Long-Term Follow-Up of the LEAP Study: Early Versus Delayed Levodopa in Early Parkinson's Disease.

BACKGROUND AND OBJECTIVE: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years. METHODS: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose. RESULTS: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups. CONCLUSIONS: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Predictors of stress resilience in Parkinson's disease and associations with symptom progression.

People with Parkinson's disease (PD) are sensitive to effects of long-term stress, but might differ in stress resilience, i.e. the ability to maintain mental health despite adversity. It is unclear whether stress resilience in PD is predominantly determined by dopamine deficiency, psychosocial factors, or both. In PD animal models, chronic stressors accelerate disease progression, but evidence in humans is lacking. Our objectives were to (1) distinguish stressor-reactive from resilient PD patients, (2) identify resilience factors, and (3) compare symptom progression between stressor-reactive and resilient patients. We conducted a longitudinal survey in Personalized Parkinson Project participants (N = 350 PD). We used the COVID-19 pandemic as a model of a stressor, aligned in time for the entire cohort. COVID-19-related stressors, perceived stress, and PD symptoms were assessed at 11 timepoints (April-October 2020). Both pre-COVID and in-COVID clinical assessments were available. We quantified stressor-reactivity as the residual between actual and predicted perceived stress relative to COVID-19-related stressors, and modeled trajectories of stressor-reactivity across timepoints. We explored pre-COVID predictors of 6-month average stressor-reactivity, and tested whether stressor-reactivity was prospectively associated with one-year clinical progression rates. Latent class trajectory models distinguished patients with high (N = 123) or low (N = 227) stressor-reactivity. Pre-existing anxiety, rumination and non-motor symptom severity predicted high stressor-reactivity (risk factors), whereas quality of life, social support, positive appraisal style and cognitive abilities predicted low stressor-reactivity (resilience factors). PD-specific factors, e.g. disease duration, motor severity, and levodopa use, did not predict stressor-reactivity. The COVID-19 pandemic did not accelerate disease progression, but worsened depressive symptoms in stressor-reactive PD patients.

Periodontitis: A Plausible Modifiable Risk Factor for Neurodegenerative Diseases? A Comprehensive Review.

The aim of this comprehensive review is to summarize recent literature on associations between periodontitis and neurodegenerative diseases, explore the bidirectionality and provide insights into the plausible pathogenesis. For this purpose, systematic reviews and meta-analyses from PubMed, Medline and EMBASE were considered. Out of 33 retrieved papers, 6 articles complying with the inclusion criteria were selected and discussed. Additional relevant papers for bidirectionality and pathogenesis were included. Results show an association between periodontitis and Alzheimer's disease, with odds ratios of 3 to 5. A bidirectional relationship is suspected. For Parkinson's disease (PD), current evidence for an association appears to be weak, although poor oral health and PD seem to be correlated. A huge knowledge gap was identified. The plausible mechanistic link for the association between periodontitis and neurodegenerative diseases is the interplay between periodontal inflammation and neuroinflammation. Three pathways are hypothesized in the literature, i.e., humoral, neuronal and cellular, with a clear role of periodontal pathogens, such as Porphyromonas gingivalis. Age, gender, race, smoking, alcohol intake, nutrition, physical activity, socioeconomic status, stress, medical comorbidities and genetics were identified as common risk factors for periodontitis and neurodegenerative diseases. Future research with main emphasis on the collaboration between neurologists and dentists is encouraged.

The Last Straw: How Stress Can Unmask Parkinson's Disease.

We discuss two people with Parkinson's disease (PD), in whom tremor manifested directly following a severely stressful event. Both were initially misdiagnosed with a functional neurological disorder. These stories highlight that stress can trigger the onset of clinical manifestations of PD, by unveiling an underlying disease that had been unfolding for many years. Thus, the sudden symptom onset after a stressful event is not unique to functional disorders, and may lead to avoidable feelings of guilt if people wrongly attribute PD to this event. It remains unclear what mechanism explains this phenomenon, and why symptoms persist after the stressful event has passed.

Care of Late-Stage Parkinsonism: Resource Utilization of the Disease in Five European Countries.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease that leads to progressive disability. Cost studies have mainly explored the early stages of the disease, whereas late-stage patients are underrepresented. OBJECTIVE: The aim is to evaluate the resource utilization and costs of PD management in people with late-stage disease. METHODS: The Care of Late-Stage Parkinsonism (CLaSP) study collected economic data from patients with late-stage PD and their caregivers in five European countries (France, Germany, the Netherlands, UK, Sweden) in a range of different settings. Patients were eligible to be included if they were in Hoehn and Yahr stage >3 in the on state or Schwab and England stage at 50% or less. In total, 592 patients met the inclusion criteria and provided information on their resource utilization. Costs were calculated from a societal perspective for a 3-month period. A least absolute shrinkage and selection operator approach was utilized to identify the most influential independent variables for explaining and predicting costs. RESULTS: During the 3-month period, the costs were €20,573 (France), €19,959 (Germany), €18,319 (the Netherlands), €25,649 (Sweden), and €12,156 (UK). The main contributors across sites were formal care, hospitalization, and informal care. Gender, age, duration of the disease, Unified Parkinson's Disease Rating Scale 2, the EQ-5D-3L, and the Schwab and England Scale were identified as predictors of costs. CONCLUSION: Costs in this cohort of individuals with late-stage PD were substantially higher compared to previously published data on individuals living in earlier stages of the disease. Resource utilization in the individual sites differed in part considerably among these three parameters mentioned. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Prevalence of Parkinson's Disease in Poland: Regional and Sex-Related Differences.

