Motor impairments are extremely heterogeneous in patients with Parkinson’s disease (PD). Because the roles of striatal-thalamo-cortical (STC) and cerebello-thalamo-cortical (CTC) circuits in motor impairments are gradually being recognized, this study was designed to investigate the underlying relationships between regional iron in the cardinal subcortical nuclei in these circuits and the different motor impairments in PD.Fifty-four PD patients and 40 normal subjects were included in this study. According to motor subscales of the UPDRS¹, patients were divided into tremor-dominant (PD-TD) and akinetic/rigid-dominant groups (PD-AR) (27 patients per group) (Table 1). The intergroup differences of magnetic susceptibility in the subcortical nuclei covering the STC and CTC circuits were measured by quantitative susceptibility mapping controlling for age and gender (shown in Fig. 1). Partial correlations analyses between magnetic susceptibility and motor impairments were performed in all patients controlling for the effects of age, gender, global cognitive function, and medication history.

Magnetic susceptibility significantly increased in the SNc for each PD group compared with the normal controls, indicating increased iron content in this region. There was no significance in magnetic susceptibility between the two patient groups in the SNc. In RN and DN, the PD-TD patients showed significantly higher magnetic susceptibility than in the controls. Intriguingly, they also showed a tendency towards increased magnetic susceptibility within these regions when compared with PD-AR patients (Fig. 2).

Because both parkinsonian tremor and akinesia/rigid concurrently occurred in the majority of our patients (46/54), in this study, correlations between regional iron content and motor impairments were performed in the 54 PD patients. For total motor impairment, increasing UPDRS motor scores and Hoehn–Yahr stages were significantly associated with increasing magnetic susceptibility in the SNc (Fig. 3, panels A and B). When examining the specific scores for tremor and akinetic/rigid, interestingly we observed significant correlations between tremor scores and magnetic susceptibility in RN and DN (Fig. 3, panels C and D) while magnetic susceptibility in the SNc and CN was correlated with the severity of akinetic/rigid (Fig. 3, panels E and F).

It is noteworthy that among the regions where we observed iron deposition, the DN and RN was the key findings that were first reported in PD studies. Furthermore, we also observed that increasing iron content in these regions positively correlated with increasing tremor severity.

Thalamic and subthalamic deep brain stimulation could alleviate tremor symptoms, including essential tremor and parkinsonian tremor^2-6, indicating the existence of a common pathway in these tremor diseases. Novellino et al ⁷ first demonstrated dentate iron accumulation in essential tremor patients. Taken together, the finding of iron deposition in the DN of PD-TD patients further extends the notion that parkinsonian tremor and essential tremor possibly share similar neuronal alteration. Thus, it can be concluded that excessive iron content in the DN might play an important role in the tremor-generating mechanism.

The RN as a pivotal intersection between the cerebellum and cerebrum⁸ suggests a role in providing cerebellar compensation in the presence of cerebral dysfunction⁹. Lewis and colleagues⁹ indicated that iron deposition in the RN probably result from increased cerebellar compensatory capacity. Because there was no statistical difference in akinetic/rigid scores between the two cohorts of PD patients in our study, the increased iron content in this region contributed primarily to the tremor symptom. It has long been thought that parkinsonian tremor may be generated by a neural mechanism compensating for akinetic/rigid^10,11. These results lead to the idea that iron deposition in the RN might be a marker for the increased compensatory function of the cerebellum in motor impairments, such as tremor.

Akinetic/rigid symptoms are highly correlated with striatal dopamine depletion resulting from nigrostriatal degeneration¹⁰. Our finding of iron content in this region, which significantly correlated with akinetic/rigid severity, further supports that relationship. Partially consistent with our findings, Bunzeck et al¹² suggested that the lower iron content in the CN is associated with more pronounced akinetic/rigid symptoms. Consequently, these findings indicate that nigral and caudate iron content may be a potential marker of akinetic/rigid progression.

Our study provides the first evidence that nigral iron deposition is a prerequisite for PD while iron deposition in the DN and RN was highly correlated with tremor generation or modulation. This is a preliminary study supporting the hypothesis that regional iron deposition in both CTC and STC circuits is related to motor impairments of tremor. Our data also show that iron content in the nuclei of the STC circuit, such as CN and SNc, may be a potential marker for assessing the progression of akinetic/rigid.