Background Handwriting changes are recognised as an early manifestation of Parkinson's disease. Whilst isolated rapid eye movement sleep behaviour disorder (iRBD) is strongly associated with future Parkinson's diagnosis, changes in handwriting remain under-explored. Objective To assess the handwriting of people with iRBD and develop a rating scale for detection of early disease clinical hallmarks. Methods Cross-sectional study involving 33 people with polysomnography-confirmed iRBD and 29 controls. Participants copied a standard sentence using pen and paper. A graphologist analysed each script blindly and designed a scale based on observed abnormal patterns which included: micrographia, sentence slope, hidden tremor, retracing, resting marks, irregular shape, excessive pen pressure, and inconsistent word spacing. Each item was scored 0/1 based on their absence/presence. Separately, three blinded movement disorders experts assessed the scripts based on their global clinical impression as well as using the rating scale. Results People with iRBD were slower to complete the task than controls (76.70 s (SD = 30.39) vs 61 s (SD = 10.71); p = 0.004). Hidden tremor was the most common feature amongst the iRBD group (72.0% vs 34.5%; p = 0.005), followed by sentence slope (60% vs 24% p = 0.005) and pen pressure (48% vs 14%; p = 0.006). Micrographia was observed in both groups (iRBD 45.4%, controls 41.4% p = 0.801). Classification accuracy of the scale for iRBD was higher than expert global assessment (AUC 0.76 vs AUC 0.62; p = 0.029). Conclusions Writing speed, tremor, pen pressure and sentence slope are handwriting features that warrant further investigation to define early patterns in people with iRBD.

BACKGROUND:Istradefylline, a selective adenosine A2A receptor antagonist, is approved as an adjunct to levodopa in Parkinson's disease, but its long-term effects on clinically meaningful outcomes are unclear. OBJECTIVE:We aimed to compare the association of istradefylline versus catechol-O-methyltransferase (COMT) inhibitors with mortality, treatment escalation, and disease progression in levodopa-treated Parkinson's disease. METHODS:We conducted a nationwide cohort study emulating a target trial using the DeSC claims database in Japan. Patients aged ≥50 years with levodopa-treated Parkinson's disease between 2014 and 2023 were included. Strategies were initiation of istradefylline versus COMT inhibitors. Primary outcomes were all-cause mortality, levodopa-equivalent daily dose (LEDD) escalation to ≥1100 mg, and dementia or psychosis. Secondary outcomes were fractures, cardiovascular events, pneumonia, and depression. Intention-to-treat and per-protocol effects were estimated using Cox models with propensity score-based overlap weighting. RESULTS:We identified 3190 istradefylline and 7986 COMT inhibitor initiators. In intention-to-treat analysis, istradefylline was associated with lower risks of mortality (hazard ratio [HR] 0.91; 95 % CI 0.84-0.99) and LEDD escalation (HR 0.83; 95 % CI 0.73-0.94). Associations were stronger in per-protocol analysis (mortality: HR 0.84, 95 % CI 0.72-0.97; LEDD escalation: HR 0.71, 95 % CI 0.59-0.84). Istradefylline was linked to higher fracture risk (intention-to-treat HR 1.13, 95 % CI 1.02-1.25; per protocol HR 1.23, 95 % CI 1.07-1.41). No differences were observed for dementia, psychosis, or other outcomes. CONCLUSIONS:Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A2A antagonists.

