Journal of Parkinson's Disease - Volume 13, issue 7

Authors: Ré, Diane B. | Rideout, Hardy J.

Article Type: Editorial

DOI: 10.3233/JPD-239004

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1077-1078, 2023

Authors: Kulcsarova, Kristina | Bang, Corinna | Berg, Daniela | Schaeffer, Eva

Article Type: Review Article

Abstract: The increasing global burden of Parkinson’s disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, …describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field. Show more

Keywords: Pesticides, microbiota, gut-brain axis, Parkinson’s disease, short-chain fatty acids, inflammation, alpha-synuclein

DOI: 10.3233/JPD-230206

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1079-1106, 2023

Authors: Chen, Yiqun | Jin, Yining | Li, Kun | Qiu, Haojie | Jiang, Zihan | Zhu, Jinrong | Chen, Siqi | Xie, Wei | Chen, Guangyong | Yang, Dehao

Article Type: Systematic Review

Abstract: Background: Multiple observational studies have yielded controversial results regarding the association between Parkinson’s disease (PD) and periodontitis. Objective: This systematic review and meta-analysis was conducted to ascertain their bidirectional relationship. Methods: A literature search for relevant studies was performed in PubMed, EMBASE, the Cochrane Library, and Web of Science databases from inception to December 19, 2022. Effect sizes (ES) with 95% confidence intervals were pooled under the random-effects model. Then, leave-one-out sensitivity analysis and contour-enhanced funnel plot were applied to assess the stability of the results. Results: A total of 34 studies and 24 …studies were included for systematic review and quantitative meta-analysis, respectively. Pooled ES indicated that periodontitis was not significantly associated with PD risk (HR = 1.13, 95% CI 0.88–1.45, n  = 3; OR = 1.94, 95% CI 0.55–6.90, n  = 7), while the Mendelian randomization study revealed no association between PD and periodontitis risk (coefficient [B] = –0.0001, standard error = 0.0001, p  = 0.19). Furthermore, PD patients exhibited higher levels of periodontal pocket depth (SMD = 1.10, 95% CI 0.53–1.67), clinical attachment level (SMD = 1.40, 95% CI 0.55–2.26), plaque index (SMD = 0.81, 95% CI 0.22–1.39), and Oral Health Impact Profile-14 score (SMD = 0.91, 95% CI 0.33–1.49) compared to healthy controls. Conclusions: Our meta-analysis identified no bidirectional association between PD risk and periodontitis risk, though the prevalence of periodontitis and poorer oral status was higher in PD patients. Show more

Keywords: Parkinson’s disease, periodontitis, systematic review, meta-analysis

DOI: 10.3233/JPD-230059

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1107-1125, 2023

Authors: Videlock, Elizabeth J. | Hatami, Asa | Zhu, Chunni | Kawaguchi, Riki | Chen, Han | Khan, Tasnin | Yehya, Ashwaq Hamid Salem | Stiles, Linsey | Joshi, Swapna | Hoffman, Jill M. | Law, Ka Man | Rankin, Carl Robert | Chang, Lin | Maidment, Nigel T. | John, Varghese | Geschwind, Daniel H. | Pothoulakis, Charalabos

Article Type: Research Article

Abstract: Background: Evidence supports a role for the gut-brain axis in Parkinson’s disease (PD). Mice overexpressing human wild type α– synuclein (Thy1-haSyn) exhibit slow colonic transit prior to motor deficits, mirroring prodromal constipation in PD. Identifying molecular changes in the gut could provide both biomarkers for early diagnosis and gut-targeted therapies to prevent progression. Objective: To identify early molecular changes in the gut-brain axis in Thy1-haSyn mice through gene expression profiling. Methods: Gene expression profiling was performed on gut (colon) and brain (striatal) tissue from Thy1-haSyn and wild-type (WT) mice aged 1 and 3 months using 3′ …RNA sequencing. Analysis included differential expression, gene set enrichment and weighted gene co-expression network analysis (WGCNA). Results: At one month, differential expression (Thy1-haSyn vs. WT) of mitochondrial genes and pathways related to PD was discordant between gut and brain, with negative enrichment in brain (enriched in WT) but positive enrichment in gut. Linear regression of WGCNA modules showed partial independence of gut and brain gene expression changes. Thy1-haSyn-associated WGCNA modules in the gut were enriched for PD risk genes and PD-relevant pathways including inflammation, autophagy, and oxidative stress. Changes in gene expression were modest at 3 months. Conclusions: Overexpression of haSyn acutely disrupts gene expression in the colon. While changes in colon gene expression are highly related to known PD-relevant mechanisms, they are distinct from brain changes, and in some cases, opposite in direction. These findings are in line with the emerging view of PD as a multi-system disease. Show more

