MRI Microscopic Fractional Anisotropy Differences in Genetic Frontotemporal Degeneration

BACKGROUND: In genetic frontotemporal degeneration (FTD), cortical and subcortical brain volume differences have been detected using volumetric MRI decades before symptoms appear. Microscopic fractional anisotropy (μFA) is a diffusion MRI metric that is sensitive to diffusion anisotropy regardless of relative fiber orientations within a voxel and is more accurate than conventional DTI metrics for detecting age-related microstructural changes in healthy individuals and differences in some neurological diseases. PURPOSE: To compare μFA, mean diffusivity (MD), and volume between genetic frontotemporal degeneration (FTD) variant carriers and non-carriers in the insula, frontal pole, and medial orbitofrontal cortex. STUDY TYPE: Cross-sectional cohort study. POPULATION: Carriers of FTD variants in C9orf72, GRN, or MAPT (n = 12; age = 56.7 ± 8.12 years; 50% female) and familial non-variant carriers (n = 8; age = 59.5 ± 10.3 years; 62.5% female). FIELD STRENGTH/SEQUENCE: 3T; Magnetization prepared rapid acquisition with gradient echoes (MPRAGE) sequence (anatomical imaging) and a diffusion echo-planar imaging sequence with modified diffusion gradients for spherical tensor encoding (μFA measurement). ASSESSMENT: MPRAGE images underwent cortical and subcortical segmentation to obtain regions of interest. MD and μFA maps were derived from diffusion MRI data. μFA, MD, and volumes were compared between FTD variant carriers (n = 5 symptomatic, and n = 7 asymptomatic) and familial non-carriers. STATISTICAL TESTS: Linear models with heteroscedasticity-consistent confidence intervals were computed to analyze between-group differences in outcomes while controlling for age (alpha = 0.05). RESULTS: p = 0.22). Post hoc contrasts showed significantly reduced insula μFA in symptomatic carriers compared to non-carriers (d = 1.57). Mean μFA in asymptomatic carriers (mean ± standard error (SE): 0.454 ± 0.010) was not significantly different to that in non-carriers (mean ± SE: 0.471 ± 0.009, p = 0.465), nor in symptomatic carriers (mean ± SE: 0.430 ± 0.012, p = 0.290). DATA CONCLUSION: μFA is reduced in the insula, a region vulnerable to early atrophy in FTD, reflecting microstructural changes in genetic FTD with greater effect sizes than MD and volume. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.