Cortical free-water imaging in familial frontotemporal dementia associated with MAPT, GRN, and C9orf72 pathogenic variants
Abstract
BACKGROUND: Familial frontotemporal lobar degeneration (FTLD) caused by pathogenic variants in C9orf72, GRN, and MAPT provides a unique framework for evaluating imaging markers of genotype-specific neurodegeneration. Conventional cortical mean diffusivity (cMD) is sensitive to microstructural injury but is influenced by extracellular free-water effects. We investigated whether cortical free water (cFW) provides a sensitive imaging readout of cortical microstructural alterations across the three major genetic forms of familial FTLD, and compared its spatial distribution and clinical relevance with cMD and free-water-corrected tissue mean diffusivity (MD-t).
METHODS: We analyzed data from 324 participants from the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, including 199 carriers of pathogenic variants in C9orf72 (n = 85), GRN (n = 56), or MAPT (n = 58), spanning asymptomatic and symptomatic stages, and 125 non-carrier family members. Surface-based cortical maps of cMD, MD-t, and cFW were generated from diffusion MRI. Group differences between each genotype and non-carrier controls were assessed using general linear models adjusted for age and sex. Associations with disease severity, measured by the CDR® plus NACC FTLD scale, and plasma neurofilament light chain (NfL) were examined within each genotype, with family-wise error correction for surface-based analyses.
RESULTS: Across C9orf72, GRN, and MAPT carriers, cFW showed the most spatially…
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