Abstract
Funding for this conference was made possible, in part, by the National Institute Of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R13NS147887. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Epigenome-Wide Association Study Using Repeated Prediagnostic Blood Samples Highlights Novel Risk Regions of Parkinson's Disease
Xiaojing Peng1, Mario H. Flores-Torres1, Marianna Cortese1, Cheng Peng1, Albert Y. Hung1, Michael A. Schwarzschild1, Alberto Ascherio1, Kjetil Bjornevik1
1Harvard T.H. Chan School of Public Health
Background: Epigenome-wide association studies (EWAS) have identified distinctive patterns of DNA methylation levels associated with PD. However, none has utilized a prospective study design.
Methods: We included Nurses’ Health Study participants who provided repeated blood samples collected up to a median of 19 years before PD onset. DNA methylation profiles (EPIC array) were obtained from 75 individuals who developed PD and 74 age-matched controls. We prospectively examined the association of epigenome-wide DNA methylation levels in blood with PD risk, age at PD onset, and time to PD onset. To further aid interpretation of results from differential methylation analysis, we conducted gene ontology and pathway enrichment analyses.
Results: In probe-wise differential methylation analysis, at a significance threshold of nominal p-value < 5 × 10−5, we identified 40 cytosine-phosphate-guanine sites (CpGs) in the first blood sample and 50 CpGs in the second sample that differed between PD cases and controls. In longitudinal analysis, we further observed significant changes in DNA methylation levels in 48 CpGs over 10 years (p-value < 5 × 10−5). Differential methylation regions analysis revealed numerous novel genomic regions, with the five most statistically significant observed near genes ETV7, SCRIB, RUNX1, ANGPT2, and MCPH1. Gene ontology and KEGG pathway analyses highlighted nominally significant pathways related to dopaminergic synapses, cytochrome P450 metabolism, nicotine addiction, and gamma-aminobutyric acid transport.
Conclusions: Our study identified novel gene regions that might play a role in the prodromal phase of PD and provided insights into epigenetic pathways contributing to PD pathogenesis.
[18F]FDG-PET as a staging neurodegeneration biomarker in the prodromal to overt neuronal α-synucleinopathy continuum
Beatrice Orso1, Ignacio Roura1,2, Pietro Mattioli1, Silvia Morbelli3, Matteo Pardini1, Dario Arnaldi1
1 University of Genoa, Italy,2 University of Barcelona, Spain,3 University of Turin, Italy
Background: [18F]FDG PET represents an endorsed neurodegeneration biomarker in neuronal α-synucleinopathies. Idiopathic/isolated REM Sleep Behavior Disorder (iRBD) represents a prodromal stage of such disorders.
Objectives: To assess [18F]FDG PET as a staging neurodegeneration biomarker, using published brain metabolic disease-related patterns, and a regional-based approach, across the prodromal to overt α-synucleinopathy continuum.
Methods: We included 83 prodromal subjects with iRBD, comprising non-converters (n = 56) and converters (n = 27) to an overt α-synucleinopathy (either Parkinson's Disease -PD- or Dementia with Lewy Bodies - DLB) according to the last available follow-up, and 85 subjects with PD (n = 40) and DLB (n = 45). For comparison, we enrolled a group of healthy subjects (n = 41). Participants underwent brain [18F]FDG PET at baseline. Analysis of covariance was used to test the ability of previously published [18F]FDG PET disease-related patterns in staging neurodegeneration along the prodromal to overt α-synucleinopathy continuum, and across the motor-predominant and the cognitive-predominant clinical trajectories. We furtherly assessed metabolic changes using a regional-based approach.
Results: All disease-related patterns effectively discriminated progression stages, from prodromal to overt α-synucleinopathies, with comparable performance. [18F]FDG PET significantly distinguished all groups along the cognitive-predominant pathway, while, in the motor-predominant pathway, converter patients were not significantly discriminated from non-converters. Regionally, the inferior parietal, precuneus and middle frontal areas exhibited the most prominent decrease in [18F]FDG uptake with progression, alongside relative parallel progressive increases in the cerebellum, pons, parahippocampal areas, putamen and pallidum.
Conclusions: All [18F]FDG PET disease-related patterns staged neurodegeneration from prodromal to overt α-synucleinopathy, best characterizing the cognitive-predominant pathway.
The “Gravity-Stress” Hypothesis: VMAT2 PET Evaluation of Postural Recalibration as a Neuroprotective Strategy in Prodromal Parkinson's Disease (iRBD)
Patrick Benavoli
[None]
Background: Idiopathic REM Sleep Behavior Disorder (iRBD) is a high-risk prodromal marker for Parkinson's Disease (PD). We propose the “Gravity-Stress” Hypothesis: that subclinical postural inefficiency - quantified by pathological Center of Pressure (CoP) displacement - imposes a chronic allostatic load. This sustained physiological stress, evidenced by elevated hair cortisol, may accelerate the neurodegeneration of dopaminergic terminals.
Objective: To determine if stabilizing the postural tonic system - validated by the normalization of CoP position and sway - can reduce chronic stress and slow the loss of dopaminergic terminal density in iRBD patients.
Methods: This randomized, sham-controlled, crossover trial involves 30 participants with vPSG-confirmed iRBD. Participants are randomized (N = 10/arm) to: (1) Proprioceptive insoles, (2) Occlusal splints, or (3) Sham insoles. Following 12 months, the sham group crosses over to the most effective active appliance observed in Phase 1. A critical intermediate goal is the clinical validation of the intervention: treatment “success” is defined by the objective normalization of CoP eccentricity on a stabilometric platform within 4 weeks.
Primary Outcome Measures:
· Neuroimaging: Annual change in VMAT2 PET binding (SUVR) in the posterior putamen and pedunculopontine nucleus (PPN). · Chronic Stress: Hair Cortisol Concentration (HCC) analyzed in 3 cm segments to quantify 90-day mean HPA-axis activity.
Secondary Outcome Measures:
· Intermediate Validation: Longitudinal stability of CoP position. · Motor Readiness: Mean/Consistency of the Falling Stick Test.
Limitations: The pilot scale (N = 30) may be susceptible to Type II errors due to the high variability of phenoconversion in iRBD. Furthermore, the reliance on hair cortisol requires strict control for external confounding factors, and the “ceiling effect” of baseline nutritional supplementation (Magnesium/Glycine) may diminish the observable delta between active and sham groups.
Hypothesis: We anticipate that participants achieving validated CoP normalization will demonstrate significantly lower rates of VMAT2 decline compared to the sham group. This would confirm that efficient “gravity-fighting” reduces the physiological “noise” that contributes to PD progression.
Conclusion: By targeting the bio-mechanical drivers of chronic stress, this study aims to validate postural recalibration as a novel intervention to delay or prevent phenoconversion in high-risk iRBD populations.
Tracing biomarker trajectories through Parkinson's disease progression and medication status from cross-sectional data in the UK Biobank
Evan Boyle1, Ludmila Voloboueva1, Katrina Paumier1, William Hagstrom1, Ferhan Qureshi1, David Brazel1
1 Octave Bioscience
Background: PD can disrupt a wide range of physiological processes, including inflammation, digestion, hormone signaling, and cognition. Multiple groups have spotlighted protein biomarkers for early detection of PD, but few comparisons of early- and late-stage changes have been performed to evaluate biomarkers’ utility for prevention, response to medication, and role in disease progression.
Methods: 602 confirmed PD patients and 6026 age- and sex-matched neurologically healthy controls (NHCs) with proteomic profiling were ascertained in the UK Biobank. Parkinson's protein abundances were standardized to z-scores relative to NHCs using age, sex, and average protein abundance. We performed Mann-Whitney U tests for cases both before and after diagnosis vs NHCs, Cox proportional hazard modeling for survival and reverse time survival analyses, and Pearson correlation for protein abundance vs time relative to the PD algorithmically determined diagnosis date. Hit biomarkers were validated using proteomic data from PPMI and assessed for responsiveness to PD medications using detailed patient dopaminergic medication histories.
Results: Dopamine decarboxylase (DDC) and prolactin (PRL) levels are altered only after diagnosis, when patients take levodopa/carbidopa and dopamine agonists. PPMI data confirmed that DDC and prolactin levels are unchanged in levodopa/carbidopa- and dopamine agonist-naive patients, respectively. Biomarkers that diverge from controls early in the disease course, such as neurofilament light chain (NEFL), hematopoietic prostaglandin D synthase (HPGDS), and neuroblast differentiation-associated protein (AHNAK), typically persist into later disease stages but only modestly correlate with time since diagnosis. By contrast, other markers that are profoundly altered in the post-diagnosis cohort, such as histidine-rich calcium-binding protein (HRC) and HER3 (ERBB3), seldom differ in patients who have not initiated dopaminergic medication.
Conclusion: We confirm that blood biomarker signals appear 7 or more years in advance of the emergence of clinical signs. Candidate biomarkers for PD exhibit diverse trajectories, and biomarkers linked to the same physiological process often share similar trajectories. Proteomic changes due to common Parkinson's medications are substantial and likely overshadow underlying pathophysiology. We conclude that successful monitoring of PD patient physiology with blood-based biomarkers should be contextualized with disease duration in addition to NHC ranges to improve reliability of biomarker-derived insights.
Multimodal stratification in prodromal Lewy body disease: Dual imaging deficits and plasma biomarkers predict rapid progression in the NaT-PROBE cohort
Keita Hiraga1, Daigo Tamakoshi1, Taiki Fukushima1, Yuki Saito1, Kenshiro Fuse1, Takashi Uematsu1, Takashi Tsuboi1, Maki Sato1, Katsunori Yokoi2, Keisuke Suzuki3, Yutaka Arahata2, Yukihiko Washimi4, Masayuki Yamamoto5, Hideaki Shimizu6, Masakazu Wakai7, Harutsugu Tatebe8, Takahiko Tokuda8,9, Akinori Nakamura10, Shumpei Niida11, Masahisa Katsuno1
1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan,2 Department of Neurology, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan,3 Innovation Center for Translational Research, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan,4 Department of Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu Aichi, Japan,5 Kumiai Kosei Hospital, Takayama, Gifu, Japan,6 Medical Examination Center, Daido Clinic, Nagoya, Japan,7 Chutoen General Medical Center, Kakegawa, Shizuoka, Japan,8 Advanced Neuroimaging Center, Institute for Quantum Medical Science, National Institutes for Quantum Science and Technology, Chiba, Japan,9 Neuroetiology and Diagnostic Science, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan,10 Department of Biomarker Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan,11 Core Facility Administration, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
Background: Our previous phase 2 clinical trial of zonisamide for disease modification in prodromal Lewy body disease (LBD), the NaT-PROBEi trial, highlighted a critical challenge in prevention trial design: the profound clinical heterogeneity of the prodromal population hindered the detection of treatment effects (Hiraga et al., NPJ Parkinsons Dis 2025). To facilitate more precise participant stratification for future disease-modifying trials, we aimed to identify robust prognostic factors by analyzing longitudinal data from our observational high-risk cohort (NaT-PROBE study).
Methods: We recruited community-dwelling adults aged ≥50 years. Participants were classified into a high-risk group (having multiple prodromal symptoms: dysautonomia, hyposmia, and/or REM sleep behavior disorder) or a low-risk group (none) based on validated questionnaires. We assessed baseline cardiac metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DaT) single-photon-emission computed tomography (SPECT). Additionally, we measured baseline plasma biomarkers for Alzheimer's disease (AD) co-pathology (amyloid-beta [Aβ] composite, phosphorylated tau 181 [p-tau181]) and neurodegeneration (neurofilament light chain [NfL]) using immunoprecipitation-mass spectrometry (IP-MS) and single-molecule array (Simoa) platforms. We analyzed the associations of these baseline markers with longitudinal changes in cognition (MoCA-J) and motor function (MDS-UPDRS III) using linear mixed-effects models.
