In the 15 years since Parkinson's Progression Markers Initiative (PPMI) launched, research conduct has advanced with broader connectivity, enabling virtual and hybrid methods for recruitment, engagement, education, and data collection. To meet evolving needs, PPMI created "myPPMI," which has grown from an informational portal to a multi-country, participant-centered, virtual research environment integrating education, screening, e-consent, longitudinal non-motor and motor assessments, and biospecimen referral. Built on a secure, cloud-native architecture with daily analytics and a multi-tier support model, myPPMI enables precision recruitment, real-time eligibility matching, and standardized low-burden data capture across studies. The platform is designed to enable focused data collection from individuals or groups based on the data they have already provided. This strategy provides the tools to establish precise subsets of high interest that could be targeted for further data acquisition. Usability testing and rapid global scaling demonstrate a generalizable, decentralized framework for biomarker-driven, Parkinson's disease research. ANN NEUROL 2026.

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

The Parkinson's Progression Markers Initiative (PPMI) has remained at the vanguard of Parkinson's disease (PD) research through evolving recruitment strategies that mirror advances in PD biology. PPMI was initially focused on untreated, early-stage PD. Over time, it has expanded to include genetic cohorts, prodromal participants identified via olfactory testing and risk factor questionnaires targeting people with rapid eye movement (REM) sleep behavior disorder (RBD). Most recently, PPMI has focused on the biology underlying PD and sought to recruit individuals defined by neuronal alpha-synuclein disease (NSD) biomarkers. This evolution from clinical to biological enrollment demonstrates the feasibility of biomarker-driven cohort design and establishes a scalable model for early detection and prevention research in neurodegenerative disease. ANN NEUROL 2026.

Abstract BackgroundCognitive impairment begins early in Parkinson disease (PD) and progresses to dementia in most people with PD, reducing quality of life and contributing to growing health-related costs. Physical exercise has potent antiaging effects and improves many outcomes in PD, including cognition. Identifying biomarkers that respond to exercise and determining how they associate with cognition and underlying disease pathology may elucidate key mechanisms for countering cognitive decline. ObjectiveThis clinical trial will test the feasibility, adherence, and safety of a 26-week home-based, combined endurance and resistance exercise intervention in people with PD. Secondary objectives are to test the effects of the exercise intervention on (1) global cognition, (2) motor symptom progression, and (3) circulating fluid-based biomarker levels. MethodsThe Exercise for Cognitive Excellence in Parkinson’s Disease study primarily evaluates the feasibility, adherence, and safety of a home-based exercise intervention in people with PD. It is secondarily a pilot randomized controlled trial that measures the effect of this intervention on cognition, motor progression, and circulating biomarkers. Thirty-one participants with PD will be randomized to either a home-based, trainer-supervised endurance and resistance training program (exercise group) or a waitlist control group for 26 weeks. Feasibility will be assessed using the average percentage of maximum heart rate (HR) for aerobic exercise and repetition maximums for resistance exercise. Adherence will be assessed using average days of exercise per week, average duration of exercise at target HR intensity for aerobic exercise, and average duration of exercise for resistance exercise. Safety will be assessed by measuring the number of adverse events and serious adverse events. The efficacy of the combined endurance and resistance exercise intervention will be measured using cognitive assessments, the Movement Disorders Society Unified Parkinson’s Disease Rating Scale, and participant-reported outcomes, all obtained at baseline and 26 weeks. Biomarkers in the periphery (blood and saliva) and brain (cerebrospinal fluid) will also be measured before and after the 26-week exercise intervention. ResultsRecruitment commenced in July 2023 and concluded in November 2025. The last participant will complete data collection in May 2026. Data will be analyzed starting in June 2026, and results are expected to be published in late 2026 and early 2027. ConclusionsPrevious studies have shown that high-intensity endurance exercise effectively slows the progression of motor symptoms in PD and that resistance exercise effectively improves cognition in PD. Establishing whether a clinically relevant, combined endurance and resistance exercise intervention is safe and feasible in PD and can improve cognition and slow motor disease progression would have a significant impact on quality of life for those with PD and their caregivers. Understanding how biomarkers respond to exercise will shed important mechanistic insight.

