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The Journal of Parkinson’s Disease is dedicated to providing an open forum for original research in basic science, translational research and clinical medicine that will expedite our fundamental understanding and improve treatment of Parkinson’s disease. The journal is international and multidisciplinary and aims to promote progress in the epidemiology, etiology, genetics, molecular correlates, pathogenesis, pharmacology, psychology, diagnosis and treatment of Parkinson’s disease.
It will publish research reports, reviews, short communications, and letters-to-the-editor and offers very rapid publication and an affordable open access option.
Authors: George, Sonia | Brundin, Patrik
Article Type: Review Article
Abstract: Currently, several α-synuclein immunotherapies are being tested in experimental Parkinson’s disease models and in clinical trials. Recent research has revealed that α-synuclein is not just an intracellular synaptic protein but also exists extracellularly. Moreover, the transfer of misfolded α-synuclein between cells might be a crucial step in the process leading to a progressive increase in deposition of α-synuclein aggregates throughout the Parkinson’s disease brain. The revelation that α-synuclein is present outside cells has increased the interest in antibody-based therapies and opens up for the notion that microglia might play a key role in retarding Parkinson’s disease progression. The objectives of …this review are to describe and contrast the use of active and passive immunotherapy in treating α-synucleinopathies and highlight the likely important role of microglia in clearing misfolded α-synuclein from the extracellular space. Show more
Keywords: alpha synuclein, microglia, immunotherapy, Parkinson’s disease
DOI: 10.3233/JPD-150630
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 413-424, 2015
Authors: Bettiol, Silvana S. | Rose, Tanith C. | Hughes, Clarissa J. | Smith, Lesley A.
Article Type: Review Article
Abstract: Background: The association between Parkinson’s disease and lifestyle exposures such as smoking, coffee and alcohol consumption have been the focus of research for several decades, with varying and often conflicting results. Objective: This paper reviews the key features of observational studies investigating the relationship between alcohol drinking and PD risk, to determine potential sources of variability between the results. Methods: Relevant literature from 2000–2014 was systematically retrieved using three databases. Primary research articles were included if they reported a measure of association between quantity and frequency of alcohol intake and PD risk, …and adjusted at least for the potential confounding factors of smoking and age. Results: Sixteen articles were identified. The seven case-control studies were more likely to report a weak protective association by level of alcohol consumption compared to the studies with prospective designs. Two studies reported the relationship between heavy (harmful to health) drinking and PD. There was weak evidence that associations varied by type of alcoholic beverage. Smoking may modify the association between alcohol intake and PD risk, however, the evidence does not support the theory that a confounder (such as an addiction-avoiding personality trait) produced the inverse associations between smoking, coffee and alcohol intake and PD risk. Methodological weaknesses of the studies, including selection and recall bias, residual confounding and lack of statistical power may in part account for their differences. Conclusion: The weak association between alcohol drinking and PD risk was found in studies at greater risk of selection and recall bias. Show more
Keywords: Alcohol, alcoholic beverages, alcohol drinking, Parkinson’s disease, review, risk factors, case-control studies, cohort studies, epidemiologic methods, lifestyle
DOI: 10.3233/JPD-150533
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 425-442, 2015
Authors: Egan, Sarah J. | Laidlaw, Ken | Starkstein, Sergio
Article Type: Review Article
Abstract: Evidence is reviewed demonstrating that cognitive behavior therapy (CBT) is effective in the treatment of depression and anxiety in Parkinson’s disease. The aims were to review the extant literature, specify a model of cognitive and behavioral maintenance factors in depression and anxiety in Parkinson’s disease and provide a guide to treatment. It is argued that treatment should take into account specific cognitive and behavioral maintaining factors. Symptoms of depression and anxiety are highly prevalent in Parkinson’s disease and therapists should consider how to augment the efficacy of CBT for patients with Parkinson’s disease. Cognitive and behavioral interventions can help people …overcome some of the challenges in living with PD by maximizing wellbeing and overall quality of life. Show more
Keywords: Parkinson’s disease, anxiety, depression, model, CBT
DOI: 10.3233/JPD-150542
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 443-451, 2015
Authors: Domingos, Josefa M. | Godinho, Catarina | Dean, John | Coelho, Miguel | Pinto, Anabela | Bloem, Bastiaan R. | Ferreira, Joaquim J.
