Visuospatial dysfunction predicts dementia-first phenoconversion in isolated REM sleep behaviour disorder.

OBJECTIVE: While isolated rapid eye movement sleep behaviour disorder (iRBD) is known as a prodrome of α-synucleinopathies, the prediction for its future phenoconversion to parkinsonism-first or dementia-first subtype remains a challenge. This study aimed to investigate whether visuospatial dysfunction predicts dementia-first phenoconversion in iRBD. METHODS: Patients with iRBD and control subjects were enrolled in this prospective cohort study. Baseline neuropsychological assessment included the Unified Parkinson's Disease Rating Scale part III, Montreal Cognitive Assessment (MoCA), Rey-Osterrieth complex figure (ROCF), Colour Trails test (CTT), Farnsworth-Munsell 100-hue test and Digit Span test. The anterior and posterior subscores of MoCA as well as their modified versions were explored. A composite score derived from ROCF and CTT was also explored. Regular follow-up was conducted to determine the phenoconversion status of iRBD patients. RESULTS: The study included 175 iRBD patients and 98 controls. During a mean follow-up of 5.1 years, 25.7% of patients experienced phenoconversion. Most of the neuropsychological tests could differentiate dementia-first but not parkinsonism-first convertors from non-convertors. The modified posterior subscore of MoCA, by integrating the Alternating Trail Making and Clock Drawing components into original the posterior subscore, which mainly reflects visuospatial function, was the strongest predictor for dementia-first phenoconversion (adjusted HR 5.48, 95% CI 1.67 to 17.98). CONCLUSION: Visuospatial dysfunction, as reflected mainly by the modified posterior subscore of MoCA, is a predictive factor for dementia-first phenoconversion in iRBD, suggesting its potential for being a biomarker for clinical prognostic prediction and potential neuroprotective trials aiming to delay or prevent dementia.

Familial α-synucleinopathy spectrum features in patients with psychiatric REM sleep behaviour disorder.

BACKGROUND: Rapid eye movement (REM) sleep behaviour disorder (RBD) is one of the earliest and most specific prodromes of the α-synucleinopathies including Parkinson's disease (PD). It remains uncertain whether RBD occurring in the context of psychiatric disorders (psy-RBD), although very common, is merely a benign epiphenomenon of antidepressant treatment, or whether it harbours an underlying α-synucleinopathy. We hypothesised that patients with psy-RBD demonstrate a familial predisposition to an α-synucleinopathy. METHODS: In this case-control-family study, a combination of family history and family study method was used to measure the α-synucleinopathy spectrum features, which included RBD, neurodegenerative prodromal markers and clinical diagnoses of neurodegenerative disorders. We compared the risk of α-synucleinopathy spectrum features in the first-degree relatives (FDRs) of patients with psy-RBD, psychiatric controls and healthy controls. RESULTS: There was an increase of α-synucleinopathy spectrum features in the psy-RBD-FDRs, including possible and provisional RBD (adjusted HR (aHR)=2.02 and 6.05, respectively), definite RBD (adjusted OR=11.53) and REM-related phasic electromyographic activities, prodromal markers including depression (aHR=4.74) and probable subtle parkinsonism, risk of prodromal PD and clinical diagnosis of PD/dementia (aHR=5.50), as compared with healthy-control-FDRs. When compared with psychiatric-control-FDRs, psy-RBD-FDRs consistently presented with a higher risk for the diagnosis and electromyographic features of RBD, diagnosis of PD/dementia (aHR=3.91) and risk of prodromal PD. In contrast, psychiatric controls only presented with a familial aggregation of depression. CONCLUSION: Patients with psy-RBD are familially predisposed to α-synucleinopathy. The occurrence of RBD with major depression may signify a subtype of major depressive disorders with underlying α-synucleinopathy neurodegeneration. TRIAL REGISTRATION NUMBER: NCT03595475.

Validation of the Revised Illness Perception Questionnaire of Obstructive Sleep Apnea among Elderly Chinese in the General Population.

