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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]

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]

Abstract REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson’s disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD−). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD−, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD− was significantly lower than HC in all these regions. PD-RBD− showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

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]

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson's disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD−). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD−, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD− was significantly lower than HC in all these regions. PD-RBD− showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients. [ABSTRACT FROM AUTHOR]

Introduction: Current neuroimaging research has revealed several brain alterations in idiopathic REM sleep behaviour disorder (iRBD) that mirror and precede those reported in PD. However, none have specifically addressed the presence of changes across the reward system, and their role in the emergence of impulse control disorders (ICDs). We aimed to compare the volumetric and functional connectivity characteristics of the reward system in relation to the psychobehavioral profile of patients with iRBD versus healthy controls and PD patients. Methods: Twenty patients with polysomnography confirmed iRBD along with 17 PD patients and 14 healthy controls (HC) underwent structural and functional resting-state brain MRI analysis. Participants completed the questionnaire for impulsive-compulsive disorders in PD (QUIP), the short UPPS-P impulsive behaviour scale, as well as neuropsychological testing of cognitive function. Results: A higher percentage of iRBD patients reported hypersexuality, compared to HC and PD (p = 0.008). Whole-brain and striatal voxel-based morphometry analyses showed no significant clusters of reduced grey matter volume between groups. However, iRBD compared to HC demonstrated functional hypoconnectivity between the limbic striatum and temporo-occipital regions. Furthermore, the presence of ICDs correlated with hypoconnectivity between the limbic striatum and clusters located in cuneus, lingual and fusiform gyrus. Conclusion: Altered functional connectivity between the limbic striatum and posterior cortical regions was associated with increased hypersexuality in iRBD. It is possible that this change may ultimately predispose individuals to the emergence of ICDs when they receive dopaminergic medications, after transitioning to PD. [ABSTRACT FROM AUTHOR]

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism. [ABSTRACT FROM AUTHOR]

• We demonstrate the feasibility of a fully automated REM sleep behaviour (RBD) screening tool using minimal sensors. • REM sleep is detected accurately and reliably in individuals with RBD, without EEG sensors. • Automated sleep staging was able to classify REM sleep with sufficient accuracy to allow for the accurate detection of RBD. Rapid-Eye-Movement (REM) sleep behaviour disorder (RBD) is an early predictor of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This study investigated the use of a minimal set of sensors to achieve effective screening for RBD in the population, integrating automated sleep staging (three state) followed by RBD detection without the need for cumbersome electroencephalogram (EEG) sensors. Polysomnography signals from 50 participants with RBD and 50 age-matched healthy controls were used to evaluate this study. Three stage sleep classification was achieved using a random forest classifier and features derived from a combination of cost-effective and easy to use sensors, namely electrocardiogram (ECG), electrooculogram (EOG), and electromyogram (EMG) channels. Subsequently, RBD detection was achieved using established and new metrics derived from ECG and EMG channels. The EOG and EMG combination provided the optimal minimalist fully-automated performance, achieving 0.57 ± 0.19 kappa (3 stage) for sleep staging and an RBD detection accuracy of 0.90 ± 0.11, (sensitivity and specificity of 0.88 ± 0.13 and 0.92 ± 0.098, respectively). A single ECG sensor achieved three state sleep staging with 0.28 ± 0.06 kappa and RBD detection accuracy of 0.62 ± 0.10. This study demonstrates the feasibility of using signals from a single EOG and EMG sensor to detect RBD using fully-automated techniques. This study proposes a cost-effective, practical, and simple RBD identification support tool using only two sensors (EMG and EOG); ideal for screening purposes. [ABSTRACT FROM AUTHOR]

Our objectives were to assess the prevalence of REM sleep behaviour disorder in patients with Essential Tremor, using video‐polysomnography and to compare REM sleep behaviour disorder features in essential tremor with those of patients with alpha‐synucleinopathies. Forty‐nine patients with essential tremor were screened with the REM Sleep Behaviour Disorder Screening Questionnaire. Patients scoring positive and those with spontaneous complaints of REM sleep behaviour disorder (n = 6) underwent video‐polysomnography. The clinical features of essential tremor were compared between patients with and without REM sleep behaviour disorder. Video‐polysomnography data were compared between patients who had essential tremor and Parkinson's disease with REM sleep behaviour disorder and those with idiopathic REM sleep behaviour disorder. Fourteen patients (23.5%) screened positive for REM sleep behaviour disorder, confirmed by video‐polysomnography in five (11.6%). All patients with essential tremor and REM sleep behaviour disorder had rest tremor, compared with 13 (34.2%) in the group with essential tremor but without REM sleep behaviour disorder (p =.009). In video‐polysomnography, patients with essential tremor and REM sleep behaviour disorder were similar to patients with Parkinson's disease with REM sleep behaviour disorder and presented worse sleep dysfunction and lower severity of REM sleep behaviour disorder compared to those with idiopathic REM sleep behaviour disorder. We found a high prevalence of REM sleep behaviour disorder in patients with essential tremor, associated with a predominance of rest tremor. Polysomnography data from patients with essential tremor and REM sleep behaviour disorder were similar to those in patients with Parkinson's disease. This suggests a relation between this subgroup of patients with essential tremor and the alpha‐synucleinopathies. [ABSTRACT FROM AUTHOR]

