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

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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.