The Motor Dysfunction Seen in Isolated REM Sleep Behavior Disorder.

BACKGROUND: Isolated Rapid Eye Movement (REM) sleep Behavior Disorder (iRBD) requires quantitative tools to detect incipient Parkinson's disease (PD). METHODS: A motor battery was designed and compared with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) in people with iRBD and controls. This included two keyboard-based tests (BRadykinesia Akinesia INcoordination tap test and Distal Finger Tapping) and two dual tasking tests (walking and finger tapping). RESULTS: We included 33 iRBD patients and 29 controls. The iRBD group performed both keyboard-based tapping tests more slowly (P < 0.001, P = 0.020) and less rhythmically (P < 0.001, P = 0.006) than controls. Unlike controls, the iRBD group increased their walking duration (P < 0.001) and had a smaller amplitude (P = 0.001) and slower (P = 0.007) finger tapping with dual task. The combination of the most salient motor markers showed 90.3% sensitivity for 89.3% specificity (area under the ROC curve [AUC], 0.94), which was higher than the MDS-UPDRS-III (minus action tremor) (69.7% sensitivity, 72.4% specificity; AUC, 0.81) for detecting motor dysfunction. CONCLUSION: Speed, rhythm, and dual task motor deterioration might be accurate indicators of incipient PD in iRBD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reading the mind in the eyes in patients with idiopathic REM sleep behavior disorder.

OBJECTIVES: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by vocalizations, jerks, and motor behaviors during REM sleep, often associated with REM-related dream content, which is considered a prodromal stage of α-synucleinopathy. The results of the Reading the Mind in the Eyes (RME) reflecting affective Theory of Mind (ToM) are inconsistent in α-synucleinopathy. The present study tried to investigate the RME in patients with iRBD. METHODS: A total of 35 patients with iRBD and 26 healthy controls were included in the study. All participants were administered the RME and the cognitive assessments according to a standard procedure. The patients with iRBD were further divided into two groups (high or low RME) according to the scores of the RME (> 21, or ≤ 20). RESULTS: The patients with iRBD had worse scores on cognitive tests compared with healthy controls involving global cognitive screening, memory, and visuospatial abilities (p < 0.05), but the scores of the RME were similar between the two groups (20.83 ± 3.38, 20.58 ± 3.43) (p ˃ 0.05). Patients with low RME had more obvious cognitive impairments than healthy controls. After applying Bonferroni correction for multiple tests, the low REM group only performed worse on the Sum of trials 1 to 5 and delayed recall of the RAVLT compared with the healthy control group (p < 0.001, = 0.002). The RME correlated with the scores of cognitive tests involving executive function, attention, memory, and visuospatial function. CONCLUSIONS: The changes in RME had a relationship with cognitive impairments, especially memory, in patients with iRBD.

Predictors of the Rapid Progression in Prodromal Parkinson's Disease: A Longitudinal Follow-Up Study.

INTRODUCTION: Parkinson's disease (PD) is characterized by a prodromal phase preceding the onset of classic motor symptoms. The duration and clinical manifestations of prodromal PD vary widely, indicating underlying heterogeneity within this stage. This discrepancy prompts the question of whether specific factors contribute to the divergent rates of progression in prodromal PD. METHODS: This study included prodromal PD patients from the Parkinson's progression marker initiative. They were followed up to assess the disease progression. The data collected during the follow-up period were analyzed to identify potential predictors of rapid disease progression in prodromal PD. RESULTS: In this study, 61 individuals with prodromal PD were enrolled. Among them, 43 patients presented with both RBD and hyposmia, 17 had hyposmia alone, and 1 had RBD alone at baseline. 13 (21.3%) prodromal PD participants exhibited rapid disease progression, with two of these cases advancing to non-neurological diseases. Significant differences were observed between the rapid progression group and no rapid progression group in terms of MDS-UPDRS II score and UPSIT score. Longitudinal analysis showed a significant increase in the MDS-UPDRS III score and MDS-UPDRS total score in the rapid progression group. Regression analyses identified the MDS-UPDRS II score and UPSIT score as predictors of rapid disease progression in prodromal PD. CONCLUSION: Our study findings suggest that the MDS-UPDRS II score and UPSIT score may serve as clinical markers associated with rapid disease progression. Further research and development of precise biomarkers and advanced assessment methods are needed to enhance our understanding of prodromal PD and its progression patterns.

