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Levodopa is the most widely used medication for the symptomatic treatment of Parkinson's disease and, despite being an "old" drug, is still considered the gold standard for offering symptomatic relief. The pharmacokinetic and pharmacodynamics of levodopa have been studied extensively. Our review explores the molecular mechanisms that affect the absorption of this drug, focusing on the large intra- and interindividual variability of absorption that is commonly encountered in daily clinical practice, and on the interaction with other medications. In addition, we will explore the clinical implications of levodopa absorption variability and address current and future strategies for researchers and clinicians.

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Freezing of gait, characterized by involuntary interruptions of walking, is a debilitating motor symptom of Parkinson's disease that restricts people's autonomy. Previous brain imaging studies investigating the mechanisms underlying freezing were restricted to scan people in supine positions and yielded conflicting theories regarding the role of the supplementary motor area and other cortical regions. We used functional near-infrared spectroscopy to investigate cortical haemodynamics related to freezing in freely moving people. We measured functional near-infrared spectroscopy activity over multiple motor-related cortical areas in 23 persons with Parkinson's disease who experienced daily freezing ('freezers') and 22 age-matched controls during freezing-provoking tasks including turning and doorway passing, voluntary stops and actual freezing. Crucially, we corrected the measured signals for confounds of walking. We first compared cortical activity between freezers and controls during freezing-provoking tasks without freezing (i.e. turning and doorway passing) and during stops. Secondly, within the freezers, we compared cortical activity between freezing, stopping and freezing-provoking tasks without freezing. First, we show that turning and doorway passing (without freezing) resemble cortical activity during stopping in both groups involving activation of the supplementary motor area and prefrontal cortex, areas known for their role in inhibiting actions. During these freezing-provoking tasks, the freezers displayed higher activity in the premotor areas than controls. Secondly, we show that, during actual freezing events, activity in the prefrontal cortex was lower than during voluntary stopping. The cortical relation between the freezing-provoking tasks (turning and doorway passing) and stopping may explain their susceptibility to trigger freezing by activating a stopping mechanism. Besides, the stopping-related activity of the supplementary motor area and prefrontal cortex seems to be out of balance in freezers. In this paper, we postulate that freezing results from a paroxysmal imbalance between the supplementary motor area and prefrontal cortex, thereby extending upon the current role of the supplementary motor area in freezing pathophysiology.

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Our language affects patients' perceptions of therapies. In Parkinson's disease, emergent response fluctuations and dyskinesias typically trigger conversations around commencing an "Advanced Therapy" which carries notions of Advanced Disease. The patient, resolute in their commitment to fighting the disease, is misled. Chasing reassurance that their disease has not yet progressed considerably; they may therefore resist a potentially life-changing therapy. Instead, we should offer a "Smart Therapy". This term more accurately and positively describes therapies on offer that stabilize response fluctuations and improve quality of life, without a focus on the negative connotations of progression to more advanced disease.

The language we use with our patients affects their perception of a therapy on offer and their willingness to take it up. In Parkinson's disease when motor response fluctuations and dyskinesias become extremely challenging and disabling for patients despite medication optimization, it might prompt conversations with the patient in appropriate circumstances about offering an "Advanced Therapy" such as deep brain stimulation surgery or continuous infusion pumps. However, from the patient's perspective, putting up a steadfast fight against their disease, this label carries unwanted and misleading connotations of Advanced Disease. This can lead to hesitation from taking up these potentially life-changing therapies. Therefore, in this Commentary we propose a rebranding in line with other modern technology like smart phones and smart homes, emphasizing the positive and personalized features of these therapies, and focusing on the goal of stabilizing symptoms and improving quality of life. We should offer patients "Smart Therapies". It's time to Get Smart!

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ABSTRACT: BACKGROUND: For people with a moderate stage of Parkinson disease (PD), dedicated care coordination combined with advance care planning (ACP) is highly needed. However, evidence is lacking. The objective of this study was to assess the feasibility and acceptability of the study processes to inform a larger randomized controlled trial, aiming the effectiveness of a combined intervention on ACP and care coordination for people with PD. METHODS: Two nurse practitioners with expertise in PD followed training on a combined intervention on ACP and care coordination. Patients were invited to participate in several sessions for a period of 12 months. Feasibility of the study was surveyed covering sample recruitment, attrition rate, eligibility, intervention delivery, number of ACP sessions, type of intervention administration, and satisfaction with the intervention. RESULTS: In total, 27 patients were invited to participate, and 20 (74%) enrolled into the study, together with 11 family caregivers; 7 patients (35%) dropped out. Most patients were men (n = 20), with a mean age of 73.4 (SD 8.2) years. In total, 71 ACP sessions were held (3.6 sessions per patient on average), of which 41% of the sessions were conducted face-to-face at home, 44% at the hospital, 11% over telephone, and 4% via a videoconference call. Patients perceived the intervention not only as supportive but also as confronting. CONCLUSION: The ACP aspect of the intervention was useful and feasible to stimulate patients to think about their current care situation as well as about future care. Care coordination was less profoundly provided and discussed.

