Jean-François Gagnon

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...

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

Isolated REM sleep behavior disorder (iRBD) is the strongest prodromal marker of synucleinopathies, including Parkinson disease (PD) and dementia with Lewy bodies (DLB). Identifying brain biomarkers that predict progression and distinguish phenoconversion trajectories remains a challenge. The glymphatic system is involved in interstitial waste clearance, and its dysfunction has been associated with pathologic protein accumulation and neurodegeneration. Diffusion tensor imaging along the perivascular space (DTI-ALPS) has been proposed as a noninvasive proxy for glymphatic function. The aim of this study was to determine whether patients with iRBD show a reduced DTI-ALPS index compared with controls and whether a lower DTI-ALPS index predicts future phenoconversion to PD or DLB. We conducted a longitudinal, multicenter cohort study using brain MRI scans from patients with polysomnography-confirmed iRBD and healthy controls recruited across 5 international centers. All participants underwent T1-weighted and diffusion-weighted MRI. DTI-ALPS indices were computed from diffusivity along projection and associative fibers adjacent to the lateral ventricles. The primary outcome was time to phenoconversion to synucleinopathy. Linear models assessed baseline group differences and clinical correlates, and Cox proportional hazard models assessed the predictive value of DTI-ALPS for time to phenoconversion. A total of 250 patients with iRBD (mean age: 66.5 ± 6.8 years; 87% male) and 178 controls (65.7 ± 6.8 years; 81% male) were included. Patients with iRBD showed a lower left DTI-ALPS index compared with controls (mean difference = -0.034, 95% CI -0.067 to -0.001; p = 0.043). Of 224 patients with iRBD followed for a mean of 6.1 ± 3.5 years, 65 phenoconverted to a synucleinopathy. Converters had a lower left DTI-ALPS index than nonconverters (mean difference = -0.050, 95% CI -0.098 to -0.003; p = 0.038). Lower left DTI-ALPS index was associated with an increased risk of conversion to PD over time (hazard ratio = 2.43, 95% CI 1.13-5.25; p = 0.012). Other diffusion metrics inside periventricular masks, namely fractional anisotropy, diffusivity metrics, and free water, did not differ between groups. Patients with iRBD exhibit a reduced DTI-ALPS index, suggesting altered glymphatic function. This reduction was associated with future phenoconversion to PD, supporting the DTI-ALPS index as a potential prognostic MRI biomarker of progression in prodromal synucleinopathies.

Years before diagnosis of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA), mild prodromal manifestations can be detected. Longitudinal follow-up of people with prodromal synucleinopathy, particularly idiopathic/isolated REM sleep behavior disorder (iRBD), enables in-depth clinical phenotyping of early disease, which could facilitate stratification for clinical trials, provide the definition of appropriate end points, or predict phenoconversion more precisely. The aim of this study was to update and expand on previous studies assessing clinical evolution from iRBD to clinically diagnosed disease, up to 14 years before diagnosis. People with polysomnography-proven iRBD were included in this prospective cohort study (2004-2023) at Center for Advanced Research in Sleep Medicine (Montreal). Participants were followed annually with comprehensive motor and nonmotor assessments until they fulfilled clinical diagnostic criteria for PD, DLB, or MSA ("phenoconversion"). Tracing backward from phenoconversion, clinical trajectories in iRBD were compared with age-expected trajectories, as well as between PD and DLB phenoconverters, using mixed-effects models. A total of 95 people with iRBD were included in the analysis (69.0 ± 8.5 years, 26% female, RBD duration 7.1 ± 7.4 years, follow-up 1-15 years) and were eventually diagnosed with either PD (n = 46), DLB (n = 43), or MSA (n = 6). Among phenoconverters, Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and quantitative motor testing showed slowly progressing changes from Y-10, followed by exponential increase approximately 4 years before phenoconversion (F(4,298) = 79.1, p < 0.001). From 4 to 5 years before phenoconversion, accelerated worsening was found in global cognition (F(3,278) = 33.7, p < 0.001) and color vision (F(3,646) = 15.9, p < 0.001). Hyposmia was evident from Y-14 and progressed linearly (F(1,37) = 15.0, p < 0.001). Autonomic manifestations were evident from Y-12. DLB phenoconverters showed faster decline in global cognition (F(3,95) = 21.0, p < 0.001) and color vision (F(3,235) = 3.5, p = 0.02) than PD phenoconverters. Participants with iRBD showed evolving motor and nonmotor impairment many years before diagnosis of manifest synucleinopathy compared with estimated age-expected references. Our results suggest that some clinical features emerge early and progress linearly while others develop gradually and progress more rapidly shortly before phenoconversion. Prodromal PD, MSA, and DLB phenoconverters showed overlapping but distinct clinical trajectories, mainly for motor testing, cognitive function, and color vision. Additional large multicenter studies including longitudinal follow-up of controls are needed.

