Journal of Parkinson's Disease - Volume 11, issue 2

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

Article Type: Other

DOI: 10.3233/JPD-219003

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 377-390, 2021

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

Article Type: Other

DOI: 10.3233/JPD-219004

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 391-393, 2021

Authors: Mestre, Tiago A. | Fereshtehnejad, Seyed-Mohammad | Berg, Daniela | Bohnen, Nicolaas I. | Dujardin, Kathy | Erro, Roberto | Espay, Alberto J. | Halliday, Glenda | van Hilten, Jacobus J. | Hu, Michele T. | Jeon, Beomseok | Klein, Christine | Leentjens, Albert F.G. | Marinus, Johan | Mollenhauer, Brit | Postuma, Ronald | Rajalingam, Rajasumi | Rodríguez-Violante, Mayela | Simuni, Tanya | Surmeier, D. James | Weintraub, Daniel | McDermott, Michael P. | Lawton, Michael | Marras, Connie

Article Type: Systematic Review

Abstract: Background: In Parkinson’s disease (PD), there is heterogeneity in the clinical presentation and underlying biology. Research on PD subtypes aims to understand this heterogeneity with potential contribution for the knowledge of disease pathophysiology, natural history and therapeutic development. There have been many studies of PD subtypes but their impact remains unclear with limited application in research or clinical practice. Objective: To critically evaluate PD subtyping systems. Methods: We conducted a systematic review of PD subtypes, assessing the characteristics of the studies reporting a subtyping system for the first time. We completed a critical appraisal of their …methodologic quality and clinical applicability using standardized checklists. Results: We included 38 studies. The majority were cross-sectional (n  = 26, 68.4%), used a data-driven approach (n  = 25, 65.8%), and non-clinical biomarkers were rarely used (n  = 5, 13.1%). Motor characteristics were the domain most commonly reported to differentiate PD subtypes. Most of the studies did not achieve the top rating across items of a Methodologic Quality checklist. In a Clinical Applicability Checklist, the clinical importance of differences between subtypes, potential treatment implications and applicability to the general population were rated poorly, and subtype stability over time and prognostic value were largely unknown. Conclusion: Subtyping studies undertaken to date have significant methodologic shortcomings and most have questionable clinical applicability and unknown biological relevance. The clinical and biological signature of PD may be unique to the individual, rendering PD resistant to meaningful cluster solutions. New approaches that acknowledge the individual-level heterogeneity and that are more aligned with personalized medicine are needed. Show more

Keywords: Parkinson’s disease, heterogeneity, subtypes

DOI: 10.3233/JPD-202472

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 395-404, 2021

Authors: Salvatore, Michael F. | Soto, Isabel | Alphonso, Helene | Cunningham, Rebecca | James, Rachael | Nejtek, Vicki A.

Article Type: Review Article

Abstract: Up to 23% of newly diagnosed, non-demented, Parkinson’s disease (PD) patients experience deficits in executive functioning (EF). In fact, EF deficits may occur up to 39-months prior to the onset of motor decline. Optimal EF requires working memory, attention, cognitive flexibility, and response inhibition underlying appropriate decision-making. The capacity for making strategic decisions requires inhibiting imprudent decisions and are associated with noradrenergic and dopaminergic signaling in prefrontal and orbitofrontal cortex. Catecholaminergic dysfunction and the loss of noradrenergic and dopaminergic cell bodies early in PD progression in the aforementioned cortical areas likely contribute to EF deficits resulting in non-strategic decision-making. Thus, …detecting these deficits early in the disease process could help identify a significant portion of individuals with PD pathology (14–60%) before frank motor impairment. A task to evaluate EF in the domain of non-strategic decision-making might be useful to indicate the moderate loss of catecholamines that occurs early in PD pathology prior to motor decline and cognitive impairment. In this review, we focus on the potential utility of the Iowa Gambling Task (IGT) for this purpose, given significant overlap between in loss of dopaminergic and noradrenergic cells bodies in early PD and the deficits in catecholamine function associated with decreased EF. As such, given the loss of catecholamines already well-underway after PD diagnosis, we evaluate the potential utility of the IGT to identify the risk of therapeutic non-compliance and a potential companion approach to detect PD in premotor stages. Show more

Keywords: Iowa gambling task, Parkinson’s disease, therapeutic compliance, decision-making

DOI: 10.3233/JPD-202449

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 405-419, 2021

Authors: Boucherie, Deirdre M. | Duarte, Gonçalo S. | Machado, Tiago | Faustino, Patrícia R. | Sampaio, Cristina | Rascol, Olivier | Ferreira, Joaquim J.

