Journal of Parkinson's Disease - Volume 13, issue 5

Authors: van Laar, Teus | Chaudhuri, K. Ray | Antonini, Angelo | Henriksen, Tove | Trošt, Maja

Article Type: Review Article

Abstract: Oral levodopa is the gold-standard therapy for treating Parkinson’s disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools …for advanced PD, and provides considerations around optimal use of infusion therapy. Show more

Keywords: Continuous subcutaneous infusion, apomorphine, carbidopa, levodopa drug combination, implantable infusion pumps, Parkinson’s disease

DOI: 10.3233/JPD-225112

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 641-657, 2023

Authors: Folkerts, Ann-Kristin | Nielsen, Jörn | Gollan, Romina | Lansu, Annika | Solfronk, Dominik | Monsef, Ina | Ernst, Moritz | Skoetz, Nicole | Zeuner, Kirsten E. | Kalbe, Elke

Article Type: Systematic Review

Abstract: Background: Fatigue is one of the most common and debilitating non-motor symptoms among patients with Parkinson’s disease (PD) and significantly impacts quality of life. Therefore, effective treatment options are needed. Objective: To provide an update on randomized controlled trials (RCTs) including pharmacological and non-pharmacological (but non-surgical) treatments that examine the effects of fatigue on PD patients. Methods: We searched the MEDLINE, EMBASE, PsycINFO, CENTRAL, and CINAHL databases for (cross-over) RCTs on pharmacological and non-pharmacological interventions for treating fatigue in PD patients until May 2021. Meta-analyses for random-effects models were calculated when two or more studies on …the same treatment option were available using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results: Fourteen pharmacological and 16 non-pharmacological intervention RCTs were identified. For pharmacological approaches, a meta-analysis could only be performed for modafinil compared to placebo (n  = 2) revealing a non-significant effect on fatigue (SMD = – 0.21, 95% CI – 0.74–0.31, p  = 0.43). Regarding non-pharmacological approaches, physical exercise (n  = 8) following different training approaches versus passive or placebo control groups showed a small significant effect (SMD = – 0.37, 95% CI – 0.69‐ – 0.05, p  = 0.02) which could not be demonstrated for acupuncture vs. sham-acupuncture (SMD = 0.16, 95% CI – 0.19–0.50, p  = 0.37). Conclusion: Physical exercise may be a promising strategy to treat fatigue in PD patients. Further research is required to examine the efficacy of this treatment strategy and further interventions. Future studies should differentiate treatment effects on physical and mental fatigue as the different underlying mechanisms of these symptoms may lead to different treatment responses. More effort is required to develop, evaluate, and implement holistic fatigue management strategies for PD patients. Show more

Keywords: Parkinson’s disease, non-motor symptoms, fatigue, therapeutics, systematic review, meta-analysis

DOI: 10.3233/JPD-225116

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 659-679, 2023

Authors: Rangwala, Rabab | Saadi, Raneh | Lee, Jungwha Julia | Reedy, Erin L. | Kantarcigil, Cagla | Roberts, Megan | Martin-Harris, Bonnie

Article Type: Systematic Review

Abstract: Background: Swallowing impairment, including altered physiology and aspiration, occur across the progression of Parkinson’s disease (PD). The phase of respiration during which a swallow is initiated has been linked to swallowing impairment and aspiration in cohorts with dysphagia following stroke and head and neck cancer treatment, but has been understudied in PD. If similar findings are shown in individuals with PD, the implications for swallowing assessment and treatment are significant. Objective: The aim of this systematic review and meta-analysis of literature was to examine respiratory-swallow coordination measures and potential implications on swallowing physiology in individuals with PD. …Methods: An extensive search of 7 databases (PubMed, EMBASE, Central, Web of Science, ProQuest Dissertations & Theses, Scopus, and CINAHL) with predetermined search terms was conducted. Inclusion criteria were individuals with PD and the use of objective evaluations of respiratory-swallow coordination. Results: Of the 13,760 articles identified, 11 met the inclusion criteria. This review supports the presence of atypical respiratory swallow patterning, respiratory pause duration and lung volume at swallow initiation in individuals with PD. The meta-analysis estimated an occurrence of 60% of non-expiration-expiration and 40% of expiration-expiration respiratory phase patterns surrounding swallowing. Conclusion: Although this systematic review supports the occurrence of atypical respiratory-swallow coordination in individuals with PD, the evidence is limited by the variability in the methods of data acquisition, analysis, and reporting. Future research examining the impact of respiratory swallow coordination on swallowing impairment and airway protection using consistent, comparable, and reproducible methods and metrics in individuals with PD is warranted. Show more

