# Longitudinal behavioral and neuropsychiatric changes and their MRI correlates in predementia C9orf72 and GRN mutation carriers

## TL;DR

This study shows that people with genetic mutations linked to frontotemporal dementia experience different neuropsychiatric changes and brain changes before dementia starts.

## Contribution

The study identifies distinct longitudinal patterns of neuropsychiatric symptoms and MRI correlates in predementia C9orf72 and GRN mutation carriers.

## Key findings

- C9orf72+ carriers showed faster increases in depression and dysexecutive disturbance scores compared to noncarriers.
- GRN+ carriers had higher increases in depression and emotional/social disturbance scores compared to noncarriers and C9orf72+ carriers.
- WMSA accumulation correlated with worsening neuropsychiatric symptoms across all groups.

## Abstract

Neuropsychiatric symptoms (NPS) progress differently among individuals with autosomal dominant familial frontotemporal dementia (FTD) caused by genetic mutations in granulin (GRN+) or chromosome 9 open reading frame 72 (C9orf72+).

To determine whether these differences begin prior to the onset of dementia, we compared the longitudinal rates of change of NPS among C9orf72+, GRN+, and noncarrier controls in the predementia phase. Additionally, we assessed whether the NPS changes were correlated with gray matter (GM) volume loss or white matter signal abnormalities (WMSAs) on magnetic resonance imaging (MRI).

Eighty-two participants (N = 10 GRN+, N = 23 C9orf72+, N = 49 noncarriers) were followed using various NPS rating scales for an average of 7.8 years. Group differences were compared using generalized linear mixed-effects models. GM volume and WMSA volumes were measured on 42 participants (N = 8 GRN+, N = 11 C9orf72+, N = 23 noncarriers) who had two MRI visits. These measures were correlated with the rates of NPS score changes.

C9orf72+ showed higher rates of increase in the Beck Depression Inventory (BDI) total and the Iowa Scales of Personality Change (ISPC) dysexecutive disturbance scores versus noncarriers. GRN+ showed higher rates of increase in the BDI total, the ISPC total, and the emotional/social disturbance scores versus noncarriers; and higher rates of increase in the ISPC emotional/social personality and distressed disturbance scores versus C9orf72+. Across all groups, faster WMSA accumulation correlated with higher rates of increase in the Neuropsychiatric Inventory Questionnaire total score.

Changes in NPS differ among C9orf72+, GRN+, and noncarrier controls prior to the onset of overt FTD.