Article Type: Review Article
Abstract: Background: There is increasing evidence to suggest a tight relationship between cognitive impairment and falls in Parkinson’s disease (PD). Here, we draw attention to a potentially significant flaw in the existent falls-related research, namely the apparent exclusion of patients with cognitive impairment or dementia. Objective: Our objective was to review all published, on-going or scheduled fall-related intervention studies, in order to investigate the extent to which cognitively impaired individuals with PD were included in these studies. Methods: We analyzed published controlled trials regarding falls and PD in commonly used databases, as well as relevant …ongoing clinical trials registered within the World Health Organization database, clinicaltrials.gov and the European Clinical Trials Database. Results: Fourteen of the fifteen published studies included had explicit cognitive exclusion criteria as part of their study protocol. Most of the 54 on-going PD fall-related studies excluded patients with cognitive impairment. Conclusions: This suggests that individuals with cognitive impairment or dementia are excluded from fall-related research studies. We strongly recommend that future work in this area should include a representative sample of patients with PD, including subjects with cognitive decline. Show more
Keywords: Falls, Parkinson disease, rehabilitation, cognition, clinical trials
DOI: 10.3233/JPD-150590
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 453-469, 2015
Authors: Zach, Heidemarie | Dirkx, Michiel | Bloem, Bastiaan R. | Helmich, Rick C.
Article Type: Research Article
Abstract: Parkinson’s disease harbours many different tremors that differ in distribution, frequency, and context in which they occur. A good clinical tremor assessment is important for weighing up possible differential diagnoses of Parkinson’s disease, but also to measure the severity of the tremor as a basis for further tailored treatment. This can be challenging, because Parkinson’s tremor amplitude is typically very variable and context-dependent. Here, we outline how we investigate Parkinson’s tremor in the clinic. We describe a simple set of clinical tasks that can be used to constrain tremor variability (cognitive and motor co-activation, several specific limb postures). This may help …to adequately characterize the tremor(s) occurring in a patient with Parkinson’s disease. Show more
Keywords: Parkinson’s disease, clinical examination, tremor
DOI: 10.3233/JPD-150650
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 471-474, 2015
Authors: Cattaneo, Carlo | Ferla, R. La | Bonizzoni, Erminio | Sardina, Marco
Article Type: Research Article
Abstract: Background: Safinamide is a novel α-aminoamide with dopaminergic and non-dopaminergic properties developed as adjunctive therapy for patients with PD. Results from a 24-month double-blind controlled study suggested that as add-on to levodopa (and other PD medications) the benefits of safinamide on dyskinesia may be related to severity of dyskinesia at baseline. Objective: This post-hoc analysis further characterized the effects of safinamide on dyskinesia in mid- to late-stage PD patients. Methods: Patients were stratified by the presence or absence of dyskinesia at baseline, and by whether or not the dose of levodopa …had been changed during the 24-month treatment period. Differences between safinamide and placebo were evaluated using the Wilcoxon rank-sum test. Results: For the overall treated population (with or without baseline dyskinesia), safinamide 100 mg/day significantly improved the dyskinesia rating scale score, compared with placebo, in the subgroup of patients with no change in levodopa dose (p = 0.0488). For patients with baseline dyskinesia, improvements over placebo were also significant (p = 0.0153) in patients with or without changes in levodopa dose, and nearly significant (p = 0.0546) in patients with no change in levodopa dose, suggesting that these improvements were not due to levodopa dose reductions. Conclusions: While no statistically significant difference in mean DRS scores was seen between safinamide and placebo in the original study population, the present post-hoc analysis helps to provide a meaningful interpretation of the long-term effects of safinamide on dyskinesia. These results may be related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, and are unlikely due to reduced dopaminergic stimulation. Show more
Keywords: Parkinson’s disease, levodopa, safinamide, dyskinesia
DOI: 10.3233/JPD-150569
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 475-481, 2015
Authors: Ughratdar, Ismail | Samuel, Michael | Ashkan, Keyoumars
Article Type: Research Article
Abstract: Functional and stereotactic neurosurgery has always been regarded as a subspecialty based on and driven by technological advances. However until recently, the fundamentals of deep brain stimulation (DBS) hardware and software design had largely remained stagnant since its inception almost three decades ago. Recent improved understanding of disease processes in movement disorders as well clinician and patient demands has resulted in new avenues of development for DBS technology. This review describes new advances both related to hardware and software for neuromodulation. New electrode designs with segmented contacts now enable sophisticated shaping and sculpting of the field of stimulation, potentially allowing …multi-target stimulation and avoidance of side effects. To avoid lengthy programming sessions utilising multiple lead contacts, new user-friendly software allows for computational modelling and individualised directed programming. Therapy delivery is being improved with the next generation of smaller profile, longer-lasting, re-chargeable implantable pulse generators (IPGs). These include IPGs capable of delivering constant current stimulation or personalised closed-loop adaptive stimulation. Post-implantation Magnetic Resonance Imaging (MRI) has long been an issue which has been partially overcome with ‘MRI conditional devices’ and has enabled verification of DBS lead location. Surgical technique is considering a shift from frame-based to frameless stereotaxy or greater role for robot assisted implantation. The challenge for these contemporary techniques however, will be in demonstrating equivalent safety and accuracy to conventional methods. We also discuss potential future direction utilising wireless technology allowing for miniaturisation of hardware. Show more
Keywords: Deep brain stimulation, technology, advances, innovations
DOI: 10.3233/JPD-150579
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 483-496, 2015
Authors: Westbay, Lauren C. | Cao, Lishan | Burnett-Zeigler, Inger | Reizine, Natalie | Barton, Brandon | Ippolito, Dolores | Weaver, Frances M. | Stroupe, Kevin T.
