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.

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

“…(3) loss of dopaminergic cells in the SNc relatively limited to the ventrolateral tier; (4) DA putaminal loss exceeds by some 40% cell loss in SNc; and (5) DA loss in the striatum and cell loss in the SNc progresses relatively orderly following a caudorostral and lateromedial pattern, respectively. 13 These features imply that regardless of whether the propagation of toxic species in PD follows an orderly caudorostral pattern, the SNc lateral projection to the caudal putamen must have intrinsic anatomofunctional characteristics that make it especially vulnerable. Importantly, PD is not spontaneously present in any other species, and humans exhibit a number of specific motor, behavioral, and cognitive properties and capacities that are probably related to our ability to undergo age-related neurodegeneration.…”

“…12 Pigmented neurons are particularly susceptible, especially in the ventral tier of the SNc, as assessed in postmortem brains and, recently, with in vivo neuromelanin-sensitve MRI. 13 Although less well characterized, there is evidence for neuronal loss in other brain regions. 14 A recent thorough review assessed all the published articles in which neuron counts in particular brain regions of PD patients were performed.…”

Bioinspired Melanin‐Based Optically Active Materials

“…Neuromelanin is related to neurodegenerative disorders such as Parkinson and Alzheimer disease. [ 10 ] A fourth type of natural melanin, called allomelanin, has recently drawn attention. [ 11 ] It is a heterogeneous group of polymers without nitrogen mostly found in bacteria, fungi, and plants; [ 12 ] and it is derived from 1,8‐dihydroxynaphthalene (DHN), 1,3,6,8‐tetrahydroxynaphthalene, and catechols.…”

Dopamine transporter imaging in neurodegenerative movement disorders: PET vs. SPECT

“…1, [33]), which are thought to represent motor functioning, mood, and cognitive functioning, respectively. The use of the striatal functional subdivisions provides a better way to assess correlations between clinical and behavioral subdomains of Parkinson symptoms with regional DAT deficit [34,35].…”