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This study investigated the relationship between rapid eye movement sleep without atonia and cognitive profiles in individuals diagnosed with isolated rapid eye movement sleep behaviour disorder, assesssing both cross-sectional associations and their link to phenoconversion in a longitudinal follow-up. Participants underwent video-polysomnography, neurological examination, neuropsychological tests and structured interviews to confirm isolated rapid eye movement sleep behaviour disorder. Rapid eye movement sleep without atonia was manually scored using the Montreal method, and participants were categorized into either high or low electromyography activity groups, based on their tonic and phasic electromyography activities. The cross-sectional study included 250 patients with isolated rapid eye movement sleep behaviour disorder, revealing that those with high tonic electromyography activity exhibited significantly lower scores in the constructional praxis recall than those with low tonic electromyography activity (p = 0.002). In the longitudinal study, 79 participants (63 isolated rapid eye movement sleep behaviour disorder and 16 phenoconversion), tracked for at least 5 years, demonstrated that high tonic electromyography activity (odds ratio: 6.14; 95% confidence interval: 1.23-30.60; p = 0.027) and lower performance on the Trail Making Test A (odds ratio: 0.23; 95% confidence interval: 0.11-0.70; p = 0.007) were associated with future phenoconversion. These results confirm the link between tonic electromyography activity and neurodegeneration in isolated rapid eye movement sleep behaviour disorder. Combining rapid eye movement sleep without atonia assessment with cognitive evaluation could serve as an early predictive marker for phenoconversion in clinical settings.

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A reduction of physiological muscle atonia during rapid eye movement sleep is characteristic in patients with rapid eye movement sleep behaviour disorder, however, it can also be found in narcolepsy patients. We evaluated rapid eye movement sleep associated electromyographic activity to set cut-off values of rapid eye movement sleep without atonia, differentiating rapid eye movement sleep behaviour disorder and narcolepsy patients from controls to enable more precise future diagnostic criteria for these disorders. We retrospectively analysed polysomnography recordings of 16 rapid eye movement sleep behaviour disorder patients, 15 narcolepsy patients, and 19 controls. The combination of phasic and tonic electromyographic activity was recorded in the mentalis and tibialis anterior muscles and analysed in 3 second miniepochs. The cut-off value for a diagnosis of rapid eye movement sleep behaviour disorder was 17.07% (100% sensitivity, 94.7% specificity, area under the curve 0.997). For the diagnosis of narcolepsy, we yielded a cut-off value of 8.4% (86.4% sensitivity, 68.4% specificity, area under the curve 0.850). Rapid eye movement sleep without atonia significantly (p = 0.046) increased in the second night half in rapid eye movement sleep behaviour disorder patients, while it remained moderately increased in the narcolepsy group. Polysomnographic evaluation proves significantly higher rates of rapid eye movement sleep without atonia in rapid eye movement sleep behaviour disorder than in narcolepsy patients, allowing differentiation from controls with high sensitivity and specificity. An increase throughout the night is characteristic for rapid eye movement sleep behaviour disorder, whereas a consistent elevation is typical in narcolepsy patients.

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Several brainstem, subcortical and cortical areas are involved in the generation of rapid eye movement (REM) sleep. The alteration of these structures as a result of a neurodegenerative process may therefore lead to REM sleep anomalies. REM sleep behaviour disorder is associated with nightmares, dream-enacting behaviours and increased electromyographic activity in REM sleep. Its isolated form is a harbinger of synucleinopathies such as Parkinson's disease or dementia with Lewy bodies, and neuroprotective interventions are advocated. This link might also be present in patients taking antidepressants, with post-traumatic stress disorder, or with a history of repeated traumatic head injury. REM sleep likely contributes to normal memory processes. Its alteration has also been proposed to be part of the neuropathological changes occurring in Alzheimer's disease.