PURPOSE: The prevalence of under-diagnosis among individuals with obstructive sleep apnea (OSA) is alarming, and may be associated with perceptions regarding OSA. To facilitate future studies on OSA, this study validated the revised version of the Illness Perception Questionnaire (IPQ-R) for OSA in a general population. METHODS: A random anonymous population-based telephone survey interviewed 580 adults aged ≥ 50 years in Hong Kong, who self-reported not having been told by doctors as having OSA, from February 5 to March 19, 2021. RESULTS: The confirmatory factor analysis identified a modified 7-factor model (i.e., timeline chronic, consequence, personal control, treatment control, illness coherence, timeline cyclical, and emotional representation) that showed satisfactory model fit index and internal consistency. Nine items were removed from the original version because of low factor loadings. No floor and ceiling effects were observed. Convergent validity was supported by the positive associations between the consequence subscale with perceived negative outcomes of OSA and between the illness coherence subscale and perceived understanding of OSA symptoms. The participants tended to endorse the items of timeline chronic, treatment control, and illness coherence but not with those of emotional representations. The mean scores of the IPQ-R subscales differed by age and education level. CONCLUSION: The modified IPQ-R of OSA showed acceptable psychometric properties. It is applicable to assessing illness perceptions of OSA in the Chinese general population aged ≥ 50 years not having received OSA diagnosis. The validated tool would support future studies and health practices related to OSA.

Prevalence and correlates of REM sleep behaviour disorder in patients with major depressive disorder: a two-phase study.

OBJECTIVE: To investigate the prevalence and clinical correlates of video polysomnography (vPSG)-confirmed rapid eye movement sleep behaviour disorder (RBD) in patients with major depressive disorder (MDD). METHODS: This is a clinic-based two-phase epidemiological study. In phase 1, patients with MDD were screened by a validated questionnaire, RBD Questionnaire-Hong Kong (RBDQ-HK). In phase 2, a subsample of both the screen-positive (RBDQ-HK >20) and screen-negative patients with MDD underwent further clinical and sleep assessment (vPSG) to confirm the diagnosis of RBD (MDD+RBD). Poststratification weighting method was used to estimate the prevalence of MDD+RBD. The total likelihood ratio and the probability of prodromal Parkinson's disease (PD) were calculated from prodromal markers and risk factors, as per the Movement Disorder Society research criteria. RESULTS: A total of 455 patients with MDD were screened (median age (IQR)=52.66 (15.35) years, 77.58% woman, 43.74% positive). Eighty-one patients underwent vPSG and 12 of them were confirmed MDD+RBD. The prevalence of MDD+RBD was estimated to be 8.77% (95% CI: 4.33% to 16.93%), with possibly male predominance. MDD+RBD were associated with colour vision and olfaction deficit and a higher probability for prodromal PD. CONCLUSIONS: Almost 9% of patients with MDD in the psychiatric outpatient clinic has vPSG-confirmed RBD. Comorbid MDD+RBD may represent a subtype of MDD with underlying α-synucleinopathy neurodegeneration. Systematic screening of RBD symptoms and necessity of vPSG confirmation should be highlighted for capturing this MDD subtype with a view to enhance personalised treatment and future neuroprotection to prevent neurodegeneration.

Residual Injurious Symptoms and Its Association With Neurodegenerative Outcomes in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: A Retrospective, Longitudinal Follow-up Study.

BACKGROUND: The risk of neurodegenerative disorders in idiopathic rapid eye movement sleep behavior disorder (iRBD) patients with residual injurious symptoms (RIS) after symptomatic treatment with clonazepam and/or melatonin is unclear. OBJECTIVE: The objective of this study was to determine the rate and correlates of RIS and its association with the risk of neurodegenerative diseases in patients with iRBD. METHODS: This was a retrospective cohort study. RIS was defined by the RBD Questionnaire-Hong Kong (RBDQ-HK) as the presence of residual sleep-related injuries or potential injurious behaviors for at least once a month after at least 1 year of treatment. RESULTS: A total of 15 out of 133 (11.3%) patients with iRBD (age at diagnosis = 66.5 ± 7.3 years, 77.4% male) had RIS after 2.7 years of treatment. Patients with RIS were younger at both onset and polysomnography-confirmed diagnosis of iRBD (years, mean ± standard deviation, 56.3 ± 6.9 vs. 61.8 ± 7.6, P = 0.01; 61.2 ± 4.2 vs. 67.2 ± 7.4, P < 0.001, respectively), had more severe behavioral symptoms at diagnosis (both RBDQ-HK total score and behavioral subscore, P = 0.01), and used a higher maximum dose of clonazepam (mg; median [interquartile range], 1.5 [1.0] vs. 1.0 [1.0], P = 0.01). RIS was probably associated with a higher risk of developing dementia with Lewy bodies (adjusted hazard ratio [95% confidence interval], 5.47 [1.71-17.46], adjusted for onset age of RBD), but not Parkinsons's disease in the follow-up. CONCLUSION: RIS is not uncommon in patients with iRBD despite long-term medication treatment. An earlier onset and more severe clinical profile are associated with RIS. The prediction of RIS toward dementia with Lewy bodies but not PD suggests that RIS may probably help to identify the specific risk of different subtypes of α-synucleinopathy. © 2020 International Parkinson and Movement Disorder Society.