Article Type: Research Article
Abstract: Background: The subthalamic nucleus (STN) and the globus pallidus internus (GPi) are both effective targets for deep brain stimulation (DBS) to relieve motor symptoms of Parkinson’s disease. However, studies have reported varied effects on mental health-related adverse events and depressed mood following DBS. Objective: The current observational study sought to compare mental health healthcare utilization and costs for three years following STN or GPi DBS. Methods: For a cohort of Veterans (n = 161) with Parkinson’s disease who participated in a larger multi-site randomized trial, we compared mental health outpatient visits, medication use, …inpatient admissions, and associated costs by DBS target site (STN vs. GPi). Results: Neither group nor time differences were significant for mental health outpatient or inpatient utilization following DBS. Overall costs associated with mental health visits and medications did not differ by time or by group. However, the percentage of patients with mental health medication use increased in the 6-month and 6 to 12 month periods post-surgery. The STN group had significantly greater increase in medication use at 6 to 12 months post-surgery compared to the GPi group (p < 0.05). Conclusion: Despite a brief increase in medication use following surgery, this study suggests that mental health healthcare use and costs are stable over time and similar between DBS targets. Prior research findings of mental health-related adverse events and mood following DBS did not translate to greater mental health service utilization in our cohort. The changes seen in the year following surgery may reflect temporary adjustments with stabilization over time. Show more
Keywords: Deep brain stimulation, Parkinson’s disease, mental health, utilization
DOI: 10.3233/JPD-140512
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 497-504, 2015
Authors: Dorsey, E. Ray | Wagner, Joseph D. | Bull, Michael T. | Rizzieri, Ashley | Grischkan, Justin | Achey, Meredith A. | Sherer, Todd | Chowdhury, Sohini | Meunier, Claire | Cappelletti, Lily | Rocker, Charlotte | Richard, Irene H. | Schwarz, Heidi | Kang, Gail | Ahmad, Stacy H. | Biemiller, Rachel A. | Biglan, Kevin M.
Article Type: Research Article
Abstract: Background: Fox Trial Finder is an online registry for individuals with and without Parkinson disease (PD) interested in participating in PD research. However, distance or disability could prevent such individuals from participating in traditional, clinic-based research at major centers. Objective: Use videoconferencing to connect participants to specialists to: (1) demonstrate feasibility of virtual research visits within this population (2) collect phenotypic data of the participants, (3) validate self-reported diagnosis, and (4) gauge interest in virtual research visits. Methods: We solicited volunteers throughout the United States through Fox Trial Finder. Interested individuals with …PD provided consent, were given web cameras if needed, completed baseline surveys, and downloaded videoconferencing software remotely. Participants had a test connection and assessment appointment which included the Montreal Cognitive Assessment (MoCA), then a virtual research visit with a neurologist who reviewed their history and assessed their PD using a modified Movement Disorders Society Unified Parkinson’s Disease Rating Scale. Neurologists assessed PD diagnosis and symptomatology. Physicians and participants were surveyed about their experience. Results: Of 204 individuals who consented, 166 (81% ) individuals from 39 states completed all visits. The mean age was 62 and mean disease duration was 8.0 years. Mean MoCA score was 26.5, and mean modified MDS-UPDRS motor score was 22.8 (out of a possible 124). Neurologists judged PD as the most likely diagnosis in 97% of cases. Overall satisfaction with the visits was 79% (satisfied or very satisfied) among neurologists and 93% among participants. Conclusions: Through virtual research visits, neurologists engaged, characterized, and validated self-reported diagnosis in individuals with PD over a broad geography. This model may facilitate future research participation. Show more
Keywords: Parkinson disease, telemedicine
DOI: 10.3233/JPD-150549
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 505-515, 2015
Authors: Silbergleit, Alice K. | LeWitt, Peter A. | Peterson, Edward L. | Gardner, Glendon M.
