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

项目摘要 突触结构和功能是包括阿尔茨海默氏症在内的几种神经退行性疾病的关键 疾病(AD)。具体地说，海马区功能失调的突触和失调的突触可塑性 是阿尔茨海默病早期记忆力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，几十年来一直在动物中研究突触的形态和密度 模型或人类死后大脑样本。然而，研究突触一直是具有挑战性的。 活人体内的结构。这项研究的目的是：(1)表征在体内的能力。 弥散磁共振技术检测阿尔茨海默病小鼠模型轴突突触密度的变化 疾病和(2)评估这种扩散度量对未来活体人脑的翻译效用 学习。 放射性药物发展的最新里程碑使研究突触小泡成为可能 体内的糖蛋白2A(SV2A)通过PET成像。用11C-UCB-J示踪剂进行的PET成像显示 轻度认知障碍和AD患者中SV2A结合的减少。尽管它的分子精度很高，但PET 成像存在成本高、空间分辨率低、电离辐射暴露等缺点。 另一方面，MRI是一种安全、非侵入性和非辐射的成像技术，它至少提供了 空间分辨率提高5倍。磁共振弥散成像的现代进展提供了反映轴突的指标 密度(即轴突和树突)通过细胞内体积分数的隔室模型。在体内使用 通过对人脑的扩散间隔模型成像，我们的实验室展示了一个显著的 轻度创伤性脑损伤导致脑白质区域轴突内体积分数降低， 正常衰老，轻度认知衰退。我们还证实了轴突内体积分数的降低。 在与认知和语言学习成绩差有关的人类海马区 跨临床AD连续体的评估。 总体而言，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 导致大脑退化，并与认知和记忆力下降有关，这被认为是由 功能失调和调节失调的突触。然而，目前还没有直接的证据，也没有详细的证据 将这些高级扩散指标和突触密度联系起来的特征。拟议的研究 旨在解决这一知识鸿沟。

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.