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Movement Disorders : Official Journal... Mar 2023Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of...
BACKGROUND
Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration.
OBJECTIVE
The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden.
METHODS
This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression.
RESULTS
Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden.
CONCLUSIONS
R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Pars Compacta; Parkinson Disease; Substantia Nigra; Retrospective Studies; Parkinsonian Disorders; Magnetic Resonance Imaging; Iron
PubMed: 36598274
DOI: 10.1002/mds.29311 -
Folia Morphologica 2023Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some...
BACKGROUND
Lead-induced neurotoxicity was marked with locomotor and Parkinsonian-like changes. Oligodendrocytes and synucleinopathy were signed to in the pathophysiology of some neurodegenerative diseases. Vitamin D3's (D3) role in substantia nigra pars compacta (SNpc) disorders is debated between neuroscientists. The aim of the study was to investigate lead-induced SNpc neurotoxic changes and explore the possible neuroprotective role of D3 and the possible involvement of oligodendrocytes and α-synuclein.
MATERIALS AND METHODS
This study included 40 adult Wistar rats assigned into four equal groups: control, lead (Pb) (in drinking water, 1,000 mg/L), Pb + D3 (D3 injection, 1,000 IU/kg IM; 3 days/week), and D3. After 8 weeks, the rats were sacrificed, and their midbrain underwent biochemical and immunoblotting analysis. Midbrain paraffin blocks were stained for histological and immunohistochemical assessment.
RESULTS
Lead (Pb) had increased significantly (p < 0.05) nigral α-synuclein and caspase-11 by immunoblotting analysis. Histologically, it induced neurodegeneration in SNpc and significantly decreased neuronal cell density by cresyl violet staining. Pb also significantly reduced SNpc tyrosine hydroxylase immunoreaction, significantly elevated glial fibrillatory acid protein (GFAP) and α-synuclein immunoreaction associated with a mild but significant increase in caspase-3. In the Pb + D3 group, all the previous deleterious changes were significantly alleviated in addition to significant upregulation of anti-oligodendrocytes immunoexpression.
CONCLUSIONS
Lead (Pb) may induce SNpc neurotoxicity presumably via activation of caspase-11 and α-synuclein. D3 may modulate this neurotoxicity probably through an oligodendrogenic effect.
Topics: Rats; Animals; Pars Compacta; alpha-Synuclein; Synucleinopathies; Lead; Rats, Wistar; Cholecalciferol
PubMed: 35099046
DOI: 10.5603/FM.a2022.0003 -
Neurobiology of Aging Mar 2020Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or...
Locus coeruleus (LC) and substantia nigra pars compacta (SNpc) degrade with normal aging, but not much is known regarding how these changes manifest in MRI images, or whether these markers predict aspects of cognition. Here, we use high-resolution diffusion-weighted MRI to investigate microstructural and compositional changes in LC and SNpc in young and older adult cohorts, as well as their relationship with cognition. In LC, the older cohort exhibited a significant reduction in mean and radial diffusivity, but a significant increase in fractional anisotropy compared with the young cohort. We observed a significant correlation between the decrease in LC mean, axial, and radial diffusivities and measures examining cognition (Rey Auditory Verbal Learning Test delayed recall) in the older adult cohort. This observation suggests that LC is involved in retaining cognitive abilities. In addition, we observed that iron deposition in SNpc occurs early in life and continues during normal aging.
Topics: Adult; Aged; Aged, 80 and over; Aging; Cognition; Diffusion Tensor Imaging; Female; Humans; Iron; Locus Coeruleus; Male; Pars Compacta; Young Adult
PubMed: 31870645
DOI: 10.1016/j.neurobiolaging.2019.11.016 -
Philosophical Transactions of the Royal... Aug 2022Oxytocin is an endogenous neuropeptide hormone that influences social behaviour and bonding in mammals. Variations in oxytocin receptor (OXTR) expression may play a role...
Oxytocin is an endogenous neuropeptide hormone that influences social behaviour and bonding in mammals. Variations in oxytocin receptor (OXTR) expression may play a role in the social deficits seen in autism spectrum disorder. Previous studies from our laboratory found a dense population of OXTR in the human substantia nigra (SN), a basal ganglia structure in the midbrain that is important in both movement and reward pathways. Here, we explore whether differences in OXTR can be identified in the dopaminergic SN pars compacta of individuals with autism. Postmortem human brain tissue specimens were processed for OXTR autoradiography from four groups: males with autism, females with autism, typically developing (TD) males and TD females. We found that females with autism had significantly lower levels of OXTR than the other groups. To examine potential gene expression differences, we performed hybridization in adjacent slides to visualize and quantify OXTR mRNA as well as mRNA for tyrosine hydroxylase. We found no differences in mRNA levels for either gene across the four groups. These results suggest that a dysregulation in local OXTR protein translation or increased OXTR internalization/recycling may contribute to the differences in social symptoms seen in females with autism. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.
