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REM sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviour with loss of muscle atonia during REM sleep and is a prodromal feature of α-synucleinopathies like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Although cortical-to-subcortical connectivity is well-studied in RBD, cerebellar and subcortical nuclei reciprocal connectivity is less established. Nonetheless, it could be relevant since RBD pathology involves brainstem structures with an ascending gradient. In this study, we utilised resting-state functional MRI to investigate 13 people with isolated RBD (iRBD), 17 with Parkinson's disease and 16 healthy controls. We investigated the connectivity between the basal ganglia, thalamus and regions of the cerebellum. The cerebellum was segmented using a functional atlas, defined by a resting-state network-based parcellation, rather than an anatomical one. Controlling for age, we found a significant group difference (F4,82 = 5.47, pFDR = 0.017) in cerebellar-thalamic connectivity, with iRBD significantly lower compared to both control and Parkinson's disease. Specifically, cerebellar areas involved in this connectivity reduction were related to the default mode, language and fronto-parietal resting-state networks. Our findings show functional connectivity abnormalities in subcortical structures that are specific to iRBD and may be relevant from a pathophysiological standpoint. Further studies are needed to investigate how connectivity changes progress over time and whether specific changes predict disease course or phenoconversion. [ABSTRACT FROM AUTHOR]

Background and purpose: Migraine and sleep disorders share a bidirectional relationship, but little is known about the specific association between migraine and rapid eye movement (REM) sleep behaviour disorder (RBD). The aim was to assess the prevalence of RBD and associated clinical characteristics in adults with migraine. Methods: This analysis is part of a cross‐sectional survey study conducted at the Headache Centre of the Charité—Universitätsmedizin Berlin between August 2020 and March 2023. At the end of their regular medical consultation, patients with migraine filled out (1) the validated RBD Screening Questionnaire (RBDSQ), (2) a questionnaire on REM sleep intrusions and (3) the Depression, Anxiety and Stress Scale 21. The primary endpoint was the percentage of patients with a positive RBD screening. A multivariate analysis was performed to identify characteristics independently associated with features of RBD. Results: A total of 751 patients (44.1 ± 13.2 years; 87.4% female) with complete RBDSQ were included in this analysis, of which 443 (58.9%) screened positive for RBD. In multivariate analysis, a positive screening for RBD was associated with younger age (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.8–0.9 per 10‐year increase; p = 0.005) and with features suggestive of REM sleep intrusions (OR 4.3, 95% CI 1.8–10.4; p = 0.001). Migraine aura remained in the model without reaching statistical significance (OR 1.3, 95% CI 0.9–1.8; p = 0.079). Discussion: Symptoms of RBD are frequent in adults with migraine. Further studies including polysomnography are required to confirm this association, and to explore potential common pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Research criteria for the diagnosis of prodromal dementia with Lewy bodies (DLB) include three clinical subtypes: mild cognitive impairment with Lewy bodies (MCI‐LB), delirium‐onset prodromal DLB, and psychiatric‐onset prodromal DLB. Late‐onset psychiatric manifestations are at a higher risk of developing dementia, but its relation to prodromal DLB remains unclear. In addition to the risk of severe antipsychotic hypersensitivity reactions, accurate discrimination from non‐DLB cases is important due to the potential differences in management and prognosis. This article aims to review a rapidly evolving psychiatric topic and outline clinical pictures of psychiatric‐onset prodromal DLB, including the proposed biomarker findings of MCI‐LB: polysomnography‐confirmed rapid eye movement sleep behaviour disorder, cardiac [123I]metaiodobenzylguanidine scintigraphy, and striatal dopamine transporter imaging. We first reviewed clinical pictures of patients with autopsy‐confirmed DLB. Regarding clinical reports, we focused on the patients who predominantly presented with psychiatric manifestations and subsequently developed DLB. Thereafter, we reviewed clinical studies regarding the diagnostic applications of the proposed biomarkers to patients with late‐onset psychiatric disorders. Clinical presentations were mainly late‐onset depression and psychosis; however, other clinical manifestations were also reported. Psychotropic medications before a DLB diagnosis may cause extrapyramidal signs, and potentially influences the proposed biomarker findings. These risks complicate clinical manifestation interpretation during the management of psychiatric symptoms. Longitudinal follow‐up studies with standardised evaluations until conversion to DLB are needed to investigate the temporal trajectories of core features and proposed biomarker findings. In patients with late‐onset psychiatric disorders, identification of patients with psychiatric‐onset prodromal DLB provides the opportunity to better understanding the distinct prognostic subgroup that is at great risk of incident dementia. Advances in the establishment of direct biomarkers for the detection of pathological α‐synuclein may encourage reorganising the phenotypic variability of prodromal DLB. [ABSTRACT FROM AUTHOR]

