Journal of Parkinson's Disease - Volume 9, issue 2

Authors: McFarthing, Kevin | Prakash, Neha | Simuni, Tanya

Article Type: Other

DOI: 10.3233/JPD-199001

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 251-264, 2019

Authors: Mohamed, Nguyen-Vi | Larroquette, Frédérique | Beitel, Lenore K. | Fon, Edward A. | Durcan, Thomas M.

Article Type: Review Article

Abstract: Studying Parkinson’s disease (PD) in the laboratory presents many challenges, the main one being the limited availability of human cells and tissue from affected individuals. As PD is characterized by a loss of dopaminergic (DA) neurons in the brain, it is nearly impossible for researchers to access and extract these cells from living patients. Thus, in the past PD research has focused on the use of patients’ post-mortem tissues, animal models, or immortalized cell lines to dissect cellular pathways of interest. While these strategies deepened our knowledge of pathological mechanisms in PD, they failed to faithfully capture key mechanisms at …play in the human brain. The emergence of induced pluripotent stem cell (iPSC) technology is revolutionizing PD research, as it allows for the differentiation and growth of human DA neurons in vitro , holding immense potential not only for modelling PD, but also for identifying novel therapies. However, to reproduce the complexity of the brain’s environment, researchers are recognizing the need to further develop and refine iPSC-based tools. In this review, we provide an overview of different systems now available for the study of PD, with a particular emphasis on the potential and limitations of iPSC as research tools to generate more relevant models of PD pathophysiology and advance the drug discovery process. Show more

Keywords: Stem cells, CRISPR, co-cultures, neuronal organoids, Parkinson’s disease, cell therapy

DOI: 10.3233/JPD-181515

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 265-281, 2019

Authors: Owen, Charlotte L. | Ibrahim, Kinda | Dennison, Laura | Roberts, Helen C.

Article Type: Review Article

Abstract: Background: Falls are common in Parkinson’s disease (PD). Increased involvement of people with Parkinson’s (PwP) in their care has been associated with enhanced satisfaction. Self-management programmes in other long-term conditions (LTCs) have led to improvements in physical and psychological outcomes. These have been more effective when targeted toward a specific behavior. Objective: This paper aimed to identify and review falls self-management interventions for PwP. Methods: A systematic review was conducted. Electronic databases were searched in June 2018. Primary research studies (any design) reporting the delivery of falls self-management interventions to PwP were included. Data was extracted …from each article and synthesised narratively. Results: Six articles were identified, relating to five different self-management interventions. All described a self-management intervention delivered alongside physiotherapy. Intervention delivery was through either group discussion (n  = 3) or falls booklets (n  = 3). Interventions were often incompletely described; the most common components were information about the condition, training/ rehearsal for psychological strategies and lifestyle advice and support. Arising from the design of articles included the effects of self-management and physiotherapy could not be separated. Three articles measured falls, only one led to a reduction. Four articles measured quality of life, only one led to improvement. No articles assessed skill acquisition or adherence to the self-management intervention. Conclusions: Few falls self-management interventions for PwP have been evaluated and reported. The components of an effective intervention remain unclear. Given the benefits of self-management interventions in other LTCs, it is important that falls self-management interventions are developed and evaluated to support PwP. Show more

Keywords: Accidental falls, parkinson’s disease, patient education as topic, review, self care

DOI: 10.3233/JPD-181524

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 283-299, 2019

Authors: Whone, Alan L. | Boca, Mihaela | Luz, Matthias | Woolley, Max | Mooney, Lucy | Dharia, Sonali | Broadfoot, Jack | Cronin, David | Schroers, Christian | Barua, Neil U. | Longpre, Lara | Barclay, C. Lynn | Boiko, Chris | Johnson, Greg A. | Fibiger, H. Christian | Harrison, Rob | Lewis, Owen | Pritchard, Gemma | Howell, Mike | Irving, Charlie | Johnson, David | Kinch, Suk | Marshall, Christopher | Lawrence, Andrew D. | Blinder, Stephan | Sossi, Vesna | Stoessl, A. Jon | Skinner, Paul | Mohr, Erich | Gill, Steven S.