Background and Objectives:Most of the research in Parkinson disease (PD) has been conducted in White populations. There is a gap in the understanding of PD in other racial/ethnic groups, such as Asian Americans (AAs) and Native Hawaiians or Pacific Islanders (NHPIs). Therefore, we aimed to test the feasibility of a longitudinal cohort and understand attitudes and barriers to research participation in a pilot study of AA, NHPI, and White patients with PD in Hawai'i. Methods:We conducted a prospective pilot study of AA, NHPI, and White patients with PD, without dementia, to compare characteristics between racial groups' self-reported quality of life (QoL), interest in participating in research, health care utilization, and barriers to accessing health care, at baseline and 6-month follow-up visits. This was a single-center study completed at the Parkinson's and Movement Disorder Center at The Queen's Medical Center in Honolulu, Hawai'i from March 2023 to June 2024. Results:Of 146 patients screened for eligibility, 79 completed study enrollment (mean 68.8 years, male = 59%). Demographics, PD history, and questionnaires from baseline and follow-up visits were analyzed for 78 participants (AA = 27, NHPI = 26, White = 25), with 1 participant who dropped out. Differences were found between groups' household income, comfort with technology, and awareness of advanced PD therapies. There was no significant difference between groups' self-reported QoL, barriers to PD care, and attitudes toward clinical research. Discussion:AA and NHPI patients with PD in this study were no less apt to participate in research compared with White patients with PD. Although there were no significant differences in the variables evaluated among different racial subgroups, our results warrant further research.

To better understand the earliest stages of alpha-synucleinopathy, the Parkinson's Progression Markers Initiative (PPMI) has enrolled participants prior to the diagnosis of Parkinson's disease (PD) or dementia with Lewy Bodies (DLB). In this review, we describe lessons learned from prior enrollment and current strategies for PPMI eligibility. Severe hyposmia remains the strongest clinical predictor of aggregated synuclein as measured by a positive cerebrospinal fluid alpha-synuclein seed amplification assay (CSF aSyn SAA). CSF aSyn SAA is positive before dopamine transporter binding decreases, as measured by dopamine imaging. PPMI's adaptive eligibility criteria have enabled efficient identification of people in the early stage of neuronal synuclein disease defined by biomarkers alone and can inform future therapeutic studies. ANN NEUROL 2026.

The Path to Prevention (P2P) platform trial is a multicenter, multi-regimen, proof of concept, phase 2A, randomized clinical trial evaluating the safety and early efficacy of investigational products for the treatment of early-stage Neuronal Alpha-Synuclein disease (NSD) populations. The P2P trial is nested within the Parkinson's Progression Markers Initiative (PPMI), which means that its conceptualization, design, and implementation are based on learnings from the PPMI study. P2P will recruit eligible participants from the PPMI cohort. P2P will also leverage PPMI infrastructure including PPMI study sites and PPMI study cores including the site management, data management, biorepository, imaging, statistical, and data science cores for study execution. This paper reviews the conceptual design of P2P focusing on its relationship with PPMI to demonstrate how the connectivity between PPMI and P2P is essential for the success of the P2P study. P2P is an important step forward in clarifying the clinical trial design and regulatory path for interventions in the early-stage NSD population. ANN NEUROL 2026.

BACKGROUND:The cerebrospinal fluid alpha-synuclein seed amplification assay (CSFasynSAA) detects alpha-synuclein aggregation in over 90% of individuals with sporadic PD (sPD). However, the clinical characteristics of sPD with negative CSFasynSAA remain undefined. OBJECTIVES:Describe clinical and neuroimaging characteristics of CSFasynSAA-negative sPD individuals in the Parkinson's Progression Markers Initiative (PPMI). METHODS:We identified sPD PPMI participants with a negative CSFasynSAA (SAA-, n = 80) or positive CSFasynSAA (SAA+, n = 856) result at baseline. For comparative analysis between groups, we used a reduced dataset (n = 79 SAA- and n = 237 SAA+) propensity-score matched on age, sex, and time since clinical diagnosis. Clinical parameters, dopamine transporter-single photon emission computed tomography (DAT-SPECT), and magnetic resonance imaging (MRI) brain volumetrics were analyzed. RESULTS:The SAA- and matched SAA+ groups had similar motor performance on the Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) and similar cognitive performance on the Montreal Cognitive Assessment (MoCA) at baseline. The proportion with severe hyposmia was 12% for SAA- versus 73% for SAA+ (P < 0.001). Per PPMI enrollment criteria all participants were classified as having an abnormal DAT-SPECT. There were no significant differences in median quantitative DAT-SPECT measures between groups. The SAA- group showed a higher degree of atrophy in subcortical brain regions including substantia nigra. Longitudinally, 14.3% of SAA- participants had a change in diagnosis versus 0.9% of SAA+ participants. CONCLUSIONS:At baseline, SAA- sPD PPMI participants have a substantially lower rate of hyposmia, but otherwise cannot be readily distinguished from SAA+ participants based on clinical characteristics. However, SAA- participants have a greater degree of subcortical brain atrophy, and approximately one out of seven SAA- participants received a change in diagnosis. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

