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

肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是成人发病的神经退行性疾病。C9 orf 72基因中的重复扩增突变是美国家族性ALS和家族性FTD的最常见原因，也占散发性ALS病例的5-8%。该项目是对携带C9 orf 72突变的人进行的前瞻性纵向研究，始于2013年。入组突变携带者（不考虑临床表型ALS、FTD、ALS-FTD）和无症状携带者。目的是了解C9 orf 72相关疾病的自然史，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18个月内3次访视时的成像、生理学和生物液体，以及36个月内每6个月进行一次电话调查。在三次亲自访视时详细进行了运动、认知和行为功能的临床评估，并在电话评估时使用了简短的工具。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。 截至2020财年末，入组的50名患者中有47名已完成36个月的研究观察期，最后一次电话评估应于2020财年末完成。我们之前报道了该队列的临床、结构成像和生理学发现，去年在实施统计方法以控制MRI扫描仪升级引入的变异性方面取得了进展。在2020财年，我们分析并发表了纵向功能成像数据，重点关注无症状携带者，合作者测量了他们的血清神经丝轻链水平。我们继续将已完成方案的参与者的去识别临床数据集上传到Neurobank存储库进行数据共享。

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.