Clinical Dementia Rating Score 0.5 Predicts Clinical Decline in Familial Frontotemporal Dementia (S48.007)

Objective: To determine whether Clinical Dementia Rating (CDR) score 0.5 is associated with higher rates of cognitive decline and regional gray matter loss in carriers of genetic mutations associated with familial frontotemporal lobar degeneration (f-FTLD), compared to normal controls. Background: Mutations in the C9ORF72 , progranulin ( GRN ) and tau ( MAPT ) genes are the leading cause of f-FTLD. Studies of the natural history of f-FTLD are needed to quantify rates of clinical decline and corresponding biomarker changes in anticipation of clinical trials. Design/Methods: We compared 157 carriers of C9ORF72 (n=85), GRN (n=49), or MAPT (n=23) mutations with 263 control individuals. Regional gray matter volumes, neuropsychological performances (composite z scores), and CDR scores were assessed during consecutive follow up visits. We assessed whether mutation carriers with CDR score 0.5 showed different slopes in the relationship between regional gray matter atrophy or neuropsychological composite scores and age, compared to controls, using linear mixed effects models. Results: Compared to normal controls: i) C9ORF72 carriers with CDR 0.5 showed a higher rate of decline in performance on the executive function composite score (−0.3%/decade; CI=−0.6,−0.001; p=0.04), while differences in the rate of regional gray matter atrophy did not reach statistical significance; ii) GRN carriers with CDR 0.5 showed higher rates of gray matter atrophy in the frontal (−5.13 mm 3 /decade; CI=−7.9,−0.5; p=0.03) and limbic (−1.36 mm 3 /decade; CI=−2.3,−0.5; p=0.003) lobes, while differences in cognitive performances did not reach statistical significance; iii) MAPT carriers with CDR 0.5 showed significantly higher rates of temporal gray matter atrophy (−11.86 mm 3 /decade; CI=−16.9,−6.8; p Conclusions: Our data show that CDR score 0.5 in f-FTLD mutation carriers is associated with gene-specific changes in rates of regional gray matter atrophy and/or cognitive performance compared to normal controls. Disclosure: Dr. Spina has nothing to disclose. Dr. Staffaroni has nothing to disclose. Dr. Bonham has nothing to disclose. Dr. Olney has nothing to disclose. Dr. Attygalle has nothing to disclose. Dr. Cobigo has nothing to disclose. Dr. Chang has nothing to disclose. Dr. Binney has nothing to disclose. Dr. Yokoyama has nothing to disclose. Dr. Kornak has nothing to disclose. Dr. Boxer has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Lee has nothing to disclose. Dr. Boeve has received research support from GE Heathcare and Axovant. Dr. Rosen has nothing to disclose.