Non-rapid eye movement sleep slow-wave activity features are associated with amyloid accumulation in older adults with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is associated with an increased risk for cognitive impairment and dementia, which likely involves Alzheimer's disease pathology. Non-rapid eye movement slow-wave activity (SWA) has been implicated in amyloid clearance, but it has not been studied in the context of longitudinal amyloid accumulation in OSA. This longitudinal retrospective study aims to investigate the relationship between polysomnographic and electrophysiological SWA features and amyloid accumulation. From the Mayo Clinic Study of Aging cohort, we identified 71 participants ≥60 years old with OSA (mean baseline age = 72.9 ± 7.5 years, 60.6% male, 93% cognitively unimpaired) who had at least 2 consecutive Amyloid Pittsburgh Compound B (PiB)-PET scans and a polysomnographic study within 5 years of the baseline scan and before the second scan. Annualized PiB-PET accumulation [global ΔPiB(log)/year] was estimated by the difference between the second and first log-transformed global PiB-PET uptake estimations divided by the interval between scans (years). Sixty-four participants were included in SWA analysis. SWA was characterized by the mean relative spectral power density (%) in slow oscillation (SO: 0.5-0.9 Hz) and delta (1-3.9 Hz) frequency bands and by their downslopes (SO-slope and delta-slope, respectively) during the diagnostic portion of polysomnography. We fit linear regression models to test for associations among global ΔPiB(log)/year, SWA features (mean SO% and delta% or mean SO-slope and delta-slope), and OSA severity markers, after adjusting for age at baseline PiB-PET, APOE ɛ4 and baseline amyloid positivity. For 1 SD increase in SO% and SO-slope, global ΔPiB(log)/year increased by 0.0033 (95% CI: 0.0001; 0.0064, P = 0.042) and 0.0069 (95% CI: 0.0009; 0.0129, P = 0.026), which were comparable to 32% and 59% of the effect size associated with baseline amyloid positivity, respectively. Delta-slope was associated with a reduction in global ΔPiB(log)/year by -0.0082 (95% CI: -0.0143; -0.0021, P = 0.009). Sleep apnoea severity was not associated with amyloid accumulation. Regional associations were stronger in the pre-frontal region. Both slow-wave slopes had more significant and widespread regional associations. Annualized PiB-PET accumulation was positively associated with SO and SO-slope, which may reflect altered sleep homeostasis due to increased homeostatic pressure in the setting of unmet sleep needs, increased synaptic strength, and/or hyper-excitability in OSA. Delta-slope was inversely associated with PiB-PET accumulation, suggesting it may represent residual physiological activity. Further investigation of SWA dynamics in the presence of sleep disorders before and after treatment is necessary for understanding the relationship between amyloid accumulation and SWA physiology.

Taxonomic intestinal microbiota differences in Lewy body spectrum disease and cohabitant controls.

BACKGROUND: Microbial dysbiosis has been reported to contribute to development of neurodegenerative diseases, however, there is a need to identify causative/prognostic indicators. OBJECTIVES: To comparatively analyze gut microbiome composition in symptomatic LBD (dementia/mild cognitive impairment), iRBD, and cohabiting controls without LBD or iRBD. METHODS: 16S rRNA amplicon sequencing was performed in 38 cases (27 LBD, 11 iRBD) and 39 cohabitant controls. 19 non-cohabitant healthy controls (HCs) were also included to contrast differences between cohabitant cases and controls. RESULTS: Microbiome composition of cohabitant controls and LBD and iRBD cases were strikingly similar. No differences were observed between LBD, and iRBD only showed reduced Bacteroides, compared with cohabitant controls. There were several taxonomic differences in gut microbiome composition between non-cohabitant HCs and cases. CONCLUSIONS: Minimal microbiome differences were observed between iRBD or LBD cases and cohabitant controls. These findings underscore the importance of using cohabiting controls in future gut microbiome studies.