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The formal identification and naming of rapid eye movement (REM) sleep behaviour disorder (RBD) in 1985-1987 is described; the historical background of RBD from 1966 to 1985 is briefly discussed; and RBD milestones are presented. Current knowledge on RBD is identified with reference to recent comprehensive reviews, allowing for a focus on research priorities for RBD: factors and predictors of neurodegenerative phenoconversion from isolated RBD and patient enrolment in neuroprotective trials; isolated RBD clinical research cohorts; epidemiology of RBD; traumatic brain injury, post-traumatic stress disorder, RBD and neurodegeneration; depression, RBD and synucleinopathy; evolution of prodromal RBD to neurodegeneration; gut microbiome dysbiosis and colonic synuclein histopathology in isolated RBD; other alpha-synuclein research in isolated RBD; narcolepsy-RBD; dreams and nightmares in RBD; phasic REM sleep in isolated RBD; RBD, periodic limb movements, periodic limb movement disorder pseudo-RBD; other neurophysiology research in RBD; cardiac scintigraphy (123I-MIBG) in isolated RBD; brain magnetic resonance imaging biomarkers in isolated RBD; microRNAs as biomarkers in isolated RBD; actigraphic, other automated digital monitoring and machine learning research in RBD; prognostic counselling and ethical considerations in isolated RBD; and REM sleep basic science research. RBD research is flourishing, and is strategically situated at an ever-expanding crossroads of clinical (sleep) medicine, neurology, psychiatry and neuroscience.

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The loss of dopamine in the striatum underlies motor symptoms of Parkinson's disease (PD). Rapid eye movement sleep behaviour disorder (RBD) is considered prodromal PD and has shown similar neural changes in the striatum. Alterations in brain iron suggest neurodegeneration; however, the literature on striatal iron has been inconsistent in PD and scant in RBD. Toward clarifying pathophysiological changes in PD and RBD, and uncovering possible biomarkers, we imaged 26 early-stage PD patients, 16 RBD patients, and 39 age-matched healthy controls with 3 T MRI. We compared mean susceptibility using quantitative susceptibility mapping (QSM) in the standard striatum (caudate, putamen, and nucleus accumbens) and tractography-parcellated striatum. Diffusion MRI permitted parcellation of the striatum into seven subregions based on the cortical areas of maximal connectivity from the Tziortzi atlas. No significant differences in mean susceptibility were found in the standard striatum anatomy. For the parcellated striatum, the caudal motor subregion, the most affected region in PD, showed lower iron levels compared to healthy controls. Receiver operating characteristic curves using mean susceptibility in the caudal motor striatum showed a good diagnostic accuracy of 0.80 when classifying early-stage PD from healthy controls. This study highlights that tractography-based parcellation of the striatum could enhance sensitivity to changes in iron levels, which have not been consistent in the PD literature. The decreased caudal motor striatum iron was sufficiently sensitive to PD, but not RBD. QSM in the striatum could contribute to development of a multivariate or multimodal biomarker of early-stage PD, but further work in larger datasets is needed to confirm its utility in prodromal groups.

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Isolated rapid-eye-movement sleep behaviour disorder (RBD) is considered the prodromal stage of α-synucleinopathies (e.g., Parkinson's disease and dementia with Lewy bodies); however, iRBD patients show a wide variety in the progression timing (5-15 years). The model of cognitive reserve (CR) might contribute to explaining this phenomenon. Our exploratory study aimed to evaluate, for the first time, the impact of CR level on cognitive performance in polysomnography-confirmed iRBD patients. Fifty-five iRBD patients (mean age ± SD: 66.38 ± 7.51; M/F 44/11) underwent clinical and neuropsychological evaluations at the time of diagnosis. The CR Index questionnaire was part of the clinical assessment. We found that iRBD patients with high levels of CR showed: (i) the lowest percentage of mild cognitive impairment (10%), and (ii) the best performance in visuo-constructive and verbal memory functions (i.e., the recall of the Rey-Osterrieth complex figure test). Our results suggest that CR might help iRBD patients better cope with the cognitive decline related to the neurodegenerative process, providing the first preliminary findings supporting CR as a possible protective factor in this condition. This might pave the way for future longitudinal studies to evaluate the role of CR as a modulating factor in the timing of iRBD conversion and cognitive deterioration development.

