The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease

Abstract

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Keywords: Parkinson’s disease; dopamine transporter; imaging; iron; neuromelanin.

Figure 1

Group differences in striatal DaT levels. (A) Functional subregions in the striatum. (B–S) Left and right panels show the results of the statistical comparison between groups in the clinically most and least affected brain hemispheres, respectively. Each panel has three columns, representing the intergroup comparison between Parkinson’s disease patients (PD) and healthy control subjects (HCs) (left), Parkinson’s disease patients and iRBD patients (middle) or iRBD patients and healthy control subjects (right). Rows correspond to the group differences at (B–G) visit 1 (V1); (H–M) visit 2 (V2); and (N–S) the inter-visit differences in longitudinal subjects. Results were adjusted for age and sex and corrected for multiple comparisons using Tukey’s test at the P < 0.05 level. For improved clarity in the visual representation of statistical differences, P-values were converted into z-scores. Cd = caudate nucleus; NAc = nucleus accumbens; Pu = putamen

Figure 2

Group differences in nigral neuromelanin and nigral iron levels. (A) Functional subregions in the substantia nigra. (B–I) Left and right panels show the results of the statistical comparison between groups in the clinically most and least affected brain hemispheres, respectively. Rows correspond to the group differences at (B–E) visit 1 (V1), and (F–I) at visit 2 (V2). Non-significant between-group comparisons were omitted. Results were adjusted for age and sex and corrected for multiple comparisons using Tukey’s test at the P < 0.05 level. For improved clarity in the visual representation of statistical differences, P-values were converted into z-scores. HCs = healthy control subjects; NM = neuromelanin; PDs = patients with Parkinson’s disease.

Figure 3

Temporal changes in striatal DaT, nigral neuromelanin and nigral iron in patients relative to healthy controls. (A–C and F–H) For all Parkinson’s disease patients relative to healthy control subjects (HCs), in each striatal region and each brain hemisphere, panels shows the mono-exponential functions fitting the regional DaT-SBR per cent change against disease duration. (D and E) For each nigral region in the most affected hemisphere, the figure also shows the mono-exponential functions fitting iron (QSM) or neuromelanin (NM SNR) per cent changes against disease duration. Cd = caudate nucleus; NAc = nucleus accumbens; NM = neuromelanin; Pu = putamen; QSM = quantitative susceptibility mapping.

Figure 4

Spatial correlation patterns between nigral neuromelanin or nigral iron and striatal DaT in the SNc. For each striatal region (putamen, caudate nucleus and nucleus accumbens) and each functional territory (sensorimotor, associative and limbic), the DaT-neuromelanin correlation patterns (A–G), the neuromelanin-iron correlation patterns (K) and the DaT-iron correlation patterns (L–R) in the SNc are shown overlaid on the brain template. The DaT-neuromelanin regional overlaps are shown for the putamen, caudate and limbic areas (H–J) along with Dice scores quantifying the relative overlap between pairs of correlation patterns. In each image, the brain template is displayed using the same intensity range in arbitrary units. All images are displayed showing the most affected brain hemisphere on the left side of the image. For improved image visualization quality, the correlation patterns (A–G, K and L–R) were spatially upsampled by a factor of four using nearest-neighbour interpolation. AS = associative; Cd = caudate nucleus; LI = limbic; NAc = nucleus accumbens; Pu = putamen; SM = sensorimotor.