This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6 ± 7.3 years, 229 males) and 243 control subjects (67.2 ± 10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P < 0.000001), constipation, (P < 0.000001) and age over 70 years (P = 0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85-11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects. [ABSTRACT FROM AUTHOR]

Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson's disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study. Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit times were assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0.001, ANOVA) and delayed colonic transit times (P = 0.01, Kruskal-Wallis). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Finding out about night-time symptoms from Parkinson's disease (PD) patients can be a challenge as many patients and their carers cannot recall many symptoms that occur during the night, resulting in an under-recognition or a large variability of responses from clinical interviews and scales. Moreover, technology-based assessments for most night-time symptoms are still not universally available for use in a patient's home environment. Therefore, most physicians rely on their clinical acumen to capture these night-time symptoms based on pieces of patients' history, bedpartner's reports, clinical features, associated symptoms or conditions. To capture more night-time symptoms, the authors identified common nocturnal symptoms based on how they manifest from dusk to dawn with selected features relevant to PD. While some symptoms occur in healthy individuals, in PD patients, they may impact differently. The authors intend this narrative review to provide a practical guide on how these common night-time symptoms manifest and highlight pertinent issues by focusing on prevalence, clinical symptomatology, and specific relationships to PD. It is also important to recognise that PD-specific sleep disturbances increase with advancing disease with additional contributions from ageing, comorbidities, and medication side effects. However, the relative contribution of each factor to individual symptom may be different in individual patient, necessitating clinical expertise for individual interpretation. While there are debatable issues in certain areas, they underlie the complexity of night-time symptoms. Understanding night-time symptoms in PD is like re-arranging jigsaw pieces of clinical information to create, but never complete, a picture for physicians to instigate appropriate management. [ABSTRACT FROM AUTHOR]

Background and purpose: Visualization of phosphorylated α‐synuclein at serine 129 (p‐syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to establish the intra‐ and inter‐laboratory reproducibility of measurement of intraneural p‐syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna). Methods: In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA‐P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p‐syn and the pan‐axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re‐evaluated to understand the reasons for the discrepancy. Results: The intra‐laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter‐laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals. Conclusions: Analysis of p‐syn showed excellent inter‐ and intra‐laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique. [ABSTRACT FROM AUTHOR]

Highlights • REM sleep behaviour disorder (RBD) detection benefits from an ensemble of metrics that incorporate sleep architecture. • RBD detection remains successful using both manual and automated sleep scoring. • Cohort outnumbers similar studies with 53 RBD participants and 53 aged-matched healthy controls. Abstract Objective Evidence suggests Rapid-Eye-Movement (REM) Sleep Behaviour Disorder (RBD) is an early predictor of Parkinson's disease. This study proposes a fully-automated framework for RBD detection consisting of automated sleep staging followed by RBD identification. Methods Analysis was assessed using a limited polysomnography montage from 53 participants with RBD and 53 age-matched healthy controls. Sleep stage classification was achieved using a Random Forest (RF) classifier and 156 features extracted from electroencephalogram (EEG), electrooculogram (EOG) and electromyogram (EMG) channels. For RBD detection, a RF classifier was trained combining established techniques to quantify muscle atonia with additional features that incorporate sleep architecture and the EMG fractal exponent. Results Automated multi-state sleep staging achieved a 0.62 Cohen's Kappa score. RBD detection accuracy improved from 86% to 96% (compared to individual established metrics) when using manually annotated sleep staging. Accuracy remained high (92%) when using automated sleep staging. Conclusions This study outperforms established metrics and demonstrates that incorporating sleep architecture and sleep stage transitions can benefit RBD detection. This study also achieved automated sleep staging with a level of accuracy comparable to manual annotation. Significance This study validates a tractable, fully-automated, and sensitive pipeline for RBD identification that could be translated to wearable take-home technology. [ABSTRACT FROM AUTHOR]

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

Pathological involvement of the noradrenergic locus coeruleus occurs early in Parkinson's disease, and widespread noradrenaline reductions are found at post-mortem. Rapid eye movement sleep behaviour disorder (RBD) accompanies Parkinson's disease and its presence predicts an unfavourable disease course with a higher propensity to cognitive impairment and orthostatic hypotension. MRI can detect neuromelanin in the locus coeruleus while 11C-MeNER PET is a marker of noradrenaline transporter availability. Here, we use both imaging modalities to study the association of RBD, cognition and autonomic dysfunction in Parkinson's disease with loss of noradrenergic function. Thirty non-demented Parkinson's disease patients [16 patients with RBD and 14 without RBD, comparable across age (66.6 ± 6.7 years), sex (22 males), and disease stage (Hoehn and Yahr, 2.3 ± 0.5)], had imaging of the locus coeruleus with neuromelanin sensitive MRI and brain noradrenaline transporter availability with 11C-MeNER PET. RBD was confirmed with polysomnography; cognitive function was assessed with a neuropsychological test battery, and blood pressure changes on tilting were documented; results were compared to 12 matched control subjects. We found that Parkinson's disease patients with RBD showed decreased locus coeruleus neuromelanin signal on MRI (P < 0.001) and widespread reduced binding of 11C-MeNER (P < 0.001), which correlated with amount of REM sleep without atonia. Parkinson's disease with RBD was also associated with a higher incidence of cognitive impairment, slowed EEG activity, and orthostatic hypotension. Reduced 11C-MeNER binding correlated with EEG slowing, cognitive performance, and orthostatic hypotension. In conclusion, reduced noradrenergic function in Parkinson's disease was linked to the presence of RBD and associated with cognitive deterioration and orthostatic hypotension. Noradrenergic impairment may contribute to the high prevalence of these non-motor symptoms in Parkinson's disease, and may be of relevance when treating these conditions in Parkinson's disease. [ABSTRACT FROM AUTHOR]

