Effect of Early Levodopa Treatment on Mortality in People with Parkinson's Disease.

BACKGROUND: The ideal timing for initiating levodopa in newly diagnosed people with Parkinson's disease (PD) is uncertain due to limited data on the long-term effects of levodopa. OBJECTIVE: The aim was to investigate whether early levodopa initiation postpones mortality (primary outcome), the requirement of device-aided therapies, and the incidence of PD-related complications, such as fall-induced injuries. METHODS: Using nationwide claims data from Dutch hospitals (2012-2020), we grouped newly diagnosed PD individuals as "early initiators" (initiating levodopa within 2 years of diagnosis) or "nonearly initiators." We used the national death registry to assess mortality and health-care claims to assess PD-related complications and device-aided therapies. We used marginal structural models to compare mortality and device-aided therapy rates between groups, and a Poisson regression model to compare PD-related complication rates. RESULTS: Among 29,943 newly diagnosed PD individuals (mean age at diagnosis: 71.6, 38.5% female), there were 24,847 early and 5096 nonearly levodopa initiators. Over a median 4.25 years, 8109 (27.1%) died. The causal risk ratio for mortality was 1.04 (95% confidence interval [CI] 0.92-1.19) for early versus nonearly initiators. The risk ratio of receiving any device-aided therapy was 3.19 (95% CI 2.56-5.80). No association was observed with incidence of PD-related complications (incidence rate ratio: 1.00, 95% CI 0.96-1.05). CONCLUSIONS: Early levodopa initiation in PD does neither postpone nor accelerate mortality or PD-related complications, nor does it precipitate earlier occurrence of PD-related complications or mortality. However, we cannot exclude that the results were influenced by residual confounding due to unmeasured risk factors of mortality.

The PRIME-NL study: evaluating a complex healthcare intervention for people with Parkinson's disease in a dynamic environment.

BACKGROUND: An innovative, integrative care model for people with Parkinson (PRIME Parkinson) has gradually been implemented in a selected region of the Netherlands since 2021. A prospective evaluation of this model (PRIME-NL study) was initiated in parallel, spanning the year prior to implementation (baseline) and the implementation period. Following publication of the original study protocol, the COVID-19 crisis delayed implementation of the full PRIME Parkinson care model by two years and hampered the recruitment of study participants. OBJECTIVE: To describe which methodological adjustments were made to the study protocol because of these developments. METHODS: We compare various outcomes between a region where PRIME Parkinson care was implemented (innovation region) versus the rest of the Netherlands (usual care region). We use healthcare claims data of virtually all people with Parkinson in the Netherlands and annual questionnaires in a representative subsample of 984 people with Parkinson, 566 caregivers and 192 healthcare professionals. Four major methodological adjustments had to be made since publication of the original protocol. First, we extended the evaluation period by two years. Second, we incorporated annual process measures of the stage of implementation of the new care model. Third, we introduced a real-time iterative feedback loop of interim results to relevant stakeholders. Fourth, we updated the statistical analysis plan. DISCUSSION: This manuscript provides transparency in how the design and analyses of the evaluation study had to be adapted to control for external influences in a dynamic environment, including eruption of the COVID-19 crisis. Our solutions could serve as a template for evaluating other complex healthcare interventions in a dynamic environment.

Digital biomarkers for non-motor symptoms in Parkinson's disease: the state of the art.

Digital biomarkers that remotely monitor symptoms have the potential to revolutionize outcome assessments in future disease-modifying trials in Parkinson's disease (PD), by allowing objective and recurrent measurement of symptoms and signs collected in the participant's own living environment. This biomarker field is developing rapidly for assessing the motor features of PD, but the non-motor domain lags behind. Here, we systematically review and assess digital biomarkers under development for measuring non-motor symptoms of PD. We also consider relevant developments outside the PD field. We focus on technological readiness level and evaluate whether the identified digital non-motor biomarkers have potential for measuring disease progression, covering the spectrum from prodromal to advanced disease stages. Furthermore, we provide perspectives for future deployment of these biomarkers in trials. We found that various wearables show high promise for measuring autonomic function, constipation and sleep characteristics, including REM sleep behavior disorder. Biomarkers for neuropsychiatric symptoms are less well-developed, but show increasing accuracy in non-PD populations. Most biomarkers have not been validated for specific use in PD, and their sensitivity to capture disease progression remains untested for prodromal PD where the need for digital progression biomarkers is greatest. External validation in real-world environments and large longitudinal cohorts remains necessary for integrating non-motor biomarkers into research, and ultimately also into daily clinical practice.

