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Background: The association between obstructive sleep apnea and cognitive functioning is not yet fully understood and could be influenced by factors such as sex, age and systemic inflammation. We determined the sex- and age-specific association between obstructive sleep apnea risk and cognitive performance, and the influence of systemic inflammation on this association., Methods: We included 25,899 participants from the Canadian Longitudinal Study of Aging comprehensive cohort, aged 45-85 years (51% women). We conducted sex- and age-specific (45-59; 60-69; ≥70) general linear models between obstructive sleep apnea risk and cognitive scores, and tested the moderating and mediating effects of high-sensitivity C-reactive protein levels. Obstructive sleep apnea risk was estimated by combining the STOP and whole-body fat percentage. Cognitive tests assessed episodic verbal memory, executive functions and psychomotor speed. Levels of high-sensitivity C-reactive protein were obtained through blood samples., Results: Higher obstructive sleep apnea risk was associated with poorer episodic memory in women aged 45-59 years, and poorer executive function (p < 0.05 on multiple tests) in women aged 45-59 and 60-69 years. No such association was found in men. High-sensitivity C-reactive protein levels mediated some associations between obstructive sleep apnea risk and executive function in women and men aged <70 years., Conclusions: Being at high-risk for obstructive sleep apnea is associated with poorer cognition in women aged <70 years. These associations were partly mediated by systemic inflammation. These results underscore the importance of obstructive sleep apnea diagnosis, treatment and appropriate follow-up, particularly in middle-aged women who might already show signs of early cognitive impairments., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Though visual illusions and hallucinations are common in dementia with Lewy bodies (DLB) and Parkinson's disease (PD), they are not typically observed clinically in prodromal stages, including isolated REM sleep behavior disorder (iRBD). False-noise errors on the pareidolia test (seeing faces when none are present) may be an effective measure of susceptibility to future hallucinations in iRBD., Methods: One hundred patients with iRBD underwent the 20-image pareidolia test. Clinical markers were assessed and a neuropsychological battery was administered. An exploratory analysis on the impact of pareidolic errors on phenoconversion was also performed., Results: In our cohort, 17 patients (17%) made false-noise pareidolic errors. These patients had significantly lower total Montreal Cognitive Assesment (MoCA) scores (26.7 ± 2.3 vs. 24.4 ± 2.6, B = -1.88, 95% CI: [-3.17, -0.59]), with lower subcomponent MoCA scores on memory and visuospatial-executive sections. Pareidolic errors were also associated with lower visuospatial, attention/executive, and memory scores on the neuropsychological tests. Furthermore, after 1.6 years follow-up, 3/16 (19%) patients making pareidolic errors had phenoconverted at time of publication compared to 6/71 (8%) patients who did not make errors., Conclusion: Pareidolic errors in patients with iRBD are associated with poorer overall cognition and may indicate higher risk of DLB., Competing Interests: Declaration of competing interest The authors have no financial disclosures in relationship to this manuscript., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Mutations in the glucocerebrosidase (GBA) gene are strongly associated with REM sleep behavior disorder (RBD). It is unclear whether GBA mutations might affect clinical phenotype or rate of phenoconversion to parkinsonism or dementia., Methods: We sequenced GBA in polysomnographic-proven idiopathic RBD (iRBD) patients. The effect of GBA mutations on clinical neurodegenerative markers and phenoconversion rate was assessed., Results: Of 102 patients sequenced, 13 (13%) had GBA mutations and 89 did not. Aside from lower self-reported age of RBD onset in subjects with GBA mutations, no significant differences were observed in any clinical marker between patients with and without mutations. However, GBA mutations were associated with 3.2-fold higher phenoconversion rate from RBD to parkinsonism and/or dementia (95% CI = 1.4-7.3, p = 0.006)., Conclusion: Although GBA mutations do not appear to affect clinical neurodegenerative markers (and thus are not differentiable as an independent subtype of iRBD), they may accelerate the conversion of RBD to defined neurodegenerative synucleinopathy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: REM sleep behaviour disorder (RBD) occurs frequently in patients with synucleinopathies such as Parkinson's disease, dementia with Lewy body, or multiple system atrophy, but may also occur as a prodromal stage of those diseases; and is termed idiopathic RBD (iRBD) when not accompanied by other