Results: We longitudinally evaluated 91 high-risk participants (mean follow-up: 3.9 [1.7] years) and 33 low-risk controls (3.4 [1.0] years). At baseline, age and MoCA-J scores were comparable between groups. However, the high-risk group exhibited slightly higher MDS-UPDRS III scores and significantly elevated plasma NfL levels compared to the low-risk group. Longitudinal stratification revealed distinct prognostic profiles within the high-risk group. Notably, participants with dual abnormalities in both DaT-SPECT and MIBG scintigraphy demonstrated significantly faster deterioration in both MoCA-J (β = -1.109, p < 0.001) and MDS-UPDRS III (β = 2.718, p < 0.001) compared to low-risk controls. Regarding plasma biomarkers, high-risk participants classified as A + or T + showed accelerated MoCA-J decline (A+: β = -0.421, p = 0.045; T+: β = -0.531, p = 0.015). Furthermore, T + status was significantly associated with a faster worsening of MDS-UPDRS III scores (β = 1.081, p = 0.007).
Conclusion: This study demonstrates that dual-positive imaging deficits (DaT/MIBG) identify a specific prodromal LBD subgroup with rapid cognitive and motor progression. Additionally, plasma AD biomarkers (A + and T+) stratify cognitive prognosis, with tau pathology further influencing motor trajectories. These multimodal markers are essential for defining fast progressors and reducing heterogeneity in future prevention trials.
Towards precision prevention: Sex-divergent neuropsychiatric phenotypes and network disruptions in a mouse model of serotonergic α-Synucleinopathy
Lluis Miquel-Rio1,2,3, Maria Sancho-Alonso1,2,3,4, Unai Sarriés-Serrano1,2,3, Celia Bretones2, Verónica Paz1,2,3, Emma Muñoz-Moreno2, Xavier López-Gil2, Vicent Teruel-Martí4, Analia Bortolozzi1,2,3
1 Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Barcelona, Spain,2 August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain,3 Biomedical Research Networking Center for Mental Health (CIBERSAM), ISCIII, Madrid, Spain,4 Human Anatomy and Embryology Department, Faculty of Medicine, University of Valencia, Valencia, Spain
Background: Parkinson's disease (PD) is a common neurodegenerative disorder defined not only by motor dysfunction but also by non-motor challenges like anxiety, depression, and cognitive decline. With an aging demographic, the societal weight of PD and its effect on quality of life have become increasingly significant. Women, in particular, face a higher burden of neuropsychiatric symptoms. Current research links these mood disorders to the serotonergic (5-HT) system, specifically noting that α-synuclein (α-Syn) builds up in the 5-HT raphe nuclei of patients with comorbid PD and depression.
Methods: Using male and female mice overexpressing human α-synuclein (h-α-Syn) in raphe 5-HT neurons induced by AAV vectors, we characterized the mood-related behavioral profile. We evaluated h-α-Syn oligomers and phospho-α-Syn levels across cortical and subcortical regions using WB and confocal microscopy. To investigate the sex-dependent mechanisms by which h-α-Syn affects emotional processing, we integrated resting-state functional MRI (rs-fMRI) with the analysis of synaptic plasticity markers (BDNF, SV2A, and PSD95).
Results: We found different behavioral profiles in PD-like mice compared to respective control groups, with females showing anxiety-like behaviors in the dark-light box and splash tests, while males showed a depressive phenotype in the tail suspension and forced swim tests. However, both males and females achieve comparable levels of h-α-Syn oligomers and p-α-Syn in different brain areas (medial prefrontal cortex-mPFC, caudate-putamen-CPu, and hippocampus-HPC). Additionally, BDNF and PSD95 levels were reduced in the analyzed brain areas of both sexes, except for the presynaptic SV2A marker, which was reduced in PD-like females and increased in PD-like males compared controls. Notably, rs-fMRI analysis showed significant sex-based differences in brain cluster connectivity. Using seed-based analysis between the mPFC to the rest of the brain, we detected significant reduced functional connectivity (p < 0.005) with frontal cortex, olfactory tract, facial and paragigantocellular nucleus, and locus coeruleus in PD-like females. Similar analyses in PD-like males showed hypo-connectivity in different clusters, e.g., motor, somatosensorial, and insular cortices, hypothalamus, dorsolateral amygdala, and external inferior coll. Sex-specific disruptions were also identified in CPu and hippocampal connectivity networks.
Conclusions: This study reveals a clear sex-dependent divergence in the behavioral outcome of PD-like α-synucleinopathy. The contrast between female-specific anxiety and male-specific depression is reflected in distinct patterns of brain hypo-connectivity and synaptic SV2A marker. Overall, our data suggest that the same underlying pathology leads to different circuit-level dysfunctions in males and females, highlighting a need for sex-tailored approaches in the management of mood disorders in PD.
Understanding the earliest phases of Parkinson's disease (PD) - an update on the prodromal effort within the Global Parkinson's Genetics Program (GP2)
Sophie I Meyer1, Manuela Tan2,1, Kajsa Atterling-Brolin3,1, Lara M Lange4,5, Maria Teresa Periñan1,6, Meron Teferra7, Sheena Waters1, Joanne Trinh4, Carolin Gabbert4, Ziv Gan-Or7,8,9, Alastair J Noyce1, The Global Parkinson's Genetics Program (GP2)1
1 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK,2 Department of Neurology, Oslo University Hospital, Oslo, Norway,3 Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden,4 Institute of Neurogenetics, University of Lübeck, Lübeck, Germany,5 Laboratory of Neurogenetics, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA,6 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, 16 Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/Consejo Superior de Investigaciones Científicas (CSIC)/Universidad de Sevilla, 41013, Seville, Spain,7 Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada,8 Clinical Research Unit, The Neuro (Montreal Neurological Institute-Hospital), Montreal, Quebec, Canada,9 Department of Human Genetics, McGill University, Montreal, Quebec, Canada
Background: The Global Parkinson's Genetics Program (GP2, http://gp2.org/) is an international collaborative project to accelerate research into the genetic architecture of PD. Alongside developing a global network for researchers and trainees, GP2 aims to harmonise clinical and genetic data for >300,000 participants worldwide. The prodromal effort in GP2 began in 2023, with the goal of capturing individuals ‘at-risk’ or in the earliest prodromal stages of PD. We aim to continue recruitment of global ‘at-risk’, early and prodromal Parkinson's disease (PD) cohorts to GP2, support existing cohorts to expand their clinico-genetic data collection and continue our contribution to GP2's global resource for studying prodromal PD.
Methods: GP2's prodromal recruitment focuses on individuals with known early features of PD (Rapid Eye Movement [REM] sleep behaviour disorder [RBD], olfactory dysfunction, and pure autonomic failure [PAF]), genetic risk factors (carriers of rare pathogenic or risk-associated GBA1 or LRRK2 variants or individuals with a high polygenic risk score), or those scoring highly on PD risk algorithms (MDS criteria or PREDICT-PD algorithm). We prioritise polysomnography (PSG)-confirmed RBD, clinically confirmed anosmia, hyposmia defined by objective smell tests, and non-manifesting GBA1/LRRK2 variant carriers. We encourage cohorts already enrolled in GP2, particularly those from underrepresented populations, to consider supported expansion by contributing extended clinical data, training staff in new data collection methods (like PSG) or undertaking new sample drives. Lastly, the GP2 prodromal interest group brings together shared-interest researchers with prodromal cohorts or experience worldwide, on a quarterly basis, to collaborate and engage with each other.
Results: Since 2023, we have engaged with >160 cohorts. Sixteen cohorts have sent samples for genotyping, contributing 5260 prodromal samples to the GP2 database, of whom 4241 have extended clinical data. We anticipate that >18,500 cohort-estimated prodromal samples will be available by the end of 2029 - forming one of the largest open access genetic and clinical datasets for prodromal PD.
Conclusion: The GP2 prodromal effort has continued to expand since its conception, contributing >5000 samples to the GP2 network to date. We are particularly interested in engaging with new investigators to set up prodromal collections in under-represented populations, where we could support data collection and genotyping.
4 year acetyl-DL-leucine therapy of 2 individuals with REM sleep behavior disorder (RBD): markedly improved RBD-symptoms and reversal of reduced baseline striatal dopamine-transporter ligand binding
Wolfgang H. Oertel1, Fanni F Geibl2, Annette Janzen1, Friederike Eilsberger3, Martin T. Henrich2, Jan Booij4
1 Department of Neurology, Philipps University Marburg, Germany,2 Department of Psychiatry and Psychotherapy, Philipps University Marburg, Germany,3 Department of Nuclear Medicine, Philipps University Marburg, Germany,4 Department of Radiology and Nuclear Medicine, University of Amsterdam, The Netherlands
Background: Isolated REM Sleep Behavior Disorder (iRBD) is considered a specific, common prodrome of the alpha-synucleinopathies Parkinson's disease (PD) and dementia with Lewy bodies - especially when combined with hyposmia. Acetyl-leucine is a modification of the amino acid leucine. Acetyl-DL-leucine (ADLL) is the racemate of the bioactive enantiomer acetyl-L-leucine (ALL) and the inactive form acetyl-D-leucine. ALL has been shown to have beneficial effects on lysosomal and mitochondrial functions and might possess potentially disease-modifying effects in prodromal PD (Oertel et al. 2024).
Methods: We investigated whether ADLL (5 g/d) has an effect on prodromal PD progression in 2 hyposmic iRBD-patients. Initial outcome parameters were RBD-severity sum-score over three weeks (RBD-SS-3), dopamine-transporter single-photon emission computerized tomography (DAT-SPECT) and metabolic “Parkinson-Disease-related-Pattern (PDRP)”-z-score in 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).
Results: After 5 weeks of ADLL-treatment, the RBD-SS-3 dropped markedly in both patients and remained reduced for >18 months of ADLL-treatment. In patient 1, the DAT-SPECT putaminal binding ratio (PBR) decreased in the 5 years pretreatment from low normal (1.88) to pathological (1.22) and the patient's FDG-PET-PDRP-z-score rose from 1.72 to 3.28 (pathological). After 22 months of ADLL-treatment, the DAT-SPECT-PBR increased to 1.67 and the FDG-PET-PDRP-z-score stabilized at 3.18. Similar results were seen in patient 2: his DAT-SPECT-PBR rose from a pretreatment value of 1.42 to 1.72 (closer to normal) and the FDG-PET-PDRP-z-score decreased from 1.02 to 0.30 after 18 months of ADLL-treatment(Oertel et al. 2024).
Follow-up: After three years under continuous ADLL therapy. the 2 iRBD patients hardly experienced any RBD symptoms (maximally severity level 2 (out of 4) - talking and non-aggressive movements during dreaming) with month long periods without RBD symptoms. Follow-up DAT-SPECT imaging revealed a stabilization of the putaminal binding ratio (PBR) in patient 1 and a further improvement of the PBR in patient 2 into the lower normal range (compared to age matched healthy controls). Both patients did not show any signs for motor impairment - assessed with the MDS-UPDRS scale part III. We will present follow-up data after 4 years of ADLL therapy in respect to the RBD-severity score (RBD-SS-3) - rated by patient and spouse - and a further DAT-SPECT. In addition, we will report on the effect of a 1- or 2-year ADLL therapy on the RBD-SS-3 and DAT-SPECT-PBR in few additional iRBD patients.
Conclusion: The results support exploration of whether ADLL might have disease-modifying properties in prodromal PD in a prospective randomized placebo controlled double blind trial.
In-Vivo and Ex-Vivo Retinal Assessment in a Mouse Model of Parkinson's Disease
YL Richard1, PY Lee1, BV Bui1, D Zhao1, A Hoang1, VHY Wong1, DI Finkelstein2, CTO Nguyen1
1 Department of Optometry and Vision Sciences, The University of Melbourne, Parkville, Victoria, Australia,2 The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
Background: The eye is an extension of the brain and in people living with Parkinson's disease changes in 3D retinal scans (optical coherence tomography, OCT) have been found. An alpha-synuclein overaccumulation model has been found to recapitulate these OCT changes but the underlying mechanisms driving these and the time course involved is not understood. This study aims to fill this gap by evaluating in vivo OCT over a range of ages and examine the time course of alpha-synuclein, mitochondrial dysfunction and oxidative stress markers in the mouse retina.
