Treatment Of Parkinson's Disease Patients Research Articles

Involvement of aberrant regulation of epigenetic mechanisms in the pathogenesis of Parkinson's disease and epigenetic-based therapies.

Parkinson's disease (PD) is known as a progressive neurodegenerative disorder associated with the reduction of dopamine-secreting neurons and the formation of Lewy bodies in the substantia nigra and basal ganglia routes. Aging, as well as environmental and genetic factors, are considered as disease risk factors that can make PD as a complex one. Epigenetics means studying heritable changes in gene expression or function, without altering the underlying DNA sequence. Multiple studies have shown the association of epigenetic variations with onset or progression of various types of diseases. DNA methylation, posttranslational modifications of histones and presence of microRNA (miRNA) are among epigenetic processes involved in regulating pathways related to the development of PD. Unlike genetic mutations, most epigenetic variations may be reversible or preventable. Therefore, the return of aberrant epigenetic events in different cells is a growing therapeutic approach to treatment or prevention. Currently, there are several methods for treating PD patients, the most important of which are drug therapies. However, detection of genes and epigenetic mechanisms involved in the disease can develop appropriate diagnosis and treatment of the disease before the onset of disabilities and resulting complications. The main purpose of this study was to review the most important epigenetic molecular mechanisms, epigenetic variations in PD, and epigenetic-based therapies.

Impact of Deep Brain Stimulation of the Subthalamic Nucleus on Neuropsychological Outcomes and Voxel‐Based‐Morphometric‐Analyses in Parkinson's Disease Patients

Parkinson's Disease (PD) is a movement disorder that is characterized by tremor, rigidity, and bradykinesia, due to significant cell‐death of the dopaminergic neurons in the substantia nigra. Deep brain stimulation (DBS) is a surgical intervention used to treat PD patients in which stimulating electrodes are placed bilaterally, most often in the subthalamic nucleus (STN). STN‐DBS is restricted to those who respond sufficiently well to a dopaminergic medication regimen. This procedure alleviates the motor symptoms associated with PD. Historically, the majority of clinical research on STN‐DBS has focused on motor outcomes. Until recently, few studies had explored the effect of STN‐DBS on post‐surgical cognitive and memory outcomes. Moreover, the relationship between cognitive outcomes and neuroanatomical changes in PD patients with STN‐DBS is largely unknown. The goal of this study was to correlate pre‐ and post‐ surgical memory and cognitive neuropsychological outcomes with volumetric changes in relevant neuroanatomical structures before and after DBS intervention. Thus far, 11 PD patients met inclusion criteria for this Colorado Multiple Institutional Review Board (COMIRB) approved study (COMIRB 16‐1060). Voxel‐based‐morphometry of cortical and subcortical brain regions were used to assess structural changes in T1‐weighted MR. Analyzed neuropsychological measures include those from the second edition of the California Verbal Language Test (CVLT‐II). Preliminary neuropsychological analyses suggest that Standard CVLT‐II Long Delayed Free recall of List Learning decreases post surgically. Further neuropsychological and neuroanatomical analyses are ongoing. This study is relevant because it will better characterize neuroanatomical and neurofunctional changes that occur with STN‐DBS so that physicians are better prepared to support their patients after STN‐DBS. Eventually, studies like this one may lead to predictive measures which allow physicians to better screen for patients who will benefit most from DBS surgery based on neuropsychological pre‐testing.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Crystal structure of the WD40 domain dimer of LRRK2

Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein with both a Ras of complex (ROC) domain and a kinase domain (KD) and, therefore, exhibits both GTPase and kinase activities. Human genetics studies have linked LRRK2 as a major genetic contributor to familial and sporadic Parkinson's disease (PD), a neurodegenerative movement disorder that inflicts millions worldwide. The C-terminal region of LRRK2 is a Trp-Asp-40 (WD40) domain with poorly defined biological functions but has been implicated in microtubule interaction. Here, we present the crystal structure of the WD40 domain of human LRRK2 at 2.6-Å resolution, which reveals a seven-bladed WD40 fold. The structure displays a dimeric assembly in the crystal, which we further confirm by measurements in solution. We find that structure-based and PD-associated disease mutations in the WD40 domain including the common G2385R polymorphism mainly compromise dimer formation. Assessment of full-length LRRK2 kinase activity by measuring phosphorylation of Rab10, a member of the family of Rab GTPases known to be important kinase substrates of LRRK2, shows enhancement of kinase activity by several dimerization-defective mutants including G2385R, although dimerization impairment does not always result in kinase activation. Furthermore, mapping of phylogenetically conserved residues onto the WD40 domain structure reveals surface patches that may be important for additional functions of LRRK2. Collectively, our analyses provide insights for understanding the structures and functions of LRRK2 and suggest the potential utility of LRRK2 kinase inhibitors in treating PD patients with WD40 domain mutations.

The Superior Colliculus in De Novo Parkinson's Disease: A Prodromal Dysfunction?

Background: The dual hit hypothesis about the pathogenesis of Parkinson's disease (PD) suggests that the brainstem can convey pathological entries to the brain. However, information about the involvement of different brainstem structures are difficult to collect in living PD patients. We have filled this gap by studying with functional brain MRI the superior colliculus (SC), a brainstem sensorimotor structure. Starting with the discovery that the SC shows abnormal visual responses in PD rat models, we aimed at studying the SC also in de novo PD patients. Methods: De novo PD patients and controls were studied using a recently developed fMRI protocol to stimulate and visualize the SC, the lateral geniculate nucleus (LGN) and the primary visual cortex (V1). The visual responses modulation of these structures was studied using luminance contrasts from 1% to 9%. We compared SC, LGN, and V1 BOLD responses of de novo PD patients with matching controls. The effects of dopaminergic treatment in PD patients were further evaluated. Findings: In the 22 enrolled PD patients, there was no modulation of the SC responses to the luminance contrasts, and the LGN was only modulated by 3%-9% luminance contrasts compared to the 22 controls. No major differences were found in V1 between both groups. Moreover, SC lack of modulation was more frequent in less affected de novo PD patients (Hoehn & Yahr stage 1). Dopaminergic treatment had no effect on SC and LGN modulation. Interpretation: De novo PD patients showed pathological responses to the luminance contrasts in the SC, suggesting that SC dysfunction could be diagnostic of PD. Since the SC seems to be more affected at stage 1 of PD, its dysfunction might be detected even earlier, supporting its potential role as a prodromal biomarker of PD. Clinical Trial Number: ClinicalTrial.gov (NCT02488395). Funding Statement: The work was funded by the University Grenoble Alpes, “La Fondation de l’Avenir” and “France Parkinson”. The Grenoble MRI facility IRMaGe was partly funded by the French program ‘Investissement d’Avenir” run by the Agence Nationale pour la Recherche (ANR-11-INBS-0006). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written informed consent to the study. The study was approved by the local ethical committee (ID RCB- 2014-A01835-42).

Utilization of Chinese herbal medicine and its association with the risk of fracture in patients with Parkinson's disease in Taiwan

Ethnopharmacological relevanceTraditional Chinese medicine (TCM) has been used for over two thousand years to treat motor impairments corresponding to the clinical manifestations of Parkinson's disease (PD). Aim of the studyThis study aimed to investigate the prescription of Chinese herbal medicine (CHM) for the management of PD and further determine whether CHM can improve motor function and decrease the risk of incident fracture. Materials and methodsPatients older than 40 years newly diagnosed with PD between January 1997 and December 2010 were selected from the National Health Insurance Research Database (NHIRD) and followed up until the end of 2013. We used 1:1 frequency matching by age, sex, index year, and initial diagnostic year to compare the TCM users and non-TCM users. We used a Cox regression model and the Kaplan-Meier method to estimate the risk of developing fracture among the TCM and non-TCM users. ResultsIn total, 7197 patients older than 40 years were newly diagnosed with PD between 1997 and 2010 in Taiwan. Among these patients, 3456 were TCM users, and 3730 were non-TCM users. We compared 2007 PD patients with comparable demographic characteristics and comorbidity profiles between the two cohorts. During the follow-up period, compared with the non-TCM cohort, fewer patients in the TCM cohort had incident fractures (adjusted hazard ratio: 0.5, 95% CI: 0.44–0.56). The cumulative incidence of fracture was lower in the TCM cohort (log-rank test, p < 0.0001). Shi-Chang-Pu (Acorus gramineus Aiton), Yuan-Zhi (Polygala tenuifolia Willd), Bei-Mu (Fritillaria cirrhosa D. Don), Hai-Piao-Xiao (Sepiella maindronide Rochebrune; Sepia esculenta Hoyle), and Tian-Ma (Gastrodia elata Blume) constituted the core Chinese herbal medicine prescriptions used to treat PD patients. ConclusionsThe present study identified the core prescription pattern for the management of PD in Taiwan. Complementary CHM therapy was associated with a reduced risk of fracture in PD patients.

