Parkinson’s Disease The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Chaperone-Based Therapies for Disease Modification in Parkinson’s Disease Mon, 21 Aug 2017 00:00:00 +0000 Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the presence of pathological intracellular aggregates primarily composed of misfolded α-synuclein. This pathology implicates the molecular machinery responsible for maintaining protein homeostasis (proteostasis), including molecular chaperones, in the pathobiology of the disease. There is mounting evidence from preclinical and clinical studies that various molecular chaperones are downregulated, sequestered, depleted, or dysfunctional in PD. Current therapeutic interventions for PD are inadequate as they fail to modify disease progression by ameliorating the underlying pathology. Modulating the activity of molecular chaperones, cochaperones, and their associated pathways offers a new approach for disease modifying intervention. This review will summarize the potential of chaperone-based therapies that aim to enhance the neuroprotective activity of molecular chaperones or utilize small molecule chaperones to promote proteostasis. Erik L. Friesen, Mitch L. De Snoo, Luckshi Rajendran, Lorraine V. Kalia, and Suneil K. Kalia Copyright © 2017 Erik L. Friesen et al. All rights reserved. Earlier Intervention with Deep Brain Stimulation for Parkinson’s Disease Wed, 16 Aug 2017 07:01:52 +0000 Neuromodulation of subcortical areas of the brain as therapy to reduce Parkinsonian motor symptoms was developed in the mid-twentieth century and went through many technical and scientific advances that established specific targets and stimulation parameters. Deep Brain Stimulation (DBS) was approved by the FDA in 2002 as neuromodulation therapy for advanced Parkinson’s disease, prompting several randomized controlled trials that confirmed its safety and effectiveness. The implantation of tens of thousands of patients in North America and Europe ignited research into its potential role in early disease stages and the therapeutic benefit of DBS compared to best medical therapy. In 2013 the EARLY-STIM trial provided Class I evidence for the use of DBS earlier in Parkinson’s disease. This finding led to the most recent FDA approval in patients with at least 4 years of disease duration and 4 months of motor complications as an adjunct therapy for patients not adequately controlled with medications. This following review highlights the historical development and advances made overtime in DBS implantation, the current application, and the challenges that come with it. Gerson Suarez-Cedeno, Jessika Suescun, and Mya C. Schiess Copyright © 2017 Gerson Suarez-Cedeno et al. All rights reserved. Programming for Stimulation-Induced Transient Nonmotor Psychiatric Symptoms after Bilateral Subthalamic Nucleus Deep Brain Stimulation for Parkinson’s Disease Tue, 15 Aug 2017 00:00:00 +0000 Background. Stimulation-induced transient nonmotor psychiatric symptoms (STPSs) are side effects following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients. We designed algorithms which (1) determine the electrode contacts that induce STPSs and (2) provide a programming protocol to eliminate STPS and maintain the optimal motor functions. Our objective is to test the effectiveness of these algorithms. Materials and Methods. 454 PD patients who underwent programming sessions after STN-DBS implantations were retrospectively analyzed. Only STPS patients were enrolled. In these patients, the contacts inducing STPS were found and the programming protocol algorithms used. Results. Eleven patients were diagnosed with STPS. Of these patients, two had four episodes of crying, and two had four episodes of mirthful laughter. In one patient, two episodes of abnormal sense of spatial orientation were observed. Hallucination episodes were observed twice in one patient, while five patients recorded eight episodes of hypomania. There were no statistical differences between the UPDRS-III under the final stimulation parameter (without STPS) and previous optimum UPDRS-III under the STPSs (). Conclusion. The flow diagram used for determining electrode contacts that induce STPS and the programming protocol employed in the treatment of these symptoms are effective. Xi Wu, Yiqing Qiu, Keith Simfukwe, Jiali Wang, Jianchun Chen, and Xiaowu Hu Copyright © 2017 Xi Wu et al. All rights reserved. Differential Diagnosis of Parkinson Disease, Essential Tremor, and Enhanced Physiological Tremor with the Tremor Analysis of EMG Mon, 14 Aug 2017 00:00:00 +0000 We investigate the differential diagnostic value of tremor analysis of EMG on Parkinson’s disease (PD), essential tremor (ET), and enhanced physiological tremor (EPT). Clinical data from 25 patients with PD, 20 patients with ET, and 20 patients with EPT were collected. The tremor frequency and muscle contraction pattern of the resting, posture, and 500 g and 1000 g overload were recorded. The frequency of PD tremor was 4–6 Hz, and the frequency of ET was also in this range; the frequency of EPT is 6–12 hz having some overlap with PD. The muscle contraction patterns of the ET and EPT group were mainly synchronous contraction, and the muscle contraction mode of the PD group was mainly alternating contraction. Having tremor latency from rest to postural position and having changes in tremor amplitude after mental concentration in PD might distinguish ET. Tremor analysis of EMG was able to distinguish PD from ET and EPT by varying the tremor frequency and muscle contraction pattern. It can also differentiate between PD and ET by the latency and concentration effect and ET and EPT by weight load effect. Jie Zhang, Yan Xing, Xiuli Ma, and Liqun Feng Copyright © 2017 Jie Zhang et al. All rights reserved. Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson’s Disease Patients: Disease, Patient, and Surgical Factors Wed, 09 Aug 2017 07:47:25 +0000 Objective. The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinson’s disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods. PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results. There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have “much” or “very much” improved CGIS. Conclusions. Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS. Hesham Abboud, Gencer Genc, Nicolas R. Thompson, Srivadee Oravivattanakul, Faisal Alsallom, Dennys Reyes, Kathy Wilson, Russell Cerejo, Xin Xin Yu, Darlene Floden, Anwar Ahmed, Michal Gostkowski, Ayman Ezzeldin, Hazem Marouf, Ossama Y. Mansour, Andre Machado, and Hubert H. Fernandez Copyright © 2017 Hesham Abboud et al. All rights reserved. Bridging the Gaps in Patient Education for DBS Surgery in Parkinson’s Disease Mon, 07 Aug 2017 09:59:53 +0000 Introduction. Improvements in quality of life, tremor, and other motor features have been recognized as superior in patients with advanced Parkinson’s disease (PD) treated with deep brain stimulation (DBS) surgery versus best medical therapy. We studied a group of patients with PD after undergoing DBS surgery in regard to expectations and satisfaction with DBS outcomes to determine gaps in patient education. Methods. This study was a retrospective, single academic center chart review and outcome questionnaire sent to patients with PD who had undergone DBS surgery between 2007 and 2014. Results. All patients surveyed indicated that benefit from DBS surgery met their overall expectations at least partially, but only 46.4% (SE: 9.6%) were in complete agreement. 3.6% (SE: 3.6%) of participants strongly disagreed that preoperative education prepared them adequately for the procedure and 17.9% (SE: 7.4%) only somewhat agreed. Conclusions. Our findings demonstrate that patients’ expectations of DBS surgery in PD were at least partially met. However, there was a considerable percentage of patients who did not feel adequately prepared for the procedure. A structured, multidisciplinary team approach in educating PD patients throughout the different stages of DBS surgery may be helpful in optimizing patients’ experience and satisfaction with surgery outcomes. Colleen D. Knoop, Robert Kadish, Kathy Hager, Michael C. Park, Paul D. Loprinzi, and Kathrin LaFaver Copyright © 2017 Colleen D. Knoop et al. All rights reserved. Dynamic Changes in the Nigrostriatal Pathway in the MPTP Mouse Model of Parkinson’s Disease Mon, 31 Jul 2017 00:00:00 +0000 The characteristic brain pathology and motor and nonmotor symptoms of Parkinson’s disease (PD) are well established. However, the details regarding the causes of the disease and its course are much less clear. Animal models have significantly enriched our current understanding of the progression of this disease. Among various neurotoxin-based models of PD, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model is the most commonly studied model. Here, we provide an overview of the dynamic changes in the nigrostriatal pathway in the MPTP mouse model of PD. Pathophysiological events, such as reductions in the striatal dopamine (DA) concentrations and levels of the tyrosine hydroxylase (TH) protein, depletion of TH-positive nerve fibers, a decrease in the number of TH-positive neurons in the substantia nigra pars compacta (SNpc), and glial activation, are addressed. This article will assist with the development of interventions or therapeutic strategies for PD. Dongping Huang, Jing Xu, Jinghui Wang, Jiabin Tong, Xiaochen Bai, Heng Li, Zishan Wang, Yulu Huang, Yufei Wu, Mei Yu, and Fang Huang Copyright © 2017 Dongping Huang et al. All rights reserved. Dual-Task Performance in GBA Parkinson’s Disease Thu, 27 Jul 2017 07:04:21 +0000 Introduction. Parkinson’s disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson’s disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients. Methods. Eleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck’s Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups. Results. Under the DT condition “walking while checking boxes,” GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs. Conclusion. This pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies. Karin Srulijes, Kathrin Brockmann, Senait Ogbamicael, Markus A. Hobert, Ann-Kathrin Hauser, Claudia Schulte, Jasmin Fritzen, Michael Schwenk, Thomas Gasser, Daniela Berg, and Walter Maetzler Copyright © 2017 Karin Srulijes et al. All rights reserved. The Effects of Group-Based versus Individual-Based Tai Chi Training on Nonmotor Symptoms in Patients with Mild to Moderate Parkinson’s Disease: A Randomized Controlled Pilot Trial Mon, 24 Jul 2017 00:00:00 +0000 Objective. To compare the effects of group-based and individual-based Tai Chi training on nonmotor symptoms in patients with mild to moderate Parkinson’s disease. Design. Randomized controlled pilot study. Methods. 