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Introduction: The PRIME-UK randomised controlled trial (RCT) aims to establish whether a model of care that seeks to be proactive, integrated and empower participants, caregivers and healthcare professionals can improve outcomes in people with parkinsonism. Given that this intervention is novel and complex, understanding whether and how the intervention will be acceptable, implementable, cost-effective and scalable across contexts are key questions beyond that of whether 'it works'. We describe an embedded process evaluation to answer these questions, which aims to support interpretation of the trial results, refinement of the intervention and support future scaling of the PRIME-Parkinson model of care., Methods and Analysis: A mixed-methods approach will be used to collect data across four process evaluation domains: implementation, mechanism of change, acceptability and context. Quantitative data will be collected prospectively from all participants and analysed descriptively with exploratory tests of relationships as power allows. Qualitative data will be collected through semistructured interviews with a purposively sampled subpopulation of participants, caregivers and staff members as well as case studies where relevant. Interview transcripts will be analysed thematically using interpretive qualitative analysis. Synthesis of quantitative and qualitative data will also be performed to draw conclusions., Ethics and Dissemination: The quantitative data will be collected as part of the main PRIME-UK RCT which was been granted NHS REC approval (21/LO/0387) on 27 July 2021. The qualitative data will be collected as part of a substudy, 'PRIME-Qual', which was granted NHS REC approval (21/LO/0388) on 14 July 2021. The mixed-methods process evaluation will be published after the conclusion of the trial in addition to the main trial findings., Trial Registration Number: NCT05127057., Competing Interests: Competing interests: KL is in receipt of PhD fellowship funding from The Gatsby Foundation and funding from Parkinson’s UK. ET is funded by a National Institute for Health and Care Research Academic Clinical Lectureship and has received a speaker honorarium from the Neurology Academy. HB and SR are partly funded by National Institute for Health and Care Research Applied Research Collaboration West (NIHR ARC West) and The Gatsby Foundation. EJH is HEFCE funded by University of Bristol for her academic work and has received research funding from the National Institute of Health Research (NIHR), The British Geriatrics Society, The Gatsby Foundation, The Alzheimer’s Society, Royal Osteoporosis Society, The Dunhill Society, Parkinson's UK. She has received travel support, honoraria and/or sat on advisory boards for Kyowa Kirin; Abbvie; Luye; the CME institute, Ever, Simbec Orion, the Neurology Academy and Bial. YB-S is partly funded by National Institute for Health and Care Research Applied Research Collaboration West (NIHR ARC West) and University of Bristol and has received funding from Parkinson’s UK, Royal Osteoporosis Society, MRC, HQIP, Templeton Foundation, Versus Arthritis, Wellcome Trust, National Institute of Health Research, Gatsby Foundation. JK and SS have no conflicts of interest. FL is funded by the High Value Nutrition National Science Challenge, New Zealand, Health Research Council, New Zealand and the University of Auckland, New Zealand. This research was supported by the National Institute for Health and Care Research Applied Research Collaboration West (NIHR ARC West)., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Introduction: Gastrointestinal (GI) symptoms are some of the most common non-motor symptoms in Parkinson's. Weight is a nutritional metric and can be affected by dysfunction of the gastrointestinal (GI) tract. This study aims to explore the change in trajectory of body mass index (BMI) in individuals with Parkinson's over the course of the disease including the prodromal and post-diagnostic periods., Methods: This was a retrospective longitudinal study of data from participants from the PRIME Parkinson UK cross-sectional study. Participants were included if they had had one or more weights and height recorded in the primary care electronic health record., Results: 287 patients were initially included but only 234 could be included in the analysis of BMI trajectory. Using a piecewise linear mixed model, we determined that there was a 'change point' in BMI trajectory. This occurred on average 3.73 years after diagnosis, when the mean BMI was 26.4 kg/m 2 . Prior to this change point, the estimated mean rate of change in BMI was -0.09 kg/m 2 (95 % credible interval -0.20,0.00 kg/m 2 ) per year. However, after the change point, we observed a more accelerated decline in BMI, with an estimated mean rate of change of -0.34 kg/m 2 (95 % credible interval -0.70,-0.07 kg/m 2 ) per year., Conclusion: There was a modest weight loss trajectory in the pre-diagnostic period consistent with clinically stable weight. However, after several years, post-diagnosis BMI loss became more marked. In clinical practice interventions could be targeted at this time point to optimize and maintain nutritional intake., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. M Lawton received fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A sustainable pandemic preparedness strategy is essential to ensure equitable access to healthcare for individuals with neurodegenerative diseases. Moreover, it is vital to provide clinicians and researchers in the neurodegenerative disease fields with resources and infrastructure to ensure continuity of their work during a (health) crisis., Methods: We established an international collaboration between researchers, clinicians, and patient representatives from the Netherlands, Poland, and the United Kingdom. We co-created a pandemic preparedness plan primarily informed by examples from those affected by or working in the field of Parkinson's disease, with potential application to other neurodegenerative diseases or the general population. This plan builds upon insights and experiences from four population-based studies during the COVID-19 pandemic. Between March and November 2023, we organised two hybrid meetings in Bristol (United Kingdom) and Rotterdam (the Netherlands), and two online meetings., Results: Research recommendations included three core factors in questionnaire design during health crises: 1) using existing, validated questions, 2) questionnaire adaptability and flexibility, and 3) testing within and outside the research group. Additionally, we addressed burden of participation, and we advocated for robust data sharing practices, underlining the importance of regulatory measures extending beyond the COVID-19 pandemic. We also shared clinical perspectives, including strategies to mitigate social isolation; challenges in virtual versus in-person consultations; and systemic changes to recognise and prevent moral injury in healthcare professionals., Conclusion: In this pandemic preparedness plan, we provide research and clinical recommendations tailored to the field of Parkinson's disease, with broader relevance to other neurodegenerative diseases and the general population. This establishes an essential framework for setting up new studies and safeguarding research and clinical practices when a new pandemic or other (health) crisis emerges., Competing Interests: Declarations. Ethics approval and consent to participate: The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare, and Sport (Population Screening Act WBO, license number 1071272–159521-PG). PRIME-XS was approved by the London—Brighton & Sussex Research Ethics Committee (REC reference 20/LO/0890). PRIME-NL has been reviewed by the ethics committee of the Radboud University Nijmegen Medical Centre on the basis of the Dutch Code of conduct for health research, the Dutch Code of conduct for responsible use, the Dutch Personal Data Protection Act and the Medical Treatment Agreement Act. The ethics committee has passed a positive judgment on the study. The Bialystok PLUS Study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Bioethical Committee of Medical University of Bialystok, protocol code: APK.002.346.2020. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: People with Parkinson's Disease (PwP) have a higher rate of hospitalisation compared to the general population. Little is known about the impact of having a co-resident and their health on hospitalisation rates of PwP., Methods: We utilised Clinical Practice Research Datalink (CPRD) GOLD data (2010-2015) to identify PwP and co-residents. We classed either the fittest or youngest adult as the primary caregiver in each household. Caregiver health was classified by the Cambridge Multimorbidity Score (CMS), primary care utilisation and prescriptions. We calculated the hospitalisation (elective, emergency) incidence rate ratios (IRRs) for PwP who lived alone compared to those with a caregiver using negative binomial regression, and whether worse caregiver health predicted higher risk of admissions., Results: We identified 3254 PwP and 4007 family members. PwP who lived alone were less likely to have an elective admission (0.79; 95 % CI 0.69-0.91) and more likely to have an emergency admission (1.40; 95 % CI 1.70-1.54). Worse caregiver health, as measured by the CMS, was associated with an increased risk of emergency admission (IRR 1.35; 95 % CI 1.17-1.57), but this attenuated and was consistent with chance in the fully adjusted model (1.04; 95 % CI 0.95-1.13). No strong associations were seen between caregiver health and elective admissions., Conclusion: PwP who live alone are at increased risk of emergency and less likely to have elective hospital admissions. It is important that health care providers support such people and ensure they receive equitable access to the potential benefits of elective procedures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Emily Henderson reports financial support was provided by Gatsby Charitable Foundation. Yoav Ben-Shlomo reports financial support was provided by Parkinson's UK. Yoav Ben-Shlomo reports financial support was provided by Royal Osteoporosis Society. Yoav Ben-Shlomo reports financial support was provided by UKRIMedical Research Council. Yoav Ben-Shlomo reports financial support was provided by Healthcare Quality Improvement Partnership. Yoav Ben-Shlomo reports financial support was provided by John Templeton Foundation. Yoav Ben-Shlomo reports financial support was provided by Wellcome Trust. YBS has received consultancy payment from Human Centric DD LTD and Parkinson's UK both of which are unrelated to this piece of research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Emma Tenison reports financial support was provided by Gatsby Charitable Foundation. Emma Tenison reports a relationship with Royal United Hospitals Bath NHS Foundation Trust that includes: employment. Emma Tenison reports a relationship with The Neurology Academy that includes: speaking and lecture fees. Emma Tenison reports a relationship with University of Bristol that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time., Objectives: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these., Methods: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters., Results: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01)., Conclusion: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid., (© 2024 International Parkinson and Movement Disorder Society.)