Methods: Human alpha-Syn transgenic mice (A53 T) mice (DOI: 10.1016/s0896-6273(02)00682-7) and wild-type littermates at 3, 5, 8 and 13 months old (n = 9 to 19 per group) underwent OCT imaging (SpectralisR) and western blot analysis of retinal tissue (n = 6/group). Markers of dopamine (Tyrosine hydroxylase,TH), alpha-synuclein (phosphorylated-129,P129), mitochondrial dysfunction (VDAC), oxidative stress (DJ-1) and inflammation (GFAP) were examined. A two-way ANOVA with Sidak's post hoc comparisons was conducted. Deming regression with Spearman correlation (rs) were conducted to correlate retinal layer thicknesses with western blot markers.
Results: A53 T mice exhibited a thinner total retinal thickness (TRT), but thickening of ganglion cell-inner plexiform layer (GCIPL) and photoreceptor (PR) segments compared to their wild-type littermates (p < 0.01 to 0.0001). A significant interaction was found for outer plexiform (OPL) and outer nuclear layer (ONL) thickness, driven by greater thinning with advancing age in A53 T mice (p < 0.01 to 0.05). Western blot analyses showed elevated levels of a-synand GFAP (p < 0.001) in A53 T mice compared to WT. An interaction effect was found with DJ1 (p < 0.05).
P129 was significantly correlated TRT, OPL, ONL, GCIPL (p < 0.05, rs = -0.38, −0.61, −0.53, 0.32), TH correlated with GCIPL (p < 0.05, rs = 0.30), VDAC with TRT, GCIPL (p < 0.05, rs = -0.42; −0.52), DJ-1 with PR (p < 0.05, rs = -0.37) and GFAP with ONL, TRT (p < 0.05 rs = -0.28, −0.39).
Conclusion: This study finds alpha-synuclein overaccumulation, there is greater inflammation and mitochondrial alterations in the retina which are associated with thinning in OCT layers corresponding to photoreceptors and total thickness, as well as thickening of a ganglion cell layer. In the future, correlation with brain markers and intervention with therapeutics would further facilitate our understanding of the mechanistic drivers of OCT and inform their utility as biomarker for PD.
Risk Disclosure Practices in Individuals with Clinical Prodromal Features of Neurodegenerative Disease: A Systematic Review
Anaya Sanjiv Navangul1, Anisa Shahid1, Laura Perez-Carbonell2, Cristina Simonet1,3, Elizabeth Coulthard4,5, Charles Marshall1,3, Alastair Noyce1,3, Laura Smith1
1 Queen Mary University of London,2 Guy's and St Thomas’ NHS Foundation Trust,3 Barts Health NHS Trust,4 University of Bristol,5 North Bristol NHS Trust
Background: Research over the past decade provides strong evidence of a detectable prodromal phase in neurodegenerative conditions. Prodromal clinical features, particularly non-motor and cognitive changes can appear years before clinical diagnosis and may facilitate early detection. However, this prognostic capability raises ethical and clinical challenges around whether, when, and how to disclose risk. In this systematic review, we synthesize multi-stakeholder perspectives on risk disclosure for clinical prodromal features in neurodegenerative disease, according to PRISMA guidelines.
Methods: This systematic review protocol has been registered on PROSPERO (ID:CRD420261279279). Keyword searches were conducted in eight databases (PubMed, Embase, PsycINFO, CINAHL, Web of Science, Scopus, Cochrane Library, Google Scholar) for studies of any design from inception to present. Studies were included if they report on risk disclosure relating to clinical prodromal features (including olfactory dysfunction, autonomic dysfunction, isolated REM sleep behavior disorder (iRBD), and mild cognitive impairment (MCI)) in neurodegenerative conditions (including Alpha-synucleinopathies and Alzheimer's disease). Data extraction focused on study design, population demographics, clinical or professional characteristics, and risk disclosure protocols and perspectives. Findings were examined separately for quantitative and qualitative data, with convergent integrated synthesis to combine findings. Cochrane risk of bias tools were used to assess study quality.
Results: A total of 1239 titles were imported into COVIDENCE, after deduplication 1013 were eligible for screening. Overall, we found a paucity of studies addressing different clinical prodromal features, with most examining risk disclosure in iRBD and MCI. Studies focused on Parkinson's disease and Alzheimer's disease, with limited literature for other conditions (e.g., dementia with Lewy bodies, multiple system atrophy). Preliminary narrative syntheses suggest patients mostly wanted to receive prognostic information; however, most were recruited from existing research cohorts. Disclosure practices reported by healthcare professionals were variable, with potential negative psychological impacts on patients and families highlighted as a concern.
Conclusions: Risk disclosure should be tailored to the individual, considering preferences, mental wellbeing, and symptomology. Further research is needed to differentiate between clinical prodromal features and neurodegenerative conditions, given differences in progression rate and certainty. Efforts to recruit individuals with prodromal markers from real-world, non-research contexts could enhance generalizability to the wider public.
A Prevention-Oriented Trial Framework for Vector-Mediated Contributors to Parkinson's Disease and Related Synucleinopathies
Jennifer Thornton
[None]
Background: Parkinson's disease (PD), dementia with Lewy bodies, and related synucleinopathies lack validated prevention strategies, despite growing evidence that environmental and biological factors may contribute to disease initiation. Epidemiologic and mechanistic data increasingly implicate peripheral tissues as potential sites of early pathology. Dermatologic and ocular conditions—including rosacea, ocular rosacea, seborrheic dermatitis, cataracts, and melanoma—are associated with elevated PD risk and may provide accessible interfaces for early detection and intervention.
Methods: We propose a prevention-oriented, randomized trial enrolling individuals newly diagnosed with PD and individuals at elevated risk based on relevant dermatologic or ocular phenotypes. Participants would undergo standardized skin and ocular swabbing with DNA-based PCR assays to detect mites (e.g., Demodex and scabies) and associated microbes or pathogens. Demodex and scabies mites inhabit sebaceous and lymph-rich tissues, where they consume sebum and lymphatic material. Sebum has been shown to be altered in Parkinson's disease. Participants would be assigned to targeted vector and/or microbe eradication therapies or to standard-of-care control groups. Post-treatment resampling would confirm eradication. Longitudinal follow-up would include clinical assessments (motor and cognitive scales), biomarker evaluation (including cutaneous phosphorylated α-synuclein using tools such as the Syn-One biopsy), and repeat microbiological sampling. Neuroimaging may be incorporated where appropriate.
Results: The primary outcome is whether confirmed eradication of vectors and associated microbes correlates with stabilization, slowed progression, or prevention of synucleinopathy-related clinical and biomarker changes. Secondary outcomes include changes in skin and ocular biomarkers, α-synuclein burden, and longitudinal clinical trajectories. This framework is supported by epidemiologic observations, including reduced PD risk following lindane treatment for scabies, and mechanistic plausibility that mites may carry neurotoxic compounds, transmit microbes, or facilitate prion-like propagation. Additional support includes evidence that house dust mites exacerbate Alzheimer's-related pathology, overlap of Lewy body pathology between Alzheimer's and Parkinson's disease, and shared lymphatic drainage pathways between ocular tissues and the central nervous system, particularly relevant in ocular rosacea.
Conclusions: This Trial Design Forum advances a testable, closed-loop, prevention-focused paradigm integrating dermatologic, ocular, microbiological, and neuropathological markers to evaluate peripheral initiation hypotheses in synucleinopathies. By directly identifying, treating, and verifying eradication of potential vector-mediated contributors, this multidisciplinary framework offers a novel approach to prevention-oriented research in Parkinson's disease and related disorders.
The Space Between: Addressing the needs of individuals at risk for neurodegenerative disease through the Proactive Brain Health Alliance
Sarah Winter1, Anissa Mitchell2, Padma Mahant MD1, Kelly Merkel2
1 CND Life Sciences,2 Parkinson and Movement Disorder Alliance
Background: Advances in research now enable earlier identification of neurodegenerative disease risk due to genetics, family history, alpha-synuclein biomarkers, or prodromal symptoms (iRBD, anosmia, constipation, mood disorders). Individuals in the “space between” risk and formal diagnosis often miss opportunities to adopt neuroprotective lifestyle changes. The Proactive Brain Health Alliance (PBHA) aims to understand the experiences and needs of those at risk or in preclinical or prodromal stages of disease, offering credible health education, evidence-based interventions, and peer connection. Prior research (Schaeffer et al., 2020) underscores the importance of follow-up education, psychosocial support, and self-advocacy resources.
Method: PBHA provides free, virtual, expert-led education on risk factors, early symptoms, neuroprotective lifestyle strategies, and research participation. Interactive discussions within a professionally facilitated support group format enable participants to engage directly with neurologists, receive emotional support, reduce stigma, network with one another, and build self-efficacy. An ongoing survey assesses participants’ experiences with risk identification, current health and disease-state knowledge, and support needs, complemented by post-program feedback polls.
Results: Among survey respondents (n = 28), 75% desire information on lifestyle modification and 75% expressed interest in clinical trials. 45% reported their healthcare provider explained their risk status, and 45% received actionable next steps. 42% cited mental health impacts, and all respondents emphasized the importance of a supportive community. Post-program polls (n = 122) showed 97.5% felt their knowledge improved and 91% planned to make lifestyle or behavioral changes.
Conclusion: Early identification of neurodegenerative risk creates both opportunities and challenges—enabling prevention through lifestyle change but revealing gaps in education and psychosocial support. PBHA findings highlight that many at-risk individuals want credible information, empowerment in risk management, and greater access to resources to mitigate the burden of early risk identification.
Retrospective Evaluation of microRNA-7-5p and Neuron-Derived Alpha-synuclein in prodromal Parkinson's disease as Phenoconversion Biomarkers
Shayan Zadegan1, Kanmani Muthiah1, Praveen Velammal1, Madhu Jatty1, Chris Adams1
1 Neurology Department, The University of Tennessee Health Science Center (UTHSC), Memphis, TN, USA
Background: Studies have found blood extra-cellular vesicle (EV) microRNA-7-5p (miR-7-5p) and neuron-derived EV (NDEV) alpha-synuclein (alpha-syn) were a marker for Parkinson's disease (PD) phenoconversion. The purpose of this study was to corroborate these previous studies and determine if combining these markers would further enrich subjects more likely to phenoconvert.
Methods: Baseline whole blood miR-7-5p, baseline NDEV alpha-syn, time to phenoconversion, baseline age, and gender data were obtained on 313 prodromal PD patients from the Parkinson Progression Marker Initiative. Time to PD phenoconversion was determined by Hoehn and Yahr scores. Log-rank analysis was used to find cutpoints for natural log-transformed miR-7-5p and NDEV alpha-syn levels. Cox regression analysis was used to calculate hazard ratios. Only missing miR-7-5p levels were imputed as 67% of subjects lacked NDEV alpha-syn levels. All statistical analyses were conducted using R software (version 4.3.2), and all tests were 2-sided.
Results: Using cox regression analysis, the cutpoints for miR-7-5p and NDEV alpha-syn were 3.31 (p = 0.008) and 2.91 (p = 0.09), respectively. In separate models using miR-7-5p and NDEV alpha-syn cutpoints, higher miR-7-5p (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.43-3.56, p < 0.001) and NDEV alpha-syn (HR 4.39, 95% CI 1.26-15.3, p = 0.020) was associated with increased phenoconversion. In a single model combining miR-7-5p and NDEV alpha-syn cutpoints, higher combined miR-7-5p and NDEV alpha-syn was associated with higher phenoconversion (HR 2.68, 95% CI 1.05-6.86, p = 0.04). In a model with baseline miR-7-5p, baseline age, and gender, higher baseline miR-7-5p (HR 1.54, 95% CI 1.15-2.06, p = 0.004) and baseline age (HR 1.05, 95% CI 1.02-1.09, p = 0.002) were associated with increased phenoconversion. In a model with baseline NDEV alpha-syn, baseline age, and gender, baseline age (HR 1.07, 95% CI 1.00-1.14, p = 0.04) but not higher baseline NDEV alpha-syn (HR 1.42, 95% CI 0.84-2.40, p = 0.2) was associated with increased phenoconversion. In a model with baseline NDEV alpha-syn, baseline miR-7-5p, gender, and baseline age, baseline age (HR 1.07, 95% CI 1.00-1.14, p = 0.046) but neither baseline miR-7-5p (HR 2.04, 95%CI 0.94-4.42, p = 0.07) nor baseline NDEV (HR 1.38, 95% CI 0.81-2.36, p = 0.2) was associated with increased phenoconversion.
