Journal of Parkinson's Disease - Volume 12, issue 3

Authors: Hogg, Elliot | Frank, Samuel | Oft, Jillian | Benway, Brian | Rashid, Mohammad Harun | Lahiri, Shouri

Article Type: Review Article

Abstract: Urinary tract infection (UTI) is a common precipitant of acute neurological deterioration in patients with Parkinson’s disease (PD) and a leading cause of delirium, functional decline, falls, and hospitalization. Various clinical features of PD including autonomic dysfunction and altered urodynamics, frailty and cognitive impairment, and the need for bladder catheterization contribute to an increased risk of UTI. Sepsis due to UTI is a feared consequence of untreated or undertreated UTI and a leading cause of morbidity in PD. Emerging research suggests that immune-mediated brain injury may underlie the pathogenesis of UTI-induced deterioration of PD symptoms. Existing strategies to prevent UTI …in patients with PD include use of topical estrogen, prophylactic supplements, antibiotic bladder irrigation, clean catheterization techniques, and prophylactic oral antibiotics, while bacterial interference and vaccines/immunostimulants directed against common UTI pathogens are potentially emerging strategies that are currently under investigation. Future research is needed to mitigate the deleterious effects of UTI in PD. Show more

Keywords: Parkinson’s disease, urinary tract infection, delirium, falls, exacerbation

DOI: 10.3233/JPD-213103

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 743-757, 2022

Authors: Polgar, Stephen | Buultjens, Melissa | Wijeratne, Tissa | Finkelstein, David I. | Mohamed, Sheeza | Karimi, Leila

Article Type: Systematic Review

Abstract: In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson’s disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham …surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson’s Disease Scale in the ‘OFF’ state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18 F-Fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD. Show more

Keywords: Parkinson’s disease, regenerative therapy, cell therapy, gene therapy, sham surgery, stem cells, placebo response

DOI: 10.3233/JPD-212610

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 759-771, 2022

Authors: Kwak, Nayoung | Park, Jinyoung | Kang, Hye-Young | Lee, Myung-Jun | Suh, Jae Kyung | Lee, Hankil

Article Type: Systematic Review

Abstract: Background: Long-term levodopa administration for treating Parkinson’s disease (PD) may shorten the duration of effect and cause dyskinesias, inducing the need for catechol-O-methyltransferase (COMT) inhibitors as adjuvant therapy. Objective: We provide pooled scientific evidence highlighting the efficacy and safety of opicapone, a newly approved COMT inhibitor, as an adjuvant to levodopa. Methods: We searched Ovid Medline, Embase, and Cochrane databases for relevant reports. Efficacy and safety were evaluated as off-time reduction and risk ratio (RR) of dyskinesia, respectively. Data were independently extracted using predefined criteria. Selected placebo-controlled trials were divided into double-blind and open-label periods. Using …a random-effects model, the mean difference (MD) of the off-time reduction (efficacy), RR for the occurrence of dyskinesia, and on-time without/with troublesome dyskinesia (TD; safety assessment) were compared between opicapone and placebo groups. Results: Five studies from three randomized controlled trials were included, and a meta-analysis was performed with 407 patients receiving opicapone 50 mg and 402 patients receiving placebo. Compared with the placebo, opicapone (50 mg) reduced off-time by 49.91 min during the double-blind period (95% confidence intervals [CIs] = –71.39, –28.43; I2  = 0%). The RR of dyskinesia was 3.43 times greater in the opicapone 50 mg group than in the placebo group (95% CI = 2.14, 5.51; I = 0%). Compared with the placebo, opicapone increased the on-time without TD by 44.62 min (95% CI = 22.60, 66.64; I2  = 0%); the on-time increase with TD did not differ between treatments. Conclusion: Opicapone can play a positive role as an adjuvant to levodopa in patients with PD by reducing off-time and prolonging on-time without PD. Show more

Keywords: Parkinson’s disease, levodopa, catechol O-methyltransferase inhibitors, dyskinesias, opicapone

DOI: 10.3233/JPD-213057

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 773-783, 2022

Authors: van der Lijn, Iris | de Haan, Gera A. | Huizinga, Famke | van der Feen, Fleur E. | Rutgers, A. Wijnand F. | Stellingwerf, Catherina | van Laar, Teus | Heutink, Joost