Hypersomnolence is associated with non-remission of major depressive disorder.

OBJECTIVE: This study aimed to investigate the prevalence, clinical correlates and the relationship between hypersomnolence and clinical outcomes in a cohort of MDD patients. METHODS: This is a cross-sectional study of a MDD cohort in an university-affiliated adult psychiatric outpatient clinic. The diagnosis of MDD and severity of depression were ascertained by the clinician with structured clinical interviews. Each participant completed the Epworth Sleepiness Scale (ESS), 1-week sleep diary, and a battery of questionnaires that assessed usual sleep pattern, insomnia, anxiety, depression, fatigue and circadian preference. Hypersomnolence was defined as ESS score ≥14 among those reported ≥7 h of nighttime sleep. Univariate analysis and multiple logistic regression were used to analyze the relationships between the variables. RESULTS: Among 252 recruited subjects, 11 % met the criteria of hypersomnolence as defined by a ESS score ≥14 despite ≥7 h of nighttime sleep. Patients with hypersomnolence had greater depression ratings, higher rates of suicidal ideations over the past week, and more likely to meet a diagnosis of atypical depression (p < 0.05) than those without hypersomnolence. Step-wise logistic regression demonstrated that hypersomnolence was an independent risk factor associated with a 3-fold increase in the risk of depression non-remission (adjusted OR 3.13; 95 % CI 1.10-8.95; p = 0.034). CONCLUSION: Patients with hypersomnolence despite seemingly adequate sleep represent a subgroup of MDD patients who have a more severe illness profile with higher non-remission rate and suicidality. The findings highlight the importance of addressing both sleep and mood symptoms in the management of MDD.

Chinese self-report version of biological rhythms interview for assessment in neuropsychiatry (C-BRIAN-SR) - psychometric properties and prospective follow-up in patients with non-seasonal depression.

This study examined the psychometric properties and longitudinal changes of the self-reporting Traditional Chinese version of Biological Rhythms Interview for Assessment in Neuropsychiatry (C-BRIAN-SR) among healthy controls (HC) and patients with major depressive episode (MDE). Eighty patients with a current MDE and 80 HC were recruited. Assessments were repeated after two weeks in HC, and upon the discharge of MDE patients to examine the prospective changes upon remission of depression. The C-BRIAN-SR score was significantly higher in the MDE than HC group. The concurrent validity was supported by a positive correlation between scores of C-BRIAN-SR, Insomnia Severity Index and the Hospital Anxiety Depression Scale. C-BRIAN-SR negatively correlated MEQ in the MDE group (r = .30, p = 0.009), suggesting higher rhythm disturbances were associated with a tendency toward eveningness. A moderate test-retest reliability was found (r = .61, p < 0.001). A cut-off of 38.5 distinguished MDE subjects from HC with 82.9% of sensitivity and 81.0% of specificity. C-BRIAN-SR score normalized in remitted MDE patients but remained higher in the non-remitted. The C-BRIAN-SR is a valid and reliable scale for measuring the biological rhythms and may assist in the screening of patients with MDE.

Association of accelerometer-measured sleep duration and different intensities of physical activity with incident type 2 diabetes in a population-based cohort study.

