Journal of Parkinson's Disease - Volume 7, issue 1

Authors: Jakubowski, Jennifer L. | Labrie, Viviane

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is a prevalent neurodegenerative illness that is often diagnosed after significant pathology and neuronal cell loss has occurred. Biomarkers of PD are greatly needed for early diagnosis, as well as for the prediction of disease progression and treatment outcome. In this regard, the epigenome, which is partially dynamic, holds considerable promise for the development of molecular biomarkers for PD. Epigenetic marks are modified by both DNA sequence and environmental factors associated with PD, and such marks could serve as a unifying predictor of at-risk individuals. Epigenetic abnormalities have been detected in PD and other age-dependent neurodegenerative diseases, …some of which were reported to occur early on and were reversible by PD medications. Emerging reports indicate that certain epigenetic differences observed in the PD brain are detectable in more easily accessible tissues. In this review, we examine epigenetic-based strategies for the development of PD biomarkers. Despite the complexities and challenges faced, the epigenome offers a new source of biomarkers with potential etiological relevance to PD, and may expand opportunities for personalized therapies. Show more

Keywords: Parkinson’s disease, biomarkers, epigenetics, DNA methylation, α-synuclein, single nucleotide polymorphism, mitochondrial DNA methylation, epigenetic clock

DOI: 10.3233/JPD-160914

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 1-12, 2017

Authors: Truban, Dominika | Hou, Xu | Caulfield, Thomas R. | Fiesel, Fabienne C. | Springer, Wolfdieter

Article Type: Review Article

Abstract: The first clinical description of Parkinson’s disease (PD) will embrace its two century anniversary in 2017. For the past 30 years, mitochondrial dysfunction has been hypothesized to play a central role in the pathobiology of this devastating neurodegenerative disease. The identifications of mutations in genes encoding PINK1 (PTEN-induced kinase 1) and Parkin (E3 ubiquitin ligase) in familial PD and their functional association with mitochondrial quality control provided further support to this hypothesis. Recent research focused mainly on their key involvement in the clearance of damaged mitochondria, a process known as mitophagy. It has become evident that there are many other …aspects of this complex regulated, multifaceted pathway that provides neuroprotection. As such, numerous additional factors that impact PINK1/Parkin have already been identified including genes involved in other forms of PD. A great pathogenic overlap amongst different forms of familial, environmental and even sporadic disease is emerging that potentially converges at the level of mitochondrial quality control. Tremendous efforts now seek to further detail the roles and exploit PINK1 and Parkin, their upstream regulators and downstream signaling pathways for future translation. This review summarizes the latest findings on PINK1/Parkin-directed mitochondrial quality control, its integration and cross-talk with other disease factors and pathways as well as the implications for idiopathic PD. In addition, we highlight novel avenues for the development of biomarkers and disease-modifying therapies that are based on a detailed understanding of the PINK1/Parkin pathway. Show more

Keywords: Parkinson’s disease, PINK1, Parkin, ubiquitin, mitochondria, mitophagy

DOI: 10.3233/JPD-160989

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 13-29, 2017

Authors: Bentea, Eduard | Verbruggen, Lise | Massie, Ann

Article Type: Review Article

Abstract: The pathological hallmarks of Parkinson’s disease are the progressive loss of nigral dopaminergic neurons and the formation of intracellular inclusion bodies, termed Lewy bodies, in surviving neurons. Accumulation of proteins in large insoluble cytoplasmic aggregates has been proposed to result, partly, from a failure in the function of intracellular protein degradation pathways. Evidence in support for such a hypothesis emerged in the beginning of the years 2000 with studies demonstrating structural and functional deficits in the ubiquitin-proteasome pathway in post-mortem nigral tissue of patients with Parkinson’s disease. These fundamental findings have inspired the development of a new generation of animal …models based on the use of proteasome inhibitors to disturb protein homeostasis and trigger nigral dopaminergic neurodegeneration. In this review, we provide an updated overview of the current approaches in employing proteasome inhibitors to model Parkinson’s disease, with particular emphasis on rodent studies. In addition, the mechanisms underlying proteasome inhibition-induced cell death and the validity criteria (construct, face and predictive validity) of the model will be critically discussed. Due to its distinct, but highly relevant mechanism of inducing neuronal death, the proteasome inhibition model represents a useful addition to the repertoire of toxin-based models of Parkinson’s disease that might provide novel clues to unravel the complex pathogenesis of this disorder. Show more

Keywords: Proteasome, lactacystin, neurodegeneration, animal model, Parkinson’s disease

DOI: 10.3233/JPD-160921

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 31-63, 2017

Authors: Hasan, Hasan | Athauda, Dilan S. | Foltynie, Thomas | Noyce, Alastair J.

