Clinical Core

额颞叶变性（FTD）是一种研究不足的临床神经退行性疾病，即使它是 阿尔茨海默病（AD）是65岁以下人群中痴呆症的最常见原因。最 与FTD相关的常见额颞叶变性（FTLD）病理学为TDP-43蛋白质病 称为FTLD-TDP。虽然可以确定罕见的突变携带者，他们在治疗期间具有FTLD-TDP病理学， 对于绝大多数患有散发性疾病的FTD患者，没有已知的生物标志物可以可靠地 将FTLD-TDP组织病理学患者与FTLD-Tau病理学患者区分开来， 存在临床FTD，但为病理性AD的非典型变体。这导致了重大差距 这些知识严重限制了我们对TDP-43相关病理生理学理解， 改善疾病的治疗试验的发展，并严重阻碍设计临床终点， 用于预后和治疗试验。因此，有必要收集数据，帮助确定具体的 更准确地描述生命期间FTLD的病理形式，并将这些数据与成像，生物流体生物标志物， 遗传学和尸检数据在这个PPG研究。此外，改善疾病的治疗试验需要- 表征与FTLD-TDP相关的表型的自然史，以鉴定临床标志物 表明有益的治疗反应。临床核心将与其他核心和项目合作， 我们对本计划中检查的多级神经网络的TDP相关退化的理解 项目补助金。为此，我们将招募散发性临床FTD患者， 可能患有FTLD-TDP病理，如语义变异型原发性进行性失语症（svPPA）， 行为变体FTD（bvFTD）与svPPA、PPA和bvFTD同时存在肌萎缩 侧索硬化症（ALS）。我们还将招募与FTLD相关的突变的症状携带者，如 PGRN和C9 orf 72。我们将每年对这些病例进行一次简短但全面的神经心理学评估， 电池，招募病例进行成像和生物流体研究，并招募病例进行尸检。我们提出四个具体的 旨在实现这些目标。

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition even though it is the most common cause of dementia after Alzheimer’s disease (AD) in people <65 years old. The most common frontotemporal lobar degeneration (FTLD) pathology associated with FTD is TDP-43 proteinopathy known as FTLD-TDP. Although rare mutation carriers can be identified who have FTLD-TDP pathology during life, there are no known biomarkers for the vast majority of FTD patients with sporadic disease that can reliably distinguish patients with FTLD-TDP histopathology from those with FTLD-Tau pathology, nor from patients who present with clinical FTD but are atypical variants of pathological AD. This has resulted in major gaps in knowledge that severely limit our understanding of TDP-43-associated pathophysiology, significantly constrain the development of disease-modifying treatment trials, and severely impede designing clinical end-points to follow for prognosis and for treatment trials. It is thus necessary to collect data that help define the specific pathologic form of FTLD during life more accurately, and relate these data to imaging, biofluid biomarker, genetic and autopsy data studied in this PPG. Moreover, disease-modifying treatment trials require well- characterized natural histories of phenotypes related to FTLD-TDP in order to identify clinical markers indicating a beneficial treatment response. The Clinical Core will work with other cores and projects to improve our understanding of the TDP-related degeneration of multilevel neural networks examined in this Program Project Grant (PPG). To these ends, we will recruit patients with sporadic clinical FTD who have a high likelihood of having FTLD-TDP pathology such as semantic variant Primary Progressive Aphasia (svPPA), behavioral variant FTD (bvFTD) co-occurring with svPPA, PPA and bvFTD with co-occurring amyotrophic lateral sclerosis (ALS). We will also recruit symptomatic carriers of mutations associated with FTLD such as PGRN and C9orf72. We will assess these cases annually with a brief but comprehensive neuropsychological battery, recruit cases for imaging and biofluid studies, and recruit cases for autopsy. We propose four Specific Aims to achieve these goals.