Specialized Allied Health Care for Parkinson's Disease: State of the Art and Future Directions.

People with Parkinson's disease (PD) experience a range of progressive motor and non-motor symptoms, that negatively affect their daily functioning, social participation and quality of life. Allied health therapies have emerged as an effective treatment approach-complementary to pharmacological and neurosurgical treatments-which reduces the impact of PD in daily life. In this article, we propose criteria for what constitutes specialized allied health care for PD, and we review allied health research in PD in terms of meeting these criteria and its outcomes for monodisciplinary approaches as well as multi- or interdisciplinary allied health interventions. We focus on the three most studied allied health disciplines in PD: physical therapy, occupational therapy and speech-language therapy. Overall, the available evidence underscores the importance and potential benefits of specialized allied health care for people with PD. Our proposed criteria and recommendations for future research might help in further delineating specialized allied health care.

Considerations on How to Prevent Parkinson's Disease Through Exercise.

The increasing prevalence of people with Parkinson's disease (PD) necessitates a high priority for finding interventions to delay or even prevent the onset of PD. There is converging evidence that exercise may exert disease-modifying effects in people with clinically manifest PD, but whether exercise also has a preventive effect or is able to modify the progression of the pathology in the prodromal phase of PD is unclear. Here we provide some considerations on the design of trials that aim to prevent PD through exercise. First, we discuss the who could benefit from exercise, and potential exercise-related risks. Second, we discuss what specific components of exercise mediate the putative disease-modifying effects. Third, we address how methodological challenges such as blinding, adherence and remote monitoring could be handled and how we can measure the efficacy of exercise as modifier of the course of prodromal PD. We hope that these considerations help in designing exercise prevention trials for persons at risk of developing PD.

Patient Experience and Feasibility of a Remote Monitoring System in Parkinson's Disease.

BACKGROUND: Remote monitoring systems have the potential to measure symptoms and treatment effects in people with Parkinson's disease (PwP) in the home environment. However, information about user experience and long-term compliance of such systems in a large group of PwP with relatively severe PD symptoms is lacking. OBJECTIVE: The aim was to gain insight into user experience and long-term compliance of a smartwatch (to be worn 24/7) and an online dashboard to report falls and receive feedback of data. METHODS: We analyzed the data of the "Bringing Parkinson Care Back Home" study, a 1-year observational cohort study in 200 PwP with a fall history. User experience, compliance, and reasons for noncompliance were described. Multiple Cox regression models were used to identify determinants of 1-year compliance. RESULTS: We included 200 PwP (mean age: 69 years, 37% women), of whom 116 (58%) completed the 1-year study. The main reasons for dropping out of the study were technical problems (61 of 118 reasons). Median wear time of the smartwatch was 17.5 h/day. The online dashboard was used by 77% of participants to report falls. Smartphone possession, shorter disease duration, more severe motor symptoms, and less-severe freezing and balance problems, but not age and gender, were associated with a higher likelihood of 1-year compliance. CONCLUSIONS: The 1-year compliance with this specific smartwatch was moderate, and the user experience was generally good, except battery life and data transfer. Future studies can build on these findings by incorporating a smartwatch that is less prone to technical issues.

Guide to Decomposition of Causal Effects Into Mediation, Interaction, and Direct Effects: Case Study on Aerobic Exercise and Parkinson Disease.

