Tau networks in AD psychosis

AD 精神病中的 Tau 网络

• 批准号: 10507415
• 负责人: Jesus J Gomar
• 金额: $ 10.64万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507415
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Area; Atrophic; Autopsy; Behavioral; Brain; Caregiver Burden; Cerebrospinal Fluid; Cerebrum; Clinical; Cognitive; Cognitive deficits; Data; Delusions; Development; Diffuse; Diffusion Magnetic Resonance Imaging; Economics; Executive Dysfunction; Functional Magnetic Resonance Imaging; Future; Generations; Goals; Hallucinations; Imaging Techniques; Impaired cognition; Impairment; Inferior; Investigation; K-Series Research Career Programs; Lateral; Link; Measures; Mediator of activation protein; Methods; Multimodal Imaging; Neurobiology; Neuropsychology; Occipital lobe; Parietal; Parietal Lobe; Pathology; Patients; Positron-Emission Tomography; Psychologist; Psychoses; Public Health; Research; Research Activity; Research Training; Rest; Role; Schizophrenia; Short-Term Memory; Specificity; Temporal Lobe; Testing; Tracer; Training; Training Activity; base; burden of illness; career; career development; effective therapy; executive function; experience; frontal lobe; functional decline; global health; gray matter; imaging approach; imaging properties; improved; in vivo; innovation; insight; molecular imaging; mortality; multimodal neuroimaging; network dysfunction; neuroimaging; phenomenological models; psychotic symptoms; radiotracer; skills; social; social cognition; tau Proteins; tau aggregation; tau-1; tractography; white matter

Project Summary/Abstract The overarching goal of this K01 application is to examine cerebral mechanisms that underlie psychotic symptoms (PS) in Alzheimer’s disease (AD) using positron emission tomography (PET), diffusion tensor imaging (DTI), and resting state functional magnetic resonance imaging (rs-fMRI) techniques. I will specifically address the role of tau pathology and structural and functional network disruptions in the manifestation of PS in AD. Cerebrospinal fluid (CSF) and post-mortem studies have suggested a role of tau pathology in the manifestation of PS in AD. However, the cerebral mechanisms that underlie this association remain poorly understood. A thorough and comprehensive plan for additional training and related career development activities is proposed based on: 1) Phenomenology of psychosis in the context of AD from both psychiatric and cognitive perspectives; 2) Tau neurobiology and tau positron emission tomography (PET) imaging; 3) Diffusion tensor imaging (DTI), tractography, and resting-state functional magnetic resonance imaging (rs-fMRI) network connectivity. These training goals are intended to provide crucial scientific skills needed to test the following hypotheses: 1) AD patients with PS will show greater tau accumulation in frontal, cingulate, lateral temporal and parieto-occipital cortices regions compared to AD without PS; 2) AD with PS will show more abnormal diffusivity, compared to AD without PS, in white matter tracts that connect frontal, cingulate, lateral temporal, parietal, and occipital lobes, and functional network connectivity abnormalities in cortical circuits involving the frontal lobe, specifically the default mode network (DMN) and the salience network (SN); in addition, I expect that tau aggregation in central nodes of the DMN will correlate with delusions, whereas tau aggregation in the SN will be associated with hallucinations; 3) Tau aggregation will be greater in the central nodes of these structural and functional networks in AD patients with PS compared to AD patients without PS; and 4) Tau aggregation in frontal, temporal and posterior cingulate regions, will correlate with social cognition and executive function impairments in AD patients with PS. I will use a second generation tau radiotracer ([18F]- PI2620) that has shown excellent imaging properties and high specificity, in combination with a comprehensive assessment of both psychiatric (delusions and hallucinations) and cognitive (social cognition and executive function impairment) manifestations of PS. The proposed combination of training and research plans will lay the ground to launch my independent career to test neurobiological hypotheses regarding behavioral manifestations of AD from a neuroimaging perspective.

项目总结/摘要 这个K01应用程序的首要目标是检查精神病患者的大脑机制， 使用正电子发射断层扫描（PET）、扩散张量 磁共振成像（DTI）和静息状态功能性磁共振成像（rs-fMRI）技术。我会特别 解决tau病理学以及结构和功能网络中断在PS表现中的作用， ad.脑脊液（CSF）和尸检研究表明，tau蛋白病理学在脑梗死中的作用。 PS在AD中的表现。然而，这种关联背后的大脑机制仍然很差 明白一个全面的额外培训和相关职业发展计划 活动是基于：1）AD背景下的精神病现象学， 认知观点; 2）Tau神经生物学和Tau正电子发射断层扫描（PET）成像; 3）扩散 张量成像（DTI）、纤维束成像和静息态功能磁共振成像（rs-fMRI）网络 连通性。这些培训目标旨在提供测试以下内容所需的关键科学技能 假设：1）具有PS的AD患者将在额叶、扣带回、外侧颞叶中显示更大的tau积聚。 AD合并PS时，AD患者的脑皮层、顶枕区的异常率高于AD不合并PS时的脑皮层、顶枕区的异常率; 与无PS的AD相比，在连接额叶、扣带回、侧颞的白色物质束中， 顶叶和枕叶，以及涉及大脑皮层回路的功能网络连接异常， 额叶，特别是默认模式网络（DMN）和显着网络（SN）;此外，我预计 在DMN的中央节点中的tau聚集将与妄想相关，而在DMN的中央节点中的tau聚集将与妄想相关。 SN将与幻觉相关; 3）Tau聚集在这些区域的中心节点中将更大。 与没有PS的AD患者相比，具有PS的AD患者的结构和功能网络;以及4）Tau 聚集在额叶，颞叶和后扣带区域，将与社会认知和 伴有PS的AD患者的执行功能障碍。我将使用第二代tau放射性示踪剂（[18F]- PI2620），其显示出优异的成像特性和高特异性，与全面的 精神（妄想和幻觉）和认知（社会认知和执行）评估 功能障碍）的表现。拟议的培训和研究计划的结合将奠定 这是我开始独立工作的基础，我的工作是测试关于行为的神经生物学假设， 从神经影像学的角度来看AD的表现。