Article Type: Review Article

Abstract: Background: The MDS-UPDRS (Movement Disorders Society – Unified Parkinson’s Disease Rating Scale) is the most widely used scale for rating impairment in PD. Subscores measuring bradykinesia have low reliability that can be subject to rater variability. Novel technological tools can be used to overcome such issues. Objective: To systematically explore and describe the available technologies for measuring limb bradykinesia in PD that were published between 2006 and 2016. Methods: A systematic literature search using PubMed (MEDLINE), IEEE Xplore, Web of Science, Scopus and Engineering Village (Compendex and Inspec) databases was performed to identify relevant technologies …published until 18 October 2016. Results: 47 technologies assessing bradykinesia in PD were identified, 17 of which offered home and clinic-based assessment whilst 30 provided clinic-based assessment only. Of the eligible studies, 7 were validated in a PD patient population only, whilst 40 were tested in both PD and healthy control groups. 19 of the 47 technologies assessed bradykinesia only, whereas 28 assessed other parkinsonian features as well. 33 technologies have been described in additional PD-related studies, whereas 14 are not known to have been tested beyond the pilot phase. Conclusion: Technology based tools offer advantages including objective motor assessment and home monitoring of symptoms, and can be used to assess response to intervention in clinical trials or routine care. This review provides an up-to-date repository and synthesis of the current literature regarding technology used for assessing limb bradykinesia in PD. The review also discusses the current trends with regards to technology and discusses future directions in development. Show more

Keywords: Hypokinesia, Parkinson disease, technology, outcome assessment, ambulatory monitoring, review

DOI: 10.3233/JPD-160878

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 65-77, 2017

Authors: Schwarzschild, Michael A.

Article Type: Article Commentary

DOI: 10.3233/JPD-160975

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 79-80, 2017

Authors: Araújo, Rui | Sorensen, Aaron A. | Konkiel, Stacy | Bloem, Bastiaan R.

Article Type: Short Communication

Abstract: A new class of social web-based metrics for scholarly publications (altmetrics) has surfaced as a complement to traditional citation-based metrics. Our aim was to study and characterize those recent papers in the field of Parkinson’s disease which had received the highest Altmetric Attention Scores and to compare this attention measure to the traditional metrics. The top 20 papers in our analysis covered a variety of topics, mainly new disease mechanisms, treatment options and risk factors for the development of PD. The main media sources for these high attention papers were news items and Twitter. The papers were published predominantly in …high impact journals, suggesting a correlation between altmetrics and conventional metrics. One paper published in a relatively modest journal received a significant amount of attention, reflecting that public attention does not always parallel the traditional metrics. None of the most influential papers in PD, as reviewed by Ponce and Lozano (2011) made it to our list, suggesting that recent publications receive higher attention scores, and that altmetrics may omit older, seminal work in the field. Show more

Keywords: Altmetric, impact factor, Parkinson’s disease, social media

DOI: 10.3233/JPD-179000

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 81-87, 2017

Authors: Heusinkveld, Lauren | Hacker, Mallory | Turchan, Maxim | Bollig, Madelyn | Tamargo, Christina | Fisher, William | McLaughlin, Lauren | Martig, Adria | Charles, David

Article Type: Short Communication

Abstract: The FDA has approved a multicenter, double-blind, Phase III, pivotal trial testing deep brain stimulation (DBS) in 280 people with very early stage Parkinson’s disease (PD; IDE#G050016). In partnership with The Michael J. Fox Foundation for Parkinson’s Research, we conducted a survey to investigate motivating factors, barriers, and gender differences among potentially eligible patients for participation in a trial testing DBS in early PD compared to standard medical treatment. The majority of survey respondents (72%) indicated they would consider learning more about participating. Early PD patients are therefore likely to consider enrolling in trials of invasive therapies that may slow …symptom progression and help future patients. Show more

Keywords: Parkinson’s disease, deep brain stimulation, surveys, patient preference

DOI: 10.3233/JPD-161031

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 89-94, 2017

Authors: Cattaneo, Carlo | Barone, Paolo | Bonizzoni, Erminio | Sardina, Marco

Article Type: Research Article

Abstract: Background: Pain, a frequent non-motor symptom in Parkinson’s Disease (PD), significantly impacts on quality of life. Safinamide is a new drug with dopaminergic and non-dopaminergic properties, approved in Europe as adjunct therapy to levodopa for the treatment of fluctuating PD patients. Results from two 24-month, double-blind, placebo-controlled studies demonstrated that safinamide has positive effects on both motor functions and quality of life in PD patients. Objective: To investigate the effects of safinamide on pain management in PD patients with motor fluctuations using pooled data from studies 016 and SETTLE. Methods: This post-hoc analysis evaluated the reduction …of concomitant pain treatments and the changes in the scores of the items related to pain of the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39). A path analysis was performed in order to examine direct and indirect associations between safinamide and PDQ-39 pain-related items assessed after 6-months of treatment. Results: The percentage of patients with no pain treatments at the end of the trials was significantly lower in the safinamide group compared to the placebo group. Safinamide 100 mg/day significantly reduced on average the individual use of pain treatments by ≈24% and significantly improved two out of three PDQ-39 pain-related items of the “Bodily discomfort” domain. Path analysis showed that the direct effect of safinamide on pain accounted for about 80% of the total effect. Conclusions: These results suggest that safinamide may have a positive effect on pain, one of the most underestimated non-motor symptoms. Prospective studies are warranted to investigate this potential benefit. Show more

Keywords: Safinamide, glutamate, pain, Parkinson’s disease

DOI: 10.3233/JPD-160911

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 95-101, 2017

Authors: Heckman, George A. | Crizzle, Alexander M. | Chen, Jonathen | Pringsheim, Tamara | Jette, Nathalie | Kergoat, Marie-Jeanne | Eckel, Leslie | Hirdes, John P.

