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Movement Disorders : Official Journal... Apr 2021Neuromelanin-sensitive magnetic resonance imaging techniques have been developed but currently require relatively long scan times. The aim of this study was to assess...
BACKGROUND
Neuromelanin-sensitive magnetic resonance imaging techniques have been developed but currently require relatively long scan times. The aim of this study was to assess the ability of black-blood delay alternating with nutation for tailored excitation-prepared T1-weighted variable flip angle turbo spin echo (DANTE T1-SPACE), which provides relatively high resolution with a short scan time, to visualize neuromelanin in the substantia nigra pars compacta (SNpc).
METHODS
Participants comprised 49 healthy controls and 25 patients with Parkinson's disease (PD). Contrast ratios of SNpc and hyperintense SNpc areas, which show pixels brighter than thresholds, were assessed between DANTE T1-SPACE and T1-SPACE in healthy controls. To evaluate the diagnostic ability of DANTE T1-SPACE, the contrast ratios and hyperintense areas were compared between healthy and PD groups, and receiver operating characteristic analyses were performed. We also compared areas under the curve (AUCs) between DANTE T1-SPACE and the previously reported gradient echo neuromelanin (GRE-NM) imaging. Each analysis was performed using original images in native space and images transformed into Montreal Neurological Institute space. Values of P < 0.05 were considered significant.
RESULTS
DANTE T1-SPACE showed significantly higher contrast ratios and larger hyperintense areas than T1-SPACE. On DANTE T1-SPACE, healthy controls showed significantly higher contrast ratios and larger hyperintense areas than patients with PD. Hyperintense areas in native space analysis achieved the best AUC (0.94). DANTE T1-SPACE showed AUCs as high as those of GRE-NM.
CONCLUSIONS
DANTE T1-SPACE successfully visualized neuromelanin of the SNpc and showed potential for evaluating PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Magnetic Resonance Imaging; Melanins; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 33314293
DOI: 10.1002/mds.28417 -
Frontiers in Neuroscience 2022Striatal dopamine transporter (DAT) imaging using I-ioflupane single photon positron emitted computed tomography (SPECT) (DaTScan, GE) identifies 5-20% of newly...
INTRODUCTION
Striatal dopamine transporter (DAT) imaging using I-ioflupane single photon positron emitted computed tomography (SPECT) (DaTScan, GE) identifies 5-20% of newly diagnosed Parkinson's disease (PD) subjects enrolling in clinical studies to have scans without evidence of dopaminergic deficit (SWEDD). These individuals meet diagnostic criteria for PD, but do not clinically progress as expected, and they are not believed to have neurodegenerative Parkinsonism. Inclusion of SWEDD participants in PD biomarker studies or therapeutic trials may therefore cause them to fail. DaTScan can identify SWEDD individuals, but it is expensive and not widely available; an alternative imaging approach is needed. Here, we evaluate the use of neuromelanin-sensitive, iron-sensitive, and diffusion contrasts in substantia nigra pars compacta (SNpc) to differentiate SWEDD from PD individuals.
METHODS
Neuromelanin-sensitive, iron-sensitive, and diffusion imaging data for SWEDD, PD, and control subjects were downloaded from the Parkinson's progression markers initiative (PPMI) database. SNpc volume, SNpc iron ( ), and SNpc free water (FW) were measured for each participant.
RESULTS
Significantly smaller SNpc volume was seen in PD as compared to SWEDD ( < 10) and control ( < 10) subjects. SNpc FW was elevated in the PD group relative to controls ( = 0.017). No group difference was observed in SNpc .
CONCLUSION
In conclusion, nigral volume and FW in the SWEDD group were similar to that of controls, while a reduction in nigral volume and increased FW were observed in the PD group relative to SWEDD and control participants. These results suggest that these MRI measures should be explored as a cost-effective alternative to DaTScan for evaluation of the nigrostriatal system.
PubMed: 36507343
DOI: 10.3389/fnins.2022.1048945 -
Neural Plasticity 2016A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also... (Review)
Review
A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also regulate adult mDA neuron survival and physiology. Mouse models with targeted disruption of some of these genes display several features reminiscent of Parkinson disease (PD), in particular the selective and progressive loss of mDA neurons in the substantia nigra pars compacta (SNpc). The characterization of these animal models has provided valuable insights into various mechanisms of PD pathogenesis. Therefore, the dissection of the mechanisms and survival signalling pathways engaged by these transcription factors to protect mDA neuron from degeneration can suggest novel therapeutic strategies. The work on En1/2-mediated neuroprotection also highlights the potential of protein transduction technology for neuroprotective approaches in PD.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Mesencephalon; Mice; Parkinson Disease; Pars Compacta; Signal Transduction; Transcription Factors
PubMed: 26881122
DOI: 10.1155/2016/6097107 -
ENeuro 2018GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range...