Keywords: Deglutition disorders, respiration, Parkinson’s disease, systematic review, meta-analysis

DOI: 10.3233/JPD-230057

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 681-698, 2023

Authors: Karacan, Ahmet Veli | Kibrit, Sema Nur | Yekedüz, Merve Koç | Doğulu, Neslihan | Kayis, Gorkem | Unutmaz, Elif Yüsra | Abali, Talha | Eminoğlu, F. Tuba | Akbostancı, M. Cenk | Yilmaz, Rezzak

Article Type: Research Article

Abstract: Background: Stigma is an important social attitude affecting the quality of life (QoL) of people with Parkinson’s disease (PwP, PD) as individuals within society. Objective: This systematic review aimed to 1) identify the factors associated with stigma in PD and 2) demonstrate culture-based diversity in the stigmatization of PwP. We also reported data from the Turkish PwP, which is an underrepresented population. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a literature search of the PubMed/Medline electronic database was performed covering the last 26 years. Articles on self-perceived stigma in PD …with a sample size >  20 and quantitative results were included. Data were extracted by independent reviewers. Results: After screening 163 articles, 57 were eligible for review, most of which were from Europe or Asia. Only two studies have been conducted in South America. No study from Africa was found. Among the 61 factors associated with stigma, disease duration, sex, and age were most frequently studied. A comparison of the investigated factors across the world showed that, while the effect of motor impairment or treatment on stigma seems to be culture-free, the impact of sex, education, marriage, employment, cognitive impairment, and anxiety on stigma may depend on culture. Conclusion: The majority of the world’s PD population is underrepresented or unrepresented, and culture may influence the perception of stigma in PwP. More diverse data are urgently needed to understand and relieve the challenges of PwP within their society. Show more

Keywords: Parkinson’s disease, stigma, stereotyping, quality of life

DOI: 10.3233/JPD-230050

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 699-715, 2023

Authors: Gelain, Daniel Pens | Bittencourt, Reykla Ramon | Bastos Mendes, Luiz Filipe | Moreira, José Claudio Fonseca | Outeiro, Tiago Fleming

Article Type: Research Article

Abstract: Oligomerization and aggregation of misfolded forms of α -synuclein are believed to be key molecular mechanisms in Parkinson’s disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α -synuclein aggregation, glycation may take place at several lysine sites and modify α -synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been …reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α -synuclein binds to RAGE. Here, we summarize the available data on α -synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies. Show more

Keywords: α-synuclein, glycation, Parkinson’s disease, RAGE, synucleinopathies

DOI: 10.3233/JPD-230070

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 717-728, 2023

Authors: Cao, Zichun | Song, Shengfang | Huang, Xuemei | Li, Chenxi | Luo, Zhehui | D’Aloisio, Aimee A. | Suarez, Lourdes | Hernandez, Dena G. | Singleton, Andrew B. | Sandler, Dale P. | Chen, Honglei

Article Type: Research Article

Abstract: Background: Large prospective studies are essential for investigating the environmental causes of Parkinson’s disease (PD), but PD diagnosis via clinical exams is often infeasible in such studies. Objective: To present case ascertainment strategy and data collection in a US cohort of women. Methods: In the Sister Study (n  = 50,884, baseline ages 55.6±9.0), physician-made PD diagnoses were first reported by participants or their proxies. Cohort-wide follow-up surveys collected data on subsequent diagnoses, medication usage and PD-relevant motor and nonmotor symptoms. We contacted self-reported PD cases and their treating physicians to obtain relevant diagnostic and treatment history. Diagnostic …adjudication was made via expert review of all available data, except nonmotor symptoms. We examined associations of nonmotor symptoms with incident PD, using multivariable logistic regression models and reported odds ratio (OR) and 95% confidence intervals (CI). Results: Of the 371 potential PD cases identified, 242 diagnoses were confirmed. Compared with unconfirmed cases, confirmed cases were more likely to report PD diagnosis from multiple sources, medication usage, and motor and nonmotor features consistently during the follow-up. PD polygenic risk score was associated with confirmed PD (ORinter-quartile range = 1.74, 95% CI: 1.45–2.10), but not with unconfirmed cases (corresponding OR = 1.05). Hyposmia, dream-enacting behaviors, constipation, depression, unexplained weight loss, dry eyes, dry mouth, and fatigue were significantly related to PD risk, with ORs from 1.71 to 4.88. Only one of the eight negative control symptoms was associated with incident PD. Conclusion: Findings support our PD case ascertainment approach in this large cohort of women. PD prodromal presentation is likely beyond its well-documented profile. Show more