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BACKGROUND: Digital health technologies (DHT) enable self-tracking of bio-behavioral states and pharmacotherapy outcomes in various diseases. However, the role of gender, encompassing social roles, expectations, and relations, is often overlooked in their adoption and use. This study addresses this issue for persons with Parkinson's disease (PD), where DHT hold promise for remote evaluations. METHODS: We conducted a cross-sectional survey study in the Netherlands, assessing the impact of gender identity, roles, and relations on health technology self-efficacy (HTSE) and attitude (HTA). An intersectional gender analysis was applied to explore how gender intersects with education, employment, disease duration, and severity in influencing HTSE and HTA. RESULTS: Among 313 participants (40% women), no significant correlation was found between gender identity or relations and HTSE or HTA. However, individuals with an androgynous (non-binary) gender role orientation demonstrated better HTSE and HTA. The exploratory intersectional analysis suggested that sociodemographic and clinical factors might affect the influence of gender role orientations on HTSE and HTA, indicating complex and nuanced interactions. CONCLUSION: This study highlights the importance of investigating gender as a multidimensional variable in PD research on health technology adoption and use. Considering gender as a behavioral construct, such as through gender roles and norms, shows more significant associations with HTSE and HTA, although effect sized were generally small. The impact of gender dimensions on these outcomes can be compounded by intersecting social and disease-specific factors. Future studies should consider multiple gender dimensions and intersecting factors to fully understand their combined effects on technology uptake and use among people with PD.

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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.

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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.

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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.

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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.

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BACKGROUND: Impulse control disorders (ICD) in Parkinson's disease (PD) are associated with a heavy burden on patients and caretakers. While recovery can occur, ICD persists in many patients despite optimal management. The basis for this inter-individual variability in recovery is unclear and poses a major challenge to personalized health care. METHODS: We adopt a computational psychiatry approach and leverage the longitudinal, prospective Personalized Parkinson Project (N=136 persons with PD, within 5 years of diagnosis) to combine dopaminergic learning theory-informed fMRI with machine learning (at baseline) to predict ICD symptom recovery after two years of follow-up. We focused on a change in QUIP-rs across the entire cohort, regardless of an ICD diagnosis. RESULTS: Greater reinforcement learning signals during gain trials but not loss trials at baseline, including those in the ventral striatum, medial prefrontal cortex and the behavioral accuracy score measured while ON medication were associated with greater recovery from impulse control symptoms two years later. These signals accounted for a unique proportion of the relevant variability over and above that explained by other known factors, such as decreases in dopamine agonist use. CONCLUSIONS: Our results provide a proof of principle for combining generative model-based inference of latent learning processes with machine learning-based predictive modeling of variability in clinical symptom recovery trajectories. Hence, we showed that RL modelling parameters predict recovery from ICD symptoms in PD.

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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.

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INTRODUCTION: Living with young onset Parkinson's disease (YOPD) not only affects the persons with YOPD, but also their families. Although caregiver burden has been researched in Parkinson's disease in general, little is known about the specific impact of having an (ex-)partner with YOPD. This exploratory study aimed to explore the impact of having an (ex-)partner with YOPD on daily life. MATERIALS AND METHODS: We used a qualitative approach including semi-structured interviews with 16 (ex-)partners of people with YOPD. Interviews were audio-taped and transcribed verbatim. Qualitative thematic analysis was used to analyze the interview data. RESULTS: Qualitative analysis revealed nine themes to describe the impact of having an (ex-)partner with YOPD: (1) Psychosocial impact, (2) Impact on taking care of children, (3) Impact on working life, (4) Impact on intimacy and (sexual) relationships, (5) Impact on daily life, (6) Acceptance and other coping strategies, (7) Thoughts about the future, (8) Autonomy and (9) Caregiver support. DISCUSSION: This study provides important findings that will inform future interventions that aim to reduce or even prevent caregiver burden, as well as to inform healthcare professionals to recognize the needs of caregivers of people with YOPD.