Article Type: Research Article

Abstract: Background: Intraputamenal glial cell line-derived neurotrophic factor (GDNF), administered every 4 weeks to patients with moderately advanced Parkinson’s disease, did not show significant clinical improvements against placebo at 40 weeks, although it significantly increased [18 F]DOPA uptake throughout the entire putamen. Objective: This open-label extension study explored the effects of continued (prior GDNF patients) or new (prior placebo patients) exposure to GDNF for another 40 weeks. Methods: Using the infusion protocol of the parent study, all patients received GDNF without disclosing prior treatment allocations (GDNF or placebo). The primary outcome was the percentage change from baseline …to Week 80 in the OFF state Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. Results: All 41 parent study participants were enrolled. The primary outcome decreased by 26.7±20.7% in patients on GDNF for 80 weeks (GDNF/GDNF; N = 21) and 27.6±23.6% in patients on placebo for 40 weeks followed by GDNF for 40 weeks (placebo/GDNF, N = 20; least squares mean difference: 0.4%, 95% CI: –13.9, 14.6, p  = 0.96). Secondary endpoints did not show significant differences between the groups at Week 80 either. Prespecified comparisons between GDNF/GDNF at Week 80 and placebo/GDNF at Week 40 showed significant differences for mean OFF state UPDRS motor (–9.6±6.7 vs. –3.8±4.2 points, p  = 0.0108) and activities of daily living score (–6.9±5.5 vs. –1.0±3.7 points, p  = 0.0003). No treatment-emergent safety concerns were identified. Conclusions: The aggregate study results, from the parent and open-label extension suggest that future testing with GDNF will likely require an 80- rather than a 40-week randomized treatment period and/or a higher dose. Show more

Keywords: Glial cell line-derived neurotrophic factor, convection enhanced delivery, Parkinson’s disease, neurorestoration

DOI: 10.3233/JPD-191576

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 301-313, 2019

Authors: Chatterjee, Diptaman | Sanchez, Daniel Saiz | Quansah, Emmanuel | Rey, Nolwen L. | George, Sonia | Becker, Katelyn | Madaj, Zachary | Steiner, Jennifer A. | Ma, Jiyan | Escobar Galvis, Martha L. | Kordower, Jeffrey H. | Brundin, Patrik

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of α -synuclein (α -syn) pre-formed fibril (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+ /– ) mouse that features several pathophysiological hallmarks of clinical PD. Objective: To test the hypothesis that the neuropathological changes in the En1+ /– …mice will promote formation of α -syn aggregates following intrastriatal injections of pathogenic human α -syn PFFs. Methods: We unilaterally injected PFFs into the striata of 1-month-old En1+ /– and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. Results: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1+ /– mice exhibited a near-threefold increase in pS129-α -syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1+ /– mice also displayed significant increases in pS129-α -syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129-α -syn-positive aggregation in En1+ /– mice in multiple cortical regions. Conclusions: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological α -syn, potentially due to En1- loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could result in a PD mouse model that predicts which experimental therapies will be effective in PD. Show more

Keywords: α-Synuclein, Parkinson’s disease, engrailed, proteinopathy, misfolded proteins, propagation, mouse models, neurodegeneration

DOI: 10.3233/JPD-191590

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 315-326, 2019

Authors: Massa, Jason | Chahine, Lana M.