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P- values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease. [ABSTRACT FROM AUTHOR]

Summary: REM sleep behaviour disorder (RBD) is common in narcolepsy type 1 (NT1). Abnormalities in the reward system have been observed in NT1, possibly related to impaired orexin projections towards the mesolimbic reward system, but also in RBD when associated with Parkinson's disease. Our study aimed to explore the psychobehavioural profile of NT1 patients with and without RBD compared with healthy controls (HC). Forty patients with NT1 were compared with 20 sex‐ and age‐matched HC. All patients with NT1 underwent a video‐polysomnography including a measure of REM sleep without atonia (RSWA). The following neuropsychobehavioural variables were assessed: apathy, impulsivity, depression, cognition, subjective and objective attention, sensation‐seeking, and behavioural addictions. The patient population included 22 patients with NT1‐RBD and 18 patients with NT1‐noRBD. Compared with the healthy controls, patients with NT1 had higher scores of apathy, impulsivity, and depression; a lower score on global cognition, and poorer self‐perceived attention. No differences were found between patients with NT1 with and without RBD in all neuropsychological variables, except for impaired objective attention in patients with NT1‐RBD. In patients with NT1, a positive correlation was observed between RSWA and both apathy and impulsivity subscale. Moreover, in patients with NT1‐RBD, RSWA was positively correlated with depression. Patients with NT1 showed higher depression, apathy, and impulsivity compared with controls. These measures correlate with the severity of RSWA, suggesting a transdiagnostic association between RBD and abnormalities of the reward system at least for patients with NT1. [ABSTRACT FROM AUTHOR]

Introduction: Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by the loss of REM sleep muscle atonia and the enactment of dreams. Acute RBD associated with alcohol withdrawal syndrome is known, but the studies are limited, particularly on its neurobiological underpinnings and management alongside the withdrawal state. This work attempts to address this using a case study and relevant literature review. Case Presentation: A 40‐year‐old male with alcohol dependence (for 20 years) reported new‐onset terrifying nightmares and violent behaviours in his sleep precipitated by alcohol withdrawal states for the last 18 months. The polysomnographic finding of REM‐without‐atonia supported the diagnosis of RBD. He was treated with chlordiazepoxide 100 mg/day (gradually tapered and stopped) and thiamine supplements. Post‐discharge, he remained abstinent and symptom‐free during the three months of follow‐up. Discussion: RBD related to alcohol withdrawal syndrome has been previously described in a few anecdotal reports. Sudden withdrawal from central nervous system suppressants like alcohol is hypothesised to cause a homeostatic imbalance in gamma‐aminobutyric acid (GABA) pathways and 'REM rebound', resulting in the clinical and polysomnographic picture of RBD. Benzodiazepines have been found to be useful in both RBD and alcohol withdrawal. Conclusions: Alcohol withdrawal syndrome may present with acute RBD, which can be treated with a short course of benzodiazepine. However, further studies are needed to explore the long‐term course of RBD in these patients. [ABSTRACT FROM AUTHOR]

