Major depressive disorder (MDD) is a risk factor for neurodegeneration, yet its heterogeneity makes identifying at-risk subtype challenging. Notably, MDD frequently co-occurs with REM sleep behavior disorder (RBD), a specific prodrome of α-synucleinopathy. It remains unclear whether comorbid MDD + RBD reflects a benign antidepressant effect, or higher neurodegenerative risk. Given growing recognition of gut-brain axis in neuropsychiatry, we aimed to delineate microbial signatures of MDD + RBD. We employed a four-group case-control design (N = 420) comprising 124 healthy controls (HC); 80 MDD without RBD features (MDD-only); 82 MDD + RBD; and 134 iRBD without psychiatric disease. All participants underwent clinical evaluation and provided fecal samples for metagenomic sequencing. Random Forest model was used to distinguish MDD + RBD, and further assessed in a validation dataset of 65 participants with MDD + RBD (n = 31) and MDD-only (n = 34). MDD + RBD exhibited prodromal neurodegenerative features, including elevated total likelihood ratio of prodromal Parkinson's Disease, olfactory deficits, and subtle motor signs. The microbial composition in MDD + RBD differed from HC and MDD-only, while resembling iRBD. Taxonomically, MDD + RBD exhibited an iRBD-like dysbiosis (e.g., enriched Akkermansia muciniphila, Ruthenibacterium lactatiformans; depleted Faecalibacterium prausnitzii), alongside depression-associated shifts (e.g., Streptococcus parasanguinis and Actinomyces oris). Functionally, MDD + RBD showed attenuated capacity of B‑vitamin biosynthesis and polysaccharides degradation, mirroring iRBD. The Random Forest machine-learning model distinguished MDD + RBD in older adults from MDD-only with an AUC of 0.73 in cross-validation and 0.79 in the validation dataset. MDD + RBD may represent a biologically distinct depression subtype associated with potential neurodegenerative risk. Gut microbiome provides a candidate approach for potential risk stratification in psychiatric populations.

REM sleep behavior disorder (RBD) is a robust prodromal marker of α-synucleinopathies: idiopathic RBD carries a 10-15-year phenoconversion risk of 80-90% to Parkinson's disease (PD) and related disorders. In major depressive disorder (MDD), comorbid RBD marks a subgroup at elevated prodromal PD risk, yet is frequently missed in psychiatric practice. Here, we developed a multimodal AI framework to detect comorbid RBD in MDD. From a clinical cohort of 329 patients, we obtained 261 video clips in 31 patients during reading and spontaneous-speech tasks, including 19 patients with MDD-RBD and 12 demographically and medication-matched MDD-only controls that, to our knowledge, formed the largest cohort of its kind worldwide. We used a dual-stream multimodal model that learned facial dynamics from video and vocal features from speech, and then combined both signals to predict comorbid RBD. In 5-fold cross-validation, our best model achieved 80.5% accuracy and 0.848 F1-score. Explainability analysis highlighted lower-face tension and variability, together with brow lowering, as candidate biomarkers requiring further validation. Predicted risk correlated with RBDQ score (r = 0.53, p = 0.005) and weakly with UPDRS motor score (r = 0.34, p = 0.067). Out-of-distribution evaluation showed broadly similar patterns, supporting the promise of multimodal AI for predicting RBD in MDD and identifying interpretable potential digital markers of prodromal synucleinopathy.

Rapid eye movement sleep behavior disorder (RBD) is the most specific prodromal marker of Parkinson's disease (PD), affecting 40-50% of PD patients. PD with RBD (RBD-PD) represents a clinically aggressive subtype characterized by more severe motor and nonmotor symptoms, prominent autonomic dysfunction, and accelerated disease progression; however, its underlying pathogenesis remains poorly understood. Here, we integrated multiplatform metabolomics and proteomics with precise clinical phenotyping to delineate molecular signatures in plasma across different PD subtypes. Our analyses demonstrated that PD patients exhibit significant metabolic reprogramming, characterized by a shift in energy metabolism from the tricarboxylic acid cycle toward glycolysis, a dysregulated urea cycle, and lipid remodeling, as well as extensive activation of inflammatory and immune responses involving the PI3K-Akt, IL-17, NF-kappaB, MAPK and TNF signaling pathways. Notably, the RBD-PD subgroup exhibited distinctive metabolic disturbances characterized by the accumulation of gut microbiota-derived toxic aromatic amino acid catabolites. Importantly, these alterations were also observed in idiopathic RBD (iRBD) patients, representing the prodromal stage of PD. By integrating metagenomic profiles, we further revealed that gut microbial dysbiosis in RBD-PD and iRBD drives a functional shift away from dietary fiber fermentation and toward enhanced degradation of protein, aromatic amino acids, glycine, and intestinal mucin glycans. This metabolic reprogramming is associated with exacerbated oxidative stress, neuroinflammation, and accelerated pathological progression. These findings provide multiomic evidence that clarifies the molecular heterogeneity in PD and highlights gut microbiota-driven dysfunction as a key contributor to both the iRBD and RBD-PD subtypes.

