PHENOCONVERSION FROM ASYMPTOMATIC TO MINIMALLY SYMPTOMATIC FTLD: PRELIMINARY DATA IN THE LEFFTDS COHORT

Abstract

The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Consortium (U01 AG045390) involves investigators at 8 centers in North America who are evaluating subjects in kindreds with mutations in microtubule associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) genes annually using a standardized battery of measures. Using a modified version of the Clinical Dementia Rating (CDR) scale, we analyzed the frequency of phenoconversion from asymptomatic (CDR=0) to minimally symptomatic (CDR=0.5) among all subjects who have been evaluated at baseline (Visit 1) and at their first annual follow-up visit (Visit 2). The clinical and genetic features of such subjects were also characterized. As of 12/31/16, 239 subjects have undergone Visit 1 assessments - CDR=0: n=148 (47 MAPT/49 GRN/52 C9orf72); CDR=0.5: n=31 (9 MAPT/13 GRN/9 C9orf72); and CDR≥1: n=60 (19 MAPT/16 GRN/24 C9orf72). Sixty-two (26%) have undergone Visit 2 assessments - CDR=0: n=25 (8 MAPT/8 GRN/9 C9orf72); CDR=0.5: n=10 (3 MAPT/5 GRN/2 C9orf72); and CDR≥1: n=27 (11 MAPT/7 GRN/9 C9orf72). Five (3%) of the CDR=0 subjects at Visit 1 have phenoconverted to CDR=0.5 at Visit 2, all of whom meet criteria for clinically possible bvFTD: 2 subjects with the V337M mutation in MAPT, 1 subject with the N279K mutation in MAPT, 1 subject with the P301L mutation in MAPT, and 1 subject with the A9D mutation in GRN. Phenoconversion to minimally symptomatic FTD has occurred in 3% of asymptomatic LEFFTDS subjects to date, primarily among MAPT mutation carriers. Future longitudinal evaluations and biomarker analyses are planned to identify predictors of outcome in asymptomatic mutation carriers.