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., (© 2024. The Author(s).)

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.

Introduction: The PRIME-NL study prospectively evaluates a new integrated and personalized care model for people with parkinsonism, including Parkinson's disease, in a selected region (PRIME) in the Netherlands. We address the generalizability and sources of selection and confounding bias of the PRIME-NL study by examining baseline and 1-year compliance data., Methods: First, we assessed regional baseline differences between the PRIME and the usual care (UC) region using healthcare claims data of almost all people with Parkinson's disease in the Netherlands (the source population). Second, we compared our questionnaire sample to the source population to determine generalizability. Third, we investigated sources of bias by comparing the PRIME and UC questionnaire sample on baseline characteristics and 1-year compliance., Results: Baseline characteristics were similar in the PRIME (n = 1430) and UC (n = 26,250) source populations. The combined questionnaire sample (n = 920) was somewhat younger and had a slightly longer disease duration than the combined source population. Compared to the questionnaire sample in the PRIME region, the UC questionnaire sample was slightly younger, had better cognition, had a longer disease duration, had a higher educational attainment and consumed more alcohol. 1-year compliance of the questionnaire sample was higher in the UC region (96%) than in the PRIME region (92%)., Conclusion: The generalizability of the PRIME-NL study seems to be good, yet we found evidence of some selection bias. This selection bias necessitates the use of advanced statistical methods for the final evaluation of PRIME-NL, such as inverse probability weighting or propensity score matching. The PRIME-NL study provides a unique window into the validity of a large-scale care evaluation for people with a chronic disease, in this case parkinsonism., (© 2024. The Author(s).)

Background: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied., Objectives: To quantify the presence, severity, impact and associated factors for motor complications in PD., Methods: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms., Results: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years)., Conclusions: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications., (© 2024 International Parkinson and Movement Disorder Society.)

Background and Objectives: People with parkinsonism who are older, living in a care home, with frailty, multimorbidity or impaired capacity to consent are under-represented in research, limiting its generalisability. We aimed to evaluate more inclusive recruitment strategies., Methods: From one UK centre, we invited people with parkinsonism to participate in a cross-sectional study. Postal invitations were followed by telephone reminders and additional support to facilitate participation. Personal consultees provided information on the views regarding research participation of adults with impaired capacity. These approaches were evaluated: (i) using external data from the Parkinson's Real World Impact assesSMent (PRISM) study and Clinical Practice Research Datalink (CPRD), a sample of all cases in UK primary care, and (ii) comparing those recruited with or without intensive engagement., Results: We approached 1,032 eligible patients, of whom 542 (53%) consented and 477 (46%) returned questionnaires. The gender ratio in PRIME-UK (65% male) closely matched CPRD (61% male), unlike in the PRISM sample (46%). Mean age of PRIME participants was 75.9 (SD 8.5) years, compared to 75.3 (9.5) and 65.4 (8.9) years for CPRD and PRISM, respectively. More intensive engagement enhanced recruitment of women (13.3%; 95% CI 3.8, 22.9%; P = 0.005), care home residents (6.2%; 1.1, 11.2%; P = 0.004), patients diagnosed with atypical parkinsonism (13.7%; 5.4, 19.9%; P < 0.001), and those with a higher frailty score (mean score 0.2, 0.1, 0.2; P < 0.001)., Conclusions: These recruitment strategies resulted in a less biased and more representative sample, with greater inclusion of older people with more complex parkinsonism., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

The epidemiology of Parkinson's disease shows marked variations in time, geography, ethnicity, age, and sex. Internationally, prevalence has increased over and above demographic changes. There are several potential reasons for this increase, including the decline in other competing causes of death. Whether incidence is increasing, especially in women or in many low-income and middle-income countries where there is a shortage of high-quality data, is less certain. Parkinson's disease is more common in older people and men, and a variety of environmental factors have been suggested to explain why, including exposure to neurotoxic agents. Within countries, there appear to be ethnic differences in disease risk, although these differences might reflect differential access to health care. The cause of Parkinson's disease is multifactorial, and involves genetic and environmental factors. Both risk factors (eg, pesticides) and protective factors (eg, physical activity and tendency to smoke) have been postulated to have a role in Parkinson's disease, although elucidating causality is complicated by the long prodromal period. Following the establishment of public health strategies to prevent cardiovascular diseases and some cancers, chronic neurodegenerative diseases such as Parkinson's disease and dementia are gaining a deserved higher priority. Multipronged prevention strategies are required that tackle population-based primary prevention, high-risk targeted secondary prevention, and Parkinson's disease-modifying therapies for tertiary prevention. Future international collaborations will be required to triangulate evidence from basic, applied, and epidemiological research, thereby enhancing the understanding and prevention of Parkinson's disease at a global level., Competing Interests: Declaration of interests YB-S receives grant funding from the Wellcome Trust, Medical Research Council, Healthcare Quality Improvement Partnership, Parkinson's UK, Templeton Foundation, Versus Arthritis, Dunhill Medical Trust, National Institute for Health and Care Research, and the Gatsby Foundation; receives book royalties from Oxford University Press and Wiley books; consulting fees from Human Centric DD; is a member of the Trial Steering Committee for the SIMPLIFIED vitamin D randomised clinical trial in chronic kidney disease patients; and is an unpaid member of the Alzheimer's Society grant board and Alzheimer's Research UK strategy committee. SD is a Dutch Veni Award recipient, and receives funding from Parkinson's UK, Parkinson NL, Davis Phinney Foundation, Edmond J Safra Foundation, Michael J Fox Foundation, Parkinson Vereniging, and Parkinson's Foundation. JL-G receives funding from Michael J Fox Foundation, National Institutes of Health (NIH)/National Institute on Aging (NIA), and Alzheimer's Association Research Fellowship to Promote Diversity (AARFD). CM receives funding from Centogene, Canadian Institutes of Health Research, Michael J Fox Foundation, International Parkinson and Movement Disorders Society, and Parkinson's Foundation; receives consulting fees from Neurocrine; and is a board member of the International Parkinson and Movement Disorders Society. MSL receives research support from the Smart Foundation and grant funding from NIH/National Institute of Neurological Disorders and Stroke (NINDS); has received honoraria from American Academy of Neurology and SUNY Downstate Department of Neurology; has received support from BIOGEN for attending a meeting; and is on the data and safety monitoring board (unpaid) for the NeuroNext/NN10 trial. CT receives grant funding from Parkinson Foundation, Michael J Fox Foundation, Gateway, Roche Genentech, Biogen, NIH/NIA, NIH/NINDS, Department of Defense, Parkinson Study Group, VA Merit, Marcus Program in Precision Medicine, and Bioelectron Technology Corporation; receives consulting fees from CNS Ratings and Grey Matter; has received honoraria from Guidemark Health, American Academy of Neurology, Druker Lecture, Beth Israel Deaconess, Boston, Cynthia L Comella Lecture, Rush University Medical Center, and Tauba Pasik and Pedro Pasik Endowed Lecture in Neurology; has received funding to attend a meeting from Neurocrine; participated on a data and safety monitoring board or advisory board for Acadia, Northwestern University Partners, Harvard University, Neurocrine, Lundbeck, Cadent, Acorda, Adamas, Amneal, Kyowa Kirin, Jazz/Cavion, and Australia Parkinson's Mission; is a committee member for Linked Clinical Trials/Cure Parkinson's Trust, International Parkinson and Movement Disorders Society–Epidemiology Working Group, Telemedicine Working Group, PanAmerican Section Nominating Committee, and American Academy of Neurology–Scientific Plenary Session Topic Committee, Movement Disorders., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Providing informal care for a person with Parkinson's disease (PD) can be a demanding process affecting several dimensions of a caregiver's life and potentially causing caregiver burden. Despite the emerging literature on caregiver burden in people with PD, little is known about the inter-relationship between quantitative and qualitative findings. Filling this knowledge gap will provide a more holistic approach to develop and design innovations aiming at reducing or even preventing caregiver burden. This study aimed to characterize the determinants of caregiver burden among informal caregivers of persons with PD, in order to facilitate the development of tailored interventions that reduce caregiver burden., Methods: We conducted a cross-sectional study in The Netherlands using a sequential mixed methods approach, entailing a quantitative study of 504 persons with PD and their informal caregivers as well as a qualitative study in a representative subsample of 17 informal caregivers. The quantitative study included a standardized questionnaire of caregiver burden (Zarit Burden Inventory) and patient-related (Beck Depression Inventory, State-Trait Anxiety Inventory, Acceptance of Illness Scale, MDS-Unified Parkinson's Disease Rating Scale part II on motor functions in daily life, Self-assessment Parkinson's Disease Disability Score), caregiver-related (Brief Coping Orientation to Problems Experience Inventory, Caregiver Activation Measurement, Multidimensional Scale of Perceived Social Support) and interpersonal determinants (sociodemographic variables including among others gender, age, education, marital status and working status). The qualitative study consisted of semi-structured interviews. Multivariable regression and thematic analysis were used to analyse quantitative and qualitative data, respectively., Results: A total of 337 caregivers were women (66.9%), and the majority of people with PD were men (N = 321, 63.7%). The mean age of persons with PD was 69.9 (standard deviation [SD] 8.1) years, and the mean disease duration was 7.2 (SD 5.2) years. A total of 366 (72.6%) persons with PD had no active employment. The mean age of informal caregivers was 67.5 (SD 9.2) years. Most informal caregivers were female (66.9%), had no active employment (65.9%) and were the spouse of the person with PD (90.7%). The mean Zarit Burden Inventory score was 15.9 (SD 11.7). The quantitative study showed that a lack of active employment of the person affected by PD was associated with a higher caregiver burden. The qualitative study revealed cognitive decline and psychological or emotional deficits of the person with PD as additional patient-related determinants of higher caregiver burden. The following caregiver-related and interpersonal determinants were associated with higher caregiver burden: low social support (quantitative study), concerns about the future (qualitative study), the caregiving-induced requirement of restrictions in everyday life (qualitative study), changes in the relationship with the person with PD (qualitative study) and a problem-focused or avoidant coping style (both studies). Integration of both data strands revealed that qualitative findings expanded quantitative findings by (1) distinguishing between the impact of the relationship with the person with PD and the relationship with others on perceived social support, (2) revealing the impact of non-motor symptoms next to motor symptoms and (3) revealing the following additional factors impacting caregiver burden: concern about the future, perceived restrictions and limitations in performing daily activities due to the disease, and negative feelings and emotional well-being. Qualitative findings were discordant with the quantitative finding demonstrating that problem-focused was associated with a higher caregiver burden. Factor analyses showed three sub-dimensions of the Zarit Burden Inventory: (i) role intensity and resource strain, (2) social restriction and anger and (3) self-criticism. Quantitative analysis showed that avoidant coping was a determinant for all three subscales, whereas problem-solved coping and perceived social support were significant predictors on two subscales, role intensity and resource strain and self-criticism., Conclusions: The burden experienced by informal caregivers of persons with PD is determined by a complex interplay of patient-related, caregiver-related and interpersonal characteristics. Our study highlights the utility of a mixed-methods approach to unravel the multidimensional burden experienced by informal caregivers of persons with chronic disease. We also offer starting points for the development of a tailored supportive approach for caregivers., (© 2023. The Author(s).)

