Olfactory dysfunction is an early, prodromal feature of Parkinson’s disease (PD), often preceding motor symptoms by years. This has fueled the hypothesis that PD pathology may originate in the olfactory bulb (OB), where early Lewy-type α-synucleinopathy is frequently observed and from which pathology could propagate to neural systems. In this context, Arshamian et al. (2022) hypothesized that isolated congenital anosmia (ICA), a rare lifelong absence of smell typically associated with bilateral OB aplasia, might confer immunity to PD. They argued that identifying a single individual with both ICA and PD would constitute a “black swan”, falsifying the claim that an intact OB is necessary for PD initiation. We describe such a case: an individual with lifelong anosmia, MRI-based evidence of bilateral OB aplasia, and a clinically established diagnosis of PD. This counterexample challenges strict OB-necessity models and suggests PD can arise despite apparent congenital absence of an intact OB.

Isolated/idiopathic rapid-eye-movement (REM)-Sleep Behavior Disorder (iRBD) is characterized by dream enactment behaviors associated with loss of REM atonia. iRBD is in most cases a prodromal synucleinopathy, and emerging evidence suggests associations between RBD and other neurological and psychiatric conditions. In this study, we performed pathway-based polygenic risk score (PRS) and rare variant burden analyses to examine these potential associations. Pathway-specific PRS were constructed from genome-wide association study summary statistics of five neurodegenerative and seven psychiatric traits across 10 biologically relevant pathway categories, including a total of 279 pathways, in 1,573 iRBD cases and 16,022 controls from the International RBD Study Group and UK Biobank. Rare variant burden tests were performed in 1,264 iRBD cases and 2,581 controls. We identified multiple potential pathways indicating shared polygenic risk between RBD and both neurodegenerative and psychiatric disorders. Lewy body diseases and post-traumatic stress disorder had the most shared polygenic risk pathways in neurological and psychiatric disorders, respectively. Two pathways, the serotonin transport pathway and the chaperone-mediated autophagy pathway, showed the strongest association with iRBD, and gene-based rare variants analyses revealed five genes associated with iRBD: GBA1, PLEKHM1, LRP2, P2RX1, and HAP1. Subsequent analysis of these genes in Parkinson's disease and dementia with Lewy bodies replicated several associations. Together, these findings provide novel insights into the shared genetic architecture underlying iRBD, neurodegenerative disorders, and psychiatric traits, with implications for early identification and mechanistic understanding.

BACKGROUND:Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease, but the local biological factors that render specific cortical regions vulnerable to atrophy remain poorly defined. In particular, it is unclear whether cortical thinning in dementia with Lewy bodies reflects generic neurodegenerative mechanisms, processes shared with Parkinson's disease and Alzheimer's disease, or dementia with Lewy bodies-specific molecular and network susceptibilities. METHODS:A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process. RESULTS:Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity. CONCLUSIONS:MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Abstract Background The clinical applicability of large language models (LLMs) in Parkinson’s disease (PD) management remains insufficiently characterized, particularly in generative responses to clinical vignette scenarios. Objective To evaluate the quality of clinical assessments and management plans generated by a general-purpose LLM (Gemini 1.5 Pro) and a medically specialized LLM (OpenEvidence), and to compare their performance. Methods Models generated free-text responses to 45 open clinical queries, focused on assessment of the situation, and recommended management plan. Two movement disorders fellows rated outputs using 5-point Likert scales, dichotomized into clinically appropriate (≥4) versus inappropriate (≤3). Discrepancies were adjudicated by a senior movement disorders specialist. Paired comparisons used McNemar’s test; qualitative analysis examined severe errors. Results Gemini 1.5 Pro and OpenEvidence showed high rates of clinically appropriate assessments (80.0% vs. 86.7%) but lower performance in management plans (48.9% vs. 57.8%). Cases in which both assessment and plan were clinically appropriate occurred in 46.7% and 55.6% of cases, respectively. None of these differences reached statistical significance. Severe errors were uncommon in assessments (6.7% vs. 8.9%) but more frequent in plans (26.7% in both), predominantly reflecting treatment strategy errors. Conclusions In generative clinical reasoning tasks involving Parkinson’s disease management vignettes, LLMs demonstrated reasonable performance in assessment, but consistent limitations in plan generation. The medically specialized LLM demonstrated several qualitative advantages but no statistically significant performance benefit over the general-purpose model. Therefore, these tools should be used with appropriate caution in Parkinson’s disease management, particularly regarding treatment recommendations.

