DOI: 10.1177/13872877261493102 ISSN: 1387-2877

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

Hyunwoo Lee, Ian R.A. Mackenzie, Mirza Faisal Beg, Karteek Popuri, Dana Wittenberg, Winston Huang, Ging-Yuek Robin Hsiung
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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.

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