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson's disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson's disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson's disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson's disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson's disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson's disease dementia [hazard ratio = 2.41 (1.94-3.00), P = 2.32 × 10-15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17-4.81), P = 7.07 × 10-09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21-3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson's disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson's disease dementia compared to Parkinson's disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson's disease dementia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: People living with Parkinson's disease experience progressive motor and non-motor symptoms, which negatively impact on health-related quality of life and can lead to an increased risk of hospitalisation. It is increasingly recognised that the current care models are not suitable for the needs of people with parkinsonism whose care needs evolve and change as the disease progresses. This trial aims to evaluate whether a complex and innovative model of integrated care will increase an individual's ability to achieve their personal goals, have a positive impact on health and symptom burden and be more cost-effective when compared with usual care., Methods: This is a single-centre, randomised controlled trial where people with parkinsonism and their informal caregivers are randomised into one of two groups: either PRIME Parkinson multi-component model of care or usual care. Adults ≥18 years with a diagnosis of parkinsonism, able to provide informed consent or the availability of a close friend or relative to act as a personal consultee if capacity to do so is absent and living in the trial geographical area are eligible. Up to three caregivers per patient can also take part, must be ≥18 years, provide informal, unpaid care and able to give informed consent. The primary outcome measure is goal attainment, as measured using the Bangor Goal Setting Interview. The duration of enrolment is 24 months. The total recruitment target is n=214, and the main analyses will be intention to treat., Discussion: This trial tests whether a novel model of care improves health and disease-related metrics including goal attainment and decreases hospitalisations whilst being more cost-effective than the current usual care. Subject to successful implementation of this intervention within one centre, the PRIME Parkinson model of care could then be evaluated within a cluster-randomised trial at multiple centres., (© 2023. The Author(s).)

Background: Specialized versus generic physiotherapy (PT) reduces Parkinson's disease (PD)-related complications. It is unclear (1) whether other specialized allied heath disciplines, including occupational therapy (OT) and speech and language therapy (S&LT), also reduce complications; (2) whether there is a synergistic effect among multiple specialized disciplines; and (3) whether each allied health discipline prevents specific complications., Objectives: To longitudinally assessed whether the level of expertise (specialized vs. generic training) of PT, OT, and S&LT was associated with the incidence rate of PD-related complications., Methods: We used claims data of all insured persons with PD in the Netherlands between January 1, 2010, and December 31, 2018. ParkinsonNet-trained therapists were classified as specialized, and other therapists as generic. We used mixed-effects Poisson regression models to estimate rate ratios adjusting for sociodemographic and clinical characteristics., Results: The population of 51,464 persons with PD (mean age, 72.4 years; standard deviation 9.8) sustained 10,525 PD-related complications during follow-up (median 3.3 years). Specialized PT was associated with fewer complications (incidence rate ratio [IRR] of specialized versus generic = 0.79; 95% confidence interval, [0.74-0.83]; P < 0.0001), as was specialized OT (IRR = 0.88 [0.77-0.99]; P = 0.03). We found a trend of an association between specialized S&LT and a lower rate of PD-related complications (IRR = 0.88 [0.74-1.04]; P = 0.18). The inverse association of specialized OT persisted in the stratum, which also received specialized PT (IRR = 0.62 [0.42-0.90]; P = 0.001). The strongest inverse association of PT was seen with orthopedic injuries (IRR = 0.78 [0.73-0.82]; P < 0.0001) and of S&LT with pneumonia (IRR = 0.70 [0.53-0.93]; P = 0.03)., Conclusions: These findings support a wider introduction of specialized allied health therapy expertise in PD care and conceivably for other medical conditions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Bladder symptoms are common in Parkinson disease (PD), affecting quality of life. Medications commonly used such as antimuscarinics can cause frequently intolerable side effects, and therefore, new, better tolerated approaches are needed. Neuromodulation techniques have an established role in urologic disorders; these techniques include tibial nerve stimulation (TNS) and sacral neuromodulation (SNM), which are localized therapies lacking the side effects associated with medication., Objectives: This study aimed to undertake a systematic review of the literature reporting the use of neuromodulation techniques for the treatment of bladder symptoms in PD and related conditions., Materials and Methods: A systematic search of data bases was conducted including MEDLINE, CENTRAL, and Web of Science. Studies were required to present specific outcomes for individuals with PD for neuromodulation interventions., Results: Ten primary studies were identified concerning detailed outcomes of neuromodulation on bladder symptoms in PD, including seven for TNS, one for SNM, and one using transcranial magnetic stimulation (TMS). Two further mixed cohort studies documented minimal data on individuals with PD. All studies demonstrated benefit in a range of outcome measures following neuromodulation. Two randomized sham-controlled studies were carried out using TNS, with one clearly demonstrating superiority over sham, although difficulties with achieving believable yet ineffective sham treatment are highlighted. Further studies reported limited, uncontrolled outcomes of SNM in patients with PD, demonstrating benefit., Conclusions: Evidence from case series suggests benefit from TNS in PD, with limited literature on SNM or TMS. Placebo effect from neuromodulation is a concern, and only limited controlled data exist. Future well-designed and sham-controlled studies need to be completed to provide definitive data on the benefit of neuromodulation in PD. Definitively proving the utility of a neuromodulation modality will allow better treatment of bladder symptoms without the need for pharmacologic measures that cause side effects., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Background: There is large individual variation in both clinical presentation and progression between Parkinson's disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting., Methods: Replicating across three large Parkinson's cohorts (Oxford Discovery cohort (n = 842)/Tracking UK Parkinson's study (n = 1807) and Parkinson's Progression Markers Initiative (n = 472)) with clinical observational measures collected longitudinally over 5-10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors ("phenotypic axes")., Results: When applied to disease severity at diagnosis, the most influential of three phenotypic axes "Axis 1" was characterised by severe non-tremor motor phenotype, anxiety and depression at diagnosis, accompanied by faster progression in cognitive function measures. Axis 1 was associated with increased genetic risk of Alzheimer's disease and reduced CSF Aβ1-42 levels. As observed previously for Alzheimer's disease genetic risk, and in contrast to Parkinson's disease genetic risk, the loci influencing Axis 1 were associated with microglia-expressed genes implicating neuroinflammation. When applied to measures of disease progression for each individual, integration of Alzheimer's disease genetic loci haplotypes improved the accuracy of progression modelling, while integrating Parkinson's disease genetics did not., Conclusions: We identify universal axes of Parkinson's disease phenotypic variation which reveal that Parkinson's patients with high concomitant genetic risk for Alzheimer's disease are more likely to present with severe motor and non-motor features at baseline and progress more rapidly to early dementia., (© 2022. The Author(s).)

