Fixel-based analysis reveals detailed white matter changes in semantic dementia

TL;DR

This study shows that fixel-based analysis provides more detailed insights into white matter changes in semantic dementia compared to traditional methods.

Contribution

The study introduces fixel-based analysis as a more sensitive method for detecting white matter alterations in semantic dementia.

Findings

FBA detected additional white matter pathways affected in semantic dementia, such as the tapetum and anterior commissure.

Both FBA and TBSS identified damage to anterior temporal lobe connected tracts in semantic dementia patients.

FBA offers greater anatomical precision and sensitivity to structural changes in white matter compared to TBSS.

Abstract

Accurately characterizing white matter (WM) microstructure is critical for understanding neurodegenerative diseases such as semantic dementia (SD). Regionally constrained techniques like tract-based spatial statistics (TBSS) rely on diffusion-tensor imaging (DTI) and assume a single fiber population per voxel, limiting their sensitivity to complex architecture. Fixel-based analysis (FBA) overcomes these constraints by resolving multiple fiber populations (fixels) within a single voxel, enabling more anatomically specific assessment of WM organization. Multi-shell diffusion MRI from 16 semantic-variant PPA (svPPA) and 15 semantic-behavioral fronto-temporal dementia (sbvFTD) cases—with imaging-confirmed left- and right-predominant temporal atrophy, respectively—and 44 neurologically healthy controls were analyzed using both TBSS-DTI and whole-brain FBA. Fiber-specific metrics of fiber density and cross-section were evaluated alongside conventional DTI measures. Both methods confirmed damage to the anterior temporal lobe (ATL) connected tracts—the uncinate fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and temporal projections of the arcuate fasciculus. FBA further detected involvement of juxtacortical and other pathways that were not captured by TBSS, including the tapetum and anterior commissure, projections to the parahippocampal gyrus and amygdala, and longer-range parietal connections. By capturing multiple fiber populations within each voxel, FBA provides greater anatomical precision and sensitivity to micro- and macro-structural changes than TBSS. This fiber-specific framework enables a more comprehensive mapping of WM degeneration in SD and helps delineate early alterations in commissural and mesial-temporal pathways that may underlie disease spread and cognitive decline.

The online version contains supplementary material available at 10.1007/s00429-025-03064-7.

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