Keywords: Parkinson’s disease, brain-gut axis, gene expression profiling, alpha-synuclein

DOI: 10.3233/JPD-223568

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1127-1147, 2023

Authors: Panagaki, Theodora | Randi, Elisa B. | Szabo, Csaba | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder that afflicts more than 10 million people worldwide. Available therapeutic interventions do not stop disease progression. The etiopathogenesis of PD includes unbalanced calcium dynamics and chronic dysfunction of the axis of the endoplasmic reticulum (ER) and mitochondria that all can gradually favor protein aggregation and dopaminergic degeneration. Objective: In Lund Human Mesencephalic (LUHMES) dopaminergic-like neurons, we tested novel incretin mimetics under conditions of persistent, calcium-dependent ER stress. Methods: We assessed the pharmacological effects of Liraglutide—a glucagon-like peptide-1 (GLP-1) analog—and the dual incretin GLP-1/GIP agonist DA3-CH in …the unfolded protein response (UPR), cell bioenergetics, mitochondrial biogenesis, macroautophagy, and intracellular signaling for cell fate in terminally differentiated LUHMES cells. Cells were co-stressed with the sarcoplasmic reticulum calcium ATPase (SERCA) inhibitor, thapsigargin. Results: We report that Liraglutide and DA3-CH analogs rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarization of the mitochondrial membrane, all to re-establish normalcy of mitochondrial function under conditions of chronic ER stress. These effects correlate with a resolution of the UPR and the deficiency of components for autophagosome formation to ultimately halt the excessive synaptic and neuronal death. Notably, the dual incretin displayed a superior anti-apoptotic effect, when compared to Liraglutide. Conclusions: The results confirm the protective effects of incretin signaling in ER and mitochondrial stress for neuronal degeneration management and further explain the incretin-derived effects observed in PD patients. Show more

Keywords: Liraglutide, GLP-1/GIP dual agonist, ER stress, cellular bioenergetics, ΔΨm , mitochondrial biogenesis, autophagy, incretin signaling, neuroprotection

DOI: 10.3233/JPD-230030

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1149-1174, 2023

Authors: McCarter, Stuart J. | Camerucci, Emanuele | Mullan, Aidan F. | Stang, Cole D. | Turcano, Pierpaolo | St. Louis, Erik K. | Boeve, Bradley F. | Savica, Rodolfo

Article Type: Research Article

Abstract: Background: Sleep disturbances are common in parkinsonian disorders; however, whether sleep disorders affect individuals with early-onset parkinsonism and whether they differ from individuals with typical-onset parkinsonism is unknown. Objective: To compare the prevalence and incidence of sleep disorders before and after parkinsonian motor symptom onset between individuals with early onset parkinsonism (age ≤50 at motor symptom onset) and typical-onset parkinsonism (age >50 at motor symptom onset). Methods: We used a population-based, 1991 to 2015 incident-cohort study of parkinsonism including 38 patients with early-onset and 1,001 patients with typical-onset parkinsonism. Presence or absence and type of sleep …disorder as well as the relationship between motor and sleep symptoms were abstracted from the medical records. Rates of sleep disorders before and after onset of parkinsonism were compared with logistic regression and Cox proportional hazards models. Results: The prevalence of sleep disorders prior to the onset of parkinsonism in early vs. typical parkinsonism (24% vs. 16% p  = 0.19) and incidence of sleep disorders after parkinsonism onset (5.85 cases per 100 person-years vs. 4.11 cases per 100 person-years; HR 1.15 95% CI: 0.74–1.77) were similar between the two groups. Early-onset parkinsonism had a higher risk for developing post-motor insomnia compared with typical-onset parkinsonism (HR 1.73, 95% CI: 1.02–2.93); the risk for developing all other sleep disorders considered was similar between groups. Conclusion: Sleep disorders are common in individuals with early-onset parkinsonism and occur with similar frequency to those with typical-onset parkinsonism, except for insomnia, which was more frequent in the early-onset group. Show more