Stimulation in Supplementary Motor Area Versus Motor Cortex for Freezing of Gait in Parkinson's Disease.

Background and PurposeFreezing of gait (FOG) is a frustrating problem in Parkinson's disease (PD) for which there is no effective treatment. Our aim was to find brain stimulation areas showing greater responses for reducing FOG.MethodsTwelve PD patients with FOG were selected for inclusion. We explored the therapeutic effect of repetitive transcranial magnetic stimulation (rTMS) in the supplementary motor area (SMA) and the motor cortex (MC). We measured the number of steps, completion time, and freezing episodes during the stand-walk-sit test before and after rTMS treatment. We also tested freezing episodes in two FOG-provoking tasks.ResultsThere was a trend for a greater reduction in freezing episodes with SMA stimulation than MC stimulation (p=0.071). FOG was significantly improved after SMA stimulation (p<0.05) but not after MC stimulation.ConclusionsOur study suggests that the SMA is a more-appropriate target for brain stimulation when treating PD patients with FOG. This study provides evidence that stimulating the SMA using rTMS is beneficial to FOG, which might be useful for future developments of therapeutic strategies.

Dopamine Modulates Serotonin Innervation in the Drosophila Brain.

Parkinson’s disease (PD) results from a progressive degeneration of the dopaminergic nigrostriatal system leading to a decline in movement control, with resting tremor, rigidity and postural instability. Several aspects of PD can be modeled in the fruit fly, Drosophila melanogaster, including α-synuclein-induced degeneration of dopaminergic neurons, or dopamine (DA) loss by genetic elimination of neural DA synthesis. Defective behaviors in this latter model can be ameliorated by feeding the DA precursor L-DOPA, analogous to the treatment paradigm for PD. Secondary complication from L-DOPA treatment in PD patients are associated with ectopic synthesis of DA in serotonin (5-HT)-releasing neurons, leading to DA/5-HT imbalance. Here we examined the neuro-anatomical adaptations resulting from imbalanced DA/5-HT signaling in Drosophila mutants lacking neural DA. We find that, similar to rodent models of PD, lack of DA leads to increased 5-HT levels and arborizations in specific brain regions. Conversely, increased DA levels by L-DOPA feeding leads to reduced connectivity of 5-HT neurons to their target neurons in the mushroom body (MB). The observed alterations of 5-HT neuron plasticity indicate that loss of DA signaling is not solely responsible for the behavioral disorders observed in Drosophila models of PD, but rather a combination of the latter with alterations of 5-HT circuitry.

Chemical Exchange Saturation Transfer MRI Signal Loss of the Substantia Nigra as an Imaging Biomarker to Evaluate the Diagnosis and Severity of Parkinson's Disease.

