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Jain, Samay, Seo-Young Park, and Diane Comer. "Patterns of Motor and Non-Motor Features in Medication-Naïve Parkinsonism." Neuroepidemiology 45, no. 1 (2015): 59–69. http://dx.doi.org/10.1159/000437228.
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Background: Parkinsonism is defined by motor features (tremor, bradykinesia, rigidity, and postural instability). Accompanying non-motor features (e.g. cognitive, autonomic, sleep disturbances) are underrecognized and undertreated. We hypothesized that clinical patterns occurring in early, medication-naïve Parkinsonism are distinguished by features such as tremor, sleep, autonomic, and cognitive dysfunction. Methods: Clinical and neuroimaging data were obtained in the Parkinson's Progression Marker Initiative. Group comparisons of Parkinsonism with dopaminergic deficits (PDD) (n = 388), controls (n = 196), and Parkinsonism with scans without evidence of dopaminergic deficits (n = 64) were done with ANOVA, chi-square, and post-hoc pairwise tests. To examine clinical patterns within the PDD group, k-means clustering was performed with non-motor or motor features, or both. Results: Among PDD, 4 non-motor patterns (% of PDD) (impulsive (14.9%), sleep-autonomic (22.9%), cognitive-olfactory (18.0%), and mild (44.1%)), 4 motor patterns (tremor plus bradykinesia (56.2%), tremor without bradykinesia (16.2%), postural instability (6.7%) and no tremor (20.9%)) and 5 combined motor/non-motor patterns (tremor with bradykinesia (42.3%), tremor without bradykinesia (15.5%), no tremor and mild non-motor features (17.0%), postural instability with sleep-autonomic disturbances (6.7%) and oldest onset cognitive-olfactory (18.6%)) were observed. Conclusions: To our knowledge, this is the first description of non-motor clinical patterns in early, medication-naïve Parkinsonism, suggesting that such features are intrinsic to Parkinsonian disorders.
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Fujimoto, S., N. Yanagisawa, and R. Tanaka. "Voluntary motor control in Parkinsonism." Electroencephalography and Clinical Neurophysiology 61, no. 3 (September 1985): S219. http://dx.doi.org/10.1016/0013-4694(85)90830-2.
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Ma, Yilong, Shichun Peng, Phoebe G. Spetsieris, Vesna Sossi, David Eidelberg, and Doris J. Doudet. "Abnormal Metabolic Brain Networks in a Nonhuman Primate Model of Parkinsonism." Journal of Cerebral Blood Flow & Metabolism 32, no. 4 (November 30, 2011): 633–42. http://dx.doi.org/10.1038/jcbfm.2011.166.
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Parkinson's disease (PD) is associated with a characteristic regional metabolic covariance pattern that is modulated by treatment. To determine whether a homologous metabolic pattern is also present in nonhuman primate models of parkinsonism, 11 adult macaque monkeys with parkinsonism secondary to chronic systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 12 age-matched healthy animals were scanned with [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET). A subgroup comprising five parkinsonian and six control animals was used to identify a parkinsonism-related pattern (PRP). For validation, analogous topographies were derived from other subsets of parkinsonian and control animals. The PRP topography was characterized by metabolic increases in putamen/pallidum, thalamus, pons, and sensorimotor cortex, as well as reductions in the posterior parietal-occipital region. Pattern expression was significantly elevated in parkinsonian relative to healthy animals ( P < 0.00001). Parkinsonism-related topographies identified in the other derivation sets were very similar, with significant pairwise correlations of region weights ( r > 0.88; P < 0.0001) and subject scores ( r > 0.74; P < 0.01). Moreover, pattern expression in parkinsonian animals correlated with motor ratings ( r > 0.71; P < 0.05). Thus, homologous parkinsonism-related metabolic networks are demonstrable in PD patients and in monkeys with experimental parkinsonism. Network quantification may provide a useful biomarker for the evaluation of new therapeutic agents in preclinical models of PD.
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Hendrix, Claudia M., Brett A. Campbell, Benjamin J. Tittle, Luke A. Johnson, Kenneth B. Baker, Matthew D. Johnson, Gregory F. Molnar, and Jerrold L. Vitek. "Predictive encoding of motor behavior in the supplementary motor area is disrupted in parkinsonism." Journal of Neurophysiology 120, no. 3 (September 1, 2018): 1247–55. http://dx.doi.org/10.1152/jn.00306.2018.
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Many studies suggest that Parkinson’s disease (PD) is associated with changes in neuronal activity patterns throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts the presupplementary motor area (pre-SMA) and SMA proper (SMAp), cortical areas known to be involved in movement planning and motor control. In this study, local field potentials (LFPs) were recorded in the pre-SMA/SMAp of a nonhuman primate during a visually cued reaching task. Recordings were made in the same subject in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinsonism. We found that in the naive animal, well before a go-cue providing instruction of reach onset and direction was given, LFP activity was dynamically modulated in both high (20–30 Hz) and low beta (10–20 Hz) bands, and the magnitude of this modulation (e.g., decrease/increase in beta amplitude for each band, respectively) correlated linearly with reaction time (RT) on a trial-to-trial basis, suggesting it may predictively encode for RT. Consistent with this hypothesis, we observed that this activity was more prominent within the pre-SMA compared with SMAp. In the parkinsonian state, however, pre-SMA/SMAp beta band modulation was disrupted, particularly in the high beta band, such that the predictive encoding of RT was significantly diminished. In addition, the predictive encoding of RT preferentially within pre-SMA over SMAp was lost. These findings add to our understanding of the role of pre-SMA/SMAp in motor behavior and suggest a fundamental role of these cortical areas in early preparatory and premovement processes that are altered in parkinsonism. NEW & NOTEWORTHY Goal-directed movements, such as reaching for an object, necessitate temporal preparation and organization of information processing within the basal ganglia-thalamocortical motor network. Impaired movement in parkinsonism is thought to be the result of pathophysiological activity disrupting information flow within this network. This work provides neurophysiological evidence linking altered motor preplanning processes encoded in pre-SMA/SMAp beta band modulation to the pathogenesis of motor disturbances in parkinsonism.
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Villalba, Rosa M., Joseph A. Behnke, Jean-Francois Pare, and Yoland Smith. "Comparative Ultrastructural Analysis of Thalamocortical Innervation of the Primary Motor Cortex and Supplementary Motor Area in Control and MPTP-Treated Parkinsonian Monkeys." Cerebral Cortex 31, no. 7 (March 2, 2021): 3408–25. http://dx.doi.org/10.1093/cercor/bhab020.
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Abstract The synaptic organization of thalamic inputs to motor cortices remains poorly understood in primates. Thus, we compared the regional and synaptic connections of vGluT2-positive thalamocortical glutamatergic terminals in the supplementary motor area (SMA) and the primary motor cortex (M1) between control and MPTP-treated parkinsonian monkeys. In controls, vGluT2-containing fibers and terminal-like profiles invaded layer II–III and Vb of M1 and SMA. A significant reduction of vGluT2 labeling was found in layer Vb, but not in layer II–III, of parkinsonian animals, suggesting a potential thalamic denervation of deep cortical layers in parkinsonism. There was a significant difference in the pattern of synaptic connectivity in layers II–III, but not in layer Vb, between M1 and SMA of control monkeys. However, this difference was abolished in parkinsonian animals. No major difference was found in the proportion of perforated versus macular post-synaptic densities at thalamocortical synapses between control and parkinsonian monkeys in both cortical regions, except for a slight increase in the prevalence of perforated axo-dendritic synapses in the SMA of parkinsonian monkeys. Our findings suggest that disruption of the thalamic innervation of M1 and SMA may underlie pathophysiological changes of the motor thalamocortical loop in the state of parkinsonism.
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Contreras-Vidal, JoséL, and George E. Stelmach. "Effects of parkinsonism on motor control." Life Sciences 58, no. 3 (December 1995): 165–76. http://dx.doi.org/10.1016/0024-3205(95)02237-6.
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Boika, A. V., N. Y. Aleinikava, V. V. Ponomarev, A. M. Ustsiamchuk, and H. I. Ivanchik. "PARKINSONISM SYNDROME FORMATION IN EXPERIMENTAL ANIMALS. NEUROINFLAMMATORY PENUMBRA." Vestnik of Vitebsk State Medical University 20, no. 4 (August 17, 2021): 53–60. http://dx.doi.org/10.22263/2312-4156.2021.4.53.