BACKGROUND:Pain affects up to 87% of people with multiple system atrophy (MSA), but it remains unclear which types of pain contribute most to the overall burden. OBJECTIVE:To estimate the frequency of different types of pain in MSA individuals. METHODS:In 2023, individuals with MSA completed a web-based survey that included the King's Parkinson's Disease Pain Questionnaire (KPPQ) and additional questions addressing pain related to MSA core features (eg, coat-hanger pain, pain due to bladder-issues, cold extremities, bruises, and pressure sores). Respondents were matched by age, gender, and disease duration with historical cohorts of individuals with Parkinson's disease (PD) and healthy controls (n = 96 each) who had previously completed the KPPQ. RESULTS:One hundred and fifty-seven MSA individuals with pain completed the survey. The most frequently reported KPPQ types of pain were nocturnal pain (73%), musculoskeletal pain (63%), and fluctuation-related pain (62%). Common additional pain sources included coat-hanger pain (59%), cold extremities (48%), and bruises (44%). All KPPQ pain types were significantly more frequent in MSA than in healthy controls, except for musculoskeletal pain (63% vs. 66%, P = 0.722). Compared with PD, MSA individuals reported less musculoskeletal (63% vs. 78%, P = 0.023), but more orofacial pain (32% vs. 12%, P < 0.001) on the KPPQ. CONCLUSIONS:MSA is associated with both non-specific and disease-related pain types, which may be neuropathic, nociceptive, nociplastic, or mixed in nature. These findings inform the development of tailored tools for identifying distinct pain sources in MSA, as each may require a specific therapeutic approach, including targeted treatment of motor and non-motor symptoms. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pilot randomised-controlled trial of nortriptyline and escitalopram compared to placebo for depressive symptoms in people with Parkinson’s disease (PD). Participants with PD and depressive symptoms received either nortriptyline, escitalopram or placebo with assessments at baseline and 8 weeks. Feasibility of the full trial was assessed using recruitment rate, loss to follow up before the 8-week primary endpoint, adherence to trial medication and rate of clinically significant adverse reactions. Intended efficacy outcomes included the BDI-II, Patient Health Questionnaire (PHQ-9), Parkinson Anxiety Scale (PAS), MDS-UPDRS and adverse effects. The aim was to recruit 46 participants to determine feasibility of the full trial. 52 participants were recruited from 24 NHS sites and randomised to nortriptyline (n = 16), escitalopram (n = 17) or placebo (n = 19). However, despite multiple strategies, recruitment took two years, and the study therefore did not reach its feasibility aim. Exploratory analyses showed that at 8 weeks depressive symptoms decreased significantly in all three arms. There was no difference in BDI-II score changes between the nortriptyline or the escitalopram when compared to the placebo arm, but PHQ-9 scores showed a greater reduction compared to placebo with nortriptyline (-3.4, 95

BACKGROUND:Little is known about how people with Parkinson's conceptualize "quality of life." OBJECTIVE:To describe the meaning of "quality of life" from the perspective of people with Parkinson's. METHODS:Participants (N = 42) were asked "What does the term 'quality of life' mean to you?" Definitions were analyzed using inductive qualitative methods. RESULTS:Quality of life is captured in a framework illustrating how activities, experiences, and coping strategies generate positive feelings that collectively shape the mental state that defines quality of life. CONCLUSIONS:People with Parkinson's typically define what constitutes a good quality of life, with health status acting as an enabler (or barrier). Multiple factors, varying across individuals and potentially changing with circumstances, shape how people view their quality of life, and offer potential avenues for sustaining it. These personal, subjective and adaptive conceptualizations of quality of life should inform the design of interventions and measurement instruments.

