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 that includes asymptomatic carriers, patients with ALS, and patients with FTD. The first goal is to understand the natural history of C9orf72-related disease: how quickly 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.
The second aim of the study is to explore candidate biomarkers of disease progression. Biomarkers that signal improvement or decline in disease activity before clinically evident deterioration are need for clinical trials. 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. Enrollment was completed in FY2018, with 50 C9orf72 mutation carriers. This included 31 patients with ALS/ALS-FTD and 15 asymptomatic carriers. To evaluate clinical progression, measures of motor, cognitive and behavioral function were obtained at baseline, and at follow-up visits at 6 and 18 months. Clinical, imaging, and physiological findings from the first half of the enrolled participants have been published. Imaging shows more extensive volume loss of extramotor areas in C9orf72 carriers with cognitive dysfunction. Ventricular enlargement and spread of white matter diffusion alterations could be detected over a 6-month period. Biospecimens were shared with collaborators at academic institutions and pharmaceutical companies, who found stable CSF levels of the repeat-associated dipeptide in longitudinal specimens, supporting its use as a pharmacodynamic marker. Collaborators found that levels of CSF phosphorylated neurofilament heavy chain were predictive of survival. To examine whether oligogenic inheritance may be a factor affecting the diversity of clinical phenotypes, exome sequencing was carried out in FY18, and analysis is ongoing. Additional activities include preparation of de-identified clinical datasets for data sharing from those participants who have completed the protocol.
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