Phenoconversion in Women and Men With Isolated REM Sleep Behavior Disorder: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) is strongly associated with synucleinopathies. Previous iRBD cohort studies have primarily focused on older (>50 years), male-predominant cohorts. Risk of phenoconversion in women and younger adults remains unclear. The study aimed to determine clinical features associated with conversion to a defined neurodegenerative disorder in women and men with iRBD. METHODS: One hundred eighty-six women and 186 men with iRBD were matched by polysomnography month. Baseline clinical variables and subsequent neurodegenerative outcomes were abstracted by chart review. Kaplan-Meier curves assessed conversion rates. Cox proportional hazards modeling evaluated factors associated with phenoconversion risk. RESULTS: Age at iRBD diagnosis was younger in women compared with men (54.9 vs 62.5 years, p < 0.01). Forty-eight patients (12.9%), including 18 women (9.7%) and 30 men (16.1%), phenoconverted during a median follow-up of 6.0 years. Conversion rates were lower in antidepressant users and patients with chronic pain or psychiatric comorbidity while rates were higher in those with vascular comorbidity. Only age at diagnosis (HR 1.09, 95% CI 1.06-1.13) was associated with phenoconversion after adjusting for RBD symptom duration; sex; antidepressant use; and psychiatric, chronic pain, and vascular comorbidities. DISCUSSION: Age at diagnosis was independently associated with phenoconversion risk in women and men with iRBD.

Clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome.

Predominant limbic degeneration has been associated with various underlying aetiologies and an older age, predominant impairment of episodic memory and slow clinical progression. However, the neurological syndrome associated with predominant limbic degeneration is not defined. This endeavour is critical to distinguish such a syndrome from those originating from neocortical degeneration, which may differ in underlying aetiology, disease course and therapeutic needs. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome that is highly associated with limbic-predominant age-related TDP-43 encephalopathy but also other pathologic entities. The criteria incorporate core, standard and advanced features, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degeneration and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate and low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic and Alzheimer's Disease Neuroimaging Initiative cohorts and applied the criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; Alzheimer's Disease Neuroimaging Initiative, n = 53) and who had Alzheimer's disease neuropathological change, limbic-predominant age-related TDP-43 encephalopathy or both pathologies at autopsy. These neuropathology-defined groups accounted for 35, 37 and 4% of cases in the Mayo cohort, respectively, and 30, 22 and 9% of cases in the Alzheimer's Disease Neuroimaging Initiative cohort, respectively. The criteria effectively categorized these cases, with Alzheimer's disease having the lowest likelihoods, limbic-predominant age-related TDP-43 encephalopathy patients having the highest likelihoods and patients with both pathologies having intermediate likelihoods. A logistic regression using the criteria features as predictors of TDP-43 achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in an external cohort achieved a balanced accuracy of 73.3%. Patients with high likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying patients with both Alzheimer's disease neuropathological change and limbic-predominant age-related TDP-43 encephalopathy from the Mayo cohort according to their likelihoods revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of decline and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of decline. The implementation of criteria for a limbic-predominant amnestic neurodegenerative syndrome has implications to disambiguate the different aetiologies of progressive amnestic presentations in older age and guide diagnosis, prognosis, treatment and clinical trials.

Rapid Eye Movement Sleep Behavior Disorder: Clinical Presentation and Diagnostic Criteria.

Rapid eye movement (REM) sleep behavior disorder (RBD) classically presents with repetitive complex motor behavior during sleep with associated dream mentation. The diagnosis requires a history of repetitive complex motor behaviors and polysomnographic demonstration of REM sleep without atonia (RSWA) or capturing dream enactment behaviors. RSWA is best evaluated in the chin or flexor digitorum superficialis muscles. The anterior tibialis muscle is insufficiently accurate to be relied upon solely for RBD diagnosis. RBD may present with parkinsonism or cognitive impairment or may present in isolation. Patients should be monitored for parkinsonism, autonomic failure, or cognitive impairment.

Contemporary diagnostic visual and automated polysomnographic REM sleep without atonia thresholds in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: Accurate diagnosis of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is crucial due to its injury potential and neurological prognosis. We aimed to analyze visual and automated REM sleep without atonia (RSWA) diagnostic thresholds applicable in varying clinical presentations in a contemporary cohort of patients with iRBD using submentalis (SM) and individual bilateral flexor digitorum superficialis (FDS) and anterior tibialis electromyography limb recordings during polysomnography. METHODS: We analyzed RSWA in 20 patients with iRBD and 20 age-, REM-, apnea-hypopnea index-matched controls between 2017 and 2022 for phasic burst durations, density of phasic, tonic, and "any" muscle activity (number of 3-second mini-epochs containing phasic or tonic muscle activity divided by the total number of REM sleep 3-second mini-epochs), and automated Ferri REM atonia index (RAI). Group RSWA metrics were comparatively analyzed. Receiver operating characteristic curves determined optimized area under the curve (AUC) and maximized specificity and sensitivity diagnostic iRBD RSWA thresholds. RESULTS: All mean RSWA metrics were higher in patients with iRBD than in controls (P < .05), except for selected anterior tibialis measures. Optimized, maximal specificity AUC diagnostic cutoffs for coprimary outcomes were: SM "any" 6.5%, 14.0% (AUC = 92.5%) and combined SM+FDS "any" 15.1%, 27.4% (AUC = 95.8%), while SM burst durations were 0.72, and 0.72 seconds (AUC 90.2%) and FDS RAI = 0.930, 0.888 (AUC 92.8%). CONCLUSIONS: This study provides evidence for current quantitative RSWA diagnostic thresholds in chin and individual 4 limb muscles applicable in different iRBD clinical settings and confirms the key value of SM or SM+FDS to assure accurate iRBD diagnosis. Evolving iRBD recognition underscores the necessity of continuous assessment with future large, prospective, well-harmonized, multicenter polysomnographic analyses. CITATION: Leclair-Visonneau L, Feemster JC, Bibi N, et al. Contemporary diagnostic visual and automated polysomnographic REM sleep without atonia thresholds in isolated REM sleep behavior disorder. J Clin Sleep Med. 2024;20(2):279-291.

