Examination of the earliest symptoms and biomarkers of FTLD MAPT carriers

描述(由申请人提供)：关于额颞叶痴呆(FTLD)遗传基础的发现为研究人员提供了前所未有的能力来表征这种疾病的症状前阶段。这种能力对于确定疾病的最早临床特征和识别可用于早期诊断和治疗研究的生物标记物至关重要。拟议的项目将检查单个家庭中接近发病年龄的FTLD基因突变个体，提供一个独特和高度受控的环境，在其中确定这种毁灭性疾病的最早临床特征和生物标志物。具体地说，这项研究建议跟踪一个已知MAPT(Tau)基因突变的大家族的后代，以确定FTLD的最早临床特征以及可能改变疾病发病和病程的变量。一个家庭的后代中至少有90名成员将被允许参加一项纵向研究，检查认知、行为、精神症状和生活方式特征。此外，这项建议包括使用最先进的神经成像工具，包括结构和功能形态、灰质和白质量化以及区域和网络分析，以检测疾病的最早迹象。个体将接受基因测试以确定携带者状态，将在基线上进行全面的特征描述，并将在研究过程中每年进行跟踪，以检查临床和影像变量随时间的变化作为携带者状态的函数。此外，这项拟议的研究将仔细分析终身体育活动、饮酒和娱乐用药的特征，以确定这些生活方式变量是否是疾病的早期表现 和/或修改疾病的发病和病程。最后，包括脑脊液和血浆在内的生物标本将被纵向收集，以努力描述大脑蛋白质水平的变化，这可能提供关于疾病发病和病程的早期信息。

DESCRIPTION (provided by applicant): Discoveries about the genetic bases of frontotemporal lobar dementia (FTLD) have provided researchers with an unprecedented ability to characterize the pre-symptomatic stages of this disease. This capability is critical to ascertaining the earliest clinical features of the disease and identifying biomarkers that can be used for early diagnosis and in treatment studies. The proposed project will examine individuals from a single family with a genetic mutation for FTLD who are approaching the age of disease onset, offering a unique and highly controlled environment in which to identify the earliest clinical features and biomarkers of this devastating disease. Specifically, this study proposes to follow the offspring generation of a large family with a known mutation in the MAPT (tau) gene to determine the earliest clinical features of FTLD and the variables which may modify disease onset and course. At least 90 members of the offspring generation of a single family will be offered participation in a longitudinal study examining cognition, behavior, psychiatric symptoms, and lifestyle features. Moreover, this proposal includes the use of state of the art neuroimaging tools including both structural and functional modalities, gray and white matter quantification, and regional and network analyses to detect the earliest signs of disease. Individuals will undergo genetic testing to determine carrier status, will be comprehensively characterized at baseline, and will be followed annually over the course of the study to examine change in clinical and imaging variables over time as a function of carrier status. Additionally, the proposed study will carefully characterize lifetime physical activity and alcohol and recreational drug use to determine if these lifestyle variables are early manifestations of disease and / or modify disease onset and course. Finally, biological specimens including cerebrospinal fluid and blood plasma will be longitudinally collected in an effort to characterize changes in brain protein levels that may provide early information regarding the onset and course of disease.