Background and purpose Rapid eye movement sleep behaviour disorder ( RBD) is related to striatal dopamine depletion. This study was performed to confirm whether clinically probable RBD (cp RBD) in patients with Parkinson's disease ( PD) is associated with a specific pattern of striatal dopamine depletion. Methods A prospective survey was conducted using the RBD Screening Questionnaire ( RBDSQ) in 122 patients with PD who had undergone dopamine transporter ( DAT) positron emission tomography scan. Results Patients with cp RBD (RBDSQ ≥ 7) exhibited greater motor deficits, predominantly in the less-affected side and axial symptoms, and were prescribed higher levodopa-equivalent doses at follow-up than those without cp RBD (RBDSQ ≤ 4), despite their similar disease and treatment durations. Compared to patients without cp RBD, those with cp RBD showed lower DAT activities in the putamen, particularly in the less-affected side in all putaminal subregions, and a tendency to be lower in the ventral striatum. In addition, greater motor deficits in patients with cp RBD than in those without cp RBD remained significant after controlling for DAT binding in the putamen and other confounding variables. Conclusions These results demonstrated that the presence of RBD in patients with PD is associated with different patterns of both motor deficit distribution and striatal DAT depletion, suggesting that the presence of RBD represents a distinct PD subtype with a malignant motor parkinsonism. [ABSTRACT FROM AUTHOR]

A screening tool can greatly facilitate the identification of individuals with rapid eye movement (REM) sleep behaviour disorder (RBD). Currently, the REM sleep behaviour disorder screening questionnaire (RBDSQ) is widely used, but its diagnostic accuracy has varied across previous studies. The aim of the present study was to systematically assess the diagnostic performance of the RBDSQ. We comprehensively searched for studies that evaluated the diagnostic performance of the RBDSQ. A bivariate mixed-effects model was used to summarize the diagnostic accuracy of the RBDSQ. Subgroup analyses were performed according to the study design and the different populations included in the studies. Ten studies were included. Using a cutoff value of 5, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.91 (95% CI 0.85-0.95), 0.77 (95% CI 0.66-0.85), 4.00 (95% CI 2.60-6.10), 0.12 (95% CI 0.07-0.19), and 34 (95% CI 16-71), respectively. A subgroup analysis revealed that the RBDSQ had excellent diagnostic accuracy for RBD screening in the general population. However, its performance in specific patient populations, especially patients with Parkinson's disease, was less satisfactory. In conclusion, the RBDSQ is an effective diagnostic screening tool for RBD in the general population, but its performance in subjects with specific neurological disorders requires more comprehensive assessments. [ABSTRACT FROM AUTHOR]

Phosphorylated alpha-synuclein (p-alpha-syn) deposits, one of the neuropathological hallmarks of Parkinson's disease (PD), have recently been detected in dermal nerve fibres in PD patients with good specificity and sensitivity. Here, we studied whether p-alpha-syn may serve as a biomarker in patients with a high risk of developing PD, such as those with REM sleep behaviour disorder (RBD). We compared the presence and distribution of p-alpha-syn deposits in dermal nerve fibres in 18 patients with RBD, 25 patients with early PD and 20 normal controls. Skin biopsy was taken at C7, Th10, and the upper and lower leg. Presynaptic dopamine transporter imaging using FP-CIT-SPECT was performed in all patients with RBD and in 11 patients with PD. All RBD patients underwent olfactory function testing. The likelihood ratio (LR) for prodromal PD was calculated for each patient based on published research criteria. Skin serial sections were assessed by double-immunofluorescence labelling with antibodies to pSer129-alpha-syn under blinded conditions. P-alpha-syn was visualized in 10/18 patients with RBD (sensitivity of 55.6%) and in 20/25 early PD patients (sensitivity of 80%) but in none of the controls (specificity of 100%). The percentage of dermal structures innervated by p-alpha-syn-positive fibres was negatively correlated with dopamine transporter binding in the FP-CIT-SPECT ( ρ = −0.377, p = 0.048), with olfactory function ( ρ = −0.668, p = 0.002), and positively correlated with the total LR for RBD to present prodromal PD ( ρ = 0.531, p = 0.023). Dermal p-alpha-syn can be considered a peripheral histopathological marker of synucleinopathy and can be detected in a subgroup of RBD patients presumably representing prodromal PD. Dermal p-alpha-syn is detectable in RBD patients without PD motor symptoms, thereby stratifying a patient group that is of great interest for clinical trials testing disease-modifying drugs. [ABSTRACT FROM AUTHOR]