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Important brainstem regions are involved in the regulation of rapid eye movement sleep. We hypothesized that brainstem stroke is associated with dysregulated rapid eye movement sleep and related muscle activity. We compared quantitative/qualitative polysomnography features of rapid eye movement sleep and muscle activity (any, phasic, tonic) between 15 patients with brainstem stroke (N = 46 rapid eye movement periods), 16 patients with lacunar/non-brainstem stroke (N = 40 rapid eye movement periods), 15 healthy controls (N = 62 rapid eye movement periods), and patients with Parkinson's disease and polysomnography-confirmed rapid eye movement sleep behaviour disorder. Further, in the brainstem group, we performed a magnetic resonance imaging-based lesion overlap analysis. The mean ratio of muscle activity to rapid eye movement sleep epoch in the brainstem group ("any" muscle activity 0.09 ± 0.15; phasic muscle activity 0.08 ± 0.14) was significantly lower than in the lacunar group ("any" muscle activity 0.17 ± 0.2, p < 0.05; phasic muscle activity 0.16 ± 0.19, p < 0.05), and also lower than in the control group ("any" muscle activity 0.15 ± 0.17, p < 0.05). Magnetic resonance imaging-based lesion analysis indicated an area of maximum overlap in the medioventral pontine region for patients with reduced phasic muscle activity index. For all groups, mean values of muscle activity were significantly lower than in the patients with Parkinson's disease and polysomnography-confirmed REM sleep behaviour disorder group ("any" activity 0.51 ± 0.26, p < 0.0001 for all groups; phasic muscle activity 0.42 ± 0.21, p < 0.0001 for all groups). For the tonic muscle activity in the mentalis muscle, no significant differences were found between the groups. In the brainstem group, contrary to the lacunar and the control groups, "any" muscle activity index during rapid eye movement sleep was significantly reduced after the third rapid eye movement sleep phase. This study reports on the impact of brainstem stroke on rapid eye movement atonia features in a human cohort. Our findings highlight the important role of the human brainstem, in particular the medioventral pontine regions, in the regulation of phasic muscle activity during rapid eye movement sleep and the ultradian distribution of rapid eye movement-related muscle activity.

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There has been increasing concern about the long-term impact of coronavirus disease 2019 (COVID-19) as evidenced by anecdotal case reports of acute-onset parkinsonism and the polysomnographic feature of increased rapid eye movement sleep electromyographic activity. This study aimed to determine the prevalence and correlates of dream-enactment behaviours, a hallmark of rapid eye movement sleep behaviour disorder, which is a prodrome of α-synucleinopathy. This online survey was conducted between May and August 2020 in 15 countries/regions targeting adult participants (aged ≥18 years) from the general population with a harmonised structured questionnaire on sleep patterns and disorders, COVID-19 diagnosis and symptoms. We assessed dream-enactment behaviours using the Rapid Eye Movement Sleep Behaviour Disorder Single-Question Screen with an additional question on their frequency. Among 26,539 respondents, 21,870 (82.2%) answered all items that were analysed in this study (mean [SD] age 41.6 [15.8] years; female sex 65.5%). The weighted prevalence of lifetime and weekly dream-enactment behaviours was 19.4% and 3.1% and were found to be 1.8- and 2.9-times higher in COVID-19-positive cases, respectively. Both lifetime and weekly dream-enactment behaviours were associated with young age, male sex, smoking, alcohol consumption, higher physical activity level, nightmares, COVID-19 diagnosis, olfactory impairment, obstructive sleep apnea symptoms, mood, and post-traumatic stress disorder features. Among COVID-19-positive cases, weekly dream-enactment behaviours were positively associated with the severity of COVID-19. Dream-enactment behaviours are common among the general population during the COVID-19 pandemic and further increase among patients with COVID-19. Further studies are needed to investigate the potential neurodegenerative effect of COVID-19.

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Recurrent dream-enactment behaviours (DEB) and rapid eye movement (REM) sleep without atonia (RSWA) are two diagnostic hallmarks of REM sleep behaviour disorder (RBD), a specific prodrome of α-synucleinopathy. Whilst isolated RSWA (without DEB) was suggested as a prodrome of RBD, the implication of 'isolated' recurrent DEB remains under-investigated. In this cross-sectional study, we sought to investigate neurodegenerative markers amongst the first-degree relatives (FDRs, aged >40 years) of patients with RBD who underwent clinical assessment for DEB, neurodegenerative markers, and video-polysomnography assessment. Isolated recurrent DEB was defined as: (i) three or more episodes of DEB, (ii) had a DEB episode in the past 1 year, and (iii) subthreshold RSWA. We identified 29 FDRs (mean [SD] age 53.4 [8.3] years, 55.2% male) with isolated recurrent DEB and 98 age and sex-matched FDRs as controls. Isolated DEB was associated with nightmare (27.6% versus 11.2%, p = 0.02), and the DEB group had a higher rate of current smoking (27.6% versus 3.1%, p = 0.006), type 2 diabetes mellitus (24.1% versus 10.2%, p = 0.003), anxiety disorder (24.1% versus 11.2%, p = 0.02), and constipation (hard lump of stool, 31.0% versus 7.1%, p < 0.001) than the control group. The present findings revealed that family relatives of patients with RBD with isolated recurrent DEB have increased risk of RBD and neurodegenerative features, which adds to the emerging data that isolated DEB is a prodromal feature of RBD and α-synucleinopathy neurodegeneration.

