Dopamine Neuron Challenge Test for early detection of Parkinson's disease.
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ABSTRACT:
SUBMITTER: Zhou J
PROVIDER: S-EPMC8677804 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We used positron emission tomography (PET) to measure the earliest change in dopaminergic synapses and glial cell markers in a chronic, low-dose MPTP non-human primate model of Parkinson's disease (PD). In vivo levels of dopamine transporters (DAT), vesicular monoamine transporter-type 2 (VMAT2), amphetamine-induced dopamine release (AMPH-DAR), D2-dopamine receptors (D2R) and translocator protein 18 kDa (TSPO) were measured longitudinally in the striatum of MPTP-treated animals. We report an early (2 months) decrease (46%) of striatal VMAT2 in asymptomatic MPTP animals that preceded changes in DAT, D2R, and AMPH-DAR and was associated with increased TSPO levels indicative of a glial response. Subsequent PET studies showed progressive loss of all pre-synaptic dopamine markers in the striatum with expression of parkinsonism. However, glial cell activation did not track disease progression. These findings indicate that decreased VMAT2 is a key pathogenic event that precedes nigrostriatal dopamine neuron degeneration. The loss of VMAT2 may result from an association with alpha-synuclein aggregation induced by oxidative stress. Disruption of dopamine sequestration by reducing VMAT2 is an early pathogenic event in the dopamine neuron degeneration that occurs in the MPTP non-human primate model of PD. Genetic or environmental factors that decrease VMAT2 function may be important determinants of PD.
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Project description:Autologous dopamine (DA) neurons are a new cell source for replacement therapy of Parkinson's disease (PD). In this study, we tested the safety and efficacy of autologous induced pluripotent stem cell (iPSC)-derived DA cells for treatment of a cynomolgus monkey PD model. Monkey bone marrow mesenchymal cells were isolated and induced to iPSCs, followed by differentiation into DA cells using a method with high efficiency. Autologous DA cells were introduced into the brain of a cynomolgus monkey PD model without immunosuppression; three PD monkeys that had received no grafts served as controls. The PD monkey that had received autologous grafts experienced behavioral improvement compared with that of controls. Histological analysis revealed no overgrowth of grafts and a significant number of surviving A9 region-specific graft-derived DA neurons. The study provided a proof-of-principle to employ iPSC-derived autologous DA cells for PD treatment using a nonhuman primate PD model.
| S-EPMC4860772 | biostudies-literature
Project description:Parkinson's disease (PD) is characterized by the selective loss of dopamine (DA) neurons in the substantia nigra compacta (SNc). The transcription factor Pitx3 is important for the differentiation and maintenance of midbrain DA neurons during development. There is highly restricted and constitutive expression of Pitx3 in the SNc and ventral tegmental area (VTA) of the midbrain after birth. In addition to its importance during development, Pitx3 also has roles in the long-term survival and maintenance of the midbrain DA neurons. In this review, we discuss the function of Pitx3 throughout the life of midbrain neurons and the contribution of Pitx3 to disease mechanisms.
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Project description:AimOxidative stress has long been considered as a major contributing factor in the pathogenesis of Parkinson's disease. However, molecular sources for reactive oxygen species in Parkinson's disease have not been clearly elucidated. Herein, we sought to investigate whether a superoxide-producing NADPH oxidases (NOXs) are implicated in oxidative stress-mediated dopaminergic neuronal degeneration.ResultsExpression of various Nox isoforms and cytoplasmic components were investigated in N27, rat dopaminergic cells. While most of Nox isoforms were constitutively expressed, Nox1 expression was significantly increased after treatment with 6-hydroxydopamine. Rac1, a key regulator in the Nox1 system, was also activated. Striatal injection of 6-hydroxydopamine increased Nox1 expression in dopaminergic neurons in the rat substantia nigra. Interestingly, it was localized into the nucleus, and immunostaining for DNA oxidative stress marker, 8-oxo-dG, was increased. Nox1 expression was also found in the nucleus of dopaminergic neurons in the substantia nigra of Parkinson's disease patients. Adeno-associated virus-mediated Nox1 knockdown or Rac1 inhibition reduced 6-hydroxydopamine-induced oxidative DNA damage and dopaminergic neuronal degeneration significantly.InnovationNox1/Rac1 could serve as a potential therapeutic target for Parkinson's disease.ConclusionWe provide evidence that dopaminergic neurons are equipped with the Nox1/Rac1 superoxide-generating system. Stress-induced Nox1/Rac1 activation causes oxidative DNA damage and neurodegeneration. Reduced dopaminergic neuronal death achieved by targeting Nox1/Rac1, emphasizes the impact of oxidative stress caused by this system on the pathogenesis and therapy in Parkinson's disease.
