Treating a neurological disorder through the gut may seem counterintuitive, yet multiple lines of evidence highlight the gut's important role in Parkinson's disease (PD). Prodromal gastrointestinal symptoms, the presence of aggregated α-synuclein in enteric neurons, increased intestinal inflammation, and impaired epithelial barrier integrity all point to gut-level involvement in PD pathophysiology. The gut microbiome, markedly altered in individuals with PD, may be a key driver of these changes. Fecal microbiota transplantation (FMT) is currently the most effective strategy for achieving broad and durable modifications of gut microbiota composition. However, FMT is a complex, multi-step procedure requiring stringent methodological control. Modulating gut bacteria has demonstrated therapeutic potential in preclinical models of PD, and recent clinical trials have begun evaluating FMT in patients, although outcomes have been variable. In this review, we examine potential explanations for these divergent results, with a particular focus on methodological differences across trials. We also outline future directions for optimizing FMT study design in PD and discuss how these insights may guide the development of next-generation microbiota-targeted therapies.

BackgroundDeep brain stimulation (DBS) for Parkinson's disease (PD) primarily improves motor symptoms but leaves non-motor symptoms (NMS) largely unattended. Neurophysiological markers associated with specific symptoms could improve DBS programming. We systematically reviewed the evidence linking basal ganglia local field potentials (LFP) to NMS in PD.MethodsThe literature search (Medline, Embase, Scopus, and Web of Science) on August 20, 2024 yielded 1066 records. Studies were included if they focused on patients with idiopathic PD treated with DBS of the subthalamic nucleus (STN) or globus pallidus interna (GPi) and reported on the relationship between LFP data and NMS. The study risk of bias was evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST). A narrative synthesis of results was provided.ResultsTwenty-one studies were included, focusing on impulse control disorders (n = 8), sleep-wake disorders (n = 5), depressive symptoms (n = 4), cognitive dysfunction (n = 3), hypomania (n = 1) and lower urinary tract symptoms (n = 1). Seven studies had a high risk of bias. Theta and alpha power in the STN were frequently associated with neuropsychiatric symptoms and cognitive function. Beta power in the STN and GPi was linked to sleep-wake disorders and urinary dysfunction.ConclusionsOverall, evidence on basal ganglia physiomarkers of NMS in PD remains limited. Further research is essential to develop patient-specific stimulation paradigms targeting NMS, which could significantly improve the quality of life of individuals with PD.OtherThis systematic review was registered with the International Prospective Register of Systematic Reviews (CRD42024495284). There was no specific funding for this study.

BackgroundThe Parkinson's Disease (PD) Home Diary (HD) is a common clinical outcome measure, but studies show only fair agreement between clinical observer and patient assessments, with no significant improvement after patient training.ObjectivesTo investigate the agreement between a clinical observer and relatives of PD patients when assessing the patient's motor status in the HD. Agreement was also assessed for relative-patient and patient-observer pairs.MethodsThis observational study included 28 PD patients with motor fluctuations and their relatives. It involved a screening visit with structured training on motor fluctuations and one day of motor ratings, where the observer, relative, and patient independently assessed the patient's motor state in the HD half-hourly.ResultsObserver, patient, and relative triads completed 445 HD assessment sets. Temporal agreement was fair for observer-relatives (Cohen's κ = 0.250) and relatives-patients (κ = 0.230), but slight for patients-observer (κ = 0.120). For observer-relatives, agreement was highest for "On without dyskinesia" (71%), and lowest for "Off" (26%). Daily time distributions differed significantly between relatives and the clinical observer for "Off" (p = 0.006) and "On without dyskinesia" (p = 0.012), but not for "On with dyskinesia" (p = 1.000).ConclusionsThis study reports fair temporal agreement of motor state assessments between relatives-observer and relatives-patients, with slight agreement between patients-observer. Relatives' assessments of daily time in different motor states showed significant differences from the clinical observer assessments. This further highlights the challenges in obtaining reliable motor status data and the need for further research into objective assessment methods.