Mediation analysis can be applied in medical research with the aim of understanding the pathways that operate between an exposure and its effects on an outcome. This method can help to improve our understanding of pathophysiologic mechanisms and may guide the choice of potential treatment strategies. Traditional mediation analysis decomposes the total effect of an intervention on the outcome into 2 effects: (1) an indirect effect, from exposure using a mediator to the outcome, and (2) a direct effect, directly from exposure to outcome. A limitation of this method is that it assumes no interaction between the exposure and the mediator, which can either lead to an over- or underestimation of clinically relevant effects. The "4-way decomposition" method has the advantage of overcoming this limitation. Specifically, the total effect of an exposure on the outcome is decomposed into 4 elements: (1) reference interaction (interaction only), (2) mediated interaction (mediation and interaction), (3) the pure indirect effect (mediation but not interaction), and (4) the direct effect (no mediation and no interaction). We provide a guide to select the most appropriate method to investigate and decompose any causal effect given the research question at hand. We explain the application of the 4-way decomposition and illustrate this with a real-world example of how aerobic exercise may influence motor function in persons with Parkinson disease.

Natural Health Products for Symptomatic Relief of Parkinson's Disease: Prevalence, Interest, and Awareness.

Background: Natural health products have emerged as a potential symptomatic therapeutic approach for people with Parkinson's disease (PD). Objective: To determine the prevalence of natural health product use, interest in natural health products, awareness of potential herb-drug interactions, and consultation of healthcare professionals regarding natural health products use among people with PD. Methods: Cross-sectional 4-item survey embedded in the PRIME-NL study, which is a population-based cohort of PD. Results: Of 367 people with PD, 36% reported having used natural health products to alleviate PD-related symptoms, with coffee, cannabis and turmeric being the most popular. Furthermore, 71% of people with PD were interested in learning more about natural health products. 39% of natural health products users were aware that these products could interact with PD medication and 39% had discussed their use with their healthcare professional. Conclusions: Natural health products are commonly used to alleviate symptoms by people with PD, but most users are unaware that these products can interact with PD medication and do not discuss their consumption with their healthcare professional.

Parkinson's disease is a complex neurodegenerative disorder for which current treatments are limited to symptomatic relief, and prescribed medication often causes side effects. In this context, there is an increasing interest in non-pharmacological interventions, and people living with Parkinson's disease may want to explore natural health products to alleviate disease-associated symptoms. Examples of these products include cannabis, coffee, or velvet bean (as a natural source of Levodopa). However, it remains unclear how many people with Parkinson's disease have ever used, or wish to use, natural health products to relieve disease-related symptoms. In addition, limited information is available to evaluate whether they are aware of possible interactions between these products and prescribed medication. Therefore, the aim of this study was to investigate these questions in a large representative group of people with Parkinson's disease. A total of 367 people responded to the survey, and 36% reported that they had used natural health products to relieve Parkinson's disease-related symptoms. Among the supplements listed in our survey, coffee (16%), cannabis (13%) and turmeric (10%) were the most popular. Additionally, 71% of participants were interested in learning more about natural health products, and we found that 39% of natural health product users were aware of possible interactions with prescribed Parkinson's disease medication. However, it appeared that only 39% of users had discussed these supplements with their healthcare provider. These observations are important because a concern regarding the integration of natural health products into clinical practice is their potential interactions with prescribed medication. Therefore, these findings support the need for additional research efforts into the health benefits and safety of these products. We conclude that natural health products are used by people with Parkinson's disease to provide symptomatic relief, and open discussions with their healthcare providers are encouraged to ensure efficacy and safety.

Assessing the validity of a Parkinson's care evaluation: the PRIME-NL study.

INTRODUCTION: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data. METHODS: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance. RESULTS: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%). CONCLUSION: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism.

How Lifetime Evolution of Parkinson's Disease Could Shape Clinical Trial Design: A Shared Patient-Clinician Viewpoint.

Parkinson's disease (PD) has a long, heterogeneous, pre-diagnostic phase, during which pathology insidiously accumulates. Increasing evidence suggests that environmental and lifestyle factors in early life contribute to disease risk and progression. Thanks to the extensive study of this pre-diagnostic phase, the first prevention trials of PD are being designed. However, the highly heterogenous evolution of the disease across the life course is not yet sufficiently taken into account. This could hamper clinical trial success in the advent of biological disease definitions. In an interdisciplinary patient-clinician study group, we discussed how an approach that incorporates the lifetime evolution of PD may benefit the design of disease-modifying trials by impacting population, target and outcome selection. We argue that the timepoint of exposure to risk and protective factors plays a critical role in PD subtypes, influencing population selection. In addition, recent developments in differential disease mechanisms, aided by biological disease definitions, could impact optimal treatment targets. Finally, multimodal biomarker panels using this lifetime approach will likely be most sensitive as progression markers for more personalized trials. We believe that the lifetime evolution of PD should be considered in the design of clinical trials, and that such initiatives could benefit from more patient-clinician partnerships.