A limbic-predominant amnestic neurodegenerative syndrome associated with TDP-43 pathology.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neuropathologically-defined disease that affects 40% of persons in advanced age, but its associated neurological syndrome is not defined. LATE neuropathological changes (LATE-NC) are frequently comorbid with Alzheimer's disease neuropathologic changes (ADNC). When seen in isolation, LATE-NC have been associated with a predominantly amnestic profile and slow clinical progression. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE-NC but also other pathologic entities. The LANS criteria incorporate core, standard and advanced features that are measurable in vivo, including older age at evaluation, mild clinical syndrome, disproportionate hippocampal atrophy, impaired semantic memory, limbic hypometabolism, absence of neocortical degenerative patterns and low likelihood of neocortical tau, with degrees of certainty (highest, high, moderate, low). We operationalized this set of criteria using clinical, imaging and biomarker data to validate its associations with clinical and pathologic outcomes. We screened autopsied patients from Mayo Clinic (n = 922) and ADNI (n = 93) cohorts and applied the LANS criteria to those with an antemortem predominant amnestic syndrome (Mayo, n = 165; ADNI, n = 53). ADNC, ADNC/LATE-NC and LATE-NC accounted for 35%, 37% and 4% of cases in the Mayo cohort, respectively, and 30%, 22%, and 9% of cases in the ADNI cohort, respectively. The LANS criteria effectively categorized these cases, with ADNC having the lowest LANS likelihoods, LATE-NC patients having the highest likelihoods, and ADNC/LATE-NC patients having intermediate likelihoods. A logistic regression model using the LANS features as predictors of LATE-NC achieved a balanced accuracy of 74.6% in the Mayo cohort, and out-of-sample predictions in the ADNI cohort achieved a balanced accuracy of 73.3%. Patients with high LANS likelihoods had a milder and slower clinical course and more severe temporo-limbic degeneration compared to those with low likelihoods. Stratifying ADNC/LATE-NC patients from the Mayo cohort according to their LANS likelihood revealed that those with higher likelihoods had more temporo-limbic degeneration and a slower rate of cognitive decline, and those with lower likelihoods had more lateral temporo-parietal degeneration and a faster rate of cognitive decline. The implementation of LANS criteria has implications to disambiguate the different driving etiologies of progressive amnestic presentations in older age and guide prognosis, treatment, and clinical trials. The development of in vivo biomarkers specific to TDP-43 pathology are needed to refine molecular associations between LANS and LATE-NC and precise antemortem diagnoses of LATE.

Identification of Sleep Patterns via Clustering of Hypnodensities.

Sleep patterns vary widely between individuals. We explore methods for identifying populations exhibiting similar sleep patterns in an automated fashion using polysomnography data. Our novel approach applies unsupervised machine learning algorithms to hypnodensities graphs generated by a pre-trained neural network. In a population of 100 subjects we identify two stable clusters whose characteristics we visualize graphically and through estimates of total sleep time. We also find that the hypnodensity representation of the sleep stages produces more robust clustering results than the same methods applied to traditional hypnograms.

Boston criteria v2.0 for cerebral amyloid angiopathy without hemorrhage: An MRI-neuropathological validation study.