Conclusion: MiR-7-5p and NDEV alpha-syn could be used together to enrich prodromal patients likely to develop PD earlier in disease-modifying clinical trials.
IMMUNE-MODULATION IN PRODROMAL PARKINSON'S DISEASE: A RANDOMISED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2a IRBD TRIAL PROTOCOL
Karolien Groenewald1, Johannes Klein1, Michele Hu1, Tim Fryer2, Simon JG Lewis3, Nicolas Dzamko3, Michelle Chua3, Andrew M. Scott4, Benjamin Nguyen4, Jana Baskar5, Dieter Hamprecht5, Jacqui Everett5, Joanna Leadbetter5, Jennifer Maschmann6, Sanket Patekar6, Graham Smith2
1 University of Oxford,2 University of Cambridge,3 Macquarie University,4 University of Melbourne,5 Syntara Limited,6 Novotech
Introduction: Isolated REM-sleep behaviour disorder (iRBD) is a well described prodromal feature of synuclein diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and less frequently multiple system atrophy (MSA). Significantly, neuro-inflammation has been reported in iRBD and is potentially a major contributor to synuclein accumulation and propagation. Previously, TSPO PET imaging has been used to demonstrate neuro-inflammation by binding to activated microglia in both iRBD (prodromal) and manifest PD. Although immune-modulating therapies have not shown direct benefit in PD, to date, there are no trials in prodromal disease. This paper describes the protocol for the first immune-modulating drug trial in iRBD that could provide evidence for an early neuro-protective intervention strategy in prodromal PD.
Methods and analysis: This is a phase 2a, randomised, double-blind, placebo-controlled, parallel-site trial of the small molecule PXS-4728A in iRBD. Forty participants with definitive iRBD, mild (sub-clinical) parkinsonism and either/both hyposmia or reduced colour discrimination will be randomised at a ratio of 3:1 (treatment: placebo) for a 12-week treatment period, followed by a 12-week washout period. The primary outcome will assess the effect of PXS-4728A on neuro-inflammation measured primarily by TSPO ([11C]-PK11195) PET binding across nigro-striato-cortical regions in the treatment arm from baseline to week 12. Drug safety and tolerability will also be assessed as a primary outcome. Secondary outcomes will include further regional and whole-brain analysis of changes in neuro-inflammation as measured by TSPO ([11C]-PK11195) PET non-displaceable binding potential from baseline to week 12. Exploratory outcomes will assess change in clinical scales of prodromal symptoms (cognitive, mood, motor and other non-motor such as dream enactment), biological markers from collected blood and CSF, and digital biomarkers (actigraphy, motor and cognitive).
Ethics and dissemination: This work is supported by Parkinson's UK through its Parkinson's Virtual Biotech program in partnership with the Parkinson's Foundation. This study is approved by the Cambridge South Research Ethics Committee, IRAS project ID 1008383, REC reference 23/EE/0256 and has been accepted by the Medicines and Healthcare products Regulatory Agency (CTA 22239/0006/001-0001). Approval was also granted by the Administration of Radioactive Substances Advisory Committee. For Australia, approval was granted by Bellberry HREC (Ref: 2023-03-289-A-5) and Macquarie University HREC (Ref: 520251690265568) under ClinicalTrials.gov ID: NCT05904717. The results of this trial will be disseminated through scientific journal publication and presentation at relevant conferences.
Environmental exposures and longitudinal change in clinical outcome measures in LRRK2 G2019S non-manifest carriers
Natalia Chunga1, Peggy Auinger2,3, Blanca Y. Valdovinos3, Renee Wilson2, Emily Hartman2, Hannah Mesmer3, William Barbosa3, Nami Shah3, Roy N. Alcalay4,5, Kevin Biglan2,6, Daniel Kinel2,3, Caroline M. Tanner7, Robert G. Holloway3, E. Ray Dorsey2,3, Ruth B. Schneider2,3
1 Department of Neurology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA,2 Center for Health + Technology, University of Rochester, Rochester, NY,3 Department of Neurology, University of Rochester, Rochester, NY,4 Department of Neurology, Columbia University, New York, NY,5 Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel,6 Eli Lilly and Company, Indianapolis, IN,7 Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA
BACKGROUND: The LRRK2 G2019S variant is the most common cause of autosomal dominant Parkinson's disease (PD) with a lifetime penetrance of ∼30%. Environmental and lifestyle factors, including protective factors such as tobacco smoking and caffeine consumption, and risk factors such as exposures to pesticides and solvents have been linked to PD. Recent studies suggest that pesticide exposure may be associated with a more severe disease course. We evaluated whether environmental exposures were associated with longitudinal changes in clinical characteristics of LRRK2 G2019S non-manifest carriers over a three-year period.
METHODS: We analyzed a remote, prospective cohort of LRRK2 G2019S carriers without PD. Environmental exposures were assessed at baseline using the PD-Risk Factor Questionnaire, which includes questions on tobacco smoking, caffeine use, and exposures to pesticides, solvents, and degreasers. Participants were followed for 36 months and completed 4 video-based visits (Baseline, Year 1, Year 2, Year 3). Visits included assessments of motor (MDS-UPDRS part II, III), cognitive (MoCA), psychiatric (Beck Depression Inventory-II, Parkinson Anxiety Scale), autonomic (Scales for Outcomes in PD-Autonomic), and sleep (Epworth Sleepiness Scale, REM Sleep Behavior Disorder Questionnaire) domains. Participants were grouped by environmental exposure status (smoking/non-smoking history, caffeine/non-caffeine use, pesticide exposure/non-exposure, and solvents or degreasers exposure/non-exposure). Longitudinal changes in clinical characteristics were compared between groups using generalized estimating equations. Bonferroni method was applied for multiple comparisons, with an adjusted significance level of p < 0.0042.
RESULTS: A total of 211 LRRK2 G2019S non-manifest carriers were enrolled, of whom 204 contributed longitudinal data with 199 (98%) completing assessments at Year 1, 192 (94%) at Year 2, and 184 (90%) at Year 3. At baseline, the mean age was 53.6 (SD 15.0) years, and there were 122 (60%) women, 197 (97%) White, 15 (7%) Hispanic, and 151 (74%) Ashkenazi Jewish participants. Eighty-two (40%) reported smoking ≥100 lifetime cigarettes, 171 (84%) current caffeine use, 139 (68%) prior pesticide exposure in non-work settings, and 24 (12%) prior solvents or degreasers exposure. After adjustment for multiple comparisons, no significant associations were observed between environmental exposures and longitudinal changes in clinical characteristics.
CONCLUSION: We did not find significant associations between environmental exposures or lifestyle factors and longitudinal change in remotely assessed clinical characteristics among LRKK2 G2019S non-manifest carriers over 36 months. Study limitations, including potential recall bias and small sample size for certain exposures, might have limited the ability to detect effects. Objective environmental exposure measures and longer follow-up may help clarify gene-environment interactions.
Integrating Serum Neurofilament Light with Multimodal Clinical Markers for Phenoconversion Prediction in Prodromal Parkinson's Disease
Marufjon Salokhiddinov1, Dileep Kumar2, Lola Abdurakhimova1
1 Kimyo International University,2 Global Research & Scientific Collaborations, United Artifical Intelligence
Background: Accurate identification of individuals at highest risk of transitioning from prodromal to clinically manifest PD is essential for the design of prevention and disease-modifying trials. Although several biomarkers demonstrate significant group-level differences, their translation into reliable individual-level prediction remains limited. Serum NfL, a blood-based indicator of neuroaxonal injury, when combined with established prodromal clinical features, may enhance phenoconversion risk stratification.
Methods: A total of 368 prodromal participants from the Parkinson's Progression Markers Initiative (PPMI) cohort with available baseline serum NfL measurements and longitudinal follow-up were included (mean follow-up 7.0 ± 2.7 years). Prodromal status was defined by the presence of REM sleep behavior disorder (RBD), hyposmia, or pathogenic genetic variants (LRRK2, GBA, SNCA). Phenoconversion was defined as a clinical diagnosis of PD. Predictors included serum NfL, MDS-UPDRS Parts I-III, University of Pennsylvania Smell Identification Test (UPSIT), REM sleep behavior scores, Montreal Cognitive Assessment (MoCA), and SCOPA-AUT autonomic function scores. Cox proportional hazards models and random survival forest models were constructed to compare three approaches: NfL alone, clinical markers alone, and an integrated NfL + clinical marker model. Model performance was assessed using time-dependent concordance indices with five-fold cross-validation. Group comparisons were performed using t-tests and chi-square tests.
Results: Among the 368 participants (mean age 63.1 ± 7.6 years; 47.3% male), 54 individuals (14.7%) converted to PD during follow-up. Phenoconverters were significantly older, more frequently male, and demonstrated higher baseline MDS-UPDRS Part II and III scores, lower UPSIT olfactory scores, higher REM sleep behavior scores, higher Epworth Sleepiness Scale scores, and slightly higher MoCA scores compared with non-converters. Baseline serum NfL concentrations did not differ between converters and non-converters. Phenoconverters included both genetic mutation carriers and sporadic prodromal cases. The integrated multimodal model combining serum NfL with clinical markers showed superior performance for individual-level phenoconversion prediction compared with single-domain models.
Conclusions: Combining serum NfL with multimodal clinical markers within a machine-learning framework enables improved individual-level prediction of phenoconversion risk in prodromal PD. Although baseline NfL levels alone do not distinguish converters from non-converters, longitudinal NfL trajectories integrated with motor, olfactory, sleep, and cognitive measures may help identify individuals at highest risk. This scalable blood-based multimodal approach holds promise for targeted enrollment in prodromal PD prevention trials.
The ISLAND Sleep Study: A community-based model to identify and monitor prodromal α-synucleinopathies
Samantha Bramich1, Alastair J Noyce2, Anna E King1, Laura Pérez-Carbonell3, Séan Higgins3, Cristina Simonet2, Aidan Bindoff1, Sharon L Naismith4, Eddy Roccati1, James C Vickers1, Jane Alty1
1 Wicking Dementia Research and Education Centre, University of Tasmania,2 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London,3 Sleep Disorders Centre, Guy's and St Thomas’ NHS Foundation Trust,4 School of Psychology, Brain and Mind Centre, University of Sydney
Background: Preventive and disease-modifying trials for Parkinson's disease (PD) and related α-synucleinopathies require reliable, scalable strategies to identify individuals in the prodromal phase. Isolated rapid eye movement sleep behaviour disorder (iRBD) is one of the most specific clinical markers of prodromal α-synucleinopathies, but it is underdiagnosed as current diagnostic pathways are resource-intensive and not widely accessible. The ISLAND (Island Study Linking Ageing and Neurodegenerative Disease) Sleep Study was designed as a community-based, multi-stage framework to identify individuals with iRBD and elevated risk of α-synucleinopathy using remote self-testing and targeted home-based diagnostic confirmation. Here, we synthesise findings from two complementary components of the study to demonstrate its relevance for preventive trial design.
Methods: 2891 community-dwelling adults aged ≥50 years were recruited from Tasmania, a rural/regional area of Australia. They completed online sleep and health questionnaires to screen for iRBD, alongside unsupervised home-based assessments of motor, cognitive, autonomic and olfactory function. Participants with probable RBD (pRBD) were compared with controls across established prodromal markers. Building on this screening framework, the Tasmania-London (TASLON) protocol applied a new structured clinical interview via telephone followed by home-based video-polysomnography (vPSG) to confirm iRBD in the probable cohort.