Introduction Changes in personality have been described in Parkinson's disease (PD), with suggestion that those with established disease tend to be risk averse with a disinclination for addictive behaviour. However, little is known about the earliest and prodromal stages. Personality and its relationship with addictive behaviours can help answer important questions about the mechanisms underlying PD and addiction. Methods 941 population-ascertained PD subjects within 3.5 years of diagnosis, 128 patients with rapid eye movement sleep behaviour disorder (RBD) and 292 control subjects were fully characterised for motor symptoms, non-motor symptoms and across the following 5 personality domains: 1) neuroticism 2) extraversion 3) conscientiousness 4) agreeableness 5) openness using the Big Five Inventory. Results Patients with early PD were more neurotic (p < 0.001), less extraverted (p < 0.001) and less open than controls (p < 0.001). RBD subjects showed the same pattern of being more neurotic (p < 0.001), less extraverted (p = 0.03) and less open (p < 0.001). PD patients had smoked less (p = 0.02) and drunk less alcohol (p = 0.03) than controls, but caffeine beverage consumption was similar. Being more extraverted (p < 0.001), more open (p < 0.001), and less neurotic (p < 0.001) predicted higher alcohol use, while being more extravert (p = 0.007) and less agreeable (p < 0.001) was associated with smoking more. Conclusions A similar pattern of personality changes is seen in PD and RBD compared to a control population. Personality characteristics were associated with addictive behaviours, suggestive of a common link, but the lower rates of addictive behaviours before and after the onset of motor symptoms in PD persisted after accounting for personality. [ABSTRACT FROM AUTHOR]

Sleep disorders are identified as common non-motor symptoms of Parkinson’s disease (PD) and recently this recognition has been expanded to include parasomnias, encompassing not only REM sleep behaviour disorder (RBD), but also other non-REM forms. RBD, a prototypical parasomnia in PD, exists even in the prodromal stage of the disease, and is characterized by the presence of dream enactment behaviours occurring alongside a loss of normal skeletal muscle atonia during REM sleep. In contrast, non-REM parasomnias are more frequently observed in the late stage PD. However, the development of these disorders often overlaps and it is not uncommon for PD patients to meet the criteria for more than one type of parasomnias, thus making a clinical distinction challenging for practicing neurologists who are not sleep specialists. Indeed, clinical recognition of the predominant form of parasomnia does not just depend on video-polysomnography, but also on an individual physician's clinical acumen in delineating pertinent clinical history to determine the most likely diagnosis and proceed accordingly. In this review article, we highlight the various forms of parasomnias that have been reported in PD, including, but not limited to, RBD, with a focus on clinical symptomatology and implications for clinical practice. In addition, we review the differences in PD-related parasomnias compared to those seen in general populations. With advances in sleep research and better technology for ambulatory home monitoring, it is likely that many unanswered questions on PD-related parasomnias will soon be resolved resulting in better management of this nocturnal challenge in PD. [ABSTRACT FROM AUTHOR]

It is well established that sleep disorders have neuropsychological consequences in otherwise healthy people. Studies of night-time sleep problems and cognition in Parkinson's disease (PD), however, paint a mixed picture, with many reporting no relationship between sleep problems and neuropsychological performance. This review aimed to meta-analyse this research and to examine the factors underlying these mixed results. A literature search was conducted of published and unpublished studies, resulting in 16 papers that met inclusion criteria. Data were analysed in the domains of: global cognitive function; memory (general, long-term verbal recognition, long-term verbal recall); and executive function (general, shifting, updating, inhibition, generativity, fluid reasoning). There was a significant effect of sleep on global cognitive function, long-term verbal recall, long-term verbal recognition, shifting, updating, generativity, and fluid reasoning. Although there are effects on memory and executive function associated with poor sleep in PD, the effects were driven by a small number of studies. Numerous methodological issues were identified. Further studies are needed reliably to determine whether disturbed sleep impacts on cognition via mechanisms of hypoxia, hypercapnia, sleep fragmentation, chronic sleep debt or decreased REM and/or slow wave sleep in PD, as this may have important clinical implications. [ABSTRACT FROM AUTHOR]

Individuals with REM sleep behaviour disorder are at significantly higher risk of developing Parkinson's disease. Here we examined visual short-term memory deficits--long associated with Parkinson's disease--in patients with REM sleep behaviour disorder without Parkinson's disease using a novel task that measures recall precision. Visual short-term memory for sequentially presented coloured bars of different orientation was assessed in 21 patients with polysomnography-proven idiopathic REM sleep behaviour disorder, 26 cases with early Parkinson's disease and 26 healthy controls. Three tasks using the same stimuli controlled for attentional filtering ability, sensorimotor and temporal decay factors. Both patients with REM sleep behaviour disorder and Parkinson's disease demonstrated a deficit in visual short-term memory, with recall precision significantly worse than in healthy controls with no deficit observed in any of the control tasks. Importantly, the pattern of memory deficit in both patient groups was specifically explained by an increase in random responses. These results demonstrate that it is possible to detect the signature of memory impairment associated with Parkinson's disease in individuals with REM sleep behaviour disorder, a condition associated with a high risk of developing Parkinson's disease. The pattern of visual short-term memory deficit potentially provides a cognitive marker of 'prodromal' Parkinson's disease that might be useful in tracking disease progression and for disease-modifying intervention trials. [ABSTRACT FROM AUTHOR]

