Higher iron in the red nucleus marks Parkinson's dyskinesia

Abstract

Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinson's disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes might reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution magnetic resonance images from 23 control and 38 PD subjects (12 with PD and history of LID [PD+DYS]) and 26 with PD and no history of LID (PD-DYS). Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinson's Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS compared with control and PD-DYS subjects; control and PD-DYS subjects did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development.

Figure 1

Model of motor function. Panel A (normal subjects): Motor tasks are accomplished through combined activity in striato- and cerebello-thalamo-cortical circuits (gray arrows) with modulation from striato-cerebellar and cerebello-striatal subcortical pathways (solid lines). Panels B & C (see Discussion): Model of motor dysfunction in PD with and without dyskinesia. In PD+DYS, decreased input from dysfunctional striatal circuits (dotted lines) leads to markedly increased activity in cerebellar circuits that set the stage for LID development (Panel B). In PD−DYS patients, the slightly increased recruitment of cerebellar circuits is not dysfunctional enough to result in predisposition for development of LID (Panel C).

Figure 2

Relative location of the substantia nigra (SN) and red nucleus (RN) on a schematic of the midbrain (A). A typical MRI image illustrates the location of the SN (green) and RN (red) in T2-weighted images (B) and the co-registered regions on the R2* (C) map in an axial section.

Figure 3

Mean SN and RN R2* values (± SD) for Control and PD subjects. (3A) In both the SN and RN, PD subjects had higher R2* values compared to control subjects. (3B) In both the SN and RN, PD subjects with a history of dyskinesia (PD+DYS) had higher R2* values compared to both control subjects and PD subjects without a history of dyskinesia (PD−DYS). PD−DYS subjects showed significantly higher R2* values in the SN compared to Controls, but this comparison did not reach significance in the RN.

Figure 4

ROC curves for discriminating between PD subjects with and without history of dyskinesia. Panel A represents the model that tests disease duration and SN R2* values alone or in combination. Panel B depicts the model that tests disease duration and RN R2* values alone or in combination.