GABA neurons in the VTA and SNc play key roles in reward and aversion through their local inhibitory control of dopamine neuron activity and through long-range projections to several target regions including the nucleus accumbens. It is not clear whether some of these GABA neurons are dedicated local interneurons or if they all collateralize and send projections externally as well as making local synaptic connections. Testing between these possibilities has been challenging in the absence of interneuron-specific molecular markers. We hypothesized that one potential candidate might be neuronal nitric oxide synthase (nNOS), a common interneuronal marker in other brain regions. To test this, we used a combination of immunolabelling (including antibodies for nNOS that we validated in tissue from nNOS-deficient mice) and cell type-specific virus-based anterograde tracing in mice. We found that nNOS-expressing neurons, in the parabrachial pigmented (PBP) part of the VTA and the SNc were GABAergic and did not make detectable projections, suggesting they may be interneurons. In contrast, nNOS-expressing neurons in the rostral linear nucleus (RLi) were mostly glutamatergic and projected to a number of regions, including the lateral hypothalamus (LH), the ventral pallidum (VP), and the median raphe (MnR) nucleus. Taken together, these findings indicate that nNOS is expressed by neurochemically- and anatomically-distinct neuronal sub-groups in a sub-region-specific manner in the VTA and SNc.
Topics: Animals; GABAergic Neurons; Mice, Inbred C57BL; Nitric Oxide Synthase Type I; Nucleus Accumbens; Pars Compacta; Substantia Nigra; Tyrosine 3-Monooxygenase; Ventral Tegmental Area
PubMed: 30456293
DOI: 10.1523/ENEURO.0381-18.2018 -
Neurobiology of Disease Jul 2022In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with... (Review)
Review
In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with inflammatory and age-related processes. Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Increasing extensive evidence supports the contribution of genetic risk variants and inflammation in the pathobiology of this disease. Functional and genetic studies demonstrate an overlap between genes linked to increased risk for PD and autoimmune diseases. Variants identified in loci adjacent to LRRK2, GBA, and HLA establish a crosstalk between the pathobiologies of the two disease spectra. Furthermore, common signalling pathways associated with the pathogenesis of genetic PD are also relevant to inflammatory signaling include MAPK, NF-κB, Wnt and inflammasome signaling. Importantly, post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines. In this review we will focus on the principal mechanisms of genetic, inflammatory and age-related risk that intersect in the pathogenesis of PD.
Topics: Dopaminergic Neurons; Humans; Immunity, Innate; Parkinson Disease; Pars Compacta; Signal Transduction
PubMed: 35405260
DOI: 10.1016/j.nbd.2022.105721 -
Frontiers in Physiology 2022Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulator of numerous aspects of neural functions. Serotonergic neurons in the dorsal and median...
Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulator of numerous aspects of neural functions. Serotonergic neurons in the dorsal and median raphe nucleus provide ascending innervation to the entire forebrain and midbrain. Another important neural modulatory system exists in the midbrain, the dopaminergic system, which is associated to reward processing and motivation control. Dopaminergic neurons are distributed and clustered in the brain, classically designated as groups A8-A16. Among them, groups A8-A10 associated with reward processing and motivation control are located in the midbrain and projected to the forebrain. Recently, midbrain dopaminergic neurons were shown to be innervated by serotonergic neurons and modulated by 5-HT, with the crosstalk between serotonergic and dopaminergic systems attracting increased attention. In birds, previous studies revealed that midbrain dopaminergic neurons are located in the A8-A10 homologous clusters. However, the detailed distribution of dopaminergic neurons and the crosstalk between serotonergic and dopaminergic systems in the bird are poorly understood. To improve the understanding of the regulation of the dopaminergic by the serotonergic system, we performed hybridization in the chick brainstem. We prepared RNA probes for chick orthologues of dopaminergic neuron-related genes; tyrosine hydroxylase () and dopa decarboxylase (), noradrenaline related genes; noradrenaline transporter () and dopamine beta-hydroxylase (), and serotonin receptor genes; , , , , , , , , , , , and We confirmed that the expression of (TH) and was well matched in all chick dopaminergic nuclei examined. This supported that the compensation of the function of dopamine transporter (DAT) by NAT is a general property of avian dopaminergic neurons. Furthermore, we showed that and were expressed in midbrain dopaminergic nuclei, suggesting the serotonergic regulation of the dopaminergic system these receptors in chicks. Our findings will help us understand the interactions between the dopaminergic and serotonergic systems in birds at the molecular level.
PubMed: 36425295
DOI: 10.3389/fphys.2022.1030621 -
Neurobiology of Disease Oct 2022Dopaminergic neurons in the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's Disease, with the ventral region degenerating more severely... (Review)
Review
Dopaminergic neurons in the substantia nigra pars compacta (SNc) differentially degenerate in Parkinson's Disease, with the ventral region degenerating more severely than the dorsal region. Compared with the dorsal neurons, the ventral neurons in the SNc have distinct dendritic morphology, electrophysiological characteristics, and circuit connections with the basal ganglia. These characteristics shape information processing in the ventral SNc and structure the balance of inhibition and disinhibition in the striatonigral circuitry. In this paper, I review foundational studies and recent work comparing the circuitry of the ventral and dorsal SNc neurons and discuss how loss of the ventral neurons early in Parkinson's Disease could affect the overall balance of inhibition and disinhibition of dopamine signals.
