Journal of Parkinson's Disease - Volume 13, issue 8

Authors: Bloem, Bastiaan R. | Kalia, Lorraine V.

Article Type: Editorial

DOI: 10.3233/JPD-239006

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1273-1276, 2023

Authors: Bhidayasiri, Roongroj | Kalia, Lorraine V. | Bloem, Bastiaan R.

Article Type: Editorial

Keywords: Parkinson’s pandemic, Parkinson’s disease, global neurology, low-to-middle income countries

DOI: 10.3233/JPD-239005

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1277-1280, 2023

Authors: Bogers, Jolien S. | Bloem, Bastiaan R. | Den Heijer, Jonas M.

Article Type: Research Article

Abstract: Parkinson’s disease is now the most rapidly growing neurodegenerative disease worldwide. It is therefore critical to identify which factors, and to what extent, contribute to the multifactorial etiology of Parkinson’s disease. Here, we address two interesting elements from the perspective of genetics, namely (a) the estimated age of several genetic risk factors related to Parkinson’s disease; and (b) the relative contribution of genetics to the etiology of Parkinson’s disease, as derived from twin studies. Based on these two perspectives, we argue that most genetic risk factors are by themselves insufficient to explain the majority of Parkinson’s disease, and that environmental …factors are required for these genetic factors to become pathophysiologically relevant. Show more

Keywords: Parkinson’s disease, etiology, genetics, environment, pesticides, MPTP

DOI: 10.3233/JPD-230250

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1281-1288, 2023

Authors: Ozoran, Hakan | Srinivasan, Rahul

Article Type: Review Article

Abstract: Despite its devastating disease burden and alarming prevalence, the etiology of Parkinson’s disease (PD) remains to be completely elucidated. PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and this correlates with the accumulation of misfolded α-synuclein. While the aggregation of α-synuclein in the form of Lewy bodies or Lewy neurites is a well-established intraneuronal hallmark of the disease process, our understanding of the glial contribution to aberrant α-synuclein proteostasis is lacking. In this regard, restoring astrocyte function during early PD could offer a promising therapeutic avenue and understanding the involvement of astrocytes in …handling/mishandling of α-synuclein is of particular interest. Here, we explore the growing body of scientific literature implicating aberrant astrocytic α-synuclein proteostasis with the seemingly inexorable pathological sequelae typifying PD. We also provide a perspective on how heterogeneity in the morphological relationship between astrocytes and neurons will need to be considered in the context of PD pathogenesis. Show more

Keywords: α-synuclein, astrocytes, mitochondria, calcium signals, aggregation, glial fibrillary acid protein, S100B, exosomes, heterogeneity, tunnelling nanotubules

DOI: 10.3233/JPD-230284

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1289-1301, 2023

Authors: Isik, Finula I. | Katzeff, Jared S. | Fu, YuHong | Kim, Woojin Scott

Article Type: Research Article

Abstract: Background: Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. A major pathological feature of MSA is the presence of α-synuclein aggregates in oligodendrocytes, the myelinating cells of the central nervous system. A genome-wide association study revealed that the CDH4 gene is associated with MSA. However, virtually nothing is known about the role of CDH4 in the context of MSA. Objective: Our aim was to compare the expression of CDH4 between MSA and control brains, and to investigate its relationship with α-synuclein in oligodendrocytes. Methods: …RNA and protein were prepared from putamen, motor cortex white matter, cerebellum, and superior occipital cortex tissues collected from MSA (N  = 11) and control (N  = 13) brains. The expression of CDH4 was measured at mRNA and protein levels by qPCR and western blotting. Oligodendrocyte cells were cultured on plates and transfected with CDH4 cDNA and its impact on α-synuclein was analyzed. Results: Firstly, we found that CDH4 in MSA brain was significantly elevated in the disease-affected motor cortex white matter in MSA (N  = 11) compared to controls (N  = 13) and unaltered in the disease-unaffected superior occipital cortex. Secondly, we determined that increases in CDH4 expression caused changes in the cellular levels of α-synuclein in oligodendrocytes. Conclusions: When put together, these results provide evidence that support the GWAS association of CDH4 with MSA. Show more

Keywords: α-synuclein, cadherins, CDH4, multiple system atrophy, oligodendrocyte

DOI: 10.3233/JPD-230298

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1303-1311, 2023

Authors: Jiang, Qirui | Zhang, Lingyu | Lin, Junyu | Wei, Qianqian | Li, Chunyu | Hou, Yanbing | Ou, Ruwei | Liu, Kuncheng | Yang, Tianmi | Xiao, Yi | Zhao, Bi | Wu, Ying | Shang, Huifang

