的大脑样本。然而，研究突触 活的人的结构。本研究的主要目的是：（1）研究在体条件下， 扩散磁共振成像技术检测阿尔茨海默病小鼠模型轴树突触密度的改变 疾病和（2）评估这种扩散度量对未来体内人脑的转化效用 问题研究 放射性药物发展的一个里程碑使研究突触囊泡成为可能 糖蛋白2A（SV 2A）在体内通过PET成像。使用11 C-UCB-J示踪剂的PET成像显示， 在轻度认知障碍和AD患者中减少SV 2A结合。尽管PET具有分子精确度， 成像具有包括高成本、低空间分辨率和电离辐射暴露在内的缺点。 另一方面，MRI是一种安全、非侵入性和非辐射性的成像技术，其提供至少 5-提高空间分辨率。扩散MRI的现代进步提供了反映神经突的指标 密度（即，轴突和树突）。使用体内 扩散室建模成像对人脑，我们的实验室证明了一个显着的 轻度创伤性脑损伤后白质区神经突内体积分数降低， 正常衰老和轻度认知能力下降我们还证明了神经突内体积分数的降低 与认知和语言学习表现不佳相关的人类海马子区 临床AD连续体的评估。 累积起来，我们和其他人在人体研究中的结果表明，这些先进的扩散指标是敏感的 大脑退化，并与认知和记忆下降有关，这被认为是由 功能失调和失调的突触。然而，没有直接证据或详细的 将这些先进的扩散度量和突触密度连接起来的特征。拟议研究 旨在弥补这一知识缺口。