symptoms. Cholinergic degeneration of the mesopontine nuclei have been described in synucleinopathies with or without RBD, but this has not yet been explored in iRBD. We sought to assess cholinergic neuronal integrity in iRBD using PET neuroimaging with the 18 F-fluoroethoxybenzovesamicol (FEOBV)., Methods: The sample included 10 participants evenly divided between healthy subjects and patients with iRBD. Polysomnography and PET imaging with FEOBV were performed in all participants. Standardized uptake value ratios (SUVRs) were compared between the two groups using voxel wise t-tests. Non-parametric correlations were also computed in patients with iRBD between FEOBV uptake and muscle tonic and phasic activity during REM sleep., Results: Compared with healthy participants, significantly higher FEOBV uptakes were observed in patients with iRBD. The largest differences were observed in specific brainstem areas corresponding to the bulbar reticular formation, pontine coeruleus/subcoeruleus complex, tegmental periacqueductal grey, and mesopontine cholinergic nuclei. FEOBV uptake in iRBD was also higher than in controls in the ventromedial area of the thalamus, deep cerebellar nuclei, and some cortical territories (including the paracentral lobule, anterior cingulate, and orbitofrontal cortex). Significant correlation was found between muscle activity during REM sleep, and SUVR increases in both the mesopontine area and paracentral cortex., Conclusion: We showed here for the first time the brain cholinergic alterations in patients with iRBD. As opposed to the cholinergic depletion described previously in RBD associated with clinical Parkinson's disease, increased cholinergic innervation was found in multiple areas in iRBD. The most significant changes were observed in brainstem areas containing structures involved in the promotion of REM sleep and muscle atonia. This suggests that iRBD might be a clinical condition in which compensatory cholinergic upregulation in those areas occurs in association with the initial phases of a neurodegenerative process leading to a clinically observable synucleinopathy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Depressive and anxiety symptoms are frequent features of PD, DLB and iRBD, and some studies suggest that depressive symptoms are a marker for neurodegeneration in iRBD. However, the pathophysiology of depressive and anxiety symptoms in iRBD is still unclear. This study aimed to investigate cortical and subcortical gray matter (GM) volume substrates of depressive and anxiety symptoms in iRBD patients., Methods: Forty-six polysomnography-confirmed iRBD patients and 31 healthy controls (HC) without cognitive or mood impairment were recruited. All participants underwent 3-T magnetic resonance imaging and completed the Beck Depression Inventory Second Edition (BDI-II) and Beck Anxiety Inventory (BAI) questionnaires. Voxel-based morphometry analysis was performed to assess GM volume in cortical and subcortical structures. Between-group comparisons and regressions were performed., Results: iRBD patients with depressive symptoms (BDI-II score > 13 or the use of antidepressants to treat depression) showed reduced GM volume in the caudate nucleus compared to HC and iRBD patients without depressive symptoms. Moreover, iRBD patients with anxiety symptoms (BAI score > 9 or the use of anxiolytics to treat anxiety) showed reduced GM volume in the left amygdala extending to the hippocampus compared to HC and iRBD patients without anxiety symptoms. In iRBD patients, higher BDI-II and BAI total scores were associated with lower GM volumes in these regions respectively., Conclusion: Depressive and anxiety symptoms in iRBD patients are related to patterns of cortical and subcortical GM volume loss., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Studies estimate that >80% of patients with idiopathic REM sleep behavior disorder (iRBD) eventually develop parkinsonism or dementia. However, a small group remains disease-free for long periods, raising the question of whether they truly have prodromal disease., Methods: We selected subjects with iRBD who were diagnosed at least 10 years previously, and were still disease free (longstanding iRBD) (n = 11). We compared them to 'early converters' (n = 27) defined as those who phenoconverted to parkinsonism or dementia within 4 years after diagnosis, and to age- and sex-matched healthy controls (n = 68). We compared the frequency and progression of numerous markers of prodromal synucleinopathy between groups, and assessed likelihood of meeting prodromal Parkinson's disease criteria., Results: After at least 10 years follow-up, almost all longstanding iRBD subjects showed multiple features of neurodegeneration, and 9/11 met criteria for prodromal PD. Evolution of markers was slower than early-converters, with an annual increase in prodromal PD probability of 3.9 ± 3.2% in longstanding iRBD compared to 12.4 ± 7.8% for early-convertors (p-value = 0.002). However, subjects with longstanding iRBD at their last visit had similar prodromal measures as the baseline evaluation of the early-convertors, with similarly-abnormal UPDRS scores, quantitative motor tests, cognition and autonomic symptoms and signs., Conclusion: Although phenoconversion rates can differ dramatically between patients, almost all individuals with iRBD in our cohort appear to have underlying neurodegeneration., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Individuals with rapid eye movement (REM)-sleep behavior disorder (RBD) are likely to progress to synucleinopathies, mainly Parkinson's disease (PD), dementia with Lewy-bodies (DLB) and multiple system atrophy (MSA). The genetics of RBD only partially overlaps with PD and DLB, and the role of LRRK2 variants in risk for RBD is still not clear., Methods: The full coding sequence, exon-intron boundaries and 5' and 3' untranslated regions of LRRK2 were sequenced using targeted next-generation sequencing. A total of 350 RBD patients and 869 controls were sequenced, and regression and burden models were used to examine the association between LRRK2 variants and RBD., Results: No pathogenic mutations that are known to cause PD were identified in RBD patients. The p.N551K-p.R1398H-p.K1423K haplotype was associated with a reduced risk for RBD (OR = 0.66, 95% CI 0.44-0.98, p = 0.0055 for the tagging p.N551K substitution). A common variant, p.S1647T, was nominally associated with risk for RBD (OR = 1.28, 95% CI 1.05-1.56, p = 0.029). Burden analysis identified associations with domains and exons that were derived by the variants of the protective haplotype, and no burden of other rare variants was identified., Conclusions: Carriers of the LRRK2 p.N551K-p.R1398H-p.K1423K haplotype have a reduced risk for developing RBD, yet PD-causing mutations probably have minor or no role in RBD. Additional work is needed to confirm these results and to identify the mechanism associated with reduced risk for RBD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Prodromal markers of Alzheimer's disease (AD) have been derived from wakefulness. However, brain perfusion during rapid-eye movement (REM) sleep could be a sensitive marker of amnestic mild cognitive impairment (aMCI), as activation of REM sleep relies more on the cholinergic system., Methods: Eight subjects with aMCI, and 16 controls, underwent two single-photon emission computed tomography (SPECT) scans with tracer injected during REM sleep then wakefulness., Results: Perfusion in the anterior cingulate cortex was significantly decreased in aMCI cases compared to controls for both conditions. That defect was much larger and more severe in REM sleep (1795 voxels) compared to wakefulness (398 voxels), and extended to the middle cingulate cortex and the olfactory cortex. Hypoperfusion in the anterior cingulate cortex during REM sleep allowed better classification than hypoperfusion found in wakefulness (93.8 vs 81.3%)., Conclusion: REM sleep imaging is a valuable tool with which to identify individuals at risk of developing AD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective/background: Neuroprotective therapy for Parkinson's disease (PD) is most likely to be effective if provided in its prodromal stages. However, identifying prodromal PD is difficult because PD is relatively uncommon, and most markers are nonspecific. Rapid eye movement (REM) sleep behavior disorder (RBD) is by far the strongest clinical marker of prodromal PD, but most patients do not seek out medical attention. Developing an efficient way of diagnosing RBD from the general community may be the most practical method to detect prodromal PD., Methods: We developed a screening strategy that began with a newspaper advertisement containing a single-question screen for RBD. All screen-positive subjects underwent an interview based on the Innsbruck RBD inventory aimed to optimize the positive predictive value. Those who passed both screens underwent confirmatory polysomnography. The proportion of screened RBD patients who met the International Parkinson and Movement Disorder Society (MDS) criteria for prodromal PD was assessed. A broad array of clinical markers of neurodegeneration was compared between newspaper-screened RBD patients and 130 RBD patients clinically referred to the sleep center., Results: Of 111 RBD-screen-positive participants, 40 (36%) passed the secondary screen, and 29 underwent full polysomnography. Of these 29 patients, 19 were ultimately proven to have RBD (PPV = 66%), 12 (63%) of whom met the criteria for prodromal PD. Compared to patients referred to the sleep center, newspaper-screened patients had similar age, sex, olfaction, autonomic function, and color vision. However, motor and cognitive assessments were slightly better in newspaper-screened patients., Conclusions: A multistep screening approach using RBD screening questionnaires and telephone follow-up can efficiently