36 community-dwelling patients with Parkinson’s disease (PD) were randomly assigned to either group-based training group () or individual-based group (). Both groups received same content of Tai Chi training 3 times a week for 13 weeks. Participants were also asked to perform home exercises daily. The Non-Motor Symptoms Scale was used to assess global nonmotor symptoms change. Sleep quality, depression, and cognition were evaluated by Parkinson’s Disease Sleep Scale, Hamilton Depression Scale, and Beijing version-Montreal Cognitive Assessment, respectively. Home exercise compliance was recorded. Results. There was no significant difference between two groups at baseline. After 13 weeks, there were no statistical significance between two groups. However, the within-group effect was different. Participants in group-based and individual-based groups showed a significant improvement on global nonmotor symptoms (, ) and sleep (, ). But only group-based training patients presented a significant improvement in cognitive impairment compared with baseline (, ). For depression, no group gained a significant improvement(, ). Group-based participants had a higher home-exercise compliance rate (HeCR) than individual-based participants did (), and HeCR showed a moderate correlation with MoCA-BJ and NMSS scores changes in this study. Conclusion. Group-based Tai Chi training is considered to be a more effective and a more labor-saving method in the clinical settings, and patients tend to have a higher compliance rate in their home exercise program. This study is registered with ChiCTR-IPR-17010388. Jing Hui Yang, Ya Qun Wang, Sai Qing Ye, You Gen Cheng, Yu Chen, and Xiao Zhen Feng Copyright © 2017 Jing Hui Yang et al. All rights reserved. Evolution of Orofacial Symptoms and Disease Progression in Idiopathic Parkinson’s Disease: Longitudinal Data from the Jönköping Parkinson Registry Sun, 16 Jul 2017 09:21:52 +0000 Background. Orofacial symptoms are common in Parkinson’s disease (PD) both as initial manifestations and late markers of disease complications. We aimed to investigate the evolution of orofacial manifestations and their prognostic value throughout PD progression. Methods. Data was obtained from “Jönköping Parkinson Registry” database on routine care visits of 314 people with idiopathic PD in southern Sweden. Information on baseline symptomatology, orofacial features, UPDRS, and medications was recorded at baseline and during each follow-up visit within an average of 4.2 (range: 1–12) years. Results. Hypomimia, affected speech, drooling, and impaired swallowing were present in 37.3%/91.6%, 14.1%/65.5%, 11.7%/55.3%, and 10.2%/34.5% at baseline/follow-up, respectively. Male sex [OR = 2.4 (95% CI: 1.0–5.9)], UPDRS motor scores [OR = 1.2 (95% CI: 1.1–1.3)], dominant rigidity [OR = 5.2 (95% CI: 1.4–19.1)], and autonomic disturbance [OR = 3.4 (95% CI: 1.1–10.9)] were risk factors for drooling. Individuals with more severe orofacial burden at baseline had shorter median time to develop UPDRS-Part III > 28 [3rd tertile = 4.7 yr, 2nd tertile = 6.2 yr, and 1st tertile = 7.8 yr; p = 0.014]. Conclusions. Majority of people with PD manifest orofacial manifestations at either early or late stages of the disease. PD severity, symmetry of motor disturbances, and autonomic disorders correlate with orofacial symptoms. Individuals with more severe orofacial burden at baseline progressed faster to more advanced stages. Seyed-Mohammad Fereshtehnejad, Örjan Skogar, and Johan Lökk Copyright © 2017 Seyed-Mohammad Fereshtehnejad et al. All rights reserved. Genetic Variants in SNCA and the Risk of Sporadic Parkinson’s Disease and Clinical Outcomes: A Review Tue, 11 Jul 2017 07:12:20 +0000 There is increasing evidence of the contribution of genetic susceptibility to the etiology of Parkinson’s disease (PD). Genetic variations in the SNCA gene are well established by linkage and genome-wide association studies. Positive associations of single nucleotide polymorphisms (SNPs) in SNCA and increased risk for PD were found. However, the role of SNCA variants in individual traits or phenotypes of PD is unknown. Here, we reviewed the current literature and identified 57 studies, performed in fourteen different countries, that investigated SNCA variants and susceptibility to PD. We discussed the findings based on environmental factors, history of PD, clinical outcomes, and ethnicity. In conclusion, SNPs within the SNCA gene can modify the susceptibility to PD, leading to increased or decreased risk. The risk associations of some SNPs varied among samples. Of notice, no studies in South American or African populations were found. There is little information about the effects of these variants on particular clinical aspects of PD, such as motor and nonmotor symptoms. Similarly, evidence of possible interactions between SNCA SNPs and environmental factors or disease progression is scarce. There is a need to expand the clinical applicability of these data as well as to investigate the role of SNCA SNPs in populations with different ethnic backgrounds. Clarissa Loureiro das Chagas Campêlo and Regina Helena Silva Copyright © 2017 Clarissa Loureiro das Chagas Campêlo and Regina Helena Silva. All rights reserved. Deep Brain Stimulation in Parkinson’s Disease: New and Emerging Targets for Refractory Motor and Nonmotor Symptoms Thu, 06 Jul 2017 07:05:45 +0000 Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by bradykinesia, tremor, rigidity, and postural instability (PI), in addition to numerous nonmotor manifestations. Many pharmacological therapies now exist to successfully treat PD motor symptoms; however, as the disease progresses, it often becomes challenging to treat with medications alone. Deep brain stimulation (DBS) has become a crucial player in PD treatment, particularly for patients who have