Neuroprotective interventions for dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are still in their early days. Clinical trials are expected to target idiopathic rapid eye movement sleep behavior disorder (iRBD), their strongest predictor. However, the presentation and progression of symptoms within this population show significant heterogeneity. We used machine learning (ML) to identify the clinical markers that are best at distinguishing iRBD patients (n=156) who developed DLB (n=26) from those who developed PD (n=34) at a mean follow-up of 4.37 years. Our model classified subsequent conversion to DLB versus PD with 0.80 accuracy, with mild cognitive impairment as best predictive feature. Cognitive tests of executive functions and verbal learning also played a major role in classifying other related pathological trajectories. These findings support the use of ML with clinical markers in iRBD, paving the way for a more targeted selection of participants in future neuroprotective trials of synucleinopathies.

Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD. Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5. Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease. Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings. NCT03623672.

Clinical and neuroanatomical correlates of daytime sleepiness in Parkinson’s disease (PD) remain inconsistent in the literature. Two studies were conducted here. The first evaluated the interrelation between non-motor and motor symptoms, using a principal component analysis, associated with daytime sleepiness in PD. The second identified the neuroanatomical substrates associated with daytime sleepiness in PD using magnetic resonance imaging (MRI). In the first study, 77 participants with PD completed an extensive clinical, cognitive testing and a polysomnographic recording. In the second study, 29 PD participants also underwent MRI acquisition of T1-weighted images. Vertex-based cortical and subcortical surface analysis, deformation-based morphometry, and voxel-based morphometry were performed to assess the association between daytime sleepiness severity and structural brain changes in participants. In both studies, the severity of daytime sleepiness and the presence of excessive daytime sleepiness (EDS; total score >10) were measured using the Epworth Sleepiness Scale. We found that individuals with EDS had a higher score on a component including higher dosage of dopamine receptor agonists, motor symptoms severity, shorter sleep latency, and greater sleep efficiency. Moreover, increased daytime sleepiness severity was associated with a larger surface area in the right insula, contracted surfaces in the right putamen and right lateral amygdala, and a larger surface in the right posterior amygdala. Hence, daytime sleepiness in PD was associated with dopaminergic receptor agonists dosage, motor impairment, and objective sleep measures. Moreover, neuroanatomical changes in cortical and subcortical regions related to vigilance, motor, and emotional states were associated with more severe daytime sleepiness.

Study Objectives: Idiopathic/isolated rapid eye movement-sleep behavior disorder (iRBD) often precedes the onset of synucleinopathies. Here, we investigated whether baseline resting-state EEG advanced spectral power and functional connectivity differed between iRBD patients who converted towards a synucleinopathy at follow-up and those who did not. Methods: Eighty-one participants with iRBD (66.89 ± 6.91 years) underwent a baseline resting-state EEG recording, a neuropsychological assessment, and a neurological examination. We estimated EEG power spectral density using standard analyses and derived spectral estimates of rhythmic and arrhythmic components. Global and pairwise EEG functional connectivity analyses were computed using the weighted phase-lag index (wPLI). Pixel-based permutation tests were used to compare groups. Results: After a mean follow-up of 5.01 ± 2.76 years, 34 patients were diagnosed with a synucleinopathy (67.81 ± 7.34 years) and 47 remained disease-free (65.53 ± 7.09 years). Among patients who converted, 22 were diagnosed with Parkinson’s disease and 12 with dementia with Lewy bodies. As compared to patients who did not convert, patients who converted exhibited at baseline higher relative theta standard power, steeper slopes of the arrhythmic component and higher theta rhythmic power mostly in occipital regions. Furthermore, patients who converted showed higher beta global wPLI but lower alpha wPLI between left temporal and occipital regions. Conclusions: Analyses of resting-state EEG rhythmic and arrhythmic components and functional connectivity suggest an imbalanced excitatory-to-inhibitory activity within large-scale networks, which is associated with later development of a synucleinopathy in patients with iRBD.