Article Type: Research Article
Abstract: Background: Characteristic features of hypokinetic dysarthria develop in Parkinson disease (PD). We hypothesized that quantified acoustic changes of voice might provide a correlate of disease severity. Objective: To determine if there are significant differences in acoustic measures of voice between mild and moderate PD; 2) To evaluate correlations between acoustic parameters of voice and subtests of the UPDRS in mild and moderate PD. Methods: Twenty six participants with PD underwent vocal acoustic testing while off PD medication, for comparison to 22 healthy controls. Participants with PD were divided into two groups based upon UPDRS activities …of daily living (ADL) ratings: summed scores were used to define mild and moderate PD. Participants voiced /i/ (“ee”) at comfort, high, and low pitch (3 trials/pitch). The CSpeech Waveform Analysis Program was used to analyze cycle-to-cycle frequency (“jitter”) and amplitude (“shimmer”) irregularities of the vocal signal, signal-to-noise ratio, and maximum phonation frequency range converted to semitones. Sections of UPDRS scores were correlated to acoustic variables of voice. Results: Key findings included a significant difference between the semitone range of the control subjects and the moderate PD group (p = 0.036). Further analyses revealed significant differences in semitone range for males between the controls vs. mild PD (p = 0.014), and controls vs. moderate PD (p = 0.005). Significant correlations were also found between acoustic findings and both the ADL and motor portions of the UPDRS. Conclusions: Acoustic analysis of voice, particularly frequency range, may provide a quantifiable correlate of diseaseprogression in PD. Show more
Keywords: Voice, phonation, motor function, Parkinson disease
DOI: 10.3233/JPD-140526
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 517-524, 2015
Authors: Simon-Tov, Shlomi | Dinur, Tama | Giladi, Nir | Bar-Shira, Anat | Zelis, Mayaan | Zimran, Ari | Elstein, Deborah
Article Type: Research Article
Abstract: Background: Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the β-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. Objective: The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. Methods: …The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. Results: Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. Conclusions: These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients. Show more
DOI: 10.3233/JPD-150585
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 525-531, 2015
Authors: Matthews, Helen | Stamford, Jon | Saha, Romi | Martin, Anne
Article Type: Research Article
Abstract: Background: The negative impact of wearing-off on the quality of life (QoL) of people with Parkinson’s (PWPs) is well established. However, most studies have been performed from the clinician’s perspective, and the needs of PwPs and care partners have been considered separately. Objective: This survey aimed to better understand the impact of wearing-off on both patient and care partner lives and to assess how often they are asked about their QoL in their specialist consultations. Methods: PwPs and care partners registered with The Cure Parkinson’s Trust database were invited to participate in …an online survey consisting of 21 questions about wearing-off and QoL. Data was collected for matched pairs (PwP and their care partner). Results: 47 matched pairs completed the survey. The five symptoms most commonly reported as troublesome were: tiredness, slowness, reduced dexterity, slowness of movement and slowness in the early morning. Overall, 47% of PwPs indicated that they discuss their QoL at all/most appointments. Whereas most PwPs and their care partners (87% and 74% , respectively) said that they understood what ‘wearing-off’ means, only 30% of PwPs and 17% of care partners gave a correct answer on further questioning. There was no evidence to support the idea that care partners notice the signs of wearing-off before the PwP. Conclusions: This matched survey underscores the broad impact that Parkinson’s has on daily life on both PwPs and their care partners, and indicates the need for improved communication between PwPs, care partners and their physicians. Show more
Keywords: Quality of life, care partner, wearing-off, Parkinson’s disease
DOI: 10.3233/JPD-150547
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 533-539, 2015
Authors: Alvarado-Bolaños, Alonso | Cervantes-Arriaga, Amin | Rodríguez-Violante, Mayela | Llorens-Arenas, Rodrigo | Calderón-Fajardo, Humberto | Millán-Cepeda, Roxanna | Leal-Ortega, Roberto | Estrada-Bellmann, Ingrid | Zuñiga-Ramírez, Carlos
Article Type: Research Article
Abstract: Background: Neuropsychiatric symptoms in Parkinson’s disease (PD) are frequent. Impact of neuropsychiatric symptoms on quality of life has recently become a relevant topic of research due to its potential to develop targeted therapies to improve quality of life. Objective: To determine the impact of neuropsychiatric symptoms in patients with PD using the Parkinson’s DiseaseQuestionnaire Short Form (PDQ-8). Methods: Consecutive patients with PD were evaluated with the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson’s disease (SEND-PD) and PDQ-8 scales separately. Association between neuropsychiatric symptoms and quality of life was explored using, means …comparisons, correlation coefficients and multiple regression models. Results: A total of 492 patients were included for the study. Overall, 44.5% had psychotic symptoms, 76.5% had alterations on mood/apathy domains, and 27% had an impulse control disorder. All neuropsychiatric symptoms had an effect on the PDQ-8 with a moderate to large effect size. Correlation coefficients ranged from 0.17 to 0.63 between neuropsychiatric symptoms and quality of life (p < 0.001, in all cases). The regression model showed that mood/apathy alterations and impulse control disorders, along with MDS-UPDRS III accounted for 49.8% of variance in the PDQ-8 simplified index (F = 122.98; p < 0.001). Mood/apathy alterations showed the highest correlation coefficient (0.63, p < 0.001) and β (0.53, p < 0.001). Conclusions: Both the presence and severity of neuropsychiatric symptoms, in particular mood/apathy alterations,had a significant impact on quality of life in subjects with PD. Show more
Keywords: Parkinson’s disease, depression, apathy, impulse control disorders, psychosis, quality of life
DOI: 10.3233/JPD-150597
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 541-548, 2015
Authors: Hayes, Heather A. | Hunsaker, Nikelle | Dibble, Leland E.