BACKGROUND:Although clinical markers (eg, motor and cognitive impairment) in isolated rapid eye movement sleep behavior disorder (iRBD) are associated with faster phenoconversion, their longitudinal trajectory patterns (linear or nonlinear) remain unclear. Additionally, evidence regarding the magnitude of neurodegenerative risk in iRBD compared to non-RBD individuals remains limited. OBJECTIVES:The aim was to investigate longitudinal changes in clinical markers and assess the magnitude of neurodegenerative risk in iRBD versus non-RBD subjects. METHODS:In this prospective matched cohort study, video-polysomnography-confirmed iRBD patients and age- and sex-matched non-RBD subjects were followed every 1.5-2 years to evaluate neurodegenerative outcomes and markers. Longitudinal marker changes and neurodegenerative risk between groups were compared. RESULTS:One-hundred thirty-three iRBD patients and 101 non-RBD subjects were followed for a mean of 6.9 ± 2.9 years. Parkinsonism-first converters were associated with motor dysfunction, whereas dementia-first converters were associated with cognitive, motor, olfactory, and color vision dysfunctions. Motor and global cognitive functions exhibited nonlinear progression in iRBD, with marked acceleration before parkinsonism or dementia diagnosis. Conversion rates in iRBD patients were 4.7% at 3 years, 30.1% at 7 years, and 79.5% at 13 years, exceeding those in non-RBD subjects (3% at 3 years and 16.1% at 13 years). iRBD patients had a higher neurodegeneration risk (hazard ratio [95% confidence interval [CI]: 9.6 [3.8, 23.8], P < 0.001). CONCLUSIONS:Motor and global cognition demonstrate nonlinear accelerating progressions during iRBD phenoconversion. iRBD carries a nearly 10-fold higher risk of future neurodegeneration than non-RBD subjects. These findings highlighted a critical window for risk stratification and early intervention before neurodegenerative disease onset in iRBD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND:Isolated REM sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, including Parkinson's disease (PD). Conventional sleep staging assigns each epoch to a single dominant stage, potentially obscuring within-epoch probabilistic features and stage mixing. We aimed to characterize alternation of probabilistic sleep-stage patterns in iRBD and to examine their clinical and neurobiological correlations. METHODS:In this case-control study, 104 patients with iRBD, 28 patients with PD and RBD (PD + RBD), and 50 controls underwent video polysomnography. Sleep-stage uncertainty and mixing were quantified using the U-Sleep 2.0 model. Clinical measures included RBD symptom severity (RBDQ-HK), motor function (UPDRS-III), and cognition (MoCA). Nigrostriatal dopaminergic function was assessed with [18F]-DOPA PET in a subgroup consisting of 40 patients with iRBD. Within the iRBD group, associations between probabilistic sleep-stage metrics and mixing with clinical measures and PET metrics were assessed using Pearson correlations. RESULTS:Both iRBD and PD + RBD groups exhibited significantly increased sleep-stage uncertainty and mixing compared with controls. Within the iRBD group, REM uncertainty was positively correlated with RBD symptom severity (RBDQ-HK score, r = 0.364, p = 0.003) and motor symptoms (UPDRS-III score, r = 0.343, p = 0.005). N2 uncertainty was negatively correlated with global cognitive performance (MoCA score, r = -0.345, p = 0.005), particularly delayed recall (r = -0.402, p < 0.001). N2-REM mixing was positively correlated with RBD symptom severity (RBDQ-HK score, r = 0.449, p < 0.001) and negatively correlated with bilateral putaminal dopaminergic uptake on PET (left: r = -0.492, p = 0.019; right: r = -0.510, p = 0.019). CONCLUSIONS:Probabilistic sleep staging reveals clinically significant alterations in sleep-stage uncertainty and stage mixing in iRBD and may provide complementary electrophysiological markers of early α-synuclein-related neurodegeneration.