Article Type: Research Article

Abstract: Background: Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by Parkinsonism, ataxia, and autonomic nervous failure. Orthostatic hypotension (OH) is the main feature of central vascular autonomic failure in MSA. Objective: The study aimed elucidate the effects of OH on cognitive function, disease milestones, and survival. Methods: A total of 444 patients with clinically established MSA were enrolled. Mild and severe OH were defined as a decrease in systolic blood pressure (SBP)/diastolic blood pressure (DBP) >20/10 mmHg and SBP/DBP ≥30/15 mmHg, respectively. Results: In this study, 215 MSA patients presented without OH, …88 had mild OH, and 141 had severe OH. The proportion of MSA-C in the severe OH subgroup was significantly higher than that in the subgroup without OH (95/46 vs. 113/102, p  = 0.021). The UMSARS I score and the frequency of supine hypertension (SH) in patients with OH were significantly higher than those in patients without OH (16.22 vs. 16.89 vs. 14.60, p  < 0.001; 77/64 vs. 29/59 vs. 32/183, p  < 0.001). Factors related to the severity of OH included sex (OR, 0.65; p  = 0.031), onset age (OR, 0.98; p  = 0.029), and SH (OR, 0.21; p  < 0.001). The median survival time of patients with severe OH was significantly lower than that of patients without OH (6.79 vs. 8.13 years, p  = 0.001). Consistently, Cox survival analysis found that compared with patients without OH, patients with severe OH had a significantly increased risk of death (OR, 2.22; p  < 0.001). Conclusion: Our large cohort study of MSA provides additional evidence for the negative impact of severe OH on survival. Show more

Keywords: Multiple system atrophy, orthostatic hypotension, survival

DOI: 10.3233/JPD-230095

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1313-1320, 2023

Authors: Jansen, Jamie A.F. | Tosserams, Anouk | Weerdesteyn, Vivian G.M. | Bloem, Bastiaan R. | Nonnekes, Jorik

Article Type: Research Article

Abstract: Background: A history of falls is the most established predictor of future falls in people with Parkinson’s disease (PD). However, predicting a first fall remains challenging. Objective: To assess whether experiencing difficulties putting on pants while standing is a viable predictor of future falling, and specifically a first fall, in persons with PD. We define this ‘Pants-sign’ as people who resort to putting on their pants only while seated. Methods: 264 persons with PD were included. Information on the Pants-sign, history of falls, disease severity (MDS-UPDRS part III), freezing of gait (N-FOGQ > 0), cognitive function (MoCA), self-reported …disability (Schwab & England scale), health-related quality of life (SF-12), Timed-Up-and-Go, and one-legged stance were determined at baseline and after one-year follow-up. The association between the Pants-sign and future falling was examined by univariate logistic regression analysis. A multivariate step-wise logistic regression with forward selection was employed to identify the strongest associations in the entire cohort and a sub-cohort of people without falls in the year prior to baseline. Results: The Pants-sign was univariably associated with a future fall (OR = 2.406, 95% CI [1.313–4.409], p  = 0.004]), but was not an independent predictor in the multivariate logistic regression; predictors were higher MDS-UPDRS part III scores (OR = 1.088, 95% CI [1.056–1.121 ], p  < 0.001] and history of falls (OR = 5.696, 95% CI [2.650–12.243], p ≤0.001]. For the sub-cohort of people without falls in the previous year (n  = 189), the Pants-sign was not associated with future falls. Conclusions: The Pants-sign is simple to assess and is associated with future falling in PD but is not an independent predictor. Show more

Keywords: Parkinson’s disease, falls, postural instability, risk factors, balance

DOI: 10.3233/JPD-230353

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1321-1327, 2023

Authors: Stocchi, Fabrizio | Rascol, Olivier | Poewe, Werner | Chaudhuri, K. Ray | Kassubek, Jan | Lopez Manzanares, Lydia | Zhang, Yi | Bowling, Alyssa | Pappert, Eric | Wu, Stacy

Article Type: Research Article

Abstract: Background: Apomorphine sublingual film (SL-APO) and subcutaneous apomorphine (SC-APO) have been used for the treatment of OFF episodes in Parkinson’s disease (PD). No study has prospectively compared efficacy and safety of these formulations. Objective: To compare SL-APO with SC-APO for treatment of OFF episodes in PD. Methods: An open-label, randomized, crossover study assessed SL-APO versus SC-APO in patients with PD and OFF episodes (N  = 113). Doses were optimized in randomly assigned order. SL-APO dose initiation (10 mg) occurred in clinic; further dose optimization (15–30 mg; 5-mg increments) occurred primarily at home. SC-APO dosing (2–6 mg; 1-mg increments) occurred entirely …in clinic. After a 3–7-day washout, patients were randomized 1 : 1 to 4 weeks of treatment with their optimized dose of SL-APO or SC-APO, followed by washout and 4 weeks of crossover treatment. Results: Propensity score matching applied on 159 patients (STN-DBS n  = 75, MED n  = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes. Results: No difference was observed between SL-APO and SC-APO for change from predose to 90 minutes postdose in Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III score at week 4 (primary endpoint), assessed by a blinded rater (–13.6 vs. –13.8, respectively; p  = NS). Overall, 72.2% of patients preferred SL-APO compared with SC-APO/no preference (p  = 0.0002) per the Treatment Preference Questionnaire (secondary endpoint). Patients reported greater satisfaction with SL-APO compared with SC-APO, per mean scores of convenience (73.7 vs. 53.5) and global satisfaction (63.9 vs. 57.6) on the Treatment Satisfaction Questionnaire for Medication (other endpoint). The safety profiles of both treatments were generally comparable and were well-tolerated. Conclusions: Patients reported overall preference for and greater satisfaction with SL-APO over SC-APO. Show more

