Journal of Parkinson's Disease - Volume 12, issue 1

Authors: Riboldi, Giulietta M. | Frattini, Emanuele | Monfrini, Edoardo | Frucht, Steven J. | Di Fonzo, Alessio

Article Type: Review Article

Abstract: Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson’s disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we …summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape. Show more

Keywords: Parkinsonian disorders, Parkinson’s disease, autosomal recessive early-onset, secondary Parkinson’s disease, dopa-responsive dystonia, adult-onset dystonia-parkinsonism, genetic counseling

DOI: 10.3233/JPD-212815

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 1-26, 2022

Authors: Shen, Si | Zhang, Chan | Xu, Yu-ming | Shi, Chang-he

Article Type: Review Article

Abstract: Parkinson’s disease is a debilitating neurodegenerative disorder whose etiology is still unclear, hampering the development of effective treatments. There is an urgent need to identify the etiology and provide further effective treatments. Recently, accumulating evidence has indicated that infection may play a role in the etiology of Parkinson’s disease. The infective pathogens may act as a trigger for Parkinson’s disease, the most common of which are hepatitis C virus, influenza virus, and Helicobacter pylori . In addition, gut microbiota is increasingly recognized to influence brain function through the gut-brain axis, showing an important role in the pathogenesis of Parkinson’s disease. …Furthermore, a series of anti-infective agents exhibit surprising neuroprotective effects via various mechanisms, such as interfering with α-synuclein aggregation, inhibiting neuroinflammation, attenuating oxidative stress, and preventing from cell death, independent of their antimicrobial effects. The pleiotropic agents affect important events in the pathogenesis of Parkinson’s disease. Moreover, most of them are less toxic, clinically safe and have good blood-brain penetrability, making them hopeful candidates for the treatment of Parkinson’s disease. However, the use of antibiotics and subsequent gut dysbiosis may also play a role in Parkinson’s disease, making the long-term effects of anti-infective drugs worthy of further consideration and exploration. This review summarizes the current evidence for the association between infective pathogens and Parkinson’s disease and subsequently explores the application prospects of anti-infective drugs in Parkinson’s disease treatment, providing novel insights into the pathogenesis and treatment of Parkinson’s disease. Show more

Keywords: Parkinson’s disease, infection, gut microbiota, neuroinflammation, drug repurposing

DOI: 10.3233/JPD-212929

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 27-44, 2022

Authors: De Miranda, Briana R. | Goldman, Samuel M. | Miller, Gary W. | Greenamyre, J. Timothy | Dorsey, E. Ray

Article Type: Review Article

Abstract: Fueled by aging populations and continued environmental contamination, the global burden of Parkinson’s disease (PD) is increasing. The disease, or more appropriately diseases, have multiple environmental and genetic influences but no approved disease modifying therapy. Additionally, efforts to prevent this debilitating disease have been limited. As numerous environmental contaminants (e.g., pesticides, metals, industrial chemicals) are implicated in PD, disease prevention is possible. To reduce the burden of PD, we have compiled preclinical and clinical research priorities that highlight both disease prediction and primary prevention. Though not exhaustive, the “PD prevention agenda” builds upon many years of research by our colleagues …and proposes next steps through the lens of modifiable risk factors. The agenda identifies ten specific areas of further inquiry and considers the funding and policy changes that will be necessary to help prevent the world’s fastest growing brain disease. Show more

Keywords: Parkinson’s disease, environment, pesticides, metals, chlorinated solvents, air pollution, preclinical research, clinical research

DOI: 10.3233/JPD-212922

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 45-68, 2022

Authors: Matzaras, Rafail | Shi, Kuangyu | Artemiadis, Artemios | Zis, Panagiotis | Hadjigeorgiou, Georgios | Rominger, Axel | Bassetti, Claudio L.A. | Bargiotas, Panagiotis

Article Type: Systematic Review

Abstract: Background: REM-sleep behaviour disorder (RBD) is a parasomnia and a common comorbidity in Parkinson’s disease (PD). There is evidence that the presence of RBD is associated with more severe PD. The differences in the clinical manifestations and the natural history are likely to imply underlying differences in the pathophysiology among PD patients with and without RBD. The increasing number of neuroimaging studies support this notion. Objective: Our primary objective was to review the current evidence regarding the brain neuroimaging findings in PD patients with RBD (PDRBD). Methods: A systematic review of articles, published in PubMed between …January 1, 2000 and September 23, 2020 was performed. We evaluate previous studies that assessed PD patients with RBD using various brain structural and functional magnetic resonance imaging (MRI) techniques and brain nuclear medicine imaging. Results: Twenty-nine studies, involving a total of 3,347 PD subjects among which 912 subjects with PDRBD, met the selection criteria and were included. The presence of RBD in PD patients is associated with structural and functional alterations in several brain regions, mainly in brainstem, limbic structures, frontotemporal cortex, and basal ganglia, raising the hypothesis of a PDRBD neuroimaging phenotype. Conclusion: The current review provides up-to-date knowledge in this field and summarizes the neurobiological/neuroimaging substrate of RBD in PD. Show more

Keywords: RBD, Parkinson’s disease, structural MRI, voxel-based morphometry, diffusion tensor imaging, neuromelanin-sensitive MRI, functional neuroimaging, nuclear medicine imaging, single photon emission computed tomography, positron emission tomography

DOI: 10.3233/JPD-212571

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 69-83, 2022

Authors: Chendo, Ines | Silva, Carlos | Duarte, Gonçalo S. | Prada, Luisa | Voon, Valerie | Ferreira, Joaquim J.