[Hitting and yelling during sleep: diagnosis and implications of REM sleep behavior disorder]. / Slaan en schreeuwen in de slaap.

Rapid eye movement (REM) sleep behavior disorder is characterized by dream enactment during REM sleep. Due to different treatment requirements, it is important to distinguish REM sleep behavior disorder from other causes of nocturnal restlessness, including sleep apnea, non-REM parasomnia and sleep-related hypermotor epilepsy. In addition, a diagnosis of isolated REM sleep behavior disorder is impactful, because it carries a greatly increased risk for the later development of Parkinson's disease and related synucleinopathies. In this clinical lesson we describe three patients with abnormal nocturnal movements and vocalizations. The history can provide important clues towards the diagnosis, but a video-polysomnography is required before REM sleep behavior disorder can be diagnosed.

Age and gender differences in non-motor symptoms in people with Parkinson's disease.

Background: Non-motor symptoms of Parkinson's disease (PD) are highly prevalent and heterogenic. Previous studies aimed to gain more insight on this heterogeneity by investigating age and gender differences in non-motor symptom severity, but findings were inconsistent. Furthermore, besides examining the single effects of age and gender, the interaction between them in relation to non-motor functioning has -as far as we know- not been investigated before. Objectives: To investigate the association of age and gender identity -as well as the interaction between age and gender identity- with non-motor symptoms and their impact on quality of life. Methods: We combined three large and independent studies. This approach resulted in a total number of unique participants of 1,509. We used linear regression models to assess the association of age and gender identity, and their interaction, with non-motor symptoms and their impact on quality of life. Results: Older people with PD generally had worse cognitive functioning, worse autonomic functioning and worse quality of life. Women with PD generally experienced more anxiety, worse autonomic functioning and worse quality of life compared to men with PD, whereas men with PD generally had worse cognitive functioning. In interaction analyses by age and gender identity, depressive symptoms and anxiety were disproportionally worse with increasing age in women compared to men. Conclusion: Our findings indicate that both age and gender -as well as their interaction- are differentially associated with non-motor symptoms of PD. Both research and clinical practice should pay more attention to demographic subgroups differences and possible different treatment approaches with respect to age and gender. We showed how combining datasets is of added value in this kind of analyses and encourage others to use similar approaches.

Towards improved screening of toxins for Parkinson's risk.

Parkinson's disease (PD) is a chronic, progressive and disabling neurodegenerative disorder. The prevalence of PD has risen considerably over the past decades. A growing body of evidence suggest that exposure to environmental toxins, including pesticides, solvents and heavy metals (collectively called toxins), is at least in part responsible for this rapid growth. It is worrying that the current screening procedures being applied internationally to test for possible neurotoxicity of specific compounds offer inadequate insights into the risk of developing PD in humans. Improved screening procedures are therefore urgently needed. Our review first substantiates current evidence on the relation between exposure to environmental toxins and the risk of developing PD. We subsequently propose to replace the current standard toxin screening by a well-controlled multi-tier toxin screening involving the following steps: in silico studies (tier 1) followed by in vitro tests (tier 2), aiming to prioritize agents with human relevant routes of exposure. More in depth studies can be undertaken in tier 3, with whole-organism (in)vertebrate models. Tier 4 has a dedicated focus on cell loss in the substantia nigra and on the presumed mechanisms of neurotoxicity in rodent models, which are required to confirm or refute the possible neurotoxicity of any individual compound. This improved screening procedure should not only evaluate new pesticides that seek access to the market, but also critically assess all pesticides that are being used today, acknowledging that none of these has ever been proven to be safe from a perspective of PD. Importantly, the improved screening procedures should not just assess the neurotoxic risk of isolated compounds, but should also specifically look at the cumulative risk conveyed by exposure to commonly used combinations of pesticides (cocktails). The worldwide implementation of such an improved screening procedure, would be an essential step for policy makers and governments to recognize PD-related environmental risk factors.