disabling motor complications from medical treatment. Well-established DBS targets include the subthalamic nucleus (STN), the globus pallidus pars interna (GPi), and to a lesser degree the ventral intermediate nucleus (VIM) of the thalamus. Studies of alternative DBS targets for PD are ongoing, the majority of which have shown some clinical benefit; however, more carefully designed and controlled studies are needed. In the present review, we discuss the role of these new and emerging DBS targets in treating refractory axial motor symptoms and other motor and nonmotor symptoms (NMS). Dustin Anderson, Grayson Beecher, and Fang Ba Copyright © 2017 Dustin Anderson et al. All rights reserved. Deep Brain Stimulation of Hemiparkinsonian Rats with Unipolar and Bipolar Electrodes for up to 6 Weeks: Behavioral Testing of Freely Moving Animals Mon, 03 Jul 2017 08:36:26 +0000 Although the clinical use of deep brain stimulation (DBS) is increasing, its basic mechanisms of action are still poorly understood. Platinum/iridium electrodes were inserted into the subthalamic nucleus of rats with unilateral 6-OHDA-induced lesions of the medial forebrain bundle. Six behavioral parameters were compared with respect to their potential to detect DBS effects. Locomotor function was quantified by (i) apomorphine-induced rotation, (ii) initiation time, (iii) the number of adjusting steps in the stepping test, and (iv) the total migration distance in the open field test. Sensorimotor neglect and anxiety were quantified by (v) the retrieval bias in the corridor test and (vi) the ratio of migration distance in the center versus in the periphery in the open field test, respectively. In our setup, unipolar stimulation was found to be more efficient than bipolar stimulation for achieving beneficial long-term DBS effects. Performance in the apomorphine-induced rotation test showed no improvement after 6 weeks. DBS reduced the initiation time of the contralateral paw in the stepping test after 3 weeks of DBS followed by 3 weeks without DBS. Similarly, sensorimotor neglect was improved. The latter two parameters were found to be most appropriate for judging therapeutic DBS effects. Kathrin Badstuebner, Ulrike Gimsa, Immo Weber, Armin Tuchscherer, and Jan Gimsa Copyright © 2017 Kathrin Badstuebner et al. All rights reserved. Comparison of Globus Pallidus Interna and Subthalamic Nucleus in Deep Brain Stimulation for Parkinson Disease: An Institutional Experience and Review Mon, 19 Jun 2017 06:10:10 +0000 Deep Brain Stimulation (DBS) has revolutionized the lives of patients of Parkinson disease, offering therapeutic options to those not benefiting entirely from medications alone. With its proven track record of outperforming the best medical management, the goal is to unlock the full potential of this therapy. Currently, the Globus Pallidus Interna (GPi) and Subthalamic Nucleus (STN) are both viable targets for DBS, and the choice of site should focus on the constellation of symptoms, both motor and nonmotor, which are key determinants to quality of life. Our article sheds light on the specific advantages and drawbacks of the two sites, highlighting the need for matching the inherent properties of a target with specific desired effects in patients. UT Southwestern Medical Center has a robust and constantly evolving DBS program and the narrative from our center provides invaluable insight into the practical realities of DBS. The ultimate decision in selecting a DBS target is complex, ideally made by a multidisciplinary team, tailored towards each patient’s profile and their expectations, by drawing upon scientific evidence coupled with experience. Ongoing research is expanding our knowledge base, which should be dynamically incorporated into an institute’s DBS paradigm to ensure that patients receive the optimal therapy. Shazia Mirza, Umar Yazdani, Richard Dewey III, Neepa Patel, Richard B. Dewey Jr., Svjetlana Miocinovic, and Shilpa Chitnis Copyright © 2017 Shazia Mirza et al. All rights reserved. Economic Burden Analysis of Parkinson’s Disease Patients in China Wed, 14 Jun 2017 00:00:00 +0000 Background and Objective. Parkinson’s Disease (PD) is a progressive neurodegenerative disorder, which is prevalent in people over 65 years old. PD reduces patients’ quality of life and exerts a heavy economic burden on patients and their families. The purpose of this research is to identify the costs of PD and to evaluate the economic distribution of medical care for PD patients in China. Methods. A professional survey was administered to 116 patients with PD. Records of medical cost were reviewed. Direct and indirect costs were analyzed. The main cost-driving factors of PD were identified using multivariate regression analysis. Results. The average annual cost per PD patient in China is $3,225.94, with direct and indirect costs accounting for $2,503.46 and $722.48, respectively. Direct costs consist of $556.27 for surgery, $44.67 for appointment fees, $605.67 for prescription medication, $460.29 for hospitalization, $71.03 for auxiliary examination, $35.64 for transportation, $10.39 for special equipment, and $719.50 for formal care. The total cost is closely related to surgical treatment, dopamine agonist, and levodopa costs. Conclusion. The cost of PD patients in China is considerable and exceeds average economic capacity, especially antiparkinson medication and caring costs. This study may provide a reference for PD healthcare optimization in the future. Jun-Xiu Yang and Lei Chen Copyright © 2017 Jun-Xiu Yang and