Introduction. The aim of our study was to find out the opinion of patients with Parkinson's Disease (PD) whose disease was preceded by REM sleep behaviour disorder (RBD) regarding early information about the high risk of phenoconversion in RBD. Clinical rationale for the study. RBD is an early clinical manifestation of a-synucleinopathies with a more than 90% risk of phenoconversion to PD, dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). It remains a subject for debate as to whether and how RBD patients should be informed about the high risk of phenoconversion. The patient's right to full knowledge regarding his or her health conflicts with the potentially destructive impact of this information on his or her mental state and quality of life of them and their relatives. Material and methods. Thirty-nine patients with PD whose disease was preceded by RBD were surveyed. Data on the course of RBD and PD was collected. Questions were asked about early information about the high risk of phenoconversion to patients with RBD and factors determining the opinion of the surveyed persons. Results. The majority (> 60%) of respondents gave a positive answer when asked whether patients should be informed about their high risk of developing PD once diagnosed with RBD. Only a few (7.7%) respondents believed that disclosing such information to the patient should be possible only after obtaining his or her consent. Respondents associated consent to information about the high risk of developing PD in people with RBD with high expectations of the healthcare system. We were unable to determine whether factors such as the gender of the subject, the clinical course of the PD, and the RBD duration had an impact on patients' opinions regarding disclosing knowledge about phenoconversion. Conclusions and clinical implications. Our study provides important information that should influence physicians' communication with patients with RBD, especially regarding how they communicate about the high risk of phenoconversion. [ABSTRACT FROM AUTHOR]

The neurodegenerative synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson's disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson's disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson's disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials. [ABSTRACT FROM AUTHOR]

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49–87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41–88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks. [ABSTRACT FROM AUTHOR]

Idiopathic rapid eye movement sleep behaviour disorder (iRBD) is now established as an important marker of the prodromal stage of Parkinson's disease and related synucleinopathies. However, although dopamine transporter (DaT) SPECT has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson's disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Further, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. iRBD patients present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson's, by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivised eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with idiopathic RBD and compared this with data from 40 patients with Parkinson's and 41 healthy controls. iRBD patients also underwent neuroimaging with DaT SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared to controls, and was not significantly different to that in Parkinson's patients. However, in iRBD patients with normal DaT SPECT/CT imaging, reward sensitivity was not significantly different to healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals. [ABSTRACT FROM AUTHOR]

Summary: Rapid eye movement (REM) sleep behaviour disorder is a REM sleep parasomnia characterised by the loss of the physiological muscle atonia during REM sleep, resulting in dream enactment behaviours that may cause injuries to patients or their bed partners. The nocturnal motor episodes seem to respond to the dream contents, which are often vivid and violent. These behavioural and oneiric features make the REM sleep behaviour disorder a potential model to study dreams. This review aims to unify the literature about dream recall in REM sleep behaviour disorder as a privileged approach to study dreams, systematically reviewing studies that applied retrospective and prospective experimental designs to provide a comprehensive overview of qualitative and quantitative aspects of dream recall in this REM sleep parasomnia. The present work highlights that the study of dreaming in REM sleep behaviour disorder is useful to understand unique aspects of this pathology and to explore neurobiological, electrophysiological, and cognitive mechanisms of REM sleep and dreaming. [ABSTRACT FROM AUTHOR]