Idiopathic REM sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies including Parkinson's disease (PD), yet its clinical heterogeneity remains underexplored. This study aimed to identify novel brain-clinical biotypes in iRBD by integrating structural MRI and clinical assessments. We included 172 patients with video-polysomnography-confirmed iRBD and 126 controls who underwent multimodal MRI and clinical evaluation. Similarity Network Fusion was used to integrate cortical thickness, surface area, subcortical volume, and clinical data, followed by spectral clustering to identify iRBD biotypes. Two distinct biotypes were identified: Biotype 1 showed widespread cortical-subcortical-cerebellar atrophy, functional hypoconnectivity, more motor and cognitive deficits with higher prodromal PD risk; Biotype 2 demonstrated increased surface area in limbic and parietal regions, cortical-cerebellar hyperconnectivity, and preserved neurocognitive function. These findings underscore the presence of distinct neurobiological subtypes in iRBD, highlighting the need for longitudinal monitoring to clarify their trajectories and implications for disease progression.

BACKGROUND:Mental disorders have become a global health challenge particularly among ageing populations, while physical activity holds substantial promise as an accessible and non-pharmacological intervention. Tracking daily steps is a simple and popular way of physical activity, but its impact on mental health remains unclear. This study aims to examine the association between accelerometer-measured step count and intensity with the risk of multiple mental disorders in the ageing adults. METHODS:This prospective cohort study included 83,578 middle-aged and elderly participants from the UK Biobank, with a median follow-up of 6.94 years. Step count and intensity were measured using accelerometers. Mental disorder incidence was determined through hospital records and death registries, encompassing depressive disorders, sleep disorders, dementia, and eight other conditions. RESULTS:An inverse dose-response relationship was observed between daily step count and intensity with the risk of mental disorders. Risk reduction plateaued at approximately 10,000, 4800, and 6500 steps for total, purposeful, and incidental steps, respectively. Higher-intensity steps provided additional benefits when sufficient step counts were achieved. Mediation analyses, incorporating physical, behavioral, neuroimaging (8.0 % of all indirect effects, p = 0.037), and blood profile (20.7 %, p = 0.003) and multi-omic biomarkers (blood proteins, 26.1 %, p < 0.001; NMR metabolites, 8.6 %, p < 0.001), identified lipid metabolism, inflammation, and brain structural changes as key mechanisms underlying the protective effects of daily steps on mental health. CONCLUSION:These findings suggest that setting daily step goals could be a promising public health strategy for promotion of mental health especially in the ageing population.

Tau interacts with α-Synuclein (α-Syn) and co-localizes with it in the Lewy bodies, influencing α-Syn pathology in Parkinson's disease (PD). However, whether these biochemical events regulate α-Syn pathology spreading from the gut into the brain remains incompletely understood. Here, we show that α-Syn and Tau co-pathology is spread into the brain in gut-inducible SYN103+/- and/or TAU368+/- transgenic mouse models, eliciting behavioral defects. Gut pathology was initially observed, and α-Syn or Tau pathology was subsequently propagated into the DMV or NTS and then to other brain regions. Remarkably, more extensive spreading and widespread neuronal loss were found in double transgenic mice (Both) than in single transgenic mice. Truncal vagotomy and α-Syn deficiency significantly inhibited synucleinopathy or tauopathy spreading. The α-Syn PET tracer [18F]-F0502B detected α-Syn aggregates in the gut and brain. Thus, α-Syn and Tau co-pathology can propagate from the gut to the brain, triggering behavioral disorders.

Objective While isolated rapid eye movement sleep behaviour disorder (iRBD) is known as a prodrome of alpha-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.