PURPOSE: The aim of the current study was to investigate the association of accelerometer-measured sleep duration and different intensities of physical activity (PA) with the risk of incident type 2 diabetes in a population-based prospective cohort study. METHODS: Altogether, 88,000 participants (mean age = 62.2 ± 7.9 years, mean ± SD) were included from the UK Biobank. Sleep duration (short: <6 h/day; normal: 6-8 h/day; long: >8 h/day) and PA of different intensities were measured using a wrist-worn accelerometer over a 7-day period between 2013 and 2015. PA was classified according to the median or World Health Organization-recommendation: total volume of PA (high, low), moderate-to-vigorous PA (MVPA) (recommended, not recommended), and light-intensity PA (high, low). Incidence of type 2 diabetes was ascertained using hospital records or death registries. RESULTS: During a median follow-up of 7.0 years, 1615 incident type 2 diabetes cases were documented. Compared with normal sleep duration, short (hazard ratio (HR) = 1.21, 95% confidence interval (95%CI): 1.03-1.41) but not long sleep duration (HR = 1.01, 95%CI: 0.89-1.15) was associated with excessive type 2 diabetes risk. This increased risk among short sleepers seems to be protected against by PA. Compared with normal sleepers with high or recommended PA, short sleepers with low volume of PA (HR = 1.81, 95%CI: 1.46-2.25), not recommended (below the World Health Organization-recommended level of) MVPA (HR = 1.92, 95%CI: 1.55-2.36), or low light-intensity PA (HR = 1.49, 95%CI: 1.13-1.90) had a higher risk of type 2 diabetes, while short sleepers with a high volume of PA (HR = 1.14, 95%CI: 0.88-1.49), recommended MVPA (HR = 1.02, 95%CI: 0.71-1.48), or high light-intensity PA (HR = 1.14, 95%CI: 0.92-1.41) did not. CONCLUSION: Accelerometer-measured short but not long sleep duration was associated with a higher risk of incident type 2 diabetes. A higher level of PA, regardless of intensity, potentially ameliorates this excessive risk.

Multimodal digital assessment of depression with actigraphy and app in Hong Kong Chinese.

There is an emerging potential for digital assessment of depression. In this study, Chinese patients with major depressive disorder (MDD) and controls underwent a week of multimodal measurement including actigraphy and app-based measures (D-MOMO) to record rest-activity, facial expression, voice, and mood states. Seven machine-learning models (Random Forest [RF], Logistic regression [LR], Support vector machine [SVM], K-Nearest Neighbors [KNN], Decision tree [DT], Naive Bayes [NB], and Artificial Neural Networks [ANN]) with leave-one-out cross-validation were applied to detect lifetime diagnosis of MDD and non-remission status. Eighty MDD subjects and 76 age- and sex-matched controls completed the actigraphy, while 61 MDD subjects and 47 controls completed the app-based assessment. MDD subjects had lower mobile time (P = 0.006), later sleep midpoint (P = 0.047) and Acrophase (P = 0.024) than controls. For app measurement, MDD subjects had more frequent brow lowering (P = 0.023), less lip corner pulling (P = 0.007), higher pause variability (P = 0.046), more frequent self-reference (P = 0.024) and negative emotion words (P = 0.002), lower articulation rate (P < 0.001) and happiness level (P < 0.001) than controls. With the fusion of all digital modalities, the predictive performance (F1-score) of ANN for a lifetime diagnosis of MDD was 0.81 and 0.70 for non-remission status when combined with the HADS-D item score, respectively. Multimodal digital measurement is a feasible diagnostic tool for depression in Chinese. A combination of multimodal measurement and machine-learning approach has enhanced the performance of digital markers in phenotyping and diagnosis of MDD.

Circadian rhythm dysfunction and psychopathology in the offspring of parents with bipolar disorder: a high-risk study in the Chinese population.

Background: Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder. Nevertheless, some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited. Aims: To examine the prevalence rates of sleep and circadian dysfunctions, mental disorders and their symptoms in the offspring of parents with (O-BD) and without bipolar disorder (O-control). Methods: The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area, China. The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders, and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, respectively. Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring. Results: Adjusting for age, sex and region of recruitment, there was a significantly higher risk of delayed sleep phase symptoms (9.55% vs 2.58%, adjusted OR: 4.04) in O-BD than in O-control. O-BD had a nearly fivefold higher risk of mood disorders (11.70% vs 3.47%, adjusted OR: 4.68) and social anxiety (6.28% vs 1.49%, adjusted OR: 4.70), a fourfold higher risk of depressive disorders (11.17% vs 3.47%, adjusted OR: 3.99) and a threefold higher risk of mood symptoms (20.74% vs 10.40%, adjusted OR: 2.59) than O-control. Subgroup analysis revealed that O-BD children (aged under 12 years) had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control, while there was a nearly 4-fold higher risk of delayed sleep phase symptoms, a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents (aged 12 years and over). Conclusions: There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterparts, confirming the central role of circadian rhythm dysfunction in bipolar disorder. The findings of the specific age-related and stage-related developmental patterns of psychopathologies and circadian dysfunction in children and adolescent offspring of parents with bipolar disorder paved the way to develop specific and early clinical intervention and prevention strategies. Trial registration number: NCT03656302.