Keywords: Early-onset Parkinsonism, incident-cohort study, sleep disorders

DOI: 10.3233/JPD-230045

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1175-1183, 2023

Authors: Pachi, Ioanna | Papadopoulos, Vassilis | Koros, Christos | Simitsi, Athina Maria | Bougea, Anastasia | Bozi, Maria | Papagiannakis, Nikos | Soldatos, Rigas Filippos | Kolovou, Dimitra | Pantes, George | Scarmeas, Nikolaos | Paraskevas, Georgios | Voumvourakis, Konstantinos | Papageorgiou, Sokratis G. | Kollias, Konstantinos | Stefanis, Nikos | Stefanis, Leonidas

Article Type: Research Article

Abstract: Background: Some reports suggest that psychotic features may occur in the early stages of Parkinson’s disease (PD), but sensitive tools have not been utilized. Objective: The aim was to evaluate the presence of psychotic symptoms using detailed scales and to assess the association with clinical characteristics. Methods: Healthy controls and patients within three years of PD onset were recruited. Participants were examined for psychotic symptoms using two different instruments: the Comprehensive Assessment of At-Risk Mental States (CAARMS) and a 10 question PD specific psychosis severity scale (10PDQ). In the PD group, medication use, motor and non-motor …symptoms were documented. Results: Based on CAARMS and 10PDQ scales, psychotic features were present in 39% (27/70) of patients and 4% (3/74) of controls. The prevalence of passage hallucinations and illusions was significantly higher in PD compared to the control group. The presence of PD-associated psychotic features was not significantly affected by medication, motor severity or global cognitive status. Higher prevalence of overall non-motor manifestations, REM sleep behavior disorder (RBD) and depressive symptoms was significantly associated with the manifestation of psychotic features in PD [(adjusted OR:1.3; 95% CI:1.1-1.6; p  = 0.003), (adjusted OR:1.3; 95% CI:1.0-1.6; p  = 0.023), and (adjusted OR:1.2; 95% CI:1.0-1.4;p  = 0.026)]. Conclusions: Psychotic phenomena mainly of minor nature are highly common in early PD. Cumulative non-motor symptoms, RBD and depressive features are associated with the presence of psychotic symptoms in this non-demented, early-stage PD population. More studies are needed to clarify the mechanisms that contribute to the onset of psychotic features in early PD. Show more

Keywords: Psychosis, hallucinations, early Parkinson’s disease

DOI: 10.3233/JPD-230056

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1185-1197, 2023

Authors: Kim, Dani J. | Rodriguez-Salgado, Ana M. | Llibre-Rodriguez, Juan J. | Acosta, Isaac | Sosa, Ana Luisa | Acosta, Daisy | Jimenez-Velasquez, Ivonne Z. | Guerra, Mariella | Salas, Aquiles | Jeyachandran, Christine | López-Contreras, Ricardo | Hesse, Heike | Tanner, Caroline | Llibre-Guerra, Jorge J. | Prina, Matthew

Article Type: Research Article

Abstract: Background: Little is known about the burden of parkinsonism and Parkinson’s disease (PD) in Latin America. Better understanding of health service use and clinical outcomes in PD is needed to improve its prognosis. Objective: The aim of the study was to estimate the burden of parkinsonism and PD in six Latin American countries. Methods: 12,865 participants aged 65 years and older from the 10/66 population-based cohort study were analysed. Baseline assessments were conducted in 2003–2007 and followed-up 4 years later. Parkinsonism and PD were defined using current clinical criteria or self-reported diagnosis. Logistic regression models assessed …the association between parkinsonism/PD with baseline health service use (community-based care or hospitalisation in the last 3 months) and Cox proportional hazards regression models with incident dependency (subjective assessment by interviewer based on informant interview) and mortality. Separate analyses for each country were combined via fixed effect meta-analysis. Results: At baseline, the prevalence of parkinsonism and PD was 7.9% (n  = 934) and 2.6% (n  = 317), respectively. Only parkinsonism was associated with hospital admission at baseline (OR 1.89, 95% CI 1.30–2.74). Among 7,296 participants without dependency at baseline, parkinsonism (HR 2.34, 95% CI 1.81–3.03) and PD (2.10, 1.37–3.24) were associated with incident dependency. Among 10,315 participants with vital status, parkinsonism (1.73, 1.50–1.99) and PD (1.38, 1.07–1.78) were associated with mortality. The Higgins I2 tests showed low to moderate levels of heterogeneity across countries. Conclusions: Our findings show that older people with parkinsonism or PD living in Latin America have higher risks of developing dependency and mortality but may have limited access to health services. Show more

Keywords: Parkinsonian disorders, Latin America, health services administration, patient care, mortality