identify prodromal PD in the general community., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To compare two different methods, one visual and the other automatic, for the quantification of rapid eye movement (REM) sleep without atonia (RSWA) in the diagnosis of REM sleep behavior disorder (RBD)., Methods: Seventy-four RBD patients (mean age, 62.14±9.67 years) and 75 normal controls (mean age, 61.04±12.13 years) underwent one night video-polysomnographic recording. The chin electromyogram (EMG) during REM sleep was analyzed by means of a previously published visual method quantifying the percentage of 30s epochs scored as tonic (abnormal, > or =30%) and that of 2s mini-epochs containing phasic EMG events (abnormal, > or =15%). For the computer quantitative analysis we used the automatic scoring algorithm known as the atonia index (abnormal, <0.8). The percentage correct classification, sensitivity, specificity, and Cohen kappa were calculated., Results: The atonia index correctly classified 82.6% of subjects, similar to the percentage of correct classifications with individual components of the visual analysis (83.2% each for tonic and phasic), and the combined visual parameters (85.9%). The sensitivity and specificity of automatic analysis (84% and 81%) was similar to the combined visual analysis (89% and 83%). The correlation coefficient between the automatic atonia index and the percentage of visual tonic EMG was high (r = -0.886, P<0.00001), with moderately high correlation with the percentage of phasic EMG (r = -0.690, P<0.00001). The agreement between atonia index and the visual parameters (individual or combined) was approximately 85% with Cohen's kappa, ranging from 0.638 to 0.693., Conclusion: Sensitivity, specificity, and correct classifications were high with both methods. Moreover, there was general agreement between methods, with Cohen's kappa values in the 'good' range. Given the considerable practical advantages of automatic quantification of REM atonia, automatic quantification may be a useful alternative to visual scoring methods in otherwise uncomplicated polysomnograms., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a well-documented risk factor for synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB). Moreover, approximately 50% of iRBD patients have mild cognitive impairment (MCI). The purpose of our study was to investigate waking electroencephalogram (EEG) abnormalities specific to iRBD patients with MCI., Methods: Forty-two polysomnographically confirmed iRBD patients, including 23 iRBD [+]MCI patients 19 patients without MCI (iRBD [-]MCI), and 37 healthy subjects participated in the study. All participants underwent a complete neuropsychologic assessment for MCI diagnosis and a waking quantitative EEG recording., Results: iRBD [+]MCI patients had a higher slow-to-fast frequency ratio than iRBD [-]MCI patients and controls in the parietal, temporal, and occipital regions. iRBD [+]MCI patients also had higher relative θ power in the parietal, temporal, and occipital regions and lower relative α power in the occipital region compared to iRBD [-]MCI patients and controls. Moreover, iRBD [+]MCI patients had higher relative θ power in the frontal and central areas and lower relative β power in the central, parietal, and temporal regions compared to controls. The dominant occipital frequency also was slower in iRBD [+]MCI patients compared to controls. No between-group differences were observed between iRBD [-]MCI patients and controls., Conclusion: In iRBD patients, only those with concomitant MCI showed waking EEG slowing in the posterior cortical regions, providing a potential marker for an increased risk for developing DLB or PD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: We aimed to compare rhythmic masticatory muscle activity typical of sleep bruxism and oromandibular myoclonus (OMM) during rapid eye movement (REM) sleep in patients with idiopathic REM sleep behavior disorder (iRBD) and in Parkinson disease (PD) patients with RBD (PD-RBD)., Methods: Sleep polygraphic data were collected from 9 age-matched controls and 28 patients (mean±standard error of the mean, 66.0±1.7 y) with a clinical and sleep laboratory diagnosis of RBD. Patients were divided into two groups: 13 patients with iRBD and 15 patients with PD-RBD. Rhythmic masticatory muscle activity, a marker of sleep bruxism, and OMM were scored blind to subject's diagnosis from jaw electromyographic recordings during sleep., Results: The rhythmic masticatory muscle activity index was significantly higher during REM sleep in iRBD subjects compared to controls (P<.01) and was significantly higher during non-REM (NREM) sleep in both subject groups compared to controls (P < or = .03). A positive sleep laboratory diagnosis of sleep bruxism was made in 25% of all patients. In iRBD, patients had more OMM during REM sleep than controls (2.4 times higher; P=.01)., Conclusion: In the presence of a high