Topics: Animals; Autism Spectrum Disorder; Female; Humans; Male; Mammals; Oxytocin; Pars Compacta; RNA, Messenger; Receptors, Oxytocin; Substantia Nigra
PubMed: 35858098
DOI: 10.1098/rstb.2021.0118 -
European Journal of Pharmacology Jan 1990The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were studied in superfused synaptosomes prepared from...
The depolarization-evoked release of gamma-aminobutyric acid (GABA) and its modulation mediated by autoreceptors were studied in superfused synaptosomes prepared from the pars compacta and from the pars reticulata of the rat substantia nigra. The release of [3H]GABA evoked by 9 mM KCl was almost totally calcium-dependent in both nigral subregions. In the presence of SK&F 89976A (N-(4,4-diphenyl-3-butenyl)nipecotic acid), a GABA uptake inhibitor added to minimize carrier-mediated homoexchange, GABA (0.3-10 microM) inhibited, in a concentration-dependent way, the K(+)-evoked overflow of [3H]GABA from both pars compacta and pars reticulata synaptosomes. Similarly to GABA, (-)-baclofen (0.3-10 microM) reduced the [3H]GABA overflow, being roughly equipotent to GABA in both nigral subregions. The (+) enantiomer of baclofen was ineffective. The overflow of [3H]GABA was not consistently affected by muscimol in either the pars compacta or the pars reticulata. The effects of GABA were bicuculline- and picrotoxin-insensitive. However, the inhibition by GABA of the [3H]GABA overflow was antagonized by phaclofen. It is concluded that (a) GABA autoreceptors are sited on GABAergic nerve endings in both the pars compacta and pars reticulata of the rat substantia nigra; (b) these autoreceptors belong to the GABAB type.
Topics: Animals; Anticonvulsants; Baclofen; Male; Muscimol; Nipecotic Acids; Potassium; Rats; Rats, Inbred Strains; Receptors, GABA-A; Substantia Nigra; Synaptosomes; Tritium; gamma-Aminobutyric Acid
PubMed: 2155793
DOI: 10.1016/0014-2999(90)90224-t -
The British Journal of Radiology Jul 2022Parkinson's disease is a neurodegenerative disorder caused by neuronal cell loss in the substantia nigra pars compacta (SNpc). We aimed to perform atlas-based...
OBJECTIVE
Parkinson's disease is a neurodegenerative disorder caused by neuronal cell loss in the substantia nigra pars compacta (SNpc). We aimed to perform atlas-based relaxometry using an anatomical SNpc atlas and obtain baseline values of SNpc regions in healthy volunteers.
METHODS
Neuromelanin (NM)-sensitive imaging of the midbrain and whole-brain 3D weighted images of 27 healthy volunteers (20 males; aged 36.3 ± 11.5 years) were obtained. An anatomical SNpc atlas was created using NM-sensitive images in standard space, and divided into medial (MG), dorsal (DG), and ventrolateral (VG) groups. Proton density (PD), T, and T values in these regions were obtained using quantitative MRI. The relationships between PD, T, and T values in each SNpc region and age were evaluated.
RESULTS
The VG PD value was significantly higher than the MG and DG values. MG, DG, and VG T values were significantly different, whereas the T value of the MG was significantly lower than the DG and VG values. Moreover, a significant negative correlation between PD and T values of the MG and age was observed.
CONCLUSION
The PD, T, and T values of the SNpc regions measured in standard space using an anatomical atlas can be used as baseline values. PD and T values of the SNpc regions may be associated with NM concentrations.
ADVANCES IN KNOWLEDGE
An anatomical SNpc atlas was created using NM-sensitive MRI and can be used for the quantitative evaluation of subsegments of the SNpc in standard space.
Topics: Healthy Volunteers; Humans; Magnetic Resonance Imaging; Male; Parkinson Disease; Pars Compacta; Protons; Substantia Nigra
PubMed: 35357890
DOI: 10.1259/bjr.20210572 -
Anatomical Science International Sep 2023Midbrain dopaminergic (DAergic) regions including ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are involved in diverse brain functions. Previous...