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Previous studies have shown that rapid eye movement sleep without atonia during polysomnography can predict the risk of phenoconversion to neurodegenerative disease in patients with isolated rapid eye movement sleep behaviour disorder. Discrepancy remains with regards to the morphology of rapid eye movement sleep without atonia that best predicts phenoconversion risk. This study aimed to ascertain the predictive value of tonic, phasic and mixed rapid eye movement sleep without atonia in patients with isolated rapid eye movement sleep behaviour disorder, at time of diagnosis. Sixty-four patients with polysomnography-confirmed isolated rapid eye movement sleep behaviour disorder, including 19 who phenoconverted during follow-up, were identified from an existing database. Tonic, phasic, mixed and "any" rapid eye movement sleep without atonia activity from the mentalis, tibialis anterior and flexor digitorum superficialis muscles was analysed blind to status using the diagnostic polysomnography. Rapid eye movement sleep without atonia variables were compared between converters and non-converters. Rapid eye movement sleep without atonia cut-offs predicting phenoconversion were established using receiver-operating characteristic analysis. The mean follow-up duration was 5.50 ± 4.73 years. Phenoconverters (n = 19) had significantly higher amounts of tonic (22.2 ± 19.1%, p = 0.0014), mixed (18.1 ± 14.1%, p = 0.0074) and "any" (mentalis muscle; 58.7 ± 28.0%, p = 0.0009) and all muscles (68.0 ± 20.8%, p = 0.0049) rapid eye movement sleep without atonia at diagnosis than non-converters. Optimal rapid eye movement sleep without atonia cut-off values predicting phenoconversion were 5.8% for tonic (73.7% sensitivity; 75.6% specificity), 7.3% for mixed (68.4% sensitivity; 73.3% specificity) and 43.6% for "any" (mentalis muscle; 68.4% sensitivity; 80.0% specificity) activity. "Any" (mentalis muscle) rapid eye movement sleep without atonia had the highest area under the curve (0.809) followed by tonic (0.799). The percentage of tonic rapid eye movement sleep without atonia was the strongest biomarker of phenoconversion in this cohort of patients with isolated rapid eye movement sleep behaviour disorder.

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Multiple system atrophy (MSA) and Parkinson's disease (PD) may share overlapping features particularly at early disease stage, including sleep alterations, but have profoundly different prognoses. Certain sleep phenomena and disorders of motor control are more prevalent in multiple system atrophy, such as REM sleep behaviour disorder (RBD). We quantitatively tested whether pervasive muscle activity during sleep occurs in subjects with multiple system atrophy versus Parkinson's disease. Laboratory polysomnographic studies were performed in 50 consecutive subjects with Parkinson's disease and 26 age- and gender-matched subjects with multiple system atrophy at <5 years from disease onset. The distributions of normalised electromyographic activity of submentalis, wrist extensor, and tibialis anterior muscles in different wake-sleep states during the night were analysed. Subjects with multiple system atrophy had significantly higher activity of submentalis, wrist extensor, and tibialis anterior muscles than subjects with Parkinson's disease during non-REM sleep, including separately in stages N1, N2, and N3, and during REM sleep, but not during nocturnal wakefulness. The activity of wrist extensor and tibialis anterior muscles during non-REM sleep and the activity of tibialis anterior muscles during REM sleep were also significantly higher in subjects with multiple system atrophy and RBD than in subjects with Parkinson's disease and RBD. In conclusion, with respect to Parkinson's disease, multiple system atrophy is characterised by a pervasive and diffuse muscle overactivity that involves axial and limb muscles and occurs not only during REM sleep, but also during non-REM sleep and between subjects with comorbid RBD.

