Nigrosome-1 neuromelanin-iron coupling profiles in idiopathic and GBA-associated Parkinson disease

BackgroundFirstly, to determine whether iron-sensitive MRI measures mediate neuromelanin (NM) loss within the substantia nigra pars compacta (SNc) and its subregion, nigrosome-1 (N1) in idiopathic Parkinsons disease (iPD) and GBA-associated Parkinsons disease (GBA-PD) versus healthy controls (HC). Secondly, to assess the diagnostic value of NM-and iron MRI metrics, including their lateralisation. MethodsEighty-six participants (HC=30, iPD = 30, GBA-PD = 26) underwent midbrain quantitative NM-MRI and susceptibility-weighted imaging (SWI). Contrast ratio (CR), normalised volume (nVol) and left-right asymmetry indices (AI) of SNc and N1 calculated. Receiver-operating analyses assessed group discrimination and onset-side prediction. Bidirectional causal mediation (5,000 bootstraps, FDR-corrected) tested Iron[-&gt;]NM[-&gt;]group and NM[-&gt;]Iron[-&gt;]group pathways. Moderation models examined the effect of GBA-mutation severity. ResultsiPD and GBA-PD showed marked NM loss and increased iron in SNc/N1, being more prominent in GBA-PD. N1 NM metrics provided the strongest discrimination (HC vs GBA-PD AUC=0.93, HC vs iPD AUC=0.83), followed by iron measures (AUC=0.78-0.89). N1 NM asymmetry yielded moderate lateralisation accuracy (AUC=0.76). Cross-sectional mediation analyses identified significant Iron[-&gt;]NM[-&gt;]group effects across SNc and N1 (q<0.01), supporting mechanistic hypotheses of iron-driven NM depletion in PD. In GBA-PD, NM-iron coupling in N1 was influenced by mutation severity, suggesting a genotype-specific disruption of NM-iron homeostasis. ConclusionsMulti-contrast MRI centered on N1 reveals an iron-driven NM imbalance that distinguishes PD from controls and it is modulated by GBA mutation severity, supporting the applicability of N1-focused NM-iron imaging as a biomarker for PD diagnosis. Note: This manuscript has been submitted to Journal of Neurology, Neurosurgery & Psychiatry for consideration.