Article Type: Research Article
Abstract: Background: Deficits in implicit motor sequence learning (IMSL) in individuals with Parkinson disease (PD) compared to age matched healthy controls (HC) are unclear. Objective: The purpose of this paper is to present results of a systematic review with a meta-analysis examining the hypothesis that IMSL is impaired in individuals with PD when compared to HC. Methods: Fifteen articles met our final criteria and assessed 299 individuals with PD and 244 HC. Raw mean and standard deviation data for the final block of repeated and final block of random practice trials were obtained …to calculate sequence-specific learning (SSL) for individuals with PD and HC. Forest plots were used to depict the comparison of the groups by assessing standardized mean difference with random effect size. Results: A significant and moderate effect size, 0.83 was found suggesting that individuals with PD demonstrated impaired SSL of motor sequences compared to HC. Conclusions: Individuals with PD demonstrate a deficit compared with HC in their ability to implicitly learn motor tasks. Existing research lacks detail on the factors which may alter IMSL, either negatively or positively, such as the design features of current IMSL paradigms utilized and disease-specific characteristics. Successful motor rehabilitation of functional tasks in persons with PD is highly dependent on IMSL; therefore, an improved knowledge of the influence of these additional variables is critical. Show more
Keywords: Implicit motor sequence learning, Parkinson disease
DOI: 10.3233/JPD-140441
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 549-560, 2015
Authors: Reimão, Sofia | Pita Lobo, Patrícia | Neutel, Dulce | Guedes, Leonor Correia | Coelho, Miguel | Rosa, Mario M. | Ferreira, Joana | Abreu, Daisy | Gonçalves, Nilza | Morgado, Carlos | Nunes, Rita G. | Campos, Jorge | Ferreira, Joaquim J.
Article Type: Research Article
Abstract: Background: Specific MR sequences have been able to identify the loss of neuromelanin in the substantia nigra (SN) of early stage Parkinson’s disease (PD) patients. Since this technique may have a significant impact in clinical patient management, easy and widely available imaging analysis is needed for routine use. Objective: In this study we compared a quantitative analysis with a visual assessment of SN neuromelanin-sensitive MR images in early stage PD patients, in terms of pattern changes recognition and diagnostic accuracy. Methods: The inclusion criteria were untreated “de novo” PD patients or a …2–5 year PD duration; in addition, age matched controls were enrolled. These were studied with a high-resolution T1-weighted MR imaging sequence at 3.0 Tesla to visualize neuromelanin. The primary outcome was the comparison of quantitative width measurement with visual assessment by experienced neuroradiologists of SN neuromelanin sensitive MR images for PD diagnosis. Results: A total of 12 “de novo” PD patients, 10 PD patients with 2–5 year disease duration and 10 healthy controls were evaluated. We obtained a good accuracy in discriminating early-stage PD patients from controls using either a quantitative width measurement of the T1 high signal or a simple visual image inspection of the SN region. Conclusions: Visual inspection of neuromelanin-sensitive MR images by experienced neuroradiologists provides comparable results to quantitative width measurement in the detection of early stage PD SN changes and may become a useful tool inclinical practice. Show more
Keywords: Neuromelanin, locus ceruleus, substantia nigra, Parkinson’s disease, MRI
DOI: 10.3233/JPD-150551
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 561-567, 2015
Authors: Tard, Céline | Demailly, Franck | Delval, Arnaud | Semah, Franck | Defebvre, Luc | Dujardin, Kathy | Moreau, Caroline
Article Type: Research Article
Abstract: Background: Brain metabolic profiles of patients with Parkinson’s disease (PD) and cognitive impairment or dementia are now available. It would be useful if data on brain metabolism were also predictive of the risk of a pejorative cognitiveevolution - especially in the multidisciplinary management of advanced PD patients. Objective: The primary objective was to determine whether a specific brain metabolic pattern is associated with cognitive decline in PD. Methods: Sixteen advanced PD patients were screened for the absence of cognitive impairment (according to the Mattis dementia rating scale, MDRS) and underwent [18 F]-fluorodeoxyglucose …positron emission tomography brain imaging in the “off drug” state. The MDRS was scored again about two years later, categorizing patients as having significant cognitive decline (decliners) or not (stables). The two groups were then compared in terms of their brain metabolism at inclusion. Results: There were six decliners and ten stables. Significant hypometabolism in the two precunei (Brodmann area (BA) 31), the left middle temporal gyrus (BA21) and the left fusiform gyrus (BA37) was found in the decliner group compared withthe stables. Conclusion: In advanced PD, a particular metabolic pattern may be associated with the onset of significant cognitive decline. Show more
DOI: 10.3233/JPD-150583
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 569-574, 2015
Authors: Canoy, Marcel | Faber, Marjan J. | Munneke, Marten | Oortwijn, Wija | Nijkrake, Maarten J. | Bloem, Bastiaan R.