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Much valuable information about the development of Parkinson’s disease (PD) has been obtained from studies on the laboratory animals. Objectives. To compare the development of neurotoxic and neuroinflammatory parkinsonism syndrome in laboratory animals. Material and methods. The number of rats in the group of neuroinflammatory model of parkinsonism syndrome (lipopolysaccharide) was 6, and in the group of neurotoxic model (rotenone) - 20. The control group consisted of 5 animals. The study was approved by the independent Ethics Committee. The development dynamics of parkinsonism syndrome of neurotoxic and neuroinflammatory genesis was assessed in the study of the motor activity of animals, as well as in the laboratory study of biomarkers of dopamine metabolism (dopamine and homovanillic acid) in blood serum and cerebrospinal fluid obtained in 7 and 21 days after the first administration of rotenone or lipopolysaccharide, and also after a single intravenous injection of allogeneic (rat) multipotent mesenchymal stromal cells (MMSC) carried out after 9 injections of rotenone. Results. A decrease in the levels of dopamine and homovanillic acid has been shown in laboratory animals on the development of Parkinson’s syndrome. In rats with a neuroinflammatory model of parkinsonism syndrome, a pre-motor stage of motor disorders development has been laboratorially confirmed. During the first weeks after the introduction of MMSC, regression of the motor symptoms of neurotoxic parkinsonism syndrome and a parallel increase in dopamine and homovanillic acid are determined. Conclusions. The effectiveness of MMSC in the early post-transplantation period is associated with the paracrine effect. It is proposed to call activated microglia, a potential therapeutic target in PD, neuroinflammatory penumbra.
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Yanbing, Ding, Huang Lixia, Chen Jun, Hu Song, Yuan Fahu, and Tu Jinwen. "Corilagin attenuates the Parkinsonismin Japanese encephalitis virus induced Parkinsonism." Translational Neuroscience 9, no. 1 (July 18, 2018): 13–16. http://dx.doi.org/10.1515/tnsci-2018-0003.
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AbstractThis study evaluates the protective effect of corilagin against Parkinsonismin Japanese encephalitis virus (JEV) induced Parkinson’s disease. The JaGAr-01 strain of virus was used to induce JE. The virus was injected into the rats (13 days age) at the midpoint between the two ears. Adult rats, 12 week after the inoculation of virus, were used for the further study. Corilagin (20 mg/kg) and levodopa with dopa decarboxylase inhibitor (LEV, 10 mg/kg) were administered intraperitoneally for the duration of one week. Bradykinesia and the levels of dopamine in the brain were estimated at the end of protocol. There was a significant decrease inthe motor function in the corilagin, LEV and LEV + corilagin treated groupscompared to the negative control group. However treatment with corilagin, LEV and LEV + corilagin significantly increases the level of dopamine in the brain compared to the negative control group. This study concludes that corilagin ameliorates the Parkinsonismin JEV induced Parkinsonism. Moreover it shows a synergistic effect when treated with LEV. Data presented in the investigation supports that corilagin can be used clinically.
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Benazzouz, A., B. Piallat, Z. G. Ni, A. Koudsie, P. Pollak, and A. L. Benabid. "Implication of the Subthalamic Nucleus in the Pathophysiology and Pathogenesis of Parkinson's Disease." Cell Transplantation 9, no. 2 (March 2000): 215–21. http://dx.doi.org/10.1177/096368970000900207.
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The subthalamic nucleus (STN) has been shown to play an important role in the control of movement and has been considered as a key structure in the functional organization of the basal ganglia. Several studies postulated that the STN plays a critical role in the pathophysiology of Parkinson's disease and that its inhibition or its lesioning can reverse the cardinal motor symptoms. Nevertheless, the beneficial effect was accompanied by dyskinetic abnormal movements. In order to avoid unpleasant and irreversible side effects we used high-frequency stimulation (HFS) of the STN instead of lesions. We have shown that parkinsonian motor symptoms, akinesia, rigidity, and tremor can be alleviated by HFS of the STN in the nonhuman primate model. Side effects were controllable and appeared only at intensities higher than that inducing the improvement of motor symptoms. In severe parkinsonian patients, bilateral STN-HFS greatly improved parkinsonian motor symptoms. Motor fluctuations were attenuated and patients became independent in most activities of daily living. It appears that STN-HFS mimics the effects of lesions by inhibiting its neuronal activity. In a rat model of parkinsonism, we studied the implication of the STN in the excitotoxicity of nigral dopamine cells. We showed that kainic acid lesioning of the STN can protect nigral dopaminergic cells against 6-hydroxydopamine-induced toxicity. The evidence reviewed in the present article clearly demonstrates that the STN is implicated in the pathophysiology and pathogenesis of Parkinson's disease.
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Darbin, Olivier, Xingxing Jin, Christof Von Wrangel, Kerstin Schwabe, Atsushi Nambu, Dean K. Naritoku, Joachim K. Krauss, and Mesbah Alam. "Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson’s Disease." International Journal of Neural Systems 26, no. 02 (February 21, 2016): 1550038. http://dx.doi.org/10.1142/s0129065715500380.
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The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25[Formula: see text]Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25[Formula: see text]Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.
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Zhong, Hui, Chunni Zhu, Yoshihiko Minegishi, Franziska Richter, Sharon Zdunowski, Roland R. Roy, Bryce Vissel, et al. "Epidural Spinal Cord Stimulation Improves Motor Function in Rats With Chemically Induced Parkinsonism." Neurorehabilitation and Neural Repair 33, no. 12 (November 5, 2019): 1029–39. http://dx.doi.org/10.1177/1545968319876891.
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Background. Epidural stimulation of the spinal cord can reorganize and change the excitability of the neural circuitry to facilitate stepping in rats with a complete spinal cord injury. Parkinson’s disease results in abnormal supraspinal signals from the brain to the spinal cord that affect the functional capacity of the spinal networks. Objective. The objective was to determine whether epidural stimulation (electrical enabling motor control, eEmc) of the lumbosacral spinal cord can reorganize the spinal networks to facilitate hindlimb stepping of rats with parkinsonism. Methods. A unilateral 6-OHDA (6-hydroxydopamine) lesion of the nigrostriatal pathway was used to induce parkinsonism. Sham rats (N = 4) were injected in the same region with 0.1% of ascorbic acid. Stimulation electrodes were implanted epidurally at the L2 and S1 (N = 5) or L2 (N = 5) spinal levels. Results. The 6-OHDA rats showed severe parkinsonism in cylinder and adjusting step tests and were unable to initiate stepping when placed in a running wheel and dragged their toes on the affected side during treadmill stepping. During eEmc, the 6-OHDA rats initiated stepping in the running wheel and demonstrated improved stepping quality. Conclusion. Stepping was facilitated in rats with parkinsonism with spinal cord stimulation. The underlying assumption is that the normal functional capacity of spinal networks is affected by supraspinal pathology associated with Parkinson’s disease, which either generates insufficient or abnormal descending input to spinal networks and that eEmc can appropriately modulate spinal and supraspinal networks to improve the motor deficits.
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Fereshtehnejad, Seyed-Mohammad, Chun Yao, Amelie Pelletier, Jacques Y. Montplaisir, Jean-François Gagnon, and Ronald B. Postuma. "Evolution of prodromal Parkinson’s disease and dementia with Lewy bodies: a prospective study." Brain 142, no. 7 (May 20, 2019): 2051–67. http://dx.doi.org/10.1093/brain/awz111.
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Abstract Parkinson’s disease has a long prodromal stage with various subclinical motor and non-motor manifestations; however, their evolution in the years before Parkinson’s disease is diagnosed is unclear. We traced the evolution of early motor and non-motor manifestations of synucleinopathy from the stage of idiopathic rapid eye movement (REM) sleep behaviour disorder until defined neurodegenerative disease. During 2004–16, we recruited and then annually followed 154 polysomnography-proven patients with idiopathic REM sleep behaviour disorder, of whom 55 phenoconverted to defined parkinsonism or dementia. Longitudinal data on multiple prodromal features, including the Unified Parkinson’s Disease Rating Scale parts I–III, quantitative motor tests, olfaction, colour vision, cognition, and autonomic functions were gathered annually (average = five follow-up visits, range: 2–12 years). The same measures were also assessed in 102 age- and sex-matched healthy control subjects. By looking backward from the time of dementia or parkinsonism diagnosis, we examined trajectories of each prodromal feature using mixed effect models. Based on analysis, olfactory loss was first to develop, with predicted onset >20 years before phenoconversion. This was followed by impaired colour vision, constipation, and erectile dysfunction, starting 10–16 years prior to phenoconversion. At 7–9 years before phenoconversion, slight urinary dysfunction and subtle cognitive decline could be detected. Among motor symptoms altered handwriting, turning in bed, walking, salivation, speech, and facial expression began to be disrupted starting 7–11 years prior to parkinsonism diagnosis, but remained mild until soon before phenoconversion. Motor examination abnormalities began 5–7 years before phenoconversion, with the alternate tap test having the longest interval (8 years before phenoconversion). Among cardinal motor phenotypes, bradykinesia appeared first, ∼5–6 years prior to phenoconversion, followed by rigidity (Year −3) and tremor (Year −2). With direct prospective evaluation of an idiopathic REM sleep behaviour disorder cohort during phenoconversion, we documented an evolution of prodromal manifestations similar to that predicted by pathological staging models, with predicted prodromal intervals as long as 20 years.