Objectives Rapid eye movement (REM) sleep behaviour disorder is frequently observed in Parkinson's disease and is characterized electrophysiologically by the absence of atonia during REM sleep. However, the night-to-night variability of REM sleep without atonia is yet to be determined in Parkinson's disease. Methods Using polysomnography, this study measured the variability of REM sleep without atonia across two consecutive nights, using the REM atonia index in 38 patients with Parkinson's disease. Results The intraclass correlation coefficient between the REM sleep atonia index across two nights was 0.816 ( F  = 9.795, p  < 0.001) and the difference between the two nights was 4.7% (standard deviation (SD) 8.2). Conclusion The REM atonia index demonstrated low variability across two consecutive nights of PSG. Furthermore, the diagnosis of REM sleep behaviour disorder based on this electrophysiological marker and other clinical variables was in agreement across the two nights. [ABSTRACT FROM AUTHOR]

Background: REM sleep behaviour disorder (RBD) is typically linked to synucleinopathies (SP). In this study we analyzed the utility and performance of RBD as a tool for the differential diagnosis of the most common forms of degenerative parkinsonism, including SPs and tauopathies. Methods: Patients with a syndromic diagnosis of degenerative parkinsonism matched for gender, age, and disease stage were assessed using a structured protocol with demographic and clinical data, including the diagnosis of probable RBD (pRBD), ascertained clinically using established criteria. Results: One hundred cases of Parkinson's disease (PD), 87 with progressive supranuclear palsy (PSP), 72 with the parkinsonian form of multiple system atrophy (MSA), 50 with dementia with Lewy bodies (DLB), and 18 with corticobasal degeneration (CBD) were included. pRBD was found in 58 (58%) of the PD patients, 59 (81.9%) of those with MSA, 37 (74%) with DLB, 32 (36.7%) with PSP, and one (5.5%) with CBD. Among the SPs, pRBD was significantly more common in MSA when compared with PD patients. Differences were also significant individually for all SPs when compared to PSP. The positive predictive value (PPV) of pRBD for a SP was 82.3%, but sensitivity was 69.4% and specificity 68.6%. Conclusions: In our sample, pRBD was more frequent in SPs than in PSP and CBD, however, its' frequency in PSP was significant. Although pRBD had a good PPV for a SP, all other measurements used for determine diagnostic performance were disappointing. [ABSTRACT FROM AUTHOR]

Background/Aims: In a questionnaire survey, we identified 36 (9%) of 417 Parkinson's disease (PD) patients with sleepwalking (SW); 72% of them also had a history of REM sleep behaviour disorder (RBD). We aimed to assess the clinical and polysomnographic characteristics of SW in PD and to compare them to patients with PD with and without a history of RBD. Methods: We performed video-polysomnography and detailed clinical examination in 30 PD patients from the above-mentioned survey: 10 patients with a history of SW, 10 patients with a history of RBD, and 10 patients with no history of either SW or RBD. Results: PD patients with SW had higher depression, anxiety and Hoehn & Yahr scores and lower activities of daily living scores than patients without a history of RBD but did not differ from patients with RBD. Patients with SW and RBD also had more often dyskinesia and hallucinations. By polysomnography, RBD was observed in 8 patients with SW and in all patients with a history of RBD. A total of 5 patients without a history of either SW or RBD had REM sleep without atonia without behavioural peculiarities. Conclusion: SW in PD is associated with depression, higher disease severity and functional disability. The simultaneous occurrence of SW and RBD (overlap parasomnia) in most patients suggests a common underlying disturbance of motor control during sleep in PD, with variable manifestations in different sleep stages. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Dementia with Lewy bodies ( DLB) is defined pathologically as neurodegeneration associated with Lewy bodies ( LB). LB-related symptoms, including olfactory dysfunction, dysautonomia, and mood and sleep disorders, are increasingly recognized as clinical signs that enable the early detection of DLB, because these symptoms often antedate dementia by years or even decades. It remains unknown if the clinical history of LB-related symptoms is sufficient for the prodromal state of DLB to be suspected in memory clinics. We retrospectively investigated the clinical courses, including olfactory dysfunction, dysautonomia, depression, and rapid eye movement sleep behaviour disorder, of 90 patients with probable DLB. The timing of LB-related symptoms that preceded or followed relative to the onset of memory loss was calculated. LB-related symptoms were present in 79 of 90 patients (87.8%) with probable DLB before or at the time of memory loss onset. These symptoms preceded the onset of memory loss between 1.2 and 9.3 years. We also report on four non-demented patients with a clinical history of LB-related symptoms in our memory clinic. All four patients showed reduced cardiac [123 I]-metaiodobenzylguanidine levels. Moreover, [18 F]fluoro-D-glucose positron emission tomography scans revealed glucose hypometabolism in the occipital cortex in two patients. One patient converted to probable DLB with the development of parkinsonism 2 years after major depression was diagnosed. Based on a clinical history of LB-related symptoms, we propose a conceptual framework to identify these symptomatic but non-demented individuals that led us to suspect the underlying pathophysiology of Lewy body disease. Further prospective study is warranted to determine the clinical significance of LB-related symptoms in non-demented patients. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Transcranial sonography (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in people with Parkinson’s disease and in approximately 10% of healthy subjects. It is hypothesized that SN hyperechogenicity in healthy subjects and patients with idiopathic rapid eye movement (REM) sleep behaviour disorder (iRBD) patients is a marker of vulnerability for Parkinson’s disease. Methods: TCS and positron emission tomography (PET) with 6-[18F] fluoro-meta-tyrosine (FMT), which can assess the level of the presynaptic dopaminergic nerve, were performed in 19 male patients with iRBD, mean age 66.4 (standard deviation [SD] 4.9) years, to assess nigrostriatal function. Results: Nine patients had pathological SN hyperechogenicity (mean age 66.8 [SD 3.9] years; 0.31 [SD 0.12] cm2) and 10 patients did not have SN hyperechogenicity (mean age 66.0 [SD 5.8] years; 0.11 [SD 0.06] cm2). FMT uptake at the putamen and caudate was significantly lower in iRBD patients with pathological SN hyperechogenicity compared with those without SN hyperechogenicity. However, no correlation was found between SN echogenicity and FMT uptake. This is in conflict with previous findings which showed that subjects with hyperechogenicity had lower FMT uptake in the striatum. Conclusion: Pathological hyperechogenic alterations in the SN in patients with iRBD may suggest the existence of preclinical SN dysfunction as determined by FMT-PET. [Copyright &y& Elsevier]