OBJECTIVE:Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal state for Lewy body disorders and exhibits biological heterogeneity that may influence clinical expression and progression. We examined clinical features in individuals with iRBD and biomarker-defined synucleinopathy. METHODS:Parkinson's Progression Markers Initiative (PPMI) is a longitudinal, multi-center observational study. Participants included polysomnogram (PSG)-confirmed iRBD individuals who were cerebrospinal fluid (CSF) α-synuclein seed amplification assay positive with no clinical diagnosis of Parkinson's disease or dementia with Lewy bodies, along with robust healthy controls (HCs). Clinical and biological features of prodromal PD and DLB, including mild cognitive impairment (MCI), subthreshold parkinsonism, and a range of neuropsychiatric, autonomic, and sensory symptoms, were assessed. RESULTS:Compared with HCs (N = 136), iRBD participants (N = 197) demonstrated worse cognitive performance, including a lower cognitive summary score (p < 0.0003, effect size = 0.41), and higher odds of subthreshold parkinsonism (OR = 24.5), and neuropsychiatric (OR = 3.5), autonomic (OR = 7.2) and sensory symptoms (OR = 13.2). Common features included hyposmia (75%), pain (54%), urinary problems (52%), constipation (49%), lightheadedness (40%) and anxiety (36%), whereas rates of MCI (32%), subthreshold parkinsonism (27%) and psychosis (7%) were lower. iRBD participants with abnormal dopamine transporter imaging had higher anxiety scores and antidepressant use. Although only 10% met criteria for prodromal DLB due to the requirement for MCI, most exhibited multi-domain impairment. INTERPRETATION:iRBD with synucleinopathy is associated with multi-domain clinical impairment before clinical neurodegenerative disease diagnosis, supporting broad clinical assessment in early biomarker-defined synuclein disease.

Falls and cognitive impairment are major sources of disability in Parkinson disease (PD). The ability to accurately identify individuals with PD at high risk for falls and cognitive impairment would provide an opportunity for intervention and potentially improve long-term outcomes. In a previous study, Assessing Telehealth Outcomes in Multiyear Extensions of Parkinson Disease Trials (AT-HOME PD), we remotely characterized participants with early PD who had participated in 1 of 2 PD clinical trials over 2 years of follow-up. These participants with advancing disease provide a unique opportunity to examine whether the capture of objective in-home measures via digital tools and bothersome symptoms via direct participant report improves the prediction of disease milestones. Assessing Telehealth Outcomes in Multiyear Extensions of Parkinson Disease Trials–2 (AT-HOME PD2) aims to examine whether digital tools and remote participant reporting can improve the prediction of falls and cognitive impairment, quantify changes in physical activity over time, and explore the relationship between physical activity and clinical progression over time. This is a decentralized observational study of up to 200 individuals with PD, with clinical and digital phenotyping for up to 3 years of follow-up. Participants are those who took part in the STEADY-PD III (NCT02168842), Study of Urate Elevation in Parkinson’s Disease, Phase 3 (SURE-PD3; NCT02642393), AT-HOME PD (NCT03538262), or PD GENEration (NCT04057794) studies. All participants complete 2 video visits per year, wear 2 wrist-worn sensors (Fitbit Charge 5 and ActiGraph CentrePoint Insight Watch) for 1 week each month, complete smartphone-based motor tasks (using the mPower 2.0 app) for 10 days each quarter, and complete online surveys (within the companion Fox Insight study) each quarter. Falls are assessed via a weekly automated telephone call. A cognitive diagnosis is determined by a consensus committee that considers scores on a global cognitive measure, detailed neuropsychological tests, a cognitive-related disability measure, and clinical information. Prediction models will be constructed, and prediction accuracy will be compared across the models. Recruitment for the study was initiated in September 2023. Enrollment is ongoing, with 142 participants enrolled as of January 2025. Within the cohort, the average age is 69.2 (SD 8.7) years; 85 (59.9%) participants are male, 137 (96.5%) are White, and 2 (1.4%) are Hispanic or Latino; and the average disease duration is 8.9 (SD 1.3) years. AT-HOME PD2 is remotely clinically and digitally phenotyping participants with midstage PD to predict falls and cognitive impairment and to provide insights into long-term progression. DERR1-10.2196/71955

