Early brain iron changes in Parkinson's disease and isolated rapid eye movement sleep behaviour disorder: a four-year longitudinal multimodal quantitative MRI study

Parkinson's disease demonstrates increased iron concentration in the substantia nigra (SN). The progression of iron and its interaction with neuromelanin content and dopaminergic dysregulation from prodromal to early-stage Parkinson's disease remain poorly understood. Using quantitative susceptibility mapping (QSM) and R2* relaxation rate, we investigated brain iron changes in patients with isolated rapid eye movement (REM) sleep behaviour disorder and early-stage Parkinson's disease. Subjects were scanned longitudinally at 3.0 Tesla MRI. QSM and R2* values were calculated in the entire SN and its anterior and posterior dorsal and ventral subdivisions. Baseline and longitudinal group differences were tested using analysis of variance of multiple linear regression models controlling for age and sex and linear mixed-effects modelling respectively. We included 44/36/28 healthy volunteers (HVs), 49/20/11 isolated REM sleep behaviour disorder, 127/88/50 Parkinson's disease at first/second/third visit respectively, separated by a 2-year interval. At baseline, there was a significant increase in QSM and R2* values in Parkinson's disease versus HVs in the posteroventral SN only (QSM: +17.6%%; R2*: +7.1%), which did not reach significance in isolated REM sleep behaviour disorder (QSM: +6.9%, R2*: +3.3%). Longitudinally, only posteroventral SN values demonstrated significant effects for Group and Visit using QSM and R2*. Further, the Group-by-Visit interaction was significant only for QSM. The posteroventral SN iron increased with disease duration and was inversely correlated with the changes in nigral neuromelanin content and striatal DaT levels in Parkinson's disease. The posteroventral nigral iron increased with the progression of the disease as well as dopaminergic denervation in Parkinson's disease. QSM was a stronger quantitative longitudinal marker than R2* in detecting regional nigral iron abnormalities as the disease progressed.