Background: In Parkinson's disease (PD), rapid eye movement (REM) sleep behaviour disorder (RBD) signifies a poorer prognosis, yet its impact on white matter (WM) degeneration remains unclear. The study examined the effect of RBD on WM alterations in PD progression., Methods: The study included 45 PD patients with possible RBD (PD-pRBD), 38 PD patients without possible RBD (PD-npRBD), and 79 healthy controls (HC). All patients underwent clinical assessments and diffusion MRI scans at least once a year for up to 4 visits. 79 HC underwent the same protocol at baseline. WM metrics, including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), were calculated using tract-based spatial statistics. Linear mixed-effects models were conducted to examine the changes in clinical features and WM fibers., Results: At baseline, PD-npRBD showed increased RD in several regions, predominantly in bilateral uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF), compared to HC (P FDR <0.05). During follow-up, PD-npRBD had further FA decrease in left UF and ILF (P FDR <0.05). PD-pRBD showed reduced FA in several regions relative to HC at baseline (P FDR <0.05), and faster FA decline in left UF and ILF than PD-npRBD during follow-up, with more extensive FA decrease in other regions such as anterior thalamic radiation and inferior fronto-occipital fasciculus (P FDR <0.05). Moreover, increased RD in the left corticospinal tract correlated with motor symptoms (p = 0.045) in PD-pRBD., Conclusions: PD patients with pRBD demonstrated more extensive WM degeneration and accelerated degeneration in the left ILF and UF during the disease course. However, due to the lack of PSG verification, these results should be interpreted cautiously while directly relating to RBD. These findings provide new insights into the neural structural basis associated with the potential impact of RBD on PD progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Parkinson’s disease (PD) is typically diagnosed when motor symptoms first occur. However, PD-related non-motor symptoms may appear several years before diagnosis. REM sleep behaviour disorder (RBD) and olfactory deficits (hyposmia) are risk factors, but they are not specific for predicting progression towards PD. Other PD-related markers, for example brain imaging markers, may help to identify preclinical PD in hyposmic RBD patients. Studies have reported abnormal structural characteristics in the corticospinal tract (CST) of PD patients, but it is unclear whether hyposmic RBD patients have similar abnormalities that may help to predict PD in these individuals. This study examined whether CST abnormalities may be a potential marker of PD risk by using diffusion tensor imaging (DTI) measures. Methods: Twenty hyposmic RBD patients, 31 PD patients, and 29 healthy controls (HCs) were studied. DTI data were collected on a 1.5 T MRI scanner and CST characteristics (FA, MD, AD, and RD) were evaluated using probabilistic tractography (with seed regions in the bilateral primary motor cortex and mediolateral cerebral peduncles). Olfactory function was assessed with the University of Pennsylvania Smell Identification Test (UPSIT). Results: Hyposmic RBD patients showed significantly higher mean diffusivity (MD) values of the right CST compared to HCs but did not differ from PD patients. PD patients showed a trend of higher MD values compared to HCs. Conclusions: Altered diffusivity in the CST seems to be associated with RBD. The combination of RBD, hyposmia, and CST alterations may be related to later development of PD with comorbid RBD.

Objectives: This study (1) describes and compares saccade and pupil abnormalities in patients with manifest alpha-synucleinopathies (αSYN: Parkinson's disease (PD), Multiple System Atrophy (MSA)) and a tauopathy (progressive supranuclear palsy (PSP)); (2) determines whether patients with rapid-eye-movement sleep behaviour disorder (RBD), a prodromal stage of αSYN, already have abnormal responses that may indicate a risk for developing PD or MSA. Methods: Ninety (46 RBD, 27 PD, 17 MSA) patients with an αSYN, 10 PSP patients, and 132 healthy age-matched controls (CTRL) were examined with a 10-min video-based eye-tracking task (Free Viewing). Participants were free to look anywhere on the screen while saccade and pupil behaviours were measured. Results: PD, MSA, and PSP spent more time fixating the centre of the screen than CTRL. All patient groups made fewer macro-saccades (> 2◦ amplitude) with smaller amplitude than CTRL. Saccade frequency was greater in RBD than in other patients. Following clip change, saccades were temporarily suppressed, then rebounded at a slower pace than CTRL in all patient groups. RBD had distinct, although discrete saccade abnormalities that were more marked in PD, MSA, and even more in PSP. The vertical saccade rate was reduced in all patients and decreased most in PSP. Clip changes produced large increases or decreases in screen luminance requiring pupil constriction or dilation, respectively. PSP elicited smaller pupil constriction/dilation responses than CTRL, while MSA elicited the opposite. Conclusion: RBD patients already have discrete but less pronounced saccade abnormalities than PD and MSA patients. Vertical gaze palsy and altered pupil control differentiate PSP from αSYN. [ABSTRACT FROM AUTHOR]