OBJECTIVES:To evaluate factors associated with sleep related injury (SRI) and persistent SRI (pSRI) in patients with isolated rapid eye movement sleep behavior disorder (iRBD). METHODS:This is a retrospective cohort study. A total of 388 patients with iRBD were involved for a comprehensive review of sleep related injuries. SRI is defined as a lifetime history of injurious behaviors to self and/or bed partner, and pSRI is considered if injurious symptoms continued to occur frequently (≥1/month). Correlations of SRI/pSRI with clinical, lifestyle and polysomnographic characteristics were analyzed. RESULTS:Lifetime SRI was reported in 322 (83 %) patients (66.3 ± 8.5 years old, male 77.0 %), with 19.3 % having severe injuries, including fractures (2.5 %) and subdural hemorrhage (1.2 %), while 7.5 % required medical attendance. SRI was related to more severe depressive features (Padj = 0.017), current alcohol drinking (Padj = 0.014) and higher mentalis phasic and tonic EMG activity (Padj = 0.042 and 0.048). After a mean follow-up of 5.1 years, 18.2 % of SRI patients (38/209) had pSRI despite intense treatment. Frequent nightmare at baseline (OR [95 % CI] = 1.43 [1.01, 2.03]), restless leg syndrome (OR [95 % CI] = 5.68 [1.42, 22.64]) and adult-onset sleepwalking (OR [95 % CI] = 2.52 [1.10, 5.76]) were associated with an increased risk of pSRI. CONCLUSIONS:SRI is common in patients with iRBD and 18 % had pSRI despite intensive treatment, emphasizing the importance of bedside safety. The identification of risk factors for SRI and pSRI underscores the need for systematic clinical screening and targeted interventions for at-risk patients.

OBJECTIVE:To determine multidimensional impulsivity levels across different early stages of α-synucleinopathy. METHODS:This cross-sectional study investigated motor and decisional impulsivity levels using a panel of computerized tasks among drug-naïve parkinsonism patients, isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) patients and their first-degree relatives (iRBD-FDRs), and control participants. Trait impulsivity and impulse control behaviors were assessed by self-reported questionnaires. RESULTS:A total of 27 drug-naïve parkinsonism patients, 157 iRBD patients, 66 iRBD-FDRs, and 82 control participants were recruited. Parkinsonism and iRBD patients had fewer numbers of extracted beads in beads task 1 and 2 (both p < 0.001), and a higher rate of irrational choice in task 1 (p = 0.046) before making decisions, and fewer numbers of pumps of unexploded blue balloons in the balloon analog risk task (p = 0.004) than control participants, indicating a higher level of reflection impulsivity and a lower level of risk taking, respectively. iRBD patients had more no-go errors in the go/no-go task than control participants (padjusted  = 0.036), suggesting a higher level of motor impulsivity. iRBD-FDRs with dream-enactment behaviors had fewer numbers of extracted beads (p = 0.047) in beads task 2 than FDRs without dream-enactment behaviors, suggesting a possible higher level of reflection impulsivity. INTERPRETATION:A complex construct of altered impulsivity with decreased risk taking, but increased reflection and motor impulsivity, has already occurred at the prodromal and early stages of α-synucleinopathy, which have implications for underlying pathophysiology and clinical management of α-synucleinopathy, especially for impulse control behaviors upon dopaminergic drug treatment. ANN NEUROL 2024;95:544-557.

BackgroundUnderstanding 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.AimsTo 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).MethodsThe 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.ResultsAdjusting 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).ConclusionsThere 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 numberNCT03656302.

