Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

Technical challenges in REM sleep microstructure classification: A study of patients with REM sleep behaviour disorder.

While commonly treated as a uniform state in practice, rapid eye movement sleep contains two distinct microstructures-phasic (presence of rapid eye movement) and tonic (no rapid eye movement). This study aims to identify technical challenges during rapid eye movement sleep microstructure visual classification in patients with rapid eye movement sleep behaviour disorder, and to propose solutions to enhance reliability between scorers. Fifty-seven sleep recordings were randomly allocated into three subsequent batches (n = 10, 13 and 34) for scoring. To reduce single-centre bias, we recruited three raters/scorers, with each trained from a different institution. Two raters independently scored each 30-s rapid eye movement sleep into 10â€…× fSEM3-s phasic/tonic microstructures based on the AASM guidelines. The third rater acted as an "arbitrator" to resolve opposite opinions persisting during the revision between batches. Besides interrater differences in artefact rejection rate, interrater variance frequently occurred due to transitioning between microstructures and moderate-to-severe muscular/electrode artefact interference. To enhance interrater agreement, a rapid eye movement scoring schematic graph was developed, incorporating proxy electrode use, filters and cut-offs for microstructure transitioning. To assess potential effectiveness of the schematic graph proposed, raters were instructed to systematically apply it in scoring for the third batch. Of the 34 recordings, 27 reached a Cohen's kappa score above 0.8 (i.e. almost perfect agreement between raters), significantly improved from the prior batches (p = 0.0003, Kruskal-Wallis test). Our study illustrated potential solutions and guidance for challenges that may be encountered during rapid eye movement sleep microstructure classification.

Defining Parkinson's Disease: Past and Future.

Parkinson's disease (PD) is the second most common still relentlessly progressive neurodegenerative disorder with a long period in which the pathophysiological process is already spreading but cardinal motor symptoms are not present. This review outlines the major developments and milestones in our understanding of PD that have shaped the way we define this disorder. Past criteria and definitions of PD have been based on clinical motor manifestations enabling diagnosis of the disease only in later symptomatic stages. Nevertheless, with advancing knowledge of disease pathophysiology and aim of early disease detection, a major shift of the diagnostic paradigm is being advocated towards a biological definition similar to other neurodegenerative disorders including Alzheimer's disease and Huntington's disease, with the ultimate goal of an earlier, disease course modifying therapy. We summarize the major pillars of this possible approach including in vivo detection of neuronal α-synuclein aggregation, neurodegeneration and genetics and outline their possible application in different contexts of use in the frame of biological PD definition.

Comorbid neurotrauma increases neurodegenerative-relevant cognitive, motor, and autonomic dysfunction in patients with REM sleep behavior disorder: A substudy of the North American Prodromal Synucleinopathy Consortium.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g., Parkinson's disease (PD), Lewy Body Dementia (LBD), and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) - henceforth "neurotrauma" (NT) - increase the odds of RBD by ~2.5-fold and is associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight-polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy (NAPS) Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory and autonomic function were completed. This cross-sectional analysis compared cases (n=24; RBD+NT) to controls (n=96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD+NT reported earlier RBD symptom onset (37.5±11.9 vs. 52.2±15.1 years of age) and a more severe RBD phenotype. Similarly, RBD+NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSION: This cross-sectional, matched case:control study shows individuals with RBD+NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD+NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.

Sleep disorders and mortality: A prospective study in the Canadian longitudinal study on aging.