Keywords: Parkinson’s disease, cohort studies, prospective studies, prodromal symptoms

DOI: 10.3233/JPD-230053

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 729-742, 2023

Authors: Han, Junhui | Liu, Mengqing | Ling, Yi | Ren, Yubo | Qiu, Yue | Liu, Yi | Yin, Yanyan

Article Type: Research Article

Abstract: Background: Endophilin A1 (EPA1) is encoded by the SH3GL2 gene, and SH3GL2 was designated as a Parkinson’s disease (PD) risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. Objective: To investigate the role of EPA1 in lipopolysaccharide (LPS)-induced PD model mice. Methods: The mice PD model was prepared by injecting LPS into the substantia nigra (SN), and the changes in the behavioral data of mice in each group were observed. The damage of dopaminergic neurons, activation of microglia, and reactive oxygen species (ROS) generation were detected …by immunofluorescence method; calcium ion concentration was detected by calcium content detection kit; EPA1 and inflammation and its related indicators were detected by western blot method. EPA1 knockdown was performed by an adeno-associated virus vector containing EPA1-shRNA-eGFP infusion. Results: LPS-induced PD model mice developed behavioral dysfunction, SN dopaminergic nerve damage, significantly increased calcium ion, calpain 1, and ROS production, activated NLRP1 inflammasome and promoted pro-inflammatory cell release, and SN EPA1 knockdown improves behavioral disorders, alleviates dopaminergic neuron damage, reduces calcium, calpain 1, ROS generation, and blocks NLRP1 inflammasome-driven inflammatory responses. Conclusion: The expression of EPA1 in the SN of LPS-induced PD model mice was increased, and it played a role in promoting the occurrence and development of PD. EPA1 knockdown inhibited the NLRP1 inflammasome activation, decreased the release of inflammatory factors and ROS generation, and alleviated dopaminergic neuron damage. This indicated that EPA1 may participating in the occurrence and development of PD. Show more

Keywords: Parkinson’s disease, Endophilin A1, calpain 1, reactive oxygen species, NLRP1

DOI: 10.3233/JPD-225098

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 743-756, 2023

Authors: Marras, Connie | Arbatti, Lakshmi | Hosamath, Abhishek | Amara, Amy | Anderson, Karen E. | Chahine, Lana M. | Eberly, Shirley | Kinel, Dan | Mantri, Sneha | Mathur, Soania | Oakes, David | Purks, Jennifer L. | Standaert, David G. | Tanner, Caroline M. | Weintraub, Daniel | Shoulson, Ira

Article Type: Research Article

Abstract: Background: Free-text, verbatim replies in the words of people with Parkinson’s disease (PD) have the potential to provide unvarnished information about their feelings and experiences. Challenges of processing such data on a large scale are a barrier to analyzing verbatim data collection in large cohorts. Objective: To develop a method for curating responses from the Parkinson’s Disease Patient Report of Problems (PD-PROP), open-ended questions that asks people with PD to report their most bothersome problems and associated functional consequences. Methods: Human curation, natural language processing, and machine learning were used to develop an algorithm to convert …verbatim responses to classified symptoms. Nine curators including clinicians, people with PD, and a non-clinician PD expert classified a sample of responses as reporting each symptom or not. Responses to the PD-PROP were collected within the Fox Insight cohort study. Results: Approximately 3,500 PD-PROP responses were curated by a human team. Subsequently, approximately 1,500 responses were used in the validation phase; median age of respondents was 67 years, 55% were men and median years since PD diagnosis was 3 years. 168,260 verbatim responses were classified by machine. Accuracy of machine classification was 95% on a held-out test set. 65 symptoms were grouped into 14 domains. The most frequently reported symptoms at first report were tremor (by 46% of respondents), gait and balance problems (>39%), and pain/discomfort (33%). Conclusion: A human-in-the-loop method of curation provides both accuracy and efficiency, permitting a clinically useful analysis of large datasets of verbatim reports about the problems that bother PD patients. Show more

Keywords: Patient-reported outcome, measurement, Parkinson’s disease, machine learning

DOI: 10.3233/JPD-225083

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 757-767, 2023

Authors: Chaudhuri, K. Ray | Kovács, Norbert | Pontieri, Francesco E. | Aldred, Jason | Bourgeois, Paul | Davis, Thomas L. | Cubo, Esther | Anca-Herschkovitsch, Marieta | Iansek, Robert | Siddiqui, Mustafa S. | Simu, Mihaela | Bergmann, Lars | Ballina, Mayra | Kukreja, Pavnit | Ladhani, Omar | Jia, Jia | Standaert, David G.

