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，其中多达三分之一的患者具有重叠的临床和病理特征。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%。2013年，我们开始对携带C9orf72突变的人进行前瞻性纵向研究，无论其临床表型如何。目的是了解c9orf72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体液标志物。影像学、生理学和生物体液将在18个月的3次就诊中收集。电话调查进行了36个月。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 in which up to one-third of patients have overlapping clinical and pathological features. 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 ALS cases thought to be sporadic. In 2013, we began a prospective longitudinal study of persons who carry the C9orf72 mutation regardless of clinical phenotype. The goals were to understand the natural history of C9orf72-related disease and to evaluate non-invasive biomarkers and biofluid markers of disease progression Imaging, physiology, and biofluids are being collected at 3 visits over 18 months. Phone surveys are conducted for 36 months. Biospecimens obtained are being shared with collaborators within and outside NIH to facilitate translational research. As of the end of FY19, 40 of the 50 C9orf72 mutation carriers enrolled have either completed the 36-month observation period of the study or are deceased. We previously reported on the clinical, imaging, and physiological findings in the first half of the enrolled participants, and in the last FY have been analyzing imaging data from the second half of the cohort, with a focus on functional networks. Statistical methods to control for variability introduced by MRI scanner upgrades were evaluated over the past year, and are being implemented. In FY19, results of an analysis of exomes sequenced in 49 carriers was presented in abstract, and a manuscript has been submitted for peer review. We continue to upload de-identified clinical datasets from those participants who have completed the protocol to the Neurobank repository for data sharing.