BACKGROUND AND OBJECTIVES: Sleep disorders are commonly linked to various health conditions, although it remains unclear to what degree they are linked with overall mortality. We compared mortality in different self-reported sleep disorders in a large population-based prospective study. METHODS: In this case-control study within the CLSA cohort, participants completed a questionnaire at baseline (2011-2015) measuring overall sleep satisfaction, daily sleep duration, sleep-onset and sleep-maintenance insomnia, daytime somnolence, REM sleep behavior disorder (RBD), restless leg syndrome (RLS), and obstructive sleep apnea (OSA). The vital status of participants was assessed in July 2019. Baseline sleep problems of participants who died (cases) were compared to those who survived (controls). For each case, five age/sex-matched controls were selected. Binary logistic regression was used to estimate the association between sleep symptoms and mortality, adjusting for age, sex, marital status, province, education, alcohol consumption, smoking, caffeine, and body mass index. In a complementary model, anxiety and depression were also added. RESULTS: Among 30,097 participants at baseline, 974 deaths were reported in 2019 (60.7 % male, age = 72.3 ± 9.4 years). In the initial analysis, mortality cases reported more baseline sleep-maintenance insomnia (12.1 % vs. 8.0 %, Adjusted OR[95%CI] = 1.62[1.15,2.29]), daytime somnolence (2.4 % vs. 1.1 %, AOR = 2.70[1.34,5.44]), and higher possible RLS (16.4 % vs. 12.4 %, AOR = 1.50[1.09,2.05]). They were also more likely to screen positive for possible OSA (33.8 % vs. 24.2 %, AOR = 1.32[1.07,1.64]); however, this effect was not related to core apnea symptoms. Sleep durations exceeding 10 h/day were also associated with increased mortality (3.4 % vs. 1.9 %, AOR = 1.83[1.04,3.24]). Other sleep symptoms/disorders, such as sleep-onset insomnia (7.3 % vs. 4.3 %, AOR = 1.54 [1.00,2.37]), possible RBD (5.3 % vs. 5.1 %, AOR = 1.02[0.62,1.69]), and overall sleep dissatisfaction (26.5 % vs. 22.6 %, AOR = 1.14[0.93,1.41]) were not different among these groups. After adding anxiety and depression to the adjustment model, all differences attenuated to become statistically non-significant, except for daytime somnolence disorder. When stratified by sex, the association between sleep disorders and mortality was only observed in women, with men showing no association. DISCUSSION: We confirm a relationship between numerous sleep disorders and mortality. This effect is most evident in women, and appears to be strongly related to co-existing anxiety and depression.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Montreal Cognitive Assessment and the Clock Drawing Test to Identify MCI and Predict Dementia in Isolated REM Sleep Behavior Disorder.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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. CLASSIFICATION OF EVIDENCE: 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.

Spoken Language Alterations can Predict Phenoconversion in Isolated Rapid Eye Movement Sleep Behavior Disorder: A Multicenter Study.

OBJECTIVE: This study assessed the relationship between speech and language impairment and outcome in a multicenter cohort of isolated/idiopathic rapid eye movement (REM) 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. ANN NEUROL 2024;95:530-543.

The Effect of Different Types of Exercise on Sleep Quality and Architecture in Parkinson Disease: A Single-Blinded Randomized Clinical Trial Protocol.

OBJECTIVES: The purpose of this trial is to (1) determine the best exercise modality to improve sleep quality and sleep architecture in people with Parkinson disease (PD); (2) investigate whether exercise-induced improvements in sleep mediate enhancements in motor and cognitive function as well as other non-motor symptoms of PD; and (3) explore if changes in systemic inflammation after exercise mediate improvements in sleep. METHODS: This is a multi-site, superiority, single-blinded randomized controlled trial. One hundred fifty persons with PD and sleep problems will be recruited and randomly allocated into 4 intervention arms. Participants will be allocated into 12 weeks of either cardiovascular training, resistance training, multimodal training, or a waiting list control intervention. Assessments will be conducted at baseline, immediately after each intervention, and 8 weeks after each intervention by blinded assessors. Objective sleep quality and sleep architecture will be measured with polysomnography and electroencephalography. Motor and cognitive function will be assessed with the Unified PD Rating Scale and the Scale for Outcomes in PD-Cognition, respectively. Subjective sleep quality, fatigue, psychosocial functioning, and quality of life will be assessed with questionnaires. The concentration of inflammatory biomarkers in blood serum will be assessed with enzyme-linked immunosorbent assays. IMPACT: This study will investigate the effect of different types of exercise on sleep quality and architecture in PD, exploring interactions between changes in sleep quality and architecture with motor and cognitive function and other non-motor symptoms of the disease as well as mechanistic interactions between systemic inflammation and sleep. The results will provide important practical information to guide physical therapists and other rehabilitation professionals in the selection of exercise and the design of more personalized exercise-based treatments aimed at optimizing sleep, motor, and cognitive function in people with PD.

Prodromal dementia with Lewy bodies in REM sleep behavior disorder: A multicenter study.