Article Type: Research Article
Abstract: In the Netherlands, the largest health technology assessment (HTA) program funds mainly (cost-)effectiveness studies and implementation research. The cost-effectiveness studies are usually controlled clinical trials which simultaneously collect cost data. The success of a clinical trial typically depends on the effect size for the primary outcome, such as health gains or mortality rates. A drawback is that in case of a negative primary outcome, relevant other (and perhaps more implicit) benefits might be missed. Conversely, positive trials can contain adverse outcomes that may also remain hidden. The capability approach (developed by Nobel Prize winner and philosopher Sen) is an instrument …that may reveal such “hidden treasures and secret pitfalls” that lie embedded within clinical trials, beyond the more traditional outcomes. Here, we exemplify the possible merits of the capability approach using a large clinical trial (funded by the HTA program in the Netherlands) that aimed to evaluate the ParkinsonNet concept, an innovative network approach for Parkinson patients. This trial showed no effects for the primary outcome, but the ParkinsonNet concept tested in this study was nevertheless met with great enthusiasm and was rapidly implemented throughout an entire country, and meanwhile also internationally. We applied the capability approach to the ParkinsonNet concept, and this analysis yielded additional benefits within several capability domains. These findings seems to substantiate the claim that richer policy debates may ensue by applying the capability approach to clinical trial data, in addition to traditional outcomes. Show more
Keywords: Cost-benefit analysis, value-based purchasing, outcome assessment, organizational innovation, patient-centered care
DOI: 10.3233/JPD-150612
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 575-580, 2015
Authors: Stephenson, Diane | Hu, Michele T. | Romero, Klaus | Breen, Kieran | Burn, David | Ben-Shlomo, Yoav | Bhattaram, Atul | Isaac, Maria | Venuto, Charles | Kubota, Ken | Little, Max A. | Friend, Stephen | Lovestone, Simon | Morris, Huw R. | Grosset, Donald | Sutherland, Margaret | Gallacher, John | Williams-Gray, Caroline | Bain, Lisa J. | Avilés, Enrique | Marek, Ken | Toga, Arthur W. | Stark, Yafit | Forrest Gordon, Mark | Ford, Steve
Article Type: Research Article
Abstract: Parkinson’s disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson’s UK and co-organized by Critical Path Institute’s (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there …is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson’s disease. Show more
Keywords: Data standards, privacy, data integration, collaboration, quantitative disease progression, regulatory science
DOI: 10.3233/JPD-150570
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 581-594, 2015
Authors: Brehm, Nadine | Rau, Katrin | Kurz, Alexander | Gispert, Suzana | Auburger, Georg
Article Type: Research Article
Abstract: Background: Parkinson’s disease (PD) is characterized by loss of midbrain dopaminergic neurons, which are affected by cytoplasmic inclusions, named Lewy pathology. The main component is alpha-synuclein (SNCA), a protein modulating SNARE-complex dependent neurotransmission. SNCA mutations trigger dominantly inherited PD variants and sporadic cases of PD via aggregation and transmission. SNCA and isoforms of the 14-3-3 family show sequence homology, protein interaction and joint aggregation, so 14-3-3 s may be key molecules of pathogenesis. Objective: We aimed to identify the relevant isoforms in midbrain and to distinguish for the first time the changes that occur very early …versus those that progress with pathology. Methods: We assessed expression of the 14-3-3 family with quantitative RT-PCR and immunoblots of differential solubility fractions in mice with A53T-SNCA overexpression longitudinally at different ages. Results: Transcript levels showed reductions at age 3 months with increases at later ages for the beta, eta and zeta isoforms. Protein levels at age 3 months exhibited a concordant reduction only for beta, while increased insolubility was observed for epsilon and zeta. At age 18 months only the reduction of 14-3-3 beta protein remained significant. Thus, the toxic gain-of-function of alpha-synuclein leads to early transitory alterations of several 14-3-3 isoforms. When the levels of soluble 14-3-3 proteins become apparently normal during later life, increasing amounts of beta, eta and zeta mRNA are produced, possibly to compensate for protein insolubility and aggregation in a SNCA/14-3-3 complex. Conclusions: These data may contribute to identify key molecular events that reflect Parkinson’s disease risk and progression. Show more
Keywords: Lewy body disease, gene expression profiles, signal transduction, biomarkers
DOI: 10.3233/JPD-150606
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 595-604, 2015
Authors: Kim, Young Eun | Kang, Suk Yun | Ma, Hyeo-Il | Ju, Young-Su | Kim, Yun Joong
Article Type: Research Article