ABSTRACT Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder. PD currently lacks effective disease-modifying treatments, likely due to its diverse clinical features and underlying neuropathology. The vascular role in PD is emerging, with vascular mechanisms increasingly implicated, yet the literature remains conflicted, motivating large-data analyses with greater statistical power. White matter lesions (WML) are an accepted imaging marker of small vessel disease. Accurate automated WML segmentation techniques are crucial for large-scale studies in PD due to the impracticality of manual segmentation for extensive datasets and to ensure consistency. Evaluation of the optimum approach in PD for large-scale analysis is lacking. This study aimed to evaluate various automated WML segmentation algorithms to determine the most accurate and reliable method, among those selected, for assessing WML for multi-site large data analysis in PD. Methods We assessed whole-brain volumetric T1-weighted and FLAIR images from 201 PD patients (mean age, 66.6 ± 7.86 years) and 64 healthy controls (HC; mean age, 66.3 ± 8.67) across three datasets: the Parkinson’s Progression Markers Initiative (PPMI), the University of Pennsylvania (UPenn) and the Montreal Neurological Institute Biobank: Clinical Biological Imaging and Genetic Repository (C-BIG). The sample included different scanners, imaging parameters and lesion loads, as would be expected for multi-site data. WML were manually segmented to provide the gold standard, and four freely available automated algorithms were evaluated: FSL’s BIANCA, FreeSurfer, SPM’s LST-LPA and U-Net-pgs using the performance metrics: Dice score, Hausdorff distance, recall, precision, F1 score, log absolute volume difference (LOGAVD) and intraclass correlation coefficient (ICC). Subgroup analyses were performed based on lesion load and lobar regions. The associations of data from these automated approaches with age, and with Fazekas and Wahlund visual rating scales, were assessed through partial correlation analysis. Results U-Net-pgs performed best overall, with the highest Dice score (PD: 0.46 ± 0.21; HC: 0.39 ± 0.21), recall (PD: 0.76 ± 0.25; HC: 0.62 ± 0.31), precision (PD: 0.49 ± 0.25; HC: 0.63 ± 0.27), F1 score (PD: 0.54 ± 0.22; HC: 0.56 ± 0.22) and ICC (PD: 0.965; HC: 0.967) and lowest Hausdorff distance (PD: 8.89 ± 3.96; HC: 6.33 ± 2.91). U-Net-pgs achieved the lowest LOGAVD in the PD group (0.31 ± 0.31) whereas BIANCA-LOO with a threshold of 0.9 was lowest in HC (0.27 ± 0.30). U-Net also showed superior performances in all lesion loads for PD and overall across various brain regions in both PD and HC. Conclusion Overall, U-Net-pgs emerged as the best performing automated method, of those we evaluated, for WML segmentation in PD and HC within a dataset collected with various scanner and image acquisition parameters. U-Net-pgs consistently outperformed other automated approaches across lesion loads and brain regions, for most metrics. The accuracy and reliability of U-Net-pgs make it a promising tool for large-scale analyses, facilitating future research investigating WML in PD.

BACKGROUND:Dysphagia and malnutrition are common in advanced Parkinson's disease and atypical parkinsonism. There is a lack of evidence to guide the use of enteral nutrition in these situations, including whether it improves survival or reduces aspiration pneumonia. OBJECTIVES:To systematically review the impact of enteral nutrition in Parkinson's disease and atypical parkinsonism on survival and morbidity (including aspiration pneumonia). METHODS:We followed PRISMA guidelines and conducted searches using PubMed and Scopus databases. ROBINS-I V2 (n = 2) and JBI Cohort Study (n = 14) checklists were used to assess risk of bias. RESULTS:We identified 16 eligible studies. Risk of bias was moderate or high in all studies. Reported enteral feeding rates in parkinsonian disorders varied widely. The rate of aspiration pneumonia following enteral feeding was around 40% in those with parkinsonism. The weighted median survival following gastrostomy insertion in Parkinson's disease was 1.35 years (n = 83; 3 studies) and in atypical parkinsonism 1.49 years (n = 46; 2 studies). One study in atypical parkinsonism found improved survival with enteral feeding compared to at-risk feeding (24 vs. 12 months), whilst another in Parkinson's disease found no difference in mortality rates. CONCLUSIONS:There is a lack of high-quality evidence on the impact of enteral feeding on prognosis and morbidity. It is unclear whether enteral feeding improves survival compared to at-risk feeding. There is a need for more robust evidence such as through enteral feeding registries with standardized data collection.