Clinical progression from prodromal to overt stages of alpha-synucleinopathies is highly heterogeneous, and there is an urgent need for reliable clinical progression markers. Exploiting the Disease Course Map (DCM) model, we investigated how clinical signs evolve in patients with idiopathic/isolated rapid-eye-movement sleep behavior disorder (iRBD), extracting clinical progression measures for use at the single-subject level. Furthermore, we correlated them with both established and innovative neurodegeneration biomarkers. We trained a DCM model using cognitive and motor scores of a longitudinal cohort of 766 iRBD patients (166 female, 67.9 ± 7.4 years). We personalized the model by extracting three parameters to describe the single subject in comparison to the averaged population data. We tested the model on a blind set of 49 iRBD patients (7 female, 68.5 ± 7.1 years) who underwent both longitudinal clinical evaluations and instrumental evaluation at the first observation. In the blind set, we correlated the individual model parameters with presynaptic dopaminergic impairment, an established biomarker of substantia nigra neurodegeneration, and cortical electrophysiological dysfunction-measured by high-density electroencephalography (HD-EEG)-an innovative neurodegeneration biomarker. We identified three individual clinical markers reflecting early/late (time shift, τ) and fast/slow (acceleration factor, α) disease progression, as well as the individual clinical trajectory (i.e., earlier motor or cognitive impairment, intermarker spacing, ω). The individual model parameters are significantly associated with phenoconversion, with a 73% chance of distinguishing between clinically stable patients (non-converters) and those converting during the longitudinal observation to an overt alpha-synucleinopathy (converters). Motor scores progress 35% faster than cognitive scores in our iRBD cohort. Converter iRBD patients exhibited a faster and earlier disease progression than non-converters, and, on average, they showed an earlier worsening of motor scores than cognitive scores, regardless of the clinical diagnosis of overt parkinsonism. Patients with iRBD who developed parkinsonism worsened earlier than those who develop dementia. At baseline, an earlier progression was related to presynaptic dopaminergic impairment and higher phase synchronization in the theta band (4-8 Hz). Higher synchronization in the theta band was also associated with an earlier worsening of motor scores than cognitive scores. In this study, we investigated a large longitudinal iRBD cohort, applying an advanced disease progression model. We found three individual clinical markers that were able to monitor disease progression and showed significant association with both established and innovative neurodegeneration biomarkers. We suggest that these clinical markers could be used as efficacy endpoints in disease-modifying clinical trials.

