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. In 2011 a large hexanucleotide repeat expansion in the C9ORF72 gene was discovered that caused both ALS and FTD. Retrospective studies using stored DNA samples that identified patients carrying the C9orf72 mutation reported that it is the commonest cause of familial ALS and familial FTD and also accounts for a significant number of sporadic ALS cases. Despite the large number of patients identified from testing of stored samples, relatively little is known about the natural history of C9ORF72-related disease: how quickly the motor weakness and cognitive dysfunction progress, whether clinical presentation influences survival, and whether subtle motor or cognitive abnormalities are detectable prior to the onset of definite symptoms. Therefore, the first aim of this project is designed to fill this knowledge gap through a 3-year prospective longitudinal study of a cohort of symptomatic individuals carrying the C9ORF72 repeat expansion and pre-symptomatic carriers who are relatives of affected patients. The second aim of the study is to explore candidate biomarkers of disease progression. Biomarkers that can signal improvement or decline in disease activity before clinically evident deterioration would be valuable to speed the cycle of clinical trials. Physiological, imaging, and biofluid biomarkers will be collected at longitudinal visits, to examine their correlation with clinical measures of progression. This is a highly collaborative study. Exploratory studies of biofluid markers are being coordinated by a collaborative investigator, Dr. Bryan Traynor, in the National Institute of Aging. All participants consent to sharing of de-identified data and specimens. The organization of the study, IRB approval, hiring of a study coordinator, and database construction were completed in FY13-4, and the first participant was enrolled in FY14. Participants undergo a structured battery of clinical ratings, neuropsychological tests, and motor measurements at enrollment and at follow-up visits to NIH to assess disease severity. Participants are typically housed at a local hotel for the 2 or 3-day visit. At these visits candidate biomarkers collected include: transcranial magnetic stimulation, electroimpedance myography; brain MRI for resting-state functional MRI, diffusion tensor imaging, and high resolution T1; plasma, serum, and CSF. Skin biopsies are obtained at one visit for extramural collaborators. At end FY15, baseline visits will be complete for 25 participants, 18 participants with 6-month follow-ups, and 4 participants with 18-month follow-up visits. Database quality checks have been completed for the first 20 baseline visits, and analysis of transcranial magnetic stimulation data and diffusion and volumetric imaging from those visits is underway. CSF specimens have been shared with investigators at Johns Hopkins and Mayo Clinic exploring repeat-associated dipeptide as a marker of disease activity.