| S-EPMC3315177 | biostudies-literature
Project description:BackgroundThe neurophysiological correlates of gastrointestinal symptoms (GISs) in Parkinson's disease (PD) are not well understood. It has been proposed that in patients with a gastrointestinal origin of PD dopaminergic neurodegeneration would be more symmetric.ObjectivesThe aim is to assess the associations between GISs and asymmetry of nigrostriatal dopaminergic neurodegeneration in PD.MethodsNinety PD patients were assessed using motor and GIS scales and 123 I-FP-CIT SPECT. We calculated the asymmetry index and the predominant side of motor symptoms and dopamine transporter (DAT) imaging defect and assessed their association with GISs.ResultsThere were no significant differences in GISs between symmetric and asymmetric dopaminergic defect. Left predominant defect was related to more GIS and higher constipation scores.ConclusionsGISs were associated with left predominant reduction in putaminal DAT binding but not asymmetry per se. It remains open whether left-sided DAT deficit is related to more pronounced GI involvement or symptom perception in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
| S-EPMC9314058 | biostudies-literature
Project description:: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson's disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1?) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1? anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1? pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P ?-synuclein (?-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.
| S-EPMC6721683 | biostudies-literature
Project description:A primary cilium is an antenna-like structure on the cell surface that plays a crucial role in sensory perception and signal transduction. Mitochondria, the 'powerhouse' of the cell, control cell survival, and death. The cellular ability to remove dysfunctional mitochondria through mitophagy is important for cell survival. We show here that mitochondrial stress, caused by respiratory complex inhibitors and excessive fission, robustly stimulates ciliogenesis in different types of cells including neuronal cells. Mitochondrial stress-induced ciliogenesis is mediated by mitochondrial reactive oxygen species generation, subsequent activation of AMP-activated protein kinase and autophagy. Conversely, abrogation of ciliogenesis compromises mitochondrial stress-induced autophagy, leading to enhanced cell death. In mice, treatment with mitochondrial toxin, MPTP elicits ciliary elongation and autophagy in the substantia nigra dopamine neurons. Blockade of cilia formation in these neurons attenuates MPTP-induced autophagy but facilitates dopamine neuronal loss and motor disability. Our findings demonstrate the important role of primary cilia in cellular pro-survival responses during mitochondrial stress.
| S-EPMC6915731 | biostudies-literature
Project description:ABSTRACT Background Neuropathological studies, based on small samples, suggest that symptoms of Parkinson's disease (PD) emerge when dopamine/nigrostriatal loss is around 50–80%. Functional neuroimaging can be applied in larger numbers during life, which allows analysis of the extent of dopamine loss more directly. Objective To quantify dopamine transporter (DaT) activity by neuroimaging in early PD. Methods Systematic review and novel analysis of DaT imaging studies in early PD. Results In our systematic review, in 423 unique cases from 27 studies with disease duration of less than 6 years, mean age 58.0 (SD 11.5) years, and mean disease duration 1.8 (SD 1.2) years, striatal loss was 43.5% (95% CI 41.6, 45.4) contralaterally, and 36.0% (95% CI 33.6, 38.3) ipsilaterally. For unilateral PD, in 436 unique cases, mean age 57.5 (SD 10.2) years, and mean disease duration 1.8 (SD 1.4) years, striatal loss was 40.6% (95% CI 38.8, 42.4) contralaterally, and 31.6% (95% CI 29.4, 33.8) ipsilaterally. In our novel analysis of the Parkinson's Progressive Marker Initiative study, 413 cases had 1436 scans performed. For a disease duration of less than 1 year, age was 61.8 (SD 9.8) years, and striatal loss was 51.2% (95% CI 49.1, 53.3) contralaterally and 39.5% (36.9, 42.1) ipsilaterally, giving an overall striatal loss of 45.3% (43.0, 47.6). Conclusions Loss of striatal DaT activity in early PD is less at 35–45%, rather than the 50–80% striatal dopamine loss estimated to be present at the time of symptom onset, based on backwards extrapolation from autopsy studies.
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Project description:Objective: Levodopa up-titration is the primary therapeutic strategy as the Parkinson's disease (PD) progresses. However, the effects of levodopa up-titration on blood pressure (BP) are inconclusive. This study aimed to investigate the effect of acute levodopa up-titration simulated by levodopa challenge test (LCT) on BP in patients with early stage PD. Methods: We monitored BP in 52 patients with early stage PD using a standardized standing test. BP was assessed in supine position after 10 min of rest and at 1 and 3 min after standing up. BP was measured in the "off-state" and the best "on-state" during LCT in the morning at hospital. In another day, "off-state" and the best "on-state" BP was measured before and after anti-PD drug uptake in the morning at home. Demographic and clinical features of the patients were evaluated and analyzed. Results: In the LCT, the prevalence of OH in the "off-state" and the best "on-state" was 11.5 and 13.5%, respectively. Additionally, the OH in the best "on-state" was associated with OH in the "off-state" and monoamine oxidase B inhibitor use. Although 38 (73.1%) patients experienced levodopa-induced hypotension during the LCT, no risk factors were identified. While BP reductions were observed after taking anti-PD drugs at home, no further reduction was seen during acute levodopa up-titration simulated by the LCT. Conclusion: Our results demonstrate that acute levodopa up-titration does not exacerbate BP reduction induced by anti-PD drugs at home. BP monitoring is critical for the management of patients with PD.
| S-EPMC8761988 | biostudies-literature
Project description:BackgroundNon-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored.MethodsWe evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models.ResultsMultiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: ?AVG = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (?AVG=0.055, SE = 0.022; p = 0.01) and visuospatial (?AVG=0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (?AVG= -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding.ConclusionsMultiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD.
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