Results: Participants screening positive for pRBD exhibited a higher prevalence of non-motor and motor features associated with prodromal PD and other α-synucleinopathies including orthostatic intolerance, olfactory impairment and hand motor dysfunction, all detectable via remote assessment. These findings demonstrate that community self-testing can capture a phenotypic profile consistent with early α-synucleinopathy. In addition, the TASLON protocol has identified 25 participants with confirmed iRBD so far, further showing that home-based vPSG can be implemented in the community to improve timely and accurate access to iRBD detection.
Conclusion: The ISLAND Sleep Study provides a scalable, stepwise model for identifying prodromal α-synucleinopathies in the community, from initial remote risk stratification to home-based diagnostic confirmation and self-administered methods for longitudinal symptom tracking. Future projects will include analysis of biospecimen samples, including blood and sebum, to investigate biological markers of iRBD. This integrated approach directly addresses key barriers to recruitment for preventive and disease-modifying trials in rural and remote parts of the world and offers a practical framework for population-level strategies in future α-synucleinopathy prevention studies.
Multimodal Remote Digital Phenotyping for Detecting and Tracking Early Parkinsonian Change in LRRK2 Carriers
T M Tariq Adnan1, Abdelrahman Abdelkader1, Md Saiful Islam1, Ehsan Hoque1, Ruth Schneider2
1 University of Rochester,2 University of Rochester Medical Center
Background: Early identification of prodromal Parkinson's disease (PD) remains a central challenge for early-stage disease characterization, particularly among genetically at-risk populations such as LRRK2 variant carriers. Advances in remote, scalable digital phenotyping offer opportunities to detect subtle motor and speech-related changes prior to clinical diagnosis. Here, we present a video-based framework for differentiating non-manifest LRRK2 G2019S carriers from controls and for longitudinally tracking motor function using remotely collected task-based recordings.
Methods: We curated a multimodal dataset comprising 950 non-PD participants—130 non-manifest LRRK2 G2019S carriers (predominantly white, 57% female, and 21% <=50 years) from a longitudinal observational cohort study (VALOR-PD) that follows carriers with and without PD, alongside 820 controls (12% non-white, 57% female, and 12% <=50 years) from complementary cross-sectional and longitudinal cohorts. Although controls were not genetically tested, the prevalence of LRRK2 G2019S in the general population is very low. Participants completed three standardized, remotely recorded kinetic tasks: bilateral finger tapping, smile expression, and a pangram utterance. From these videos, we extracted interpretable hand kinematics, facial action units, and acoustic speech measures.
To assess whether subtle digital motor signatures distinguish genetically at-risk individuals before clinical manifestation, we retrained UFNet—a multimodal fusion architecture originally developed for PD classification—as a binary classifier separating non-manifest LRRK2 carriers from controls. In parallel, we introduce PD Weigh-In, a complementary digital framework for quantifying Parkinsonian motor burden on a continuous scale.
Results: UFNet achieved strong discrimination, with an AUROC of 0.94, accuracy of 0.92, specificity of 0.95, and sensitivity of 0.77, demonstrating that remotely acquired task-derived features capture signals associated with genetic risk status despite the absence of overt clinical symptoms. In parallel, PD Weigh-In, validated on the complete longitudinal VALOR-PD cohort (38 manifest PD and 130 non-manifest LRRK2 carriers), demonstrated moderate to strong alignment with clinician-rated remote MDS-UPDRS Part III scores (Spearman r ≈ 0.84). Notably, in two participants who developed manifest PD during follow-up, digital severity trajectories mirrored clinically observed worsening based on remotely collected assessments.
Conclusions: These findings highlight the potential of remote, video-based multimodal assessments to support early risk stratification, longitudinal symptom tracking, and scalable monitoring in genetically at-risk populations. Such low-burden digital measures may complement traditional clinical evaluations and inform future study designs.
Slow-SPEED UK: A Double-Blind Randomised Feasibility Trial of a Remote Gamified Physical Activity Programme in Adults with Hyposmia
Viktoria Azoidou1, Thomas Oosterhof2, Eleanor Mitchell1, Bastiaan Bloem2, Carl Philpott3, Sirwan Darweesh2, Alastair Noyce1
1 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.,2 Center of Expertise for Parkinson and Movement Disorders, Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.,3 Norfolk Smell & Taste Clinic, James Paget University Hospital, Gorleston, Norfolk, UK; and Rhinology & Olfactology Research Group, Norwich Medical School, University of East Anglia, Norwich, UK.
Background: Parkinson's disease (PD) lacks proven disease-modifying therapies, underscoring the need for prevention-focused interventions during the prodromal phase. Hyposmia is among the most prevalent prodromal markers and is associated with an approximately fourfold increased risk of PD. Exercise is safe, scalable, and biologically plausible as a preventive strategy; however, long-term, harmonized prevention trial designs in at-risk populations remain limited. Slow-SPEED UK (Slowing Parkinson's Early through Exercise Dosage) evaluates the feasibility of delivering a sustained, fully remote, gamified physical activity intervention in adults with hyposmia.
Methods: Slow-SPEED UK is an 18-month, double-blind, randomized controlled feasibility trial embedded within the international Slow-SPEED program. One hundred ten adults aged ≥40 years with University of Pennsylvania Smell Identification Test-confirmed hyposmia (≤15th percentile) and low baseline physical activity (<7000 steps/day) are randomized 1:1 to a full-dose intervention (+100% individualized step target) or an active control (+10%). Both groups receive a wrist-worn activity tracker, smartphone application, and gamified behavioral support with a virtual coach in Slow-SPEED App chatbox supporting throughout the trial. Assessments are conducted at baseline (in person), 9 months (remote), and 18 months (in person). Optional blood sampling and skin-punch biopsies are collected in a subset to assess feasibility of biospecimen acquisition. The primary objective is to assess the feasibility, acceptability, and safety of a remote 18-month physical-activity programme, with the primary endpoint being change in average daily step count. Secondary objectives are exploratory, examining moderate-to-vigorous physical activity levels, digital mobility and fitness measures, prodromal motor and non-motor features, optional biological measures, participant-reported outcomes, and feasibility of long-term remote monitoring, all analyzed descriptively to inform future trials.
Results: Recruitment is scheduled to begin in January 2026. Planned analyses include feasibility metrics, safety outcomes, and baseline cohort characteristics. Exploratory descriptive analyses will examine physical activity patterns, digital mobility markers, prodromal motor and non-motor features, and acceptability of optional biomarker collection. Preliminary results will be available by April 2026 to be presented at the trial design forum. Final results are expected in September 2027.
Conclusion: Slow-SPEED UK provides a rigorously designed platform for prevention-oriented PD trial development by testing the feasibility of a long-term, remote, gamified exercise intervention in individuals with prodromal features. Additionally, harmonization with parallel cohorts in the Netherlands and United States aims to strengthen scalability and inform future definitive prevention trials using non-pharmacological strategies.
Advancing Primary Prevention of Parkinson's Disease
Jennifer Purks1, Sneha Mantri2, Rhoda Au3, Anastasia Barnes1, James Beck2, Kathleen Blake4, Wendy Dahl5, Briana de Miranda6, Ray Dorsey7, Ruogu Fang5, J. Daniel Fenn1, Sue Goldie8, Samuel M. Goldman9, Paulina Gonzalez-Latapi10, Diego Guarin5, Brittany Kryzyzanowski7, Nicole Lessard2, Andi Lipstein Fristedt2, Tejas R. Mehta1, Monica Norcini11, Peggy Borum5, Dawn Schiehser1, Michael A. Schwarzschild12, Caroline (Carlie) Tanner9, Alexis Temkin13, J. Bryan Unruh14, Chris Vulpe15, Kristin Wallock2, Cordelia Walz2, Michael S. Okun1
1 University of Florida Health, Norman Fixel Institute for Neurological Diseases,2 Parkinson's Foundation,3 Boston University,4 Parkinson's Foundation Patient Advisory Council,5 University of Florida,6 University of Alabama at Birmingham,7 Atria Health and Research Institute,8 Harvard University,9 University of California - San Francisco,10 Northwestern University,11 Fresco Parkinson Institute Italia Onlus Foundation,12 Massachusetts General Hospital,13 Environmental Working Group,14 University of Florida, Institute of Food and Agricultural Sciences,15 University of Florida, Center for Environmental and Human Toxicology
Background: Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, with profound individual, family, health system, and societal economic impacts. Strategies to prevent PD are urgently needed. To this end, a Primary PD Prevention Think Tank was held at the University of Florida by the Parkinson's Foundation and the Fixel Institute.
Methods: Over two days of discussion, expert attendees from a wide variety of disciplines, including movement disorders neurology, environmental sciences, agriculture, public policy, public health, and patient advocate groups, convened. The group reviewed prevention research in PD, analyzed lessons learned from prevention research across other disorders, and discussed ways to inform regulatory and policy actions to advance primary prevention in PD. The group also discussed secondary and tertiary PD prevention.
Results: The Think Tank consensus yielded 7 key action items for the PD community, both domestically and internationally, to consider for primary prevention: policy and behavior change, science communication, coalition-building, cohort phenotyping, counts of incidence and prevalence, cross-disciplinary strategy, and scientific and financial commitment at all levels. These action items have additional benefits applicable to secondary and tertiary PD prevention.
Conclusion: The current rapid rise in both global PD incidence and prevalence necessitates urgent action. This rate of increase in PD suggests that environmental exposures (including in water, soil, and air) and/or lifestyle factors may contribute to the diagnosis of manifest motor PD, in conjunction with genetic predisposition. Exposures may be active (e.g., spraying pesticides, ingesting dopamine-blocking or dopamine-toxic agents) or passive (e.g., volatilization of toxicants with distant spread, contamination of groundwater or other sources). Steps to address these issues may decrease rates of disability, premature death from PD, and overall disease burden, and these themes should be incorporated into PD prevention research.
Discordant Sibling Analysis Reveals Peripheral Biomarker Patterns in GBA1-Associated Parkinson's Disease
Tommaso Filidei1, Pierfrancesco Mitrotti1, Luca Gallo1, Rosaria Calabrese2, Loris Bandirali1, Rita Stiuso2, Marta Picascia2, Cristina Tassorelli1, Enza Maria Valente1, Silvia Paola Caminiti1, Micol Avenali1
1 Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy,2 IRCCS Mondino Foundation, Pavia, Italy
Background: Mutations in the glucocerebrosidase gene (GBA1) represent one of the most important genetic risk factors for Parkinson's disease, yet disease penetrance is incomplete and highly variable. Understanding biological factors associated with disease expression among genetically at-risk individuals is essential for early risk stratification and prevention-oriented trial design. Sibling-based analyses, comparing affected and unaffected carriers within the same family, provide a powerful approach to minimize genetic and environmental confounding. The aim of this study was to explore intrafamilial differences in peripheral biomarkers among GBA1 mutation carriers with discordant Parkinson's disease status.
Methods: We conducted an exploratory, sibling-based observational study including families with GBA1 mutation carriers. Families with at least two siblings with available baseline measurements of glucocerebrosidase activity and alpha-synuclein levels in peripheral blood mononuclear cells were included. Intrafamilial comparisons were performed between Parkinson's disease-affected siblings and non-manifesting carriers. Given the paired design and small sample size, non-parametric statistical methods were applied, including Wilcoxon signed-rank tests, exact permutation tests, and bootstrap resampling. Log transformation was applied to alpha-synuclein values to reduce skewness.