Background: Bladder symptoms are common in Parkinson's disease (PD), affecting half of all individuals. These have significant impact on quality of life as well as implications for morbidity, contributing to falls and hospital admission. The treatment of bladder symptoms can be complicated by the tendency to side-effects in people with PD including cognitive impairment and gait instability with anti-muscarinics. The development of new, better treatments is therefore warranted. Tibial nerve stimulation is a form of neuromodulation demonstrated to improve overactive bladder symptoms in non-neurogenic cohorts. Previously requiring hospital attendance, we aim to explore the use of this intervention using a simple device that can be used by patients at home., Methods: STRIPE is a phase II randomised control trial of tibial nerve stimulation delivered by the Geko™ device, a small, self-adhesive neuromuscular stimulation device currently used for thromboembolism prophylaxis post-surgery. Active tibial nerve stimulation will be compared to sham stimulation, with participants blinded to treatment allocation and undertaking outcome assessment whilst still blinded. Participants will be asked to self-administer stimulation at home twice per week, for 30 min per session, over the course of 3 months. Primary outcome measure will be the International Consultation on Incontinence Overactive Bladder Questionnaire (OAB) at week 12. Secondary outcomes will include pre- and post-intervention bladder diary (frequency, urgency episodes, nocturia), patient perception of global change, bowel function and bladder-related quality of life. Participants will be recruited from the Proactive Integrated Management and Empowerment (PRIME) cross-sectional trial in which participants have been screened for bladder symptoms and invited to take part, as well as clinician referral from around the region., Discussion: This trial will involve a randomised control trial of a novel and easy to use method of delivering tibial nerve stimulation for PD in the patient's own home. This may potentially have huge benefit, avoiding the problems with side effects that can be seen with anti-muscarinics and providing a new potential modality of treatment., Trial Registration: ISRCTN11484954. Registered on 22 June 2021., (© 2022. The Author(s).)

Background: Type 2 diabetes (T2DM) is an established risk factor for developing Parkinson's disease (PD), but its effect on disease progression is not well understood., Objective: The aim of this study was to investigate the influence of T2DM on aspects of disease progression in PD., Methods: We analyzed data from the Tracking Parkinson's study to examine the effects of comorbid T2DM on PD progression and quality of life by comparing symptom severity scores assessing a range of motor and nonmotor symptoms., Results: We identified 167 (8.7%) patients with PD and T2DM (PD + T2DM) and 1763 (91.3%) patients with PD without T2DM (PD). After controlling for confounders, patients with T2DM had more severe motor symptoms, as assessed by Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (25.8 [0.9] vs. 22.5 [0.3] P = 0.002), and nonmotor symptoms, as assessed by Non-Motor Symptoms Scale total (38.4 [2.5] vs. 31.8 [0.7] P < 0.001), and were significantly more likely to report loss of independence (odds ratio, 2.08; 95% confidence interval [CI]: 1.34-3.25; P = 0.001) and depression (odds ratio, 1.62; CI: 1.10-2.39; P = 0.015). Furthermore, over time, patients with T2DM had significantly faster motor symptom progression (P = 0.012), developed worse mood symptoms (P = 0.041), and were more likely to develop substantial gait impairment (hazard ratio, 1.55; CI: 1.07-2.23; P = 0.020) and mild cognitive impairment (hazard ratio, 1.7; CI: 1.24-2.51; P = 0.002) compared with the PD group., Conclusions: In the largest study to date, T2DM is associated with faster disease progression in Parkinson's, highlighting an interaction between these two diseases. Because it is a potentially modifiable metabolic state, with multiple peripheral and central targets for intervention, it may represent a target for alleviating parkinsonian symptoms and slowing progression to disability and dementia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: An unmet need remains for sensitive outcome measures in neuroprotective trials. The study aims to determine whether a composite clinical motor score, combining the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III motor examination score, Purdue Pegboard Test, and Timed Up and Go, provides greater sensitivity in detecting motor change in early disease than the MDS-UPDRS III alone., Methods: The Oxford Discovery longitudinal cohort study involves individuals with isolated rapid eye movement sleep behaviour disorder (iRBD) (n=272, confirmed polysomnographically, median follow-up: 1.6 years), idiopathic Parkinson's disease (PD) (n=909, median follow-up: 3.5 years, baseline: <3.5 years disease duration) and controls (n=316, age-matched and sex-matched, without a first-degree family history of PD). Motor and non-motor assessments were performed at each in-person visit., Results: Compared with the MDS-UPDRS III, the composite clinical motor score demonstrated a wider score distribution in iRBD and controls, lower coefficient of variation (37% vs 67%), and higher correlation coefficients with self-reported measures of motor severity (0.65 vs 0.61) and overall health status (-0.40 vs -0.33). Greater score range in mild to moderate PD, higher magnitude of longitudinal change in iRBD and longitudinal score linearity suggest better sensitivity in detecting subtle motor change. The composite clinical motor score was more accurate than the MDS-UPDRS III in predicting clinical outcomes, requiring 64% fewer participants with PD and 51% fewer participants with iRBD in sample size estimations for a hypothetical 18-month placebo-controlled clinical trial., Conclusion: The composite clinical motor score may offer greater consistency and sensitivity in detecting change than the MDS-UPDRS III., Competing Interests: Competing interests: CL was funded by the NIHR Oxford BRC. TB was funded by the Wellcome Trust Doctoral Training Fellowship. TQ is currently a short term Consultant for Jazz Pharmaceuticals and a CI for an NIHR grant for a therapeutic trial in OSA., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson's disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson's disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson's disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson's disease clinical scores (e.g. Unified Parkinson's Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson's disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson's disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson's disease and may provide a way to distinguish variations within Parkinson's disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson's disease. The assay distinguished multiple system atrophy patients from Parkinson's disease patients and in contrast to Parkinson's disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Parkinson's disease (PD) comorbid with rapid eye movement sleep behavior disorder (RBD) may show more severe motor and nonmotor symptoms, suggesting a distinct PD subtype., Objective: The aim of this study was to investigate the impact of RBD on the longitudinal change of motor and nonmotor symptoms in patients with PD., Methods: Patients with early PD (diagnosed within 3.5 years) recruited from 2010 to 2019 were followed every 18 months in the Oxford Parkinson's Disease Centre Discovery cohort. At each visit, we used standard questionnaires and measurements to assess demographic features and motor and nonmotor symptoms (including RBD, daytime sleepiness, mood, autonomic symptoms, cognition, and olfaction). Data were analyzed with linear mixed effects and Cox regression models. Possible RBD (pRBD) was longitudinally determined according to RBD Screening Questionnaire scores., Results: A total of 923 patients were recruited (mean age: 67.1 ± 9.59 years; 35.9% female), and 788 had follow-up assessment(s) (mean: 4.8 ± 1.98 years, range: 1.3-8.3). Among them, 33.3% were identified as pRBD (PD + pRBD). Patients with PD + pRBD had more severe baseline symptoms and showed faster progression on Movement Disorder Society-Unified Parkinson's Disease Rating Scale parts I and III, Purdue Pegboard test, and Beck Depression Inventory scores. Moreover, PD + pRBD was associated with an increased level of risk for mild cognitive impairment (hazard ratio [HR] = 1.36, 95% confidence interval [CI]: 1.01-1.83), freezing of gait (HR = 1.42, 95% CI: 1.10-1.86), and frequent falling (HR = 1.62, 95% CI: 1.02-2.60)., Conclusions: Patients with PD + pRBD progress faster on motor, mood, and cognitive symptoms, confirming a more aggressive PD subtype that can be identified at baseline and has major clinical implications. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background: Falls are a common complication of Parkinson's disease. There is a need for new therapeutic options to target this debilitating aspect of the disease. Cholinergic deficit has been shown to contribute to both gait and cognitive dysfunction seen in the condition. Potential benefits of using cholinesterase inhibitors were shown during a single centre phase 2 trial. The aim of this trial is to evaluate the effectiveness of a cholinesterase inhibitor on fall rate in people with idiopathic Parkinson's disease., Methods: This is a multi-centre, double-blind, randomised placebo-controlled trial in 600 people with idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 4) with a history of a fall in the past year. Participants will be randomised to two groups, receiving either transdermal rivastigmine or identical placebo for 12 months. The primary outcome is the fall rate over 12 months follow-up. Secondary outcome measures, collected at baseline and 12 months either face-to-face or via remote video/telephone assessments, include gait and balance measures, neuropsychiatric indices, Parkinson's motor and non-motor symptoms, quality of life and cost-effectiveness., Discussion: This trial will establish whether cholinesterase inhibitor therapy is effective in preventing falls in Parkinson's disease. If cost-effective, it will alter current management guidelines by offering a new therapeutic option in this high-risk population., Trial Registration: REC reference: 19/SW/0043. EudraCT: 2018-003219-23., Iscrtn: 41639809 (registered 16/04/2019). ClinicalTrials.gov Identifier: NCT04226248 PROTOCOL AT TIME OF PUBLICATION: Version 7.0, 20th January 2021., (© 2021. The Author(s).)