Understanding vascular contributions to disease is a major unmet need. White matter lesions (WML) are an accepted imaging marker of cerebral small vessel disease, giving insights into its related pathologies. A unified approach for WML analyses in large multi-site data is lacking despite the need for pooling of data to overcome the limitations of often small heterogenous MRI studies which make subtyping and identifying patterns within disease groups difficult. Our ENIGMA-PD-WML pipeline is an open-source containerized pipeline containing all the code and packages required for pre-processing, processing and post-processing of T1-weighted and FLAIR data, outputting accurate and reproducible binary WML maps using a UNet approach. The pipeline provides a standardized image analysis approach for WML and outputs data in both native and MNI space to allow for sharing and pooling of data from multiple sites for large-data analysis. In addition to a reliable standardized approach for WML segmentation, key priorities when developing the pipeline included: usability, i.e., requiring minimal manual input and technical expertise to use, and suitability to run on various MRI scanners and acquisition parameters as is common in multi-site data. This paper describes the pipeline in detail, with rationale for each step, providing transparency and facilitating its usage to overcome reproducibility issues in large-scale WML analyses.

Background:Online exercise groups for people with Parkinson's disease (PwP) are increasing in popularity, but little is known about PwP's experiences with them. Objective:To explore the views and experiences of PwP who have utilised Parkinson's disease-specific online exercise groups. Methods:A qualitative study utilising semistructured interviews and thematic analysis in a purposive sample of PwP who had participated in an online exercise group. Results:Nine participants (5 females) with a mean age of 69.5 (63-78) years and a mean disease duration of 9.1 (3-20) years participated. Analysis revealed three overarching themes: 'Considerations of online exercise groups for PwP', which highlighted the pros and cons of attending online exercise classes; 'Online exercise class qualities', including the importance of a tailored approach, clearly communicated aims and the importance of a well-informed instructor; and 'Accessibility', which included considerations of convenience of access, costs and technological access. Conclusion:Online exercise groups may play an important role in future Parkinson's disease management by offering greater access to exercise. They may also perpetuate inequalities for PwP and lack the social engagement many PwP seek. Hybrid group exercise, a combination of online and face-to-face classes, could provide this. Providers must develop classes that are tailored to PwP and delivered by well-informed instructors.

Background:Self-management approaches in people with Parkinson's disease (PD) have potential to improve patient outcomes and reduce complications leading to hospital admissions. We aimed to evaluate the clinical and cost-effectiveness of the UCL Live Well with Parkinson's toolkit, a facilitated self-management intervention for people with PD. Methods:This two-arm randomised controlled trial in England (Trial Registration: ISRCTN92831552) recruited community-dwelling people with PD from NHS sites and self-referral. They were randomly assigned to the intervention or treatment as usual (TAU), and assessed at baseline, 6- and 12-month follow-up. The primary outcome was the PDQ-39 score, a PD-specific health-related quality of life measure, at 12-months with planned subgroup analyses. Secondary outcomes included non-motor and motor activities of daily living (MDS-UPDRS part I&II), utility values and QALYs derived from the EQ-5D-5L, and total health and social care costs over 12-months. The economic evaluation was based on cost-utility analysis using cost per QALY. All assessors were blinded to group allocation. Analysis was by intention to treat. Findings:166 participants were randomised to the intervention and 180 to TAU, with 12-month follow-up assessments available in 141 (84.9%) and 164 (91.1%), respectively. The primary endpoint (PDQ-39 score) was similar for patients in the intervention and TAU groups (-1.03; 95% CI (-3.03 to 0.97)). Subgroup analyses of PDQ-39 scores in underserved groups however favoured the intervention (-4.0; 95% CI (-6.8 to -1.1)). The combined MDS-UPDRS part I + II score was improved in the intervention compared to the TAU group (-2.61; 95% CI (-4.58 to -0.64)). QALYs were not different between groups (0.018; 95% CI (-0.006 to 0.042) but total health and social care costs over 12-months were lower in the intervention group compared to TAU (-£1282; 95% CI (-£2700 to -£118)), driven mainly by reduced unplanned hospital admissions. Adverse events were similar in both groups. The Live Well with Parkinson's intervention alongside TAU was 99% cost-effective compared to TAU at a decision threshold of £20,000 per QALY and 98% at £30,000. Interpretation:The UCL Live Well with Parkinson's toolkit did not significantly improve health-related quality of life scores overall but improved activities of daily living and reduced health-care costs in comparison to TAU, mainly through reduced unplanned hospital admissions. Funding:National Institute for Health and Care Research RP-PG-1016-20001.