Mapping the landscape of sleep medicine training across Asia.

STUDY OBJECTIVES: This study assessed the current state of sleep medicine accreditation and training in Asia by conducting a comprehensive survey across 29 Asian countries and regions facilitated by the Asian Society of Sleep Medicine (ASSM) to identify existing gaps and provide recommendations for future enhancements. METHODS: The ASSM Education Task Force Committee designed a survey to gather data on accreditation, education, and training standards in sleep medicine, including information on challenges in enhancing education in the field. RESULTS: With an 86% (25 countries/regions) response rate, the survey showed that sleep medicine is recognized as an independent specialty in just nine countries/regions (36% of the countries/regions surveyed). Ten countries/regions have established sleep medicine training programs, with Japan and Saudi Arabia offering it as a distinct specialty. Significant disparities in training and accreditation standards were identified, with many countries/regions lacking formalized training and practice guidelines. The survey also revealed that most local sleep societies across Asia support the development of an Asian Sleep Medicine Training Curriculum led by the ASSM. However, several barriers significantly impede the establishment and development of sleep medicine training programs, including the scarcity of trained specialists and technologists and the absence of national accreditation for sleep medicine. CONCLUSIONS: The survey highlights the need for standardized sleep medicine training and accreditation across Asia. Developing an Asian Sleep Medicine Training Curriculum and promoting ASSM accreditation guidelines are key recommendations. Implementing these strategies is essential for advancing sleep medicine as a widely recognized discipline throughout Asia.

Craniofacial phenotyping by photogrammetry in Chinese prepubertal children with obstructive sleep apnea.

STUDY OBJECTIVES: This study aimed to examine the craniofacial phenotype of Chinese prepubertal children with and without obstructive sleep apnea (OSA) using a quantitative photographic analysis technique and to develop a prediction model for OSA diagnosis based on the photogrammetric data. Potential ethnic differences in the association between OSA and photogrammetric data between Chinese and Caucasian children were also examined. METHODS: This was a cross-sectional study. Chinese children aged 5-12 years old, suspected to have OSA were recruited from our sleep clinic. Frontal and side photos were taken for craniofacial phenotyping by photogrammetry. Polysomnography was performed and participants were divided into three groups: non-OSA (obstructive apnea hypopnea index (OAHI) < 1/h), mild OSA (OAHI between 1/h and 5/h), and moderate-to-severe (MS) OSA (OAHI ≥ 5/h). Prediction models were built from 70% of training data using logistic regression and evaluated on the remaining 30% of test data for receiver operating characteristic (ROC) curve construction. RESULTS: This study included 90 participants (mean age: 8.2 ± 1.6 years, 67 males). Non-OSA, mild OSA, and MS OSA groups included 32, 31, and 27 participants, respectively. There were significant trends for an increasing maxillary-mandibular relationship angle (p = .002) and a decreasing anterior mandibular height to whole face length ratio (p < .001) with increasing OSA severity. A prediction model built with clinical measurements and the two photogrammetric features yielded an area under the ROC curve (AUC) of 0.81 (95% C.I.: 0.64-0.96). CONCLUSIONS: Craniofacial features obtained by photogrammetry are significantly different between OSA groups in prepubertal children. Increased maxillary-mandibular relationship angle is an OSA feature found in both Asian and Caucasian children.

Detection of Suicidal Ideation in Clinical Interviews for Depression Using Natural Language Processing and Machine Learning: Cross-Sectional Study.