frequency of rhythmic masticatory muscle activity during REM sleep, RBD may be suspected and further neurologic assessment is recommended., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Since its original description, idiopathic rapid eye movement sleep behavior disorder (RBD) has become a well-established risk factor for neurodegenerative disease. Studies from sleep centers have found that at least 40-65% of patients with idiopathic RBD will develop a defined neurodegenerative phenotype over 10 years. This elevated risk of neurodegeneration has been recently confirmed in a population-based study of probable RBD. When a defined syndrome develops, it is almost always a 'synucleinopathy' (Parkinson's disease, Dementia with Lewy Bodies or multiple system atrophy). Often, manifestations of parkinsonism and cognitive impairment overlap. The ability of RBD to predict disease has major implications for development of neuroprotective therapy. First, RBD is a prodromal marker with a disease risk sufficiently high for design of neuroprotective trials. Second, study of idiopathic RBD allows prospective testing of other predictive markers of neurodegeneration. Third, it allows an unprecedented direct examination of the evolution of prodromal disease into defined neurodegenerative syndromes. This review summarizes what is known about the risk of neurodegeneration in idiopathic RBD, the utility of prodromal/predictive markers in synuclein-mediated neurodegeneration, and the evolution of motor and non-motor markers in prodromal stages., (Copyright © 2012. Published by Elsevier B.V.)

Objectives: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD., Methods: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA])., Results: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies., Conclusions: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Sleepiness, cognitive deficits, abnormal event-related potentials (ERP), and slowing of the waking electroencephalography (EEG) activity have been reported in patients with obstructive sleep apnea (OSA). Our study aimed at evaluating if an association exists between the severity of ERP abnormalities and EEG slowing to better understand cerebral dysfunctions in OSA., Methods: Twelve OSA patients and 12 age-matched controls underwent an overnight polysomnographic recording, an EEG recording of 10 min of wakefulness, and an auditory ERP protocol known to specifically recruit attention. P300 and P3a ERP components were measured as well as the spectral power in each frequency band of the waking EEG. Pearson product moment correlations were used to measure associations between ERP characteristics and EEG spectral power in OSA patients and control subjects., Results: A positive correlation between the late P300 amplitude and θ power in the occipital region was observed in OSA subjects (P<.01). A positive correlation was also found between P3a amplitude and β1 power in central region in OSA subjects (P<.01). No correlation was observed for control subjects., Conclusions: ERP abnormalities observed in an attention task are associated with a slowing of the waking EEG recorded at rest in OSA., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Rapid eye movement sleep behavior disorder is found in 33-46% of patients with Parkinson's disease and was shown to be associated with cognitive deficits. Our goal was to improve our understanding of the role of this sleep disorder in cerebral dysfunction occurring in Parkinson's disease using a visual cognitive task and event-related potentials., Methods: Sixteen patients with Parkinson's disease and rapid eye movement sleep behavior disorder, 15 patients with Parkinson's disease without rapid eye movement sleep behavior disorder and 16 healthy control subjects were included. The amplitude and latency of event-related potentials were compared between groups., Results: No group differences were found for reaction times or accuracy. A Group effect was found for P2 wave amplitude; patients with rapid eye movement sleep behavior disorder had increased P2 in comparison with the control group (p < 0.05). Patients with Parkinson's disease alone were not different from the two other groups for this component. Prolonged novelty P3 latencies on Cz were associated with longer disease durations among patients with Parkinson's disease (p < 0.01)., Conclusion: Co-morbid Parkinson's disease and rapid eye movement sleep behavior disorder were associated with abnormal visual P2 component of event-related potentials. Although patients with Parkinson's disease alone were not significantly different from patients with combined Parkinson's disease and rapid eye movement sleep behavior disorder, their P2 amplitudes were not sufficiently abnormal to differ from that of control subjects. This study confirms that rapid eye movement sleep behavior disorder accentuates cerebral dysfunctions in Parkinson's disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)