Neuropsychiatric Features of C9ORF72 Mutation-Associated bvFTD and FTD-ALS (IN9-2.003)

Abstract

Objective: To characterize neuropsychiatric features associated with C9ORF72 mutations in behavioral variant frontotemporal dementia (bvFTD) and FTD-amyotrophic lateral sclerosis (FTD-ALS). Background Hexanucleotide repeat expansions in the C9ORF72 gene may be the most common genetic cause of bvFTD and FTD-ALS, but the neuropsychiatric features associated with C9ORF72 mutations remain largely uncharacterized. Design/Methods: Four hundred and sixteen patients with FTD or related disorders and asymptomatic family members evaluated at UCSF were tested for C9ORF72 expansion (C9+: N=37). Eighty-six cases (C9+/bvFTD=12; C9-/bvFTD=47; C9+/FTD-ALS=11; C9-/FTD-ALS=16) underwent blinded chart review to identify first reported neuropsychiatric symptoms. Neuropsychiatric Inventory (NPI) scores at first evaluation were analyzed for all C9+ cases and a subset of C9-/bvFTD controls matched for disease severity according by MMSE and CDR-SB. Results:First neuropsychiatric symptoms: In C9+/bvFTD, delusions and aggression were more frequently reported as presenting symptoms (p=0.04). In C9+/FTD-ALS, more rash/careless actions (p=0.04) and greater disinhibition were seen (p=0.13), whereas apathy, anxiety and depression were less frequently reported (p=0.09, 0.12 and 0.12) compared to C9-/FTD-ALS patients. By first evaluation: On the NPI, C9+/bvFTD cases had less disinhibition (p=0.04), aberrant motor (p=0.03) and eating behaviors (p=0.08), but higher anxiety (p=0.12) than C9- bvFTDs. In FTD-ALS, C9+ and C9- NPI scores did not differ. Total NPI scores did not differ by genotype in either group. Conclusions: In bvFTD, C9ORF72 mutation carriers9 first neuropsychiatric symptoms are more frequently delusions and aggression. Later they develop greater anxiety than non-carriers with bvFTD but show less disinhibition or aberrant eating/motor behaviors. In FTD-ALS, C9ORF72 mutation carriers display greater disinhibition as their first symptom, but later become neuropsychiatrically indistinct from non-carriers with FTD-ALS. Further investigation in larger samples will improve differentiation of the neuropsychiatric features caused by C9ORF72 mutations. 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. Takada has nothing to disclose. Dr. Sha has nothing to disclose. Dr. Rankin has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Khan has nothing to disclose. Dr. Karydas 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.