Differential Effect of the C9ORF72 Hexanucleotide Repeat on Brain Morphology in bvFTD and FTD-ALS (IN9-2.005)

Abstract

Objective: To identify effects of the C9ORF72 repeat variant on brain atrophy patterns in behavioral variant frontotemporal dementia (bvFTD) and FTD-amyotrophic lateral sclerosis (ALS). Background The GGGGCC repeat in the noncoding region of C9ORF72 was recently found to be a major contributor to genetic risk for FTD and ALS in both familial and sporadic cases. Whether the C9 variant confers specific morphological characteristics to degeneration associated with bvFTD/FTD-ALS is unknown. Design/Methods: Four-hundred-sixteen patients with FTD or related disorders and asymptomatic family members evaluated at UCSF were tested for C9ORF72 expansion (C9+:n=37). DARTEL-based voxel-based morphometry (VBM) analyses of combined gray-white maps were performed on structural MRIs from 25 bvFTD cases (C9+:n=6, C9-:n=19), 9 FTD-ALS cases (C9+:n=5, C9-:n=4), and 164 cognitively normal older adults. Comparisons were analyzed for: bvFTD(C9+) versus controls; bvFTD(C9-) versus controls; interaction of (C9+)x(bvFTD) versus bvFTD(C9-) and controls; FTD-ALS(C9+) versus controls; FTD-ALS(C9-) versus controls; interaction of (C9+)x(FTD-ALS) versus FTD-ALS(C9-) and controls. Results: BvFTD(C9+) cases demonstrated greater lateral parietal (right>left) and bilateral thalamic, and less medial frontal atrophy than bvFTD(C9-) cases. A significant interaction was found where bvFTD(C9+) patients showed greater thalamic (left>right; T=5.00, p FWE =0.05; T=4.05 p uncorr uncorr uncorr left), particularly in the medial occipital lobes and cerebellum, and less medial frontal and brainstem atrophy than FTD-ALS(C9-) cases. A significant interaction was found where FTD-ALS(C9+) cases demonstrated more atrophy in the right superior frontal gyrus (T=4.73, p FWE =0.03), bilateral central sulcus (T=3.67-3.70, p FWE =0.07) and inferior frontal pars triangularis (T=3.58, p FWE =0.07). Conclusions: We found greater posterior and thalamic atrophy in C9+ than in sporadic bvFTDs, and greater posterior and less brainstem atrophy in FTD/ALS(C9+) cases. If confirmed in larger samples, these findings suggest C9ORF72 confers specific atrophy patterns to bvFTD and FTD/ALS with potential clinical ramifications. Supported by: In part by M01-RR0079 General Clinical Research Center; the National Institute on Aging (NIA) grants 5-P01 AG19724 and P50 AG023501; the State of California, Alzheimer9s Disease Research Center of California (ARCC) grant 03-7527; NIH grants R01AG038791, R01AG031278. Disclosure: Dr. Yokoyama has nothing to disclose. Dr. Takada has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Karydas has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Fong has nothing to disclose. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Coppola has nothing to disclose. Dr. Seeley has received personal compensation for activities with Korea Novartis. Dr. Boxer has received personal compensation for activities with BMS, Plexxikon and Phloronol as a consultant. Dr. Boxer has received research support from Elan, Forest, Genentech, Medivation, BMS, Janssen and Pfizer Pharmaceuticals. Dr. Miller has received personal compensation for activities with Allon Therapeutics, Inc. and TauRx Therapeutics, Ltd. Dr. Miller has received research support from Novartis. Dr. Rankin has nothing to disclose.