Results: Five families met inclusion criteria, providing five sibling pairs for glucocerebrosidase activity and four complete sibling pairs for alpha-synuclein. Glucocerebrosidase activity showed heterogeneous intrafamilial differences, with small effect sizes and inconsistent directionality; non-parametric and permutation tests were not significant, and the bootstrap 95% confidence interval for the mean paired difference included zero. In contrast, alpha-synuclein levels were higher in the Parkinson's disease-affected sibling in all complete pairs, with a mean paired difference of approximately +341 units (bootstrap 95% confidence interval 106.88-673.91). Log transformation confirmed the direction of the effect, and resampling analyses supported a positive sibling-based association despite p values not reaching conventional significance thresholds.
Conclusion: In a sibling-based analysis of GBA1 mutation carriers, peripheral biomarkers showed distinct patterns associated with disease expression. While glucocerebrosidase activity exhibited heterogeneous intrafamilial differences, alpha-synuclein levels were consistently higher in Parkinson's disease-affected siblings. These findings highlight the value of sibling-based biomarker studies for identifying modifiers of disease penetrance and support their relevance for early risk stratification and prevention-oriented Parkinson's disease trial design.
Phenoconversion in Pure Autonomic Failure: A Systematic Review and Meta-Analysis
Sasivimol Virameteekul1, Ilenia Bonini1, Nicole Campese1, Philipp Mahlknecht1, Manuela Tan Werner Poewe1, Alastair J. Noyce1, Alessandra Fanciulli1, Eduardo de Pablo-Fernández1
1 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, UK
Importance: pure autonomic failure (PAF) can be the prodromal presentation of Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) although phenoconversion rates and predictors have not been systematically reported.
Objective: to estimate phenoconversion rates for MSA, PD and DLB separately and grouped as central α-synucleinopathies, and identify clinical predictors of phenoconversion in patients with PAF.
Data sources: PubMed and EMBASE databases from inception to June 2025.
Study selection: longitudinal studies including confirmed PAF patients reporting data on incidence and/or predictors of phenoconversion.
Data extraction and synthesis: studies were screened and data extracted by two independent investigators according to PRISMA guidelines. Meta-analysis was performed using generic inverse-variance random-effects models.
Main outcome(s) and measure(s): PD, DLB, MSA, and central α-synucleinopathy phenoconversion incidence rates as per 100 person-years were the main outcome. Incidence rates were log-transformed and pooled using random-effects meta-analysis. Clinical predictors of phenoconversion were reported as secondary outcomes. Prediction intervals and meta-regression explored study-level moderators.
Results: Nine studies comprising 900 individuals with PAF were included. During 6.4 ± 2.0 years of follow up, 270 of 900 individuals with PAF (30%) phenoconverted to a central α-synucleinopathy (12% to MSA, 11% to DLB, 7% to PD) with a pooled incidence rate of 5.09 per 100 person-years (95% CI 3.79-6.85). Phenoconversion rates for MSA [1.96 (95% CI 1.29-2.99)] were highest in the first years of follow-up, whilst Lewy body disorders showed more constant phenoconversion rates [DLB 1.56 (95% CI 0.94-2.61); PD 1.35 (95% CI 0.75-2.41)]. Hyposmia was the only predictor with diagnostic value to distinguish between PD / DLB (hyposmia 1.88, 95% CI 1.26-2.97) and MSA phenoconverters, although REM sleep behaviour disorder (RBD) and subtle motor signs were consistent predictors of phenoconversion to any central α-synucleinopathy. Heterogeneity was partly explained by follow-up duration.
Conclusions and relevance: PAF is a possible prodromal presentation of PD, DLB or MSA with phenoconversion incidence rates similar to RBD. A combination of clinical (RBD, subtle motor signs, hyposmia) and in-development biomarkers may help refine the phenoconversion trajectories of people with PAF providing an invaluable opportunity for early diagnosis and intervention.
Quantitative Landscape Analysis of Disease-Modifying Parkinson's Therapies in Preclinical Development
Jamir Pitton Rissardo1, Ana Leticia Fornari Caprara1
1 Cooper University Hospital
OBJECTIVE: To quantitatively describe therapeutic modalities, biological targets, and development stages within the preclinical Parkinson's disease (PD) therapeutic pipeline using structured data mining of the Parkinson's Hope List.
BACKGROUND: Parkinson's disease remains without an approved disease-modifying therapy despite increasing mechanistic understanding. The expanding number of investigational programs underscores the need for quantitative synthesis to identify dominant translational priorities and emerging therapeutic strategies.
DESIGN/METHODS: The November 2025 Parkinson's Hope List was systematically reviewed. All research-stage entries were extracted and standardized. Programs were categorized by development stage, therapeutic modality, and mechanistic target using structured fields and keyword-based annotation of mechanism descriptions. Descriptive analyses were performed to quantify distributions and cross-relationships among categories.
RESULTS: A total of 114 unique Parkinson's disease research-stage therapeutic programs were identified, all designated as disease-modifying. Eighty programs (70.2%) were classified as preclinical, while thirty-four (29.8%) were in discovery. Therapeutic modalities were predominantly new chemical entities, accounting for 83 programs (72.8%). Additional modalities included 13 gene therapy programs (11.4%), 9 cell-based therapies (7.9%), 6 repurposed agents (5.3%), and 3 reformulated compounds (2.6%). Mechanistic analysis identified 13 programs targeting alpha-synuclein aggregation, propagation, or clearance, 10 targeting lysosomal or GBA-related pathways, 7 targeting inflammatory signaling including inflammasome or toll-like receptor pathways, 5 targeting LRRK2, 5 addressing mitochondrial dysfunction or mitophagy, 6 targeting microbiome-related mechanisms, and 7 employing immunotherapeutic strategies such as antibodies, vaccines, or immune cell modulation. Of the 13 gene therapy programs, 3 focused specifically on GBA-related approaches, while others targeted PARKIN, Klotho signaling, or RNA-based mechanisms.
CONCLUSIONS: This quantitative analysis demonstrates that the current Parkinson's disease therapeutic pipeline is heavily weighted toward early-stage, disease-modifying strategies, with substantial convergence on proteostasis, lysosomal biology, immune signaling, mitochondrial integrity, and gut-brain axis mechanisms. The dominance of preclinical programs and small-molecule approaches highlights both the breadth of innovation and the substantial translational distance remaining before clinical validation.
Rethinking the PD Gut: A declining microbial ecosystem?
Bianca Palushaj1
1 Stanford University
Objective: To overcome the limitations of relative abundance-based microbiome analyses by quantifying absolute microbial changes in Parkinson's disease (PD) and integrating these with immune transcriptomics data to provide deeper mechanistic insights into the microbiome-immune-brain axis.
Background: PD is characterized by both motor symptoms, such as bradykinesia, and non-motor symptoms, including gastrointestinal dysfunction. Increasing evidence points to the gut as a key player in PD pathophysiology, and the gut microbiome has become a major focus of investigation. Prior studies have compared the relative abundance of bacterial taxa between PD and non-PD participants; however, relative abundance data are inherently proportional, meaning that an apparent increase in one taxon may reflect a proportional shift rather than a true change in its absolute quantity. This limitation can obscure the extent and nature of microbial dysbiosis and its potential mechanistic role in disease.
Methods: We quantified total microbial load and absolute abundance of bacterial taxa in stool samples from PD participants (n = 112) and non-PD controls (n = 83), of whom 96% shared a household with a PD participant to minimize environmental confounding. We developed a machine learning model to predict total microbial load and validated predicted against measured values. We also performed bulk RNA-seq on peripheral blood mononuclear cells (PBMCs) and are collaborating to implement a novel technique, Host-Microbe Groups Interaction Model (HM-GIM), which uses a probabilistic deep learning to simultaneously infer groups of host genes and microbes and dependencies between them.
Results: Total microbial load, measured by 16S rRNA bacterial copies per dry gram of stool, was significantly reduced in PD (p = 0.00467). This finding was supported by our machine learning predictions, showing a near 1:1 relationship between measured and predicted total microbial load (R2 = 0.92, Spearman's r = 0.96). Comparing absolute abundance analyses with published relative abundance results revealed both corroborating and contradictory findings, highlighting the limitations of relying solely on relative abundance measures and revealing novel disease association. Notably, species associated with PD tend to be depleted rather than enriched.
Conclusion: Together, these findings suggest that the PD gut environment is less supportive of microbial growth. Defining environmental shifts is essential for guiding the development of future microbiome-based therapeutics in PD. By integrating absolute microbiome quantification with immune transcriptomics, this study moves beyond descriptive taxonomic shifts to a more mechanistically informative framework for understanding gut-immune-brain interactions in PD.
Proactive monitoring to prevent complications in Parkinson's disease: Protocol for a single-arm real-world feasibility study
Tessa F. Peerbolte1, Marjan J. Meinders2, Bas R. Bloem1, Sirwan K.L. Darweesh1, Sanne W. van den Berg1
1 Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Center of Expertise for Parkinson and Movement Disorders, Nijmegen, The Netherlands.,2 Radboud university medical center, Research Institute for Medical Innovation, Department of Neurology, Center of Expertise for Parkinson's and Movement Disorders, Nijmegen, Netherlands
Background: Medical complications in Parkinson Disease (PD) significantly increase hospitalization rates, mortality, and healthcare costs, while imposing substantial burden on patients and caregivers. Falls, pneumonia, urinary tract infections, mood disorders, and psychosis are among the most impactful complications. These complications are preceded by modifiable causal factors, suggesting opportunities for prevention. Remote monitoring could enable early detection of these factors and support proactive care. However, its feasibility for preventing complications in PD remains unclear.
Objective: This study aims to evaluate the real-world feasibility of a remote monitoring service for early-detection of causal factors and proactive care to prevent PD complications.
Methods: This is a single-arm feasibility study using a sequential explanatory mixed-methods design. 40 people with Parkinson disease (PwP), their specialized Parkinson nurse and outpatient clinic assistants of the Radboudumc will be recruited. For three months, PwP will participate in a remote monitoring service involving completion of scheduled questionnaires via an application to assess causal factors for complications. Alerts are generated when predefined thresholds are met, prompting follow-up by healthcare professionals. Pre- and post-intervention questionnaires, electronic medical records and use data will quantitatively assess feasibility across three service domains: Tool (system usability, satisfaction, perceived value), Team (impact on organisation and care), and Routine (integration in daily life and clinical practice). Other outcomes describe the detection rate of causal factors, the nature of follow-up care provided in response to the alerts, and the occurrence of complications and hospital admission. We will qualitatively explore the experiences of PwP, their nurses and outpatient clinic assistants with using the remote monitoring service. Semi-structured interviews will be conducted in a purposively selected subsample with varying levels of intervention satisfaction and use. The interviews will be audio-recorded, transcribed verbatim, coded by two independent researchers, and analysed using thematic analysis.
Results: The study will explore the feasibility of remote monitoring of complications in real-world clinical practice across three service domains. Overall feasibility will be primarily determined based on usability measured by the system usability scale (SUS) and implementation fidelity. Our intervention will be considered feasible if the mean SUS score is ≥68, and ≥80% of the monitoring questionnaires are completed by PwP, alerts are opened by healthcare professionals and alerts did result in a follow-up from a healthcare professional.
Conclusion: Findings will inform the design of a future efficacy trial and provide recommendations for refining the implementation of proactive care using a remote monitoring service into PD management.