Article Type: Research Article

Abstract: Background: Patients with Parkinson’s disease (PD) and/or Parkinsonism are affected by a complex burden of comorbidity. Many ultimately require institutional care, where they may be subject to the application of physical restraints or the prescription of antipsychotic medications, making them more vulnerable to adverse outcomes. Objectives: The objectives of this paper are to: 1) describe the clinical complexity of older institutionalized persons with PD; and 2) examine patterns and predictors of restraint use and prescription of antipsychotics in this population. Methods: Population-based cross-sectional cohort study. Residents with PD and/or Parkinsonism living in long-term care (LTC) facilities …in 6 Canadian provinces and 1 Northern Territory and Complex Continuing Care (CCC) facilities in Manitoba and Ontario, Canada. The RAI MDS 2.0 instrument was used to assess all LTC residents and CCC residents. Clinical characteristics and the prevalence of major comorbidities were examined. Multivariate modeling was used to identify the characteristics of PD residents most associated with the prescription of antipsychotics and the use of restraints in LTC and CCC facilities. Results: Residents with PD in LTC and CCC exhibit a high prevalence of dementia, major psychiatric disorders, stroke, heart failure, chronic obstructive pulmonary disease and diabetes mellitus. More than 90% of LTC and CCC residents with PD had cognitive impairment; with more than half having moderate to severe impairment. Residents with PD were more likely to receive antipsychotics than those without PD. Antipsychotic use was associated with psychosis and aggressive behaviours, but also with unsteady gait and higher comorbidity and medication count. Similarly, although more common in CCC than LTC facilities, both psychosis and aggressive behaviours were associated with restraint use, as was greater cognitive and functional impairment, and urinary incontinence. Younger age, male gender, and lower physician access were all associated with greater antipsychotic and restraint use. Conclusions: LTC and CCC residents with PD are very complex medically. Use of antipsychotics and restraints is common, and their use is often associated with factors other than psychosis or aggression. Show more

Keywords: Parkinson’s disease, Resident Assessment Instrument, minimum data set, nursing home, restraints, antipsychotics

DOI: 10.3233/JPD-160931

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 103-115, 2017

Authors: Hauser, Robert A. | Li, Ruosha | Pérez, Adriana | Ren, Xuehan | Weintraub, Dan | Elm, Jordan | Goudreau, John L. | Morgan, John C. | Fang, John Y. | Aminoff, Michael J. | Christine, Chadwick W. | Dhall, Rohit | Umeh, Chizoba C. | Boyd, James T. | Stover, Natividad | Leehey, Maureen | Zweig, Richard M. | Nicholas, Anthony P. | Bodis-Wollner, Ivan | Willis, Allison | Kieburtz, Karl | Tilley, Barbara C. | for the NINDS NET-PD Investigators

Article Type: Research Article

Abstract: Background: Monoamine oxidase type B (MAO-B) inhibitors exhibit neuroprotective effects in preclinical models of PD but clinical trials have failed to convincingly demonstrate disease modifying benefits in PD patients. Objective: To perform a secondary analysis of NET-PD LS1 to determine if longer duration of MAO-B inhibitor exposure was associated with less clinical decline. Methods: The primary outcome measure was the Global Outcome (GO), comprised of 5 measures: change from baseline in the Schwab and England (ADL) scale, the 39-item Parkinson’s Disease Questionnaire (PDQ-39), the UPDRS Ambulatory Capacity Scale, the Symbol Digit Modalities Test, and the most …recent Modified Rankin Scale. A linear mixed model was used to explore the association between the cumulative duration of MAO-B inhibitor exposure and the GO, adjusting for necessary factors and confounders. Associations between MAO-B inhibitor exposure and each of the five GO components were then studied individually. Results: 1616 participants comprised the analytic sample. Mean observation was 4.1 (SD = 1.4) years, and 784 (48.5%) participants received an MAO-B inhibitor. The regression coefficient of cumulative duration of MAO-B inhibitor exposure (in years) on the GO was – 0.0064 (SE = 0.002, p  = 0.001). Significant associations between duration of MAO-B inhibitor exposure and less progression were observed for ADL (p  < 0.001), Ambulatory Capacity (p  < 0.001), and the Rankin (p  = 0.002). Conclusions: Our analysis identified a significant association between longer duration of MAO-B inhibitor exposure and less clinical decline. These findings support the possibility that MAO-B inhibitors slow clinical disease progression and suggest that a definitive prospective trial should be considered. Show more

Keywords: Parkinson’s disease, MAO-B inhibitor, rasagiline, selegiline, treatment, disease modification

DOI: 10.3233/JPD-160965

Citation: Journal of Parkinson's Disease, vol. 7, no. 1, pp. 117-127, 2017