Article Type: Systematic Review

Abstract: Background: Psychotic symptoms are highly frequent in Parkinson’s disease (PD) patients and are associated with poor prognosis. They include hallucinations, delusions, and minor psychotic phenomena, including sense of presence, passage hallucinations, and illusions. Objective: To evaluate the frequency of psychosis in PD patients. Methods: A systematic review and meta-analysis of clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies reporting the frequency of psychosis, hallucinations, and delusions in PD. Results: Electronic database search wielded 3536 articles, an additional 91 were identified through citation chaining. Of these, 163 were fully inspected, 57 …removed, and 106 included as relevant for neuropsychiatric events frequency, with 32 meeting our inclusion criteria (psychosis and/or specific psychotic phenomena). The pooled frequency of psychosis was 20.7% (95% CI 14.5 to 28.6; I2  = 94%, 15 studies; combined n  = 2919). None of the pre-defined meta-regressions or subgroup analyses were statistically significant or helped explain the statistical heterogeneity. The pooled frequency of any form of hallucination was 21.6% (95% CI 14.7 to 30.6; I2  = 95%; 18 studies; combined n  = 3161). Duration of PD at baseline and mean baseline Hoehn & Yahr stage helped explain the statistical heterogeneity in the meta-analysis of hallucinations. Conclusion: Based on the available evidence, around a fifth of PD patients experience psychosis or hallucinations. The risk of developing hallucinations is likely moderated by the disease duration, Hoehn & Yahr stage, and the cognitive status. Show more

Keywords: Parkinson disease, psychotic disorders, systematic review, meta-analysis, hallucinations, delusions, illusions

DOI: 10.3233/JPD-212930

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 85-94, 2022

Authors: Wyse, Richard K. | Stott, Simon R.W. | Mursaleen, Leah | Matthews, Helen | Dawson, Valina L. | Dawson, Ted M.

Article Type: Article Commentary

Abstract: A recent breakthrough paper published in Science Translational Medicine has provided compelling evidence that inhibition of Parkin Interacting Substrate (PARIS) may offer clinical researchers an important new therapeutic approach since it shows considerable promise as an important biological target potentially capable of pharmaceutical intervention to slow long term neurodegeneration in patients with Parkinson’s disease (PD). We present several PD-relevant perspectives on this paper that were not discussed in that otherwise entirely scientific narrative. We also outline the some of the work leading up to it, including the massive drug screen that proved necessary to discover a clinically suitable inhibitor …of PARIS (Farnesol), as well as relevant PD research within the wider drug class, issues surrounding its future formulation, and next steps in translating this new knowledge into the clinic to evaluate possible long-term PD patient benefits. Show more

Keywords: Farnesol, PARIS, Parkin, PGC-1α , iLCT, neuroprotection, nanoformulation

DOI: 10.3233/JPD-212945

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 95-103, 2022

Authors: Finkelstein, David I. | Shukla, Jay J. | Cherny, Robert A. | Billings, Jessica L. | Saleh, Eiman | Stefanova, Nadia | Barnham, Kevin J. | Adlard, Paul A.

Article Type: Research Article

Abstract: Background: An elevation in iron levels, together with an accumulation of α-synuclein within the oligodendrocytes, are features of the rare atypical parkinsonian disorder, Multiple System Atrophy (MSA). We have previously tested the novel compound ATH434 (formally called PBT434) in preclinical models of Parkinson’s disease and shown that it is brain-penetrant, reduces iron accumulation and iron-mediated redox activity, provides neuroprotection, inhibits alpha synuclein aggregation and lowers the tissue levels of alpha synuclein. The compound was also well-tolerated in a first-in-human oral dosing study in healthy and older volunteers with a favorable, dose-dependent pharmacokinetic profile. Objective: To evaluate the efficacy …of ATH434 in a mouse MSA model. Methods: The PLP-α-syn transgenic mouse overexpresses α-synuclein, demonstrates oligodendroglial pathology, and manifests motor and non-motor aspects of MSA. Animals were provided ATH434 (3, 10, or 30 mg/kg/day spiked into their food) or control food for 4 months starting at 12 months of age and were culled at 16 months. Western blot was used to assess oligomeric and urea soluble α-synuclein levels in brain homogenates, whilst stereology was used to quantitate the number of nigral neurons and glial cell inclusions (GCIs) present in the substantia nigra pars compacta. Results: ATH434 reduced oligomeric and urea soluble α-synuclein aggregation, reduced the number of GCIs, and preserved SNpc neurons. In vitro experiments suggest that ATH434 prevents the formation of toxic oligomeric “species of synuclein”. Conclusion: ATH434 is a promising small molecule drug candidate that has potential to move forward to trial for treating MSA. Show more