DOI: 10.3233/JPD-230114

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1199-1211, 2023

Authors: Dagay, Andrew | Oz, Shani | Katzav, Shlomit | Wasserman, Danielle | Tauman, Riva | Thaler, Avner | Giladi, Nir | Mirelman, Anat

Article Type: Research Article

Abstract: Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is a leading predictor of Parkinson’s disease (PD). Diagnosis is performed in the sleep laboratory by detecting pathological REM sleep without atonia (RSWA). The evidence on the overnight distribution of RSWA% is conflicting. Objective: To investigate the temporal distribution of the number of ocular movements per REM sleep minute (REM density), and RSWA% in people with PD and non-PD controls. Methods: All participants underwent a single overnight evaluation in a sleep laboratory. Clinical evaluation was performed on a separate day. REM density and RSWA% were compared between …PD and controls both across four sleep periods and individual REM cycles. Results: A total of 51 participants with recorded RSWA in polysomnography laboratory were included, 28 with PD aged 64±9 years with a disease duration of 3.3±2.9 years, and 23 controls aged 55±8 years. People with PD had lower REM density and higher RSWA% compared to controls. As expected, REM density was higher towards the morning. In contrast, RSWA% was equally distributed across the night, for both PD and controls. Conclusions: PD pathology affects REM sleep features, but not the overnight distribution of those features. While REM density increased towards the end of the night, RSWA% was equally distributed across the night for both PD and controls. Our findings have clinical implications for diagnosing RBD, as quantification of RSWA% in any sleep cycle is sufficient for reliably evaluating total RSWA% and reduced REM density may be a marker of PD. Show more

Keywords: Parkinson’s disease, sleep, rapid eye movement sleep behavior disorder, sleep disorders, REM sleep without atonia, REM density

DOI: 10.3233/JPD-230116

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1213-1223, 2023

Authors: van der Lijn, Iris | de Haan, Gera A. | van der Feen, Fleur E. | Vrijling, Anne C.L. | Stellingwerf, Catharina | Fuermaier, Anselm B.M. | Langenberg, Pia | van Laar, Teus | Heutink, Joost

Article Type: Research Article

Abstract: Background: People with Parkinson’s disease (PD) frequently experience reading difficulties. Little is known about what functional impairments distinguish people with PD with and without reading difficulties and how these should guide rehabilitation. Objective: To provide concrete advice for an efficient stepped care model for reading difficulties in PD, based on extensive functional assessments. Methods: This study included 74 people with PD in a neurovisual rehabilitation setting who underwent assessment of visual, visuoperceptual, and cognitive functions. Outcomes were compared between those with frequent (RD+; N = 55) and infrequent reading difficulties (RD–; N = 19). Aids and advice provided during rehabilitation …were registered. Results: Only a few functions appeared to distinguish RD+ and RD–. Visual functions (i.e., contrast sensitivity, g = 0.76; reading acuity, g = 0.66; visual acuity, g = 0.54) and visuoperceptual functions (i.e., visual attention, g = 0.58, visual motor speed, g = 0.56) showed significant worse scores in RD+ compared to RD–. Aids and advice applied consisted mainly of optimizing refraction, improving lighting, and optimizing text size and spacing. Conclusion: The test battery showed significant differences between RD+ and RD–on only a few tests on visual and visuoperceptual functions. The applied aids and advice matched well with these impairments. Therefore, we recommend a stepped care model, starting with a short test battery on these functions. If this battery indicates functional impairments, this can be followed by standard aids and advice to improve reading. Only in case of insufficient effect additional testing should take place. Show more

Keywords: Parkinson’s disease, reading, rehabilitation, vision disorders, visual perception, cognition, quality of life

