Journal of Parkinson's Disease - Volume 11, issue 3

Authors: McFarthing, Kevin | Rafaloff, Gary | Baptista, Marco A.S. | Wyse, Richard K. | Stott, Simon R. W.

Article Type: Review Article

Abstract: Background: Despite the COVID-19 pandemic, there has been considerable activity in the clinical development of novel and improved drug-based therapies for the neurodegenerative condition of Parkinson’s disease (PD) during 2020. The agents that were investigated can be divided into “symptomatic” (alleviating the features of the condition) and “disease modifying” (attempting to address the underlying biology of PD) treatments, ST and DMT respectively, with further categorisation possible based on mechanism of action and class of therapy. Objective: Our goal in this report was to provide an overview of the pharmacological therapies –both ST and DMT - in clinical trials …for PD during 2020–2021, with the aim of creating greater awareness and involvement in the clinical trial process. We also hope to stimulate collaboration amongst commercial and academic researchers as well as between the research and patient communities. Methods: We conducted a review of clinical trials of drug therapies for PD using trial data obtained from the ClinicalTrials.gov and World Health Organisation (WHO) registries, and performed a breakdown analysis of studies that were active as of February 18th 2021. We also assessed active drug development projects that had completed one clinical phase but were yet to start the next. Results: We identified 142 trials on ClinicalTrials.gov and 14 studies on the WHO registries that met our analysis criteria. Of these 156 trials, 91 were ST and 65 were DMT, Of the 145 trials registered on ClinicalTrials.gov in our 2020 analysis, 45 fell off the list and 42 were added. Despite this change, the balance of ST to DMT; the distribution across phases; the profile of therapeutic categories; and the proportion of repurposed therapies (33.5%); all remained very similar. There are only two DMTs in phase 3, and we identified 33 in-between-phase projects. Conclusions: Despite the effects of the coronavirus pandemic, investment and effort in clinical trials for PD appears to remain strong. There has been little change in the profile of the clinical trial landscape even though, over the past year, there has been considerable change to the content of the list. Show more

Keywords: Clinical trials, studies, Parkinson’s, disease modification, neuroprotection, immunotherapy, inflammation, gene therapy

DOI: 10.3233/JPD-219006

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 891-903, 2021

Authors: Siddiqi, Bernadette | Koemeter-Cox, Andrew

Article Type: Position Paper

Abstract: The current base of knowledge around Parkinson’s disease has been assembled in partnership with a cohort of participants that does not resemble the diversity of people with the disease. This poor representation in research results in an incomplete picture of the disease and disparities in care. The Michael J. Fox Foundation has defined four major areas of action: 1) identifying barriers and solutions to research participation; 2) funding inclusive research with greater participant diversity; 3) building a clinician/researcher workforce committed to health equity; and 4) supporting a more holistic understanding of PD. While factors driving disparities, including broader societal challenges, …are complex, it is imperative that the PD research, care, and patient communities move in a decisive and coordinated fashion to identify and implement strategies that advance treatments for everyone with PD and eliminate care inequities. Show more

Keywords: Health disparities, minority health, The Michael J. Fox Foundation, research diversity, health equity, Parkinson’s research, clinical research, research participation, research Inclusivity, Parkinson’s disease

DOI: 10.3233/JPD-212593

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 905-908, 2021

Authors: Barker, Roger A. | Björklund, Anders | Frucht, Steven J. | Svendsen, Clive N.

Article Type: Position Paper

Abstract: The use of stem cell-derived dopamine neurons or deep brain stimulation (DBS) represents two alternative approaches to treat Parkinson’s Disease. DBS is a widely used FDA-approved treatment and stem cell-derived dopamine neuron replacement has now evolved to the first in-human clinical trials. In this debate, we discuss which of these approaches will evolve to be the treatment of choice for Parkinsonian patients in the future.

Keywords: Stem cells, dopamine neurons, DBS, brain repair

DOI: 10.3233/JPD-219008

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 909-917, 2021

Authors: Chen, Yancong | Sun, Xuemei | Lin, Yali | Zhang, Zixuan | Gao, Yinyan | Wu, Irene X.Y.

