Transthyretin as Potential Biomarker for C9ORF72-related Diseases (I8-2A)

OBJECTIVE: Identification of a biomarker for diseases caused by repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ). BACKGROUND: To date, a GGGGCC-repeat expansion in C9ORF72 is the most common genetic cause of two fatal neurodegenerative diseases: frontotemporal dementia (FTD) and motor neuron disease (MND). No validated biomarker exists to diagnose C9ORF72 -related diseases, predict disease progression, or monitor the effects of potential therapies. DESIGN/METHODS: We performed the first genome-wide brain expression analysis in C9ORF72 expansion carriers using Whole-Genome DASL HT Assays (Illumina). Our study cohort consisted of C9ORF72 expansion carriers (n=32) as well as disease controls (n=30) and controls without neurological diseases (n=20). Additionally, we employed quantitative real-time PCR, enzyme-linked immunosorbent assays (ELISA), and Western blotting techniques. RESULTS: We discovered that transthyretin ( TTR ) is significantly up-regulated in the cerebellum when comparing C9ORF72 expansion carriers to disease controls (fold-change=5.7; p-value=5.0e-04) or to controls without neurological diseases (fold-change=7.4; p-value=4.3e-04). TTR up-regulation was validated using quantitative real-time PCR, which confirmed the up-regulation in C9ORF72 expansion carriers (n=44) as compared to disease controls (n=30; p-value=4.5e-06) and to controls without neurological diseases (n=20; p-value=2.1e-05), but also as compared to patients with other diseases, such as Alzheimer’s disease (n=20; p-value=7.9e-06) and progressive supranuclear palsy (n=20; p-value=5.2e-04). Our findings, therefore, indicate that TTR up-regulation is specific to C9ORF72 -related diseases. Moreover, we demonstrated that the changes in RNA levels of TTR are reflected by changes in its protein levels in the cerebellum, plasma, and cerebrospinal fluid (CSF). CONCLUSIONS: Based on our findings, TTR may serve as a biomarker for C9ORF72 -related diseases, and additionally, could help to unravel biomarker patterns in sporadic diseases. Furthermore, our identification of TTR, which has neuroprotective effects, might also point towards compensatory mechanisms that influence the presentation and/or progression of C9ORF72 -related diseases, and that could uncover targets for new therapeutic approaches. Disclosure: Dr. Van Blitterswijk has nothing to disclose. Dr. Finch has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Bieniek has nothing to disclose. Dr. Dejesus-Hernandez has nothing to disclose. Dr. Gendron has nothing to disclose. Dr. Asmann has nothing to disclose. Dr. Heckman has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Josephs has nothing to disclose. Dr. Parisi has nothing to disclose. Neurology, Deputy Editor, Dr. Petersen has received personal compensation for activities with Pfizer Inc. and Janssen Alzheimer9s Immunotherapy. Dr. Petrucelli has nothing to disclose. Dr. Boeve has received research support from GE Healthcare. Dr. Graff-Radford has received personal compensation for activities with Codman and Cytox as a scientific advisory board member or a consultant. Dr. Graff-Radford has received royalty payments for UpToDate. Dr. Boylan has received research support from Biogen Idec, Cytokinetics, Inc., and Neuraltus Pharmaceuticals, Inc. Dr. Dickson has nothing to disclose. Dr. Rademakers has nothing to disclose.