Ronald B. Postuma’s research while affiliated with McGill University and other places

In recent decades, numerous clinical trials have aimed to delay or prevent Parkinson's disease (PD) progression. Despite the theoretical promise and encouraging preclinical data, none have shown clear efficacy in slowing or preventing PD progression, related to several key limitations. Conventional motor and non-motor scales often fall short in detecting early disease changes, while the heterogeneity of PD phenotypes complicates treatment efficacy. The timing of interventions is also critical, as most trials target patients already in advanced stages of neurodegeneration. A deeper understanding of the preclinical phase and the emergence of new pathological frameworks have shifted the focus toward preventing the onset of clinical PD. Recent advances in biomarker research, including tissue, fluid, and imaging markers, are poised to transform PD research by improving patient selection, stratification, and disease progression monitoring. New biologically grounded frameworks for classifying synucleinopathies aim to distinguish biological subtypes from clinical phenotypes, enabling more targeted prevention trials. Successful PD prevention trials will require early enrollment of individuals at the highest risk, employing low-risk personalized interventions, with biomarkers or sensitive clinical markers as endpoints. Early involvement of key stakeholders will be essential to ensure that trials are timely, ethically sound, and aligned with the needs of the PD community.

A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells into the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and α-synuclein (α-syn), two Lewy body-associated proteins. Further, T cell reactivity towards α-syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and α-syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.

Isolated REM sleep behavior (iRBD) is a male predominant parasomnia characterized by abnormal dream-enacting movements in REM sleep. It is the prodromal manifestation most strongly associated with the development of synucleinopathies, such as Parkinson’s disease or dementia with Lewy bodies. While individuals with iRBD exhibit significant cortical atrophy shaped by distinct gene expression, sex-specific differences in structural brain changes remain unknown. In this study, we investigate the effect of sex on brain atrophy in iRBD and examine the gene expression underpinning the brain abnormalities in a large international multicentric MRI dataset with polysomnography-confirmed iRBD. T1-weighted scans from 408 individuals with iRBD and 480 healthy controls were acquired. Vertex-based cortical surface reconstruction and segmentation were conducted, and general linear models were used to quantify brain atrophy and assess the sex effect on cortical thickness in iRBD compared to controls. We then used a high resolution parcellation to further characterize the sex differences and conduct imaging transcriptomics analyses. Gene enrichment analyses were performed to identify genes associated with sex differences in cortical atrophy in iRBD. Males with iRBD showed significantly more cortical thinning compared to females with iRBD and controls, despite similar age and clinical features. The gene enrichment analysis revealed that female-specific resilience in cortical atrophy was associated with overexpression of oestrogen-related receptors. These findings provide mechanistic insight of sex-specific neuroprotection in prodromal stages of synucleinopathies, highlighting the critical impact of sex on the progression of neurodegenerative diseases.

Accurate quantification of REM sleep without atonia (RSWA) is essential in the diagnosis of idiopathic/isolated REM sleep behaviour disorder (iRBD). This study aims to validate RBDtector , a free and open‐source tool for automated RSWA quantification using the Sleep Innsbruck Barcelona (SINBAR) scoring method, by comparing its performance against human visual scoring in a large independent cohort of subjects with iRBD and healthy controls. Muscle activity from 118 iRBD participants and 37 healthy controls that underwent polysomnography was analysed by RBDtector and compared with human visual scoring. Diagnostic performance was evaluated using receiver operating characteristic curves, and optimal cut‐offs for iRBD screening and diagnosis were determined. The results of RSWA quantification were applied to survival analyses of time to phenoconversion. RBDtector showed excellent agreement with human visual scoring, particularly in ‘any’ RSWA activity (Pearson's correlation = 0.89, R ² = 0.79, p < 0.001). RBDtector identified iRBD subjects with 95.6% sensitivity and 95.5% specificity by using a cutoff of 33.0% for combined ‘any’ RSWA activity in the submentalis and flexor digitorum superficialis muscles, with each muscle in isolation providing comparable results. In iRBD patients, each 10% increase in submentalis ‘any’ activity was associated with a 23% increase in the risk of phenoconversion (HR = 1.23, 95% CI [1.06, 1.44], p = 0.008), while no associations were observed with increased activity in the flexor digitorum superficialis or tibialis anterior. RBDtector provides accurate, automated RSWA quantification comparable to human visual scoring, offering a reliable and efficient method to support the diagnosis of iRBD and identify iRBD at a higher risk of phenoconversion.

Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD), a parasomnia with dream enactment behaviors and excessive muscle activity during REM sleep, is an early stage synucleinopathy. The neurophysiological hallmark of RBD is REM sleep without atonia (RWSA), i.e. the loss of physiological muscle atonia during REM sleep. RBD pathophysiology is not fully clarified yet, but clinical and basic science suggest that ɑ-syn pathology begins in the lower brainstem where REM atonia circuits are located, including the sublaterodorsal tegmental/subcoeruleus nucleus and the ventral medulla, then propagates rostrally to brain regions such as the substantia nigra, limbic system, cortex. Genetically, there is only a partial overlap between RBD, PD and DLB, and individuals with iRBD may represent a specific subpopulation. A genome-wide association study identified five loci, which all seem to revolve around the GBA1 pathway. iRBD patients often show subtle motor, cognitive, autonomic and/or sensory signs, neuroimaging alterations as well as biofluid and tissue markers of neurodegeneration (in particular pathologic α-synuclein aggregates), which can be useful for risk stratification. Patients with iRBD represent thus the ideal population for neuroprotective/neuromodulating trials. This review provides insights into these aspects, highlighting and substantiating the central role of iRBD in treatment development strategies for synucleinopathies.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by the loss of muscle atonia and abnormal, often violent, movements and vocalizations during REM sleep. It is the strongest prodromal marker for progression to synucleinopathies such as dementia with Lewy bodies (DLB) and Parkinson disease (PD). iRBD individuals already show brain changes consistent with manifest synucleinopathies, but their mechanisms remain poorly understood. The glymphatic system is involved in the brain clearance of waste products and its defect has been associated with a higher likelihood of pathological burden and neurodegeneration. The presence of glymphatic system dysfunction revealed by neuroimaging in iRBD and its association with disease progression remain uninvestigated, including its potential to predict conversion toward distinct trajectories of synucleinopathies. We analyzed diffusion-weighted imaging data from a large international multicentric cohort of polysomnography-confirmed iRBD individuals and healthy controls. We used diffusion tensor imaging along the perivascular space to assess glymphatic function and derived a glymphatic index based on the diffusivity occurring within masks placed on associative and projection fibers adjacent to the lateral ventricles. The index was compared between groups and correlated with motor and cognitive features. Cox regression models assessed the relationship between glymphatic index and the likelihood of conversion to PD, DLB or remaining disease-free. Our analyses included 250 polysomnography-confirmed iRBD participants (mean age 66.5, 87% men) and 178 controls (65.7, 81% men). There was a significantly reduced glymphatic index in iRBD individuals compared to controls. Among the 224 iRBD individuals followed longitudinally (6.1 years, 1-16 years), 65 developed a neurodegenerative disease. iRBD converters exhibited lower glymphatic index compared to non-converters. Lower glymphatic index was associated with a higher risk of phenoconversion towards PD over time compared to remaining disease-free (hazard ratio = 2.43, 95% CI = 1.13-5.25, P = 0.012). This study reports glymphatic dysfunction in iRBD and its potential for predicting conversion to PD, underscoring its utility in identifying at-risk iRBD individuals.

Blood-based biomarkers for Alzheimer’s disease (AD) pathology have been intensively investigated as markers for AD-related neurodegeneration. Comorbid AD pathology is common in dementia with Lewy bodies (DLB). Accordingly, we hypothesized that plasma biomarkers associated with AD pathology might be useful to predict DLB in a cohort of idiopathic/isolated REM sleep behavior disorder (iRBD), an incipient synucleinopathy. The aim of this study was to determine whether plasma amyloid-β and pTau181 biomarkers can predict DLB. This longitudinal single-center (Canada) cohort study included 158 polysomnography-confirmed iRBD individuals between September 2004 and October 2022, each providing blood plasma samples, who were then offered prospective follow-up. Plasma Aβ40, Aβ42 and pTau181 levels were measured using NeuroToolKit, a prototype assays panel of neurodegeneration (Roche Diagnostics International Ltd). The primary outcome was the association between plasma biomarkers at baseline and eventual development of DLB. Correlations between plasma markers and baseline cognitive tests were assessed. A total of 142 iRBD participants (109 men [77%], mean ± SD age, 67.6 ± 8.0 years) were included in the final analysis. On prospective follow-up (2.9 ± 2.1 years after sampling), 32 individuals phenoconverted to a defined neurodegenerative syndrome (18 DLB, 13 PD, 1 MSA). The combined phenoconvertor group had lower baseline plasma Aβ42/40 ratio compared to non-phenoconvertors (mean ± SD, 0.103 ± 0.010 vs. 0.114 ± 0.012, p < 0.001), and higher pTau181 levels (0.993 ± 0.354 vs. 0.784 ± 0.266pg/ml, p = 0.008). When divided by phenoconversion subtype, significant differences were seen selectively in DLB-convertors (Aβ42/40 = 0.101 ± 0.010, difference -0.011, 95% CI [-0.016; -0.005], p < 0.001; pTau181 = 1.144 ± 0.326 pg/ml, difference 0.282 pg/ml, 95% CI [0.146; 0.418], p < 0.001). Cross-sectional analysis showed that plasma pTau181 (but not Aβ42/40) correlated with cognitive tests across various domains. Our results indicate that plasma Aβ42/40 ratio and pTau181 can predict conversion to DLB in iRBD.

Isolated rapid eye movement sleep behavior disorder is a prodrome of α-synucleinopathies. Using positron emission tomography, we assessed changes in Parkinson’s disease-related motor and cognitive metabolic networks and caudate/putamen dopaminergic input in a 4-year longitudinal imaging study of 13 male subjects with this disorder. We also correlated times to phenoconversion with baseline network expression in an independent validation sample. Expression values of both Parkinson’s disease-related networks increased over time while dopaminergic input gradually declined in the longitudinal cohort. While abnormal functional connections were identified at baseline in both networks, others bridging these networks appeared later. These changes resulted in compromised information flow through the networks years before phenoconversion. We noted an inverse correlation between baseline network expression and times to phenoconversion to Parkinson’s disease or dementia with Lewy bodies in the validation sample. Here, we show that the rate of network progression is a useful outcome measure in disease modification trials.