Keywords: Apomorphine sublingual film, subcutaneous apomorphine, carbidopa/levodopa, Parkinson’s disease, OFF episode

DOI: 10.3233/JPD-230072

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1329-1342, 2023

Authors: Zeissler, Marie-Louise | McFarthing, Kevin | Raphael, Karen G. | Rafaloff, Gary | Windle, Richard | Carroll, Camille B.

Article Type: Research Article

Abstract: Background: Design of disease modification (DM) trials for Parkinson’s disease (PD) is challenging. Successful delivery requires a shared understanding of priorities and practicalities. Objective: To seek stakeholder consensus on phase 3 trials’ overall goals and structure, inclusion criteria, outcome measures, and trial delivery and understand where perspectives differ. Methods: An international expert panel comprising people with Parkinson’s (PwP), care partners (CP), clinical scientists, representatives from industry, funders and regulators participated in a survey-based Delphi study. Survey items were informed by a scoping review of DM trials and PwP input. Respondents scored item agreement …over 3 rounds. Scores and reasoning were summarized by participant group each round until consensus, defined as≥70% of at least 3 participant groups falling within the same 3-point region of a 9-point Likert scale. Results: 92/121 individuals from 13 countries (46/69 PwP, 13/18 CP, 20/20 clinical scientists, representatives from 8/8 companies, 4/5 funders, and 1/1 regulator) completed the study. Consensus was reached on 14/31 survey items: 5/8 overall goals and structure, 1/8 Eligibility criteria, 7/13 outcome measures, and 1/2 trial delivery items. Extent of stakeholder endorsement for 428 reasons for scores was collated across items. Conclusions: This is the first systematic multi-stakeholder consultation generating a unique repository of perspectives on pivotal aspects of DM trial design including those of PwP and CP. The panel endorsed outcomes that holistically measure PD and the importance of inclusive trials with hybrid delivery models. Areas of disagreement will inform mitigating strategies of researchers to ensure successful delivery of future trials. Show more

Keywords: Parkinson’s disease, disease modification, clinical trial, Delphi survey

DOI: 10.3233/JPD-230109

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1343-1356, 2023

Authors: Yuk, Jin-Sung | Jeong, Seong Ho

Article Type: Research Article

Abstract: Background: The relationship between menopausal hormone therapy (MHT) and risk of Parkinson’s disease (PD) remains controversial. Objective: This nationwide population-based cohort study investigated the association between MHT and PD development. Methods: Data from the National Health Insurance System of South Korea from 2007 to 2020 were used. The MHT group included women who underwent MHT for the first time between 2011–2014, while the non-MHT group included women who visited a healthcare provider for menopause during the same period but never received hormonal therapy. We used propensity score matching (1 : 1) to adjust for potential confounders, and Cox …regression models to assess the association between MHT and PD. Results: We selected 303,260 female participants (n  = 151,630 per MHT and non-MHT groups). The median age of the participants was 50 (48–54) years, and the follow-up period lasted 7.9 (6.9–8.9) years. Cox regression analysis revealed an increased risk of PD with MHT (hazard ratio [HR] 1.377, 95% confidence interval [CI] 1.184–1.602), particularly with tibolone (HR 1.554, 95% CI 1.297–1.861) and estrogen alone (HR 1.465, 95% CI 1.054–2.036). Tibolone and estrogen alone were linked to PD within three years; however, no association was observed after three years. In contrast, the use of combined estrogen-progesterone was linked to a higher risk of PD, which increased with the duration of MHT (HR 1.885, 95% CI 1.218–2.918 for over five years). Conclusions: This study demonstrated that the MHT is closely associated with the risk of PD in a regimen- and duration-specific manner. Show more

Keywords: Hormone therapy, Parkinson’s disease, estrogen, progesterone

DOI: 10.3233/JPD-230230

Citation: Journal of Parkinson's Disease, vol. 13, no. 8, pp. 1357-1367, 2023