BACKGROUND: Updated criteria for the clinical-MRI diagnosis of cerebral amyloid angiopathy (CAA) have recently been proposed. However, their performance in individuals without intracerebral hemorrhage (ICH) or transient focal neurological episodes (TFNE) is unknown. We assessed the diagnostic performance of the Boston criteria version 2.0 for CAA diagnosis in a cohort of individuals presenting without symptomatic ICH. METHODS: Fifty-four participants from the Mayo Clinic Study of Aging or Alzheimer's Disease Research Center were included if they had an antemortem MRI with gradient-recall echo sequences and a brain autopsy with CAA evaluation. Performance of the Boston criteria v2.0 was compared to v1.5 using histopathologically verified CAA as the reference standard. RESULTS: Median age at MRI was 75 years (IQR 65-80) with 28/54 participants having histopathologically verified CAA (i.e., moderate-to-severe CAA in at least 1 lobar region). The sensitivity and specificity of the Boston criteria v2.0 were 28.6% (95%CI: 13.2-48.7%) and 65.3% (95%CI: 44.3-82.8%) for probable CAA diagnosis (AUC 0.47) and 75.0% (55.1-89.3) and 38.5% (20.2-59.4) for any CAA diagnosis (possible + probable; AUC: 0.57), respectively. The v2.0 Boston criteria was not superior in performance compared to the prior v1.5 criteria for either CAA diagnostic category. CONCLUSIONS: The Boston criteria v2.0 have low accuracy in patients who are asymptomatic or only have cognitive symptoms.. Additional biomarkers need to be explored to optimize CAA diagnosis in this population.

Sleep Disorders in Early-Onset Parkinsonism: A Population-Based Study.

BACKGROUND: Sleep disturbances are common in parkinsonian disorders; however, whether sleep disorders affect individuals with early-onset parkinsonism and whether they differ from individuals with typical-onset parkinsonism is unknown. OBJECTIVE: To compare the prevalence and incidence of sleep disorders before and after parkinsonian motor symptom onset between individuals with early onset parkinsonism (age ≤50 at motor symptom onset) and typical-onset parkinsonism (age >50 at motor symptom onset). METHODS: We used a population-based, 1991 to 2015 incident-cohort study of parkinsonism including 38 patients with early-onset and 1,001 patients with typical-onset parkinsonism. Presence or absence and type of sleep disorder as well as the relationship between motor and sleep symptoms were abstracted from the medical records. Rates of sleep disorders before and after onset of parkinsonism were compared with logistic regression and Cox proportional hazards models. RESULTS: The prevalence of sleep disorders prior to the onset of parkinsonism in early vs. typical parkinsonism (24% vs. 16% p = 0.19) and incidence of sleep disorders after parkinsonism onset (5.85 cases per 100 person-years vs. 4.11 cases per 100 person-years; HR 1.15 95% CI: 0.74-1.77) were similar between the two groups. Early-onset parkinsonism had a higher risk for developing post-motor insomnia compared with typical-onset parkinsonism (HR 1.73, 95% CI: 1.02-2.93); the risk for developing all other sleep disorders considered was similar between groups. CONCLUSION: Sleep disorders are common in individuals with early-onset parkinsonism and occur with similar frequency to those with typical-onset parkinsonism, except for insomnia, which was more frequent in the early-onset group.

Association of Polysomnographic Sleep Parameters With Neuroimaging Biomarkers of Cerebrovascular Disease in Older Adults With Sleep Apnea.

BACKGROUND AND OBJECTIVES: Our objective was to determine whether polysomnographic (PSG) sleep parameters are associated with neuroimaging biomarkers of cerebrovascular disease (CVD) related to white matter (WM) integrity in older adults with obstructive sleep apnea (OSA). METHODS: From the population-based Mayo Clinic Study of Aging, we identified participants without dementia who underwent at least 1 brain MRI and PSG. We quantified 2 CVD biomarkers: WM hyperintensities (WMHs) from fluid-attenuated inversion recovery (FLAIR)-MRI, and fractional anisotropy of the genu of the corpus callosum (genu FA) from diffusion MRI. For this cross-sectional analysis, we fit linear models to assess associations between PSG parameters (NREM stage 1 percentage, NREM stage 3 percentage [slow-wave sleep], mean oxyhemoglobin saturation, and log of apnea-hypopnea index [AHI]) and CVD biomarkers (log of WMH and log of genu FA), respectively, while adjusting for age (at MRI), sex, APOE ε4 status, composite cardiovascular and metabolic conditions (CMC) score, REM stage percentage, sleep duration, and interval between MRI and PSG. RESULTS: We included 140 participants with FLAIR-MRI (of which 103 had additional diffusion MRI). The mean ± SD age was 72.7 ± 9.6 years at MRI with nearly 60% being men. The absolute median (interquartile range [IQR]) interval between MRI and PSG was 1.74 (0.9-3.2) years. 90.7% were cognitively unimpaired (CU) during both assessments. For every 10-point decrease in N3%, there was a 0.058 (95% CI 0.006-0.111, p = 0.030) increase in the log of WMH and 0.006 decrease (95% CI -0.012 to -0.0002, p = 0.042) in the log of genu FA. After matching for age, sex, and N3%, participants with severe OSA had higher WMH (median [IQR] 0.007 [0.005-0.015] vs 0.006 [0.003-0.009], p = 0.042) and lower genu FA (median [IQR] 0.57 [0.55-0.63] vs 0.63 [0.58-0.65], p = 0.007), when compared with those with mild/moderate OSA. DISCUSSION: We found that reduced slow-wave sleep and severe OSA were associated with higher burden of WM abnormalities in predominantly CU older adults, which may contribute to greater risk of cognitive impairment, dementia, and stroke. Our study supports the association between sleep depth/fragmentation and intermittent hypoxia and CVD biomarkers. Longitudinal studies are required to assess causation.