Lei Chen. All rights reserved. Does Dopamine Depletion Trigger a Spreader Lexical-Semantic Activation in Parkinson’s Disease? Evidence from a Study Based on Word Fluency Tasks Sun, 11 Jun 2017 00:00:00 +0000 It has been hypothesised that, in Parkinson’s disease (PD), dopamine might modulate spreading activation of lexical-semantic representations. We aimed to investigate this hypothesis in individuals with PD without dementia by assessing word frequency and typicality in verbal fluency tasks. We predicted that the average values of both of these parameters would be lower in PD patients with respect to healthy controls (HC). We administered letter-cued and category-cued fluency tasks to early PD patients in two experimental conditions: the tasks were administered both after 12–18 hours of dopaminergic stimulation withdrawal (“OFF” condition) and after the first daily dose of dopaminergic therapy (“ON” condition). HC were also given the two tasks in two conditions with the same intersession delay as PD patients but without taking drugs. Results showed that in both OFF and ON treatment conditions PD patients did not differ from HC in word frequency or typicality. Moreover, in the PD group, no significant difference was found between the experimental conditions. Our results show that semantic spreading was not altered in the PD sample examined; this suggests that in early PD the functioning of the semantic system is relatively independent from the activity of dopamine brain networks. S. Zabberoni, G. A. Carlesimo, A. Peppe, C. Caltagirone, and A. Costa Copyright © 2017 S. Zabberoni et al. All rights reserved. Subthalamic Nucleus Deep Brain Stimulation in Early Stage Parkinson’s Disease Is Not Associated with Increased Body Mass Index Tue, 06 Jun 2017 07:03:20 +0000 Previous studies suggest that deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson’s disease (PD) leads to weight gain. This study analyzes changes in body mass index (BMI) in 29 subjects from a prospective, single-blind trial of DBS in early stage PD (age 50–75, Hoehn & Yahr stage II off medication, treated with antiparkinsonian medications for ≥6 months but <4 years, and without a history of motor fluctuations, dyskinesias, or dementia). Subjects were randomized to DBS plus optimal drug therapy (DBS+ODT; ) or ODT () and followed for 24 months. Weight and height were recorded at baseline and each follow-up visit and used to calculate BMI. BMIs were compared within and between groups using nonparametric -tests. Mean BMI at baseline was 29.7 in the ODT group and 32.3 in the DBS+ODT group (). BMI change over two years was not different between the groups (, ODT = −0.89; DBS+ODT = −0.17). This study suggests that STN-DBS is not associated with weight gain in subjects with early stage PD. This finding will be tested in an upcoming FDA-approved phase III multicenter, randomized, double-blind, placebo-controlled, pivotal clinical trial evaluating DBS in early stage PD ( identifier NCT00282152). Sarah H. Millan, Mallory L. Hacker, Maxim Turchan, Anna L. Molinari, Amanda D. Currie, and David Charles Copyright © 2017 Sarah H. Millan et al. All rights reserved. Colonic Oxidative and Mitochondrial Function in Parkinson’s Disease and Idiopathic REM Sleep Behavior Disorder Sun, 04 Jun 2017 10:58:32 +0000 Objective. To determine potential mitochondrial and oxidative alterations in colon biopsies from idiopathic REM sleep behavior disorder (iRBD) and Parkinson’s disease (PD) subjects. Methods. Colonic biopsies from 7 iRBD subjects, 9 subjects with clinically diagnosed PD, and 9 healthy controls were homogenized in 5% w/v mannitol. Citrate synthase (CS) and complex I (CI) were analyzed spectrophotometrically. Oxidative damage was assessed either by lipid peroxidation, through malondialdehyde and hydroxyalkenal content by spectrophotometry, or through antioxidant enzyme levels of superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (Gpx1), and catalase (CAT) by western blot. The presence of mitochondrial DNA (mtDNA) deletions was assessed by long PCR and electrophoresis. Results. Nonsignificant trends to CI decrease in both iRBD (; 23% decrease) and PD patients (; 37% decrease) were found compared to controls (, : NS). Lipid peroxidation was maintained among groups (iRBD: , PD: , and controls: ; : NS). Antioxidant enzymes SOD2 (iRBD: , PD: , and controls: ) and Gpx1 (iRBD , PD: , and controls: ) did not show significant differences between groups. CAT was only detected in 2 controls and 1 iRBD subject. One iRBD patient presented a single mtDNA deletion. C. Morén, Í. González-Casacuberta, J. Navarro-Otano, D. Juárez-Flores, D. Vilas, G. Garrabou, J. C. Milisenda, C. Pont-Sunyer, M. Catalán-García, M. Guitart-Mampel, E. Tobías, F. Cardellach, F. Valldeoriola, A. Iranzo, and E. Tolosa Copyright © 2017 C. Morén et al. All rights reserved. Sirtuin-2 Protects Neural Cells from Oxidative Stress and Is Elevated in Neurodegeneration Sun, 28 May 2017 07:26:58 +0000 Sirtuins are highly conserved lysine deacetylases involved in ageing, energy production, and lifespan extension. The mammalian SIRT2 has been implicated in Parkinson’s disease (PD) where studies suggest SIRT2 promotes neurodegeneration. We therefore evaluated the effects of SIRT2 manipulation in toxin treated SH-SY5Y cells and determined the expression and activity of SIRT2 in postmortem brain tissue from patients with PD. SH-SY5Y viability in response to oxidative stress induced by diquat or rotenone was measured following SIRT2 overexpression or inhibition of