BACKGROUND:Alzheimer's disease (AD) co-pathology contributes to dementia in PD, but its role in earlier cognitive impairment remains uncertain. OBJECTIVE:To determine if p-tau217, a biomarker of early AD, is associated with cognitive impairment in PD. METHODS:Plasma p-tau217 levels in 167 PD patients without dementia and 63 controls were related to performance on standard neuropsychological testing, and to cognitive impairment as defined by a MoCA score <26 and by self-report. Plasma GFAP, NfL and APOE ε4 carrier status were also examined. RESULTS:No significant differences in p-tau217, GFAP and NfL level were observed between groups (pFDR > 0.08). Higher p-tau217 was associated with worse visuospatial function and greater self-reported cognitive impairment, but these associations did not survive correction (pFDR > 0.08). There was no association with cognitive impairment (pFDR > 0.08). CONCLUSION:These results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Digital Health Technologies (DHTs) enable remote, objective and frequent assessments of motor signs in people living with Parkinson’s (PwP). It remains unclear whether participant satisfaction with daily DHT interactions relates to long-term adherence and clinical outcomes. To quantify PwP’s satisfaction with daily remote DHT monitoring and its relationships with DHT adherence, motor disease severity, and anxiety and depression. Data from 710 participants living with early-stage Parkinson’s were analyzed from the PASADENA Phase IIa (NCT03100149; n=293) and PADOVA Phase IIb (NCT04777331; n=417) studies. At baseline, PASADENA participants (H&Y 1–2) were treatment-naive or on stable MAO-Bi, PADOVA participants (H&Y 1–2) were on stable L-DOPA or MAO-Bi. Remote monitoring with the Roche PD Mobile Application included active tests (AT), surveys, and passive monitoring (PM) via a study watch and phone, over 2 years (PASADENA) or 76–172 weeks (PADOVA). Towards the end of both studies (follow-up), participants completed questionnaires on DHT acceptance (Likert-scale: 1=very negative, 5=very positive) and open feedback. “Global satisfaction” with the DHT was defined as the mean Likert score from 4 comparable questions in the PASADENA and PADOVA questionnaires. Open feedback was analyzed qualitatively. Spearman’s correlations related global satisfaction levels with overall DHT adherence, self-reported motor experiences of daily living (MDS-UPDRS Part II), clinician-rated motor sign severity (MDS-UPDRS Part III) and, for PASADENA, anxiety and depression (HADS). Global satisfaction was 4.2/5 (SD=0.7) in PASADENA and 3.9/5 (SD=0.7) in PADOVA, reflecting overall positive sentiments. Most participants rated all DHT aspects positively, including study devices and app (PASADENA: 3.6±1.0; PADOVA: 3.4±1.0) and daily active testing (PASADENA: 3.9±1.3; PADOVA: 3.9±1.2). Respondents highlighted areas for improvement in open feedback, including technical issues (PASADENA: 20%; PADOVA: 29%), repetitive ATs/surveys (PASADENA and PADOVA:13%) and device usability (PASADENA: 10%; PADOVA:12%). Higher global satisfaction ratings were weakly-to-moderately associated with higher adherence levels in PASADENA (AT: ρ=0.40; PM smartphone [PMsp]: ρ=0.29; PM smartwatch [PMsw]: ρ=0.23; all P<.001) and PADOVA (AT: ρ=0.24; PMsp: ρ=0.18; PMsw: ρ=0.17; all P<.001). Global satisfaction showed negligible-to-weak and inconsistent associations (-.11≤ρ≤.14) with MDS-UPDRS Parts II and III across studies. In PASADENA, lower global satisfaction ratings were weakly associated with higher levels of anxiety (ρ=−.15, P=.02) and depression (ρ=−0.11, P=.06). Participants living with early-stage Parkinson’s were generally satisfied with daily DHT testing in clinical trials over ~1.5–3 years. Satisfaction was positively associated with adherence but not robustly with motor disease severity, anxiety and depression. Improving device design, battery life and test variety may boost satisfaction and adherence, strengthening DHT-based monitoring. ClinicalTrials.gov NCT03100149 (PASADENA), NCT04777331 (PADOVA)

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

Abstract Isolated/idiopathic rapid-eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early form of α -synuclein-related neurodegenerative diseases, including Parkinson’s disease and dementia with Lewy bodies. Clinical reports suggest that iRBD is more common in individuals with Post-Traumatic Stress Disorder (PTSD) compared to those without PTSD. We conducted polygenic risk score (PRS), genetic correlation, and Mendelian randomization analyses to explore potential genetic and/or causal associations between PTSD and iRBD. Dopamine transporter imaging binding status was also examined in iRBD patients with ( N = 6) and without PTSD ( N = 32). While not supporting a causal relationship, genetic analyses revealed a significant association between PTSD and iRBD, consistent with the exploratory imaging substudy. These findings suggest that individuals genetically at risk for PTSD may also be at higher risk for iRBD. Further investigation of iRBD in individuals with PTSD may help inform potential neurodegenerative risk.

Background: Middle-aged and older adults (>55 years old) have a high risk of developing Parkinson’s disease (PD); however, many non-motor symptoms (NMSs) indicative of PD are also common in middle-aged and older adults without a neurological disease diagnosis. Objective: To identify symptoms specific to PD in comparison to controls without a neurological disease diagnosis. Design: This is a systematic review and meta-analysis. Data source and methods: We performed a meta-analysis, using Embase, SciSearch, MEDLINE, and BIOSIS from January 1, 2001, until April 1, 2025. We included observational studies reporting the prevalence of NMSs using the non-motor symptom questionnaire or non-motor symptom scale in the PD population versus controls. Using a random effects model, we generated a pooled estimate for the prevalence risk ratio (RR) for each symptom. Results: The meta-analyses included 15 studies, involving 7393 PD patients and 2742 controls. It showed 28 out of 30 NMSs were more common in the PD population, with excessive drooling (RR = 7.30 (95% confidence interval; CI 5.05–10.57)), visual hallucinations (RR = 6.48 (95% CI 3.61–11.64)) and taste/smell issues (RR = 4.67 (95% CI 3.07–7.10)) being the most specific symptoms (having the largest RRs). Conclusion: Planning screening campaigns to identify PD among middle-aged and older adults is difficult, due to the high numbers that are needed to screen using tools that are not specific enough. We showed that excessive drooling and taste/smell issues are highly specific NMSs of PD, as they have high RRs. More research is needed to assess their usefulness to be included as an enrichment factor in screening campaigns for PD patients in a middle-aged and older adult population.

Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a usually prodromal manifestation of neurodegenerative disorders with α-synuclein pathology: Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Clinical trials in the iRBD population face substantial barriers: limited access to well-characterized cohorts, inconsistent assessment protocols across centers, and the absence of validated biomarkers of disease burden. The North American Prodromal Synucleinopathy (NAPS) Consortium was established to address these challenges and facilitate clinical trials for neuroprotective therapies targeting synucleinopathy at the earliest known stages. In this multi-site, longitudinal, observational study, nine academic centers across North America will enroll and follow over 500 individuals with iRBD from existing sleep centers. Sixty control participants, matched for age, sex, and race will also be recruited. A harmonized protocol—including a standardized clinical battery assessing motor, cognitive, autonomic, psychiatric, sensory, and sleep function; structured diagnostic adjudication; biospecimen collection; and centralized analysis of both polysomnography and neuroimaging data—is outlined herein and reflects NAPS Stage 2. Each participants completes these assessments annually, and are replaced in the event of phenoconversion. By unifying assessments and expanding geographic reach, NAPS lays the groundwork for efficient, well-powered clinical trials designed to delay or prevent progression of iRBD to overt PD, DLB, or MSA—ultimately enabling earlier, more effective therapeutic intervention for neurodegenerative disease. Registered at clinicaltrials.gov (NCT05826457).

BACKGROUND:Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathy such as Parkinson's disease (PD). Brain cholinergic alterations have been reported in these diseases, but direct comparisons of terminal density between iRBD and clinically manifest PD have not yet been performed. OBJECTIVES:To assess brain cholinergic terminal density in iRBD using positron emission tomography (PET) with [18F]-fluoroethoxybenzovesamicol (FEOBV), and to compare findings with both healthy controls and patients with PD. METHODS:Forty-six participants (16 with polysomnography-confirmed iRBD, 12 with PD, and 18 controls) underwent high-resolution PET neuroimaging with FEOBV. Voxel-wise analyses and effect size mapping were conducted to compare the groups, using standardized uptake value ratios (SUVRs). Correlations were performed between whole-cortex SUVR and clinical measures. RESULTS:Compared to controls, both the iRBD and PD groups exhibited significant cortical cholinergic denervation of similar magnitudes (11-12 %). Effect size mapping revealed very large losses (Cohen's ds < -1.5) in the posterior cortex in both patient groups, predominantly occipital-parietal in iRBD and occipital-temporal in PD. In iRBD, lower cortical uptake was associated with poorer performance on executive and visuospatial tests. Moreover, in iRBD but not in PD, there was a trend toward higher FEOBV uptake in subcortical areas, including brainstem regions. CONCLUSIONS:Cholinergic denervation in iRBD is comparable in extent to that in PD, with subtle topographic distinctions, and correlates with cognitive deficits.

