Multimodal imaging measures to assess synaptic dysfunction in Alzheimer's disease

阿尔茨海默病（AD）是最常见的与年龄相关的神经退行性疾病， 进行性认知缺陷的情况。寻找治疗AD的方法的紧迫性从未如此强烈。突触 功能障碍和突触丧失是AD病理生理学的核心缺陷。更好地理解突触 因此，开发有效的治疗干预措施势在必行。在这个R21中，我们提出了一个 多模态成像研究结合结构和功能突触的措施，同时表征 AD患者的突触功能障碍。我们研究的多模态组成包括脑磁图 (MEG)以探测突触生理学和正电子发射断层扫描（PET）以探测突触密度， 以及淀粉样蛋白（Aβ）和tau沉积的体内定量。这一建议代表了一个非常 第一个将两种复杂的技术联合收割机结合起来研究AD中的突触失效。一方面，MEG提供 神经振荡的定量光谱特征，其代表了最直接、非侵入性的测量 人类大脑中神经元和突触的功能。结合脑磁图精细的时空分辨率 光谱分析与神经质量模型（NMM）的数学应用是一种强大的技术， 来自人类受试者的非侵入性神经成像的神经元水平细节。另一方面， 与突触囊泡结合的糖蛋白2A（SV 2A）最近可用于测量体内突触 大脑中的密度。在这里，我们建议使用新的第二代SV 2A配体，18F-SynVesT-1， 这是AD研究的第一次。定义突触密度和突触生理学之间的关系， 它们与Aβ和tau蛋白的特异性关系将拓宽目前AD病理生理学的概念， 为早期干预性临床试验提供新的突触生物标志物。我们将进行一次横向试点 45名参与者的研究：25名Aβ阳性轻度认知障碍（MCI）和轻度AD痴呆（CDR<1）， 20名年龄匹配的认知未受损个体（10名Aβ阴性和10名Aβ阳性）。所有参与者将 接受静息状态MEG、结构MRI、SV 2A（18F-18F-SynVesT-1）、Aβ 3示踪剂PET成像 （florbetaben）和tau（flortaucipir），并完成认知和神经心理学评估。我们的中央 假设兴奋性和抑制性神经元缺陷与突触密度降低相关（18F- SynVesT-1），并与Aβ和tau沉积（分别为florbetaben和flortaucipir）在早期临床阶段， AD.我们将致力于两个关键目标。在目标1中，我们将确定受损的突触之间的关系 生理学（MEG和NMM）和突触密度（18F-SynVesT-1保留）。在目标2中，我们将检查 18F-SynVesT-1 PET结合缺陷与AD病理生理学和认知功能之间的关系 早期临床阶段AD患者的损伤。这个项目将产生重要的数据来定义突触失败 在AD患者中的研究和初步数据，以设计未来的研究，将AD患者的临床研究与 基础科学的机械发现。

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, a relentless and fatal condition of progressive cognitive deficits. The urgency to find a cure for AD has never been stronger. Synaptic dysfunction and synapse loss are core deficits in AD pathophysiology. A better understanding of synaptic dysfunction in AD is imperative to develop effective therapeutic interventions. In this R21, we propose a multimodal imaging study combining structural and functional synaptic measures simultaneously to characterize synaptic failure in patients with AD. The multimodal composition of our study includes magnetoencephalography (MEG) to probe synapse physiology and positron emission tomography (PET) to probe synapse density, together with in-vivo quantification of amyloid (Aβ) and tau depositions. This proposal represents one of the very first to combine two sophisticated technologies to study synaptic failure in AD. On one hand, MEG provides quantitative spectral signatures of neural oscillations which represents the most direct, non-invasive, measures of neuronal and synaptic function in the human brain. Combining the fine spatiotemporal resolution of MEG spectral analyses with mathematical application of neural mass model (NMM) is a powerful technique to examine neuronal level details from non-invasive neuroimaging in human subjects. On the other hand, radioligands that bind to the synaptic vesicle glycoprotein 2A (SV2A) has recently become available to measure in-vivo synaptic density in the human brain. Here we propose to use a new second generation SV2A ligand, 18F-SynVesT-1, for the first time in AD research. Defining the relationships between synaptic density and synapse physiology and their specific relationships to Aβ and tau will broaden the current conceptualizations of AD pathophysiology and provide novel synaptic biomarkers for early interventional clinical trials. We will conduct a cross sectional pilot study of 45 participants: 25 Aβ-positive mild cognitive impairment (MCI) and mild-AD-dementia (CDR<1), and 20 age-matched cognitively unimpaired individuals (10 Aβ-negative and 10 Aβ-positive). All participants will undergo resting state MEG, structural MRI, 3-tracer PET imaging for SV2A (18F-18F-SynVesT-1), Aβ (florbetaben), and tau (flortaucipir), and complete cognitive and neuropsychological assessments. Our central hypothesis is that excitatory and inhibitory neuronal deficits will be correlated with reduced synaptic density (18F- SynVesT-1), and with Aβ and tau depositions (florbetaben and flortaucipir, respectively) in early clinical stage of AD. We will address two key aims. In Aim 1, we will determine the relationship between impaired synapse physiology (MEG and NMM) and synapse density (18F-SynVesT-1 retention) in AD. In Aim 2, we will Examine the associations between binding deficits of 18F-SynVesT-1 PET and AD pathophysiology and cognitive impairments in early clinical stage AD patients. This project will generate crucial data to define synaptic failure in patients with AD and preliminary data to design future studies linking clinical investigations in AD patients to mechanistic findings from basic science.