Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS)

描述(申请人提供)：额颞叶变性(FTLD)是一种神经退行性疾病，通常表现为行为改变和痴呆，有时还与帕金森症和/或肌萎缩侧索硬化症有关。FTLD在65岁以下的人群中至少与阿尔茨海默病一样常见，对受影响的个人及其亲属来说是毁灭性的。这些特点加强了目前努力开发治疗这种疾病的重要性，特别是在症状前阶段。FTLD是由两种主要蛋白质-微管相关蛋白tau和TAR DNA结合蛋白分子量43的功能障碍引起的。FTLD通常表现为一种显性遗传性家族性疾病(f-FTLD)，通常是由于微管相关蛋白tau(MAPT)、原颗粒蛋白(PGRN)或染色体9开放阅读框架72(C9ORF72)基因的突变所致，这些基因加在一起至少占f-FTLD的50%。已经确定了几种影响tau蛋白或原颗粒蛋白/TDP-43蛋白病理生理学的药物，但如何评估药物的疗效尚不清楚，特别是在症状前个体。重要的是，f-FTLD是目前唯一可以研究症状前或非常早期症状阶段的人的实际环境，使其成为测试旨在延迟症状出现的药物的最佳环境。基于其他家族性神经退行性综合征的数据，我们预计f-FTLD的临床和生物标记物的变化速度是复杂的，在症状前早期下降速度较慢，随后在症状出现前几年加速，并持续到症状阶段。这项拟议的研究将招募300名已知MAPT、PGRN或C9ORF72突变的f-FTLD家族成员(100名有症状突变携带者、100名无症状突变携带者和100名非携带者)，包括8个中心[梅奥诊所罗切斯特(n=70名受试者)、加州大学旧金山分校(n=70名)、宾夕法尼亚大学(n=70名)、梅奥诊所佛罗里达分校(n=18名)、哈佛大学(n=18名)、哥伦比亚大学(n=18名)、华盛顿大学(n=18名)和不列颠哥伦比亚大学(n=18名)]，以获得年度评估，包括关键的磁共振成像(MRI)测量、脑脊液分析、血液、行为、神经和功能评估每个参与者总共有四次评估。将解决几个目标，重点是生物流体和神经成像生物标记物，最终目标是确定哪些措施是评估潜在疾病修改或预防治疗效果的最佳措施。

DESCRIPTION (provided by applicant): Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder that typically presents as behavioral changes and dementia, sometimes also associated with parkinsonism and/or amyotrophic lateral sclerosis. FTLD is at least as common as Alzheimer's disease in people under the age of 65, and is devastating for affected individuals and their relatives. These features reinforce the importance of current effort to develop treatments for this disorder, particularly in the presymptomatic phase. FTLD is caused by dysfunction of two major proteins-microtubule associated protein tau and TAR DNA binding protein molecular weight 43. FTLD often presents as a dominantly inherited familial disorder (f-FTLD), usually due to mutations in the microtubule associated protein tau (MAPT), progranulin (PGRN), or chromosome 9 open reading frame 72 (C9ORF72) genes, which together account for at least 50% of f-FTLD. Several agents which impact tau or progranulin/TDP-43 protein pathophysiology have been identified, but it is not clear how efficacy of drugs can be assessed, particularly in presymptomatic individuals. Importantly, f- FTLD is currently the only practical context in which people in presymptomatic or very early symptomatic stages can be studied, making it the best context for testing drugs aimed at delaying symptom onset. Based on data from other familial neurodegenerative syndromes, we expect that the rates of clinical and biomarker change in f-FTLD are complex, with slower rates of decline in the early presymptomatic phase, followed by acceleration several years prior to development of symptoms and continuing through the symptomatic phase. The proposed study will enroll 300 members of f-FTLD families with a known mutation in MAPT, PGRN, or C9ORF72 (100 symptomatic mutation carriers, 100 asymptomatic mutation carriers, and 100 non-carriers) across 8 centers [Mayo Clinic Rochester (n=70 subjects), University of California at San Francisco (n=70), University of Pennsylvania (n=70), Mayo Clinic Florida (n=18), Harvard University (n=18), Columbia University (n=18), Washington University (n=18) and University of British Columbia (n=18)] to obtain annual assessments including key magnetic resonance imaging (MRI) measures, cerebrospinal fluid analysis, blood, behavioral, neuropsychological and functional assessment, for a total of four assessments per participant. Several aims will be addressed which focus on biofluid and neuroimaging biomarkers, with the ultimate goal of identifying which measures are optimal for assessing efficacy of potential disease-modifying or preventative therapies.