Article Type: Research Article

Abstract: Background: In patients with early parkinsonism, misdiagnosis may occur in >30% of cases. This can have detrimental consequences clinically and in clinical trials. Dopamine transporter (DAT) SPECT imaging can help improve diagnostic accuracy. Objective: To describe characteristics of individuals initially diagnosed with idiopathic Parkinson’s disease (iPD) and with abnormal DAT SPECT imaging who had a change in diagnosis on follow-up. Methods: Data were obtained from the biomarker study Parkinson’s Progression Markers Initiative (PPMI). PPMI is a multicenter, observational study that enrolled 423 individuals with a diagnosis of iPD of ≤2 years duration and with abnormal DAT …SPECT imaging. Participants were assessed at least annually, and diagnosis was documented by the site neurologist. Characteristics of those that had a change in diagnosis were compared to those with stable diagnosis. Results: 390 subjects were included. Eight (2%) had a change in diagnosis. The diagnosis was changed to multiple system atrophy in 5 cases, dementia with Lewy bodies in 2, and corticobasal degeneration in 1. Revision of diagnosis occurred 2–5.2 years from enrollment. Mean motor score was higher (26.9 vs 20.6; p  = 0.01), DAT binding lower (1.056 vs 1.406; p  = 0.01), genetic risk score lower (–0.016 vs –0.022; p  = 0.0470), and olfaction score higher (28.75 vs 22.05; p  = 0.03) in those whose diagnosis changed compared to those who did not. Conclusion: Diagnosis remained stable in most individuals with early parkinsonism diagnosed with iPD and with abnormal DAT imaging. A small number had a revision in diagnosis. Clinical and biomarker abnormalities were greater at baseline in those whose diagnosis changed. Show more

Keywords: Parkinson’s disease, parkinsonism, movement disorders, SPECT, DAT scan, multiple system atrophy, atypical parkinsonism

DOI: 10.3233/JPD-181517

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 327-334, 2019

Authors: Kalyani, H.H.N | Sullivan, Karen | Moyle, Gene | Brauer, Sandy | Jeffrey, Erica Rose | Roeder, Luisa | Berndt, Sara | Kerr, Graham

Article Type: Research Article

Abstract: Dance-based interventions have been proposed for the management of Parkinson’s disease (PD) symptoms. This review critically appraises and synthesises the research on the effects of dance interventions on gait, cognition and dual-tasking in PD, through a meta-analysis of peer-reviewed literature from seven databases. Eligible studies included people with PD, used a parallel-group or cohort design with a dance-based intervention, reported outcome measures of gait, cognition or dual-tasking, and were published in English up until September 2017. Of the initial 1079 articles, 677 articles were reviewed for eligibility, and 25 articles were retained. Only 12 articles had sufficient common assessment items …for meta-analysis. Two independent reviewers extracted the data and assessed the risk of bias of each study using the Cochrane risk-of-bias tool. Based on pre-post change scores, gait speed, Timed Up and Go (TUG) test performance, freezing of gait questionnaire, and six-minute walk test times significantly improved after a dance intervention compared to controls. Global cognition assessed with Montreal Cognitive Assessment, and cognitive dual-tasking measured using dual-task TUG, also exhibited greater improvement in dance groups. There was limited evidence to determine the most effective intensity, frequency, duration of dance interventions or the most beneficial music. Findings must be interpreted cautiously because of the lack of randomised control trials, and the moderate to high risk of bias of studies. However, the results of papers with level-I and level-II.1 evidence suggest that dance may have the potential to ameliorate PD symptoms, particularly gait, global cognition and cognitive dual-tasking. Show more

DOI: 10.3233/JPD-181516

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 335-349, 2019

Authors: Sleeman, Isobel | Lawson, Rachael A. | Yarnall, Alison J. | Duncan, Gordon W. | Johnston, Fionnuala | Khoo, Tien K. | Burn, David J.

Article Type: Research Article

Abstract: Background: Urate and homocysteine are potential biomarkers for disease progression in Parkinson’s disease (PD). Baseline serum urate concentration has been shown to predict motor but not cognitive decline. The relationship between serum homocysteine concentration and cognitive and motor impairment is unknown. Objectives: The aim of this study was to examine the association between baseline serum urate and homocysteine, and prospective measures of disease progression and cognition over 54 months in early PD. Methods: 154 newly diagnosed PD participants and 99 age-matched controls completed a schedule of assessments at baseline, 18, 36 and 54 months. The Movement …Disorders Society Unified Parkinson’s Disease Scale Part III (MDS-UPDRS III) was used to assess motor severity. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Serum samples drawn at baseline were analysed for urate, homocysteine, red cell folate and vitamin B12 concentrations. Results: Baseline urate was 331.4±83.8 and 302.7±78.0μ mol/L for control and PD participants, respectively (p  = 0.015). Baseline homocysteine was 9.6±3.3 and 11.1±3.8μ mol/L for controls and PD participants, respectively (p  < 0.01). Linear mixed effects modelling showed that lower baseline urate (β = 0.02, p  < 0.001) and higher homocysteine (β = 0.29, p  < 0.05) predicted decline in motor function. Only higher homocysteine concentrations at baseline, however, predicted declining MoCA scores over 54 months (β = 0.11, p  < 0.01). Conclusions: Lower serum urate concentration is associated with worsening motor function; while higher homocysteine concentration is associated with change in motor function and cognitive decline. Therefore, urate and homocysteine may be suitable biomarkers for predicting motor and cognitive decline in early PD. Show more