Abstract Introduction Previous evidence suggested that the alteration of rest-activity pattern occurred in patients with isolated rapid eye movement behavior disorder (iRBD), a prodromal stage of α-synucleinopathy with implication to future phenoconversion. Nonetheless, it remains unclear whether this rest-activity pattern alteration has already emerged in the prodromal stage of RBD, and whether it would be related to conversion of iRBD into parkinsonism-first or dementia-first subtype of α-synucleinopathy. Methods We performed 1) a case-control study to compare the rest-activity pattern measured by 7-day actigraphy among prodromal RBD subjects (n = 21) and their age-, sex-, and body mass index-matched control subjects (n = 52) and patients with iRBD (n = 63); and 2) a longitudinally follow-up study to investigate the predictive value of altered rest-activity pattern to parkinsonism-first or dementia-first subtype of α-synucleinopathy in full sample of patients with iRBD (n = 170). Prodromal RBD subjects were defined as subjects who had recurrent dream-enactment behaviors but with subthreshold REM sleep electromyography activity. Generalized linear model was employed to assess rest-activity pattern in prodromal RBD subjects and competing risk regression model was used to determine the predictive value of rest-activity pattern to RBD phenoconversion. Results Similar to patients with iRBD, prodromal RBD subjects had more daytime probable napping (percentage and duration) and lower average weekly activity level and physical activity level during active period as compared to control subjects. Of 170 patients with iRBD, 166 were successfully followed up with a mean follow-up duration of 4.6 years. Lower average weekly activity level, amplitude, and physical activity level during active period were associated with a higher risk of parkinsonism-first subtype of α-synucleinopathy, instead of dementia-first subtype. Conclusion Our study found that altered rest-activity pattern has already emerged in prodromal stage of RBD. As for iRBD patients, lower physical activity level and amplitude might serve as predictive markers of parkinsonism-first conversion. Support (if any) No

Abstract Introduction Idiopathic/isolated REM sleep behavior disorder (iRBD) is regarded as the most specific prodromal stage of ⍺-synucleinopathies including Parkinson’s disease (PD). Striatal dopamine dysfunction is a pathological hallmark in PD, which has been similarly reported in iRBD as a sensitive marker for detecting early ⍺-synucleinopathies. In contrary, although there is a broad consensus that patients with PD have striatal volumes reduction, studies in iRBD are relatively scarce and inconsistent. In this study, we aim to investigate the difference of striatal nuclei volumes between iRBD and controls and their correlation with clinical presentations. Methods Altogether 105 patients (mean age=68.19, male 76.2%) with polysomnography-confirmed iRBD and 85 age and sex comparable controls (mean age=66.74, male 64.7%) underwent 3-tesla MRI and clinical assessments. FreeSurfer automatic segmentation pipelines measured the size of bilateral striatal nuclei including caudate, putamen, pallidum and accumbens area. The comparisons of the volume of individual striatal nucleus were made between iRBD and controls with age, sex, handness, and total intracranial volume as covariates. Correlations were performed to investigate the association between striatal nuclei volume and clinical domains in motor (Unified Parkinson’s Disease Rating Scale, Part III), cognitive (Montreal Cognitive Assessment, MoCA), visual (pareidolia), autonomic function (Scales for Outcomes in Parkinson’s Disease - Autonomic Dysfunction, SCOPA-AUT) and mood symptoms (Hospital Anxiety and Depression Scale). Results There were smaller volumes in the bilateral putamen (t=-2.13/-2.32, p=0.03/0.02, left/right side respectively) and accumbens area (t=-2.58/-2.07, p=0.01/0.04, left/right side respectively) in iRBD comparing to controls. In addition, MoCA score was significantly positively correlated with the volumes of bilateral putamen (r=0.212/0.213, p=0.032/0.033), while pareidolia score was significantly negatively correlated with volumes of bilateral putamen (r=-0.205/-0.233, p=0.039/0.018,) and accumbens area (r=-0.249/-0.279, p=0.012/0.004, left/right respectively). The SCOPA-AUT score was significantly negatively correlated with volumes of the left putamen (r=-0.286, p=0.014) and the left accumbens area (r=-0.245, p=0.037). No other correlations with mood and motor features were found. Conclusion In this large case-control study, PD-like striatal atrophy was already present in patients with iRBD, which were significantly associated with worse cognitive performance, visual and autonomic dysfunction. Support (if any) This study was supported by Hong Kong Health and Medical Research Fund, 08191416.