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease, or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% men) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e., a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, p = 0.0007) and tissue deformation (r = 0.52, p = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function, and can be recreated using the dynamics of agent-based modelling, structural connectivity, and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology. [ABSTRACT FROM AUTHOR]

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Purpose of Review: With the voxel-based morphometry (VBM), structural imaging studies turned into new directions aiming to explore neurological disorders differently. This approach helps identify possible pathophysiological correlations between neuroanatomical grey matter (GM) structures in patients with sleep dysfunction. This article reviews recent findings on GM structure in various sleep disorders and possible causes of disturbed sleep and discusses the future perspectives. Recent Findings: At present, research on the effect of GM volume changes in specific brain areas on the pathogenesis of sleep disturbances is incomplete. It remains unknown if the GM thickness reduction in patients with REM sleep behaviour disorder, obstructive sleep apnea, restless legs syndrome, and insomnia is due to complex disease presentation or direct response to disturbed sleep. Additionally, many VBM studies have yielded inconsistent results showing either reduction or increase in GM. Summary: The spatiotemporal complexity of whole-brain networks and state transitions during sleep and the role of GM changes increase new debates. Having multimodal data from large sample studies can help model sleep network dynamics in different disorders and provide novel data for possible therapeutic interventions. [ABSTRACT FROM AUTHOR]