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FLEMINGER, S. "CONTROL OF SIMULTANEOUS MOVEMENTS DISTINGUISHES DEPRESSIVE MOTOR RETARDATION FROM PARKINSON'S DISEASE AND NEUROLEPTIC PARKINSONISM." Brain 115, no. 5 (1992): 1459–80. http://dx.doi.org/10.1093/brain/115.5.1459.
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Hughes, Katherine C., Xiang Gao, Jessica M. Baker, Christopher Stephen, Iris Y. Kim, Linda Valeri, Michael A. Schwarzschild, and Alberto Ascherio. "Non-motor features of Parkinson’s disease in a nested case–control study of US men." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 12 (August 3, 2018): 1288–95. http://dx.doi.org/10.1136/jnnp-2018-318275.
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BackgroundSeveral non-motor features may individually contribute to identify prodromal Parkinson’s disease (PD), but little is known on how they interact.MethodsWe conducted a case–control study nested within the Health Professionals Follow-up Study in a large cohort of men age 40–75 at recruitment in 1986. Cases (n=120) had confirmed PD, were<85 in January 2012, returned a 2012 questionnaire with questions on probable rapid eye movement sleep behaviour disorder (RBD) and constipation sent to all cohort participants and completed in 2014 the Brief Smell Identification Test and a questionnaire assessing parkinsonism and other non-motor PD features (including depressive symptoms, excessive daytime sleepiness, impaired colour vision and body pain). Controls (n=6479) met the same criteria as cases, except for the PD diagnosis.ResultsConcurrent constipation, probable RBD and hyposmia were present in 29.3% of cases and 1.1% of controls, yielding an age-adjusted OR of 160(95%CI 72.8to353) for three features versus none. The odds of PD increased exponentially with additional non-motor features (OR for 6–7 features versus none: 1325; 95%CI333to5279). Among men without PD, the number of non-motor features was associated with odds of parkinsonism (OR for 6–7 features versus none: 89; 95%CI21.2to375). We estimated that in a population with a prodromal PD prevalence of 2%, concurrent constipation, probable RBD and hyposmia would have a maximum sensitivity of 29% and a positive predictive value (PPV) of 35%. The PPV could increase up to 70% by including additional features, but with sharply decreased sensitivity.ConclusionsConcurrent constipation, probable RBD and hyposmia are strongly associated with PD. Because these features often precede motor symptoms and their co-occurrence could provide an efficient method for early PD identification.
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Cooper, Christine, Federico Rodriguez-Porcel, Travis Turner, Gonzalo Revuelta, Jens Jensen, Vanessa Hinson, and Leonardo Bonilha. "4302 Decreased structural basal ganglia motor loop connections in Vascular Parkinsonism compared to Parkinson’s disease and healthy aging." Journal of Clinical and Translational Science 4, s1 (June 2020): 94. http://dx.doi.org/10.1017/cts.2020.295.
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OBJECTIVES/GOALS: This study uses diffusion kurtosis imaging (DKI) to investigate the structural profiles of basal ganglia (BG) motor circuitry in Vascular Parkinsonism (VP), Parkinson’s disease (PD), and healthy aging controls (HC). VP is a clinical diagnosis of lower body predominant parkinsonism without significant benefit from levodopa. VP is distinct from PD, yet the concept of VP remains debated due to the inability of prior studies to identify specific causative changes. One reason for this may be limitations in measuring intricate BG connectivity in vivo. Given the predominant lower body parkinsonism symptoms in VP, we hypothesized that VP would be associated with decreased connectivity specifically within the BG motor loop. METHODS/STUDY POPULATION: We obtained DKI brain imaging in subjects with VP (N = 7), PD (N = 21), and HCs (N = 58), the latter of which had cardiovascular risk factors but no neurological symptoms. The VP and PD groups were evaluated by a parkinsonism-focused motor exam and brief cognitive testing. We compared BG motor loop connectivity between groups and investigated for correlation between connectivity and clinical scores. To account for differences in fiber counts due to the different imaging scanners and protocols between cohorts, we used a BG motor loop proportion, which was the ratio of the BG motor loop fiber count over a control loop, the visual processing pathway. We used Kruskal-Wallis rank sum test with post-hoc Dunn tests to assess imaging findings between subject groups, and Pearson’s correlation to look for correlation between clinical scores and fiber counts. RESULTS/ANTICIPATED RESULTS: The whole brain connectome showed the fewest number of fibers in VP, followed by PD, and then HC (p<0.0001). The BG motor loop proportion fiber count of the BG motor loop was lower in the VP group, compared to the PD and HC cohorts (p = 0.031). In the VP group, the whole brain connectome fiber count correlated with a gait and balance subscore of the Movement Disorders Society - Unified Parkinson Disease Rating Scale (R = −0.87, p = 0.01). DISCUSSION/SIGNIFICANCE OF IMPACT: This study indicates that VP is associated with decreased structural connectivity, with a disproportionate degree of loss in the BG motor circuitry. While the etiology for this susceptibility to injury and preferential damage to BG remains to be defined, these findings can provide an important starting point for a biological understanding of VP, and a potential future marker for diagnosis and tracking disease progression.
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Strafella, A., P. Ashby, A. Lozano, and A. E. Lang. "Pallidotomy Increases Cortical Inhibition in Parkinson's Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 24, no. 2 (May 1997): 133–36. http://dx.doi.org/10.1017/s0317167100021466.
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ABSTRACT:Background:Pallidotomy helps parkinsonian symptoms. We tested the hypothesis that this might be due to changes in inhibition in the motor cortex.Methods:We examined 15 patients with parkinsonism before and after posteroventral pallidotomy. Magnetic stimuli were delivered over the motor cortex, while subjects maintained a 30% maximum voluntary contraction of the contralateral first dorsal interosseus (FDI).Results:Weak stimuli inhibited voluntary muscle activity, while slightly stronger stimuli caused short latency facilitation from activation of the corticospinal neurons. After pallidotomy magnetic stimulation, at the threshold for the short latency facilitation, resulted in more inhibition than before.Conclusions:Pallidotomy increases cortical inhibition. This may be associated with improved control of movements.
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Nakai, Mitsukazu, Toru Itakura, Ichiro Kamei, Kunio Nakai, Yutaka Naka, Harumichi Imai, and Norihiko Komai. "Autologous transplantation of the superior cervical ganglion into the brain of parkinsonian monkeys." Journal of Neurosurgery 72, no. 1 (January 1990): 91–95. http://dx.doi.org/10.3171/jns.1990.72.1.0091.
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✓ The effect of autologous transplantation of the superior cervical ganglion (SCG) into the brain of parkinsonian monkeys was studied through quantitative measurement of animal behavior. The motor activity of the monkey was measured with a telemetry system during the experiment. After experimental parkinsonism was induced by repeated intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), three monkeys were treated with autologous transplantation of the SCG into both caudate nuclei. One monkey served as a control without SCG transplantation after MPTP treatment. Three SCG-transplanted monkeys showed biphasic (acute and chronic) behavioral amelioration of parkinsonism after transplantation. In the acute stage, the animals showed transient hyperkinesia with aggressive behavior and loss of circadian rhythm. In the chronic stage following acute hyperkinesia, the animals regained normal behavior and circadian rhythm without aggressiveness. In contrast with the transplanted monkeys, the control monkey failed to show recovery of the bradykinesia and muscle rigidity.
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Ammann, Claudia, Michele Dileone, Cristina Pagge, Valentina Catanzaro, David Mata-Marín, Frida Hernández-Fernández, Mariana H. G. Monje, et al. "Cortical disinhibition in Parkinson’s disease." Brain 143, no. 11 (November 2020): 3408–21. http://dx.doi.org/10.1093/brain/awaa274.
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Abstract In Parkinson’s disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson’s disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson’s disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson’s disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson’s Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson’s disease.