Objectives: Hyposmia is a common feature of Parkinson's disease (PD), yet there is no standard method to define it. A comparison of four published methods was performed to explore and highlight differences., Materials and Methods: Olfactory testing was performed in 2097 cases of early PD in two prospective studies. Olfaction was assessed using various cut-offs, usually corrected by age and/or gender. Control data were simulated based on the age and gender structure of the PD cases and published normal ranges. Association with age, gender, and disease duration was explored by method and study cohort. Prevalence of hyposmia was compared with the age and gender-matched simulated controls. Between method agreement was measured using Cohen's kappa and Gwet's AC1., Results: Hyposmia was present in between 69.1% and 97.9% of cases in Tracking Parkinson's cases, and between 62.2% and 90.8% of cases in the Parkinson's Progression Marker Initiative, depending on the method. Between-method agreement varied (kappa 0.09-0.80, AC1 0.55-0.86). The absolute difference between PD cases and simulated controls was similar for men and women across methods. Age and male gender were positively associated with hyposmia (p < .001, all methods). Odds of having hyposmia increased with advancing age (OR:1.06, 95% CI:1.03, 1.10, p < .001). Longer disease duration had a negative impact on overall olfactory performance., Conclusions: Different definitions of hyposmia give different results using the same dataset. A standardized definition of hyposmia in PD is required, adjusting for age and gender, to account for the background decline in olfactory performance with ageing, especially in men., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Culminating evidence shows that current care does not optimally meet the needs of persons with parkinsonism, their carers and healthcare professionals. Recently, a new model of care was developed to address the limitations of usual care: Proactive and Integrated Management and Empowerment in Parkinson's Disease (PRIME Parkinson). From 2021 onwards, PRIME Parkinson care will replace usual care in a well-defined region in The Netherlands. The utility of PRIME Parkinson care will be evaluated on a single primary endpoint (parkinsonism-related complications), which reflects the health of people with parkinsonism. Furthermore, several secondary endpoints will be measured for four dimensions: health, patient and carer experience, healthcare professional experience, and cost of healthcare. The reference will be usual care, which will be continued in other regions in The Netherlands., Methods: This is a prospective observational study which will run from January 1, 2020 until December 31, 2023. Before the new model of care will replace the usual care in the PRIME Parkinson care region all baseline assessments will take place. Outcomes will be informed by two data sources. We will use healthcare claims-based data to evaluate the primary endpoint, and costs of healthcare, in all persons with parkinsonism receiving PRIME Parkinson care (estimated number: 2,000) and all persons with parkinsonism receiving usual care in the other parts of The Netherlands (estimated number: 48,000). We will also evaluate secondary endpoints by performing annual questionnaire-based assessments. These assessments will be administered to a subsample across both regions (estimated numbers: 1,200 persons with parkinsonism, 600 carers and 250 healthcare professionals)., Discussion: This prospective cohort study will evaluate the utility of a novel integrated model of care for persons with parkinsonism in The Netherlands. We anticipate that the results of this study will also provide insight for the delivery of care to persons with parkinsonism in other regions and may inform the design of a similar model for other chronic health conditions., (© 2021. The Author(s).)

Objective: We sought to identify an abbreviated test of impaired olfaction amenable for use in busy clinical environments in prodromal (isolated REM sleep behavior disorder [iRBD]) and manifest Parkinson disease (PD)., Methods: Eight hundred ninety individuals with PD and 313 controls in the Discovery cohort study underwent Sniffin' Stick odor identification assessment. Random forests were initially trained to distinguish individuals with poor (functional anosmia/hyposmia) and good (normosmia/super-smeller) smell ability using all 16 Sniffin' Sticks. Models were retrained using the top 3 sticks ranked by order of predictor importance. One randomly selected 3-stick model was tested in a second independent PD dataset (n = 452) and in 2 iRBD datasets (Discovery n = 241, Marburg n = 37) before being compared to previously described abbreviated Sniffin' Stick combinations., Results: In differentiating poor from good smell ability, the overall area under the curve (AUC) value associated with the top 3 sticks (anise/licorice/banana) was 0.95 in the Development dataset (sensitivity 90%, specificity 92%, positive predictive value 92%, negative predictive value 90%). Internal and external validation confirmed AUCs ≥0.90. The combination of the 3-stick model determined poor smell, and an RBD screening questionnaire score of ≥5 separated those with iRBD from controls with a sensitivity, specificity, positive predictive value, and negative predictive value of 65%, 100%, 100%, and 30%., Conclusions: Our 3-Sniffin'-Stick model holds potential utility as a brief screening test in the stratification of individuals with PD and iRBD according to olfactory dysfunction., Classification of Evidence: This study provides Class III evidence that a 3-Sniffin'-Stick model distinguishes individuals with poor and good smell ability and can be used to screen for individuals with iRBD., (© 2021 American Academy of Neurology.)