BACKGROUND:Interest in Parkinson's disease (PD) prevention trials is growing, and genetically at-risk individuals may be ideal candidates. LRRK2 G2019S is the most common autosomal dominant genetic cause of PD and exhibits incomplete penetrance. OBJECTIVE:In a remote, prospective cohort study of LRRK2 G2019S carriers without PD, we examined change over time to better understand the natural history of LRRK2 PD. METHODS:Clinical measures completed during annual video visits included the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS parts I-III), Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Epworth Sleepiness Scale (ESS), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Beck Depression Inventory-II (BDI-II), Parkinson Anxiety Scale (PAS), and Montreal Cognitive Assessment (MoCA). To examine change from baseline to year two, we performed mixed model repeated measures analysis. To compare change over two years between different subgroups, we used generalized estimating equations. RESULTS:We enrolled 211 LRRK2 G2019S carriers without PD, of whom 201 (mean (standard deviation) 53.9 (14.9) years of age, 119 (59 %) women, 151 (75 %) Ashkenazi Jewish) contributed longitudinal data. Over two years, mean change ± standard error (effect size) for the MoCA was 0.71 ± 0.12 (0.43), MDS-UPDRS part II 0.07 ± 0.15 (0.03), MDS-UPDRS part III 0.17 ± 0.19 (0.06), SCOPA-AUT -0.50 ± 0.27 (0.13), ESS -0.27 ± 0.15 (0.13), RBDSQ -0.32 ± 0.13 (0.18), BDI-II -0.11 ± 0.32 (0.02), and PAS -0.94 ± 0.29 (0.22). CONCLUSION:Remotely administered motor, sleep, and autonomic measures were stable over two years. We need more sensitive measures of disease progression (e.g., biomarkers) and a better understanding of predictors of development of clinically manifest LRRK2 PD.

BACKGROUND:Neuronal α-synuclein disease (NSD) is defined by the presence of an in vivo biomarker of neuronal alpha-synuclein (n-asyn) pathology. The NSD integrated staging system (NSD-ISS) for research describes progression across the disease continuum as stages 0 to 6. OBJECTIVE:The aim was to assess 5-year longitudinal change in NSD-ISS in early disease. METHODS:Analysis included a subset of participants from the Parkinson's Progression Markers Initiative (PPMI) enrolled before 2020 as Parkinson's disease (PD) patients, prodromal PD patients, or healthy controls (HC) who met NSD criteria. Staging was defined based on biomarkers of n-asyn and dopaminergic dysfunction in early stages, clinical features, and severity of functional impairment in stages 3 to 6. Stages were determined annually for 5 years. RESULTS:Of 576 NSD participants, 494 were enrolled as PD patients, 74 prodromal PD patients, and 8 HCs. At baseline, 24% of participants were stage 2B, 56% Stage 3, 13% stage 4, and less than 5% in other stages. At year 5, the respective percentages for stages 2B to 4 were 11%, 50%, and 34%, indicating progression through NSD stages. Progression was driven by functional impairment in the predominantly motor domain (95%) for stage 2B to 3, increasing degree of nonmotor dysfunction for stages 3 to 4 (46%), and a combination of domains for stages 4 to 5. Initiation of dopaminergic medications led to stage regression in 8% of participants in Stage 3 but 41% in stage 4. CONCLUSIONS:Our analysis supports the utility of NSD-ISS in defining the stages of disease progression, at least in the early clinical and prodromal stages (2B, 3, or 4), suggesting the value of NSD-ISS as a potential research tool for drug development. Further research involving preclinical cohorts is a crucial next step. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background Care for persons with Parkinson's disease (PD) is to a great extent carried out by care partners. It is important to understand their needs to ease their burden and help with their important role. Objective To present (1) what is known about needs in caregiving for someone with PD from both qualitative and quantitative papers; and (2) to identify research gaps in the existing literature to guide future research. Methods A systematic search was conducted, searching PubMed, CINAHL, PsychINFO, and MEDLINE for both qualitative and quantitative studies examining care partner needs in Parkinson's disease published from the start of the databases up to 13 November 2024. The best-fit framework synthesis method was employed for qualitative data extraction and analysis. The Critical Appraisal Skills Programme (CASP) and the Newcastle-Ottawa Scale (NOS) were used for quality assessment of studies. Results Forty-eight qualitative studies, ten quantitative studies, and three mixed methods studies met the eligibility criteria. All studies were of observational, cross-sectional design. A total of nine themes (the need for information, the need to be heard, PD healthcare, emotional support, daily living, financial support, skills, care partner physical well-being, and respite care) were identified from qualitative data and all quantitative data could fit this framework. Quantitative data on the frequency of needs and when they arise over the course of PD were scarce. Only one quantitative study made use of a validated measurement instrument to measure care partner needs, the Family Needs Questionnaire. Conclusions Care partner needs in PD are wide-ranging. A significant gap identified is the absence of quantitative data to determine the prevalence, timing, and factor contributing to the needs revealed by the qualitative research.

