Pathologic Substrates of Neuropsychiatric Symptoms in Aphasic Dementia

失语性痴呆神经精神症状的病理基础

基本信息

批准号：
10388575
负责人：
Rachel M Keszycki
金额：
$ 4.68万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10388575
关键词：
Affective Symptoms Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Amygdaloid structure Amyloid Anatomy Anterior Anxiety Aphasia Atrophic Autopsy Behavior Behavioral Behavioral Symptoms Bilateral Biological Biological Markers Brain Brain Pathology Brain region Caregivers Cerebrospinal Fluid Clinical Cognitive Control Groups DNA-Binding Proteins Data Dementia Desire for food Development Diagnosis Diagnostic Disease Disease Progression Disinhibition Distress Environment Etiology Family Frontotemporal Lobar Degenerations Future Goals Human Impaired cognition International Knowledge Language Lead Left Mental Depression Methods Microglia Microscopic Moods Motivation Nerve Degeneration Neuroanatomy Neurobehavioral Manifestations Neurons Neuropsychology Onset of illness Participant Pathologic Pathology Patients Pattern Persons Phenotype Positron-Emission Tomography Prefrontal Cortex Prevalence Primary Progressive Aphasia Process Prognosis Psychoses Public Health Regulation Research Research Training STEM field Specimen Symptoms Synapses Syndrome Tauopathies Testing Time Training Transact Work area striata base biomedical referral center brain behavior cerebral atrophy cingulate cortex density diagnostic accuracy diagnostic criteria digital digital pathology doctoral student effective therapy experience longitudinal analysis multidisciplinary neural network neurodegenerative dementia neuroimaging neuroinflammation neuropathology neuropsychiatric symptom neuropsychiatry protein TDP-43 psychiatric symptom response translational scientist

项目摘要

PROJECT SUMMARY. The increasing prevalence of dementia worldwide is considered a looming public health crisis, and few effective treatments are available to alleviate patients’ cognitive decline and associated psychiatric symptoms. Primary progressive aphasia (PPA) is a clinical dementia syndrome defined as an initial, focal decline in language abilities and atrophy of the language-dominant hemisphere. While not a core diagnostic criterion, most persons with PPA also develop severe neuropsychiatric symptoms, such as apathy and disinhibition, which are distressing and burdensome to both patients and their caregivers. Determining the biological substrates of these symptoms is challenging because one dementia syndrome can result from several underlying pathologies. In PPA, for example, underlying neuropathologies include Alzheimer’s disease (AD) and frontotemporal lobar degeneration with tauopathy (FTLD-tau) or TAR DNA-binding protein 43 (FTLD-TDP). The exact biological substrates causing neuropsychiatric symptoms to emerge and worsen over time in dementia syndromes are unclear. Understanding how regional distributions of various pathologies lead to neuropsychiatric presentations may serve as a valuable antemortem biomarker and deepen our knowledge of brain-behavior relationships. A central hypothesis is that each pathology will be associated with distinct neuropsychiatric signatures that change predictably with disease progression. To investigate this, the proposed research will identify the neuropsychiatric symptoms unique to AD, FTLD-tau, and FTLD-TDP within one dementia syndrome (PPA). The focus of Aim 1 of this study is to characterize distinct neuropsychiatric phenotypes of multiple underlying pathologies as they lead to PPA. It is hypothesized that symptoms will initially diverge between neuropathologies and will converge in the final stages of disease. Unique and shared neuropsychiatric symptoms will be assessed longitudinally between AD, FTLD-tau, and FTLD-TDP in PPA relative to each other and to a cognitively healthy group. The goal of Aim 2 is to determine relationships between neuropsychiatric signatures and pathologic markers in frontal and limbic brain regions. It is expected that hemispheric and regional densities of different these markers will show strong associations with salient neuropsychiatric symptoms. Bilateral frontal and limbic regions will be analyzed for pathologic inclusions, neuronal and synaptic integrity, and neuroinflammatory (microglia) markers, which will be quantified in whole hemisphere sections using unbiased stereology and digital pathology methods. This project will occur within the Northwestern Alzheimer’s Disease Center, which is a multidisciplinary, international PPA referral center that will provide access to over 50 postmortem brains from persons with PPA and thus represents an ideal environment for the proposed research and training. The public health impact of this study is substantial as AD, FTLD-tau, and FTLD-TDP underlie the majority of neurodegenerative dementias, and results have the potential to inform diagnostic and treatment approaches for patients with dementia.

项目摘要：全球痴呆症患病率不断上升被认为是迫在眉睫的公共卫生问题。危机，并且很少有有效的治疗方法可以缓解患者的认知能力下降和相关的精神疾病原发性进行性失语 (PPA) 是一种临床痴呆综合征，定义为最初的局灶性衰退。语言能力和语言主导半球的萎缩虽然不是核心诊断标准，大多数患有 PPA 的人还会出现严重的神经精神症状，例如冷漠和去抑制，这确定患者及其护理人员的生物底物都是令人痛苦和负担的。这些症状具有挑战性，因为一种痴呆综合征可能是由多种潜在病理引起的。例如，在 PPA 中，潜在的神经病理学包括阿尔茨海默病 (AD) 和额颞叶 tau 蛋白变性 (FTLD-tau) 或 TAR DNA 结合蛋白 43 (FTLD-TDP) 的确切生物学特性。导致痴呆症中出现神经精神症状并随着时间的推移而恶化的底物是不清楚。了解各种病理的区域分布如何导致神经精神病学表现可能作为一种有价值的生前生物标志物，加深我们对大脑行为关系的了解。中心假设是，每种病理学都与不同的神经精神特征相关，这些特征会改变为了研究这一点，拟议的研究将确定神经精神学。一种痴呆综合征 (PPA) 中 AD、FTLD-tau 和 FTLD-TDP 的独特症状目标 1 的重点。这项研究旨在表征多种潜在病理的不同神经精神表型，因为它们导致首创的是，神经病理学之间的症状最初会有所不同，然后会在不同的神经病理学中趋同。疾病的最后阶段将纵向评估独特和共同的神经精神症状。 PPA 中的 AD、FTLD-tau 和 FTLD-TDP 相互之间以及与认知健康组的关系目标目标。 2 是确定额叶和边缘神经精神特征与病理标志物之间的关系预计不同这些标记的半球和区域密度将显示出很强的强度。将分析与显着神经精神症状的关联。病理包涵体、神经元和突触完整性以及神经炎症（小胶质细胞）标记物，这些将被该项目使用无偏见的体视学和数字病理学方法对整个半球切片进行量化。将在西北阿尔茨海默病中心内进行，该中心是一个多学科的国际 PPA 转诊中心将提供 50 多个 PPA 患者死后大脑的接触机会，从而代表一个拟议研究和培训的理想环境。这项研究对公共健康的影响是巨大的。因为 AD、FTLD-tau 和 FTLD-TDP 是大多数神经退行性痴呆的基础，结果表明为痴呆症患者的诊断和治疗方法提供信息的潜力。