Background: There are currently no treatments that stop or slow the progression of Parkinson's disease (PD). Case-control genome-wide association studies have identified variants associated with disease risk, but not progression. The objective of the current study was to identify genetic variants associated with PD progression., Methods: We analyzed 3 large longitudinal cohorts: Tracking Parkinson's, Oxford Discovery, and the Parkinson's Progression Markers Initiative. We included clinical data for 3364 patients with 12,144 observations (mean follow-up 4.2 years). We used a new method in PD, following a similar approach in Huntington's disease, in which we combined multiple assessments using a principal components analysis to derive scores for composite, motor, and cognitive progression. These scores were analyzed in linear regression in genome-wide association studies. We also performed a targeted analysis of the 90 PD risk loci from the latest case-control meta-analysis., Results: There was no overlap between variants associated with PD risk, from case-control studies, and PD age at onset versus PD progression. The APOE ε4 tagging variant, rs429358, was significantly associated with composite and cognitive progression in PD. Conditional analysis revealed several independent signals in the APOE locus for cognitive progression. No single variants were associated with motor progression. However, in gene-based analysis, ATP8B2, a phospholipid transporter related to vesicle formation, was nominally associated with motor progression (P = 5.3 × 10 -6 )., Conclusions: We provide early evidence that this new method in PD improves measurement of symptom progression. We show that the APOE ε4 allele drives progressive cognitive impairment in PD. Replication of this method and results in independent cohorts are needed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: To guide decision-making about driving ability, some patients with Parkinson's disease (PD) undergo specialist driving assessment. However, decisions about driving safety in most patients need to be made without this definitive test. There is no consensus on what predicts unsafe driving in PD nor a validated prediction tool to guide clinician decision-making and the need to refer for further assessment., Objectives: To describe the characteristics of patients with PD assessed at a Driving Mobility Centre and investigate factors that predict driving assessment outcome., Methods: Retrospective cohort study of patients with PD assessed between 2012 and 2016. Descriptive analyses and logistic models to determine factors predicting a negative outcome., Results: There were 86 assessments of patients with PD. The mean age was 70 years (±9.2), 86% were male, median disease duration 7 years (interquartile range 5-12.5 years) and 59% were referred by the Driver and Vehicle Licensing Agency. In total, 62% had a negative 'not drive' outcome. The Rookwood Driving Battery (RDB), depth of vision deficit, usual driving frequency, age, duration license held and response time were all predictors in univariable analysis. The RDB was the best predictor of assessment failure, conditional on other variables in a backward stepwise model (odds ratio 1.29; 95% confidence interval 1.05, 1.60; P = 0.015)., Conclusions: This is the first study to describe patients with PD undergoing driving assessments in the UK. In this population, RDB performance was the best predictor of outcome. Future prospective studies are required to better determine predictors of driving ability to guide development of prediction tools for implementation into clinical practice., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Predicting prognosis in Parkinson's disease (PD) has important implications for individual prognostication and clinical trials design and targeting novel treatments. Blood biomarkers could help in this endeavor., Methods: We identified 4 blood biomarkers that might predict prognosis: apolipoprotein A1, C-reactive protein, uric acid and vitamin D. These biomarkers were measured in baseline serum from 624 Parkinson's disease subjects (median disease duration, 1.0 years; interquartile range, 0.5-2.0) from the Oxford Discovery prospective cohort. We compared these biomarkers against PD subtypes derived from clinical features in the baseline cohort using data-driven approaches. We used multilevel models with MDS-UPDRS parts I, II, and III and Montreal Cognitive Assessment as outcomes to test whether the biomarkers predicted subsequent progression in motor and nonmotor domains. We compared the biomarkers against age of PD onset and age at diagnosis. The q value, a false-discovery rate alternative to P values, was calculated as an adjustment for multiple comparisons., Results: Apolipoprotein A1 and C-reactive protein levels differed across our PD subtypes, with severe motor disease phenotype, poor psychological well-being, and poor sleep subtype having reduced apolipoprotein A1 and higher C-reactive protein levels. Reduced apolipoprotein A1, higher C-reactive protein, and reduced vitamin D were associated with worse baseline activities of daily living (MDS-UPDRS II)., Conclusion: Baseline clinical subtyping identified a pro-inflammatory biomarker profile significantly associated with a severe motor/nonmotor disease phenotype, lending biological validity to subtyping approaches. No blood biomarker predicted motor or nonmotor prognosis. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Background: Freezing of gait (FOG) is a common symptom of Parkinson's disease (PD) which can result in falls and fall related injuries, poor quality of life and reduced functional independence. It is a heterogeneous phenomenon that is difficult to quantify and eludes a unified pathophysiological framework., Objective: Our aim was to document the occurrence and nature of freezing, cognitive stops and stumbles in people with PD during walks with varying cognitive loads and conditions designed to elicit FOG., Methods: 130 people with PD walked under four conditions (normal walking, walking plus easy and hard dual-tasks, and a FOG elicitation condition. Video and accelerometry recordings were examined to document freezes and other gait disruptions., Results: Participants experienced 391 freezes, 97 cognitive stops and 73 stumbles in the trial walks; with total gait disruptions increasing with task complexity. Most freezes in the FOG elicitation condition occurred during turning and approach destination. People who experienced freezing during the walks were more likely to have Postural Instability and Gait Difficulty (PIGD) subtype, longer disease duration and more severe UPDRS part II and part III sub-scores than people who did not freeze. They also took higher doses of levodopa, reported freezing in the past month, more prior falls, had poorer executive function, poorer proprioception, slower reaction time, poorer standing and leaning balance, more depressive symptoms, lower quality of life and greater fear of falling. PD disease duration, reduced controlled leaning balance and poor proprioception were identified as independent and significant determinants of freezing in logistic regression analysis., Conclusion: The multiple motor and cognitive factors identified as being associated with freezing, including poor proprioception and impaired controlled leaning balance provide new insights into this debilitating PD symptom and may contribute to potential new targets for rehabilitation.

Our objective was to define the prevalence and clinical features of genetic Parkinson's disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Unified Parkinson's Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features. Of the 2262 participants recruited to the Tracking Parkinson's study, 424 had young-onset Parkinson's disease (age at onset ≤ 50) and 1799 had late onset Parkinson's disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 'Kompetitive' allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent of patients with age at onset ≤30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to young-onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson's disease. We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson's disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls., Methods: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinson's Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinson's Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations., Results: Data from 921 cases of PD at baseline, 768 cases at 18 months, and 531 cases at 36 months were included, with 21% to 25% screening positive for ICBs at each visit. Interviews of ICB screen-positive individuals revealed that 10% met formal criteria for impulse control disorders (ICD), while 33% had subsyndromal ICD (ICB symptoms without reaching the formal diagnostic criteria for ICD). When these data were combined through the use of multiple imputation, the prevalence of PD-ICB was estimated at 19.1% (95% confidence interval 10.1-28.2). On follow-up, 24% of cases of subsyndromal ICD had developed full symptoms of an ICD. PD-ICD was associated with dopamine agonist use, motor complications, and apathy but not PD-RBD. ICD prevalence in the RBD group (1%) was similar to that in controls (0.7%)., Conclusions: ICBs occur in 19.1% of patients with early PD, many persisting or worsening over time. RBD is not associated with increased ICD risk. Psychosocial drivers, including mood and support networks, affect severity., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: L-dopa responsiveness in Parkinson's disease (PD) varies, but the clinical correlates and significance of this are ill-defined., Methods: Patients were assessed before and after their usual morning L-dopa dose, using the MDS Unified PD Rating Scale Part 3 (MDS UPDRS 3), and rated as definite responders (≥24.5% improvement) or limited responders (<24.5%)., Results: 1007 cases, mean age 66.1 years (SD 9.1) at diagnosis, were assessed 3.4 (SD 0.9) years after diagnosis. The L-dopa response was definite in 614 cases (61.0%), median reduction in MDS UPDRS 3 scores was 42.0%, (IQR 33.3, 53.1), and was limited in 393 cases (39.0%), median reduction in MDS UPDRS 3 scores 11.5% (IQR 4.3, 18.2). Definite responders were younger (66.3 years at study entry, SD 9.3) than limited responders (69.2 years, SD 8.4, p < 0.001). The MDS UPDRS 3 score at study entry in definite responders (21.0, SD 10.5) was significantly lower than in limited responders (24.7, SD 13.4, p < 0.001). The MDS UPDRS 3 increase over 18 months was less in definite responders at 3.0 (SD 10.4), compared to limited responders (6.4, SD 11.0, p < 0.001). The levodopa equivalent daily dose (LEDD) was not significantly different at study entry (definite responders 317 mg, SD 199, vs limited responders 305 mg, SD 191, p = 0.53). However, LEDD was significantly higher at the time of the L-dopa challenge test in definite responders (541 mg, SD 293) compared to limited responders (485 mg, SD 215, p = 0.01). Responsiveness to L-dopa was unaffected by the challenge test dose (p = 0.54)., Conclusions: The main determinants of variation in the L-dopa response in early PD are age and motor severity. A limited L-dopa response is associated with faster motor progression., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: We recently demonstrated that 998 features derived from a simple 7-minute smartphone test could distinguish between controls, people with Parkinson's and people with idiopathic Rapid Eye Movement sleep behavior disorder, with mean sensitivity/specificity values of 84.6-91.9%. Here, we investigate whether the same smartphone features can be used to predict future clinically relevant outcomes in early Parkinson's., Methods: A total of 237 participants with Parkinson's (mean (SD) disease duration 3.5 (2.2) years) in the Oxford Discovery cohort performed smartphone tests in clinic and at home. Each test assessed voice, balance, gait, reaction time, dexterity, rest, and postural tremor. In addition, standard motor, cognitive and functional assessments and questionnaires were administered in clinic. Machine learning algorithms were trained to predict the onset of clinical outcomes provided at the next 18-month follow-up visit using baseline smartphone recordings alone. The accuracy of model predictions was assessed using 10-fold and subject-wise cross validation schemes., Results: Baseline smartphone tests predicted the new onset of falls, freezing, postural instability, cognitive impairment, and functional impairment at 18 months. For all outcome predictions AUC values were greater than 0.90 for 10-fold cross validation using all smartphone features. Using only the 30 most salient features, AUC values greater than 0.75 were obtained., Interpretation: We demonstrate the ability to predict key future clinical outcomes using a simple smartphone test. This work has the potential to introduce individualized predictions to routine care, helping to target interventions to those most likely to benefit, with the aim of improving their outcome., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Objective: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis., Methods: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial., Results: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81)., Conclusions: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Background: Falls are common in Parkinson's disease so any intervention that reduced falls risk would be of value. One potential intervention is the use of cholinesterase inhibitor (ChEi) drugs., Objective: To establish the minimum clinically important difference (MCID) for fall rates to inform the effect estimate for sample size calculations of future clinical trials., Methods: We performed a Delphi study assembling a panel of experts in Parkinson's disease from academic and clinical medicine in order to reach a consensus of opinion. Responses from a panel were summarised and resent to the group, until consensus was reached., Results: 780 clinicians, who had been caring for people with Parkinson's for an average of 14 years, were contacted via three routes. The median (Interquartile range (IQR)) MCID after round 1 was 25% (IQR 20-30%) which equates to the prevention of 5 (IQR 4-6) falls per year. Increasing consensus after round two confirmed the MCID of 25%, narrowing the (IQ) range to 20%-25%. This was unchanged when the panel were shown the number of participants that would need to be recruited to a clinical trial in order to achieve this difference., Conclusions: We have established that an expert panel of PD specialists consider that an intervention that demonstrated a 25% (IQR 20-25%) relative reduction in falls rate would be clinically meaningful. This estimate can be used to help determine the sample size for any future clinical trial., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Parkinson's disease (PD) and frailty are two conditions that are increasingly common with advancing age, yet little is known about their relationship., Objective: The aim of this study was to examine the co-occurrence of frailty in people with PD; to describe the measures used to assess frailty in PD, and assess the prevalence of frailty in subjects with PD., Methods: We conducted a systematic review of Pubmed and Embase in April 2018. Studies that assessed frailty in subjects with PD were included in the review and data was extracted on the prevalence of frailty in subjects with PD. Due to heterogeneity of studies a meta-analysis was not performed., Results: Eight studies were included in the review, of which 7 were cross-sectional and 1 a prospective cohort study. Mean age of participants with PD in the studies ranged from 66 to 85 years. The majority (6/8) used the 5-item, Fried criteria to measure frailty, with the remainder using index-based measures. 5 studies provided data on the prevalence of frailty in PD, which ranged from 29% to 67%., Conclusions: Few studies have quantified the prevalence of frailty in PD, but those that have suggest a high concurrence of these two conditions.