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Cuesta, M. J., A. M. Sánchez-Torres, T. Cabada, P. Lecumberri, R. Lorente-Omeñaca, J. M. López-Ilundain, M. Ribeiro, L. Moreno-Izco, and M. Gómez. "Parkinsonism and basal ganglia volumes in first-episode psychosis." European Psychiatry 33, S1 (March 2016): S87. http://dx.doi.org/10.1016/j.eurpsy.2016.01.046.
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IntroductionParkinsonian motor signs are the most frequent of the genuine motor abnormalities present in drug-naïve patients with schizophrenia, and are also present in patients with a first-episode of psychosis (FEP).ObjectiveTo study whether there are differences in basal ganglia volumes depending on the presence of Parkinsonism in FEP.MethodsForty-six patients with a FEP were included in the study. Twenty-three controls were included to normalise patients’ brain volume data. Parkinsonism was assessed with the UKU scale. Brain volumes were obtained with MRI (1.5 Tesla Siemens Avanto). Reconstruction and volumetric segmentation was made with the Freesurfer© software (http://surfer.nmr.mgh.harvard.edu/). Patients were divided into two groups, considering the presence/absence of Parkinsonism (UKU total score cutoff point = 4). Patients have been treated with antipsychotics a mean of less than 2 months. There were not significant differences in the total exposure to antipsychotics between both groups. ANCOVAS were performed including gender as covariate.ResultsPatients with Parkinsonism showed a trend towards significance to exhibit reduced volumes in the left caudate and right putamen (Fig. 1).ConclusionsFEP patients who exhibit Parkinsonian signs tend to show reduced left caudate and right putamen volumes in the early phases of psychotic illness, after correcting by gender.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Teulings, Hans-Leo, José L. Contreras-Vidal, George E. Stelmach, and Charles H. Adler. "Parkinsonism Reduces Coordination of Fingers, Wrist, and Arm in Fine Motor Control." Experimental Neurology 146, no. 1 (July 1997): 159–70. http://dx.doi.org/10.1006/exnr.1997.6507.
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Ameen, Angie M., Amany Y. Elkazaz, Hala M. F. Mohammad, and Bassant M. Barakat. "Anti-inflammatory and neuroprotective activity of boswellic acids in rotenone parkinsonian rats." Canadian Journal of Physiology and Pharmacology 95, no. 7 (July 2017): 819–29. http://dx.doi.org/10.1139/cjpp-2016-0158.
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There is evidence that inflammation and oxidative stress contribute to the neurodegenerative changes observed in Parkinson’s disease. Unfortunately, there is a lack of curative treatment for this debilitating movement disorder. Boswellic acids (BAs) are pentacyclic triterpene molecules of plant origin that have been utilized for treating many inflammatory conditions. The current study was conducted to explore the protective role of BAs against rotenone-induced experimental parkinsonism. Twenty-four rats were assigned to one of four treatment groups. The first two groups were a vehicle group (no rotenone) and a rotenone control group in which rats received rotenone (1 mg/kg) every 48 h. The next 2 groups received rotenone (1 mg/kg every 48 h) plus protective oral doses of BAs (125 or 250 mg/kg daily). Rats in the rotenone group showed motor dysfunction when tested in the open-field arena and cylinder and rotarod tests. Moreover, inflammatory markers increased, whereas the dopamine level was lower in the striata of rats in the rotenone group versus those in the vehicle group. BAs taken by rats with rotenone-induced parkinsonism showed enhanced general motor performance, reduced inflammatory markers, and increased striatal dopamine level and nigral tyrosine hydroxylase immunostaining. In conclusion, BAs are promising agents in slowing the progression of Parkinson’s disease if appropriate data become available about their safety and efficacy in humans.
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Sanders, Teresa H. "Phase-amplitude coupling, an indication of bursting in parkinsonism, is masked by periodic pulses." Journal of Neurophysiology 115, no. 3 (March 1, 2016): 1587–95. http://dx.doi.org/10.1152/jn.00801.2015.
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Interactions between neural oscillations in the brain have been observed in many structures including the hippocampus, amygdala, motor cortex, and basal ganglia. In this study, one popular approach for quantifying oscillation interactions was considered: phase-amplitude coupling. The goals of the study were to use simulations to examine potential causes of elevated phase-amplitude coupling in parkinsonism, to compare simulated parkinsonian signals with recorded local field potentials from animal models of parkinsonism, to investigate possible relationships between increased bursting in parkinsonian single cells and elevated phase-amplitude coupling, and to uncover potential noise and artifact effects. First, a cell model that integrates incremental input currents and fires at realistic voltage thresholds was modified to allow control of stochastic parameters related to firing and burst rates. Next, the input currents and distribution of integration times were set to reproduce firing patterns consistent with those from parkinsonian subthalamic nucleus cells. Then, local field potentials were synthesized from the output of multiple simulated cells with varying degrees of synchronization and compared with subthalamic nucleus recordings from animal models of parkinsonism. The results showed that phase-amplitude coupling can provide important information about underlying neural activity. In particular, signals synthesized from synchronized bursting neurons showed increased oscillatory interactions similar to those observed in parkinsonian animals. Additionally, changes in bursting parameters such as the intraburst rate, the mean interburst period, and the amount of synchronization between neurons influenced the phase-amplitude coupling in predictable ways. Finally, simulation results revealed that small periodic signals can have a surprisingly large masking effect on phase-amplitude coupling.
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Kim, Ji Sun, Jinyoung Youn, Hyeeun Shin, and Jin Whan Cho. "Nonmotor Symptoms in Drug-Induced Parkinsonism and Drug-Naïve Parkinson Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 40, no. 1 (January 2013): 36–41. http://dx.doi.org/10.1017/s0317167100012920.
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AbstractBackground:The clinical manifestations of drug-induced parkinsonism (DIP) and Parkinson disease (PD) are nearly indistinguishable, making it difficult to differentiate DIP from PD, especially in the early stages. We compared non-motor symptoms between patients with DIP and those with drug-naïve PD in the early stages using the Non Motor Symptoms Scale (NMSS).Methods:We prospectively enrolled 28 patients with DIP, 35 patients with drug-naïve PD, and 32 controls with no history of neurological diseases or related medical problems. We investigated demographic characteristics, medical and drug history, parkinsonian motor symptoms, and non-motor symptoms. We used the NMSS to evaluate non-motor symptoms in all patients.Results:The total NMSS scores were higher in patients with PD than those with DIP, as were the scores for certain domains, including the cardiovascular, sleep/fatigue, urinary, sexual, and miscellaneous domains. When controlling for age and gender, the correlation analysis revealed that scores for urinary symptoms (urgency, frequency and nocturia), sleep disturbances (daytime sleep, restless legs), concentration, taste or smell were significantly associated with PD.Conclusions:Our data suggest that non-motor symptoms, particularly urinary symptoms, excessive daytime sleepiness, restless leg syndrome, attention deficit and hyposmia may be helpful to differentiate between DIP and PD in the early stages.
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Kammermeier, Stefan, Damien Pittard, Ikuma Hamada, and Thomas Wichmann. "Effects of high-frequency stimulation of the internal pallidal segment on neuronal activity in the thalamus in parkinsonian monkeys." Journal of Neurophysiology 116, no. 6 (December 1, 2016): 2869–81. http://dx.doi.org/10.1152/jn.00104.2016.
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Deep brain stimulation of the internal globus pallidus (GPi) is a major treatment for advanced Parkinson's disease. The effects of this intervention on electrical activity patterns in targets of GPi output, specifically in the thalamus, are poorly understood. The experiments described here examined these effects using electrophysiological recordings in two Rhesus monkeys rendered moderately parkinsonian through treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), after sampling control data in the same animals. Analysis of spontaneous spiking activity of neurons in the basal ganglia-receiving areas of the ventral thalamus showed that MPTP-induced parkinsonism is associated with a reduction of firing rates of segments of the data that contained neither bursts nor decelerations, and with increased burst firing. Spectral analyses revealed an increase of power in the 3- to 13-Hz band and a reduction in the γ-range in the spiking activity of these neurons. Electrical stimulation of the ventrolateral motor territory of GPi with macroelectrodes, mimicking deep brain stimulation in parkinsonian patients (bipolar electrodes, 0.5 mm intercontact distance, biphasic stimuli, 120 Hz, 100 μs/phase, 200 μA), had antiparkinsonian effects. The stimulation markedly reduced oscillations in thalamic firing in the 13- to 30-Hz range and uncoupled the spiking activity of recorded neurons from simultaneously recorded local field potential (LFP) activity. These results confirm that oscillatory and nonoscillatory characteristics of spontaneous activity in the basal ganglia receiving ventral thalamus are altered in MPTP-induced parkinsonism. Electrical stimulation of GPi did not entrain thalamic activity but changed oscillatory activity in the ventral thalamus and altered the relationship between spikes and simultaneously recorded LFPs.
