Clinical Core

额颞退行性变(FTD)是一种临床上研究较少的神经退行性疾病，尽管它是 继阿尔茨海默病(AD)之后，65岁人群中导致痴呆症的最常见原因。最多的 与FTD相关的普通额颞叶变性(FTLD)病理是TDP-43蛋白病 称为FTLD-TDP。虽然可以识别出罕见的突变携带者，但他们在 生活中，对于绝大多数患有散发性疾病的FTD患者来说，还没有已知的生物标志物可以可靠地 FTLD-TDP组织病理学患者与FTLD-Tau病理患者之间的区别 临床表现为FTD，但为病理性AD的非典型变种。这导致了以下方面的重大差距 严重限制我们对TDP-43相关病理生理学理解的知识，显著限制了 疾病修正治疗试验的发展，并严重阻碍临床终点的设计 跟踪进行预后和治疗试验。因此，有必要收集数据来帮助定义特定的 更准确地了解FTLD的生活病理形态，并将这些数据与成像、生物流体生物标志物、 这份PPG研究的遗传和尸检数据。此外，疾病修正治疗试验需要良好的- 确定FTLD-TDP相关表型的自然病史以确定临床标记物 表明有益的治疗反应。临床核心将与其他核心和项目合作，以改进 我们对本程序中所考察的多层神经网络的TDP相关退化的理解 项目助学金(PPG)。为此，我们将招募散发性临床FTD患者，这些患者具有 有FTLD-TDP病理的可能性，如语义变异型原发性进行性失语(SvPPA)， 行为变异型FTD(BvFTD)与svPPA、PPA和bvFTD并存，并伴有肌营养不良 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C9orf72。我们将每年对这些病例进行简短但全面的神经心理学评估 小组，招募病例进行成像和生物流体研究，并招募病例进行尸检。我们提出了四个具体的 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.