Gender-aware Parkinson's care: a design-based study of patient perspectives on gender norms and gender-sensitive care.

Background: Gender dimensions are progressively recognised as a relevant social determinant of health in people with Parkinson's disease (PD). However, little is known about the impact of gender norms and stereotypes on illness experiences of men and women with PD and what they consider important focal points for gender-sensitive PD care. Methods: We conducted two equity-centred design (ECD) sessions on December 7, 2022 and December 8, 2022, at the Radboud University Medical Centre in the Netherlands. This participatory multi-method approach includes patients in the research and design process and was used to explore the impact of gender norms and stereotypes in illness experiences and generate patient-driven recommendations for gender-aware Parkinson's care. Quantitative survey data and design-based data were descriptively analysed, and qualitative focus group discussions were thematically analysed. Findings: This study included thirteen men and fifteen women with PD in the Netherlands. All participants were of Dutch descent, with a median age of 65.5 years and a median clinical disease duration of 4.2 years. The gendered stereotype that "people with PD are old men" affected both men's and women's perception of living with the disease and the perceptions of their social environment. Men described masculine stereotypes related to physical strength and provider roles, while women expressed those related to feminine physical appearance and caregiver roles, influencing their illness experiences. For some, these norms influenced personal behaviours, while for others, they affected experiences through societal attitudes. Interpretation: Our findings suggested that several gender norms and stereotypes influence the illness experiences of men and women with PD, manifesting at ideological, interpersonal, and internalised levels. Some participants internalised these norms, affecting their coping behaviours, while others encountered them in broader ideological contexts that shaped societal attitudes and interpersonal relationships. To advance gender sensitive PD care, it's essential to explore the impact of gender roles and norms, especially regarding how they might impede coping strategies, care access and utilisation for individuals of diverse gender identities. Funding: The Gatsby Foundation and co-funded by the PPP Allowance by Health∼Holland. Travel reimbursements for participants were made available through a Parkinson's Foundation grant (PF-FBS-2026).

[Risk factors for Parkinson's disease: possibilities for prevention and intervention]. / Risicofactoren voor de ziekte van Parkinson.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.

Exploring the levodopa-paradox of freezing of gait in dopaminergic medication-naïve Parkinson's disease populations.

The relationship between dopaminergic treatment and freezing of gait (FOG) in Parkinson's disease (PD) is complex: levodopa is the most effective symptomatic treatment for FOG, but long-term pulsatile levodopa treatment has also been linked to an increase in the occurrence of FOG. This concept, however, continues to be debated. Here, we compared the occurrence of FOG between a levodopa-naive PD cohort and a levodopa-treated cohort. Forty-nine treatment-naive patients and 150 levodopa-treated patients were included. The time since first motor symptoms was at least 5 years. Disease severity was assessed using the MDS-UPDRS part III. Occurrence of FOG was assessed subjectively (new freezing-of-gait-questionnaire) and objectively (rapid turns test and Timed Up-and-Go test). The presence of FOG was compared between the levodopa-treated and levodopa-naive groups using a chi-square test of homogeneity. We also performed a binomial Firth logistic regression with disease duration, disease severity, country of inclusion, location of measurement, and executive function as covariates. Subjective FOG was more common in the levodopa-treated cohort (n = 41, 27%) compared to the levodopa-naive cohort (n = 2, 4%, p < 0.001). The association between FOG and levodopa treatment remained after adjustment for covariates (OR = 6.04, 95%Cl [1.60, 33.44], p = 0.006). Objectively verified FOG was more common in the levodopa-treated cohort (n = 21, 14%) compared to the levodopa-naive cohort (n = 1, 2%, p = 0.02). We found an association between long-term pulsatile levodopa treatment and an increased occurrence of FOG. Future studies should further explore the role of nonphysiological stimulation of dopamine receptors in generating FOG, as a basis for possible prevention studies.