Implementation of prediction modeling to assess oral and gut microbial signatures associated with brain or body-first Parkinson's disease - a Fox Insight data study
Julie Andersen1, Gordon Lithgow1, Açucena Rodrigues Dos Santos Soares2, Jeremy Tachiki3, Eli Febbo4, Kevin Schneider1, David Furman1, Minna Schmidt1
1 The Buck Institute,2 Compass UOL,3 Brown University,4 Middlebury College
Parkinson's disease (PD) is an age-related neurodegenerative syndrome. The progressive nature of PD has been suggested to correlate not only with continued loss of dopaminergic innervation in the striatum but also with the spread of α-synuclein aggregates throughout the brain and in the periphery (Braak hypothesis). More. recently, studies have shown that Parkinson's can occur from separate etiologies — the gastrointestinal (GI) system and the olfactory bulb (OB). As such, there are now believed to be two Parkinson's subtypes — body-first and brain-first, respectively. Given that environmental factors are considered to increase the risk of Parkinson's and the microbiome is strongly amenable to change from various environmental triggers, microbial signatures can present helpful biomarkers in diagnosis, progression, and uncover underlying disease mechanisms. However, microbial signatures have not yet been examined in relationship to the etiological differences between body-first and brain-first PD. In order to approach this question, we analyzed human microbiome and questionnaire data made available from Fox Insight (Michael J. Fox Foundation) to determine whether bacterial signatures from stool and saliva samples can predict body-first or brain-first Parkinson's. After filtering the data, we found the 31 participants could be grouped into one of the two groups. Our results show that there are three gut bacteria and three saliva bacteria which show strong predictive strength in distinguishing body-first from brain-first individuals. From stool samples, these bacteria are Phocaeicola dorei, Phocaeicola vulgatus, and Ruminococcus bicirculans. From saliva samples, these bacteria are Neissera subflava, Haemophilus influenzae, and Rothia SGB49305. Importantly, P. dorei and R. bicirculans are more abundant in those with brain-first PD, while P. vulgatus is more abundant in body-first individuals. From saliva samples, we see that N. subflava and H. influenzae are more abundant in individuals with brain-first PD, while R. SGB49305 is more abundant in body-first PD. In the future, we hope to model how altering these microbiomes with ‘exercise-probiotics’ (bacterial hits we uncovered in a parallel project exploring the effects of exercise on the PD microbiome) may impact Parkinson's symptoms.
National Digital Screening for Parkinson's Disease and Prodromal PD by the “CheckPD” Platform in Thailand: Clinical Profile Analysis and the Implementation of Lifestyle Intervention “EAT MOVE SLEEP”
Jirada Sringea1, Saisamorn Phumphid1, Chanawat Anan1, Teerawat Laosombut1, Jeeranun Meesri1, Sunaree Wekhinhiran1, Natthaphat Leabthong1, Piyapon Rattanajun1, Pattamon Panyakaew1, Suppata Maytharakcheep1, Onanong Phokaewvarangkul1, Warongporn Phuenpathom1, Priya Jagota1, Varis Ratanasirisawad1, Watchara Rattanachaisit2, Tittaya Prasertpan3, Ornanong Udomsirithamrong4, Appasone phoumin5, Nontakorn Likhitwitayawuid1,6, Thanachporn Saengmanee1,7, Zar Kyi Win1, Nurhussneeda Jeh-voh1, Decho Surangsrirat8, Peerapon Vateekul8, Roongroj Bhidayasiri1,9
1 Chulalongkorn Centre of Excellenc for Parkinson's Disease and Related Disorders,2 Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand.,3 Sawanpracharak Hospital, Nakhon Sawan, Thailand.,4 Bangkok Hospital Chiang Mai, Thailand.,5 Department of Internal Medicine Faculty of Medicine University of Health Sciences, Vientiane Capital, Lao PDR,6 Golden Jubilee Medical Center, Faculty of Medicine, Siriraj Hospital, Mahidol University, Thailand.,7 Chiangmai Neurological Hospital, Thailand.,8 Digital Healthcare Platform Innovation Group, National Science and Technology Development Agency, Pathum Thani, Thailand.,9 The Academy of Science, The Royal Society of Thailand, Bangkok, Thailand.
Background: Parkinson's disease (PD) and prodromal PD remain underdiagnosed in Thailand. Early and accurate identification of early PD or prodromal phase is important for early intervention. We developed and validated the “CheckPD”, a digital mobile population screening platform. This AI-driven platform incorporates a 20-items (yes-no) question PD symptoms, alongside objective digital assessment including an alternate finger tapping, tremor, voice, and balance and gait analysis. This project has been implemented nationwide through both onsite and online screening methodologies.
Method: Adults over 40 years old, or anyone with a history of suspected prodromal symptoms- including acting out of dream, hyposmia, constipation, depression, or first-degree relative with PD-have been encouraged to enroll in the screening platform. After screening results indicate an elevated risk of PD, participants can register to further clinical evaluation-including motor examination (MDS-UPDRS III), smell test (16-item identification Sniffins’ stick), and other standard questionnaires to confirm PD or having prodromal features. All will receive education of EAT MOVE SLEEP lifestyle intervention.
Result: A total of 38,878 participants (70.9% female) were enrolled, with the majority (51%) residing in central Thailand. Among them, 606 individuals (288 males, 307 females, 11 prefer not to say) were identified: 203 with PD (130 newly diagnosed, 73 known cases) and 403 with prodromal features. The PD group was significantly older than the prodromal group (66.0 ± 12.2 vs 63.8 ± 11.8 years; p = 0.033).
Compared to the having prodromal features group, the PD exhibited significantly higher scores on the 20-item screening questionnaire (9.6 ± 6.2 vs 6.6 ± 5.1; p < 0.001), HAM-D (8.7 ± 9.6 vs 7.0 ± 5.5; p = 0.018), and MDS-UPDRS III(12.5 ± 16.5 vs 2.4 ± 4.3; p < 0.001). Cognitive performance (MoCA/TMSE) and smell test were significantly lower in the PD group (22.4 ± 5.1 vs. 24.8 ± 4.0 and 7.6 ± 5.8 vs. 9.4 ± 2.8, respectively; both p < 0.001). No significant differences were found in RBDQuestionnaire, ESS, or ROME IV scores.
The most prevalent motor complaint in both groups was slowness of movement (PD: 85.7%, having prodromal features: 59.8%), while excessive daytime sleepiness was the leading non-motor symptom (PD: 51.2%, having prodromal features: 56.4%). Regarding RBD symptoms, frequent dreaming was most common (PD 77.3%, having prodromal features: 66.3%). Notably, leather odor was the most frequently misidentified scent across both groups.
Objective digital assessments revealed that the PD group had significantly higher postural tremor scores compared to the prodromal group (5.09 ± 3.37 vs. 4.24 ± 3.00; p = 0.005). However, no statistically significant differences were observed between the PD and having prodromal features groups in other digital motor tasks.
Conclusion: This project is the first Nationwide PD and prodromal PD digital screening platform in Thailand. This platform effectively identifies high-risk individuals through a combination of AI-driven questionnaires and objective digital motor assessments by facilitating early clinical diagnosis and providing lifestyle intervention to improve long-term outcomes.
Substantia nigra and locus coeruleus volumes correlate with 123-I-ioflupane SPECT and motor phenotype in idiopathic REM sleep behavior disorder: Results from the NAPS Study
Daniel Huddleston1,2, Xiangchuan Chen1, Hernis De La Cruz3, Alon Avidan4, Donald Bliwise1, Meghan Campbell3, Susan Criswell5, Albert Davis3, Kevin Duff6, Kaylena Ehgoetz Martens7, Jonathan Elliott6, Tanis Ferman8, Julie Fields9, Leah Forsberg9, Jean-Francois Gagnon10, Ziv Gan-Or11, Michael Howell12, Michele Hu13, Xiaoping Hu14, Kejal Kantarci9, Paul Kotzbauer3, Jason Langley14, Miranda Lim6, Jessica Locke6, Val Lowe9, Stuart McCarter9, Jennifer McLeland3, Mitchell Miglis15, Emmanuel Mignot15, Toji Miyagawa9, Lee Neilson6, Kendall Nichols1, Amelie Pelletier16, Owen Ross8, Carlos Schenck12, Wolfgang Singer9, Erik St Louis9, Oliver Sum-Ping15, Lynn Marie Trotti1, Xiong Chengjie3, Aleks Videnovic17, Brad Boeve9, Ron Postuma18, Yo-El Ju3, _ On Behalf of The NAPS Consortium1
1 Emory University,2 Lightbox Science, Inc.,3 Washington University School of Medicine,4 University of California at Los Angeles,5 Barrow Neurological Institute,6 Oregon Health & Science University,7 University of Waterloo,8 Mayo Clinic, Jacksonville,9 Mayo Clinic, Rochester,10 Université du Québec à Montréal,11 The Neuro (Montreal Neurological Institute),12 University of Minnesota,13 University of Oxford,14 University of California, Riverside,15 Stanford University,16 McGill University,17 Massachusetts General Hospital / Harvard Medical School,18 Hôpital du Sacré-Cœur de Montréal
Background: There is an urgent need for neuroimaging biomarkers to improve trial designs for synucleinopathies to accelerate development of neuroprotective treatments. Establishment of neuromelanin-sensitive MRI (NM-MRI) biomarkers’ association with dopaminergic function and clinical phenotype is a necessary step in their validation. Biomarker diagnosis and monitoring are crucial in prodromal synucleinopathy, e.g., idiopathic REM sleep behavior disorder (RBD), in which most clinical features are absent or mild. To support validation of NM-MRI measures for prodromal biomarker applications, we assessed association between NM-MRI substantia nigra pars compacta (SNc) and locus coeruleus (LC) volume measurements and 1) dopaminergic dysfunction assessed with 123-I-ioflupane SPECT (DaTscan, GE) and 2) parkinsonian motor deficits assessed with the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) in the NAPS RBD cohort.
Method: The North American Prodromal Synucleinopathy Consortium (NAPS, U19AG071754) is a 9-site longitudinal study of individuals with polysomnogram-confirmed RBD. A detailed multimodal dataset is collected from NAPS participants including MDS-UPDRS-III, NM-MRI, and DaTscan. We studied baseline data from 194 individuals with RBD enrolled in NAPS with NM-MRI and clinical data available; 122 had DaTscan datasets. NM-MRI datasets were collected with a magnetization transfer prepared 2D-gradient echo sequence; automated image processing was used to extract SNc and LC volumes, and a centralized quality control process was maintained. DaTscan was collected with a standardized clinical protocol and analyzed using DaTQUANT (GE). Correlations between NM-MRI measures and 1) DaTscan striatal binding ratio (SBR) in putamen, and 2) MDS-UPDRS-III were carried out with SPSS 29.0 using bivariate Spearman correlation and partial correlation controlling for age and sex (2-tailed). False discovery rate correction (FDR) was used to correct for multiple comparisons.
Results: Statistically significant bivariate Spearman correlations were observed between 1) SNc volume and posterior putamen SBRs (Left: p = 0.033, rho=0.193, n = 122; Right: p = 0.041, rho = 0.185, n = 122), 2) LC volume and posterior putamen SBRs (Left: p < 0.0001, rho=0.374, n = 118; Right:p < 0.001, rho=0.305, n = 118), and 3) both SNc and LC volumes with MDS-UPDRS-III (SNc: p = 0.003, rho = -0.215, n = 192; LC: p = 0.008, rho = -0.194, n = 187). These findings remained statistically significant after FDR correction for multiple comparisons. SNc and LC volume correlations with posterior putamen SBRs remained significant controlling for age and sex.
Conclusion: Volume loss in SNc and LC, assessed with NM-MRI, correlates with dopaminergic dysfunction and parkinsonian motor deficits in RBD. These findings add support for their application as biomarkers for biologic staging and clinical trials in prodromal synucleinopathy.
Toward Preventive Trials in Parkinson's Disease: Translating Genetic Risk into Trial-Eligible GBA1 and LRRK2 Cohorts in GP2
Lara M. Lange1,2, Kajsa Atterling Brolin3,4, Emily Navarro-Jones5,6, Manuela Tan4,7, Sophie I. Meyer4, Dan Vitale8,9, Andrew Singleton10, Cornelis Blauwendraat10,11, Mike Nalls8,9, Alastair J Noyce4,12, Huw R. Morris5,6
1 Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA,2 Institute of Neurogenetics, University of Lübeck, Lübeck, Germany,3 Translational Neurogenetics Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden,4 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, UK,5 UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK,6 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK,7 Department of Neurology, Oslo University Hospital, Oslo, Norway,8 DataTecnica, Washington, DC, USA,9 Center for Alzheimer's and Related Dementias, National Institute on Aging, Bethesda, MD, USA,10 Global Parkinson's Genetics Program (GP2), Chevy Chase, MD, USA,11 Coalition of Aligning Science (CAS), Chevy Chase, MD, USA,12 Department of Neurology, The Royal London Hospital, Barts Health NHS Trust, London, UK
Background: Preventive and disease-modifying trials in Parkinson's disease (PD) increasingly target genetically defined populations, particularly carriers of pathogenic and high-risk variants in GBA1 and LRRK2. However, the global distribution of these clinical and at-risk populations remains poorly characterized, limiting equitable implementation of precision medicine and prevention strategies. The Global Parkinson's Genetics Program (GP2) aims to advance precision medicine by integrating large-scale clinico-genetic data from diverse populations worldwide and by establishing a framework to identify and characterize individuals relevant for genetically-stratified and preventive interventions.