Article Type: Review Article

Abstract: Background: Numerous systematic reviews (SRs) and meta-analyses on non-genetic risk factors for Parkinson’s disease (PD) development have been published with inconsistent conclusions. Objective: This overview of SRs aimed to summarize evidence on non-genetic factors for the development of PD from the published SRs, and explore the reasons behind the conflicting results. Methods: Three international databases were searched for SRs with meta-analyses summarized evidence on non-genetic factors for PD development. The Assessing the Methodological Quality of Systematic Reviews 2 tool was used to appraise the methodological quality of included SRs. Pooled effect estimations were extracted from each …meta-analysis. Results: Forty-six SRs covered six categories, and more than 80 factors were included in this overview. Thirty-nine SRs (84.7%) were judged to be of critically low methodological quality. Evidence from prospective studies showed that physical activity, smoking, coffee, caffeine, tea, fat intake, ibuprofen use, calcium channel blocker use, statin use, thiazolidinediones, and high serum urate levels significantly reduced the risk of PD, while dairy intake, diabetes, hormone replacement therapy, depression, mood disorder, bipolar disorder, and aspirin use significantly increased the risk of PD. Differences in study designs (e.g., cohort studies, case-control studies) accounted for the conflicting results among included SRs. Conclusion: Modifiable lifestyle factors such as physical activity and tea and coffee drinking may reduce the risk of PD, which may offer PD prevention strategies and hypotheses for future research. However, the designs of primary studies on PD risk factors and related SRs need to be improved and harmonized. Show more

Keywords: Risk factors, Parkinson’s disease, systematic review, meta-analysis

DOI: 10.3233/JPD-202521

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 919-935, 2021

Authors: Doppler, Kathrin

Article Type: Review Article

Abstract: Alpha-synuclein deposits are detectable in skin biopsies of patients with Parkinson’s disease and other synucleinopathies like multiple system atrophy by immunohistochemical staining. As they are easily to obtain, they appear a promising tool for the pre-mortem histopathological confirmation of the disease and as a potential outcome measure in studies targeting alpha-synuclein aggregates. Good sensitivity, specificity, and practicability are the most important requirements of a biomarker. The review gives an overview on all three aspects, addresses methodological problems and the lack of standardized procedures as a major problem and gives an outlook on the future of skin biopsy as a potential …diagnostic tool in synucleinopathies. Show more

Keywords: Parkinson’s disease, synucleinopathy, skin, alpha-synuclein

DOI: 10.3233/JPD-202489

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 937-947, 2021

Authors: Marie, Anaıs | Darricau, Morgane | Touyarot, Katia | Parr-Brownlie, Louise C. | Bosch-Bouju, Clémentine

Article Type: Review Article

Abstract: Evidence shows that altered retinoic acid signaling may contribute to the pathogenesis and pathophysiology of Parkinson’s disease (PD). Retinoic acid is the bioactive derivative of the lipophilic vitamin A. Vitamin A is involved in several important homeostatic processes, such as cell differentiation, antioxidant activity, inflammation and neuronal plasticity. The role of vitamin A and its derivatives in the pathogenesis and pathophysiology of neurodegenerative diseases, and their potential as therapeutics, has drawn attention for more than 10 years. However, the literature sits in disparate fields. Vitamin A could act at the crossroad of multiple environmental and genetic factors of PD. The …purpose of this review is to outline what is known about the role of vitamin A metabolism in the pathogenesis and pathophysiology of PD. We examine key biological systems and mechanisms that are under the control of vitamin A and its derivatives, which are (or could be) exploited for therapeutic potential in PD: the survival of dopaminergic neurons, oxidative stress, neuroinflammation, circadian rhythms, homeostasis of the enteric nervous system, and hormonal systems. We focus on the pivotal role of ALDH1A1, an enzyme expressed by dopaminergic neurons for the detoxification of these neurons, which is under the control of retinoic acid. By providing an integrated summary, this review will guide future studies on the potential role of vitamin A in the management of symptoms, health and wellbeing for PD patients. Show more

Keywords: Neuroinflammation, vitamin A, retinoic acid, ALDH1A1, oxidative stress, RAR RXR receptors

DOI: 10.3233/JPD-212671

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 949-970, 2021

Authors: Suzuki, Keisuke

Article Type: Review Article

Abstract: Sleep disturbances are among the common nonmotor symptoms in patients with Parkinson’s disease (PD). Sleep can be disrupted by nocturnal motor and nonmotor symptoms and other comorbid sleep disorders. Rapid eye movement sleep behavior disorder (RBD) causes sleep-related injury, has important clinical implications as a harbinger of PD and predicts a progressive clinical phenotype. Restless legs syndrome (RLS) and its related symptoms can impair sleep initiation. Excessive daytime sleepiness (EDS) is a refractory problem affecting patients’ daytime activities. In particular, during the COVID-19 era, special attention should be paid to monitoring sleep problems, as infection-prevention procedures for COVID-19 can affect …patients’ motor symptoms, psychiatric symptoms and sleep. Therefore, screening for and managing sleep problems is important in clinical practice, and the maintenance of good sleep conditions may improve the quality of life of PD patients. This narrative review focused on the literature published in the past 10 years, providing a current update of various sleep disturbances in PD patients and their management, including RBD, RLS, EDS, sleep apnea and circadian abnormalities. Show more

Keywords: Parkinson’s disease, sleep disturbances, excessive daytime sleepiness, REM sleep behavior disorder, restless legs syndrome, sleep apnea syndrome

DOI: 10.3233/JPD-202425

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 971-992, 2021

Authors: Guilherme, Evelyn M. | Moreira, Roberta de Fátima Carreira | de Oliveira, Adriele | Ferro, Alyne Montero | Di Lorenzo, Valéria A. Pires | Gianlorenço, Anna Carolyna L.