Background: Given the growing evidence for an environmental contribution to the etiology of Parkinson's disease (PD), searching for local and regional differences in PD prevalence in multiple areas across the world may further clarify the role of environmental toxins. Objective: To provide local and regional prevalence estimates of PD in Poland. Methods: We analyzed the prevalence of PD and its trend over the last decade (2010 to 2019) based on data from the National Health Fund in Poland. We specifically examined sex differences in PD prevalence, as well as differences across Polish regions. Results: During the above period, the prevalence of PD in Poland increased from 226 per 100,000 to 269 per 100,000 inhabitants. Unexpectedly, we found that PD was 1.2-times more common in women than men. The increase in prevalence over the past decade was different between both sexes: an increase from 250 to 283 per 100,000 for women (13.3% increase), and from 200 to 254 per 100,000 for men (27.1% increase). In addition, we observed differences in prevalence across different Polish regions, with some regions having up to 51% lower prevalence rates than others. Conclusions: The prevalence of PD in Poland is in line with previously reported prevalence rates across Europe. However, unlike the situation in most of the world, PD was more prevalent in women than men. We discuss several possible explanations as well as potential measures that might help to reduce the growth of PD.

Gait Adaptability and the Effect of Ocular Disorders on Visually Guided Walking in Parkinson's Disease.

Gait disorders are a disabling feature of Parkinson's disease (PD). To avoid falls, people with PD should be able to adequately adapt their gait. This requires correct response inhibition and integration of visual information. In this small pilot study, we investigated PD-related impairments in gait adaptability and the influence of ocular disorders thereon. Compared with controls, persons with PD were less able to adapt their gait in unexpected situations (U = 21.5, p = 0.013), with only a small influence of ocular disorders on precision stepping (U = 6, p = 0.012 in the ML-direction and in the AP-direction, (U = 20, p = 0.456). This shows that people with PD have more difficulty with precision stepping than healthy controls and experience more problems with adapting their gait. We found only a small impact of ocular disorders on successfully execute precision stepping. The ability to adapt gait, particularly in challenging environmental conditions or with impaired vision, may provide a useful assessment and training option for fall prevention in PD.

Parkinson's Disease in Sub-Saharan Africa: Pesticides as a Double-Edged Sword.

Long-term exposure to pesticides used in agriculture is increasingly being identified as a risk factor for developing Parkinson's disease. How chronic pesticide exposure might contribute to the growth of Parkinson's disease in the mainly agricultural communities of Sub-Saharan Africa has thus far received limited attention. There are specific concerns in this area of the world: aging of the population, in combination with chronic exposure to widely used pesticides, including those that have been restricted elsewhere in the world because of neurotoxicity and other health risks. Of interest, the prevalence of Parkinson's disease among specific (semi)nomadic populations in Tanzania seems very low, possibly due to their lack of exposure to agricultural chemicals. But at the same time, pesticides have also brought important benefits to this part of the world. Specifically, in Sub-Saharan Africa, pesticides have been directly helpful in preventing and controlling famine and in containing major human infectious diseases. This creates a complex risk-benefit ratio to the use of pesticides within a global perspective, and urgently calls for the development and implementation of affordable alternatives for areas such as Sub-Saharan Africa, including non-neurotoxic compounds and non-chemical alternatives for the use of pesticides.

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.

The sound of Parkinson's disease: A model of audible bradykinesia.

INTRODUCTION: Evaluation of bradykinesia is based on five motor tasks from the MDS-UPDRS. Visually scoring these motor tasks is subjective, resulting in significant interrater variability. Recent observations suggest that it may be easier to hear the characteristic features of bradykinesia, such as the decrement in sound intensity or force of repetitive movements. The objective is to evaluate whether audio signals derived during four MDS-UPDRS tasks can be used to detect and grade bradykinesia, using two machine learning models. METHODS: 54 patients with Parkinson's disease and 28 healthy controls were filmed while executing the bradykinesia motor tasks. Several features were extracted from the audio signal, including number of taps, speed, sound intensity, decrement and freezes. For each motor task, two supervised machine learning models were trained, Logistic Regression (LR) and Support Vector Machine (SVM). RESULTS: Both classifiers were able to separate patients from controls reasonably well for the leg agility task, area under the receiver operating characteristic curve (AUC): 0.92 (95%CI: 0.78-0.99) for LR and 0.93 (0.81-1.00) for SVM. Also, models were able to differentiate less severe bradykinesia from severe bradykinesia, particularly for the pronation-supination motor task, with AUC: 0.90 (0.62-1.00) for LR and 0.82 (0.45-0.97) for SVM. CONCLUSION: This audio-based approach discriminates PD from healthy controls with moderate-high accuracy and separated individuals with less severe bradykinesia from those with severe bradykinesia. Sound analysis may contribute to the identification and monitoring of bradykinesia.

Parkinson's Disease Is Predominantly an Environmental Disease.

Parkinson's disease is the world's fastest growing brain disorder, and exposure to environmental toxicants is the principal reason. In this paper, we consider alternative, but unsatisfactory, explanations for its rise, including improved diagnostic skills, aging populations, and genetic causes. We then detail three environmental toxicants that are likely among the main causes of Parkinson's disease- certain pesticides, the solvent trichloroethylene, and air pollution. All three environmental toxicants are ubiquitous, many affect mitochondrial functioning, and all can access humans via various routes, including inhalation and ingestion. We reach the hopeful conclusion that most of Parkinson's disease is thus preventable and that we can help to create a world where Parkinson's disease is increasingly rare.