Association between white matter T1w/T2w ratio and cognitive function in frontotemporal dementia mutation carriers

Background Frontotemporal dementia (FTD) is characterized by progressive cognitive, behavioral, and language deficits. Early white matter (WM) changes on MRI are associated with TAR DNA-binding protein 43 (TDP-43) pathology, often caused by progranulin ( GRN ) or chromosome 9 open reading frame 72 ( C9orf72 ) mutations. Post-mortem studies suggest prominent myelin loss in GRN carriers compared to C9orf72 carriers or controls. The T1-weighted/T2-weighted (T1w/T2w) ratio is an MRI marker sensitive to WM properties, including myelin lipid content. Objective This study used the T1w/T2w ratio to investigate WM integrity in familial FTD. We hypothesized that (1) GRN mutation carriers would show reduced T1w/T2w ratios compared to non-carrier controls; (2) C9orf72 mutation carriers would not differ significantly from non-carriers; and (3) lower T1w/T2w ratios would associate with cognitive deficits. Methods Eighty participants ( GRN = 12, C9orf72 = 28, non-carrier controls = 40) completed neuropsychological testing across multiple cognitive domains and structural MRI. After generating standardized T1w/T2w ratio maps, mean values were extracted from JHU Atlas-based WM lobe regions. General linear models evaluated group differences and MRI-cognition associations. Results GRN carriers exhibited significantly lower T1w/T2w ratios in frontal and parietal lobe WM compared to non-carriers. Conversely, C9orf72 carriers did not differ from non-carriers. Across all participants, lower frontal T1w/T2w ratios were associated with poorer working memory, language, and visuospatial function. Lower parietal ratios were associated with poorer visuospatial function. Conclusions This study provides evidence for a reduction in the T1w/T2w ratio in GRN mutation carriers. This reduction associates with key cognitive impairments, highlighting a vulnerability of WM microstructural integrity in GRN -related FTD.