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Maurice, Nicolas, Martine Liberge, Florence Jaouen, Samira Ztaou, Marwa Hanini, Jeremy Camon, Karl Deisseroth, Marianne Amalric, Lydia Kerkerian-Le Goff, and Corinne Beurrier. "Striatal Cholinergic Interneurons Control Motor Behavior and Basal Ganglia Function in Experimental Parkinsonism." Cell Reports 13, no. 4 (October 2015): 657–66. http://dx.doi.org/10.1016/j.celrep.2015.09.034.
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Bankiewicz, Krzysztof S., Robert J. Plunkett, David M. Jacobowitz, Linda Porrino, Umberto di Porzio, William T. London, Irwin J. Kopin, and Edward H. Oldfield. "The effect of fetal mesencephalon implants on primate MPTP-induced parkinsonism." Journal of Neurosurgery 72, no. 2 (February 1990): 231–44. http://dx.doi.org/10.3171/jns.1990.72.2.0231.
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✓ Parkinsonism or hemiparkinsonism was induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in four rhesus monkeys, which then received homologous fetal mesencephalon implants into the caudate nuclei. Cavities were prepared in the medial caudate nucleus 2 to 5 weeks before the fetal grafts were implanted. Control studies were conducted in unoperated MPTP-treated animals. Significant behavioral improvement, which occurred within weeks of implantation of fetal mesencephalon, was sustained for up to 7 months. No recovery was seen in the unoperated control animals. Histological examination revealed numerous surviving tyrosine hydroxylase (TH)-immunoreactive cell bodies. In addition to the graft, abundant TH-immunoreactive fibers were observed in the host caudate nucleus ventral to the region of the implanted and the nonimplanted cavities. Since TH-immunoreactive cell bodies of the substantia nigra compacta (A-9 cells) were destroyed by MPTP treatment and the ventral tegmental area (A-10) remained intact, it is concluded that sprouting of remaining host dopaminergic fibers occurs. These newly formed fibers appeared to emanate from the mesolimbic projection to the striatum. It is likely that the newly sprouted dopaminergic fibers account for the motor improvement elicited by precavitation and fetal mesencephalon implantation. These results suggest that the mechanism of recovery of parkinsonian primates after implantation of fetal dopaminergic tissue into the caudate nucleus is by stimulation of sprouting from host neurons. They also suggest that, with identification of the factors responsible for the formation of the new dopaminergic neuronal processes and with further development, tissue implantation may be an effective therapy for Parkinson's disease in humans.
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Moggio, Lucrezia, Annalisa Petraroli, Nicola Marotta, Andrea Demeco, Ilaria Pino, Cinzia Marinaro, Marianna Barletta, and Antonio Ammendolia. "Rehabilitation in primary lateral sclerosis mimicking parkinsonism: A case report." NeuroRehabilitation 47, no. 4 (December 22, 2020): 381–86. http://dx.doi.org/10.3233/nre-201527.
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BACKGROUND: Primary lateral sclerosis (PLS) is an upper motor neurons disease that on rare occasions may determine bradykinesia and motor fatigue. To date, no rehabilitative treatment has been described as useful for these patients. CASE PRESENTATION: A 68-year-old male developed dysarthria, spastic laugh, impairments of handwriting and fine motor, gait and dysphagia disorders for both solids and liquids over the period from 2015 to December 2018, with normal DaT scans and no clinical benefits from therapy with levodopa, pramipexole and baclofen. The patient underwent exercises for gait training and balance control with sensory treadmill and stabilometric platform and kinesiotherapy to improve fine motor skills of both hands and postural changes, five days a week for two weeks. Based on our data, the patient showed an improvement in balance and gait parameters in T2 compared to T1. CONCLUSION: Thanks to the synergistic action of a combined treatment of physical and instrumental therapy, despite the rare pathology and complex disability, the patient had important benefits in terms of performance and independence in daily activity.
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Rodsiri, Ratchanee, Hattaya Benya-aphikul, Narudol Teerapattarakan, Oraphan Wanakhachornkrai, Weerawan Boonlert, Rossarin Tansawat, Ruedeekorn Wiwattanapatapee, Boonchoo Sritularak, and Kittisak Likhitwitayawuid. "Neuroprotective Effect of Oxyresveratrol in Rotenone-Induced Parkinsonism Rats." Natural Product Communications 15, no. 10 (October 2020): 1934578X2096619. http://dx.doi.org/10.1177/1934578x20966199.
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Oxyresveratrol, a polyphenolic compound, has been reported as having antioxidant and anti-inflammatory effects. This study determined the neuroprotective effects of oxyresveratrol, extracted from the heartwood of Artocarpus lakoocha Roxburgh (Moraceae), on parkinsonism induced by rotenone. Male Wistar rats were divided into control, rotenone (PD), and rotenone plus oxyresveratrol (OXY) groups. The OXY rats received oxyresveratrol (300 mg/kg orally) on days 1-20. Rotenone (3 mg/kg subcutaneously) was given to PD and OXY rats on days 15, 16, 18, and 20. Motor function was determined by the rotarod test. Brains were collected to analyze dopaminergic neurons, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) and catalase activities. OXY rats exhibited a longer latency to fall than PD rats in the rotarod test ( P < 0.01) on day 16. The number of dopaminergic neurons in PD rats was lower than that in controls ( P < 0.01), while that of OXY rats was not different from controls. OXY rats showed a reduction in MDA levels ( P < 0.01) and increased catalase activity ( P < 0.05), while SOD activity was unaltered. The results suggest that oxyresveratrol pretreatment ameliorates motor impairment induced by rotenone and preserves dopaminergic neurons. The neuroprotective mechanism of oxyresveratrol is involved with its antioxidant properties.
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Prakash, KG, BM Bannur, C. Madhavrao, Saniya K, S. Viveka, and M. J. Sudha. "Anti-Depressant and Neuroprotective Effects of Captopril and Perindopril in Paraquat Model of Parkinsonism." Biomedical and Pharmacology Journal 12, no. 04 (November 22, 2019): 1715–22. http://dx.doi.org/10.13005/bpj/1800.
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Non-motor symptoms such as depression, dementia, autonomic nervous system problems may be more evident in the later part of Parkinsonism. L-dopa is largely ineffective for non-motor symptoms. The objective of the present study was to evaluate the anti-depressant and neuroprotective role of captopril and perindopril in paraquat mice model of Parkinsonism. Adult Swiss albino mice were divided into five groups of six each. Parkinsonism was induced with paraquat (7mg/kg bodyweight at an interval of 2 days) in four groups. Experimental group was treated with captopril (20mg/kg intraperitoneal) and perindopril (5mg/kg intraperitoneal). Depression influences on behaviour was studied with forced swim test and tail suspension test. Oxidative stress markers – glutathione, lipid peroxidation assay, myeloperoxidase activity, catalase, superoxide dismutase, monoamine oxidase A and B are carried out in one hemisection of the mice brain to evaluate the neuroprotective role of the test drugs. The test group mice exposed to captopril and perindopril had significantly less immobility time in both forced swim test and tail suspension test in comparison to the paraquat group, indicating anti-depressant effects of these drugs. Lipid peroxidation, myeloperoxidase activity, catalase, superoxide dismutase, monoamine oxidase B levels were significantly increased in both captopril and perindopril groups in comparison to the control group. Captopril and perindopril have shown beneficial effects for depression (as evidenced through forced swimming test and tail suspension test) in paraquat model of Parkinsonism. These drugs reduce the oxidative stress in paraquat mice model of Parkinsonism
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West, Timothy O., Luc Berthouze, David M. Halliday, Vladimir Litvak, Andrew Sharott, Peter J. Magill, and Simon F. Farmer. "Propagation of beta/gamma rhythms in the cortico-basal ganglia circuits of the parkinsonian rat." Journal of Neurophysiology 119, no. 5 (May 1, 2018): 1608–28. http://dx.doi.org/10.1152/jn.00629.2017.
