Natural history and biomarker discovery in C9orf72 Amyotrophic lateral sclerosis and frontotemporal dementia

肌萎缩性侧索硬化症（ALS）和额颞叶痴呆（FTD）是成人发病的神经退行性疾病。在美国，C9orf72基因的重复扩增突变是家族性ALS和家族性FTD的最常见原因，也占散发性ALS病例的5-8%。该项目是一项对携带C9orf72突变的人进行的前瞻性纵向研究，始于2013年。突变携带者，无论临床表型如何，ALS、FTD、ALS-FTD和无症状携带者均被纳入研究。目的是了解c9orf72相关疾病的自然历史，并评估疾病进展的非侵入性生物标志物和生物流体标志物。这包括在18个月内3次的影像学、生理和生物体液检查，以及在36个月内每6个月一次的电话调查。运动、认知和行为功能的临床评估在三次面对面访问中进行了详细的评估，并在电话评估中使用了简短的工具。获得的生物标本正在与NIH内外的合作者共享，以促进转化研究。

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are adult-onset neurodegenerative disorders. A repeat expansion mutation in the C9orf72 gene is the commonest cause of familial ALS and familial FTD in the US and also accounts for a 5-8% of sporadic ALS cases. This project, a prospective longitudinal study of persons who carry the C9orf72 mutation began in 2013. Mutation carriers, regardless of clinical phenotype ALS, FTD, ALS-FTD, and asymptomatic carriers were enrolled. The goals were to understand the natural history of C9orf72-related disease and to evaluate non-invasive biomarkers and biofluid markers of disease progression. This included imaging, physiology, and biofluids at at 3 visits over 18 months, and phone surveys at 6-month intervals for 36 months. Clinical assessment of motor, cognitive, and behavioral function were carried out in detail at the three in-person visits, and with brief instruments at phone assessments. Biospecimens that were obtained are being shared with collaborators within and outside NIH to facilitate translational research. As of end FY20, the 36-month observation period of the study has been completed for 47 of the 50 patients enrolled, and the last phone assessments should be completed by the end of CY 2020. We previously reported on the clinical, structural imaging, and physiological findings in this cohort, and last year made progress on implementing statistical methods to control for variability introduced by MRI scanner upgrades. In FY2020, we analyzed and published longitudinal functional imaging data, with a focus on asymptomatic carriers, in whom collaborators had measured serum neurofilament light chain levels. We continue to upload de-identified clinical datasets from participants who have completed the protocol to the Neurobank repository for data sharing.