The early diagnosis of Parkinson's disease (PD) and the accurate evaluation of disease severity are crucial for intervention and treatment in PD patients. In this study, we applied chemical exchange saturation transfer (CEST) imaging to patients at different stages of PD and explored the clinical value of the CEST signal loss of the substantia nigra as an imaging biomarker of PD. The measured CEST signal intensities (including amide proton transfer-weighted or APTw, and total CEST or CESTtotal) of the substantia nigra in PD patients showed a significantly decreased tendency with PD progression. Compared to normal controls, the APTw and CESTtotal intensities of PD patients significantly decreased at both the early and advanced or late stages. These APTw and CESTtotal values of the substantia nigra were also significantly lower in advanced or late stage PD patients than in early stage PD patients. For PD patients with unilateral symptoms, the APTw and CESTtotal values in the substantia nigra on the affected side were significantly lower than those in normal controls. Both the APTw and CESTtotal values of PD were significantly correlated with the severity of disease and disease duration. Our findings suggest that the CEST MRI signal of the substantia nigra is a potential imaging biomarker for the diagnosis and monitoring of the severity of PD.

Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis.

There is uncertainty about the efficacy and tolerability of zonisamide for Parkinson's disease (PD). We performed a meta-analysis of zonisamide treatment in PD patients who received antiparkinson drugs such as levodopa. The primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) Part III scores, wearing-off time, and discontinuation rate due to all causes. Secondary outcome measures were UPDRS total and subscale scores; discontinuation rates due to adverse events, inefficacy, and death; and individual adverse events. Four randomized placebo-controlled trials including 1,068 PD patients were analyzed. All studies were conducted in Japan. UPDRS Part III scores were significantly lower with zonisamide than with placebo (weighted mean difference [WMD], -2.56; 95% confidence interval [CI]; -4.20 to -0.92; p = 0.002). Further, zonisamide significantly decreased the wearing-off time compared with placebo (standardized mean difference, -0.24; 95% CI, -0.39 to -0.09; p = 0.001). Discontinuation rates due to all causes were similar between the zonisamide and placebo groups (risk ratio, 1.29; 95% CI, 0.90 to 1.84; p = 0.16). While zonisamide also decreased both UPDRS Part II (off-time) and UPDRS total scores compared to placebo (UPDRS Part II [off-time] scores: WMD, -0.79; UPDRS total scores: WMD, -2.51), there were no significant differences in other secondary outcomes between the two groups. Our results suggested that zonisamide combination therapy was beneficial in treating motor symptoms in PD patients receiving antiparkinson drugs and was well tolerated in Japanese patients. Future studies in populations other than the Japanese are needed.

The need for non-oral therapy in Parkinson's disease; a potential role for apomorphine

In the course of Parkinson's disease (PD), oral medication may lose its effectiveness due to several reasons, like dysphagia, impaired absorption from the gastro-intestinal tract and delayed emptying of the stomach. If these problems occur, a non-oral therapy should be considered. Examples of non-oral therapies are transdermal patches, (e.g. rotigotine) which may overcome motor and nonmotor nighttime problems, and may serve as well to treat daytime response-fluctuations, if oral therapies fail to do so. Other options are injections with apomorphine to treat early morning dystonia and random off-periods during daytime, as well as continuously infused subcutaneous apomorphine for random fluctuations in PD patients. Low-dose apomorphine infusions also may be useful in the peri-operative phase, when PD patients may not be able to swallow oral medication. Finally, levodopa-carbidopa intestinal gel (LCIG) infusions or DBS have shown to be effective non-oral options to treat PD patients adequately, if they are not properly controlled by oral options.

Short- and Long-Term Outcomes of Deep Brain Stimulation in Patients 70 Years and Older with Parkinson Disease

Parkinson disease (PD) is a common neurodegenerative disease in elderly patients that may be treated with deep brain stimulation (DBS). DBS is an accepted surgical treatment in PD patients <70 years that demonstrates marked improvement in disease symptomology. Patients ≥70 years historically have been excluded from DBS therapy. Our objective is to evaluate the short- and long-term outcomes in patients with PD ≥70 years who underwent DBS at our center. In our single-center study, we retrospectively assessed a prospective registry of patients with PD treated with DBS who were ≥70 years old at the time of their procedure. Univariate analyses and 1-sample paired t test were used to evaluate data. Motor scores were evaluated with the Unified Parkinson's Disease Rating Scale III, and the effects on medication requirements were evaluated with levodopa equivalence daily doses (LEDD). Thirty-seven patients were followed for an average of 42.2 months post-DBS. The average ages at diagnosis and at the time of DBS surgery were 63.05 years and 72.45 years, respectively. Significant reductions in the average Unified Parkinson's Disease Rating Scale III score were observed (preoperative 31.8; postoperative 15.6; P < 0.0001). Significant reductions in the average LEDD (preoperative 891.94 mg; postoperative 559.6 mg; P= 0.0008) and medication doses per day (preoperative 11.54; postoperative 7.97; P= 0.0112) also were present. DBS is effective in treating elderly patients with PD. Patients experienced improvement in motor function, LEDD, and medication doses per day after DBS. Our results suggest that DBS is an effective treatment modality in elderly patients with PD.