DOI: 10.3233/JPD-230124

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1225-1237, 2023

Authors: Yang, Xiao-Li | Guo, Yu | Chen, Shu-Fen | Cui, Mei | Shao, Rong-Rong | Huang, Yu-Yuan | Luo, Yu-Fan | Dong, Zhi-Yuan | Dong, Qiang | Wu, Dan-Hong | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD) has not been systematically studied in patients with multiple system atrophy (MSA). Objective: We sought to explore whether MSA patients suffer from a heavier CSVD burden relative to healthy individuals and whether CSVD has a relationship with motor, cognitive, and emotional dysfunction in patients with MSA. Methods: This study consecutively recruited 190 MSA patients and 190 matched healthy controls whose overall CSVD burden and single CSVD imaging markers (including white matter hyperintensity (WMH), microbleeds, lacunes, and enlarged perivascular spaces (EPVS)) were measured. Of the MSA patients, 118 completed multi-dimensional outcome …assessments. Spearman’s correlations and multivariable linear regressions were performed. Results: We observed a greater burden of overall CSVD, WMH, and EPVS in MSA patients compared with controls, but not for microbleeds and lacunes. Motor dysfunction and cognitive impairment were significantly worse in subjects with severe CSVD than those with none-to-mild CSVD. In patients with MSA, the severity of CSVD burden was positively associated with motor impairments as measured by the Unified Multiple System Atrophy Rating Scale-II (β= 2.430, p  = 0.039) and Scale for the Assessment and Rating of Ataxia (β= 1.882, p  = 0.015). Of CSVD imaging markers, different associations with MSA outcomes were displayed. WMH was associated with motor, cognitive, and emotional deficits, while the EPVS in the centrum semiovale, basal ganglia, and hippocampus regions was correlated only with motor severity, anxiety, and cognition, respectively. Similar findings were noted in MSA-cerebellar and MSA-parkinsonian patients. Conclusions: Concomitant CSVD may be correlated with worse multi-dimensional dysfunction in patients with MSA. Show more

Keywords: Multiple system atrophy, cerebral small vessel disease, motor function, cognition, emotion

DOI: 10.3233/JPD-230166

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1239-1252, 2023

Authors: Zajac, Jenna A. | Porciuncula, Franchino | Cavanaugh, James T. | McGregor, Colin | Harris, Brian A. | Smayda, Kirsten E. | Awad, Louis N. | Pantelyat, Alexander | Ellis, Terry D.

Article Type: Research Article

Abstract: Background: Reduced motor automaticity in Parkinson’s disease (PD) negatively impacts the quality, intensity, and amount of daily walking. Rhythmic auditory stimulation (RAS), a clinical intervention shown to improve walking outcomes, has been limited by barriers associated with the need for ongoing clinician input. Objective: To assess the feasibility, proof-of-concept, and preliminary clinical outcomes associated with delivering an autonomous music-based digital walking intervention based on RAS principles to persons with PD in a naturalistic setting. Methods: Twenty-three persons with PD used the digital intervention independently for four weeks to complete five weekly 30-minute sessions of unsupervised, overground …walking with music-based cues. The intervention progressed autonomously according to real-time gait sensing. Feasibility of independent use was assessed by examining participant adherence, safety, and experience. Intervention proof-of-concept was assessed by examining spatiotemporal metrics of gait quality, daily minutes of moderate intensity walking, and daily steps. Preliminary clinical outcomes were assessed following intervention completion. Results: Participants completed 86.4% of sessions and 131.1% of the prescribed session duration. No adverse events were reported. Gait speed, stride length, and cadence increased within sessions, and gait variability decreased (p  < 0.05). Compared to baseline, increased daily moderate intensity walking (mean Δ = +21.44 minutes) and steps (mean Δ = +3,484 steps) occurred on designated intervention days (p  < 0.05). Quality of life, disease severity, walking endurance, and functional mobility were improved after four weeks (p  < 0.05). Conclusions: Study findings supported the feasibility and potential clinical utility of delivering an autonomous digital walking intervention to persons with PD in a naturalistic setting. Show more

Keywords: Gait, physical activity, rehabilitation, rhythmic auditory stimulation

DOI: 10.3233/JPD-230169

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1253-1265, 2023

Authors: Garg, Udit | Gujral, Jaskeerat | Gandhi, Om H. | Dahodwala, Nabila | Goldner, Linda Joy | Hughes, Sara | Reichwein, Suzanne | Zelouf, Lauren | Aamodt, Whitley W.

Article Type: Article Commentary

Abstract: Parkinson’s disease (PD) causes unique motor and non-motor symptoms. Despite symptomatic treatment with pharmacotherapies, many persons with PD report feelings of loneliness and demoralization as their disease progresses. These symptoms greatly interfere with quality of life, necessitating novel treatment strategies. In this report, we introduce a new student-led program to improve psychosocial well-being among persons with PD by pairing them with college students. Through weekly one-on-one meetings, students gain a deeper understanding of PD, while patients gain a new social outlet and purpose. Based on the program’s initial successes, we advocate for the adoption of similar programs at universities worldwide.

Keywords: Parkinson disease, loneliness, social isolation, demoralization, quality of life

DOI: 10.3233/JPD-230179

Citation: Journal of Parkinson's Disease, vol. 13, no. 7, pp. 1267-1271, 2023