Ronald B. Postuma

Background and ObjectivesClinical trials in REM sleep behavior disorder (RBD) to delay or prevent the development of Parkinson disease (PD), dementia with Lewy bodies (DLBs), and multiple system at...

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.

Background and ObjectivesIdiopathic REM sleep behavior disorder (iRBD) is a marker of early neurodegenerative synucleinopathy. Nigrostriatal dopaminergic dysfunction is often considered the primary...

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;100:S26–S35

LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson's disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants received single doses of BIIB094 10-150 mg or placebo. In part B, 42 participants, stratified by LRRK2 variant status, received four doses of BIIB094 40-120 mg or placebo every 4 weeks. Adverse events were reported by 64.5% (20/31) of participants in part A and by 84.8% (28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in CSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, NCT03976349 ; EudraCT number, 2018-002995-42.

Background: Prasinezumab previously showed signals of slowing motor progression in early-stage Parkinson’s disease (PD) participants who were treatment-naïve or receiving monoamine oxidase type B inhibitors (MAO-Bis). The PrAsinezumab in early Parkinson’s Disease in levodopa (L-DOPA)- or MAO-Bi-treated patients efficacy and safety eVAluation (PADOVA; NCT04777331) trial evaluated its efficacy and safety in early-stage PD participants receiving stable symptomatic medication.Methods: This Phase IIb, multicentre, double-blind, placebo-controlled, randomised trial recruited participants with early-stage PD (3 months to 3 years from diagnosis, Hoehn and Yahr 1–2) on stable symptomatic medication from 110 centres in nine countries. Participants were randomised (1:1) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks via permuted blocks (stratified by symptomatic medication, L-DOPA or MAO-Bi) for ≥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 Movement Disorder Society-sponsored revision of the Unified PD Rating Scale Part III off-medication score).Findings: 586 individuals were randomised (293 per group); 550 completed double-blind treatment. The primary analysis showed a non-significant trend for delayed motor progression with prasinezumab versus placebo (hazard ratio [HR] 0·84 [95% confidence interval [CI] 0·69–1·01]; p=0·0657). A pre-specified covariate-adjusted analysis showed a nominally significant effect (HR 0·81 [0·67–0·98]; nominal p=0·0334). The treatment effect was more pronounced in the L-DOPA-treated subgroup (non-adjusted, HR 0·79 [95% CI 0·63–0·99], nominal p=0·0438; covariate-adjusted, HR 0·76 [95% CI 0·61–0·95], nominal p=0·0175). Biomarker evidence of an impact on underlying disease pathology was observed using neuromelanin- and iron-sensitive magnetic resonance imaging. Prasinezumab was well tolerated.Interpretation: PADOVA provides evidence of prasinezumab’s clinical and biological activity in early-stage PD supporting continued investigation in the ongoing Phase III PARAISO trial.

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.

The 2015 International Parkinson and Movement Disorder Society (MDS) Diagnostic criteria for Parkinson Disease are based on expert consensus opinion and defines core motor features, ‘Absolute Exclusion Criteria’ and a balance of ‘Supportive Criteria’ and ‘Red Flags’. To assess validity of each criterion in pathologically-confirmed cases, a scoping literature review between 1988-2024 using search terms for clinicopathological PD and atypical parkinsonian disorders identified 28 articles. Supportive criteria were higher in PD, with excellent levodopa response and rest tremor most useful. Absolute exclusion criteria and red flags were present more often in atypical parkinsonian disorders. However, supranuclear gaze palsy, rapid progression of gait impairment to wheelchair requirement and bilateral symptoms were reported in >5% PD. Data was limited by few appropriate pathological studies with sufficient clinical data; challenges in applying highly-specific definitions to retrospective studies and likely co-pathologies. This review provides empiric data to support some items of the MDS Criteria with future potential refinement.