Cognitive and Psychiatric Effects of STN versus GPi Deep Brain Stimulation in Parkinson's Disease: A Meta-Analysis of Randomized Controlled Trials.

BackgroundDeep brain stimulation (DBS) of either the subthalamic nucleus (STN) or the globus pallidus interna (GPi) can reduce motor symptoms in patients with Parkinson’s disease (PD) and improve their quality of life. However, the effects of STN DBS and GPi DBS on cognitive functions and their psychiatric effects remain controversial. The present meta-analysis was therefore performed to clarify these issues.MethodsWe searched the PUBMED, EMBASE, and the Cochrane Central Register of Controlled Trials databases. Other sources, including internet-based clinical trial registries and grey literature sources, were also searched. After searching the literature, two investigators independently performed literature screens to assess the quality of the included trials and to extract the data. The outcomes included the effects of STN DBS and GPi DBS on multiple cognitive domains, depression, anxiety, and quality of life.ResultsSeven articles related to four randomized controlled trials that included 521 participants were incorporated into the present meta-analysis. Compared with GPi DBS, STN DBS was associated with declines in selected cognitive domains after surgery, including attention, working memory and processing speed, phonemic fluency, learning and memory, and global cognition. However, there were no significant differences in terms of quality of life or psychiatric effects, such as depression and anxiety, between the two groups.ConclusionsA selective decline in frontal-subcortical cognitive functions is observed after STN DBS in comparison with GPi DBS, which should not be ignored in the target selection for DBS treatment in PD patients. In addition, compared to GPi DBS, STN DBS does not affect depression, anxiety, and quality of life.

Intranasal Dopamine Reduces In Vivo [(123)I]FP-CIT Binding to Striatal Dopamine Transporter: Correlation with Behavioral Changes and Evidence for Pavlovian Conditioned Dopamine Response.

Purpose: Dopamine (DA), which does not cross the blood-brain barrier, has central and behavioral effects when administered via the nasal route. Neither the mechanisms of central action of intranasal dopamine (IN-DA), nor its mechanisms of diffusion and transport into the brain are well understood. We here examined whether IN-DA application influences dopamine transporter (DAT) binding in the dorsal striatum and assessed the extent of binding in relation to motor and exploratory behaviors. We hypothesized that, based on the finding of increased extracellular DA in the striatum induced by application of IN-DA, binding of [123I]FP-CIT to the DAT should be decreased due to competition at the receptor.Methods: Rats were administered 3 mg/kg IN-DA and vehicle (VEH), with IN-DA injection either preceding or following VEH. Then motor and exploratory behaviors (traveled distance, velocity, center time, sitting, rearing, head-shoulder motility, grooming) were assessed for 30 min in an open field prior to administration of [123I]FP-CIT. DAT binding after IN-DA and VEH was measured with small animal SPECT 2 h following administration of the radioligand.Results: (1) After IN-DA application, striatal DAT binding was significantly lower as compared to VEH, indicating that the nasally delivered DA had central action and increased DA levels comparable to that found previously with L-DOPA administration; and (2) DAT binding in response to intranasal VEH was lower when IN-DA application preceded VEH treatment. This finding is suggestive of Pavlovian conditioning of DA at the level of the DAT, since the DA treatment modified (decreased) the binding in response to the subsequent VEH treatment. VEH treatment also reduced motor and exploratory behaviors more when applied before, as compared to when it followed IN-DA application, also indicative of behavioral Pavlovian conditioning akin to that found upon application of various psychostimulant drugs.Conclusions: The results: (a) demonstrate a direct central action of intranasally applied DA on the DAT in the dorsal striatum, indicating enhanced DA availability; and (b) provide first evidence of a Pavlovian conditioned DA response at the DAT. The latter results have relevance to understanding neurochemical mechanisms that underlie placebo action in the treatment of Parkinsonian patients.

Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several lines of evidence suggest that neurodegeneration in PD is accelerated by a vicious cycle in which apoptosis in dopaminergic neurons triggers the activation of microglia and harmful inflammatory processes that further amplify neuronal death. Recently, we demonstrated that the deletion of collapsin response mediator protein 4 (CRMP4) suppresses inflammatory responses and cell death in a mouse model of spinal cord injury, leading to improved functional recovery. We thus hypothesized that Crmp4-/- mice may have limited inflammatory responses and a decrease in the loss of SNc dopaminergic neurons in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We observed CRMP4 expression in neurons, astrocytes, and microglia/macrophages following the injection of 25mg/kg MPTP. We compared the number of dopaminergic neurons and the inflammatory response in SNc between Crmp4+/+ and Crmp4-/- mice after MPTP injection. Limited loss of SNc dopaminergic neurons and decreased activations of microglia and astrocytes were observed in Crmp4-/- mice. These results suggest that CRMP4 is a novel therapeutic target in the treatment of PD patients. We demonstrated that genetic CRMP4 deletion delays a vicious cycle of inflammation and neurodegeneration in a Parkinson's disease mouse model. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection to wild-type mice induces collapsin response mediator protein 4 (CRMP4) up-regulation in neurons, astrocytes, and microglia. CRMP4-deficient mice show reduced inflammation and suppressed dopaminergic neuronal death after MPTP injection. These findings suggest that CRMP4 deletion may be a new therapeutic strategy against Parkinson's diseases.

Parkinson Disease-Mediated Gastrointestinal Disorders and Rational for Combinatorial Therapies.

A gradual loss of dopamine-producing nerve cells gives rise to a common neurodegenerative Parkinson’s disease (PD). This disease causes a neurotransmitter imbalance in the brain and initiates a cascade of complications in the rest of the body that appears as distressing symptoms which include gait problems, tremor, gastrointestinal (GI) disorders and cognitive decline. To aid dopamine deficiency, treatment in PD patients includes oral medications, in addition to other methods such as deep brain stimulation and surgical lesioning. Scientists are extensively studying molecular and signaling mechanisms, particularly those involving phenotypic transcription factors and their co-regulatory proteins that are associated with neuronal stem cell (SC) fate determination, maintenance and disease state, and their role in the pathogenesis of PD. Advancement in scientific research and “personalized medicine” to augment current therapeutic intervention and minimize the side effects of chemotherapy may lead to the development of more effective therapeutic strategies in the near future. This review focuses on PD and associated GI complications and summarizes the current therapeutic modalities that include stem cell studies and combinatorial drug treatment.

Wirelessly programmed deep brain stimulation of the bilateral subthalamic nucleus for the treatment of primary Parkinson′s disease: study protocol for a multicenter, randomized, parallel-controlled optimal-efficiency trial