INTRODUCTION: Isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) is a powerful early predictor of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). This provides an opportunity to directly observe the evolution of prodromal DLB and to identify which cognitive variables are the strongest predictors of evolving dementia. METHODS: IRBD participants (n = 754) from 10 centers of the International RBD Study Group underwent annual neuropsychological assessment. Competing risk regression analysis determined optimal predictors of dementia. Linear mixed-effect models determined the annual progression of neuropsychological testing. RESULTS: Reduced attention and executive function, particularly performance on the Trail Making Test Part B, were the strongest identifiers of early DLB. In phenoconverters, the onset of cognitive decline began up to 10 years prior to phenoconversion. Changes in verbal memory best differentiated between DLB and PD subtypes. DISCUSSION: In iRBD, attention and executive dysfunction strongly predict dementia and begin declining several years prior to phenoconversion. HIGHLIGHTS: Cognitive decline in iRBD begins up to 10 years prior to phenoconversion. Attention and executive dysfunction are the strongest predictors of dementia in iRBD. Decline in episodic memory best distinguished dementia-first from parkinsonism-first phenoconversion.

DNA Methylation Age Acceleration as a Potential Biomarker for Early Onset of Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) is the strongest prodromal marker for α-synucleinopathies. The Horvath DNA methylation age (DNAm-age) is an epigenetic clock reflecting biological aging. We found an association of DNAm-age acceleration with RBD age at onset at baseline (N = 162, B = -0.68, standard error [SE] = 0.12, p = 2.59e-08) and follow-up (n = 45, B = -1.07, SE = 0.21, p = 9.73e-06). The result remained similar after accounting for genetic risk factors (eg, RBD polygenic risk score). On average, RBD patients with faster versus slow/normal epigenetic aging had a 5.2-year earlier phenoconversion, and the Cox regression analysis revealed a trend toward significance (n = 53, hazard ratio = 1.05, 95% confidence interval = 0.99-1.11, p = 0.06). Our findings suggest that DNAm-age acceleration is a potential biomarker for earlier RBD onset. ANN NEUROL 2023.

Is REM Sleep Behavior Disorder Changing? Secular Changes Versus Referral Patterns.

Background: Since 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal. Objective: To assess if, over time, milder iRBD cases are presenting earlier. Methods: Disease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later") and by referral type ("self-referral" vs. "conventional-referral") in three large centers. Results: In Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects. Conclusions: Increased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion.

Identifying prodromal symptoms at high specificity for Parkinson's disease.

Introduction: To test drugs with the potential to prevent the onset of Parkinson's disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems). Objective: We aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls. Methods: We investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6. Results: Constipation had an adjusted odds ratio, 6.14 [95% CI: 2.94-12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88-48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively. Discussion: Clinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD.

HLA in isolated REM sleep behavior disorder and Lewy body dementia.

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Effects of Season and Daylight Saving Time Shifts on Sleep Symptoms: Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: There has been conflicting evidence regarding the association between seasonal changes and daylight saving time (DST) and sleep disorders. This topic is of particular interest currently because the United States and Canada are considering the elimination of seasonal clock changes. The aim of this study was to compare sleep symptoms among participants who were interviewed in different seasons and before/after the transition into DST and standard time (ST). METHODS: A total of 30,097 people aged 45-85 years taking part in the Canadian Longitudinal Study on Aging were studied. Participants completed a questionnaire on sleep duration, satisfaction, sleep-onset insomnia, sleep-maintenance insomnia, and hypersomnolence symptoms. Sleep disorders were compared between participants who were interviewed during different seasons and at different times of the year (DST/ST). Data were analyzed using χ2, analysis of variance, binary logistic, and linear regression tests. RESULTS: Among participants interviewed in different seasons, we found no difference in dissatisfaction with sleep, sleep onset, sleep maintenance, and hypersomnolence. Those interviewed in summer had slightly shorter sleep duration compared with those in winter (6.76 ± 1.2 vs 6.84 ± 1.3 hours). Participants interviewed 1 week before vs 1 week after DST transition showed no difference in sleep symptoms, except for a 9-minute decrease in sleep duration a week after transition. However, those who were interviewed a week after transition to ST compared with a week before reported more dissatisfaction with sleep (28% vs 22.6%, adjusted odds ratio [aOR] 1.34, 95% CI 1.02-1.76), higher sleep-onset insomnia (7.1% vs 3.3%, aOR 2.26, 95% CI 1.19-4.27), higher sleep-maintenance insomnia (12.9% vs 8.2%, aOR 1.64, 95% CI 1.02-2.66), and more hypersomnolence with adequate sleep (7.3% vs 3.6%, aOR 2.08, 95% CI 1.14-3.79). DISCUSSION: We found small seasonal variations in sleep duration but no difference in other sleep symptoms. The transition from DST to ST was associated with a transient increase in sleep disorders.