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 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 each of 4 visits over 3 years. Biospecimens obtained are being shared with collaborators within and outside NIH, to facilitate translational research. As of the end of FY 17, 45 C9orf72 mutation carriers have been enrolled in the natural history study. We have published clinical, imaging, and physiological findings from the first half of the enrolled participants followed through 18 months. To capture clinical progression, measures of motor, cognitive and behavioral function were needed. 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 levels of the dipeptide made by the repeat expansion in longitudinal specimens, supporting its use as a pharmacodynamic markers. Other spinal fluid proteins were found to be associated with disease activity. These measures show promise as biomarkers that will be useful for clinical trials. To better understand changes in brain tissue that produce the alterations in diffusion imaging, in FY17 we completed analysis and published a study of diffusion tensor imaging in autopsy brains of patients with ALS with or without the C9orf72 mutation, and correlated fractional anistropy measures with histology. Tissue changes underlying loss of fractional anisotropy included axonal loss, but more striking was the microglial infiltration, which was more pronounced in C9orf72 ALS patients.