Pathologic Substrates of Neuropsychiatric Symptoms in Aphasic Dementia

失语性痴呆神经精神症状的病理基础

• 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
• 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' s Disease; Alzheimer' s disease diagnosis; Alzheimer' 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

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。全球痴呆症的越来越多被认为是公共卫生的损失 危机，几乎没有有效的治疗方法可以减轻患者的认知能力下降和相关的精神病学 主要进行性失语症（PPA）是一种临床痴呆综合征，定义为初始局灶性下降 语言能力和语言主导性半球的萎缩。虽然不是核心诊断标准，但 大多数患有PPA的人还会出现严重的神经精神症状，例如冷漠和抑制，这是 对患者及其护理人员感到痛苦和磨碎。确定 这些符号具有挑战性，因为一种痴呆症综合征可能是由几种潜在的病理引起的。 例如，在PPA中，潜在的神经病理学包括阿尔茨海默氏病（AD）和额叶lobar tauopathy（FTLD-TAU）或TAR DNA结合蛋白43（FTLD-TDP）的变性。确切的生物学 导致神经精神症状出现的底物出现，随着时间的流逝，痴呆症综合征的时间更糟 不清楚。了解各种病理的区域分布如何导致神经精神病学的表现 可以用作宝贵的Anthertem生物标志物，并加深我们对脑行为关系的了解。一个 中心假设是，每种病理学都将与改变的不同神经精神签名有关 可以预见的是疾病进展。为了调查这一点，拟议的研究将确定神经精神病学 AD，FTLD-TAU和FTLD-TDP独有的症状（PPA）。目标1的重点 这项研究是为了表征多种潜在病理学的不同神经精神表型 到PPA。假设符号最初会在神经病理学之间发散，并会在 疾病的最后阶段。独特的和共同的神经精神症状将在纵向评估 PPA相对于彼此的AD，FTLD-TAU和FTLD-TDP以及认知健康的群体。目标的目标 2是确定额和边缘中神经精神签名与病理标记之间的关系 大脑区域。预计这些标记的半球和区域密度将显示出很强 与明显的神经精神症状的关联。将分析双边额叶和边缘区域 病理夹杂物，神经元和突触完整性以及神经炎症（小胶质细胞）标记，这将是 使用无偏的立体学和数字病理学方法在整个半球部分进行量化。这个项目 将发生在西北阿尔茨海默氏病中心，这是一个多学科的国际PPA 推荐中心将为患有PPA的人提供50多名验尸大脑的访问权限，从而代表 一个 拟议研究和培训的理想环境。这项研究的公共卫生影响很大 作为AD，FTLD-TAU和FTLD-TDP，大多数神经退行性痴呆症是 为痴呆症患者提供诊断和治疗方法的潜力。