It is established that one of the best predictors of a future diagnosis of Parkinson's disease is a current diagnosis of rapid eye movement behaviour disorder (RBD). In such patients, this provides a unique opportunity to study brain physiology and behavioural motor features of RBD that may precede early-stage Parkinson's disease. Based on prior work in early-stage Parkinson's disease, we aim to determine if the function of corticostriatal and cerebellar regions are impaired in RBD using task-based functional MRI and if structural changes can be detected within the caudate, putamen and substantia nigra in RBD using free-water imaging. To assess motor function, we measured performance on the Purdue Pegboard Test, which is affected in patients with RBD and Parkinson's disease. A cohort of 24 RBD, 39 early-stage Parkinson's disease and 25 controls were investigated. All participants were imaged at 3 Telsa. Individuals performed a unimanual grip force task during functional imaging. Participants also completed scales to assess cognition, sleep and motor symptoms. We found decreased functional activity in both RBD and Parkinson's disease within the motor cortex, caudate, putamen and thalamus compared with controls. There was elevated free-water-corrected fractional anisotropy in the putamen in RBD and Parkinson's disease and elevated free-water in the putamen and posterior substantia nigra in Parkinson's disease compared with controls. Participants with RBD and Parkinson's disease performed significantly worse on all tasks of the Purdue Pegboard Test compared with controls. The both hands task of the Purdue Pegboard Test was most sensitive in distinguishing between groups. A subgroup analysis of early-stage RBD (<2 years diagnosis) confirmed similar findings as those in the larger RBD group. These findings provide new evidence that the putamen is affected in early-stage RBD using both functional and free-water imaging. We also found evidence that the striatum, thalamus and motor cortex have reduced functional activity in early-stage RBD and Parkinson's disease. While the substantia nigra shows elevated free-water in Parkinson's disease, we did not observe this effect in early-stage RBD. These findings point to the corticostriatal and thalamocortical circuits being impaired in RBD patients., Competing Interests: E.R.T., D.J.A., M.B.S., M.L.H., R.C. and X.Y.L. have no competing interests. R.B.B. receives funding for his participation on the Scientific Advisory Board of Cerebra Medical and for participation on the Data Monitoring and Safety Board for ApniMed. M.S.J. receives funding from the National Institutes of Health, the Administration for Community Living, the Florida Department of Elderly Affairs, the Veterans Health Administration and Applied Cognition. E.A.C. receives funding from the National Institute of Health. D.E.V. receives funding from the National Institute of Health, FDA and is co-founder of Automated Imaging Diagnostics, LLC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Parkinson's Disease (PD) is frequently associated with a spectrum of sleep-related disorders, including insomnia, Excessive Daytime Sleepiness (EDS), REM sleep Behaviour Disorder (RBD), Restless Legs Syndrome (RLS), and Sleep-related Breathing Disorders (SBDs). These disorders significantly impact PD patients' Quality of Life (QoL) and present unique diagnostic and therapeutic challenges., Methods: This review has explored the intricate relationship between PD and sleep-related disorders, emphasizing their distinctive features and underlying neurobiological mechanisms. It aimed to consolidate current knowledge to optimize clinical management and improve patient care. The profound impact of these disorders on QoL has been evaluated, along with precise diagnostic methodologies. Additionally, various therapeutic strategies, including pharmacological treatments, nonpharmacological interventions, and device-aided therapies, have been examined., Results: Sleep-related disorders are prevalent among PD patients. Specifically, RBD exhibits a prevalence of 40-50%, often preceding the onset of motor symptoms, indicating its potential as an early marker of PD. Despite their significant impact on QoL, these non-motor symptoms are frequently under-recognized and inadequately managed in clinical practice. Pharmacological treatments, along with nonpharmacological interventions, like cognitive-behavioral therapy for insomnia and lifestyle modifications, have shown varied efficacy. Device-aided therapies have also demonstrated the potential to improve sleep-related disorders and overall non-motor symptom burden., Conclusion: Effective management of sleep-related disorders in PD calls for personalized, comprehensive, and multimodal therapeutic approaches. This requires the collaborative efforts of neurologists, sleep specialists, psychiatrists, and other healthcare professionals. Future research should focus on the intricate relationship between PD and sleep disorders, aiming to develop innovative treatments and significantly improve patient outcomes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiac 123 I-MIBG scintigraphy is used to assess the function of postganglionic presynaptic cardiac sympathetic nerve endings. 123 I-MIBG cardiac uptake is markedly reduced in patients with isolated rapid eye movement sleep behaviour disorder, similar to Parkinson's disease and dementia with Lewy bodies. As a result, it can be used as an early biomarker of isolated rapid eye movement sleep behaviour disorder. Most patients with isolated rapid eye movement sleep behaviour disorder develop synucleinopathies: Parkinson's disease, dementia with Lewy bodies or multiple system atrophy. We aimed to investigate whether cardiac postganglionic denervation is present in patients with isolated rapid eye movement sleep behaviour disorder, as well as its possible usefulness as a marker for Lewy body disease status. This retrospective cohort study examined 306 patients (236 men and 70 women; mean age: 68.2 years; age range: 43-87 years) with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder who were followed for 1-3 months and underwent 123 I-MIBG scintigraphy. We retrospectively analysed data from 306 patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, and their longitudinal outcomes were documented at two centres. Among isolated rapid eye movement sleep behaviour disorder patients, reduced 123 I-MIBG uptake was observed in the early and delayed images in 84.4 and 93.4% of patients, respectively, whereas 88.6% of the patients had a high washout rate. This large Japanese two-cohort study ( n = 306) found that 91 patients (29.7%) developed an overt synucleinopathy (51 Parkinson's disease, 35 dementia with Lewy bodies, 4 multiple system atrophy, and 1 cerebellar ataxia) during a mean follow-up duration of 4.72 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.4% at 5 years, 41.4% at 8 years and 52.5% at 10 years. On the other hand, among patients with heart-to-mediastinum ratio < 2.2 in the delayed images ( n = 286), 85 (29.7%) developed Parkinson's disease or dementia with Lewy bodies during a mean follow-up duration of 4.71 ± 3.94 years, with a conversion risk of 14.5% at 3 years, 25.6% at 5 years, 42.0% at 8 years and 51.0% at 10 years. Among the 33 patients who underwent repeat 123 I-MIBG scintigraphy, there was a progressive decline in uptake over the next 4.2 years, with patients exhibiting reduced uptake progressing to Parkinson's disease or dementia with Lewy bodies. In contrast, patients without decreased 123 I-MIBG uptake progressed to multiple system atrophy. Reduced cardiac 123 I-MIBG uptake was detected in over 90% of isolated rapid eye movement sleep behaviour disorder patients, with progression to Parkinson's disease or dementia with Lewy bodies, rather than multiple system atrophy, over time. Reduced 123 I-MIBG uptake is a robust maker for Lewy body disease among isolated rapid eye movement sleep behaviour disorder patients., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background REM sleep behavior disorder (RBD) is a prodromal marker for Parkinson's disease (PD) and other alpha-synucleinopathies. Sleep talking (ST) is an isolated symptom and is frequent in PD and RBD. Here, we investigate the associations of ST and RBD with the mortality of PD patients. Patients and methods A total of 1,500 PD patients were randomly selected from the registry of the Finnish Parkinson's Association. Of the 855 that participated at baseline, 645 gave permission for follow-up studies. We gathered a completely filled sleep questionnaire and mortality information from 384 subjects. The Nelson-Aalen test and Cox hazard ratios (HR) were used for mortality analyses. Results The mean follow-up time was 4.3 years (0.3-7.0). PD patients with RBD or frequent ST had more non-motor symptoms. Depression, hallucinations, constipation, and excessive daytime sleepiness were more prevalent among subjects with RBD. Subjects with RBD and frequent ST (talking in their sleep ≥ once per week) had increased mortality (HR: 1.90, 95% CI: 1.18-3.06). RBD without frequent ST was not associated with mortality (HR: 0.77, 95% CI: 0.4-1.5). Frequent ST was associated with increased mortality when adjusted for age, PD duration, depression, gender, RBD, BMI, and hallucinations (HR: 2.22, 95% CI: 1.10-4.51). Additionally, age, duration of PD, arterial hypertension, and lower BMI were associated with increased mortality. Male gender, dopaminergic medication, depression, and hallucinations were not significantly associated with mortality. Conclusions RBD with frequent ST and ST alone appear to be risk factors for mortality in PD. Frequent ST may be a sign representing wider neurodegeneration. RBD subjects and frequent sleep talkers demonstrated more non-motor symptoms compared to PD without RBD or ST. Our findings have clinical implications. It remains to be seen if frequent ST indicates a poorer prognosis. Prospective studies are needed to find whether frequent ST is also a risk factor for developing PD., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Partinen et al.)