deacetylase activity, along with α-synuclein aggregation. SIRT2 in human tissues was evaluated using Western blotting, immunohistochemistry, and fluorometric activity assays. In SH-SY5Y cells, elevated SIRT2 protected cells from rotenone or diquat induced cell death and enzymatic inhibition of SIRT2 enhanced cell death. SIRT2 protection was mediated, in part, through elevated SOD2 expression. SIRT2 reduced the formation of α-synuclein aggregates but showed minimal colocalisation with α-synuclein. In postmortem PD brain tissue, SIRT2 activity was elevated compared to controls but also elevated in other neurodegenerative disorders. Results from both in vitro work and brain tissue suggest that SIRT2 is necessary for protection against oxidative stress and higher SIRT2 activity in PD brain may be a compensatory mechanism to combat neuronal stress. Preeti Singh, Peter S. Hanson, and Christopher M. Morris Copyright © 2017 Preeti Singh et al. All rights reserved. A Randomized Controlled Trial of Chinese Medicine on Nonmotor Symptoms in Parkinson’s Disease Tue, 23 May 2017 06:55:33 +0000 Nonmotor symptoms (NMS) of Parkinson’s disease (PD) have devastating impacts on both patients and their caregivers. Jiawei-Liujunzi Tang (JLT) has been used to treat some NMS of PD based on the Chinese medicine theory since Qing dynasty. Here we report a double-blind, randomized, placebo-controlled, add-on clinical trial aiming at evaluating the efficacy and safety of the JLT in treating NMS in PD patients. We randomly assigned 111 patients with idiopathic PD to receive either JLT or placebo for 32 weeks. Outcome measures were baseline to week 32 changes in Movement Disorder Society-Sponsored Revision of Unified PD Rating Scale (MDS-UPDRS) Parts I–IV and in NMS assessment scale for PD (NMSS). We observed improvements in the NMSS total score (), mood/cognition (), and reduction in hallucinations (). In addition, post hoc analysis showed a significant reduction in constipation (). However, there was no evidence of improvement in MDS-UPDRS Part I total score () at week 32. Adverse events (AEs) were mild and comparable between the two groups. In conclusion, long-term administration of JLT is well tolerated and shows significant benefits in improving NMS including mood, cognition, and constipation. Ka-Kit Chua, Adrian Wong, Kam-Wa Chan, Yin-Kei Lau, Zhao-Xiang Bian, Jia-Hong Lu, Liang-Feng Liu, Lei-Lei Chen, Ka-Ho Chan, Kim-Pong Tse, Anne Chan, Ju-Xian Song, Justin Wu, Li-Xing Zhu, Vincent Mok, and Min Li Copyright © 2017 Ka-Kit Chua et al. All rights reserved. Physiotherapy in Parkinson’s Disease: Building ParkinsonNet in Czechia Mon, 22 May 2017 08:19:14 +0000 Objective. We conducted a questionnaire survey to investigate the availability and quality of physiotherapy (PT) for Parkinson’s disease (PD). Background. Despite evidence about the benefits of PT, there is no data regarding its use in Czechia. Methods. Questionnaires were sent to 368 PD patients seen in a single movement disorders centre within two years (inclusion criteria: idiopathic PD, Hoehn and Yahr stage <5, and residence in Prague) and to 211 physical therapists (PTs) registered in Prague. The patient questionnaire evaluated limitations in 6 core areas and in activities of daily living and inquired about experience with PT. The PTs questionnaire evaluated knowledge about PD, number of PD patients treated yearly, and details of therapy. Results. Questionnaires were returned by 248 patients and 157 PTs. PT was prescribed to 70/248 patients. The effects were satisfactory in 79% and lasted >3 months in 60/64. About half of the PTs have no experience with PD patients, 26% reported <3, and 5% see >10 yearly. The most widely used techniques were neurodevelopmental treatments. Conclusion. Present PD healthcare model in Czechia is suboptimal (low PT prescription, non-evidence-based PT). Implementation of European PT Guidelines for PD and the introduction of an efficient model of care are needed. Ota Gal, Martin Srp, Romana Konvalinkova, Martina Hoskovcova, Vaclav Capek, Jan Roth, and Evzen Ruzicka Copyright © 2017 Ota Gal et al. All rights reserved. Effect of a Traditional Chinese Herbal Medicine Formulation on Cell Survival and Apoptosis of MPP+-Treated MES 23.5 Dopaminergic Cells Thu, 18 May 2017 07:40:34 +0000 Progressive degeneration of dopaminergic neurons in the substantia nigra (SN) is implicated in Parkinson’s disease (PD). The efficacy of these currently used drugs is limited while traditional Chinese medicine (TCM) has been used in the management of neurodegenerative diseases for many years. This study was designed to evaluate the effect of a modified traditional Chinese herbal medicine decoction, Cong Rong Jing (CRJ), on cell survival and apoptosis of 1-methyl-4-phenylpyridinium- (MPP+-) treated MES23.5 dopaminergic cells. CRJ was prepared as a decoction from three Chinese herbs, namely, Herba Cistanches, Herba Epimedii, and Rhizoma Polygonati. We reported here that CRJ significantly enhanced the cell survival of MES23.5 cells after the exposure of MPP+ and inhibited the production of intracellular reactive oxygen species (ROS) induced by MPP+. CRJ also prevented the MPP+-treated MES23.5 cells from apoptosis by reducing the externalization of phosphatidylserine and enhancing the Bcl-2/Bax protein expression ratio. Signaling proteins such as JAK2, STAT3, and ERK1/2 were also involved in the action of CRJ. Taken together, these results provide a preliminary mechanism to support clinical application of the TCM formulation in PD and