Amélie Pelletier

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...

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.

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.

Idiopathic/isolated REM sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies and Parkinson disease. Despite evidence of abnormal cerebral perfusion in iRBD, there is currently no pattern that can predict whether an individual will develop dementia with Lewy bodies or Parkinson disease. The objective was to identify a perfusion signature associated with conversion to dementia with Lewy bodies in iRBD. Patients with iRBD underwent video-polysomnography, neurologic and neuropsychological assessments, and baseline ^99mTc-HMPAO SPECT to assess relative cerebral blood flow. Partial least squares correlation was used to identify latent variables that maximized covariance between 27 clinical features and relative gray matter perfusion. Patient-specific scores on the latent variables were used to test the association with conversion to dementia with Lewy bodies compared with that with Parkinson disease. The signature's expression was also assessed in 24 patients with iRBD who underwent a second perfusion scan, 22 healthy controls, and 19 individuals with Parkinson disease. Of the 137 participants, 93 underwent SPECT processing, namely 52 patients with iRBD (67.9 years, 73% men), 19 patients with Parkinson disease (67.3 years, 37% men), and 22 controls (67.0 years, 73% men). Of the 47 patients with iRBD followed up longitudinally (4.5 years), 12 (26%) developed a manifest synucleinopathy (4 dementia with Lewy bodies and 8 Parkinson disease). Analysis revealed 2 latent variables between relative blood flow and clinical features: the first was associated with a broad set of features that included motor, cognitive, and perceptual variables, age, and sex; the second was mostly associated with cognitive features and RBD duration. When brought back into the patient's space, the expression of the first variable was associated with conversion to a manifest synucleinopathy, whereas the second was associated with conversion to dementia with Lewy bodies. The expression of the patterns changed over time and was associated with worse motor features. This study identified a brain perfusion signature associated with cognitive impairment in iRBD and transition to dementia with Lewy bodies. This signature, which can be derived from individual scans, has the potential to be developed into a biomarker that predicts dementia with Lewy bodies in at-risk individuals.

Patients with isolated/idiopathic REM sleep behavior disorder (iRBD) are at high risk for developing mild cognitive impairment (MCI) and dementia with Lewy bodies (DLB). However, there is a lack of scientific knowledge regarding the accuracy of cognitive screening tools to identify these conditions in iRBD. This study aimed to determine in iRBD the psychometrics of 2 screening tests to discriminate patients with MCI and those at risk of DLB. We retrospectively selected and followed 64 patients with polysomnography-confirmed iRBD seen in sleep clinic between 2006 and 2021, 32 with MCI (mean age 68.44 years, 72% men), 32 without MCI (67.78 years, 66% men), and 32 controls (69.84 years, 47% men). Participants underwent a neurologic evaluation and neuropsychological assessment for MCI diagnosis. They also completed the Montreal Cognitive Assessment (MoCA) and Clock Drawing Test (CDT). Fifty-three patients were followed (mean of 5.10 ± 2.64 years); 6 developed DLB, and 16 developed Parkinson disease. An independent cohort of 10 patients with iRBD who later developed DLB was also recruited and followed. Receiver operating characteristic curves with area under the curve (AUC) were performed assessing the discriminant value of the MoCA and CDT. The cut-off values that best differentiated patients who developed DLB from controls were on the MoCA total score (≤25/30 with 100% [95% CI 61%-100%] sensitivity and 78% [61%-89%] specificity, AUC = 0.888) and delayed recall (≤3/5 with 83% [44%-97%] sensitivity and 78% [61%-89%] specificity, AUC = 0.875). Both values yielded a sensitivity of 90% (60%-98%) to detect patients at risk of DLB in the independent cohort. Cutoffs that best discriminated patients with MCI from controls were: ≤25/30 (MoCA total score) with 72% [55%-84%] sensitivity, 78% [61%-89%] specificity, AUC = 0.803 and ≤2/5 (MoCA delayed recall) with 63% [45%-77%] sensitivity, 94% [80%-98%] specificity, AUC = 0.843. No acceptable optimal values were found for the CDT. In iRBD, the MoCA demonstrates adequate psychometric properties to identify patients most at risk of developing DLB and to screen for MCI, whereas the CDT does not. This study provides Class II evidence that the MoCA, but not the CDT, is useful in screening patients with iRBD for the risk of developing DLB.