Pathologic Substrates of Neuropsychiatric Symptoms in Aphasic Dementia

项目摘要。全球范围内痴呆症的患病率不断上升，被认为是一个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减轻患者的认知下降和相关的精神疾病 症状原发性进行性失语症（PPA）是一种临床痴呆综合征，定义为初始的局灶性衰退， 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PPA患者也会出现严重的神经精神症状，如冷漠和抑制解除， 对病人和他们的护理者都是痛苦和负担的。确定生物基质 这些症状是具有挑战性的，因为一种痴呆综合征可由几种潜在的病理引起。 例如，在PPA中，潜在的神经病理学包括阿尔茨海默病（AD）和额颞叶痴呆。 伴有tau病变的变性（FTLD-tau）或TAR DNA结合蛋白43（FTLD-TDP）。准确的生物学 在痴呆综合征中引起神经精神症状出现并随时间恶化的底物是 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 可以作为一个有价值的生前生物标志物，并加深我们对大脑行为关系的认识。一 中心假设是，每种病理都与不同的神经精神特征相关， 随着疾病的进展而变化为了调查这一点，拟议的研究将确定神经精神病 一种痴呆综合征（PPA）内的AD、FTLD-tau和FTLD-TDP特有的症状。目标1的重点 本研究旨在描述多种潜在病理的不同神经精神表型， 到PPA。据推测，症状最初将在神经病理学之间分歧，并将在神经病理学之间收敛。 疾病的最后阶段。将对独特和共有的神经精神症状进行纵向评估， PPA中的AD、FTLD-tau和FTLD-TDP相对于彼此以及相对于认知健康组。Aim的目标 二是确定额叶和边缘系统神经精神特征与病理标志物的关系 大脑区域。预计不同这些标记的半球和区域密度将显示出强烈的 与突出的神经精神症状相关。将分析双侧额叶和边缘区， 病理性内含物、神经元和突触完整性以及神经炎性（小胶质细胞）标志物，这些将是 使用无偏体视学和数字病理学方法在整个半球切片中定量。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，国际PPA 转诊中心将提供超过50个来自PPA患者的死后大脑，因此代表了 一个 为研究和培训提供理想的环境。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， 为痴呆患者提供诊断和治疗方法的潜力。

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.