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PURPOSE: To investigate the contributors to self-rated health in people with late-stage Parkinson's disease (PD) and cognitive impairment. METHODS: A secondary analysis of baseline data from the international Care of Late-Stage Parkinsonism (CLaSP) cohort study was conducted. Participants with PD and either dementia or mild cognitive impairment or MMSE < 24/30 in the absence of major depression were included if they had completed the EQ-5D-3L assessment (n = 277). Factors associated with self-rated health (EQ-5D-3L Index and Visual Analogue Scale) were investigated through multivariable linear regression. RESULTS: More severe PD (motor and non-motor) was associated with worse self-rated health. The EQ-5D-3L dimensions of Mobility, Self-Care and Usual Activities were almost universally affected; the latter two particularly severely. Being unable to perform usual activities or having moderate to extreme anxiety or depression were significantly associated with EQ-5D-3L Visual Analogue Scale, suggesting these are particularly valued. Worse motor impairment and function and the non-motor symptom domains of mood, perception, sexual function, and miscellaneous (e.g., pain) were associated with worse self-rated health, whereas greater burden of gastrointestinal symptoms was associated with better self-rated health in multivariate analysis. Better self-rated health was associated with recent PD nurse consultation, and higher doses of dopaminergic medication. CONCLUSION: Improvement of activities of daily living, mood and anxiety should be prioritised in clinical practice, with consideration of perception and sexual function in this population. Recent nurse consultations and higher antiparkinsonian doses are associated with better self-rated health, suggesting there is no room for a therapeutic nihilism in this population of people within a complex phase of PD.

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BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. METHODS/DESIGN: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. DISCUSSION: This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023).

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BACKGROUND: People with Parkinson's disease (PD) are very sensitive to the effects of stress. The prevalence of stress-related neuropsychiatric symptoms is high, and acute stress worsens motor symptoms. Animal studies suggest that chronic stress may accelerate disease progression, but evidence for this in humans is lacking. Mindfulness-based interventions (MBIs) train participants to focus on the present moment, on purpose and without judgement. Previous studies suggest that MBIs may alleviate stress and reduce depression and anxiety in PD. We aim to demonstrate the efficacy of Mindfulness-Based Cognitive Therapy (MBCT) as a non-pharmacologic treatment strategy for neuropsychiatric (and motor) symptoms in PD, and to identify the mechanisms underlying stress and stress reduction in PD. METHODS: In a prospective randomized controlled trial (RCT), we investigate whether 8 weeks of MBCT, as compared to care as usual, can reduce symptoms of anxiety and depression in people with PD. We aim to include 124 PD patients, who experience mild-moderate symptoms of anxiety and depression, are eligible for magnetic resonance imaging (MRI) and naïve to mindfulness, and who have a disease duration ≤ 10 years. Every participant is followed for 12 months. Clinical and biochemical assessments take place at baseline (T0), after 2 months (T1), and after 12 months (T2); MRI assessments take place at T0 and T2. Our primary outcome is the total score on the Hospital Anxiety and Depression Scale (HADS) at T1, while correcting for the HADS score at T0, age, and gender. Beyond testing the effects of MBCT on symptoms of anxiety and depression in PD, we explore whether MBCT: (1) has an effect on motor symptom severity, (2) influences cerebral and biochemical markers of stress, and (3) leads to a change in biomarkers of PD progression. DISCUSSION: MIND-PD is one of the first RCTs with a 1-year follow-up to investigate the effects of MBCT on symptoms of anxiety and depression in PD, and to explore possible mechanisms underlying stress and stress reduction in PD. Insight into these mechanisms can pave the way to new treatment methods in the future. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05779137. Registered on 12 January 2023.

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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.

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Parkinson's disease (PD) is a chronic and complex neurodegenerative disorder. Conventional pharmacological or surgical therapies alone are often insufficient at adequately alleviating disability. Moreover, there is an increasing shift toward person-centered care, emphasizing the concept of "living well". In this context, arts-based interventions offer great promise, functioning as platforms for creative expression that could provide novel mechanisms to promote quality of life. Here we present a qualitative review of arts-based interventions for PD, including music, dance, drama, visual arts, and creative writing. For each, we discuss their applications to PD, proposed mechanisms, evidence from prior studies, and upcoming research. We also provide examples of community-based projects. Studies to date have had relatively small sample sizes, but their findings suggest that arts-based interventions have the potential to reduce motor and non-motor symptoms. They may also empower people with PD and thereby address issues of self-esteem, foster personal problem-solving, and augment holistic well-being. However, there is a paucity of research determining optimal dosage and symptom-specific benefits of these therapies. If art were a drug, we would have to perform appropriately powered studies to provide these data before incorporating it into routine patient care. We therefore call for further research with properly designed studies to offer more rigorous and evidence-based support for what we intuitively think is a highly promising approach to support individuals living with PD. Given the possible positive impact on people's lives, arts-based approaches merit further development and, if proven to be effective, systematic inclusion within integrated management plans.

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