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. 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.