Background: Deep brain stimulation (DBS) is a commonly used neurosurgical approach for the debilitating motor symptoms of Parkinson's disease (PD). A number of neurostimulation products have been developed, including the Medtronic implantable neurostimulator (Medtronic USA, Inc., USA) and a wirelessly programmed implantable neurostimulator (Sceneray Co. Ltd., China) with protection by independent intellectual property rights in China. This study will validate the safety and efficacy of implantable neurostimulators in the treatment of primary PD. Methods/Design: This is a prospective, single-blind, randomized parallel-controlled optimal-efficiency trial, which will be performed in five research centers. Sixty-four patients with middle-stage and advanced-stage idiopathic PD will be randomly assigned to an experimental group and a control group according to a 1:1 ratio. An implantable neurostimulator will be implanted in each participant in both groups, but the stimulator will be activated within 1 month of surgery in the experimental group, while the patients in the control group will not receive stimulation until 3 months after implantation. After 3 months, patients in both groups will receive stimulation from the implanted neurostimulator. Beginning 6 hours after implantation, all participants will receive anti-PD drugs such as dopamine receptor agonists and compound levodopa. The primary outcome measure in this study will be changes in motor function score (Unified Parkinson's Disease Rating Scale (UPDRS)-III), relative to the baseline value, in patients from each group upon withdrawal of medications for 12 hours at 3 months after surgery. The secondary outcome measures for this study include (1) changes in UPDRS-I, II, III, and IV scores in patients from each group under the influence of medication at 3, 6, 9, and 12 months after surgery relative to baseline values; (2) changes in UPDRS-III scores upon withdrawal of medications 12 months after surgery in stimulation on and off modes relative to baseline value; (3) patient satisfaction. Safety indices are the numbers and incidences of adverse events. Discussion: This study is the first to investigate the safety and efficacy of a wirelessly programmed implantable neurostimulator enforced with protection by independent intellectual property rights in China through a randomized controlled trial. If safe and effective outcomes are acquired, this implantable neurostimulator will become a new option for treatment of PD patients. Trial registration: This trial was registered at http://www.chictr.org.cn (registration number ChiCTR-INR-16008951) on 1 August 2016. Ethics: The study protocol has been approved by the Ethics Committee of Tangdu Hospital of the Fourth Military Medical University of China (approval number: 2012009); Ethics Committee of Changhai Hospital of China (approval number: CHEC2012-044); Clinical Trial Ethics Committee, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine of China (approval number: 2012-67); Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University of China (approval number: 2012-7); Ethics Committee of First Affiliated Hospital of Guangzhou Medical University of China (approval number: 2013-8). The study protocol will be performed in strict accordance with the Declaration of Helsinki, formulated by the World Medical Association. Informed consent: Signed informed consent will be obtained from the patients or their relatives.

Estrogen receptor-mediated effect of δ-tocotrienol prevents neurotoxicity and motor deficit in the MPTP mouse model of Parkinson’s disease

Neuroprotection following signal transduction has been investigated recently as a strategy for Parkinson's disease (PD) therapy. While oxidative stress is important in the pathogenesis of PD, neuroprotection using antioxidants such as α-tocopherol have not been successful. δ-tocotrienol (δT3), a member of the vitamin E family, has received attention because of activities other than its antioxidative effects. In the present study, we examined the estrogen receptor-β (ERβ)-mediated neuroprotective effects of δT3 in a mouse model of PD. ERβ is expressed in neuronal cells, including dopaminergic neurons in the substantia nigra. Daily forced oral administration of δT3 inhibited the loss of dopaminergic neurons in the substantia nigra. In addition, the ER inhibitor tamoxifen canceled the neuroprotective effects of δT3. Moreover, δT3 administration improved the performance of the PD mice in the wheel running activity, while tamoxifen inhibited this improved performance. These results suggest that the oral administration of δT3 may be useful in the treatment of PD patients, and ERβ may be a candidate target for the neuroprotection activity of δT3.

Minimally invasive motor cortex stimulation for Parkinson's disease.

Extra/intradural strip electrode implantation on motor cortex may be possible minimally invasive neurosurgical method for therapeutic neuromodulation in Parkinson's disease (PD). The aim of this review is to assess motor cortex stimulation (MCS) efficacy and safety in advanced PD. Sixteen published articles were included with a total of 130 PD patients treated. In almost all results are from prospective observational open labeled study, only in two studies blinded assessment was carried out. Negative results are reported in three studies. Significant improvement in motor symptoms with remarkable effect on axial symptoms, L-dopa-induced dyskinesia and quality of life are outlined in thirteen studies. Surgical technique involved implant of four-contact strip electrode over M1 in epidural space with exception of few cases in which implant was carried out in subdural space. Surgical procedure was performed contralateral to most affected side with exception of five patients in which it was carried at dominant hemisphere; in four patients electrode implant was bilateral but stimulation was carried out simultaneously on both sides only in two cases. Complications and adverse events occurred very rarely for extradural MCS whereas with higher rate for subdural MCS. Based on review of current literature extra/intradural MCS represents an alternative to deep brain stimulation (DBS) to surgically treat PD patients who are not candidate for DBS. MCS is a minimally invasive neuromodulation procedure with low morbidity-mortality that can relieve all three major symptoms of PD on both sides simultaneously and bilaterally; it has significant effectiveness on axial symptoms, gait disturbances and therapy complications.

