Progression of neuropsychiatric symptoms in pre‐dementia GRN and C9orf72 mutation carriers

Abstract

AbstractBackgroundNeuropsychiatric symptoms (NPS) are common in frontotemporal dementia (FTD) patients and may precede the clinical diagnosis of dementia. We hypothesized that GRN and C9orf72 mutation carriers have increased baseline burden and rates of progression of NPS compared to non‐carriers prior to the onset of dementia. To investigate, we examined a longitudinal cohort of FTD mutation carriers and non‐carrier family members.MethodWe analyzed data from 80 participants (21 C9orf72+ mutation carriers, 10 GRN+ mutation carriers, and 49 non‐carrier family members (NCs); mean±SD age in years: 47±13, 51±9, and 54±13 respectively) recruited through the University of British Columbia FTD Study. NPS were assessed annually with Neuropsychiatric Inventory (NPI), Frontal Behavioural Inventory (FBI) and Iowa Scale of Personality Change (ISPC) with a mean follow‐up of 5.8 years. For ISPC, we used both the “Change” (“Now” minus “Before”) and the “Now” measures. If a participant developed FTD during the follow‐up (N=2), we only analyzed observations collected before the conversion. We initially compared the baseline burden of NPI, FBI and ISPC adjusted for age and sex, among C9orf72+ carriers, GRN+ carriers and NCs. We then used random‐intercept mixed models to compare the rates of progression of NPS among genetic groups using total NPI, FBI, ISPC change and ISPC now scores as outcome measures and genetic status, sex, respective baseline scores, expected years to onset (EYO) and genetic group*EYO interaction term as dependent variables.ResultThere were no significant group differences in baseline demographic features or neuropsychiatric measures. In longitudinal assessments, NCs demonstrated minimal change in NPS measures. GRN+ carriers had significantly higher progression rates of NPI (p<0.0001) and ISPC “Now” (p=0.0004) compared to NCs. However, there were no significant differences in the NPS progression rates between C9orf72+ carriers and NCs.ConclusionAlthough there was no baseline difference in the burden of NPS among the genetic groups, GRN+ carriers had a faster progression of NPS compared to NCs prior to the onset of dementia. Future work is warranted to investigate the potential association between the NPS trajectories and structural/functional brain changes in FTD mutation carriers.