Objectives: To use a data-driven approach to determine the existence and natural history of subtypes of Parkinson's disease (PD) using two large independent cohorts of patients newly diagnosed with this condition., Methods: 1601 and 944 patients with idiopathic PD, from Tracking Parkinson's and Discovery cohorts, respectively, were evaluated in motor, cognitive and non-motor domains at the baseline assessment. Patients were recently diagnosed at entry (within 3.5 years of diagnosis) and were followed up every 18 months. We used a factor analysis followed by a k-means cluster analysis, while prognosis was measured using random slope and intercept models., Results: We identified four clusters: (1)  fast motor progression with symmetrical motor disease, poor olfaction, cognition and postural hypotension; (2) mild motor and non-motor disease with intermediate motor progression; (3) severe motor disease , poor psychological well-being and  poor sleep with an intermediate motor progression; (4) slow motor progression with tremor-dominant, unilateral disease. Clusters were moderately to substantially stable across the two cohorts (kappa 0.58). Cluster 1 had the fastest motor progression in Tracking Parkinson's at 3.2 (95% CI 2.8 to 3.6) UPDRS III points per year while cluster 4 had the slowest at 0.6 (0.1-1.1). In Tracking Parkinson's, cluster 2 had the largest response to levodopa 36.3% and cluster 4 the lowest 28.8%., Conclusions: We have found four novel clusters that replicated well across two independent early PD cohorts and were associated with levodopa response and motor progression rates. This has potential implications for better understanding disease pathophysiology and the relevance of patient stratification in future clinical trials., Competing Interests: Competing interests: NB has received payment for advisory board attendance from UCB, Teva Lundbeck, Britannia, GSK, Boehringer and honoraria from UCB Pharma, GE Healthcare, Lily Pharma and Medtronic. He has received research grant support from GE Healthcare, Wellcome Trust, MRC and Parkinson’s UK and royalties from Wiley. RAB received grants from Parkinson’s UK, NIHR, Cure Parkinson’s Trust, Evelyn Trust, Rosetrees Trust, MRC and EU along with payment for advisory board attendance from Oxford Biomedica and LCT, and honoraria from Wiley and Springer. DJB received grants from NIHR, Wellcome Trust, GlaxoSmithKline Ltd, Parkinson’s UK and Michael J Fox Foundation. TF received payment for advisory board meetings for Abbvie and Oxford Biomedica, and honoraria for presentations at meetings sponsored by Medtronic, St Jude Medical, Britannia and Teva pharmaceuticals. HRM has received grants from Parkinson’s UK, grants from Medical Research Council UK, during the conduct of the study; grants from Welsh Assembly Government, personal fees from Teva, personal fees from Abbvie, personal fees from Teva, personal fees from UCB, personal fees from Boerhinger-Ingelheim, personal fees from GSK, non-financial support from Teva, grants from Ipsen Fund, non-financial support from Medtronic, grants from MNDA, grants from PSP Association, grants from CBD Solutions, grants from Drake Foundation and personal fees from Acorda, outside the submitted work. In addition, HRM has a patent and is a co-applicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140) pending. DGG received payment for advisory board attendance from AbbVie and honoraria from UCB Pharma, GE Healthcare and Acorda., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Objective: We sought to identify motor features that would allow the delineation of individuals with sleep study-confirmed idiopathic REM sleep behavior disorder (iRBD) from controls and Parkinson disease (PD) using a customized smartphone application., Methods: A total of 334 PD, 104 iRBD, and 84 control participants performed 7 tasks to evaluate voice, balance, gait, finger tapping, reaction time, rest tremor, and postural tremor. Smartphone recordings were collected both in clinic and at home under noncontrolled conditions over several days. All participants underwent detailed parallel in-clinic assessments. Using only the smartphone sensor recordings, we sought to (1) discriminate whether the participant had iRBD or PD and (2) identify which of the above 7 motor tasks were most salient in distinguishing groups., Results: Statistically significant differences based on these 7 tasks were observed between the 3 groups. For the 3 pairwise discriminatory comparisons, (1) controls vs iRBD, (2) controls vs PD, and (3) iRBD vs PD, the mean sensitivity and specificity values ranged from 84.6% to 91.9%. Postural tremor, rest tremor, and voice were the most discriminatory tasks overall, whereas the reaction time was least discriminatory., Conclusions: Prodromal forms of PD include the sleep disorder iRBD, where subtle motor impairment can be detected using clinician-based rating scales (e.g., Unified Parkinson's Disease Rating Scale), which may lack the sensitivity to detect and track granular change. Consumer grade smartphones can be used to accurately separate not only iRBD from controls but also iRBD from PD participants, providing a growing consensus for the utility of digital biomarkers in early and prodromal PD., (Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: To examine the influence of the glucocerebrosidase ( GBA ) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function., Methods: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia., Results: We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage., Conclusions: Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA -PD., Clinical Trial Registration: NCT02881099; Results., Competing Interests: Competing interests: YB-S has received grant funding from the MRC, NIHR, Parkinson’s UK, NIH and ESRC. RSW is supported by a UCL Excellence Fellowship and has received funding from the Academy of Medical Sciences and the NIHR, the MRC and the Wellcome Trust. NB has received payment for advisory board attendance from UCB, Teva Lundbeck, Britannia, GSK, Boehringer and honoraria from UCB Pharma, GE Healthcare, Lily Pharma, Medtronic. He has received research grant support from GE Healthcare, Wellcome Trust, Medical Research Council, Parkinson’s UK and National Institute for Health Research. RAB has received grants from Parkinson’s UK, NIHR, Cure Parkinson’s Trust, Evelyn Trust, Rosetrees Trust, MRC and EU along with payment for advisory board attendance from Oxford Biomedica LCT and FCDI and honoraria from Wiley and Springer. DJB has received grants from NIHR, Wellcome Trust, GlaxoSmithKline Ltd, Parkinson’s UK and Michael J Fox Foundation. JH has received honoraria from Eisai and grant support from MRC/Wellcome, Parkinson’s UK and the Michael J Fox Foundation. DGG has received grants from Michael’s Movers, The Neurosciences Foundation, and Parkinson’s UK, and honoraria from UCB Pharma and GE Healthcare, and consultancy fees from Acorda Therapeutics. HRM has received grants from Medical Research Council UK, Wellcome Trust, Parkinson’s UK, Ipsen Fund, Motor Neurone Disease Association, Welsh Assembly Government, PSP Association, CBD Solutions and Drake Foundation, and payment for advisory board attendance and lectures from Teva, AbbVie, Boehringer Ingelheim, and GSK. NWW is supported by the MRC and NIHR UCLH Biomedical research centre. TF has received grants from Michael J Fox Foundation, Cure Parkinson’s Trust, Brain Research trust, John Black Charitable Foundation, Rosetrees trust and honoraria for speaking at meetings from Bial, Profile Pharma and Medtronic., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Rapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models., Methods: Clinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson's (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations., Results: Compared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson's Disease Rating Scale (UPDRS)-III, timed "get-up-and-go", Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson's compared to 0.3% (95% CI 0.009%, 2%) of controls., Conclusions: RBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions., (© Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Objective: To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients., Methods: Recently diagnosed (<3.5 years) PD cases fulfilling United Kingdom (UK) brain bank criteria in Tracking Parkinson's, a UK multicenter prospective natural history study were assessed by retrospective application of the MDS criteria., Results: In 2000 cases, 1835 (91.7%) met MDS criteria for PD, either clinically established (n = 1261, 63.1%) or clinically probable (n = 574, 28.7%), leaving 165 (8.3%) not fulfilling criteria. Clinically established cases