Article Type: Systematic Review

Abstract: Background: Parkinson’s disease (PD) non motor symptoms may present early in the disease course and worsen with advancing disease. Respiratory changes can affect individuals to remain physically active, contributing to a reduction of functionality and quality of life. Objective: The aim of this systematic review is to synthesize evidence of respiratory disorders in patients with PD. Methods: An electronic search was performed up to November 2020 on PubMed-MEDLINE, Embase, Web of Science, Lilacs, Cinahl, and Cochrane using the following keyword combination: [(“Parkinson disease”) AND (“respiratory function tests” OR “evaluation”) AND (“respiratory system” OR “respiration disorders” OR …“respiratory muscles”)]. Results: The electronic search resulted in 601 references in English or Portuguese. The selection process and data extraction were made by two independent reviewers. We selected 19 studies including cross-sectional studies that investigated the respiratory disorders in patients with PD through pulmonary function, respiratory muscle strength, or physical capacity evaluation. We excluded studies that considered patients with other diseases. Eighteen studies evaluated the pulmonary function in patients with PD, eleven studies verified the influence of PD on respiratory muscle strength, and three studies assessed the physical capacity through functional tests. Conclusion: The evidence showed that PD patients have higher chances to present a pulmonary dysfunction, either obstructive or restrictive, when compared to healthy subjects. In addition, these patients present lower respiratory muscle strength and a consequent decrease in physical capacity in endurance exercises. The respiratory impairment in PD seems to be directly related to the progression of the disease. Show more

Keywords: Disability evaluation, Parkinson’s disease, respiration disorders, respiratory function tests, respiratory muscle, respiratory system, spirometry

DOI: 10.3233/JPD-212565

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 993-1010, 2021

Authors: Sackner-Bernstein, Jonathan

Article Type: Research Article

Abstract: Background: The hallmark of Parkinson’s disease is depletion of dopamine in the basal ganglia. Models of Parkinson’s disease include dopamine as a contributor to disease progression. However, intraneuronal levels of dopamine have not been reported. Objective: Meta-analytic methods were utilized to determine intracellular dopamine levels in Parkinson’s disease. Methods: A systematic review of the literature and frequentist meta-analyses were performed. Dopamine levels were scaled for cell and axon numbers as well as VMAT2 protein levels. Results: Reduced tissue dopamine, dopaminergic cell bodies and VMAT2 protein were confirmed. The ratio of Parkinson’s to normal brain …intracellular dopamine scaled for either cell or axon number, each with VMAT2 level in the caudate ranged from 1.49 to 1.87 (p  = 0.51 and p  = 0.12, respectively) and in the putamen from 0.75 to 4.61 (p  = 0.40 and 0.001, respectively). Conclusion: Free, intracellular dopamine levels are not reduced in Parkinson’s disease compared to normals to a similar degree as are total tissue concentrations, supporting the relevance of modulating VMAT2, neuromelanin and/or dopamine synthesis as rational neuroprotective strategies. Show more

Keywords: Parkinson’s disease, dopamine, dopaminergic neurons, cytosolic dopamine, intracellular dopamine, dopamine toxicity, dopamine oxidation

DOI: 10.3233/JPD-212715

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1011-1018, 2021

Authors: Björklund, Anders

Article Type: Article Commentary

Abstract: In two recent postmortem studies, Jeffrey Kordower and colleagues report new findings that open up for an interesting discussion on the status of GDNF/NRTN signaling in patients with Parkinson’s disease (PD), adding an interesting perspective on the, admittedly very limited, signs of restorative effects previously seen in GDNF/NRTN-treated patients. Their new findings show that the level of the GDNF signaling receptor Ret is overall markedly reduced relative to the non-PD controls, and most severely, up to 80%, in nigral neurons containing α -synuclein inclusions, accompanied by impaired signaling downstream of the Ret receptor. Notably, however, the vast majority of the …remaining nigral neurons retained a low level of Ret expression, and hence a threshold level of signaling. Further observations made in two patients who had received AAV-NRTN gene therapy 8–10 years earlier suggest the intriguing possibility that NRTN is able to restore Ret expression and upregulate its own signaling pathway. This “wind-up” mechanism, which is likely to depend on an interaction with dopaminergic transcription factor Nurr1, has therapeutic potential and should encourage renewed efforts to turn GDNF/NRTN therapy into success, once the recurring problem of under-dosing is resolved. Show more

Keywords: Parkinson’s disease, neurturin, Ret, Nurr1, phospho-S6

DOI: 10.3233/JPD-212706

Citation: Journal of Parkinson's Disease, vol. 11, no. 3, pp. 1019-1022, 2021