Background: Assessing patients' suicide risk is challenging, especially among those who deny suicidal ideation. Primary care providers have poor agreement in screening suicide risk. Patients' speech may provide more objective, language-based clues about their underlying suicidal ideation. Text analysis to detect suicide risk in depression is lacking in the literature. Objective: This study aimed to determine whether suicidal ideation can be detected via language features in clinical interviews for depression using natural language processing (NLP) and machine learning (ML). Methods: This cross-sectional study recruited 305 participants between October 2020 and May 2022 (mean age 53.0, SD 11.77 years; female: n=176, 57%), of which 197 had lifetime depression and 108 were healthy. This study was part of ongoing research on characterizing depression with a case-control design. In this study, 236 participants were nonsuicidal, while 56 and 13 had low and high suicide risks, respectively. The structured interview guide for the Hamilton Depression Rating Scale (HAMD) was adopted to assess suicide risk and depression severity. Suicide risk was clinician rated based on a suicide-related question (H11). The interviews were transcribed and the words in participants' verbal responses were translated into psychologically meaningful categories using Linguistic Inquiry and Word Count (LIWC). Results: Ordinal logistic regression revealed significant suicide-related language features in participants' responses to the HAMD questions. Increased use of anger words when talking about work and activities posed the highest suicide risk (odds ratio [OR] 2.91, 95% CI 1.22-8.55; P=.02). Random forest models demonstrated that text analysis of the direct responses to H11 was effective in identifying individuals with high suicide risk (AUC 0.76-0.89; P<.001) and detecting suicide risk in general, including both low and high suicide risk (AUC 0.83-0.92; P<.001). More importantly, suicide risk can be detected with satisfactory performance even without patients' disclosure of suicidal ideation. Based on the response to the question on hypochondriasis, ML models were trained to identify individuals with high suicide risk (AUC 0.76; P<.001). Conclusions: This study examined the perspective of using NLP and ML to analyze the texts from clinical interviews for suicidality detection, which has the potential to provide more accurate and specific markers for suicidal ideation detection. The findings may pave the way for developing high-performance assessment of suicide risk for automated detection, including online chatbot-based interviews for universal screening.

Association between accelerometer-measured amplitude of rest-activity rhythm and future health risk: a prospective cohort study of the UK Biobank.

BACKGROUND: The health effects of rest-activity rhythm are of major interest to public health, but its associations with health outcomes remain elusive. We aimed to examine the associations between accelerometer-measured rest-activity rhythm amplitude and health risks among the general UK population. METHODS: We did a prospective cohort analysis of UK Biobank participants aged 43-79 years with valid wrist-worn accelerometer data. Low rest-activity rhythm amplitude was defined as the first quintile of relative amplitude; all other quintiles were classified as high rest-activity rhythm amplitude. Outcomes of interest were defined using International Classification of Diseases 10th Revision codes and consisted of incident cancer and cardiovascular, infectious, respiratory, and digestive diseases, and all-cause and disease-specific (cardiovascular, cancer, and respiratory) mortality. Participants with a current diagnosis of any outcome of interest were excluded. We assessed the associations between decreased rest-activity rhythm amplitude and outcomes using Cox proportional hazards models. FINDINGS: Between June 1, 2013, and Dec 23, 2015, 103 682 participants with available raw accelerometer data were enrolled. 92 614 participants (52 219 [56·4%] women and 40 395 [42·6%] men) with a median age of 64 years (IQR 56-69) were recruited. Median follow-up was 6·4 years (IQR 5·8-6·9). Decreased rest-activity rhythm amplitude was significantly associated with increased incidence of cardiovascular diseases (adjusted hazard ratio 1·11 [95% CI 1·05-1·16]), cancer (1·08 [1·01-1·16]), infectious diseases (1·31 [1·22-1·41]), respiratory diseases (1·26 [1·19-1·34]), and digestive diseases (1·08 [1·03-1·14]), as well as all-cause mortality (1·54 [1·40-1·70]) and disease-specific mortality (1·73 [1·34-2·22] for cardiovascular diseases, 1·32 [1·13-1·55] for cancer, and 1·62 [1·25-2·09] for respiratory diseases). Most of these associations were not modified by age older than 65 years or sex. Among 16 accelerometer-measured rest-activity parameters, low rest-activity rhythm amplitude had the strongest or second- strongest associations with nine health outcomes. INTERPRETATION: Our results suggest that low rest-activity rhythm amplitude might contribute to major health outcomes and provide further evidence to promote risk-modifying strategies associated with rest-activity rhythm to improve health and longevity. FUNDING: National Natural Science Foundation of China and China Postdoctoral Science Foundation.