were significantly more likely to have limb rest tremor (89.3%), a good l-dopa response (79.5%), and olfactory loss (71.1%), than clinically probable cases (60.6%, 44.4%, and 34.5% respectively), but differences between probable PD and 'not PD' cases were less evident. In cases not fulfilling criteria, the mean MDS UPDRS3 score (25.1, SD 13.2) was significantly higher than in probable PD (22.3, SD 12.7, p = 0.016) but not established PD (22.9, SD 12.0, p = 0.066). The l-dopa equivalent daily dose of 341 mg (SD 261) in non-PD cases was significantly higher than in probable PD (250 mg, SD 214, p < 0.001) and established PD (308 mg, SD 199, p = 0.025). After 30 months' follow-up, 89.5% of clinically established cases at baseline remained as PD (established/probable), and 86.9% of those categorized as clinically probable at baseline remained as PD (established/probable). Cases not fulfilling PD criteria had more severe parkinsonism, in particular relating to postural instability, gait problems, and cognitive impairment., Conclusion: Over 90% of cases clinically diagnosed as early PD fulfilled the MDS criteria for PD. Those not fulfilling criteria may have an atypical parkinsonian disorder or secondary parkinsonism that is not correctly identified by the UK Brain Bank criteria, but possibly by the new criteria., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: Changes in personality have been described in Parkinson's disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction., Methods: 941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory., Results: Patients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more., Conclusions: A similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Impaired olfaction is an important feature in Parkinson's disease (PD) and other neurological diseases. A variety of smell identification tests exist such as "Sniffin' Sticks" and the University of Pennsylvania Smell Identification Test (UPSIT). An important part of research is being able to replicate findings or combining studies in a meta-analysis. This is difficult if olfaction has been measured using different metrics. We present conversion methods between the: UPSIT, Sniffin' 16, and Brief-SIT (B-SIT); and Sniffin' 12 and Sniffin' 16 odour identification tests., Methods: We used two incident cohorts of patients with PD who were tested with either the Sniffin' 16 (n = 1131) or UPSIT (n = 980) and a validation dataset of 128 individuals who took both tests. We used the equipercentile and Item Response Theory (IRT) methods to equate the olfaction scales., Results: The equipercentile conversion suggested some bias between UPSIT and Sniffin' 16 tests across the two groups. The IRT method shows very good characteristics between the true and converted Sniffin' 16 (delta mean = 0.14, median = 0) based on UPSIT. The equipercentile conversion between the Sniffin' 12 and 16 item worked well (delta mean = 0.01, median = 0). The UPSIT to B-SIT conversion showed evidence of bias but amongst PD cases worked well (mean delta = -0.08, median = 0)., Conclusion: We have demonstrated that one can convert UPSIT to B-SIT or Sniffin' 16, and Sniffin' 12 to 16 scores in a valid way. This can facilitate direct comparison between tests aiding future collaborative analyses and evidence synthesis., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiovascular disease (CVD) influences phenotypic variation in Parkinson's disease (PD), and is usually an indication for statin therapy. It is less clear whether cardiovascular risk factors influence PD phenotype, and if statins are prescribed appropriately., Objectives: To quantify vascular risk and statin use in recent-onset PD, and examine the relationship between vascular risk, PD severity and phenotype., Methods: Cardiovascular risk was quantified using the QRISK2 calculator (high ≥20%, medium ≥10 and <20%, low risk <10%). Motor severity and phenotype were assessed using the Movement Disorder Society Unified PD Rating Scale (UPDRS) and cognition by the Montreal cognitive assessment., Results: In 2909 individuals with recent-onset PD, the mean age was 67.5 years (SD 9.3), 63.5% were men and the mean disease duration was 1.3 years (SD 0.9). 33.8% of cases had high vascular risk, 28.7% medium risk, and 22.3% low risk, while 15.2% of cases had established CVD. Increasing vascular risk and CVD were associated with older age (p<0.001), worse motor score (p<0.001), more cognitive impairment (p<0.001) and worse motor phenotype (p=0.021). Statins were prescribed in 37.2% with high vascular risk, 15.1% with medium vascular risk and 6.5% with low vascular risk, which compared with statin usage in 75.3% of those with CVD., Conclusions: Over 60% of recent-onset PD patients have high or medium cardiovascular risk (meriting statin usage), which is associated with a worse motor and cognitive phenotype. Statins are underused in these patients, compared with those with vascular disease, which is a missed opportunity for preventive treatment., Trial Registration Number: GN11NE062, NCT02881099., Competing Interests: NPB has received payment for advisory board attendance from UCB, Teva Lundbeck, Britannia, GSK, Boehringer and honoraria from UCB Pharma, GE Healthcare, Lily Pharma, Medtronic. He has received research grant support from GE Healthcare, Wellcome Trust, MRC and Parkinson's UK and royalties from Wiley. RAB has received grants from Parkinson's UK, NIHR, Cure Parkinson's Trust, Evelyn Trust, Rosetrees Trust, MRC and EU along with payment for advisory board attendance from Oxford Biomedica and LCT, and honoraria from Wiley and Springer. DJB has received grants from NIHR, Wellcome Trust, GlaxoSmithKline, Parkinson's UK and Michael J Fox Foundation. He has acted as consultant for GSK. TF has received payment for advisory board meetings for Abbvie and Oxford Biomedica, and honoraria for presentations at meetings sponsored by Medtronic, St Jude Medical, Britannia and Teva pharmaceuticals. HRM has received grants from Medical Research Council UK, Wellcome Trust, Parkinson's UK, Ipsen Fund, Motor Neurone Disease Association, Welsh Assembly Government, PSP Association, CBD Solutions and Drake Foundation, and payment for advisory board attendance and lectures from Acorda, Teva, AbbVie, Medtronic, Boehringer Ingelheim, UCB and GSK. MTMH has received grants from Parkinson's UK, Michael J Fox Foundation, GE Healthcare, NIHR and Cure Parkinson's Trust. DGG has received grants from Parkinson's UK, Michael's Movers, the Paul Hamlyn Foundation, payment for advisory board attendance from AbbVie and honoraria from UCB Pharma, GE Healthcare and Acorda., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: The purpose of this study was to examine the relationship between vascular disease (and vascular risk factors), cognition and motor phenotype in Parkinson's disease (PD)., Methods: Recently diagnosed PD cases were enrolled in a multicenter prospective observational longitudinal cohort study. Montreal cognitive assessment (normal >23, mild cognitive impairment 22 to 23 or lower but without functional impairment, and dementia 21 or less with functional impairment) and Movement Disorder Society Unified PD Rating Scale part 3 (UPDRS 3) scores were analyzed in relation to a history of vascular events and risk factors., Results: In 1759 PD cases, mean age 67.5 (standard deviation 9.3) years, mean disease duration 1.3 (standard deviation 0.9) years, 65.2% were men, 4.7% had a history of prior stroke or transient ischemic attack, and 12.5% had cardiac disease (angina, myocardial infarction, heart failure). In cases without a history of vascular disease, hypertension was recorded in 30.4%, high cholesterol 27.3%, obesity 20.7%, diabetes 7.2%, and cigarette smoking in 4.6%. Patients with prior stroke or transient ischemic attack were more likely to have cognitive impairment (42% vs 25%) and postural instability gait difficulty (53.5% vs 39.5%), but these findings were not significant after adjustment for age, sex, and disease duration (P = .075). The presence of more than 2 vascular risks was associated with worse UPDRS 3 motor scores (beta coefficient 4.05, 95% confidence interval 1.48, 6.61, p = .002) and with cognitive impairment (ordinal odds ratio 2.24, 95% confidence interval 1.34, 3.74, p = .002). In 842 patients (47.8%) with structural brain imaging, white matter leukoaraiosis, but not lacunar or territorial infarction, was associated with impaired cognition (p = .006) and postural instability gait difficulty (p = .010)., Conclusion: Vascular comorbidity is significantly associated with cognitive and gait impairment in patients with early PD, which may have prognostic and treatment implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)