Fixel-based analysis reveals whole-brain white matter microstructural alterations in axial spondyloarthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disorder that may influence the central nervous system through systemic inflammation. While functional brain alterations have been reported, white matter microstructural changes remain poorly understood. This study investigated white matter alterations in axSpA using fixel-based analysis (FBA). Thirty-nine axSpA patients (mean age 28.5 ± 6.3 years) and 41 healthy controls (29.1 ± 5.8 years) underwent diffusion MRI. FBA assessed fiber density (FD), fiber-bundle cross-section (FC), and combined fiber density and cross-section (FDC) across the whole brain. Group differences were analyzed controlling for age, sex, and education. Clinical correlations were assessed with False Discovery Rate (FDR) correction. Compared to controls, axSpA patients showed significantly increased FC in the left external capsule (EC) and increased FDC in the right EC and right uncinate fasciculus (UF) (family-wise error corrected P < 0.05). No significant FD alterations were observed. In exploratory analyses, left EC FC showed a nominal positive correlation with physical function scores (Rho = 0.21, uncorrected P = 0.037), but this association did not survive FDR correction (adjusted P > 0.05). axSpA involves asymmetric white matter remodeling with increased bundle cross-section in corticostriatal and limbic pathways. These findings likely reflect active neuroinflammatory processes—such as maladaptive structural remodeling or compensatory hypertrophy—likely representing a distinct mechanism from the atrophy observed in later stages of neurodegeneration. FBA provides sensitive metrics for detecting these subtle macrostructural alterations in axSpA.Registry: chictr.org.cn, TRN: ChiCTR2500111024, Registration date: 23rd October 2025.