Topics: Basal Ganglia; Dopaminergic Neurons; Humans; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 35820645
DOI: 10.1016/j.nbd.2022.105815 -
Neuropharmacology Dec 2021Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces...
Methamphetamine (meth) increases monoamine oxidase (MAO)-dependent mitochondrial stress in substantia nigra pars compacta (SNc) axons; chronic administration produces SNc degeneration that is prevented by MAO inhibition suggesting that MAO-dependent axonal mitochondrial stress is a causal factor. To test whether meth similarly increases mitochondrial stress in ventral tegmental area (VTA) axons, we used a genetically encoded redox biosensor to assess mitochondrial stress ex vivo. Meth increased MAO-dependent mitochondrial stress in both SNc and VTA axons. However, despite having the same meth-induced stress as SNc neurons, VTA neurons were resistant to chronic meth-induced degeneration indicating that meth-induced MAO-dependent mitochondrial stress in axons was necessary but not sufficient for degeneration. To determine whether L-type Ca channel-dependent stress differentiates SNc and VTA axons, as reported in the soma, the L-type Ca channel activator Bay K8644 was used. Opening L-type Ca channels increased axonal mitochondrial stress in SNc but not VTA axons. To first determine whether mitochondrial stress was necessary for SNc degeneration, mice were treated with the mitochondrial antioxidant mitoTEMPO. Chronic meth-induced SNc degeneration was prevented by mitoTEMPO thereby confirming the necessity of mitochondrial stress. Similar to results with the antioxidant, both MAO inhibition and L-type Ca channel inhibition also prevented SNc degeneration. Taken together the presented data demonstrate that both MAO- and L-type Ca channel-dependent mitochondrial stress is necessary for chronic meth-induced degeneration.
Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Animals; Antioxidants; Calcium Channels, L-Type; Dopaminergic Neurons; Male; Methamphetamine; Mice; Mitochondria; Monoamine Oxidase Inhibitors; Neurodegenerative Diseases; Pars Compacta; Ventral Tegmental Area
PubMed: 34610287
DOI: 10.1016/j.neuropharm.2021.108817 -
Brain : a Journal of Neurology Nov 2021In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron...
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.
Topics: Aged; Cohort Studies; Corpus Striatum; Dopamine; Female; Humans; Iron; Longitudinal Studies; Magnetic Resonance Imaging; Male; Melanins; Middle Aged; Parkinson Disease; Prospective Studies; Substantia Nigra; Time Factors
PubMed: 33978742
DOI: 10.1093/brain/awab191 -
Brain Communications 2021The loss of melanized neurons in the substantia nigra pars compacta is a primary feature in Parkinson's disease. Iron deposition occurs in conjunction with this loss....
The loss of melanized neurons in the substantia nigra pars compacta is a primary feature in Parkinson's disease. Iron deposition occurs in conjunction with this loss. Loss of nigral neurons should remove barriers for diffusion and increase diffusivity of water molecules in regions undergoing this loss. In metrics from single-compartment diffusion tensor imaging models, these changes should manifest as increases in mean diffusivity and reductions in fractional anisotropy as well as increases in the free water compartment in metrics derived from bi-compartment models. However, studies examining nigral diffusivity changes from Parkinson's disease with single-compartment models have yielded inconclusive results and emerging evidence in control subjects indicates that iron corrupts diffusivity metrics derived from single-compartment models. We aimed to examine Parkinson's disease-related changes in nigral iron and diffusion measures from single- and bi-compartment models as well as assess the effect of iron on these diffusion measures in two separate Parkinson's cohorts. Iron-sensitive data and diffusion data were analysed in two cohorts: First, a discovery cohort consisting of 71 participants (32 control participants and 39 Parkinson's disease participants) was examined. Second, an external validation cohort, obtained from the Parkinson's Progression Marker's Initiative, consisting of 110 participants (58 control participants and 52 Parkinson's disease participants) was examined. The effect of iron on diffusion measures from single- and bi-compartment models was assessed in both cohorts. Measures sensitive to the free water compartment (discovery cohort: = 0.006; external cohort: = 0.01) and iron content (discovery cohort: < 0.001; validation cohort: = 0.02) were found to increase in substantia nigra of the Parkinson's disease group in both cohorts. However, diffusion markers derived from the single-compartment model (i.e. mean diffusivity and fractional anisotropy) were not replicated across cohorts. Correlations were seen between single-compartment diffusion measures and iron markers in the discovery cohort (iron-mean diffusivity: = -0.400, = 0.006) and validation cohort (iron-mean diffusivity: = -0.387, = 0.003) but no correlation was observed between a measure from the bi-compartment model related to the free water compartment and iron markers in either cohort. In conclusion, the variability of nigral diffusion metrics derived from the single-compartment model in Parkinson's disease may be attributed to competing influences of increased iron content, which tends to drive diffusivity down, and increases in the free water compartment, which tends to drive diffusivity up. In contrast to diffusion metrics derived from the single-compartment model, no relationship was seen between iron and the free water compartment in substantia nigra.
PubMed: 34805996
DOI: 10.1093/braincomms/fcab251