Article Type: Research Article

Abstract: Background: Levodopa-carbidopa intestinal gel (LCIG) improves motor and non-motor symptoms in patients with advanced Parkinson’s disease (aPD). Objective: To present the final 36-month efficacy and safety results from DUOGLOBE (DUOdopa/Duopa in Patients with Advanced Parkinson’s Disease – a GLobal OBservational Study Evaluating Long-Term Effectiveness; NCT02611713). Methods: DUOGLOBE was an international, prospective, long-term, real-world, observational study of patients with aPD initiating LCIG in routine clinical care. The primary endpoint was change in patient-reported “Off” time to Month 36. Safety was assessed by monitoring serious adverse events (SAEs). Results: Significant improvements in “Off” time were maintained …over 3 years (mean [SD]: –3.3 hours [3.7]; p  < 0.001). There were significant improvements to Month 36 in total scores of the Unified Dyskinesia Rating Scale (–5.9 [23.7]; p  = 0.044), Non-Motor Symptoms Scale (–14.3 [40.5]; p  = 0.002), Parkinson’s Disease Sleep Scale-2 (–5.8 [12.9]; p  < 0.001), and Epworth Sleepiness Scale (–1.8 [6.0]; p  = 0.008). Health-related quality of life and caregiver burden significantly improved through Months 24 and 30, respectively (Month 24, 8-item Parkinson’s Disease Questionnaire Summary Index, –6.0 [22.5]; p  = 0.006; Month 30, Modified Caregiver Strain Index, –2.3 [7.6]; p  = 0.026). Safety was consistent with the well-established LCIG profile (SAEs: 54.9% of patients; discontinuations: 54.4%; discontinuations due to an adverse event: 27.2%). Of 106 study discontinuations, 32 patients (30.2%) continued LCIG outside the study. Conclusion: DUOGLOBE demonstrates real-world, long-term, reductions in motor and non-motor symptoms in patients with aPD treated with LCIG. Show more

Keywords: DUOGLOBE, Parkinson’s disease, levodopa-carbidopa intestinal gel, dyskinesia, real-world data

DOI: 10.3233/JPD-225105

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 769-783, 2023

Authors: Li, Hui | Jia, Xuejia | Chen, Min | Jia, Xiuqin | Yang, Qi

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) varies in occurrence, presentation, and severity between males and females. However, the sex effects on the patterns of brain structure, cross-sectionally and longitudinally, are still unclear. Objective: We aimed to compare sex differences in brain features cross-sectionally and longitudinally using grey matter volume (GMV) and cortical thickness in a large sample of newly diagnosed drug-naive PD patients. Methods: Cognitive assessments and structural MR images of 262 PD patients (171 males) and 113 healthy controls (68 males) were selected from the Parkinson’s Progression Markers Initiative. Of these, 97 PD patients (66 males) completed …12- and 24-month follow-up examinations. After regressing out the expected effects of age and sex, brain maps of GMV and cortical thickness were compared using two-sample t tests cross-sectionally and were compared using repeated measurement analyses of variance longitudinally. Results: At baseline, male PD patients exhibited a greater extent of brain atrophy and cortical thickness reduction than females, which mainly occurred in the cerebellum, frontal lobe, parietal lobe, and temporal lobe. At follow-up, female and male PD patients showed similar dynamics of disease progression, as both groups declined over time while the females maintained the advantage. The cortical thickness of the right precentral gyrus at baseline was negatively associated with the longitudinal changes of motor function in male PD patients. Conclusion: The current findings might demonstrate sex effect in neuroanatomy during the course of PD, provide new insights into the neurodegenerative process, and facilitate the development of more effective sex-specific therapeutic strategies. Show more

Keywords: Parkinson’s disease, sex differences, structural MRI, cross-sectional, longitudinal

DOI: 10.3233/JPD-225125

Citation: Journal of Parkinson's Disease, vol. 13, no. 5, pp. 785-795, 2023