possibly other neurodegenerative diseases associated with ROS injury and apoptosis. Shuifen Ye, Ho Kee Koon, Wen Fan, Yihui Xu, Wei Wei, Chuanshan Xu, and Jing Cai Copyright © 2017 Shuifen Ye et al. All rights reserved. Quantitative Analysis of Motor Status in Parkinson’s Disease Using Wearable Devices: From Methodological Considerations to Problems in Clinical Applications Thu, 18 May 2017 00:00:00 +0000 Long-term and objective monitoring is necessary for full assessment of the condition of patients with Parkinson’s disease (PD). Recent advances in biotechnology have seen the development of various types of wearable (body-worn) sensor systems. By using accelerometers and gyroscopes, these devices can quantify motor abnormalities, including decreased activity and gait disturbances, as well as nonmotor signs, such as sleep disturbances and autonomic dysfunctions in PD. This review discusses methodological problems inherent in wearable devices. Until now, analysis of the mean values of motion-induced signals on a particular day has been widely applied in the clinical management of PD patients. On the other hand, the reliability of these devices to detect various events, such as freezing of gait and dyskinesia, has been less than satisfactory. Quantification of disease-specific changes rather than nonspecific changes is necessary. Masahiko Suzuki, Hiroshi Mitoma, and Mitsuru Yoneyama Copyright © 2017 Masahiko Suzuki et al. All rights reserved. Genetic Variations and mRNA Expression of NRF2 in Parkinson’s Disease Tue, 02 May 2017 09:21:44 +0000 Nuclear factor erythroid 2-like 2 (NRF2) encodes a transcription factor regulating mechanisms of cellular protection and is activated by oxidative stress. NRF2 has therefore been hypothesized to confer protection against Parkinson’s disease and so far an NRF2 haplotype has been reported to decrease the risk of developing disease and delay disease onset. Also NRF2 adopts a nuclear localization in Parkinson’s disease, which is indicative of increased NRF2 activity. We have investigated the association between NRF2 and Parkinson’s disease in a Swedish case-control material and whether NRF2 expression levels correlate with NRF2 genetic variants, disease, or disease onset. Using pyrosequencing, we genotyped one intronic and three promoter variants in 504 patients and 509 control subjects from Stockholm. Further, we quantified NRF2 mRNA expression in EBV transfected human lymphocytes from patients and controls using quantitative real-time reverse transcription PCR. We found that one of the promoter variants, rs35652124, was associated with age of disease onset ( = 14.19, value = 0.0067). NRF2 mRNA expression levels however did not correlate with the rs35652124 genotype, Parkinson’s disease, or age of onset in our material. More detailed studies on NRF2 are needed in order to elucidate how this gene affects pathophysiology of Parkinson’s disease. Caroline Ran, Karin Wirdefeldt, Lovisa Brodin, Mehrafarin Ramezani, Marie Westerlund, Fengqing Xiang, Anna Anvret, Thomas Willows, Olof Sydow, Anders Johansson, Dagmar Galter, Per Svenningsson, and Andrea Carmine Belin Copyright © 2017 Caroline Ran et al. All rights reserved. Ex Vivo and In Vivo Characterization of Interpolymeric Blend/Nanoenabled Gastroretentive Levodopa Delivery Systems Wed, 26 Apr 2017 07:30:03 +0000 One approach for delivery of narrow absorption window drugs is to formulate gastroretentive drug delivery systems. This study was undertaken to provide insight into in vivo performances of two gastroretentive systems (PXLNET and IPB matrices) in comparison to Madopar® HBS capsules. The pig model was used to assess gastric residence time and pharmacokinetic parameters using blood, cerebrospinal fluid (CSF), and urine samples. Histopathology and cytotoxicity testing were also undertaken. The pharmacokinetic parameters indicated that levodopa was liberated from the drug delivery systems, absorbed, widely distributed, metabolized, and excreted. were 372.37, 257.02, and 461.28 ng/mL and MRT were 15.36, 14.98, and 13.30 for Madopar HBS capsules, PXLNET, and IPB, respectively. In addition, X-ray imaging indicated that the gastroretentive systems have the potential to reside in the stomach for 7 hours. There was strong in vitro-in vivo correlation for all formulations with values of 0.906, 0.935, and 0.945 for Madopar HBS capsules, PXLNET, and IPB, respectively. Consequently, PXLNET and IPB matrices have pertinent potential as gastroretentive systems for narrow absorption window drugs (e.g., L-dopa) and, in this application specifically, enhanced the central nervous system and/or systemic bioavailability of such drugs. Ndidi C. Ngwuluka, Yahya E. Choonara, Girish Modi, Lisa C. du Toit, Pradeep Kumar, Leith Meyer, Tracy Snyman, and Viness Pillay Copyright © 2017 Ndidi C. Ngwuluka et al. All rights reserved. Cognitive Function Characteristics of Parkinson’s Disease with Sleep Disorders Tue, 18 Apr 2017 07:21:27 +0000 Objective. The aim of this study was to investigate the cognitive function characteristics of Parkinson’s disease (PD) with sleep disorders. Methods. Consecutive patients with PD (), patients with primary sleep disorders (), and healthy control subjects () were assessed. The patients with PD were classified into sleep disorder (PD-SD) and non-sleep disorder (PD-NSD) groups. Results. Among 96 patients with PD, 69 were diagnosed with a sleep disorder. There were 38 sleep disorder cases, 31 RBD cases, and 27 NSD cases. On the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and