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Much of the motor impairment associated with Parkinson’s disease is thought to arise from pathological activity in the networks formed by the basal ganglia (BG) and motor cortex. To evaluate several hypotheses proposed to explain the emergence of pathological oscillations in parkinsonism, we investigated changes to the directed connectivity in BG networks following dopamine depletion. We recorded local field potentials (LFPs) in the cortex and basal ganglia of rats rendered parkinsonian by injection of 6-hydroxydopamine (6-OHDA) and in dopamine-intact controls. We performed systematic analyses of the networks using a novel tool for estimation of directed interactions (nonparametric directionality, NPD). We used a “conditioned” version of the NPD analysis that reveals the dependence of the correlation between two signals on a third reference signal. We find evidence of the dopamine dependency of both low-beta (14–20 Hz) and high-beta/low-gamma (20–40 Hz) directed network interactions. Notably, 6-OHDA lesions were associated with enhancement of the cortical “hyperdirect” connection to the subthalamic nucleus (STN) and its feedback to the cortex and striatum. We find that pathological beta synchronization resulting from 6-OHDA lesioning is widely distributed across the network and cannot be located to any individual structure. Furthermore, we provide evidence that high-beta/gamma oscillations propagate through the striatum in a pathway that is independent of STN. Rhythms at high beta/gamma show susceptibility to conditioning that indicates a hierarchical organization compared with those at low beta. These results further inform our understanding of the substrates for pathological rhythms in salient brain networks in parkinsonism. NEW & NOTEWORTHY We present a novel analysis of electrophysiological recordings in the cortico-basal ganglia network with the aim of evaluating several hypotheses concerning the origins of abnormal brain rhythms associated with Parkinson’s disease. We present evidence for changes in the directed connections within the network following chronic dopamine depletion in rodents. These findings speak to the plausibility of a “short-circuiting” of the network that gives rise to the conditions from which pathological synchronization may arise.
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Lin, Chin-Hsien, Pei-I. Tsai, Han-Yi Lin, Nobutaka Hattori, Manabu Funayama, Beomseok Jeon, Kota Sato, et al. "Mitochondrial UQCRC1 mutations cause autosomal dominant parkinsonism with polyneuropathy." Brain 143, no. 11 (November 2020): 3352–73. http://dx.doi.org/10.1093/brain/awaa279.
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Abstract Parkinson’s disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson’s disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson’s disease probands with autosomal-dominant Parkinson’s disease and 1934 patients with sporadic Parkinson’s disease revealed another two variants in UQCRC1 in the probands with familial Parkinson’s disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson’s disease.
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Mazzoni, P., B. Shabbott, and J. C. Cortes. "Motor Control Abnormalities in Parkinson's Disease." Cold Spring Harbor Perspectives in Medicine 2, no. 6 (March 27, 2012): a009282. http://dx.doi.org/10.1101/cshperspect.a009282.
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Garcia-Rill, E., B. Luster, S. D’Onofrio, and S. Mahaffey. "Arousal, motor control, and Parkinson’s disease." Translational Neuroscience 6, no. 1 (January 1, 2015): 198–207. http://dx.doi.org/10.1515/tnsci-2015-0021.
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AbstractThis review highlights the most important discovery in the reticular activating system (RAS) in the last 10 years, the manifestation of gamma (γ) band activity in cells of the RAS, especially in the pedunculopontine nucleus (PPN), which is in charge of the high frequency states of waking and rapid eye movement sleep. This discovery is critical to understanding the modulation of movement by the RAS and how it sets the background over which we generate voluntary and triggered movements. The presence of γ band activity in the RAS is proposed to participate in the process of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions. Early findings using stimulation of this region to induce arousal, and also to elicit stepping, are placed in this context. This finding also helps explain the novel use of PPN deep brain stimulation for the treatment of Parkinson’s disease, although considerable work remains to be done.
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Dodson, Paul D., Jakob K. Dreyer, Katie A. Jennings, Emilie C. J. Syed, Richard Wade-Martins, Stephanie J. Cragg, J. Paul Bolam, and Peter J. Magill. "Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism." Proceedings of the National Academy of Sciences 113, no. 15 (March 21, 2016): E2180—E2188. http://dx.doi.org/10.1073/pnas.1515941113.
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Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.
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Hughes, Katherine C., Xiang Gao, Jessica M. Baker, Christopher D. Stephen, Iris Y. Kim, Linda Valeri, Michael A. Schwarzschild, and Alberto Ascherio. "Non-Motor Features of Parkinson’s Disease in Women." Journal of Parkinson's Disease 11, no. 3 (August 2, 2021): 1237–46. http://dx.doi.org/10.3233/jpd-202409.
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Background: Non-motor symptoms are common in Parkinson’s disease (PD) and some, including hyposmia, constipation, and REM sleep behavior disorder, often precede the clinical diagnosis. Objective: To assess the relation between combinations of non-motor features and presence of PD among women. Methods: A nested case-control study was conducted among women in the Nurses’ Health Study. Women were eligible if they responded to screening questions for constipation and probable REM sleep behavior disorder (pRBD) on a 2012 questionnaire and were under age 85 on January 1, 2012. 87 women with confirmed PD and 14,170 women without PD agreed to participate and completed in 2015 the Brief Smell Identification Test to assess hyposmia, as well as a questionnaire to assess parkinsonism and other non-motor PD features, including depressive symptoms, excessive daytime sleepiness, impaired color vision, and body pain. Results: In age-adjusted logistic models, each non-motor feature was significantly associated with PD, and the odds of PD increased exponentially with the number of features. Women with constipation, pRBD, and hyposmia had an age-adjusted OR for PD of 211 (95% CI 84.2–529) compared to women with none of these features. The odds of having PD rose further with the presence of additional non-motor signs. Comparing women with at least 6 of the 7 features assessed in this study to women with one or none, the age-adjusted OR for PD was 356 (95% CI 113–1126). Conclusion: Results suggest that these non-motor features could be useful in discriminating PD patients from controls in women, and since they often appear during the prodromal period of PD, their combinations may prove useful for identifying populations at high risk of developing PD.
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Marusiak, Jarosław, Beth Fisher, Anna Jaskólska, Krzysztof Słotwiński, Sławomir Budrewicz, Magdalena Koszewicz, Katarzyna Kisiel-Sajewicz, Bartosz Kamiński, and Artur Jaskólski. "Eight Weeks of Aerobic Interval Training Improves Psychomotor Function in Patients with Parkinson’s Disease—Randomized Controlled Trial." International Journal of Environmental Research and Public Health 16, no. 5 (March 11, 2019): 880. http://dx.doi.org/10.3390/ijerph16050880.
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Background: This study examined the generalized effects of cycle ergometer aerobic interval training (AIT) on psychomotor behaviors in individuals with Parkinson’s disease (PD), including bimanual motor control, cognitive function, and neurological motor and non-motor parkinsonian signs. Methods: Twenty mild to moderate PD patients were randomly allocated to the following groups: (1) trained group (PD-TR, n = 10), which besides receiving usual care, underwent an 8-week moderate intensity AIT program; or (2) control group (PD-CO, n = 10) which received usual care, including participation in conventional physical therapy. Both groups were tested before and after the 8-week AIT program period with the following assessments: (1) laboratory analyses of bimanual motor control, (2) psychological evaluation of cognitive function, and (3) an evaluation of neurological parkinsonian signs. Results: The PD-TR group exhibited improved (1) bimanual motor control, reflected by a decreased time (p = 0.013) and increased rate of grip force development (p = 0.013) in the manipulating hand and a decreased time delay between grip force initiation in the manipulating and stabilizing hand (p = 0.020); (2) executive function, reflected by decreased performance time in part II of the Stroop Test (p = 0.007); and (3) neurological parkinsonian signs, reflected by an amelioration of upper-extremity bradykinesia (p = 0.015) and improvement in daily life manual functions (p = 0.004), mood, and intellectual function (p = 0.005). Conclusions: Following an 8-week moderate intensity AIT program, patients with PD exhibited improved psychomotor behaviors, reflected by bimanual motor control, executive function, and neurological parkinsonian signs.
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Guridi, J., R. González-Redondo, and J. A. Obeso. "Clinical Features, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesias in Parkinson’s Disease." Parkinson's Disease 2012 (2012): 1–15. http://dx.doi.org/10.1155/2012/943159.
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Dyskinetic disorders are characterized by excess of motor activity that may interfere with normal movement control. In patients with Parkinson’s disease, the chronic levodopa treatment induces dyskinetic movements known as levodopa-induced dyskinesias (LID). This paper analyzed the pathophysiology, clinical manifestations, pharmacological treatments, and surgical procedures to treat hyperkinetic disorders. Surgery is currently the only treatment available for Parkinson’s disease that may improve both parkinsonian motor syndrome and LID. However, this paper shows the different mechanisms involved are not well understood.
