Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system

Abstract

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

Keywords: Parkinson’s disease; dopamine transporter; magnetic resonance imaging; neuromelanin; positron emission tomography.

Figure 1

Region of interest definition in the substantia nigra and striatum. Bottom right: Sagittal midline view of a 3D T₁-weighted MPRAGE template, derived using DARTEL with 30 Parkinson’s disease and 15 healthy control participants. The red line annotations illustrate the position of the coronal and axial planes corresponding to the sections depicted in A–C. (A and B) ¹¹C-PE2I ADD images overlaid onto the structural MPRAGE_REG from two levels of the coronal plane either side of the anterior commissure along the y-axis. Regions of the pre-commissural striatum (A) consist of ventral putamen (1, red), dorsal putamen (2, green) and caudate (3, purple). Regions of the post-commissural striatum (B) include putamen (4, orange) and caudate (5, blue). (C) An axial slice of the neuromelanin-sensitive T₁-weighted template derived using DARTEL (n = 45) at the level of the SNc, including delineation of the dorsal (6, red) (SNc^dor) and ventral (7, blue) (SNc^ven) tiers, as well as cerebral peduncle (8, yellow). Descriptive anatomy demonstrates projections from the dorsal tier (6, red) to striatal regions 1–3 while the ventral tier (7, blue) projects to regions 2–5 (Lynd-Balta and Haber, 1994; Haber et al., 2000; Haber, 2014).

Figure 2

Neuromelanin loss in the ventral and dorsal tiers of the substantia nigra pars compacta in Parkinson’s disease as compared to healthy controls. Strip plot illustrating neuromelanin contrast ratio values for individuals of both Parkinson’s disease (PD) and healthy control (HC) groups and for each subregion of the SNc (ventral tier, dorsal tier). Filled circles represent individuals within the Parkinson’s disease group and open grey circles represent individuals within the healthy control group. Crossbars represent 95% confidence intervals about the estimated marginal mean derived from the mixed ANOVA analysis.

Figure 3

Lateralization of neuromelanin loss and DAT density in the ventral and dorsal tiers of the substantia nigra pars compacta for the clinically-defined most and least affected sides. Strip plots showing neuromelanin contrast ratio (A) and ¹¹C-PE2I BP_ND (B) values for individuals within the Parkinson’s disease group as a function of the clinically-defined most/least affected side and subregion of the SNc (ventral tier, dorsal tier). Filled blue circles represent the ventral tier while open red circles represent the dorsal tier. Points between the clinically-defined most and least affected sides are connected with either a solid blue line (ventral tier) or dashed red line (dorsal tier) to illustrate asymmetry within individuals. Crossbars represent 95% confidence intervals about the mean.

Figure 4

Association between neuromelanin in the substantia nigra pars compacta ventral tier and nigrostriatal dopamine transporter binding. Scatterplots and simple linear regression showing positive relationships between neuromelanin contrast ratio in the SNc^ven and ¹¹C-PE2I BP_ND in the pre-commissural dorsal putamen (A), pre-commissural caudate (B), post-commissural putamen (C), post-commissural caudate (D) and SNc^ven (E) in the clinically-defined most affected (filled blue circles, solid line) and least affected sides (open circles, dashed line). Grey shaded areas represent 95% confidence intervals. **Significant result following Benjamini-Hochberg FDR correction for all correlational tests. *Significance at P < 0.05. BP_ND = non-displaceable binding potential; LA = least affected; MA = most affected.

Figure 5

Association between neuromelanin in the substantia nigra pars compacta dorsal tier and nigrostriatal dopamine transporter binding. Scatterplots and simple linear regression showing positive relationships between neuromelanin contrast ratio in the SNc^dor and ¹¹C-PE2I BP_ND in the pre-commissural dorsal putamen (A), pre-commissural ventral putamen (B), pre-commissural caudate (C) and SNc^dor (D) in the clinically-defined most affected (filled red circles, solid line) and least affected sides (open circles, dashed line). Grey shaded areas represent 95% confidence intervals. **Significant result following Benjamini-Hochberg FDR correction for all correlational tests. *Significance at P < 0.05. BP_ND = non-displaceable binding potential; LA = least affected; MA = most affected.

Figure 6

Relationship between measures of clinical severity and regional neuromelanin and dopamine transporter binding. Pearson’s correlation matrix with measures of clinical severity by row and neuromelanin contrast ratio in the SNc and ¹¹C-PE2I BP_ND in the SNc and striatum by column. Tiles are colour coded and labelled with the value of the correlation coefficient. **Significant result following Benjamini-Hochberg FDR correction for all correlational tests. *Significance at P < 0.05. BP_ND = non-displaceable binding potential; Post-C = post-commissural; Pre-C = pre-commissural.