Non-pharmacological and non-surgical interventions are increasingly recognised as essential components of management of Parkinson’s disease (PD). However, as PD progresses to its advanced stages, limited mobility, cognitive impairment, treatment-refractory symptoms, and increasing dependence on care partners dominate. However, the evidence base for therapies in this stage becomes scarce. Most clinical practice guidelines and systematic reviews address PD as a whole, without highlighting specific recommendations tailored to advanced disease stage. This narrative review examines the current evidence for non-pharmacological and non-surgical therapies specifically in the context of advanced PD. This includes physiotherapy and exercise, freezing of gait management, dysphagia rehabilitation, nutrition and dietetics, neuropsychiatric care, autonomic dysfunction, pain management, and palliative care. We synthesised evidence from recent systematic reviews of clinical practice guidelines, scoping reviews of rehabilitation interventions in advanced PD, systematic reviews and meta-analyses of non-pharmacological treatments for specific symptom domains, the published literature on advanced PD management, and expert consensus. A recent systematic review identified 40 summary statements for non-pharmacological interventions in PD, yet these were developed without stage-specific differentiation. A scoping review of rehabilitation interventions specifically targeting advanced PD identified only 13 studies, predominantly focused on physical functioning. On the other hand, while interventions for freezing of gait, swallowing therapies, cognitive behavioural therapy for neuropsychiatric symptoms, non-invasive brain stimulation, non-pharmacological autonomic management, and multimodal exercise have demonstrated promise in PD, robust evidence for advanced PD remains largely absent. People with advanced PD represent a neglected population in non-pharmacological therapy research. There is a clear need for inclusion of people with advanced PD in guideline development and a holistic approach addressing factors such as demoralisation, caregiver strain, autonomic dysfunction, and spiritual wellbeing alongside physical rehabilitation.

Apathy is one of the most prevalent and disabling non-motor symptoms in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), collectively referred to as Lewy body disorders (LBDs). It is associated with reduced quality of life, accelerated cognitive decline, increased caregiver burden, and poorer functional outcomes, yet remains underrecognized and undertreated. A Working Group of the International Parkinson and Movement Disorder Society's Non-Motor Symptoms Study Group conducted a comprehensive review of the literature and developed a position paper through iterative expert discussion and critical appraisal of available data. This review aims to provide a structured, expert-informed synthesis of the current evidence on the clinical features, neurobiology, assessment, and management of apathy in LBDs and to define priorities for future research and clinical trials. Apathy in LBDs is a multidimensional syndrome encompassing reward insensitivity, negative affect, executive dysfunction, and auto-activation deficits. Converging evidence implicates dysfunction within distributed frontal-striatal-limbic networks and multi-neurotransmitter systems, including dopaminergic, serotonergic, noradrenergic, and cholinergic pathways. Although several pharmacological and nonpharmacological interventions have been explored, few randomized controlled trials have specifically targeted apathy, and no treatment can currently be considered definitively efficacious. Methodological heterogeneity, inadequate phenotyping, and inconsistent outcome measures have limited therapeutic progress. Apathy should be recognized as a primary clinical and research priority in LBDs. Future adequately powered, mechanistically informed trials using standardized diagnostic criteria and validated outcome measures are urgently needed to advance treatment development. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND:Parkinson's disease (PD) is associated with an increased rate of mortality. It is unclear whether this is due to complications and comorbidities associated with the disease or the disease process of PD itself. METHODS:We undertook a cohort study in patients with PD in an electronic primary care record database. Mortality rate ratios and risk differences per 1000 person-years were calculated for each complication and comorbidity using multivariable Poisson regression analysis. RESULTS:There were 10,104 patients with incident PD and 55,664 controls. The rate of falls, dementia, hallucinations, postural hypotension, stroke, depression, anxiety, sleep disorders, gastrointestinal and urinary disorders, headaches, epilepsy, and myocardial infarction was higher in individuals with PD compared to controls. Conversely, the rates of chronic obstructive pulmonary disease (COPD), congestive heart failure, and gout were lower. In the PD group, the comorbidities of dementia, falls, stroke, cancer, chronic heart failure, COPD, myocardial infarction, and gastrointestinal disorders were associated with higher mortality rates. However, for all comorbidities, the increase in mortality rate was similar to or lower in the PD group compared to people without PD, except for falls which tended to be associated with higher mortality in the PD group. CONCLUSION:This study provides data on the increased rate of mortality associated with different complications and comorbidities in PD. The mortality associated with these alone, however, does not explain the increased mortality in PD. This underscores the need for treatments to slow the underlying disease process.