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Alagudurai Krishnamoorthy and Murugan Sevanan. "Chrysin exerts anti-oxidant properties and restores motor function in MPTP induced mouse model of Parkinson disease." International Journal of Research in Pharmaceutical Sciences 11, no. 3 (July 29, 2020): 4388–94. http://dx.doi.org/10.26452/ijrps.v11i3.2657.
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Parkinson's disease (PD) is a neurodegenerative disorder. It is characterized by a loss in substantianigra and striatum of dopaminergic neurons. The present study is to measure the antioxidant activity of chrysin and to assess behaviour in MPTP mice model of Parkinson's disease. Methods: Male C57BL/6J mice divided into six groups (n=9). Different concentration (50, 100, 200 mg/kg) of chrysin was administered for five consecutive days, MPTP administered 80 mg/kg (2 X 40 mg/kg 16 h interval) via intraperitoneal. After 48 hours of MPTP injection, a behavioural assessment was performed. After behavioural analysis, animals were sacrificed, and brains were collected. Collected brains were subjected for the analysis of Molecular studies, Biochemistry and Histopathology. Chrysin increased Glutathione peroxidase and Nitric oxide activity compared to MPTP induced mice. Similarly, when compared with the MPTP treated group, TRX 1 also increased in chrysin treated (100 and 200mg/kg) groups. It shows chrysin's antioxidant scavenging activity, and these modifications lead to major behavioural changes in mice treated with chrysin, these results being comparable with standard drug L-Dopa. All the groups were compared with the control groups. The results evidenced that chrysin protects neurons by modulating the antioxidant mechanism against MPTP induced Parkinsonism.
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Oza, Chintan S., David T. Brocker, Christina E. Behrend, and Warren M. Grill. "Patterned low-frequency deep brain stimulation induces motor deficits and modulates cortex-basal ganglia neural activity in healthy rats." Journal of Neurophysiology 120, no. 5 (November 1, 2018): 2410–22. http://dx.doi.org/10.1152/jn.00929.2017.
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Deep brain stimulation (DBS) is an effective therapy for movement disorders, including Parkinson’s disease (PD), although the mechanisms of action remain unclear. Abnormal oscillatory neural activity is correlated with motor symptoms, and pharmacological or DBS treatment that alleviates motor symptoms appears to suppress abnormal oscillations. However, whether such oscillatory activity is causal of motor deficits such as tremor remains unclear. Our goal was to generate abnormal oscillatory activity in the cortex-basal ganglia loop using patterned subthalamic nucleus DBS and to quantify motor behavior in awake healthy rats. Stimulation patterns were designed via model-based optimization to increase power in the low-frequency (7–11 Hz) band because these oscillations are associated with the emergence of motor symptoms in the 6-hydroxydopamine lesioned rat model of parkinsonism. We measured motor activity using a head-mounted accelerometer, as well as quantified neural activity in cortex and globus pallidus (GP), in response to 5 stimulation patterns that generated a range of 7- to 11-Hz spectral power. Stimulation patterns induced oscillatory activity in the low-frequency band in the cortex and GP and caused tremor, whereas control patterns and regular 50-Hz DBS did not generate any such effects. Neural and motor-evoked responses observed during stimulation were synchronous and time-locked to stimulation bursts within the patterns. These results identified elements of irregular patterns of stimulation that were correlated with tremor and tremor-related neural activity in the cortex and basal ganglia and may lead to the identification of the oscillatory activity and structures associated with the generation of tremor activity. NEW & NOTEWORTHY Subthalamic nucleus deep brain stimulation is a promising therapy for movement disorders such as Parkinson’s disease. Several groups reported correlation between suppression of abnormal oscillatory activity in the cortex-basal ganglia and motor symptoms, but it remains unclear whether such oscillations play a causal role in the emergence of motor symptoms. We demonstrate generation of tremor and pathological oscillatory activity in otherwise healthy rats by stimulation with patterns that produced increases in low-frequency oscillatory activity.
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Lobb, C. J., A. K. Zaheer, Y. Smith, and D. Jaeger. "In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism." Journal of Neurophysiology 110, no. 12 (December 15, 2013): 2792–805. http://dx.doi.org/10.1152/jn.00441.2013.
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Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.
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Cuenca-Bermejo, Lorena, Elisa Pizzichini, Valeria Gonçalves, María Guillén-Díaz, Elena Aguilar-Moñino, Consuelo Sánchez-Rodrigo, Ana-María González-Cuello, Emiliano Fernández-Villalba, and María Herrero. "A New Tool to Study Parkinsonism in the Context of Aging: MPTP Intoxication in a Natural Model of Multimorbidity." International Journal of Molecular Sciences 22, no. 9 (April 21, 2021): 4341. http://dx.doi.org/10.3390/ijms22094341.
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The diurnal rodent Octodon degus (O. degus) is considered an attractive natural model for Alzheimer’s disease and other human age-related features. However, it has not been explored so far if the O. degus could be used as a model to study Parkinson’s disease. To test this idea, 10 adult male O. degus were divided into control group and MPTP-intoxicated animals. Motor condition and cognition were examined. Dopaminergic degeneration was studied in the ventral mesencephalon and in the striatum. Neuroinflammation was also evaluated in the ventral mesencephalon, in the striatum and in the dorsal hippocampus. MPTP animals showed significant alterations in motor activity and in visuospatial memory. Postmortem analysis revealed a significant decrease in the number of dopaminergic neurons in the ventral mesencephalon of MPTP animals, although no differences were found in their striatal terminals. We observed a significant increase in neuroinflammatory responses in the mesencephalon, in the striatum and in the hippocampus of MPTP-intoxicated animals. Additionally, changes in the subcellular expression of the calcium-binding protein S100β were found in the astrocytes in the nigrostriatal pathway. These findings prove for the first time that O. degus are sensitive to MPTP intoxication and, therefore, is a suitable model for experimental Parkinsonism in the context of aging.
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Adekeye, A. O., A. K. Adefule, P. Shallie, H. B. Akpan, and D. A. Adekomi. "Cholecalciferol attenuates induced Parkinson’s like-disease variation and cellular morphology of striatum and substantial Nigra." Anatomy Journal of Africa 7, no. 2 (August 28, 2018): 1258–73. http://dx.doi.org/10.4314/aja.v7i2.176679.
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Parkinson’s disease is the commonest motor neurodegenerative disorder which affects the dopaminergic neurons and causes significant loss of dopamine. 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin in the nigrostriatal pathway leading to this motor disorder. Cholecalciferol (Vitamin D3) has been described as an active neurosteriod with antioxidant properties ubiquitously present in the brain. The study hypothesized that stimulation of vitamin D receptor by cholecalciferol could reduce autophagic cell death and degeneration following a state of drug induced parkinsonism in mice. The aim of the research was to observe the cytoarchitectural, histochemical, neurobehavioural and immunohistochemical effects of cholecalciferol on striatum and substantia nigra in mice model of MPTP-induced Parkinson’s disease. Fifty adult male C57BL/6J mice weighing about 25-35g were randomly selected and assigned into 5 groups for this study. The mice were then subjected to neurobehavioural, neurochemical and neuropathological evaluations. The results obtained showed a significant reduction (*p<0.05) in the estimated markers of oxidative stress with high dose of vitamin D3 following MPTP induction. There was also statistical significant reduction (**p<0.01, ***p<0.001) in the expression of GFAP-immuno-positive cells in the substantia nigra of the experimental mice when compared with the control group. It can be inferred that the administration of Vitamin D3 was associated with significant attenuation of focal effects linked with MPTP in mice model of Parkinson’s Disease.Keywords: Aging, Neurodegeneration, Dopaminergic neuron, Vitamin D3, Environmental toxins
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Konczak, Jürgen, Daniel M. Corcos, Fay Horak, Howard Poizner, Mark Shapiro, Paul Tuite, Jens Volkmann, and Matthias Maschke. "Proprioception and Motor Control in Parkinson's Disease." Journal of Motor Behavior 41, no. 6 (November 6, 2009): 543–52. http://dx.doi.org/10.3200/35-09-002.
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Abbs, J. H., D. E. Hartman, and B. Vishwanat. "Orofacial motor control impairment in Parkinson's disease." Neurology 37, no. 3 (March 1, 1987): 394. http://dx.doi.org/10.1212/wnl.37.3.394.
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BRONSTEIN, A. M., and C. KENNARD. "PREDICTIVE OCULAR MOTOR CONTROL IN PARKINSON'S DISEASE." Brain 108, no. 4 (1985): 925–40. http://dx.doi.org/10.1093/brain/108.4.925.