OBJECTIVE:Age at onset of neurodegenerative disease has significant implications in differentiating disease profiles. We aimed to determine whether age at onset could identify clinical and neurodegenerative profiles in patients with isolated/idiopathic rapid eye movement sleep behavior disorder (iRBD) - a prodromal stage of α-synucleinopathies. METHODS:In this retrospective cohort study, the time of the first episode of dream-enactment behaviors that the patient/bed-partners recalled at the time of the patient's first visit to sleep clinic was collected. The distribution of age at onset was examined and patients were dichotomized into early- and late-onset groups based on the intersection point of underlying two Gaussian distributions of onset age. RESULTS:A total of 241 patients were included. The intersection of underlying two Gaussian models of onset age was 64.6 years, yielding 168 early- (median onset age: 58.0 years, range: 38.0-64.0) and 73 late-onset patients (median onset age: 70.0 years, range: 65.0-82.0). Among them, 154 of early- and 68 late-onset patients were followed-up. Late-onset patients had milder RBD symptoms, but worse sleep, cognition, olfactory and motor functions, and a higher risk of phenoconversion (adjusted hazard ratio (aHR) = 2.2, 95% confidence interval (CI) = 1.2-3.9), especially to probable dementia with Lewy bodies (DLB) (aHR = 8.9, 95% CI = 3.0-26.2), than early-onset patients. CONCLUSIONS:Late-onset iRBD was associated with a higher level of neurodegenerative markers and a quicker phenoconversion, especially to probable DLB. Age at onset of iRBD could help identify clinical features and predict prognosis of iRBD.

BackgroundRapid 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.MethodsIn 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.ResultsThere 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.ConclusionPatients 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 numberNCT03595475.

Solar eclipse is a daytime phenomenon that significantly disturbs the ionosphere, but whether the eclipse induces ionospheric irregularities in the nighttime remains unknown. In this study, we analyzed the dense total electron content (TEC) observations from the ground‐based Global Navigation Satellite System receivers over East and South Asia to examine the development of the irregularities in the nighttime on the day of the 21 June 2020 annular solar eclipse. The rate of TEC index (period <5 min) indicates the occurrence of the irregularities that evolve from the large or coarse structures with a period ranging from hours to dozens of minutes in the nighttime due to the eclipse. We take advantage of the data‐adaptive analysis method, Hilbert‐Huang transform, to derive the instantaneous amplitude and frequency of the TEC time series, which exposes the temporal and spatial evolutions of the irregularities from larger structures continuously.

Abstract Introduction Increased impulsivity is a common neuropsychiatric feature in patients with Parkinson’s disease (PD), especially attributed to the use of dopaminergic medications. Interestingly, emerging evidence suggested that impulsivity had changed in drug-naïve PD patients. However, it remains unclear whether impulsivity has been altered in prodromal stage of PD, namely isolated rapid eye movement sleep behavior disorder (iRBD) and their high-risk relatives. Methods This was a cross-sectional study with four groups of subjects, including early drug-naive PD patients, patients with iRBD and their first-degree relatives (iRBD-FDRs, a high-risk group with potential prodromal RBD features), and controls. A panel of neuropsychological computerized tasks, including go/no-go task, four-choice serial reaction time task (4CSRTT), beads task, balloon analogue risk task (BART) and delay/effort discounting task, would measure various dimensions of motor and decisional impulsivity. Results A total of 331 subjects were recruited, including 27 early drug-naïve PD patients (mean age ± SD: 70.1 ± 5.8 years, 77.8% man), 152 iRBD patients (67.2 ± 6.6 years, 77.6% man), 68 iRBD-FDRs (63.2 ± 6.4 years, 51.5% man), and 84 controls (67.4 ± 8.1years, 61.9% man). Early drug-naïve PD and iRBD patients had fewer numbers of extracted beads in beads task 1 (P< 0.001) and task 2 (P< 0.001) in making decisions and fewer numbers of pumps of unexploded blue balloons in BART (P< 0.001) than controls and iRBD-FDRs, suggesting a higher level of reflection impulsivity and a lower level of risk taking, respectively. In addition, early drug-naïve PD and iRBD patients had more no-go errors in go/no-go task (P=0.023), suggesting a marginally lower level of response inhibition in PD and iRBD groups. Early drug-naïve PD and iRBD patients had more premature responses in 4CSRTT than iRBD-FDRs (P=0.008). The delay and effort discounting indexes were comparable among four groups. Conclusion While risk taking and response inhibition decreased, reflection impulsivity actually increased in iRBD and drug-naïve PD patients. These novel findings indicated that a complex construct of altered impulsivity has already occurred at the earlier stage (at iRBD) of α-synucleinopathy, which will have implications for pathophysiology and clinical management. Support (if any) This study has been supported by the General Research Fund (14116119).