Abstract: Background: Although the hummingbird sign (HBS) is a distinctive feature of progressive supranuclear palsy (PSP) VS. idiopathic Parkinson’s disease (IPD) and other parkinsonian disorders, there are no consensus criteria for its identification. Objective: To develop consensus criteria for the HBS to enable accurate communication between researchers and physicians, we developed a new radiologic rating scale for the HBS (the HBS-RS), and the inter-rater reliability (IRR) and diagnostic validity of the HBS-RS were evaluated. Methods: Two raters blinded to the clinical diagnoses reviewed T1 midsagittal magnetic resonance images of 133 patients with IPD …(n = 93) or PSP (n = 40). The existence of the HBS was assessed in two steps that were separated by two weeks; the first was based on their own experience and the second was according to the HBS-RS. The HBS-RS comprises 4 items (contour of the third ventricle floor, shape of the beak, shape of the hummingbird head, and midbrain atrophy), with weighted scores from 0 to 2. Results: The IRR of individual items in the HBS-RS and of the composite scores showed moderate-to-good agreement (Cohen’s kappa [κ ], 0.479–0.766) and were observed to be highest for the contour of the third ventricle floor. The sensitivities and specificities varied depending on the cut-off for each item or for the composite scores. The sensitivities for each item were high (85.0–92.5) at a low cut-off (0 VS. 1 or 2). The specificities reached more than 80% when the composite scores of the HBS-RS were used. Receiver operating characteristic curves for the total HBS-RS scores showed fair diagnostic accuracy for PSP (AUC, 0.76 and 0.73). Conclusions: The HBS-RS is a simple and measurable visual assessment tool to identify the HBS, with adjustable diagnostic validity for PSP. The results suggest that the HBS-RS may be used for objective measurements of the HBS in research and in the clinic. Show more
Keywords: Progressive supranuclear palsy, idiopathic Parkinson’s disease, hummingbird sign, magnetic resonance imaging, inter-rater reliability
DOI: 10.3233/JPD-150537
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 605-612, 2015
Authors: Münte, Thomas F. | Joppich, Gregor | Däuper, Jan | Schrader, Christoph | Dengler, Reinhard | Heldmann, Marcus
Article Type: Research Article
Abstract: Background: The generation of random sequences is considered to tax executive functions and has been reported to be impaired in Parkinson’s disease (PD) previously. Objective: To assess the neurophysiological markers of random number generation in PD. Methods: Event-related potentials (ERP) were recorded in 12 PD patients and 12 age-matched normal controls (NC) while either engaging in random number generation (RNG) by pressing the number keys on a computer keyboard in a random sequence or in ordered number generation (ONG) necessitating key presses in the canonical order. Key presses were paced by an …external auditory stimulus at a rate of 1 tone every 1800 ms. As a secondary task subjects had to monitor the tone-sequence for a particular target tone to which the number “0” key had to be pressed. This target tone occurred randomly and infrequently, thus creating a secondary oddball task. Results: Behaviorally, PD patients showed an increased tendency to count in steps of one as well as a tendency towards repetition avoidance. Electrophysiologically, the amplitude of the P3 component of the ERP to the target tone of the secondary task was reduced during RNG in PD but not in NC. Discussion: The behavioral findings indicate less random behavior in PD while the ERP findings suggest that this impairment comes about, because attentional resources are depleted in PD. Show more
Keywords: Parkinson’s disease, random number generation, dual task, event-related potentials
DOI: 10.3233/JPD-150575
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 613-620, 2015
Authors: Lamotte, Guillaume | Rafferty, Miriam R. | Prodoehl, Janey | Kohrt, Wendy M. | Comella, Cynthia L. | Simuni, Tanya | Corcos, Daniel M.
Article Type: Correction
DOI: 10.3233/JPD-159001
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 621-621, 2015
Authors: Sierra, María | Carnicella, Sébastien | Strafella, Antonio P. | Bichon, Amélie | Lhommée, Eugénie | Castrioto, Anna | Chabardes, Stephan | Thobois, Stéphane | Krack, Paul
Article Type: Review Article
Abstract: Neuropsychiatric symptoms are common non-motor symptoms in Parkinson’s disease (PD). Apathy and impulse control disorders (ICD) are two opposite motivational expressions of a continuous behavioural spectrum involving hypo- and hyperdopaminergia. Both syndromes share pathological (decreased vs increased) dopamine receptor stimulation states. Apathy belongs to the spectrum of hypodopaminergic symptoms together with anhedonia, anxiety and depression. Apathy is a key symptom of PD which worsens with disease progression. Animal models, imaging and pharmacological studies concur in pointing out dopaminergic denervation in the aetiology of parkinsonian apathy with a cardinal role of decreased tonic D2/D3 receptor stimulation. ICDs are part of the …hyperdopaminergic behavioural spectrum, which also includes punding, and dopamine dysregulation syndrome (DDS), which are all related to non-physiological dopaminergic stimulation induced by antiparkinsonian drugs. According to clinical data tonic D2/D3 receptor stimulation can be sufficient to induce ICDs. Clinical observations in drug addiction and PD as well as data from studies in dopamine depleted rodents provide hints allowing to argue that both pulsatile D1 and D2 receptor stimulation and the severity of dopaminergic denervation are risk factors to develop punding behavior and DDS. Imaging studies have shown that the brain structures involved in drug addiction are also involved in hyperdopaminergic behaviours with increase of bottom-up appetitive drive and decrease in prefrontal top down behavioural control. Show more
Keywords: Apathy, Parkinson’s disease, impulse control disorders, dopamine dysregulation syndrome, punding
DOI: 10.3233/JPD-150535
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 625-636, 2015
Authors: Damier, Philippe
Article Type: Review Article
