Early degeneration of motor pathways in prodromal Parkinson’s disease: A fixel-based structural connectivity analysis

Abstract Background Idiopathic REM sleep behavior disorder (iRBD) and hyposmia are the strongest clinical indicators of prodromal Parkinson’s disease, reflecting distinct proposed pathways of α-synuclein pathology propagation. According to the body-first/brain-first model, iRBD represents a body-first phenotype with early brainstem involvement, whereas hyposmia may reflect a brain-first phenotype with early limbic involvement. We therefore hypothesized that these markers would show distinct fiber-specific white matter alterations, with iRBD and hyposmia primarily affecting brainstem and limbic pathways, respectively. Methods Diffusion and structural MRI from prodromal participants in the Parkinson’s Progression Markers Initiative (PPMI; n = 88) were analyzed using fixel-based analysis, which quantifies macro- and microstructural fiber-specific measures of fiber density, fiber cross-section, and fiber density-cross-section. We assessed the association between these measures and RBD severity, olfactory performance, and motor symptom severity. In a subset with polysomnography data (n = 37), we compared fiber-specific metrics between polysomnography-confirmed and polysomnography-negative iRBD. Voxel-based morphometry was also conducted to assess grey matter volume correlates of prodromal symptom severity. Results Greater RBD severity was associated with reduced fiber cross-section in the pons, right internal capsule, and left temporal lobe, corresponding to the right corticospinal tract and left inferior longitudinal fasciculus. The lower fiber cross-section in the latter was associated with vivid dreams. Polysomnography-confirmed iRBD showed lower fiber density in the midbrain and bilateral internal capsules, corresponding to left corticospinal and right frontopontine tracts. Lower corticospinal fiber density predicted worse fine motor performance. No diffusion or grey matter correlates emerged for hyposmia. Conclusions Prodromal Parkinson’s disease shows selective degeneration of corticospinal, frontopontine, and inferior longitudinal fasciculus pathways that scale with iRBD severity, showing early brainstem and motor pathways involvement in body-first phenotypes. The association between reduced corticospinal fiber density and fine motor impairment demonstrates that these tract-level alterations are not only detectable in the prodromal phase but are already clinically meaningful. No detectable diffusion or grey matter correlates were observed for hyposmia. These findings identify iRBD-specific white matter vulnerability in the prodromal phase and highlight fiber-specific diffusion metrics as sensitive markers of early Parkinson’s disease-related change.