Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 \ub1 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials

528 REM Sleep Without Atonia in Idiopathic REM Sleep Behavior Disorder in the North American Prodromal Synucleinopathy Cohort

Abstract Introduction Idiopathic/isolated REM sleep behavior disorder (iRBD) is a prodromal alpha-synucleinopathy characterized by dream enactment behavior and REM sleep without atonia (RSWA). We sought to define quantitative RSWA diagnostic thresholds in the North American Prodromal Synucleinopathy (NAPS) Consortium cohort. We analyzed RSWA between iRBD patients across participating NAPS sleep centers, compared to normative controls, and hypothesized that previous diagnostic RSWA thresholds were overestimates. Methods All digital polysomnography files were converted to European Data Format and scored at a central laboratory (Mayo Clinic) which standardized display scoring montages, channel sensitivities, and filtering, and scripted computational analyses for visual scoring. RSWA was quantitatively analyzed in the submentalis (SM) and anterior tibialis (AT) muscles in iRBD (n=86) patients and controls (n=118) utilizing well validated visual (Mayo) and automated (RAI) methods. Parametric statistics were used to compare RSWA metrics, and RSWA thresholds were developed using receiver operating characteristic curves. Results RSWA was significantly higher for the RAI and all visual individual and combined muscle activity metrics in iRBD compared to controls (all p<0.001). Average SM phasic measures were: 14.2% (Mayo), 17.9% (McGill), 18.5% (UCLA), and 9.4% (Washington University). Average AT phasic measures at each site were: 26.7% (Mayo), 17.1% (McGill), 23.3% (UCLA), and 17.4% (Washington University). Average SM/AT ‘any’ measures at each site were: 45.4% (Mayo), 35.9% (McGill), 53.4% (UCLA), and 23.5% (Washington University). Overall cohort RBD diagnostic thresholds (AUC, specificity/sensitivity) were: SM phasic 4.9% (90.0, 82.2%/83.7%); AT phasic 7.6% (88.7%, 82.2%/81.4%) and combined SM/AT ‘any’ 13% (94.6, 83.9%/96.5%). Conclusion RSWA thresholds in the NAPS cohort were substantially lower than previously reported, suggesting previously overestimated diagnostic RSWA thresholds due to smaller, enriched patient samples and overfit statistical modeling. Confirmation of these findings in the complete NAPS cohort (n=300 iRBD patients across all 10 NAPS centers) is planned. Support (if any)

Targeted enrichment outperforms other enrichment techniques and enables more multi-species RNA-Seq analyses.

Enrichment methodologies enable the analysis of minor members in multi-species transcriptomic data. We compared the standard enrichment of bacterial and eukaryotic mRNA to a targeted enrichment using an Agilent SureSelect (AgSS) capture for Brugia malayi, Aspergillus fumigatus, and the Wolbachia endosymbiont of B. malayi (wBm). Without introducing significant systematic bias, the AgSS quantitatively enriched samples, resulting in more reads mapping to the target organism. The AgSS-enriched libraries consistently had a positive linear correlation with their unenriched counterparts (r2 = 0.559-0.867). Up to a 2,242-fold enrichment of RNA from the target organism was obtained following a power law (r2 = 0.90), with the greatest fold enrichment achieved in samples with the largest ratio difference between the major and minor members. While using a single total library for prokaryote and eukaryote enrichment from a single RNA sample could be beneficial for samples where RNA is limiting, we observed a decrease in reads mapping to protein coding genes and an increase in multi-mapping reads to rRNAs in AgSS enrichments from eukaryotic total RNA libraries compared to eukaryotic poly(A)-enriched libraries. Our results support a recommendation of using AgSS targeted enrichment on poly(A)-enriched libraries for eukaryotic captures, and total RNA libraries for prokaryotic captures, to increase the robustness of multi-species transcriptomic studies

Targeted enrichment outperforms other enrichment techniques and enables more multi-species RNA-Seq analyses.

Enrichment methodologies enable the analysis of minor members in multi-species transcriptomic data. We compared the standard enrichment of bacterial and eukaryotic mRNA to a targeted enrichment using an Agilent SureSelect (AgSS) capture for Brugia malayi, Aspergillus fumigatus, and the Wolbachia endosymbiont of B. malayi (wBm). Without introducing significant systematic bias, the AgSS quantitatively enriched samples, resulting in more reads mapping to the target organism. The AgSS-enriched libraries consistently had a positive linear correlation with their unenriched counterparts (r2 = 0.559-0.867). Up to a 2,242-fold enrichment of RNA from the target organism was obtained following a power law (r2 = 0.90), with the greatest fold enrichment achieved in samples with the largest ratio difference between the major and minor members. While using a single total library for prokaryote and eukaryote enrichment from a single RNA sample could be beneficial for samples where RNA is limiting, we observed a decrease in reads mapping to protein coding genes and an increase in multi-mapping reads to rRNAs in AgSS enrichments from eukaryotic total RNA libraries compared to eukaryotic poly(A)-enriched libraries. Our results support a recommendation of using AgSS targeted enrichment on poly(A)-enriched libraries for eukaryotic captures, and total RNA libraries for prokaryotic captures, to increase the robustness of multi-species transcriptomic studies

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

International audienceObjective: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD).Methods: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.Results: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.Interpretation: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75

Spoken language alterations can predict phenoconversion in isolated REM sleep behavior disorder: a multicentric study.

OBJECTIVE This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD). METHODS Patients with iRBD from 7 centers speaking Czech, English, German, French, and Italian languages underwent a detailed speech assessment at baseline. Story-tale narratives were transcribed and linguistically annotated using fully automated methods based on automatic speech recognition and natural language processing algorithms, leading to the 3 distinctive linguistic and 2 acoustic patterns of language deterioration and associated composite indexes of their overall severity. Patients were then prospectively followed and received assessments for parkinsonism or dementia during follow-up. The Cox proportional hazard was performed to evaluate the predictive value of language patterns for phenoconversion over a follow-up period of 5 years. RESULTS Of 180 patients free of parkinsonism or dementia, 156 provided follow-up information. After a mean follow-up of 2.7 years, 42 (26.9%) patients developed neurodegenerative disease. Patients with higher severity of linguistic abnormalities (hazard ratio [HR = 2.35]) and acoustic abnormalities (HR = 1.92) were more likely to develop a defined neurodegenerative disease, with converters having lower content richness (HR = 1.74), slower articulation rate (HR = 1.58), and prolonged pauses (HR = 1.46). Dementia-first (n = 16) and parkinsonism-first with mild cognitive impairment (n = 9) converters had higher severity of linguistic abnormalities than parkinsonism-first with normal cognition converters (n = 17). INTERPRETATION Automated language analysis might provide a predictor of phenoconversion from iRBD into synucleinopathy subtypes with cognitive impairment, and thus can be used to stratify patients for neuroprotective trials. This article is protected by copyright. All rights reserved