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

评估阿尔茨海默病突触功能障碍的多模态成像方法

• 批准号: 10448946
• 负责人: Kamalini Gayathree Ranasinghe
• 金额: $ 48.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448946
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Basic Science; Binding; Biological Assay; Biological Markers; Brain; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Coupled; Data; Dementia; Deposition; Detection; Development; Disease; Early Intervention; Electrophysiology (science); Event; Excitatory Synapse; Functional disorder; Funding Agency; Future; Generations; Glycoproteins; Goals; Half-Life; Human; Imaging Techniques; Impaired cognition; Impairment; Individual; Inferior; Inhibitory Synapse; Investigation; Language; Ligands; Link; Magnetic Resonance Imaging; Magnetoencephalography; Mathematics; Measures; Medial; Mediating; Memory; Modeling; Molecular; Multimodal Imaging; Neurologic; Neurons; Neuropsychology; Participant; Pathologic; Pathologic Processes; Pathology; Patients; Physiology; Pilot Projects; Population; Positron-Emission Tomography; Property; Proteins; Records; Research; Resolution; Resources; Rest; Senile Plaques; Synapses; Synaptic Vesicles; Techniques; Technology; Temporal Lobe; Therapeutic Intervention; Time; Toxic effect; Tracer; Transgenic Organisms; Visuospatial; abeta accumulation; abeta deposition; age related neurodegeneration; base; cingulate cortex; clinical investigation; cognitive function; cohort; cost; density; design; early detection biomarkers; entorhinal cortex; human imaging; human subject; imaging properties; imaging study; in vivo; indexing; innovation; insight; mild cognitive impairment; molecular imaging; multimodality; neocortical; neuroimaging; neurophysiology; novel; radioligand; recruit; relating to nervous system; research clinical testing; spatiotemporal; synaptic failure; synaptic function; tau Proteins; tau aggregation; therapeutically effective; uptake; β-amyloid burden

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.

阿尔茨海默氏病（AD）是最常见的与年龄相关的神经退行性疾病，一种友好而致命的 进行性认知缺陷的状况。寻找AD治疗的紧迫性从未有过强大。突触 功能障碍和突触丧失是AD病理生理学的核心定义。更好地理解突触 AD的功能障碍必须制定有效的治疗干预措施。在此R21中，我们提出了一个 多模式成像研究结合了结构和功能突触措施，以表征 AD患者的突触失败。我们研究的多模式组成包括磁脑摄影 （MEG）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。该提议代表了一个 首先结合两种复杂技术来研究AD中的突触衰竭。一方面，梅格提供 神经振荡的定量光谱特征，代表最直接，无创措施 人脑中的神经元和突触功能。结合MEG的精细空间时间分辨率 通过数学应用神经质量模型（NMM）进行的光谱分析是检查的强大技术 神经元水平的细节来自人类受试者的非侵入性神经影像学。另一方面，放射线 与突触囊泡糖蛋白2a（SV2A）结合，最近已用于测量体内突触 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 AD研究的第一次。定义合成密度与突触生理学与 他们与Aβ和TAU的具体关系将扩大AD病理生理学的当前概念和 为早期介入临床试验提供新型的突触生物标志物。我们将进行横截面飞行员 45名参与者的研究：25个Aβ阳性的轻度认知障碍（MCI）和轻度AD痴呆症（CDR <1）和 20个年龄匹配的认知无损个体（10个Aβ阴性和10个Aβ阳性）。所有参与者都会 进行静止状态MEG，结构MRI，SV2A（18F-18F-Synvest-1）的3-追踪PET成像，Aβ （Florbetaben）和Tau（Flortaucipir），以及完整的认知和神经心理学评估。我们的中心 假设是兴奋性和抑制性神经元定义将与突触密度降低相关（18f- Synvest-1），以及Aβ和TAU沉积（分别为Florbetaben和Flortaucipir）在早期的临床阶段 广告。我们将解决两个关键目标。在AIM 1中，我们将确定突触受损之间的关系 AD中的生理学（MEG和NMM）和突触密度（18f-synvest-1保留）。在AIM 2中，我们将检查 18F合奏-1 PET的结合缺陷与AD病理生理学与认知之间的关联 早期临床阶段AD患者的损害。该项目将产生关键数据以定义突触失败 在AD和初步数据的患者中，设计了将AD患者临床研究联系起来的未来研究 基础科学的机械发现。