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Timeline of Rapid Eye Movement Sleep Behavior Disorder in Overt Alpha-Synucleinopathies.

OBJECTIVE: The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age- and sex-matched controls in a population-based incident-cohort study. METHODS: We used a population-based, 1991 to 2010 incident-cohort study of alpha-synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined. RESULTS: Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0-217.2, p < 0.0001), higher in dementia with Lewy bodies than in Parkinson disease (OR = 2.57, 95% CI: 1.50-4.40, p = 0.0004), and higher in men than in women with Parkinson disease, dementia with Lewy bodies, or Parkinson disease dementia (OR = 3.70, 95% CI: 2.07-6.62, p < 0.0001), but did not increase mortality risk. INTERPRETATION: Our cohort had RBD incidence of 3.4%. Overall RBD increased to 23.8% after 15 years, with an overall incidence of 2.5 cases per 100 person-years. With 53 times greater lifetime incidence in alpha-synucleinopathy patients than in controls, RBD was more likely to develop in dementia with Lewy bodies than in Parkinson disease or Parkinson disease dementia, and in men than in women, but did not increase mortality risk within our cohort. ANN NEUROL 2021;89:293-303.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies.

OBJECTIVE: The TMEM175/GAK/DGKQ locus is the 3rd strongest risk locus in genome-wide association studies of Parkinson disease (PD). We aimed to identify the specific disease-associated variants in this locus, and their potential implications. METHODS: Full sequencing of TMEM175/GAK/DGKQ followed by genotyping of specific associated variants was performed in PD (n = 1,575) and rapid eye movement sleep behavior disorder (RBD) patients (n = 533) and in controls (n = 1,583). Adjusted regression models and a meta-analysis were performed. Association between variants and glucocerebrosidase (GCase) activity was analyzed in 715 individuals with available data. Homology modeling, molecular dynamics simulations, and lysosomal localization experiments were performed on TMEM175 variants to determine their potential effects on structure and function. RESULTS: Two coding variants, TMEM175 p.M393T (odds ratio [OR] = 1.37, p = 0.0003) and p.Q65P (OR = 0.72, p = 0.005), were associated with PD, and p.M393T was also associated with RBD (OR = 1.59, p = 0.001). TMEM175 p.M393T was associated with reduced GCase activity. Homology modeling and normal mode analysis demonstrated that TMEM175 p.M393T creates a polar side-chain in the hydrophobic core of the transmembrane, which could destabilize the domain and thus impair either its assembly, maturation, or trafficking. Molecular dynamics simulations demonstrated that the p.Q65P variant may increase stability and ion conductance of the transmembrane protein, and lysosomal localization was not affected by these variants. INTERPRETATION: Coding variants in TMEM175 are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting GCase activity. ANN NEUROL 2020;87:139-153.

Sleep-wake cycle dysregulation in idiopathic REM sleep behaviour disorder.

Alteration of the circadian sleep-wake rhythm has been suggested in patients affected by idiopathic rapid eye movement sleep behaviour disorder. Because actigraphy is the validated instrument to monitor the sleep-wake cycle, the aim of the present study was to investigate the circadian sleep-wake rhythm in patients with idiopathic rapid eye movement sleep behaviour disorder compared with healthy aged controls. Fourteen-day actigraphic recording, a comprehensive sleep interview, and cognitive and behavioural domains were investigated in patients affected by idiopathic rapid eye movement sleep behaviour disorder, and compared with controls similar for age, sex and cognitive performances. Patients with idiopathic rapid eye movement sleep behaviour disorder showed reduced relative amplitude and alteration of both sleep and wake compared with controls. Patients with idiopathic rapid eye movement sleep behaviour disorder also showed subjective sleep and wake complaints, and higher scores at the Beck Depression Inventory, compared with controls. Beck Depression Inventory scores correlated with sleep actigraphic parameters, such as sleep latency, sleep efficiency, time in bed, and relative amplitude. Therefore, the present study showed the dysregulation of the sleep-wake cycle in patients with idiopathic rapid eye movement behaviour disorder. Moreover, depressive symptoms documented in patients with idiopathic rapid eye movement sleep behaviour disorder correlated with the sleep-wake rhythm dysregulation.