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PURPOSE: An increased blood pressure variability (BPV) has been reported to be associated with older age and cognitive dysfunction; however, associations between increased BPV and rapid eye movement sleep behaviour disorder (RBD) has not been thoroughly investigated in patients without clinical Lewy body diseases. MATERIALS AND METHODS: In frailty outpatient clinic, we evaluated ambulatory BP, RBD screening questionnaire (RBDSQ), and beat-to-beat heart rate variability during positional change from sitting to standing in 112 elderly hypertensive patients. RESULTS: The mean age was 81.2 ± 6.3 years (68% male). There were 15 patients who had probable RBD (RBDSQ scores ≥ 5). Patients with RBD had a greater body mass index, coefficient of variation (CV) in 24-h diastolic BP (23.5 ± 6.1 versus 18.7 ± 5.8, p = 0.005), awake diastolic BP (23.0 ± 7.7 versus 18.6 ± 6.2, p = 0.017), and nocturnal systolic BP (14.9 ± 5.5 versus 12.0 ± 4.4, p = 0.025) compared with those without RBD, while systolic BP, diastolic BP, and cognitive function did not differ significantly between patients with and without RBD. Patients with RBD exhibited larger orthostatic BP fall compared with patients without RBD (-4.9 ± 11.0 versus 7.5 ± 11.8, p = 0.009) and lower CV of R-R intervals while standing (1.3 ± 0.6 versus 2.4 ± 1.5, p = 0.039). Multiple regression analysis revealed that patients with RBD had significantly greater CV of nocturnal systolic BP independent of age, sex, BMI, history of diabetes and dyslipidaemia, and use of antihypertensive drugs (p = 0.008). CONCLUSION: An increased BPV in ambulatory BP, associated with autonomic dysfunction, can be observed in patients with probable RBD even in elderly patients without clinical presentation of Lewy body diseases.

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PURPOSE OF REVIEW: Rapid eye movement (REM) sleep behaviour disorder (RBD) is considered the expression of the initial neurodegenerative process underlying synucleinopathies and constitutes the most important marker of their prodromal phase. This article reviews recent research from longitudinal research studies in isolated RBD (iRBD) aiming to describe the most promising progression biomarkers of iRBD and to delineate the current knowledge on the level of prediction of future outcome in iRBD patients at diagnosis. RECENT FINDINGS: Longitudinal studies revealed the potential value of a variety of biomarkers, including clinical markers of motor, autonomic, cognitive, and olfactory symptoms, neurophysiological markers such as REM sleep without atonia and electroencephalography, genetic and epigenetic markers, cerebrospinal fluid and serum markers, and neuroimaging markers to track the progression and predict phenoconversion. To-date the most promising neuroimaging biomarker in iRBD to aid the prediction of phenoconversion is striatal presynaptic striatal dopaminergic dysfunction. There is a variety of potential biomarkers for monitoring disease progression and predicting iRBD conversion into synucleinopathies. A combined multimodal biomarker model could offer a more sensitive and specific tool. Further longitudinal studies are warranted to iRBD as a high-risk population for early neuroprotective interventions and disease-modifying therapies.

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Pinpointing the brain dysconnectivity in idiopathic rapid eye movement sleep behaviour disorder (iRBD) can facilitate preventing the conversion of Parkinson's disease (PD) from prodromal phase. Recent neuroimage investigations reported disruptive brain white matter connectivity in both iRBD and PD, respectively. However, the intrinsic process of the human brain structural network evolving from iRBD to PD still remains largely unknown. To address this issue, 151 participants including iRBD, PD and age-matched normal controls were recruited to receive diffusion MRI scans and neuropsychological examinations. The connectome-wide association analysis was performed to detect reorganization of brain structural network along with PD progression. Eight brain seed regions in both cortical and subcortical areas demonstrated significant structural pattern changes along with the progression of PD. Applying machine learning on the key connectivity related to these seed regions demonstrated better classification accuracy compared to conventional network-based statistic. Our study shows that connectome-wide association analysis reveals the underlying structural connectivity patterns related to the progression of PD, and provide a promising distinct capability to predict prodromal PD patients.

