Pathologic Substrates of Neuropsychiatric Symptoms in Aphasic Dementia

项目总结。全球痴呆症的日益流行被认为是一个迫在眉睫的公共卫生问题 危机，几乎没有有效的治疗方法来缓解患者的认知衰退和相关的精神疾病 症状。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 语言能力和语言占主导地位的大脑半球的萎缩。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，如冷漠和去抑制，这 对病人和他们的照顾者来说都是令人痛苦和负担的。确定细菌的生物底物 这些症状是具有挑战性的，因为一个痴呆症候群可能是由几种潜在的病理引起的。 例如，在PPA中，潜在的神经病理包括阿尔茨海默病(AD)和额颞叶 牛磺酸变性(FTLD-tau)或TAR DNA结合蛋白43(FTLD-TDP)。确切的生物学特征 导致痴呆综合征中神经精神症状随着时间的推移而出现和恶化的底物是 不清楚。了解各种病理的区域分布如何导致神经精神病学的表现 可以作为一个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。一个 中心假设是，每种病理都与不同的神经精神病学特征相关联，这些特征会改变 可以预见的是疾病的发展。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在一个痴呆综合征(PPA)中特有的症状。目标1的重点是 这项研究旨在描述多种潜在病理的不同神经精神病学表型。 致PPA。据推测，症状最初将在不同的神经病理之间分化，并将在 疾病的最后阶段。独特和共同的神经精神症状将在以下两个方面进行纵向评估 PPA中AD、FTLD-tau和FTLD-TDP之间的相互关系以及与认知健康组的关系。目标的目标 二是确定额叶和边缘神经精神症状与病理标记物之间的关系 大脑区域。预计这些标记的半球和区域密度不同将表现出较强的 与显著的神经精神症状有关。将分析双侧额叶和边缘区域 病理包涵体，神经元和突触完整性，以及神经炎性(小胶质细胞)标记物，这将是 使用无偏的体视学和数字病理学方法在整个大脑半球切片中进行量化。这个项目 将发生在西北阿尔茨海默病中心，这是一个多学科的国际PPA 转诊中心，将提供50多个PPA患者的尸检大脑，从而代表 一个 建议的研究和培训的理想环境。这项研究对公众健康的影响是巨大的。 由于AD、FTLD-tau和FTLD-TDP是大多数神经退行性痴呆的基础，结果显示 为痴呆症患者的诊断和治疗方法提供信息的可能性。

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.