Keywords: Synuclein, iron, parkinsonism, neuroprotection, drug development

DOI: 10.3233/JPD-212877

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 105-115, 2022

Authors: Visanji, Naomi P. | Ghani, Mahdi | Yu, Eric | Kakhki, Erfan Ghani | Sato, Christine | Moreno, Danielle | Naranian, Taline | Poon, Yu-Yan | Abdollahi, Maryam | Naghibzadeh, Maryam | Rajalingam, Rajasumi | Lozano, Andres M. | Kalia, Suneil K. | Hodaie, Mojgan | Cohn, Melanie | Statucka, Marta | Boutet, Alexandre | Elias, Gavin J.B. | Germann, Jürgen | Munhoz, Renato | Lang, Anthony E. | Gan-Or, Ziv | Rogaeva, Ekaterina | Fasano, Alfonso

Article Type: Research Article

Abstract: Background: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed “surgicogenomics”. Objective: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson’s disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. Methods: Retrospective clinical data was extracted from 150 patient’s charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data …were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. Results: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1 , IP6K2 , and PRSS3 ). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2 . Conclusion: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD. Show more

Keywords: Parkinson’s disease, deep brain stimulation, gait apraxia, postural instability, genotyping

DOI: 10.3233/JPD-212730

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 117-128, 2022

Authors: Jeong, Seong Ho | Chung, Seok Jong | Yoo, Han Soo | Jung, Jin Ho | Baik, Kyoungwon | Lee, Yang Hyun | Lee, Phil Hyu | Sohn, Young H.

Article Type: Research Article

Abstract: Background: Premorbid educational attainment is a well-known proxy of reserve, not only with regard to cognition, but also to motor symptoms. Objective: In the present study, we investigated the relationship between educational attainment and long-term motor prognosis in patients with Parkinson’s disease (PD). Methods: We analyzed 466 patients with de novo PD without dementia who underwent dopamine transporter (DAT) scans and were followed up more than 2 years. Patients were divided into three groups: low education (years-of-education ≤6, n  = 125), intermediate education (6 <years-of-education < 12, n  = 108), and high education (years-of-education ≥12, n  = 233). The effects …of educational attainment on the development of levodopa-induced dyskinesia (LID), wearing-off, and freezing-of-gait, and longitudinal increase in levodopa-equivalent doses (LEDs) were assessed. Results: Multiple regression analysis showed that higher education was associated with milder parkinsonian symptoms after adjusting for DAT availability in the posterior putamen. Survival analysis showed that the rate of LID was significantly lower in the high education group than in the low education group (HR = 0.565, p  = 0.010). A linear mixed model showed that the high education group had lower LED than the low education group until a period of 30 months; however, this difference in LED was not observed thereafter. Conclusion: The present study demonstrated that premorbid educational attainment has protective effects on the development of LID in patients with PD and has sparing effects on LED during the early treatment period. These results suggest that high educational attainment has a beneficial effect on motor outcomes in patients with PD. Show more

Keywords: Parkinson’s disease, education attainment, motor prognosis

DOI: 10.3233/JPD-212791

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 129-136, 2022

Authors: Staunton, Hannah | Kelly, Kim | Newton, Louise | Leddin, Mathias | Rodriguez-Esteban, Raul | Chaudhuri, K. Ray | Weintraub, Daniel | Postuma, Ronald B. | Martinez-Martin, Pablo

Article Type: Research Article

Abstract: Background: Individuals with Parkinson’s disease (PD) develop a significant disease burden over time that contributes to a progressive decline in health-related quality of life. There is a paucity of qualitative research to understand symptoms and impacts in individuals with early-stage PD (i.e., Hoehn and Yahr stage 1–2 and ≤2 years since diagnosis). Objective: The collection of qualitative data to inform the selection of clinical outcome assessments for clinical trials is advocated by regulators. This patient-centered, multistage study sought to create a conceptual model of symptoms and their impact for individuals with early-stage PD. Methods: Symptoms and …impacts of PD were gathered from a literature review of qualitative research, a quantitative social media listening analysis, and qualitative patient concept elicitation interviews (n  = 35). Clinical experts provided input to validate and finalize the concepts. Results: The final conceptual model consisted of 27 symptoms categorized into ‘motor’ or ‘non-motor’ domains, and 39 impacts divided into five domains. Most frequently reported symptoms in early-stage PD were ‘tremors’ (89%), ‘stiffness and rigidity’, and ‘fatigue’ (69%, both). Most frequently reported impacts included ‘anxiety’ (74%), ‘eating and drinking’ (71%), followed by ‘exercise/sport’ and ‘relationship with family/family life’ (66%, both). Conclusion: This study provides initial insights relating to the symptom and impact burden of early-stage PD patients. The conceptual model can be used to help researchers to develop and select optimal patient-centered outcomes to measure treatment benefit in clinical trials. These findings could inform future qualitative research and the development of outcomes specifically for early-stage PD patients. Show more

Keywords: Impacts, Parkinson’s disease, qualitative research, quality of life, social media, symptoms

DOI: 10.3233/JPD-202457

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 137-151, 2022