Associations of timing of physical activity with all-cause and cause-specific mortality in a prospective cohort study.

There is a growing interest in the role of timing of daily behaviors in improving health. However, little is known about the optimal timing of physical activity to maximize health benefits. We perform a cohort study of 92,139 UK Biobank participants with valid accelerometer data and all-cause and cause-specific mortality outcomes, comprising over 7 years of median follow-up (638,825 person-years). Moderate-to-vigorous intensity physical activity (MVPA) at any time of day is associated with lower risks for all-cause, cardiovascular disease, and cancer mortality. In addition, compared with morning group (>50% of daily MVPA during 05:00-11:00), midday-afternoon (11:00-17:00) and mixed MVPA timing groups, but not evening group (17:00-24:00), have lower risks of all-cause and cardiovascular disease mortality. These protective associations are more pronounced among the elderly, males, less physically active participants, or those with preexisting cardiovascular diseases. Here, we show that MVPA timing may have the potential to improve public health.

Gut microbiome dysbiosis across early Parkinson's disease, REM sleep behavior disorder and their first-degree relatives.

The microbiota-gut-brain axis has been suggested to play an important role in Parkinson's disease (PD). Here we performed a cross-sectional study to profile gut microbiota across early PD, REM sleep behavior disorder (RBD), first-degree relatives of RBD (RBD-FDR), and healthy controls, which could reflect the gut-brain staging model of PD. We show gut microbiota compositions are significantly altered in early PD and RBD compared with control and RBD-FDR. Depletion of butyrate-producing bacteria and enrichment of pro-inflammatory Collinsella have already emerged in RBD and RBD-FDR after controlling potential confounders including antidepressants, osmotic laxatives, and bowel movement frequency. Random forest modelling identifies 12 microbial markers that are effective to distinguish RBD from control. These findings suggest that PD-like gut dysbiosis occurs at the prodromal stages of PD when RBD develops and starts to emerge in the younger RBD-FDR subjects. The study will have etiological and diagnostic implications.

Prediction of Dropout in a Randomized Controlled Trial of Adjunctive Light Treatment in Patients with Non-Seasonal Depression and Evening Chronotype.

The current study examined the possible predictors of dropout during a five-week light treatment (LT) with a gradual advance protocol in 93 patients with unipolar non-seasonal depression and evening chronotypes by comparing their clinical characteristics and performing a logistic regression analysis. Nineteen out of ninety-three (20%) subjects (80% female, 46.5 ± 11.7 years old) dropped out during the 5-week light treatment. Treatment non-adherence (i.e., receiving LT for less than 80% of the prescribed duration) over the first treatment week predicted a five-fold increase in risk of dropout during light therapy (OR: 5.85, CI: 1.41-24.21) after controlling for potential confounders, including age, gender, treatment group, rise time at the baseline, patient expectation, and treatment-emergent adverse events. There is a need to incorporate strategies to enhance treatment adherence and retention in both research and clinical settings. Chinese clinical trial registry (ChiCTR-IOR-15006937).

Evolution of Prodromal REM Sleep Behavior Disorder to Neurodegeneration: A Retrospective Longitudinal Case-Control Study.