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INTRODUCTION: Retinal impairment has previously been described in Parkinson's Disease (PD), also in early stage of disease. Idiopathic Rapid-eye-movement sleep Behavior Disorder (iRBD) is considered the strongest marker in the diagnosis of "Prodromal PD". Thus, we evaluated the thickness of retinal layers and the microvascular retinal pattern in a group of iRBD patients compared to PD and healthy subjects (HCs). METHODS: retinal layer's thickness and microvascular pattern among PD, iRBD and HCs were assessed using Spectral-Density Optical Coherence Tomography (SD-OCT) and OCT-Angiography (OCT-A), respectively. RESULTS: Forty-one eyes from 21 PD, 37 eyes from 19 iRBD and 33 eyes from 17 HCs were analysed. Peripapillary Retinal Nerve Fiber Layer (RNFL) was thinner in PD and RBD compared to HCs. All macular retinal layers, except for retinal pigment epithelium, resulted to be significantly thinner in iRBD and in PD compared to HCs, also adjusting by age, sex and hypertension. Macular RNFL and ganglionic cell layer were thinner in PD compared to iRBD. Moreover, in iRBD, a peculiar microvascular pattern was found, characterized by a higher vascularization of the deep capillary plexus with respect both PD patients and HCs. CONCLUSION: in PD and iRBD patients retina was thinner than HCs, and values of iRBD were between PD and HCs. Moreover, in iRBD, a peculiar microvascular pattern has been found, characterized by a higher vascularization of the deep capillary plexus. Our findings suggest that retina might be considered a biomarker of neurodegeneration in iRBD, easily estimable using non-invasive tool such as OCT and OCT-A.

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Patients with idiopathic rapid-eye-movement (REM) sleep behaviour disorder (iRBD) have a high risk of converting into manifest α-synucleinopathies. Eye movements (EMs) are controlled by neurons in the lower brainstem, midbrain and frontal areas, and may be affected by the early neurodegenerative process seen in iRBD. Studies have reported impairment of the oculomotor function in patients with Parkinson's disease (PD) during wakefulness, but no studies have investigated EMs during sleep. We aimed to evaluate nocturnal EMs in iRBD and PD, hypothesizing that these patients present abnormal EM distribution during sleep. Twenty-eight patients with periodic limb movement disorder (PLMD), 24 iRBD, 23 PD without RBD (PDwoRBD), 29 PD and RBD (PDwRBD) and 24 controls were included. A validated EM detector automatically identified EM periods between lights off and on. The EM coverage was computed as the percentage of time containing EMs during stable wake after lights off, N1, N2, N3 and REM sleep. Between-group comparisons revealed that PDwRBD had significantly less EM coverage during wake and significantly higher EM coverage during N2 compared to controls and PLMD patients. PDwoRBD showed significantly less EM coverage during wake compared to controls and higher EM coverage during N2 compared to controls and PLMD. Finally, iRBD showed less coverage of EM during wake compared to controls. The same trend was observed between iRBD and controls in N2 but was not significant. The different profiles of EM coverage in iRBD and PD with/without RBD may mirror different stages of central nervous system involvement across neurodegenerative disease progression.

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Idiopathic rapid eye movement sleep behaviour disorder (RBD) is now recognized as an early manifestation of α-synucleinopathies. Increasing experimental studies demonstrate that manipulative lesion or inactivation of the neurons within the sublaterodorsal tegmental nucleus (also known as the subcoeruleus nucleus in humans) can induce RBD-like behaviours in animals. As current RBD animal models are not established on the basis of α-synucleinopathy, they do not represent the pathological substrate of idiopathic RBD and thus cannot model the phenoconversion to Parkinson's disease. The purpose of this study was therefore to establish an α-synucleinopathy-based RBD animal model with the potential to convert to parkinsonian disorder. To this end, we first determined the functional neuroanatomical location of the sublaterodorsal tegmental nucleus in wild-type C57BL/6J mice and then validated its function by recapitulating RBD-like behaviours based on this determined nucleus. Next, we injected preformed α-synuclein fibrils into the sublaterodorsal tegmental nucleus and performed regular polysomnographic recordings and parkinsonian behavioural and histopathological studies in these mice. As a result, we recapitulated RBD-like behaviours in the mice and further showed that the α-synucleinopathy and neuron degeneration identified within the sublaterodorsal tegmental nucleus acted as the neuropathological substrates. Subsequent parkinsonian behavioural studies indicated that the α-synucleinopathy-based RBD mouse model were not stationary, but could further progress to display parkinsonian locomotor dysfunction, depression-like disorder, olfactory dysfunction and gastrointestinal dysmotility. Corresponding to that, we determined α-synuclein pathology in the substantia nigra pars compacta, olfactory bulb, enteral neuroplexus and dorsal motor nucleus of vagus nerve, which could underlie the parkinsonian manifestations in mice. In conclusion, we established a novel α-synucleinopathy-based RBD mouse model and further demonstrated the phenoconversion of RBD to Parkinson's disease in this animal model.