Article Type: Review Article

Abstract: Background: A global overview of drug development programs in Parkinson’s disease over the last few decades is lacking, while such programs are challenging given the multifaceted and heterogeneous nature of the disease. Objective: To indirectly assess drug development programs in Parkinson’s disease, exploring some factors associated with compound attrition at different trial phases. Methods: We assessed all Parkinson’s disease trials in the WHO trials portal, from inception (1999) to September 2019. Independent authors selected trials and extracted data. The success rate was the number of compounds that progressed to the next drug development phase divided by …the number of compounds in that phase. Results: Overall, 357 trials (studying 152 compounds) fulfilled our inclusion criteria, with 62 (17.3%) phase 1 trials, 135 (37.8%) phase 2 trials, 85 (23.8%) phase 3 trials, and 53 (14.8%) phase 4 trials. The success rate was 42.4% from phase 2 to 3. Original compounds received regulatory approval by the FDA in 21.4% of cases, compared with 6.7% of repurposed compounds, representing an overall success rate of 14.9%. We found 172 trials (48.2%) conducted for repurposing previously licensed compounds. These figures were approximately the same regarding approval by the EMA. Most compounds were approved to treat parkinsonism and motor fluctuations. Conclusion: We found a moderate-to-high success rate in all phases of drug development. This was largely based on the success of original compounds, despite almost half of the identified trials attempting compound repurposing. Show more

Keywords: Clinical development, drug development, clinical trials, parkinson’s disease

DOI: 10.3233/JPD-202184

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 421-429, 2021

Authors: Fearon, Conor | Fasano, Alfonso

Article Type: Review Article

Abstract: Studies focusing on the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), and Parkinson’s disease (PD) have provided conflicting results. We review the literature to investigate: 1) Are PD patients at higher risk for contracting COVID-19 and are there specific contributing factors to that risk? 2) How does COVID-19 affect PD symptoms? 3) How does COVID-19 present in PD patients? 4) What are the outcomes in PD patients who contract COVID-19? 5) What is the impact of COVID-19 on PD care? 6) Does COVID-19 increase the risk of developing PD? A literature search was performed …from 1979 to 2020 using the terms: ‘Parkinson’s disease’ and ‘parkinsonism’ combined with: ‘COVID-19’; ‘SARS-CoV-2’ and ‘coronavirus’. It does not appear that PD is a specific risk factor for COVID-19. There is evidence for direct/indirect effects of SARS-CoV-2 on motor/non-motor symptoms of PD. Although many PD patients present with typical COVID-19 symptoms, some present atypically with isolated worsening of parkinsonian symptoms, requiring increased anti-PD therapy and having worse outcomes. Mortality data on PD patients with COVID-19 is inconclusive (ranging from 5.2%to 100%). Patients with advanced PD appear to be particularly vulnerable. Single cases of acute hypokinetic-rigid syndrome have been described but no other convincing data has been reported. The rapidity with which COVID-19 has swept across the globe has favored the proliferation of studies which lack scientific rigor and the PD literature has not been immune. A coordinated effort is required to assimilate data and answer these questions in larger PD cohorts. Show more

Keywords: Parkinson’s disease, COVID-19, review

DOI: 10.3233/JPD-202320

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 431-444, 2021

Authors: Artusi, Carlo Alberto | Romagnolo, Alberto | Ledda, Claudia | Zibetti, Maurizio | Rizzone, Mario Giorgio | Montanaro, Elisa | Bozzali, Marco | Lopiano, Leonardo

Article Type: Review Article

Abstract: Background: Many studies on Parkinson’s disease (PD) patients affected by Coronavirus-disease-2019 (COVID-19) were recently published. However, the small sample size of infected patients enrolled in most studies did not allow to draw robust conclusions on the COVID-19 impact in PD. Objective: We aimed to assess whether the prevalence and outcome of COVID-19 in PD patients are different from those observed in the general population. Methods: We conducted a systematic review of studies reporting data on PD patients with a diagnosis of COVID-19 (PD-COVID+). We extracted prevalence, clinical-demographic data, outcome, and mortality. We also analyzed risk or …protective factors based on comparisons between PD-COVID+ and control populations with PD without COVID-19 or without PD with COVID-19. Results: We included 16 studies reporting on a total of 11,325 PD patients, 1,061 with a confirmed diagnosis of COVID-19. The median infection prevalence ranged from 0.6% to 8.5%. PD-COVID+ patients had a median age of 74 and a disease duration of 9.4 years. Pooling all PD-COVID+ patients from included studies, 28.6% required hospitalization, 37.1% required levodopa dose increasing, and 18.9% died. The case fatality was higher in PD-COVID+ patients than the general population, with longer PD duration as a possible risk factor for worse outcome. Amantadine and vitamin D were proposed as potential protective factors. Conclusion: Available studies indicate a higher case fatality in PD patients affected by COVID-19 than the general population. Conversely, current literature does not definitively clarify whether PD patients are more susceptible to get infected. The potential protective role of vitamin D and amantadine is intriguing but deserves further investigation. Show more

Keywords: Parkinson’s disease, COVID-19, infection, outcome, mortality, amantadine