BACKGROUND AND OBJECTIVES: Individuals with a history of recurrent dream-enactment behaviors, but with subthreshold REM sleep without atonia levels for REM sleep behavior disorder (RBD) diagnosis, are currently classified to have prodromal RBD (pRBD). However, the REM sleep-elevated EMG diagnostic cutoff, progression trajectory, and long-term neurodegenerative outcome of pRBD are not well understood. This study aimed to delineate the evolution of REM sleep EMG levels, determine the EMG cutoff score for diagnosing pRBD, and examine the risk for neurodegenerative diseases of pRBD. METHODS: This retrospective longitudinal case-control study recruited patients with pRBD and age-matched, sex-matched, and follow-up duration-matched controls who were free of neurodegenerative disease at baseline in the Sleep Assessment Unit, the Chinese University of Hong Kong from 1997 to 2018. Patients and controls underwent clinical and video-polysomnography (PSG) assessments at baseline and follow-up(s). REM sleep EMG activity level on mentalis and anterior tibialis (AT) muscles on video-PSG at each visit was scored. The diagnosis of neurodegenerative diseases was confirmed by a neurologist. RESULTS: A total of 44 patients (age 67.4 ± 8.2 years, 6 females) and 44 controls were recruited. The combined REM sleep EMG level on mentalis and AT muscles of patients with pRBD significantly increased during 8.2 ± 3.3 years of follow-up (from 19.3% ± 9.7% to 47.3% ± 27.4% with estimated annual increase of 3.9%), yielding 29 patients with pRBD (66%) meeting the full-blown RBD diagnostic criteria. Baseline REM sleep mentalis and AT muscles EMG activity of patients who developed full-blown RBD could favorably differentiate pRBD from controls (6.3% for mentalis "any" and 9.1% for combination of mentalis any and bilateral AT muscles phasic EMG with an area under the curve of 0.88 [0.78-0.98] and 0.97 [0.92-1.00], respectively). Patients with pRBD had a higher risk for neurodegenerative diseases (9 developed Parkinson disease and 3 developed dementia with Lewy bodies) when compared with controls (5 developed Alzheimer disease, adjusted hazard ratio = 2.95, 95% CI = 1.02-8.54). DISCUSSION: pRBD has a predictive progression in both pathophysiology and neurodegenerative outcome. This finding has significant implications to the nosological status of pRBD, the current REM sleep-related EMG diagnostic criteria, spectrum concept of RBD, and future neuroprotective intervention. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EMG activity during REM sleep predicts the development of pRBD.

The Associations of Electronic Media Use With Sleep and Circadian Problems, Social, Emotional and Behavioral Difficulties in Adolescents.

Background: Electronic media use (EMU) becomes one of the most common activities in adolescents. The present study investigated the deleterious influence of excessive EMU and EMU before bedtime on social, emotional, and behavioral difficulties (SEBD) in adolescents. The role of sleep and circadian problems in mediating the association of EMU with SEBD was examined. Methods: A cross-sectional survey study was conducted with 3,455 adolescents (55.7% female, mean age = 14.8 ± 1.57 years, 36.6% monthly family income < HK$15,000) between December 2011 and March 2012 in Hong Kong. The associations of EMU with sleep and circadian problems and SEBD were analyzed using multiple binary logistic regression and path analysis. Sleep problems were measured by the Insomnia Severity Index and the reduced Horne and Östberg Morningness and Eveningness Questionnaire. Circadian problems were calculated based on established formulas. SEBD was measured using the Strengths and Difficulties Questionnaire. Participants' mental health status was assessed by the General Health Questionnaire. Results: A longer duration of EMU, excessive EMU (daily duration ≥ 2 h), and bedtime EMU (an hour before bedtime) were associated with the risk of sleep and circadian problems, poor mental health, and SEBD (p < 0.05). Insomnia, eveningness, social jetlag, and sleep deprivation were found to mediate the associations of EMU (including bedtime EMU of computers, electronic game consoles, phones, and televisions, together with excessive EMU of computers for leisure purposes and phones) with mental health and SEBD. Conclusions: The findings suggest the need for setting up guidelines and advocacy for education for appropriate EMU and intervention for the associated sleep and circadian problems to ameliorate EMU-related mental and behavioral health problems in adolescents.

Personality profile and its association with conversion to neurodegenerative disorders in idiopathic REM sleep behavior disorder.

Patients with Parkinson's disease (PD) were described less extraverted and more neurotic. It remained unclear whether similar personality traits could be found in idiopathic rapid eye movement sleep behavior disorder (iRBD), a prodromal stage of PD, and could predict phenoconversion to neurodegenerative disorders. We aimed to investigate the personality profile and its association with future neurodegenerative phenoconversion in iRBD patients. One hundred and eighty-five video-polysomnography confirmed iRBD patients and 91 age- and sex-matched controls underwent personality assessment using the NEO five-factor inventory, and 171 iRBD patients were followed up. Our results showed that iRBD was marginally negatively associated with extraverted personality trait (B = -0.28, 95% confidence interval (CI) = -0.55, -0.001). During a median follow-up of 5.9 years, 47 iRBD patients (27.5%) had phenoconversion. More neurotic (adjusted hazard ratio (HR) = 2.0, 95% CI = 1.3, 3.1) and less extraverted personality traits (adjusted HR = 0.53, 95% CI = 0.36, 0.77) were associated with an increased risk of phenoconversion in iRBD patients. Our findings suggest that personality profile may be a potential prodromal marker of iRBD.