Midbrain dopaminergic (DAergic) regions including ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) are involved in diverse brain functions. Previous studies demonstrated that the VTA/SNc to nucleus accumbens (NAc) pathway is critical in reward and motivation. Moreover, DAergic innervations within the insular cortex (IC) are reported to play important roles in pain regulation. To investigate whether VTA/SNc sends collateral projections to NAc and IC, we injected retrograde tracer Fluoro-Gold (FG) into the NAc and Fluorescent retrograde tracer beads (RetroBeads) into the ipsilateral IC in rats. Then, to detect whether collateral projection neurons participate in neuropathic pain, parts of the rats received the spare nerve injury (SNI) surgery. The immunofluorescence staining results showed that FG, RetroBeads, and FG/RetroBeads double-labeled neurons were distributed in the VTA/SNc bilaterally with an ipsilateral predominance. The proportion of FG/RetroBeads double-labeled neurons to the total number of FG and RetroBeads-labeled neurons was 16.7% and 30.3%, respectively. About 90.3% of FG/RetroBeads double-labeled neurons showed DAergic neuron marker tyrosine hydroxylase (TH)-immunoreactive (IR), whereas, only 7.5% exhibited a subset of GABAergic inhibitory projection neuron marker parvalbumin (PV)-IR. One week after SNI, about 53.1% and 33.6% of FG- and RetroBeads-labeled neurons were FG/Fos- and RetroBeads/Fos-IR neurons, respectively. Finally, about 35.9% of the FG/RetroBeads double-labeled neurons showed Fos-IR. The present study indicates that parts of DAergic and PV-IR GABAergic neurons in the VTA/SNc send collateral projections to both NAc and IC, which are activated under SNI-induced neuropathic pain, and probably contribute to the regulation of nociception.
Topics: Rats; Animals; Ventral Tegmental Area; Nucleus Accumbens; Pars Compacta; Insular Cortex; Substantia Nigra; Dopamine; Neuralgia; Tyrosine 3-Monooxygenase
PubMed: 37160827
DOI: 10.1007/s12565-023-00728-4 -
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 -
NeuroImage. Clinical 2020To date there are no validated MRI biomarkers to assist diagnosis of Parkinson's disease (PD). Our aim was to investigate PD related iron changes in the substantia nigra...
BACKGROUND
To date there are no validated MRI biomarkers to assist diagnosis of Parkinson's disease (PD). Our aim was to investigate PD related iron changes in the substantia nigra pars compacta (SNpc) as defined by neuromelanin-sensitive MR contrast.
METHODS
Thirty-nine PD participants and 33 healthy controls were scanned at 3.0-T using a 16-echo gradient echo sequence to create R* maps for the evaluation of iron content to find the overlap with a neuromelanin based SNpc mask. The SNpc overlap percentage with the R* map, and the R* values in both the whole SNpc and the overlap volume were compared between PD and control groups, and correlated with clinical features for PD participants. Finally, the diagnostic performance of the SNpc overlap percentage was evaluated using ROC analysis.
RESULTS
PD related iron changes mostly occur in the lateral-ventral part of the neuromelanin SNpc. The R* values in the whole SNpc and the SNpc overlap volume, and the SNpc overlap percentage were larger in PD participants than in controls. Furthermore, the SNpc overlap percentage was positively correlated with the disease duration in PD. The SNpc overlap percentage provided excellent diagnostic accuracy for discriminating PD participants from controls (AUC = 0.93), while the R* values in the whole SNpc or the overlap volume were less effective.
CONCLUSION
The overlap between the iron content as determined by R* mapping and neuromelanin in the substantia nigra pars compacta has the potential to be a neuroimaging biomarker for diagnosing Parkinson's disease.
Topics: Biomarkers; Humans; Iron; Magnetic Resonance Imaging; Neuroimaging; Parkinson Disease; Pars Compacta; Substantia Nigra
PubMed: 32889398
DOI: 10.1016/j.nicl.2020.102391 -
Biological Trace Element Research Mar 2024Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in...
Therapeutic Effects of Selenium on Alpha-Synuclein Accumulation in Substantia Nigra Pars Compacta in a Rat Model of Parkinson's Disease: Behavioral and Biochemical Outcomes.
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 μg 6-OHDA/5 μl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.
Topics: Rats; Male; Animals; Parkinson Disease; alpha-Synuclein; Pars Compacta; Selenium; Apomorphine; Oxidopamine; Rats, Wistar; Selenoproteins; Disease Models, Animal
PubMed: 37386228
DOI: 10.1007/s12011-023-03748-3