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，是一种无情而致命的疾病 进行性认知缺陷的状况。找到治疗阿尔茨海默病的方法的紧迫性前所未有地强烈。突触 功能障碍和突触丢失是AD病理生理学的核心缺陷。更好地理解突触 AD的功能障碍是开发有效的治疗干预措施的当务之急。在本R21中，我们建议 同时结合结构和功能突触测量的多模式成像研究 阿尔茨海默病患者的突触衰竭。我们研究的多模式组合包括脑磁图 (脑磁图)探测突触生理和正电子发射断层扫描(PET)探测突触密度， 以及体内淀粉样蛋白(Aβ)和tau沉积的量化。这项提议代表了非常重要的 首先，结合两项复杂的技术来研究AD的突触故障。一方面，梅格提供了 神经振荡的定量光谱特征，代表最直接、非侵入性的测量 在人脑中的神经元和突触功能。结合脑磁图的精细时空分辨率 光谱分析与神经质量模型(NMM)的数学应用是一种强有力的检测技术 来自人类受试者非侵入性神经成像的神经元水平细节。另一方面，放射性配体 结合突触囊泡糖蛋白2A(SV2A)最近已可用于测量体内突触 人脑中的密度。在这里，我们建议使用新的第二代SV2A配体，18F-SynVesT-1，用于 这是AD研究中的第一次。明确突触密度与突触生理的关系 它们与Aβ和tau的特殊关系将拓宽目前AD病理生理学的概念化和 为早期介入临床试验提供新的突触生物标志物。我们将进行一次横断面试验 对45名参与者的研究：25名β阳性的轻度认知障碍和轻度AD痴呆(CDR&lt；1)，以及 20名年龄匹配的认知正常个体(10名Aβ阴性，10名Aβ阳性)。所有参与者将 接受静息状态脑磁图、结构磁共振、3-示踪剂正电子发射计算机断层扫描检查SV2a(18F-18F-SynVesT-1)、Aβ (氟倍他滨)和tau(氟他西平)，并完成认知和神经心理评估。我们的中央 假设兴奋性和抑制性神经元缺陷将与突触密度降低相关(18F- SynVesT-1)，并与Aβ和tau沉积(分别为氟倍他滨和氟他西平)在早期临床阶段 广告。我们将解决两个主要目标。在目标1中，我们将确定受损突触之间的关系 AD的生理学(MEG和NMM)和突触密度(18F-SynVesT-1保留)。在目标2中，我们将研究 18F-SynVesT-1PET结合缺陷与AD病理生理及认知功能的关系 临床早期阿尔茨海默病患者的损害。该项目将产生关键数据来定义突触故障 和初步数据来设计未来的研究，将AD患者的临床调查与 来自基础科学的机械论发现。

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.