REM sleep behaviour disorder in essential tremor: A polysomnographic study.

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.

Altered structure and functional connectivity of the central autonomic network in idiopathic rapid eye movement sleep behaviour disorder.

Evidence suggests peripheral autonomic structures may contribute to autonomic dysfunction in idiopathic rapid eye movement sleep behaviour disorder (iRBD). However, whether the central autonomic network (CAN) is affected in iRBD remains unclear. Magnetic resonance imaging data were acquired from 65 participants (32 patients with iRBD and 33 matched healthy controls). We investigated the CAN in patients with iRBD using a combined voxel-based morphometry and resting-state functional connectivity analysis and characterised the relationships between alterations of the CAN and autonomic symptoms. Patients with iRBD had significantly reduced grey matter volume in the brainstem, anterior cingulate and insula compared with healthy controls. Functional connectivity analysis revealed reduced functional connectivity between the brainstem and the cerebellum posterior lobe, temporal lobe and anterior cingulate in patients with iRBD. In patients with iRBD, both reduced grey matter volume and decreased functional connectivity of the CAN were negatively correlated with the Scales for Outcomes in Parkinson's Disease-Autonomic scores. The present study demonstrated that both the structure and the functional connectivity of the CAN were abnormal in patients with iRBD. In addition, correlation analysis suggested that CAN abnormalities may also play a role in the development of autonomic symptoms in iRBD.

Prevalence and predictors of mood disturbances in idiopathic REM sleep behaviour disorder.

Depression and anxiety are commonly associated with synucleinopathies. Mood disturbances have also been reported in patients with idiopathic REM sleep behaviour disorder (iRBD) and are difficult to treat due to exacerbation of sleep symptoms with standard antidepressants. Despite this, detailed prevalence studies of mood symptomatology and contributors to mood disturbances in iRBD are limited. Mood, sleep, autonomic, cognitive and motor symptoms were assessed in 49 well-characterized patients with iRBD using a variety of clinical scales. Spearman correlations, factor analysis and multiple linear regression were used to uncover associations between mood and non-motor and motor symptoms. The prevalence of significant depression was 17.0% and that of anxiety was 14.6% in the iRBD cohort. Age and disease duration were not correlated with these affective symptoms in iRBD patients. We found depression was significantly predicted by the presence and severity of motor, sleep and cognitive symptoms. Anxiety was predicted by the severity of nocturnal and daytime sleep-related symptoms, cognitive symptoms and autonomic symptoms, with a differential effect depending on the questionnaire used. Depression and anxiety are common in iRBD patients and can be significantly explained by specific sets of non-motor and motor symptoms. These associations provide insight into the underlying pathophysiology and emphasize the importance of a holistic approach to mood disturbance in this population, which may circumvent the reliance on pharmacotherapy that can exacerbate dream enactment behaviour.

Nocturnal eye movements in patients with idiopathic rapid eye movement sleep behaviour disorder and patients with Parkinson's disease.

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.

α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson's disease model.

Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.

Cognitive fluctuations in Lewy body dementia: towards a pathophysiological framework.

Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson's disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.

Retina thickness as a marker of neurodegeneration in prodromal lewy body disease.

OBJECTIVES: We investigated retinal change and its relationship with neurodegeneration markers in a prodromal Parkinson cohort. METHODS: A total of 30 patients with idiopathic rapid eye movement sleep behavior disorder were recruited. Participants underwent olfactory testing, macular optical coherence tomography, microperimetry, contrast sensitivity test, and brain N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography. We measured the ganglion cell complex thicknesses and investigated its correlation with olfactory function and striatal dopamine transporter availability. A linear mixed-effect model was applied with adjustment for multiple comparisons. RESULTS: The parafoveal ganglion-cell-complex thickness in this cohort lay between our healthy control and drug-naïve Parkinson's disease group data. Idiopathic rapid eye movement sleep behavior disorder patients also had contrast sensitivity impairment as in Parkinson's disease with a nonsignificant change in macular sensitivities. Macular ganglion cell complex thickness correlated with olfactory scores and with striatal dopamine transporter availabilities. CONCLUSIONS: Macular ganglion cell complex thinning may be a marker of neurodegeneration in prodromal Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

REM Sleep Behavior Disorder in Parkinson's Disease: Effects on Cognitive, Psychiatric, and Functional outcomes.

OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) affects 33-46% of patients with Parkinson's disease (PD) and may be a risk factor for neuropsychological and functional deficits. However, the role of RBD on neuropsychological functioning in PD has yet to be fully determined. We, therefore, examined differences in neurocognitive performance, functional capacity, and psychiatric symptoms among nondemented PD patients with probable RBD (PD/pRBD+) and without (PD/pRBD-), and healthy comparison participants (HC). METHODS: Totally, 172 participants (58 PD/pRBD+; 65 PD/pRBD-; 49 HC) completed an RBD sleep questionnaire, psychiatric/clinical questionnaires, performance-based and self-reported functional capacity measures, and underwent a comprehensive neuropsychological battery assessing attention/working memory, language, visuospatial function, verbal and visual learning and memory, and executive function. RESULTS: Controlling for psychiatric symptom severity, the PD/pRBD+ group had poorer executive functioning and learning performance than the PD/pRBD- group and poorer neuropsychological functioning across all individual cognitive domains than the HCs. In contrast, PD/pRBD- patients had significantly lower scores than HCs only in the language domain. Moreover, PD/pRBD+ patients demonstrated significantly poorer medication management skills compared to HCs. Both PD groups reported greater depressive and anxiety severity compared to HCs; PD/pRBD+ group also endorsed greater severity of apathy compared to HCs. CONCLUSIONS: The presence of pRBD is associated with poorer neuropsychological functioning in PD such that PD patients with pRBD have poorer cognitive, functional, and emotional outcomes compared to HC participants and/or PD patients without pRBD. Our findings underscore the importance of RBD assessment for improved detection and treatment of neuropsychological deficits (e.g., targeted cognitive interventions).

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

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.

Cortical hypoperfusion in patients with idiopathic rapid eye movement sleep behavior disorder detected with arterial spin-labeled perfusion MRI.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is an important risk factor for α-synucleinopathy. OBJECTIVE: We investigated alterations in the cerebral blood flow (CBF) based on arterial spin-labeled (ASL) imaging in patients with iRBD to determine brain perfusion changes associated with the disorder. METHODS: Fifteen patients with iRBD and twenty age-gender-matched healthy controls were enrolled. Cortical perfusions were compared between the two groups after the ASL data was co-registered to the high-resolution T1-weighted images. RESULTS: No significant differences were detected between the groups in regard to age, gender, education, or UPDRS-III score. The iRBD group showed a lower MMSE score than the healthy controls (27.07 ± 2.25 vs. 28.55 ± 1.23, p < 0.05). Compared with the healthy controls, the iRBD group showed significantly decreased CBF values in the right inferior frontal gyrus, right middle frontal gyrus, and right insula (p < 0.05 corrected). CONCLUSION: The cortical hypoperfusion areas in patients with iRBD were similar to the patterns in patients with α -synucleinopathies. ASL perfusion MRI is a potential approach to find biomarkers in preclinical stages of α -synucleinopathies.

Abnormal things happening during sleep: parasomnias.

Parasomnias are characterized by abnormal experiences, dreams, movements and behavior during sleep. They may occur in the middle of the sleep during REM (rapid eye movement) or NREM (non-rapid eye movement), during falling asleep or waking up. Characteristically for REM behavior disorder is an increased muscle tone although usually REM is defined by an absence of muscle tone. For these forms aggressive dreams may lead to violating bed partners or self-injury of the sleeping person. Even killing bed partners has been described. Many of the patients develop a kind of Parkinson's disease (synucleinopathies). The rate of phenoconversion is more than 30% in 5 years and nearly 100% after 15 years. There are several recommendations regarding a safe sleeping environment. Medicinal treatment consists of either melatonin or clonazepam.

Vulnerability of multiple large-scale brain networks in dementia with Lewy bodies.

Aberrations of large-scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed-based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large-scale resting-state networks' integrity and their interactions. We found both local and long-distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network-level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network-level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.