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This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson's disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson's disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson's disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson's disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra's morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson's disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification.

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BACKGROUND: Idiopathic rapid eye movement sleep behaviour (iRBD) is considered as a risk factor for Parkinson's disease (PD) development. Evaluation of repetitive movements with finger tapping, which serves as a principal task to measure the extent of bradykinesia in PD, may undercover potential PD patients. The aim of this study was to explore whether finger tapping abnormalities, evaluated with a 3D motion capture system, are already present in RBD patients. METHODS: Finger tapping data was acquired using a contactless 3D motion capture system from 40 RBD subjects and compared to 25 de-novo PD patients and 25 healthy controls. Objective assessment of amplitude decrement, maximum opening velocity and their combination representing finger tapping decrement was performed in the sequence of the first ten tapping movements. The association between instrumental finger tapping data and semi-quantitative clinical evaluation was analyzed. RESULTS: While significant differences between PD and controls were found for all investigated finger tapping measures (p < 0.002), RBD differed from controls in finger tapping amplitude (p = 0.004) and velocity (p = 0.007) decrement but not in maximal opening velocity. A significant relationship between the motor score from the Movement Disorders Society - Unified Parkinson's Disease Rating Scale and finger tapping decrement was shown for both patient groups, ie RBD (r = 0.36, p = 0.02) and PD (r = 0.60, p = 0.002). CONCLUSIONS: In our group of RBD patients we demonstrated amplitude decrement of repetitive movements, which may correspond with prodromal bradykinesia. Our findings suggest instrumental analysis of finger tapping abnormalities as a potential novel clinical marker reflecting subclinical motor disturbances in RBD.

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AIM: Rapid eye movement sleep behaviour disorder (RBD) is characterized by abnormal behaviours accordant with nightmares during rapid eye movement sleep and is considered a prodromal marker of dementia with Lewy body. Most common in the elderly population, RBD is generally treated with clonazepam (CZP), a long-term acting benzodiazepine antiepileptic. As such, alternative drugs for RBD are urgently needed to minimize the adverse effects peculiar to benzodiazepines. The efficacy of yokukansan (YKS), a traditional Japanese herbal medicine, on RBD was initially reported by Shinno et al. in 2008. However, no study has compared YKS with CZP. Therefore, this study aimed to clarify the possibility of using YKS as an alternative to CZP. METHODS: This was a retrospective cohort study conducted at Jikei University Affiliated Hospital. The subjects were selected from 36 outpatients who had been diagnosed with RBD based on the International Classification of Sleep Disorders, third edition. Of the 23 who met the inclusion criteria but not the exclusion criteria, 11 were treated with YKS monotherapy, and 12 were treated with CZP monotherapy. The primary outcome was the total score on the Japanese version of the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (RBDQ-JP), and the secondary outcomes were the scores from the eight-item Short-Form Health Survey and factors 1 and 2 of the RBDQ-JP. RESULTS: The mean total RBDQ-JP score significantly improved from 52.5 to 21.7 (P = 0.002) after treatment with YKS (mean dosage: 3.0 g/day), which was similar to the change after CZP treatment (from 43.8 to 21.3). On RBDQ-JP factor 1 (dream content), the mean score on five of six items significantly improved after treatment with YKS. There was no significant change in Short-Form Health Survey scores after treatment with either drug. Potassium concentrations were within the normal range in patients treated with YKS. CONCLUSIONS: The present results suggest that a small amount of YKS may be an alternative to CZP for RBD, without remarkable adverse events. Further study is needed to prospectively clarify the efficacy and safety of YKS in more detail.

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