Abstract: Our knowledge of the cerebral bases of decision making has grown considerably in the past decade. The dopamine system is closely involved in many aspects of the decisional process. It is therefore not surprising that the dysfunctions that occur in Parkinson’s disease (PD) can alter some patients’ decisions. Put simply, a decision is the final step of a process in which a subject weighs up the potential benefits and costs associated with each of the different options available for a given choice. The option that appears to have the best ratio of benefits to costs is chosen. In some PD …patients, dopamine agonists destabilize the balance: the benefits are given an inappropriately high weighting relative to the costs, leading patients to take decisions they would not otherwise have taken. This might be one of the explanations for impulse control disorders observed in some PD patients. Dysfunction of the subthalamic nucleus (STN) induced by dopamine replacement or by deep brain stimulation is another mechanism that can alter decision making. The STN plays an active role in the decisional process, especially by slowing down the process when the difference between the options to be considered in a given choice is small (e.g. a win-win choice). Deep brain stimulation applied to the STN may interfere with its monitoring role and lead to an impulsive choice. Attention disorders and frontal lobe dysfunction, highly prevalent in the course of PD, are other factors that may alter a patient’s decision making. Patients and caregivers need to be aware of this, since the consequences can sometimes be detrimental. Show more
Keywords: Parkinson’s disease, dopamine, decision making, reinforcement learning, subthalamic nucleus, deep-brain stimulation, impulse control disorder
DOI: 10.3233/JPD-150600
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 637-642, 2015
Authors: Agid, Yves
Article Type: Review Article
DOI: 10.3233/JPD-150573
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 643-645, 2015
Authors: Klingelhoefer, Lisa | Reichmann, Heinz
Article Type: Review Article
Abstract: Gastrointestinal (GI) disturbances in Parkinson’s disease (PD) are varied, involve the upper and lower GI tract and are evident in all stages of the disease. Recognition and re-evaluation of these non motor symptoms (NMS) due to the course of PD is important. They have a major impact on the efficacy of oral antiparkinsonian medication and health related quality of life. Treatment needs to be tailored to the specific patient case with evaluation of PD stage, the specific GI NMS and comorbidities. This article provides an overview of the pharmacological and non-pharmacological therapeutic options for GI NMS in PD.
Keywords: Gastrointestinal non motor symptoms, gastrointestinal symptoms, NMS, Parkinson’s disease, PD, gastric symptoms, therapy, gut
DOI: 10.3233/JPD-150574
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 647-658, 2015
Authors: Aarsland, Dag | Kramberger, Milica Gregoric
Article Type: Review Article
Abstract: Parkinson’s disease (PD) is characterized by motor symptoms, but focused and extensive research in the last years has provided new knowledge in the field of non-motor symptoms. Non-motor symptoms include neuropsychiatric symptoms such as depression, anxiety, psychosis, apathy, impulse control disorders, and occur in the majority of patients with PD. They are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies commonly used for treatment of PD can induce or worsen such symptoms. This paper discusses the epidemiology, clinical features and treatment approaches for neuropsychiatric …symptoms (NPS) in PD in the perspective of clinical practice and management. The prevalence rates of various NPS are high, various demographic, clinical and treatment related variables have shown to be associated with higher risk of NPS. Randomized controlled trials of pharmacological and non-pharmacological treatments of NPS in PD are sparse. Current evidence supports tricyclic antidepressants as efficacious treatment of depression in PD and antipsychotic clozapine as efficacious choice for psychosis. Further studies to evaluate various other management strategies of NPS in PD are required. Neuropsychiatric symptoms in PD should be considered an integral part of the disease; hence a multidisciplinary approach is essential to improve the overall outcome of PD also through raised awareness and enriched knowledge on NPS. Show more
Keywords: Neuropsychiatric symptoms, Parkinson’s disease, depression, anxiety, psychosis, apathy, suicide
DOI: 10.3233/JPD-150604
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 659-667, 2015
Authors: Magen, Iddo | Torres, Eileen Ruth | Dinh, Diana | Chung, Andrew | Masliah, Eliezer | Chesselet, Marie-Françoise
Article Type: Research Article
Abstract: Background: Patients with Parkinson’s disease (PD) may exhibit deficits in “Theory of Mind”, the ability to read others’ mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits. Objective: To …determine whether Thy1-aSyn mice present alterations in their response to social stimuli. Methods: We have submitted Thy1-aSyn mice to tests adapted from autism models. Results: At 7–8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3–4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction. Conclusion: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alpha-synuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life. Show more
Keywords: Theory of mind, mGluR5, autistic disorder
DOI: 10.3233/JPD-140503
Citation: Journal of Parkinson's Disease, vol. 5, no. 3, pp. 669-680, 2015
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