Worldwide, the incidence, prevalence, disability, and mortality associated with Parkinson's disease (PD) have increased substantially, placing an immense strain on healthcare systems across countries of all income levels, prompting the use of the term "Parkinson pandemic" to emphasize the urgent need for coordinated strategies to address its worldwide impact. This narrative review explores the regional differences in the dramatic increase in PD burden, along with its genetic, environmental, and socioeconomic determinants worldwide. Furthermore, it discusses the healthcare access in different regions and proposes strategies to combat this pandemic. The rising burden of PD is largely driven by population aging, increased life expectancy, and potentially by greater exposure to by-products of industrialization-such as pesticides, air pollution and heavy metals- and declining smoking rates, which vary across world regions. Differences in prevalence, demographic, genetic and lifestyle factors, the impact of urbanization and environmental risk factors, as well as inequality and disparities in access to care and healthcare services, have been outlined, mandating the development of tailored and region-specific strategies to mitigate the pandemic and reduce its burden globally and regionally. These strategies include exploring relevant genetic and environmental determinants, promoting research, increasing public awareness, facilitating early diagnosis and optimal management, improving access to healthcare services, supporting caregivers, encouraging the adoption of protective lifestyle factors, ensuring the availability of essential medications and controlling environmental exposures such as toxicants.

Plain language summaryCelebrating the legacy of two decades of Parkinson's disease research in South AfricaParkinson's disease (PD) has been well-studied in Western Countries, but there are far fewer studies in other parts of the world, especially in Africa. This lack of research is partly because there are insufficient neurologists in many African countries, leading to missed or incorrect diagnoses. Stigma around PD and the absence of national disease registries also make research more difficult. To help fill this gap, our team has spent the past 20 years studying PD in South Africa. We have built a collection of almost 2,000 South African participants and report our main findings here. Overall, we found only 20 PD-causing variants in our collection of 689 unrelated PD cases. Interestingly, some of these genetic findings appear to be unique to South Africans, likely due to the unique genetic composition of the country's population. Our functional studies showed how variants in genes, such as PRKN and LRRK2, disrupt the function of mitochondria. Mitochondria are tiny structures in cells that supply the energy required for the cells to function. Cells die when they do not have the necessary energy, potentially explaining why brain cells die in PD. A third part of our research focuses on curcumin, a natural compound found in turmeric known for its antioxidant and anti-inflammatory effects. Using cell models, including cells from individuals with PD, we found that curcumin can protect cells from damage caused by paraquat, a harmful chemical which has been linked to the development of PD. However, this rescue is only seen when curcumin is given before the damage occurs. This suggests that curcumin may help prevent neuronal loss in PD. In summary, our work adds to global knowledge about the genetics, disease processes, and possible treatments for PD. It also shows what a small African laboratory can achieve, despite limited personnel and resources.

Synucleinopathies are a group of neurodegenerative disorders characterized pathologically by the presence of neuronal and/or oligodendrocyte inclusions composed of aggregated alpha-synuclein (αS). These disorders can be divided into two major sub-types: Lewy body disease and multiple system atrophy, which have distinct clinical and pathological profiles. As is seen with other neurodegenerative diseases, recent evidences suggest that the conformation and molecular organization of αS amyloid filaments deposited in brains might dictate the distinct pathological and clinical profiles in synucleinopathies. Resolving the structure of disease-specific αS aggregates becomes, therefore, of clinical interest. Until recently, the specific conformations of these aggregates at molecular resolution have remained elusive. This is now possible due to the advent and development of cryo-electron microscopy (cryo-EM) technology. This review aims to cover the recent advances in the structural biology of αS amyloid filaments implicated in synucleinopathies, raising a number of critical questions that continue to be investigated. What can we learn from these structures? What are the main structural differences between experimental systems and human tissue derived protein aggregates? What factors drive these differences? Do the amplified assemblies represent faithfully the seed structures? How these new findings improve our understanding of the molecular mechanisms behind fibril formation in disease? Can this knowledge be exploited for the design of diagnostic and therapeutical strategies? These aspects and the recent advances in the field will be addressed and discussed in this work.

Deep brain stimulation (DBS) is an established therapy for advanced medication-resistant Parkinson's disease (PD), yet its ability to alter the course of the disease remains uncertain. Although preclinical research using toxin-induced PD models demonstrate neuroprotective effects, clinical studies in PD patients undergoing DBS have not substantiated these findings. This disconnect may be attributed to factors such as the initiation of DBS late in disease, stimulation protocols targeting symptoms rather than pathology, and the limited translational relevance of animal models lacking hallmark alpha-synuclein (α-Syn) aggregation. Incorporating α-Syn-based models may bridge this gap by facilitating the discovery of early electrophysiological biomarkers of pathological progression, refining stimulation parameters to enhance α-Syn clearance, and assessing if early DBS intervention can mitigate neurodegeneration. Yet, only a limited number of DBS studies have employed α-Syn models to date. This review examines the translational gap between preclinical neuroprotection claims and clinical outcomes, focusing on how α-Syn-based models could resolve current limitations in DBS research. Prioritizing these models could clarify whether DBS has the potential to extend beyond symptomatic relief and directly engage PD's underlying neurodegenerative mechanisms. Achieving this goal requires systematic investigation of DBS influences on α-Syn accumulation and its electrophysiological correlates in disease-relevant models.