MoCA subtests, patients in the PD-SD, primary sleep disorder, and PD-NSD groups exhibited lower scores than those in the control group. Moreover, the PD-SD patients exhibited more significant cognitive impairment than was observed in the primary sleep disorder patients. In the PD-SD subgroup, the attention scores on the MoCA and on MoCA subtests were lower in the PD with RBD group than in the PD with insomnia group. Conclusion. PD with sleep disorders may exacerbate cognitive dysfunction in patients. PD associated with different types of sleep disorders differentially affects cognitive functions, and patients with PD with RBD exhibited poorer cognitive function than was seen in patients with PD with insomnia. Jing Huang, Wenyan Zhuo, Yuhu Zhang, Hongchun Sun, Huan Chen, Peipei Zhu, Xiaobo Pan, Jianhao Yang, and Lijuan Wang Copyright © 2017 Jing Huang et al. All rights reserved. Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons Mon, 03 Apr 2017 08:11:05 +0000 Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, vascular endothelial growth factor-A (VEGF-A). Studies demonstrated that VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about the mechanism of action of VEGF-B in pathological processes. We explore its potential as a homeostatic protective factor that improves mitochondrial function in the setting of cardiovascular and neurological disease, with a specific focus on dopaminergic neurons in Parkinson’s disease. Beatrice Caballero, Scott J. Sherman, and Torsten Falk Copyright © 2017 Beatrice Caballero et al. All rights reserved. LRRK2 G2019S Mutation: Prevalence and Clinical Features in Moroccans with Parkinson’s Disease Thu, 30 Mar 2017 12:19:16 +0000 Background. The LRRK2 G2019S mutation is the most common genetic determinant of Parkinson’s disease (PD) identified to date. This mutation, reported in both familial and sporadic PD, occurs at elevated frequencies in Maghreb population. In the present study, we examined the prevalence of the G2019S mutation in the Moroccan population and we compared the motor and nonmotor phenotype of G2019S carriers to patients with idiopathic Parkinson’s disease. Methods. 100 PD patients were assessed for motor and nonmotor symptoms, current medication, and motor complication including motor fluctuations and dyskinesia. The LRRK2 G2019S mutation was investigated by direct sequencing in patients and ethnically matched controls, all of Moroccan origin. Results. Among the 100 PD Moroccan patients, 41 (41%) were carriers of the G2019S mutation. The mutation frequency was higher among probands with autosomal dominant inheritance (76%) than among sporadic ones (28%). Interestingly, G2019S mutation was also found in 5% of control individuals. Clinically, patients carrying the G2019S mutation have more dystonia (OR = 4.6, p = 0.042) and more sleep disorders (OR = 2.4, p = 0.045) than noncarriers. Conclusions. The LRRK2 G2019S prevalence in Morocco is the highest in the world reported to date. Some clinical features in G2019S carriers such as dystonia and sleep disturbances are worth noting. Ahmed Bouhouche, Houyam Tibar, Rafiqua Ben El Haj, Khalil El Bayad, Rachid Razine, Sanaa Tazrout, Asmae Skalli, Naima Bouslam, Loubna Elouardi, Ali Benomar, Mohammed Yahyaoui, and Wafa Regragui Copyright © 2017 Ahmed Bouhouche et al. All rights reserved. MRI-Guided Focused Ultrasound in Parkinson’s Disease: A Review Thu, 30 Mar 2017 00:00:00 +0000 MRI-guided focused ultrasound is a new technology that enables intracranial ablation. Since lesioning ameliorates some of the symptoms of PD, this technology is being explored as a possible treatment for medication resistant symptoms in PD patients. The purpose of this paper is to review the clinical use and treatment outcomes of PD patients treated to date with this technology. Ilana Schlesinger, Alon Sinai, and Menashe Zaaroor Copyright © 2017 Ilana Schlesinger et al. All rights reserved. Are Patients Ready for “EARLYSTIM”? Attitudes towards Deep Brain Stimulation among Female and Male Patients with Moderately Advanced Parkinson’s Disease Tue, 28 Mar 2017 07:53:42 +0000 Objective. To explore, in female and male patients with medically treated, moderately advanced Parkinson’s disease (PD), their knowledge and reasoning about Deep Brain Stimulation (DBS). Methods. 23 patients with PD (10 women), aged 46–70, were interviewed at a mean of 8 years after diagnosis, with open-ended questions concerning their reflections and considerations about DBS. The interviews were transcribed verbatim and analysed according to the difference and similarity technique in Grounded Theory. Results. From the patients’ narratives, the core category “Processing DBS: balancing symptoms, fears and hopes” was established. The patients were knowledgeable about DBS and expressed cautious and well considered attitudes towards its outcome but did not consider themselves ill enough to undergo DBS. They were aware of its potential side-effects. They considered DBS as the last option when oral medication is no longer sufficient. There was no difference between men and women in their reasoning and attitudes towards DBS. Conclusion. This study suggests that knowledge about the pros and cons of DBS exists among PD patients and that they have a cautious attitude towards DBS. Our patients did not seem to endorse an earlier implementation of DBS, and they considered that it should be the last resort when really needed. Maria Sperens, Katarina Hamberg, and Gun-Marie Hariz Copyright © 2017 Maria Sperens et al. All rights reserved.