Structural and functional brain connectivity in presymptomatic familial frontotemporal dementia

Abstract

Objective: We aimed to investigate whether cognitive deficits and structural and functional connectivity changes can be detected before symptom onset in a large cohort of carriers of microtubule-associated protein tau and progranulin mutations.

Methods: In this case-control study, 75 healthy individuals (aged 20-70 years) with 50% risk for frontotemporal dementia (FTD) underwent DNA screening, neuropsychological assessment, and structural and functional MRI. We used voxel-based morphometry and tract-based spatial statistics for voxelwise analyses of gray matter volume and diffusion tensor imaging measures. Using resting-state fMRI scans, we assessed whole-brain functional connectivity to frontoinsula, anterior midcingulate cortex (aMCC), and posterior cingulate cortex.

Results: Although carriers (n = 37) and noncarriers (n = 38) had similar neuropsychological performance, worse performance on Stroop III, Ekman faces, and Happé cartoons correlated with higher age in carriers, but not controls. Reduced fractional anisotropy and increased radial diffusivity throughout frontotemporal white matter tracts were found in carriers and correlated with higher age. Reductions in functional aMCC connectivity were found in carriers compared with controls, and connectivity between frontoinsula and aMCC seeds and several brain regions significantly decreased with higher age in carriers but not controls. We found no significant differences or age correlations in posterior cingulate cortex connectivity. No differences in regional gray matter volume were found.

Conclusions: This study convincingly demonstrates that alterations in structural and functional connectivity develop before the first symptoms of FTD arise. These findings suggest that diffusion tensor imaging and resting-state fMRI may have the potential to become sensitive biomarkers for early FTD in future clinical trials.

Figure 1. Relationship between age and neuropsychological performance, structural and functional connectivity in mutation carriers

Relation between age and performance on Stroop III (higher scores represent worse performance) (A), fractional anisotropy value in peak voxel in age correlation analysis (table e-2) (B), and mean bilateral frontoinsula connectivity with anterior midcingulate cortex cluster from correlation analysis (table e-3) (C).

Figure 2. Alterations in diffusion tensor imaging measures in mutation carriers

Maps illustrate significant decreases in fractional anisotropy (FA) (A1) and increases in radial diffusivity (DR) (A2) in mutation carriers compared with controls, and significant decreases in FA (B1) and increases in DR (B2) with higher age in carriers. Thresholded statistic images were thickened using tbss_fill in FSL (FMRIB's Software Library) for better visibility. Color bar represents p values.

Figure 3. Alterations in diffusion tensor imaging measures in progranulin (GRN) and microtubule-associated protein tau (MAPT) mutation carriers

Maps illustrate significant decreases in fractional anisotropy (FA) in GRN mutation carriers compared with controls from their families (A) and significant decreases in FA (B1) and increases in mean diffusivity (B2), radial diffusivity (B3), and axial diffusivity (B4) in MAPT mutation carriers compared with controls from their families. Thresholded statistic images were thickened using tbss_fill in FSL (FMRIB's Software Library) for better visibility. Color bar represents p values.

Figure 4. Alterations in frontoinsula and anterior midcingulate cortex (aMCC) connectivity in mutation carriers

Maps illustrate clusters of significantly decreasing bilateral frontoinsula connectivity in mutation carriers (A) with higher age, significantly decreased aMCC connectivity in mutation carriers compared with controls (B), and decreasing aMCC connectivity with higher age in mutation carriers (C). Color bar represents z scores.