DOI: 10.3233/JPD-202463

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 445-454, 2021

Authors: Borghammer, Per

Article Type: Review Article

Abstract: A new model of Parkinson’s disease (PD) pathogenesis is proposed, the α -Synuclein Origin site and Connectome (SOC) model, incorporating two aspects of α -synuclein pathobiology that impact the disease course for each patient: the anatomical location of the initial α -synuclein inclusion, and α -synuclein propagation dependent on the ipsilateral connections that dominate connectivity of the human brain. In some patients, initial α -synuclein pathology occurs within the CNS, leading to a brain-first subtype of PD. In others, pathology begins in the peripheral autonomic nervous system, leading to a body-first subtype. In brain-first cases, it is proposed that the …first pathology appears unilaterally, often in the amygdala. If α -synuclein propagation depends on connection strength, a unilateral focus of pathology will disseminate more to the ipsilateral hemisphere. Thus, α -synuclein spreads mainly to ipsilateral structures including the substantia nigra. The asymmetric distribution of pathology leads to asymmetric dopaminergic degeneration and motor asymmetry. In body-first cases, the α -synuclein pathology ascends via the vagus to both the left and right dorsal motor nuclei of the vagus owing to the overlapping parasympathetic innervation of the gut. Consequently, the initial α -synuclein pathology inside the CNS is more symmetric, which promotes more symmetric propagation in the brainstem, leading to more symmetric dopaminergic degeneration and less motor asymmetry. At diagnosis, body-first patients already have a larger, more symmetric burden of α -synuclein pathology, which in turn promotes faster disease progression and accelerated cognitive decline. The SOC model is supported by a considerable body of existing evidence and may have improved explanatory power. Show more

Keywords: Parkinson’s disease, alpha-synuclein, connectome, autonomic nervous system, pathogenesis, etiology

DOI: 10.3233/JPD-202481

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 455-474, 2021

Authors: Smilowska, Katarzyna | van Wamelen, Daniel J. | Pietrzykowski, Tomasz | Calvano, Alexander | Rodriguez-Blazquez, Carmen | Martinez-Martin, Pablo | Odin, Per | Chaudhuri, K. Ray

Article Type: Systematic Review

Abstract: Background: Despite optimal dopaminergic treatment most patients in moderate to advanced stages of Parkinson’s disease (PD) experience progressively increasing disabilities, necessitating a shift from oral medication to device-aided therapies, including deep brain stimulation (DBS), intrajejunal levodopa-carbidopa infusion (IJLI), and continuous subcutaneous apomorphine infusion (CSAI). However, these therapies are costly, limiting their implementation. Objectives: To perform a systematic review on cost-effectiveness analyses for device-aided therapies in PD. Methods: References were identified by performing a systematic search in the PubMed and Web of Science databases in accordance with the PRISMA statement. In the absence of universal cost-effectiveness definitions, …the gross domestic product per capita (GDP) in the country where a study was performed was used as a cut-off for cost-effectiveness based on cost per quality adjusted life year (QALY) gained. Results: In total 30 studies were retrieved. All device-aided therapies improved quality of life compared to best medical treatment, with improvements in QALYs between 0.88 and 1.26 in the studies with long temporal horizons. For DBS, nearly all studies showed that cost per QALY was below the GDP threshold. For infusion therapies only three studies showed a cost per QALY below this threshold, with several studies with long temporal horizons showing costs below or near the GDP threshold. Conclusion: Of the device-aided therapies, DBS can be considered cost-effective, but the majority of infusion therapy studies showed that these were less cost-effective. However, long-term use of the infusion therapies appears to improve their cost-effectiveness and in addition, several strategies are underway to reduce these high costs. Show more

Keywords: Parkinson’s disease, cost-effectiveness, deep brain stimulation, quality adjusted life year, levodopa-carbidopa intestinal gel, continuous subcutaneous apomorphine infusion

DOI: 10.3233/JPD-202348

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 475-489, 2021

Authors: HØrmann Thomsen, Trine | Wallerstedt, Susanna M. | Winge, Kristian | Bergquist, Filip

Article Type: Article Commentary

Abstract: People with Parkinson’s disease (PwP) have been suggested to be more vulnerable to negative psychological and psycho-social effects of the COVID-19 pandemic. Our aim was to assess the potential impact of the COVID-19 pandemic in PwP. A Danish/Swedish cohort of 67 PwP was analysed. Health-related quality of life (HRQL), depression, anxiety, apathy, sleep and motor symptom-scores were included in the analysis. Additionally, the Danish participants provided free-text descriptions of life during the pandemic. Overall, the participants reported significantly better HRQL during the COVID-19 period compared with before. Reduced social pressure may be part of the explanation. Despite worsened anxiety, night …sleep improved. Show more

DOI: 10.3233/JPD-202342

Citation: Journal of Parkinson's Disease, vol. 11, no. 2, pp. 491-495, 2021