Abstract: REM sleep behaviour disorder (RBD) is a REM sleep-related parasomnia which may be considered a “dissociated state of wakefulness and sleep”, given that conflicting elements of REM sleep (dreaming) and of wakefulness (sustained muscle tone and movements) coexist during the episodes, leading to motor and behavioural manifestations reminiscent of an enacted dream. RBD has been reported in association with α-synucleinopathies: around a third of patients with Parkinson’s disease (PD) have full-blown RBD. Recent data indicate that PD patients with RBD are more prone to hallucinations than PD patients without this parasomnia. However it is still not clear why RBD in PD is associated with an increased prevalence of VHs. Data exist which suggest that visual hallucinations in PD may be the result of untimely intrusions of REM visual imagery into wakefulness. RBD, which is characterised by a REM sleep dissociation pattern, might be a condition that particularly favours such intrusions. However, other hypotheses may be advanced. In fact, deficits in attentional, executive, visuoperceptual and visuospatial abilities have been documented in RBD and found to occur far more frequently in PD with RBD than in PD without RBD. Neuropsychological deficits involving visual perception and attentional processes are thought to play an important role in the pathophysiology of VHs. On this basis, RBD in PD could be viewed as a contributory risk factor for VHs. [Copyright &y& Elsevier]

Rapid eye movement sleep behaviour disorder (RBD) is one of many sleep disorders seen in patients with parkinsonism. RBD is a parasomnia in which there is loss of normal skeletal muscle atonia and prominent motor activity during rapid eye movement sleep. Sufferers exhibit vigorous limb movements and dream enactment. RBD may occur occasionally or on a regular basis. This phenomenon is closely associated not only with idiopathic Parkinson's disease but also with the other synucleinopathies. RBD was first identified as a disease entity by Schenk and co-workers in 1986. In this article, the relationship between RBD, parkinsonism and areas of the brain involved in sleep regulation will be examined. It will also explore patient assessment, possible exacerbating factors and treatment options. [ABSTRACT FROM AUTHOR]

Objective Two common and characteristic sleep disturbances have been described in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD); excessive daytime sleepiness and REM sleep behaviour disorder (RBD). This study is an analysis of a secondary outcome measure of a larger study already reported, aimed to determine whether memantine has an effect on the sleep disturbances in DLB and PDD patients. Methods Patients with DLB or PDD were included in a placebo-controlled, randomised controlled study of memantine (20 mg per day) for 24 weeks. The Stavanger Sleep Questionnaire and the Epworth Sleepiness Scale were used to evaluate the effect on sleep disturbances. Results Forty two patients started treatment; 20 with memantine and 22 with placebo. The primary analysis was the comparison of change between the two groups during a 24-week period, using the modified ITT population (last observation carried forward). At 24 weeks, patients treated with memantine were less physically active during sleep while patients in the placebo group worsened. Mean difference between the groups (0.5 [0.05-0.90]) was significant (p = 0.006). No significant change was observed in severity of excessive daytime sleepiness. Conclusions Memantine decreases probable REM sleep behaviour disorder in patients with DLB and PDD. Both diagnostic groups contributed equally to the outcome. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Aim: In this study, we sought to evaluate the utility of actigraphy for examining symptoms of rapid eye movement sleep behaviour disorder (RSBD). Methods: Twenty-two patients with idiopathic Parkinson''s Disease (mean age=63.4 years, SD=7.5) underwent neurological assessment and completed sleep diaries, self-report sleep questionnaires and 2-weeks of actigraphy. They also completed the rapid eye movement sleep behavior disorder questionnaire and were classified as screening negative (RSBD−, n =9) or positive (RSBD+, n =13) for RSBD according to published criteria. Key outcome data were the number of wake bouts and duration of arousals during the sleep interval as determined by actigraphy. Results: Patients classified as RSBD+ demonstrated a higher number of wake bouts than those who were RSBD− (p =0.011). Conclusions: These results suggest that actigraphy may be a viable tool to assist in the early identification of RSBD. In turn, this could guide early intervention approaches. [Copyright &y& Elsevier]