Article Type: Systematic Review

Abstract: Background: Scientific research increasingly focuses on visual symptoms of people with Parkinson’s disease (PD). However, this mostly involves functional measures, whereas self-reported data are equally important for guiding clinical care. Objective: This review provides an overview of the nature and prevalence of self-reported visual complaints by people with PD, compared to healthy controls. Methods: A systematic literature search was performed. Studies from three databases (PubMed, PsycInfo, and Web of Science) were screened for eligibility. Only studies that reported results of visual self-reports in people with idiopathic PD were included. Results: One hundred and thirty-nine …eligible articles were analyzed. Visual complaints ranged from function-related complaints (e.g., blurred vision, double vision, increased sensitivity to light or changes in contrast sensitivity) to activity-related complaints (e.g., difficulty reading, reaching, or driving). Visual complaints were more prevalent in people with PD compared to healthy controls. The presence of visual complaints leads to a reduced quality of life (QoL). Increased prevalence and severity of visual complaints in people with PD are related to longer disease duration, higher disease severity, and off-state. Conclusion: A large proportion of people with PD have visual complaints, which negatively affect QoL. Complaints are diverse in nature, and specific and active questioning by clinicians is advised to foster timely recognition, acknowledgement, and management of these complaints. Show more

Keywords: Activities of daily living, Parkinson’s disease, quality of life, self report, systematic review, vision disorders

DOI: 10.3233/JPD-202324

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 785-806, 2022

Authors: Ritz, Beate R. | Kusters, Cynthia D.J.

Article Type: Article Commentary

Abstract: This commentary discusses the strengths and limitations of utilizing the Mendelian randomization (MR) approach in Parkinson’s disease (PD) studies. Epidemiologists proposed to employ MR when genetic instruments are available that represent reliable proxies for modifiable lifelong exposures which elude easy measurement in studies of late onset diseases like PD. Here, we are using smoking as an example. The great promise of the MR approach is its resilience to confounding and reverse causation. Nevertheless, the approach has some drawbacks such as being liable to selection- and survival-bias, it makes some strong assumptions about the genetic instruments employed, and requires very large …sample sizes. When interpreted carefully and put into the context of other studies that take both genetics and the environment into consideration, MR studies help us to not only ask interesting questions but also can support causal inference and provide novel insights. Show more

Keywords: Parkinson’s disease, mendelian randomization, smoking, review

DOI: 10.3233/JPD-223188

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 807-812, 2022

Authors: Lin, Rong-Rong | Tao, Qing-Qing | Wu, Zhi-Ying

Article Type: Research Article

Abstract: DJ-1 mutations are rare causes of autosomal recessive early-onset Parkinson’s disease (AR-EOPD) and relatively rarely reported in the Chinese population. Here, we used the whole-exome sequencing and Sanger sequencing to investigate DJ-1 mutations in the Chinese population and confirmed the pathogenicity of the mutation using primary fibroblasts established from skin biopsies. We identified a novel homozygous mutation (c.390delA, p.D131Tfs* 3) in DJ-1 in a consanguineous Chinese family. The proband in this family had parkinsonism at the age of 22. His brain MRI indicated brain iron accumulation in the basal ganglia and cerebellum. The novel mutation caused DJ-1 …protein deficiency, led to mitochondrial dysfunction, inhibited cell proliferation, and anti-oxidant defense. Show more

Keywords: Brain iron accumulation, DJ-1, Parkinson’s disease

DOI: 10.3233/JPD-213033

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 813-819, 2022

Authors: Lewis, Mechelle M. | Albertson, Richard M. | Du, Guangwei | Kong, Lan | Foy, Andrew | Huang, Xuemei

Article Type: Research Article

Abstract: Background: Recent randomized clinical trials using hydrophobic statins reported no influence on Parkinson’s disease (PD) clinical progression. Hydrophobicity is a key determinant for blood-brain barrier penetrance. Objective: Investigate a potential effect of statins on PD progression. Methods: Statin use was determined at baseline and subtyped according to hydrophobicity in 125 PD patients participating in the PD Biomarker Program (PDBP, 2012–2015) at our site. Clinical (N  = 125) and susceptibility MRI (N  = 86) data were obtained at baseline and 18-months. Movement Disorders Society-Unified PD Rating Scales were used to track progression of non-motor (MDS-UPDRS-I) and motor (MDS-UPDRS-II) symptoms, …and rater-based scores (MDS-UPDRS-III) of patients in the “on” drug state. R2* values were used to capture pathological progression in the substantia nigra. Associations between statin use, its subtypes, and PD progression were evaluated with linear mixed effect regressions. Results: Compared to statin non-users, overall statin or lipophilic statin use did not significantly influence PD clinical or imaging progression. Hydrophilic statin users, however, demonstrated faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 4.8, p  = 0.010)] and nigral R2* (β= 3.7, p  = 0.043). A similar trend was found for MDS-UPDRS-II (β= 3.9, p  = 0.10), but an opposite trend was observed for rater-based MDS-UPDRS-III (β= –7.3, p  = 0.10). Compared to lipophilic statin users, hydrophilic statin users also showed significantly faster clinical progression of non-motor symptoms [MDS-UPDRS-I (β= 5.0, p  = 0.020)], but R2* did not reach statistical significance (β= 2.5, p  = 0.24). Conclusion: This study suggests that hydrophilic, but not lipophilic, statins may be associated with faster PD progression. Future studies may have clinical and scientific implications. Show more