Isolated REM sleep behavior disorder (iRBD) is a parasomnia that reflects an evolving α-synucleinopathy disorder, providing an opportunity to study early pathological changes. While diffusion tensor imaging (DTI) studies have shown white matter changes in iRBD, Neurite Orientation Dispersion and Density Imaging (NODDI) may offer better biological specificity in characterizing microstructural alterations through measures of Neurite Density Index (NDI), Orientation Dispersion Index (ODI), and Free Water Fraction (FWF). We included 77 participants with polysomnography-confirmed iRBD from the North American Prodromal Synucleinopathy (NAPS) Consortium and 154 age- and sex-matched cognitively unimpaired controls from the Mayo Clinic Study of Aging. White matter microstructure was evaluated using standardized multi-shell diffusion on 3T MRI, quantifying DTI metrics (fractional anisotropy, FA; and mean diffusivity, MD) and NODDI parameters across bilateral white matter tracts defined by the JHU “Eve” WM atlas. Group differences were assessed using conditional logistic regression, with correlations to motor performance evaluated using the Purdue Pegboard and Alternating Finger Tapping tests. Compared to controls, iRBD participants demonstrated widespread and bidirectional white matter changes across major white matter pathways (see Figure 1 for glass brain visualizations). While predominantly showing decreases, FA exhibited some increases, particularly in the corticospinal tract. MD showed a largely opposite pattern with predominantly increased values across tracts. NODDI metrics revealed complex bidirectional patterns: ODI was broadly increased across multiple tracts with focal decreases, while NDI showed a pattern of predominantly decreased values alongside localized increases. FWF demonstrated a mixed pattern with predominant decreases across most tracts. In addition, both DTI and NODDI metrics showed extensive, moderate correlations with the Purdue Pegboard Test and Alternating Finger Tapping performance ( T  = 2.0, p  < 0.05, Figure 2). Our study highlighted widespread and complex bidirectional white matter microstructural alterations in individuals with iRBD, demonstrating significant correlations with dexterity and motor performance even during the prodromal stage. These results suggest that extensive white matter abnormalities occur early in prodromal α-synucleinopathies and highlight the value of advanced diffusion imaging techniques in characterizing iRBD and its potential prediction of phenoconversion to overt neurodegenerative disorders.

BACKGROUND:Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS:This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS:Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION:Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING:F Hoffmann-La Roche.

Sensitive and scalable biomarkers are critical for tracking progression during the prodromal phase of Parkinson's disease, particularly in idiopathic REM sleep behavior disorder (iRBD). We evaluated the Roche PD Mobile Application version 2, a smartphone-based platform, in 51 individuals with polysomnography-confirmed iRBD, 89 patients with early Parkinson's disease, and 22 healthy controls over 12 months. Participants completed daily active tasks generating validated digital summary measures. Adherence was high (73%). Baseline digital bradykinesia scores discriminated between groups (p < 0.001) and were higher in phenoconverters versus non-converters (p = 0.003; Cohen's d = 1.10). Over 50 weeks, bradykinesia (Cohen's d = 0.50) and speech (Cohen's d = 0.79) scores worsened significantly. Sample size modeling showed that digital bradykinesia required 132 participants per arm to detect a 50% treatment effect, fewer than the best-performing clinical measure. These findings support digital bradykinesia as a sensitive endpoint for prodromal Parkinson's disease trials.

We describe the design of the first non-pharmacological Parkinson's disease prevention trials worldwide: the randomised 'Slow-SPEED' trials. Three trials examine the feasibility and preliminary efficacy of a gamified, remotely administered exercise intervention vs. active control over 18-36 months in complementary prodromal subgroups: iRBD(n = 110; Netherlands), hyposmia(n = 110; United Kingdom) or LRRK2/GBA1 mutation carriers(n = 600; United States). These trials will provide unique insights for large-scale Parkinson's prevention studies. Protocols are registered at ClinicalTrials.gov(NCT06193252[1-5-2024];NCT06600438[9-19-2024];NCT06993142[5-28-2025]).

Although many studies have reported the presence of daytime sleepiness in Parkinson's disease (PD), either a weak or no association has been found between self-reported and current objective measures of daytime sleepiness in this population. Changes in resting state quantitative electroencephalography (qEEG) have been associated with increased subjective sleepiness induced by sleep deprivation in young and older adults. The aim of this study was to investigate the relationship between resting state qEEG and self-reported daytime sleepiness in adults with PD. Sixty-two participants with PD underwent polysomnographic recording and clinical assessment. Daytime sleepiness severity was measured with the Epworth Sleepiness Scale (ESS). Resting state EEG was recorded 30 min after awakening. Spectral power and functional connectivity analyses (weighted-phase lag index, amplitude-amplitude coupling) were performed on artefact-free resting state EEG in 2 Hz mini bands from 0.5 to 12 Hz. Partial correlations and a hierarchical regression were used to evaluate the relationship between the qEEG metrics and ESS scores. Lower phase synchronisation in the low alpha band (8-10 Hz) within the occipital cortex was the best EEG predictor of higher daytime sleepiness severity in PD. Our results are in line with some findings of previous studies conducted in healthy young participants that reported lower alpha connectivity after sleep deprivation, suggesting disrupted arousal networks may contribute to daytime sleepiness in PD. Lower alpha phase synchronisation within the occipital cortex could serve as a proxy for daytime sleepiness in PD.