Abstract: Objective: To assess whether the presence of probable REM sleep behaviour disorder (pRBD) influences the long-term outcome of Parkinson''s Disease (PD) patients undergoing Subthalamic Nucleus Deep Brain Stimulation (STN-DBS). Background: RBD is a parasomnia characterized by loss of muscular atonia and complex motor behaviours during REM sleep, frequently reported in PD patients. Recent evidence suggests that RBD is associated with akinetic rigid disease type and increased frequency of falls. We wondered whether the presence of RBD would also influence the long-term outcome of STN-DBS. Methods: Forty-one consecutive PD patients treated with bilateral STN-DBS were assessed. The diagnosis of pRBD was based on a clinical interview investigating the occurrence of diagnostic criteria for RBD. The Unified Parkinson''s Disease Rating Scale was used to compare the on- and off-medication conditions preoperatively and the on-stimulation/on- and off-medication conditions 1 and 3 years postoperatively. The general linear model for multivariate measures was used to analyse the interaction of pRBD with STN-DBS outcome measures. Results: pRBD was present in 12 out of 41 patients (29%) undergoing STN-DBS. Patients with pRBD had a significantly poorer outcome three years after STN-DBS compared to patients without pRBD, in particular for axial symptoms. Conclusions: Our findings suggest that the presence of pRBD in PD patients undergoing STN-DBS may be associated with a less favourable outcome and a more prominent development of axial symptoms over time. [Copyright &y& Elsevier]

In idiopathic rapid eye movement sleep behaviour disorder (RBD), an association with visuoperceptive disorders has been described. However, such an association has not been clearly established in RBD secondary to Parkinson’s disease (PD). We compared visuoperceptive function in four groups of non-demented patients (parkinsonian patients with or without RBD, patients with idiopathic RBD and control participants) via a procedure enabling the analysis of the various components of visual information processing and in order to answer the following question: is RBD associated with visuoperceptive and/or attentional disorders in PD and, if so, where is the dysfunction located along the visual pathway? Sensorial aspects of visual information were evaluated using a contrast sensitivity test, perceptual aspects were assessed using a contour-based object identification test and visual attention was measured in an attentional capture paradigm. The diagnosis of RBD was confirmed by polysomnography. We observed a higher object identification threshold (OIT) (1) in PD patients with RBD compared with PD patients without RBD and with controls and (2) in idiopathic RBD patients compared with controls. There were no significant OIT differences between PD patients with RBD and idiopathic RBD patients or between PD patients without RBD and controls. We did not find any significant inter-group differences in any of the other visuoperceptive tests. RBD, idiopathic or secondary to PD, is associated with perceptual closure dysfunction. Our results suggest that this perceptual dysfunction is specifically associated with RBD and may be related to a non-dopaminergic impairment. [ABSTRACT FROM AUTHOR]

Idiopathic rapid eye movement sleep behaviour disorder is an important risk factor in the development of Parkinson's disease. Numerous potential predictive markers of Parkinson's disease may present before motor symptoms emerge, but testing of these markers in rapid eye movement sleep behaviour disorder has been performed only in small studies. There has been no comparison of markers between patients with idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease, and between men and women. We evaluated an array of potential Parkinson's disease predictive markers in 159 patients; including 68 with idiopathic rapid eye movement sleep behaviour disorder, 36 controls, 34 Parkinson's patients with rapid eye movement sleep behaviour disorder and 21 Parkinson's patients without rapid eye movement sleep behaviour disorder. Compared with controls, patients with idiopathic rapid eye movement sleep behaviour disorder demonstrated substantial olfactory loss (P < 0.001). Olfaction was more impaired in Parkinson's disease than idiopathic rapid eye movement sleep behaviour disorder and did not differ between Parkinson's patients with, or without, rapid eye movement sleep behaviour disorder. Numerous measures of motor function including the Unified Parkinson Disease Rating Scale alternate tap, Purdue Peg Board and Timed ’Up and Go‘ were impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.01). All of these motor measures were worse with Parkinson's disease than with idiopathic rapid eye movement sleep behaviour disorder, regardless of rapid eye movement sleep behaviour disorder status. Autonomic symptoms and systolic blood pressure drop were impaired in patients with idiopathic rapid eye movement sleep behaviour disorder compared with controls (P = 0.003). Orthostatic abnormalities in Parkinson's disease were found in the group with rapid eye movement sleep behaviour disorder (P < 0.001). However, Parkinson's patients without rapid eye movement sleep behaviour disorder were not different than controls and had less impairment than those with idiopathic rapid eye movement sleep behaviour disorder (P = 0.004) and Parkinson's patients with rapid eye movement sleep behaviour disorder (P < 0.001). Colour vision was impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.001). However, only Parkinson's patients with rapid eye movement sleep behaviour disorder had abnormalities significantly different than controls (P < 0.001), and there were significant differences between Parkinson's patients with or without rapid eye movement sleep behaviour disorder (P < 0.04). Idiopathic rapid eye movement sleep behaviour disorder patients had slightly increased harm avoidance scores on personality testing (P = 0.04). Other than slightly better performances among women in the Purdue Peg Board, there was no difference in any measure between men and women, suggesting similar pathogenic processes underlying rapid eye movement sleep behaviour disorder. Patients with idiopathic rapid eye movement sleep behaviour disorder demonstrate abnormalities in numerous potential markers of neurodegenerative disease—these markers are heterogeneous, generally correlate with each other and occur equally in men and women. Although these abnormalities are usually intermediate between control values and Parkinson's patients, autonomic dysfunction and colour vision appear to be more linked to rapid eye movement sleep behaviour disorder status than Parkinson's disease, suggesting a unique pathophysiology of these abnormalities. [ABSTRACT FROM PUBLISHER]