Background: Significant number of patients with Parkinson's disease (PD) gradually progress to Parkinson's disease dementia (PDD). Recent proposal for updating current diagnostic criteria for PDD recommends alternative screening tests and broader functional assessments. Objective: To evaluate the diagnostic concordance among algorithms for PDD based on Level I (i.e., screening) criteria and to assess their predictive validity for Level II (i.e., neuropsychological battery) diagnosis. Methods: A cross-sectional retrospective analysis of 190 patients with PD who underwent a comprehensive neuropsychological assessment. A total of 68 diagnostic algorithms were operationalized using combinations of scores derived from the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Functional impairment was based either on the Functional Assessment Questionnaire (FAQ) item 9 or the FAQ total score. Diagnostic concordance was evaluated using Cohen's κ. Predictive validity for Level II classification was assessed using projection predictive variable selection. Results: Estimated PDD rates ranged from 2.1% up to 16.8%. Concordance was moderate to high among algorithms using the same functional impairment definition (κFAQ total = 0.75, κFAQ 9 = 0.86) but substantially lower when functional impairment definitions differed (κ = 0.43). A parsimonious screening model combining MoCA Five Words and MMSE Sevens adequately approximated Level II classification and yielded a prevalence-adjustable heuristic decision rule. Conclusions: Diagnostic outcomes for PDD are sensitive to the choice of cognitive and functional instruments suggesting that different algorithms may capture partially distinct constructs. Minimal screening using selected items can approximate Level II PDD diagnosis, but this simplification entails a trade-off between sensitivity and specificity.

Gastroparesis (GP), defined as delayed gastric emptying (GE) without mechanical obstruction, is an underdiagnosed non-motor symptom of Parkinson's disease (PD) that may affect levodopa pharmacokinetics and contribute to motor fluctuations. In PD, GP pathophysiology involves Lewy pathology in the enteric nervous system, neurohormonal dysregulation, gut microbiota alterations, and adverse effects of medications, including levodopa. Disruption of the gut-brain axis further exacerbates gastrointestinal dysmotility, leading to malnutrition, reduced quality of life, and increased hospitalization rates. Clinically, GP delays GE, resulting in erratic levodopa absorption and unpredictable ON/OFF responses. Diagnosis is challenging due to symptom overlap with other gastrointestinal disorders and the lack of validated scales specific to GP in PD. Gastric scintigraphy remains the reference method for assessing GE, although its use is limited by methodological variability and interference from ongoing PD treatments.This review critically examines the epidemiology, pathophysiology, and clinical consequences of GP in PD, and highlights its bidirectional relationship with levodopa pharmacokinetics, particularly its contribution to motor fluctuations. We discuss current pharmacological management strategies, with a focus on the efficacy and safety profile of domperidone. Finally, we propose the hypothesis that the future integration of digestive biomarkers and longitudinal clinical data could contribute to a more individualized treatment approach.

Plain language summaryOff-state dyspnea induced by diaphragmatic-chest wall asynchrony in Parkinson's disease: A novel observation and review of the literatureIn the clinical care of patients with Parkinson's disease (PD), dyspnea is a frequent symptom alongside the classic motor symptoms such as bradykinesia and rigidity. However, the underlying mechanisms of dyspnea in Parkinson's disease and how it is affected by dopaminergic medications like levodopa and dopamine agonists, which represent the mainstay treatment of motor symptoms in Parkinson's disease, are not yet fully understood. Various diagnostic tools exist to help clinicians evaluate patients with respiratory issues. In this case study, we report on the utilization of electromyography of the diaphragm, a previously not described diagnostic tool in the field of PD-related dyspnea, to study a patient with Parkinson's disease presenting with recurrent unexplained dyspnea when the dopaminergic medication wears off. We identified an altered sequence of respiratory motion, that is the contraction of diaphragm and excursion of the chest wall, during medication-off in this patient. We propose that the diaphragm-chest wall asynchrony, being a novel finding, likely leads to impaired mechanical output during breathing and contributes to the patient's experience of dyspnea when the medication wears off.