Chronic L-DOPA induces hyperactivity, normalization of gait and dyskinetic behavior in MitoPark mice.

Dopamine (DA) replacement therapy continues to be the gold standard treatment for Parkinson's disease (PD), as it improves key motor symptoms including bradykinesia and gait disturbances. With time, treatment induces side effects in the majority of patients, known as L-DOPA-induced dyskinesia (LID), which are often studied in animals by the use of unilateral, toxin-induced rodent models. In this study, we used the progressive, genetic PD model MitoPark to specifically evaluate bilateral changes in motor behavior following long-term L-DOPA treatment at three different stages of striatal DA depletion. Besides locomotor activity, we assessed changes in gait with two automated gait analysis systems and the development of dyskinetic behavior. Long-term treatment with a moderate, clinically relevant dose of L-DOPA (8 mg/kg) gradually produced age-dependent hyperactivity in MitoPark mice. In voluntary and forced gait analyses, we show that MitoPark mice with severe DA depletion have distinct gait characteristics, which are normalized to control levels following long-term L-DOPA treatment. The cylinder test showed an age-dependent and gradual development of bilateral LID. Significant increase in striatal FosB and prodynorphin expression was found to accompany the behavior changes. Taken together, we report that MitoPark mice model both behavioral and biochemical characteristics of long-term L-DOPA treatment in PD patients and provide a novel, consistent and progressive animal model of dyskinesia to aid in the discovery and evaluation of better treatment options to counteract LID.

Systemically administered neuregulin-1β1 rescues nigral dopaminergic neurons via the ErbB4 receptor tyrosine kinase in MPTP mouse models of Parkinson's disease.

Previously, we demonstrated that systemically injected extracellular domain of neuregulin-1β1 (Nrg1β1), a nerve growth and differentiation factor, passes the blood-brain barrier and rescues dopaminergic neurons of substantia nigra in the 6-hydroxydopamine-mouse model of Parkinson's disease (PD). Here, we studied the effects of peripherally administered Nrg1β1 in another toxin-based mouse model of PD. For this purpose, (i) nigrostriatal pathway injury was induced by treatment of adult wild-type mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in acute and subchronic paradigms; and (ii) Nrg1β1 or saline (control) were administered 1 h before each MPTP injection. We found that Nrg1β1 significantly reduced the loss of nigral dopaminergic neurons in both intoxication paradigms (7 days post-injection). However, Nrg1β1 did not reverse MPTP-induced decrease in dopamine levels and dopaminergic fibers in the striatum. We also show that MPTP conversion to its toxic metabolite 1-methyl-4-phenylpyridinium as well as levels of dopamine transporter, mediating intracellular uptake of 1-methyl-4-phenylpyridinium, are unaffected by Nrg1β1. Finally, neuroprotective properties of Nrg1β1 on nigral dopaminergic neurons are specifically mediated by ErbB4 as revealed through the study of ErbB4 knockout mice. In conclusion, systemically administered Nrg1β1 protects midbrain dopaminergic neurons against this PD-related toxic insult. Thus, Nrg1β1 may have a benefit in the treatment of PD patients. Previously, we demonstrated that systemically administered neuregulin-1β1 (Nrg1β1) passes the blood-brain barrier, phosphorylates ErbB4 receptors and elevates dopamine (DA) levels in the nigrostriatal system of healthy mice. Nrg1β1 protects nigral DAergic neurons in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). Here, we show that Nrg1β1 rescues nigral DAergic neurons also against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced cell death. ErbB4 expression is essential for the neuroprotective effect of Nrg1β1 on midbrain DAergic neurons. Nrg1β1 might be beneficial in PD treatment.