Keywords: Parkinson’s disease, urate, homocysteine, disease progression, prospective study

DOI: 10.3233/JPD-181535

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 351-359, 2019

Authors: Markaki, Ioanna | Klironomos, Stefanos | Svenningsson, Per

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (SVD), often manifesting as white matter lesions (WMLs), and Parkinson’s disease (PD) are common disorders whose prevalence increases with age. Vascular risk factors contribute to SVD, but their role in PD is less clear. Objectives: The study objective was to investigate the frequency and grade of WMLs in PD, and their association with clinical and biochemical parameters. Methods: In total, 100 consecutive patients with available magnetic resonance imaging were included. Vascular risk factors including smoking, hypertension, diabetes type 2, atrial fibrillation, heart insufficiency and hypercholesterolemia were assessed. In 50 patients that …had underwent lumbar puncture, cerebrospinal fluid (csf) levels of beta-amyloid1-42 , tau and phospho-tau were measured. Results: WMLs were present in 86 of 100 patients. Increasing WML severity was independently associated with increased age and lower csf beta-amyloid1-42 . Conclusions: In our study, WMLs were very common in patients with PD, and were associated with low levels of csf beta-amyloid1-42 . Longitudinal studies would increase understanding of the interplay between WMLs and amyloid pathology in PD. Show more

Keywords: Parkinson’s disease, cerebral small vessel disease, amyloid-beta, cerebrospinal fluid

DOI: 10.3233/JPD-181486

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 361-367, 2019

Authors: Fründt, Odette | Grashorn, Wiebke | Buhmann, Carsten | Forkmann, Katarina | Mainka, Tina | Bingel, Ulrike | Schmidt, Katharina

Article Type: Research Article

Abstract: Background: Pain is highly prevalent in patients with Parkinson’s disease (PD), but underlying pathophysiological mechanisms are largely unclear. Alterations in somatosensory processing might contribute to sensory abnormalities in PD. Objective: This study investigated sensory processing in PD patients. Methods: We used the standardized “Quantitative Sensory Testing” (QST) protocol (German Research Network on Neuropathic Pain) to investigate 13 somatosensory parameters in 19 PD patients naïve to dopaminergic medication and 19 healthy controls matched for age, gender, and handedness. We tested for differences in sensory parameters between i) drug-naïve PD patients and healthy controls, ii) patients’ more and …less affected body side, and iii) for an association of somatosensory parameters with disease-specific factors. Results: We did not observe any significant group differences in somatosensory parameters between PD patients and healthy subjects. In PD patients, QST mean z-scores did not differ between the predominantly and the less affected body side, PD patients with and without PD-specific chronic pain or between different PD subtypes. Age, but not PD disease severity, was associated with a greater loss of function in thermal and mechanical detection thresholds. Conclusions: Somatosensory processing, as assessed with the well-established QST protocol, was normal in drug-naïve PD patients. Thus, somatosensory abnormalities previously reported in medicated PD patients might rather be a result of dopaminergic medication, or may occur later in the course of the disease or with increasing age. Show more

Keywords: QST, quantitative sensory testing, Parkinson’s disease, drug-naïve

DOI: 10.3233/JPD-181513

Citation: Journal of Parkinson's Disease, vol. 9, no. 2, pp. 369-378, 2019