Methods: We screened short-read whole-genome sequencing and array genotyping data from GP2's most recent data release for carriers of pathogenic and high-risk GBA1 and LRRK2 variants. The cohort included individuals with manifest PD, prodromal features of PD, including REM sleep behavior disorder and hyposmia, and unaffected participants from 11 genetically-defined ancestries. Genetic data were integrated with harmonized clinical and demographic information, where available.
Results: Among 65,509 individuals with PD, we identified 9019 (13.8%) potentially trial-eligible genetic variant carriers, including 6789 GBA1, 2084 LRRK2, and 146 dual GBA1-LRRK2 carriers. Individuals with manifest PD were further stratified by clinical characteristics to evaluate potential eligibility to participate in clinical trials, including disease duration (≤3, ≤5, or ≤7 years), motor severity (Hoehn & Yahr stage ≤2 or ≤3), and cognitive function (MoCA score ≥26 points or ≥20 and <26).
Additionally, we identified 319 (6.1%) GBA1 and 26 (0.5%) LRRK2 rare high risk variant carriers among a total of 5269 individuals from prodromal cohorts. Finally, out of 45,574 unaffected individuals, 3727 (8.2%) GBA1 and 786 (1.7%) LRRK2 variant carriers were identified.
Overall, variant carriers were distributed across multiple global regions, including areas currently underrepresented in gene-targeted and preventive trials.
Conclusion: These findings highlight a substantial global pool of genetically defined individuals with PD who may be eligible for current therapeutic trials, while also identifying large numbers of at-risk and prodromal variant carriers relevant for future prevention strategies. Our results underscore the value of GP2 as a scalable and collaborative resource to identify and characterize such individuals and to support harmonized clinical and biomarker data collection. By facilitating earlier identification of genetically at-risk populations and enabling longitudinal follow-up, GP2 can help accelerate preventive and disease-modifying trials and improve equitable access to emerging precision medicine approaches. Continued expansion of these efforts will be critical to advance precision prevention and therapeutic development in PD.
Longitudinal Data on the Prodromal Synucleinopathy Rating Scale Among Patients with REM Sleep Behavior Disorder in the North American Prodromal Synucleinopathy (NAPS) Consortium
Brad Boeve1, Yuzheng Nie2, Ruijin Lu2, Hernis De La Cruz2, Alon Avidan3, Don Bliwise4, Meghan Campbell2, Susan Criswell5, Albert Davis2, Kevin Duff6, Jonathan Elliott6, Tanis Ferman1, Julie Fields1, Leah Forsberg1, Jean-Francois Gagnon7, Michael Howell8, Dan Huddleston4, Miranda Lim6, Jessica Locke6, Stuart McCarter1, Jenny McLeland2, Mitchell Miglis9, Toji Miyagawa1, Lee Neilson6, Kendall Nichols4, Amelie Pelletier7, Carlos Schenck8, Erik St Louis1, Oliver Sum-Ping9, Lynn Marie Trotti4, Aleksandar Videnovic10, Chengjie Xiong2, Ron Postuma11, Yo-El Ju2
1 Mayo Clinic,2 Washington University,3 UCLA,4 Emory University,5 Barrow Neurological Institute,6 Oregon Health & Science University,7 Université du Québec à Montréal,8 University of Minnesota,9 Stanford University,10 Massachusetts General Hospital,11 Montreal Neurological Institute-Hospital
Background: Clinical trials in REM sleep behavior disorder (RBD) are anticipated in the near future, in which interventions to delay the onset or prevent the development of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy will be tested. The Prodromal Synucleinopathy Rating Scale (PSRS) was developed by the NAPS Consortium investigators to capture the breadth and evolution of clinical burden in those with RBD.
Methods: Ratings on the PSRS range from no symptoms/signs (score of 0) to more severe symptoms/signs (max score of 2-4 depending on the domain) were based on clinical judgement for the cognitive (COG), behavioral/psychiatric (PSY), motor-axial (MAX), motor-appendicular (MAP), autonomic (AUT), sleep (SLP), and sensory (SEN) domains. The total sum score (SUM) was also calculated. Wilcoxon signed-rank test compared the difference in PSRS SUM and its domains between visits 1 (V1) and 2 (V2).
Results: Data from 269 participants (82% male, mean age 66 ± 10 yrs) were analyzed. The median (IQR) duration between V1 and V2 was 12 (11-12) months. From V1 to V2, the score increased for COG (p < 0.0001), PSY (p < 0.0001), MAX (p < 0.0001), MAP (p < 0.0001), AUT (p < 0.0001) but not for SLP or SEN. Comparing V1 to V2, the frequencies of an increased/stable/decreased score for each domain were COG: 32%/54%/14%, PSY: 35%/49%/16%, MAX: 33%/58%/8%, MAP: 33%/55%/12%, AUT: 41%/42%/17%, SLP: 15%/57%/28%, and SEN: 18%/66%/16%. The SUM increased (mean 6 ± 3 to 8 ± 3, p < 0.0001) and the frequencies of an increased/stable/decreased SUM score were 58%/14%/28%.
Conclusions: In this large cohort of individuals with RBD followed longitudinally over one year, over half had an increase in the total SUM score. Although additional longitudinal work is needed in larger samples, the current results suggest potential utility for the PSRS as a measure of synucleinopathy clinical burden for future disease-modifying therapies in those with RBD.
MC1R loss-of-function variants accelerate motor decline and phenoconversion in Parkinson's disease
Jackson Schumacher1,2, Xinyuan Zhang3, Jian Wang4,2, Johannes M. Dijkstra5, Hirohisa Watanabe5, Xiang Gao6, Michael A. Schwarzschild1,2, Marianna Cortese7, Xiqun Chen1,2
1 Massachusetts General Hospital and Harvard Medical School,2 Aligning Science Across Parkinson's (ASAP) Collaborative Reserarch Network,3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School,4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center,5 Department of Neurology, School of Medicine, Fujita Health University, Toyoake, Japan,6 Department of Nutrition and Food Hygiene, School of Public Health, Institute of Nutrition, Fudan University, Shanghai, China,7 Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
Background Melanocortin 1 receptor (MC1R) is a key regulator of pigmentation and oxidative stress implicated in Parkinson's disease (PD) risk. We previously showed that MC1R activation, including peripheral administration of agonists already in clinical use, is neuroprotective in models of PD. Approximately 60-70% of individuals of European descent carry at least one MC1R loss-of-function (LoF) variant. Here, we tested whether MC1R LoF variants are associated with PD progression and phenoconversion in the Parkinson's Progression Markers Initiative (PPMI) cohort.
Methods We analyzed 383 PPMI participants with sporadic PD (231 MC1R carriers and 152 non-carriers) as well as 426 participants with monogenic PD (LRRK2 and GBA carriers, stratified by MC1R status) over 12 years of follow-up. Rate of motor decline (MDS-UPDRS III OFF-state) was assessed using linear mixed-effects models adjusted for potential confounders. Additionally, we evaluated the risk of phenoconversion in 49 prodromal participants (33 MC1R carriers and 16 non-carriers) using Cox proportional hazards regression.
Results MC1R carriers exhibited 29.5% faster motor decline (p = 0.006) than non-carriers, primarily driven by worsening bradykinesia (35.4%; p = 0.001) and bulbar function decline (25.3%; p = 0.033). Motor decline was allele dose-dependent, with homozygotes (n = 20) exhibiting more than twice the effect of heterozygotes (n = 211; β=1.16 vs. 0.53 points/year; p-trend=0.003). Variant penetrance further modulated motor decline, with high-penetrance (R) carriers (n = 111) exhibiting a stronger effect than low-penetrance (r) carriers (n = 120; β=0.61 vs. 0.52 points/year; p-trend=0.011). Findings were consistent in a pooled analysis of sporadic and monogenic PD and directionally consistent in the unmedicated Sure-PD3 cohort. Among prodromal participants, MC1R carriers showed a 4.84-fold increased risk of phenoconversion compared to non-carriers (p = 0.041).
Conclusion MC1R LoF variants are carried by the majority of PD patients of European descent, defining a large and readily identifiable subgroup with more aggressive disease progression and increased risk of phenoconversion. The selective association of MC1R with bradykinesia and bulbar function is consistent with a mechanism operating through dopaminergic pathways. Together with preclinical evidence that MC1R activation rescues dopaminergic neurodegeneration in PD models, these findings support MC1R as a therapeutic target for PD with implications for prognostic stratification and therapeutic development.
Polyamine metabolism and PI3K-Akt signaling modulate neuronal vulnerability in Parkinson's disease α-synuclein models
Wei-Ling Tsou1, Bedri Ranxhi1, Zoya Bangash1,
1 Department of Pharmacology, Wayne State University School of Medicine,2 Departments of Neurology and Pharmacology, and Sastry Foundation Endowed Chair in Parkinson Disease Research, Wayne State University School of Medicine
Background: Neuroprotective approaches in Parkinson's disease (PD) increasingly focus on modifiable pathways that influence neuronal resilience, especially mechanisms that reduce α-synuclein (α-Syn) toxicity. Emerging evidence implicates multiple metabolic and signaling networks including those maintaining polyamine homeostasis and kinase pathways in α-Syn-associated degeneration. However, how these pathways intersect to influence neuroprotection remains incompletely defined.
Methods: We integrated findings from three complementary Drosophila α-Syn studies examining genetic, transcriptional, and pharmacologic modifiers of toxicity. First, polyamine pathway enzymes were manipulated genetically to determine how altering polyamine flux affects the toxicity of genetic insertion of human α-Syn . Second, neuronal overexpression of a key polyamine inter-conversion enzyme, spermidine/spermine N1-acetyltransferase 1 (SAT1), was evaluated for effects on survival, α-Syn levels, transcriptomic responses, and mitochondrial-autophagy signatures. Third, the PI3KAkt signaling was inhibited pharmacologically or genetically to assess effects on organismal outcomes and α-Syn accumulation. Outcomes included lifespan, locomotor performance, protein analyses, and pathway-level transcriptional profiling.
Results: Genetic modulation of polyamine enzymes revealed enzyme-specific neuroprotective effects: knockdown of ornithine decarboxylase-1, spermidine synthase, and spermine oxidase (SMOX) reduced α-Syn toxicity, whereas knockdown of SAT1 worsened phenotypes, all indicating distinct roles for individual components of intracellular polyamine metabolism. Conversely, overexpression of SAT1 or SMOX decreased α-Syn levels and improved survival. In a mechanistic extension, neuronal SAT1 overexpression attenuated α-Syn toxicity, altered stress-responsive transcriptional signatures, and was associated with increased engagement of mitochondrial-linked quality-control markers. Additional experiments demonstrated that partial inhibition of PI3K-Akt signaling produced reproducible improvements in survival and locomotor performance together with reduced α-Syn accumulation, with downstream transcriptional evidence implicating NF-κB-related signaling as the mechanism.
Conclusion: Together, these results identify polyamine metabolism and PI3K-Akt signaling as biologically relevant modulators of neuronal vulnerability in α-Syn models. Genetic and pharmacologic manipulation of these pathways consistently altered toxicity across independent assays, indicating that metabolic state and stress signaling are integral determinants of neurodegenerative susceptibility. These findings establish polyamine-linked metabolic control as a mechanistic axis influencing α-syn-associated pathology and provide a framework for evaluating specific pathway-targeted strategies in neuroprotection.