Substantia nigra (SN) hyperechogenicity—a sonographic vulnerability marker for Parkinson’s disease (PD)—has been recently described in patients with idiopathic REM sleep behaviour disorder (RBD). It is not known whether subjects with narcolepsy (who frequently have associated RBD) also show SN hyperechogenicity. The aim of this study was to (1) evaluate SN echogenicity in narcolepsy and (2) determine whether transcranial sonography (TCS) differs in narcoleptic subjects with and without RBD. A total of 16 patients with narcolepsy–cataplexy (7 had a concomitant, video-polysomnographically based diagnosis of RBD) were examined with TCS by two investigators blinded to the clinical data. The size of the SN echogenic area in both subgroups was within the range previously described for healthy subjects. The brainstem raphe, however, was reduced in five of seven narcoleptic subjects with RBD, whereas only two of nine narcoleptic subjects without RBD exhibited this TCS finding. We conclude that evaluation of SN echogenicity does not discriminate between both subgroups. The absence of SN hyperechogenicity in narcoleptic patients with RBD supports the hypothesis that SN hyperechogenicity in patients with presumed idiopathic RBD is an additional risk marker for subsequent evolvement of PD rather than an RBD-immanent finding. Reduced echogenicity of the brainstem raphe might indicate an involvement of the serotonergic system in narcoleptic subjects with RBD. [ABSTRACT FROM AUTHOR]

Rapid eye movement sleep behaviour disorder (RBD) may serve as a useful indicator to approach Parkinson’s disease (PD); however, PD patients do not always exhibit RBD. We wondered whether the presence of RBD would be reflected in the expansion of PD lesions and represent the same PD entity. We examined the clinical differences between PD with and without RBD and studied the frequency of RBD-like symptoms (RBD-s) and clinical differences in 150 PD patients, including 81 patients (54.0%) who satisfied the International Classification of Sleep Disorders, Revised, minimum clinical criteria for RBD. RBD-s preceding the appearance of parkinsonism were found in 44.4% of patients. Statistically, the presence of RBD-s was associated with ages above 65 years, male gender, constipation, dopa-induced dyskinesia and ‘sleep attack’, with odds ratios of 3.709, 2.469, 2.184, 5.046 and 6.562, respectively. No differences were found between the 2 groups with regard to symptoms at PD onset, disease duration, Hoehn-Yahr stage, hallucination, dementia, wearing-off, orthostatic hypotension, cerebral blood flow and antiparkinsonism drugs. In the early stage, RBD and autonomic system dysfunction are important factors in the progression of PD. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by elaborate behaviours during REM sleep usually associated with action-filled dreams. Typical behaviours are screaming, grasping, punching, kicking and occasionally jumping out of bed, which are potentially harmful for the patient and their bed partner. Polysomnographic (PSG) recording reveals a loss of atonia and an excessive phasic motor activity during REM sleep. RBD affects mainly men over 50 years and its prevalence in the general population is estimated around 0.5%. It may occur in acute or chronic forms. The latter may be isolated (idiopathic RBD), or associated with other neurological diseases (symptomatic RBD), especially with a group of neurodegenerative disease called alpha-synucleinopathies, which includes Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy. The idiopathic form accounts for up to 60% of the cases reported in the literature. Small clinical follow-up studies revealed that a proportion of these patients will eventually develop a parkinsonian syndrome and/or a DLB in the years following the RBD diagnosis, while some patients will remain idiopathic for decades. Recent studies found evidence of neural dysfunction during both wakefulness and sleep in iRBD, such as an impairment of the cortical activity, specific neuropsychological deficits, signs of autonomic dysfunction, deficit of colour discrimination, subtle abnormalities in quantitative measures of motor and gait speed and an olfactory impairment. The notion of “idiopathic” RBD is currently challenged and the use of a more conservative term of “cryptogenic” RBD has been suggested. [ABSTRACT FROM AUTHOR]