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Justin, Shajil Anand, Senthil Gobalakrishnan, and Sylvia Santhakumari Asirvatham. "Effect of silybin in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) induced parkinsonism in mice." International Journal of Basic & Clinical Pharmacology 6, no. 10 (September 23, 2017): 2414. http://dx.doi.org/10.18203/2319-2003.ijbcp20174369.
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Background: Parkinson disease (PD) is a major neurological disorder known since ancient times. Though drugs are available for therapy, still effective drug targeting the etiopathogenesis is always going on.Methods: After obtaining permission from animal ethics committee, the mice were divided into four groups of eight each (normal control, experimental control with normal diet only, silybin 300mg/kg, silybin 600mg/kg). At the end of 55 days the mice were subjected to overnight fasting followed by plasma and liver biochemical analysis.Results: The mice treated with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) developed motor dysfunction and behavioural changes similar to PD, which was tested with rotarod test, photoactometer test and hang test which revealed the impaired performance, hypo-locomotion and impaired neuromuscular strength respectively. Treatment with silybin reversed the motor dysfunction significantly (p≤0.001) in a dose dependent manner. Biochemical analysis measured the oxidant (TBARS, SOD, CAT) and antioxidants (GPx and GSH) which revealed the oxidant activity of MPTP and antioxidant activity of silybin. Histopathological evaluation showed the cytoprotective effect of silybin.Conclusions: Silybin by its antioxidant property has a neuroprotective activity both in motor activity and behaviourally in the MPTP induced Parkinson disease in mice. Hence present study offers a conclusive evidence that silybin is a neuroprotective. Diet supplemented with silybin can protect against neurodegenerative disorders and prevent the progression of neurodegeneration.
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Biondetti, Emma, Rahul Gaurav, Lydia Yahia-Cherif, Graziella Mangone, Nadya Pyatigorskaya, Romain Valabrègue, Claire Ewenczyk, et al. "Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease." Brain 143, no. 9 (August 28, 2020): 2757–70. http://dx.doi.org/10.1093/brain/awaa216.
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Abstract This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson’s disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson’s disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson’s disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson’s disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra’s morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson’s disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.
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Friehs, G. M., R. G. Parker, L. S. He, S. J. Haines, D. A. Turner, and T. J. Ebner. "Lesioning of the Striatum Reverses Motor Asymmetry in the 6-Hydroxydopamine Rodent Model of Parkinsonism." Journal of Neural Transplantation and Plasticity 2, no. 2 (1991): 141–56. http://dx.doi.org/10.1155/np.1991.141.
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In the rat several paradigms of grafting of adrenal medulla into the striatum were studied following the induction of a parkinsonian model, using a unilateral 6-hydroxydopamine (6-OHDA) lesion of thesubstantia nigra. Direct autologous grafting of adrenal medulla into the caudate-putamen complex, a radiofrequency lesion of the striatum alone, and a radiofrequency lesion followed by delayed grafting of adrenal medulla were compared by analyzing rotational behavior. Direct grafting of adrenal medulla produced an overall reduction in apomorphine induced turning behavior by 43.5% when compared with controls. Radiofrequency lesioning of the striatum without graft showed the best improvement over control animals with a 92% reduction in the total number of rotations induced by apomorphine. Delayed grafting into the caudate lesion cavity also produced a dramatic reduction in motor asymmetry but did not improve the behavioral outcome over that of the lesion alone. Animals receiving only radiofrequency lesions exhibited a band of increased tyrosine hydroxylase like immunoreactivity bordering the lesion cavity. Graft survival was limited in the nonlesioned animals but appeared enhanced in the animals whose striatum was previously lesioned. Lesion location within the striatum influenced the behavioral outcome. Large reductions in apomorphine-induced rotations could result from small lesions of the dorso-lateral striatum. These findings indicate that selective destruction of the caudate-putamen complex without tissue transplantation produces a dramatic reduction in the motor asymmetry of 6-OHDA treated rats. Suggested explanations for the decrease in induced rotational behavior with radiofrequency lesions include a decrease in the number of striatal dopamine receptors following cell destruction and lesioninduced recovery of host dopaminergic afferents. Striatal damage in critical areas can reverse some of the motor behavior associated with the 6-OHDA model and needs to be considered when evaluating the effects of neural grafting in this model.
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Slovin, Hamutal, Moshe Abeles, Eilon Vaadia, Iris Haalman, Yifat Prut, and Hagai Bergman. "Frontal Cognitive Impairments and Saccadic Deficits in Low-Dose MPTP-Treated Monkeys." Journal of Neurophysiology 81, no. 2 (February 1, 1999): 858–74. http://dx.doi.org/10.1152/jn.1999.81.2.858.
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Frontal cognitive impairments and saccadic deficits in low-dose MPTP-treated monkeys. There is considerable overlap between the cognitive deficits observed in humans with frontal lobe damage and those described in patients with Parkinson’s disease. Similar frontal impairments have been found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of Parkinsonism. Here we provide quantitative documentation of the cognitive, oculomotor, and skeletomotor dysfunctions of monkeys trained on a frontal task and treated with low-doses (LD) of MPTP. Two rhesus monkeys were trained to perform a spatial delayed-response task with frequent alternations between two behavioral modes (go andno-go). After control recordings, the monkeys were treated with one placebo and successive LD MPTP courses. Monkey Cdeveloped motor Parkinsonian signs after a fourth course of medium-dose (MD) MPTP and later was treated with combined dopaminergic therapy (CDoT). There were no gross motor changes after the LD MPTP courses, and the average movement time (MT) did not increase. However, reaction time (RT) increased significantly. Both RT and MT were further increased in the symptomatic state, under CDoT. Self-initiated saccades became hypometric after LD MPTP treatments and their frequency decreased. Visually triggered saccades were affected to a lesser extent by the LD MPTP treatments. All saccadic parameters declined further in the symptomatic state and improved partially during CDoT. The number ofgo mode (no-response, location, and early release) errors increased after MPTP treatment. The monkeys made more perseverative errors while switching from the go to the no-gomode. Saccadic eye movement patterns suggest that frontal deficits were involved in most observed errors. CDoT had a differential effect on the behavioral errors. It decreased omission errors but did not improve location errors or perseverative errors. Tyrosine hydroxylase immunohistochemistry showed moderate (∼70–80%) reduction in the number of dopaminergic neurons in the substantia nigra pars compacta after MPTP treatment. These results show that cognitive and motor disorders can be dissociated in the LD MPTP model and that cognitive and oculomotor impairments develop before the onset of skeletal motor symptoms. The behavioral and saccadic deficits probably result from the marked reduction of dopaminergic neurons in the midbrain. We suggest that these behavioral changes result from modified neuronal activity in the frontal cortex.
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BERTHOLO, Ana Paula, Carina FRANÇA, Wilma Silva FIORINI, Egberto Reis Barbosa, and Rubens Gisbert CURY. "Medical management after subthalamic stimulation in Parkinson’s disease: a phenotype perspective." Arquivos de Neuro-Psiquiatria 78, no. 4 (April 2020): 230–37. http://dx.doi.org/10.1590/0004-282x20190188.
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Abstract Subthalamic nucleus deep brain stimulation (STN DBS) is an established treatment that improves motor fluctuations, dyskinesia, and tremor in Parkinson’s disease (PD). After the surgery, a careful electrode programming strategy and medical management are crucial, because an imbalance between them can compromise the quality of life over time. Clinical management is not straightforward and depends on several perioperative motor and non-motor symptoms. In this study, we review the literature data on acute medical management after STN DBS in PD and propose a clinical algorithm on medical management focused on the patient’s phenotypic profile at the perioperative period. Overall, across the trials, the levodopa equivalent daily dose is reduced by 30 to 50% one year after surgery. In patients taking high doses of dopaminergic drugs or with high risk of impulse control disorders, an initial reduction in dopamine agonists after STN DBS is recommended to avoid the hyperdopaminergic syndrome, particularly hypomania. On the other hand, a rapid reduction of dopaminergic agonists of more than 70% during the first months can lead to dopaminergic agonist withdrawal syndrome, characterized by apathy, pain, and autonomic features. In a subset of patients with severe dyskinesia before surgery, an initial reduction in levodopa seems to be a more reasonable approach. Finally, when the patient’s phenotype before the surgery is the severe parkinsonism (wearing-off) with or without tremor, reduction of the medication after surgery can be more conservative. Individualized medical management following DBS contributes to the ultimate therapy success.