Actigraphy has a consolidated role in Insomnia and Circadian Rhythm Sleep-Wake Disorders (CRSWD) and recent studies have highlighted the use of actigraphy for narcolepsy and REM sleep behaviour disorder (RBD). This review aims at summarising the results of studies published over the last decade regarding the use of actigraphy. Thirty-five studies proved eligible, and results were analysed separately for insomnia, narcolepsy and RBD. Actigraphy showed to consistently differentiate insomnia patients from healthy controls. Furthermore, the application of advanced analytical techniques has been shown to provide both unique insights into the physiology of insomnia and sleep misperception and to improve the specificity of actigraphy in detecting wakefulness within sleep periods. Regarding narcolepsy, several studies showed that actigraphy can detect peculiar sleep/wake disruption and the effects of pharmacological treatments. Finally, although the number of studies in RBD patients is still limited, the available evidence indicates a reduced amplitude of the activity pattern, sleep-wake rhythm dysregulation and daytime sleepiness. Therefore, the potential use of these markers as predictors of phenoconversion should be further explored. In conclusion, quantitative actigraphy presents a renewed interest when considering the possibility of using actigraphy in clinical sleep medicine to diagnose, monitor, and follow sleep disorders other than CRSWD. [ABSTRACT FROM AUTHOR]