Importance: Investigating associations between life course sleep duration and Parkinson's disease (PD) may help clarify the role of sleep in early detection and/or prevention of PD. Objective: To characterize life course sleep duration trajectories and their associations with PD risk and age at onset (AAO). Design: Two ongoing online cohorts: Parkinson's Progression Markers Initiative (PPMI)-Online (discovery; started in 2021) and Fox Insight (FI; validation; started in 2018). Setting: Participants reported sleep duration across life stages, with PD-related follow-ups every three months. Participants: A convenience sample of 5,660 individuals with PD and 10,245 without PD from PPMI-Online, and 1,929 participants with PD from FI. Exposures: Self-reported sleep duration from ages 18 to 80+ in PPMI-Online and 12 to 66+ in FI. Latent class growth analysis (LCGA) identified sleep trajectories. Main Outcomes and Measures: PD risk and AAO were assessed using logistic and linear regression, adjusting for demographics, lifestyle, comorbidities. Results: The combined sample included 17,834 participants [age at sleep report 67.2±7.83 years; 9,735 (54.6%) female]. LCGA identified nine sleep trajectories in PPMI-Online, stable in early adulthood but diverging in midlife (stable, increasing, decreasing). Midlife sleep reductions (6-7 to ≤5-6 hours/day: OR = 1.90, 95% CI 1.61-2.24, P < .001; 7-8 to ≤6-7 hours/day: OR = 1.64, 95% CI 1.40-1.91, P < .001) and consistent short sleep (<=6 hours/day throughout adulthood: OR = 1.41, 95% CI 1.19-1.67, P < .001) demonstrated increased PD risk. Short sleep in early adulthood or midlife also had earlier AAO. The strongest effects were seen in those with ≤6 hours/day throughout adulthood (PPMI-Online: β= -2.45 years, 95% CI -3.33 to -1.56, P <.001) and those with a continuous decrease since adolescence (FI: β = -4.23 years, 95% CI -5.52 to -2.93, P < .001). These effects were independent of rapid eye movement sleep behavior disorders. Conclusions and Relevance: Self-reported short sleep in early adulthood and midlife sleep reductions are associated with increased PD risk and earlier AAO. Self-perceived midlife sleep reduction may be a marker for future PD. Persons with chronic short sleep may be candidates for preventive intervention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at www.ppmi-info.org and https://foxinsightinfo.michaeljfox.org/insight/explore/insight.jsp I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at www.ppmi-info.org and https://foxinsightinfo.michaeljfox.org/insight/explore/insight.jsp

The global burden of Parkinson's disease is rising. Large-scale genetic studies have confirmed that extrinsic or environmental factors, rather than genetic predisposition, play a dominant role in its cause. Increasing evidence implicates three classes of toxicants-certain pesticides, the dry-cleaning chemicals trichloroethylene and perchloroethylene, and air pollution-in the development of Parkinson's disease. These toxicants are widely prevalent, impair mitochondrial or lysosomal function, or both, and contribute to, if not cause, the disease. Parkinson's disease could be thus largely preventable. Uncertainties remain regarding the relevant doses, timing, and routes of exposure, the nature of genetic and environmental interactions, the effects of combined exposures, the role of the microbiome, and the identity of other environmental risks. Methodological limitations and structural challenges hinder our understanding. However, improved measurement of toxicant exposure in individuals and the environment, long-term prospective studies, increased funding for prevention, and policy changes can precipitate the fall of the burden of Parkinson's disease.