Keywords: Parkinson’s disease, lipophilic statins, hydrophilic statins, MDS-UPDRS scores, susceptibility imaging, MRI, substantia nigra, R2*

DOI: 10.3233/JPD-212819

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 821-830, 2022

Authors: Vazquez-Mayorga, Emmanuel | Grigoruta, Mariana | Dagda, Raul | Martinez, Bridget | Dagda, Ruben K.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in …the midbrain may be a new anti-PD therapeutic alternative. Objective: We surmised that pharmacological activation of PKA via intraperitoneal administration of Forskolin exerts anti-PD effects in symptomatic PTEN-induced kinase 1 knockout (PINK1-KO), a bona fide in vivo model of PD. Methods: By using a beam balance and a grip strength analyzer, we show that Forskolin reverses motor symptoms and loss of hindlimb strength with long-lasting therapeutic effects (> 5 weeks) following the last dose. Results: In comparison, intraperitoneal treatment with Levodopa temporarily (24 h) reduces motor symptoms but unable to restore hindlimb strength in PINK1-KO rats. By using immunohistochemistry and an XF24e BioAnalyzer, Forskolin treatment reverses SN neurons loss, elevates brain energy production and restores PKA activity in SN in symptomatic PINK1-KO rats. Conclusion: Overall, our collective in vivo data suggest that Forskolin is a promising disease-modifying therapeutic alternative for PD and is superior to Levodopa because it confers long-lasting therapeutic effects. Show more

Keywords: Parkinson’s disease, PKA, forskolin, Levodopa, bioenergetics, therapeutics

DOI: 10.3233/JPD-213016

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 831-850, 2022

Authors: Brown, Gregory | Du, Guangwei | Farace, Elana | Lewis, Mechelle M. | Eslinger, Paul J. | McInerney, James | Kong, Lan | Li, Runze | Huang, Xuemei | De Jesus, Sol

Article Type: Research Article

Keywords: Parkinson’s disease, deep brain stimulation, MRI, R2*, neuropsychiatric outcomes

DOI: 10.3233/JPD-212833

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 851-863, 2022

Authors: Tan, Yi Jayne | Saffari, Seyed Ehsan | Zhao, Yi | Ng, Ebonne Y.L. | Yong, Alisa C.W. | Ng, Samuel Y.E. | Chia, Nicole S.Y. | Choi, Xinyi | Heng, Dede | Neo, Shermyn | Xu, Zheyu | Tay, Kay Yaw | Au, Wing Lok | Tan, Eng-King | Tan, Louis C.S. | Ng, Adeline S.L.

Article Type: Short Communication

Abstract: The alpha-synuclein gene promoter (SNCA-Rep1) is associated with Parkinson’s disease (PD), but its relationship with performance across individual cognitive domains in early PD is unknown. This study aims to investigate Rep1 polymorphism and longitudinal change in cognition in early PD. In this longitudinal study, Rep1 allele lengths (“long” and “short”) were determined in 204 early PD patients. All participants underwent annual neuropsychological assessments and followed up for 3 years. Linear-mixed model was performed to investigate the association of Rep1 status and longitudinal change in individual cognitive domains. At 3 years, significant decline in executive function was observed in long Rep1 …allele carriers vs short allele carriers, controlling for potential confounders. This is the first longitudinal study demonstrating that long Rep1 allele carriers are at higher risk for executive dysfunction in early PD. Show more

Keywords: Parkinson’s disease, SNCA Rep1 promoter, cognition, genetics

DOI: 10.3233/JPD-213029

Citation: Journal of Parkinson's Disease, vol. 12, no. 3, pp. 865-870, 2022