Background:Reduced social engagement is associated with increased risk of incident Parkinson's disease (PD). Online peer support provides opportunities to develop new social connections. A digital social forum was recently embedded within PREDICT-PD, an online UK cohort study that stratifies participants for risk of future PD, to explore the feasibility of digital social engagement as an intervention to modify PD risk. Objective:This study reports on the content of messages exchanged on the forum to better understand how this was used and experienced. Methods:364 public posts from 218 distinct users were analysed using thematic analysis. Results:Members created a sense of community through disclosing personal information and reaching out to others. Experiences were shared in relation to symptom appraisal, emotional impacts and routes to diagnosis. Practical advice, resources and information were exchanged to aid symptom management and proactive lifestyle changes. Users discussed their aspirations for timely diagnosis and treatment within healthcare, further research funding to aid prevention and treatment, and greater awareness of PD within society. Technical issues with the forum were reported, and accessibility was viewed as a potential barrier. Conclusions:The online forum provided a peer support environment for people with similar health experiences to connect, exchange information and emotional support, and engage in discussions around political and social issues unique to PD. This highlights the potential of leveraging online peer support to promote social engagement in prodromal PD. Further research is needed to examine the effect on PD risk and develop accessible technologies.

Background:Clinical rating scales for Parkinson's disease (PD) have limitations in the accurate assessment of disease severity, which may obscure treatment effects in clinical management and trials. Body-worn sensors can provide data for continuous and more precise monitoring of motor features of PD in patients' daily lives. However, little information exists on the clinical validity of sensor-derived data. Objectives:We assessed the clinical validity of outputs from three different machine learning models using trunk- or wrist-worn sensors in patients with PD, assessing their correlations with scores on clinical scales assessing motor severity and impact on function. Methods:Wrist- and/or trunk-worn sensors were worn by patients with PD, who had been assessed using the MDS-UPDRS and the EQ-5D-5L, for up to one week. Output data were analyzed using three different algorithms: One trained on a publicly available dataset using trunk sensor data and two previously derived from wrist sensor data. Clinical validity was examined by examining correlations of sensor-derived outputs with individual items of the MDS-UPDRS and EQ-5D-5L. Results:For the trunk-worn sensor-derived outputs, the strongest positive correlations were found between output data and axial features such as arising from a chair, posture, and body bradykinesia and aspects of daily functioning on the MDS-UPDRS Part II and health-related quality of life (EQ-5D-5L domain) scores. For the wrist-worn sensor-derived outputs, the strongest positive correlations were seen between output data and postural tremor, rest tremor amplitude, and ability to undertake hobbies. Outputs from both body locations were correlated with MDS-UPDRS II and EQ-5D-5L scores (r > 0.7). In participants who wore both trunk and wrist sensors, percentage of time spent in different activities was similar between trunk- and wrist-worn devices, except for time spent "Lying down" derived from the trunk-worn sensor compared to time spent "Sleeping" derived from the wrist-worn sensor algorithm. Conclusion:These data provide preliminary evidence for the clinical validity of single sensor assessments as measures of severity of motor features and motor functioning in patients with PD for use in clinical trials and practice. The results should be confirmed in large and more diverse populations and expanded to include other assessment methods such as laboratory-based motor measurements.