Isolated Rapid Eye Movement Sleep (REM) behaviour disorder (iRBD) is a prodromal sign of neurodegenerative disorders. Empirical findings point to a role of non-REM (NREM) sleep alterations in neurodegenerative processes. Therefore, the interest in NREM sleep electroencephalography (EEG) of iRBD is progressively increasing. The present review aims to provide an updated state of the art on NREM sleep electrophysiology in iRBD. First, we describe findings on NREM EEG power spectra. Then, we consider specific NREM sleep EEG hallmarks (i.e., slow waves, slow oscillations, K-complexes, sleep spindles). Finally, we focus on NREM sleep instability. The reviewed literature is small and heterogeneous, but rapidly growing. The most consistent findings point to alteration of sleep spindles and cyclic alternating pattern in RBD. A larger discrepancy characterized results on slow wave activity, but recent studies using a topographical approach provide promising results. Evidence on the relationship of NREM sleep alterations with neurodegenerative processes in iRBD, as well as longitudinal changes, are scarce. We discuss the main methodological limitations, highlighting possible future directions. • The literature on NREM sleep EEG in RBD is small and heterogenous but rapidly growing. • The most consistent findings point to an alteration of sleep spindles and CAP in RBD. • Albeit heterogeneous, alterations in the slow wave activity range have been observed. • The role of RBD-related NREM sleep alterations in neurodegeneration is unclear. • Longitudinal and topographical evaluations of NREM sleep EEG in RBD are needed. [ABSTRACT FROM AUTHOR]

Introduction: The aim of our study was to find out the opinion of patients with Parkinson's Disease (PD) whose disease was preceded by REM sleep behaviour disorder (RBD) regarding early information about the high risk of phenoconversion in RBD., Clinical Rationale for the Study: RBD is an early clinical manifestation of α-synucleinopathies with a more than 90% risk of phenoconversion to PD, dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). It remains a subject for debate as to whether and how RBD patients should be informed about the high risk of phenoconversion. The patient's right to full knowledge regarding his or her health conflicts with the potentially destructive impact of this information on his or her mental state and quality of life of them and their relatives., Material and Methods: Thirty-nine patients with PD whose disease was preceded by RBD were surveyed. Data on the course of RBD and PD was collected. Questions were asked about early information about the high risk of phenoconversion to patients with RBD and factors determining the opinion of the surveyed persons., Results: The majority ( > 60%) of respondents gave a positive answer when asked whether patients should be informed about their high risk of developing PD once diagnosed with RBD. Only a few (7.7%) respondents believed that disclosing such information to the patient should be possible only after obtaining his or her consent. Respondents associated consent to information about the high risk of developing PD in people with RBD with high expectations of the healthcare system. We were unable to determine whether factors such as the gender of the subject, the clinical course of the PD, and the RBD duration had an impact on patients' opinions regarding disclosing knowledge about phenoconversion., Conclusions and Clinical Implications: Our study provides important information that should influence physicians' communication with patients with RBD, especially regarding how they communicate about the high risk of phenoconversion.

Background: Rapid eye movement sleep behaviour disorder (RBD) is considered to be one of the most frequent and important prodromal symptoms of Parkinson's disease (PD). We aimed to study the neurophysiological abnormalities in patients of PD-RBD and PD without RBD (PD-nRBD) using transcranial magnetic stimulation (TMS)., Methods: Twenty patients each of PD-RBD and PD-nRBD were included in the study in addition to 20 age and gender-matched healthy controls. RBD was identified using the RBD screening questionnaire (RBDSQ). All the subjects were evaluated with single and paired-pulse TMS and parameters such as resting motor threshold (RMT), central motor conduction time (CMCT), silent period (SP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded., Results: The mean age of the controls and PD patients with and without RBD was comparable. There were no significant differences in RMT, CMCT and silent period between the two patient groups. SICI was present in all the three groups with significant inhibition noted in PD-RBD group (p < 0.001). ICF was absent in patients of PD-RBD (0.19 ± 0.11) and PD-nRBD (0.7 ± 0.5) when compared to controls (1.88 ± 1.02) with profound impairment in patients with PD-RBD (p < 0.001). The mean MoCA score was found to be significantly different in all the three groups with a worse score in patients with RBD (23.10 ± 2.55; p < 0.001)., Conclusions: PD-RBD patients have significantly greater inhibition and reduced intracortical facilitation suggesting enhanced GABAergic and reduced glutaminergic transmission. These abnormalities may underlie the different pathophysiological process observed in these patients.