OBJECTIVE:Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation. METHODS:The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA). RESULTS:As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile). INTERPRETATION:Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials. ANN NEUROL 2025;97:730-740.

ABSTRACTBackgroundREM sleep behavior disorder (RBD) is an early manifestation of alpha-synucleinopathy in many cases. Dream enactment behavior (DEB), the clinical hallmark of RBD, has many etiologies and cannot be used alone to predict underlying alpha-synucleinopathy. We compared the proportion of people with alpha-synucleinopathy, as measured by CSF alpha-synuclein seed amplification assay (CSFasynSAA), between people with polysomnographic-confirmed RBD (RBD-PSG) and people who reported DEB on a questionnaire and were further selected with smell testing and DAT-SPECT.MethodsParticipants were enrolled in the Parkinson’s Progression Marker Initiative (PPMI) and ≥60 years old without a diagnosis of Parkinson’s disease. Participants had either RBD-PSG or self-reported DEB. Self-reported DEB participants had to have hyposmia (<10thpercentile for age/sex) and at least mild DAT-SPECT abnormality (<100% age/sex-expected). We compared CSFasynSAA between RBD-PSG and self-reported DEB with hyposmia (DEB+Hypos). RBD-PSG participants also underwent smell testing and DAT-SPECT; we determined the predictive value of these tests in RBD-PSG with regards to CSFasynSAA.ResultsCSFasynSAA was positive in 171/240 (71%) of RBD-PSG and %) 180/210 (86%) of DEB+Hypos participants. Among RBD-PSG, hyposmia strongly predicted CSFasynSAA+ (PPV: 92% [95% CI 87%-97%]). Smell identification was more accurate than DAT-SPECT in predicting CSFasynSAA+ in RBD-PSG (AUC for UPSIT: 0.89 [95% CI 0.84 – 0.94]; AUC for DAT-SPECT: 0.65 [95% CI 0.58 – 0.73]).ConclusionsSmell testing may be an effective and scalable method to identify people with alpha-synucleinopathy among those with self-reported DEB. Among individuals with RBD diagnosed by PSG, smell testing improved prediction of positive CSF alpha-synuclein biomarker.

Background: Little is known about the relationship between parkinsonism or Parkinson's disease (PD) and frailty in Latin America. Objective: The study aimed to determine the cross-sectional and prospective associations between parkinsonism and PD with frailty in a large multi-country cohort in Latin America. Frailty was assessed using three different models to explore which definitions are more appropriate to screen for frailty in a PD population. Methods: 12,865 older adults (aged >= 65 years) from the 10/66 population-based cohort study in six Latin American countries were analyzed. Logistic regression models assessed the cross-sectional association between parkinsonism/PD with baseline frailty. Individual country analyses were combined via fixed-effect meta-analysis. In non-frail participants who were followed up for 4 years, Cox proportional hazards regression models assessed the prospective association between parkinsonism/PD with incident frailty accounting for competing risk of mortality. Results: At baseline, the prevalence of parkinsonism and PD was 7% and 2%, respectively, and the prevalence of frailty varied across the three models with rates of 18% for frailty phenotype, 20% for frailty index and 30% for multidimensional frailty model. PD was associated with baseline and incident frailty after accounting for age, sex, and education: odds ratios and 95% confidence intervals (95% CI) for frailty were 2.49 (95% CIs 1.87-3.31), 2.42 (95% CIs 1.80-3.25), and 1.57 (95% CIs 1.16-2.21), and cause-specific hazard ratios were 1.66 (95% CIs 1.07-2.56), 1.78 (95% CIs 1.05-3.03), and 1.58 (95% CIs 0.91-2.74). Similar results were found for parkinsonism. Conclusion: Parkinsonism and PD were cross-sectionally and prospectively associated with frailty in Latin America. Routine screening for frailty in PD patients may aid earlier detection of those at greater risk of adverse outcomes.