Sleep disturbances associated with DPPX autoantibodies: a case series.

STUDY OBJECTIVES: To describe a case series of patients with prominent sleep disturbances and their polysomnography findings in six patients with dipeptidyl-peptidase-like protein-6 (DPPX) autoimmunity syndrome. METHODS: Of 13 patients with DPPX autoimmunity evaluated at Mayo Clinic, 6 were seen by Sleep Medicine with polysomnography and were assessed with blood and cerebrospinal fluid, neuroimaging, neuropsychological testing, and evaluation tailored to clinical presentation. RESULTS: Median age of our six DPPX autoimmunity patients was 57 (range 27-70) years, with one woman. All patients had prominent gastrointestinal disturbances, most with prominent and early weight loss, and a spectrum of neuropsychiatric disturbances including cognitive impairment, myoclonus, exaggerated startle, and dysautonomia. Sleep disturbances included insomnia and obstructive sleep apnea in six patients, periodic leg movements of sleep in four, and REM sleep behavior disorder in two. Polysomnography demonstrated REM sleep-atonia loss in four patients, and ambiguous sleep with status dissociatus (mixed features of wakefulness, non-rapid eye movement [NREM], and REM sleep) appeared in one patient. Five of six patients showed neurological improvement with immunotherapy, including three with at least partial improvement in sleep disturbances. CONCLUSION: Our patients with DPPX autoimmunity syndrome had prominent sleep disturbances including sleep-disordered breathing, REM sleep behavior disorder, and abnormal NREM sleep architecture with highly variable clinical presentations. DPPX autoimmunity should be considered in cases with a triad of sleep disturbance, neurological features of hyperexcitability, and systemic symptoms of gastrointestinal disturbance and weight loss. Future prospective studies of DPPX autoimmunity syndrome including detailed sleep evaluation and follow-up are necessary.

Emergence of restless legs syndrome during opioid discontinuation.

STUDY OBJECTIVES: The development of restless legs syndrome (RLS) has been rarely reported during and following opioid withdrawal. We aimed to determine the presence and severity of RLS symptoms during and after supervised opioid tapering. METHODS: Ninety-seven adults enrolled in the Mayo Clinic Pain Rehabilitation Center who underwent supervised prescription opioid tapering were prospectively recruited. RLS presence and severity was assessed with the Cambridge-Hopkins Questionnaire 13 and International Restless Legs Syndrome Study Group Rating Severity Scale at admission, midpoint, and dismissal from the program as well as 2 weeks, 4 weeks, and 3 months after completion. Frequency and severity of RLS symptoms were compared between admission and each time point. RESULTS: Average age of the cohort was 52.6 ± 13.3 years with a morphine milligram equivalent dose for the cohort of 45.6 ± 48.3 mg. Frequency of RLS symptoms increased from 28% at admission to peak frequency of 41% at 2 weeks following discharge from the Mayo Pain Rehabilitation Clinic (P = .01), returning to near baseline frequency 3 months after opioid discontinuation. International Restless Legs Syndrome Study Group Rating Severity Scale increased from baseline and then remained relatively stable at each time point following admission. Thirty-five (36.1%) participants developed de novo symptoms of RLS during their opioid taper, with those being exposed to higher morphine milligram equivalent doses having higher risk of developing RLS. CONCLUSIONS: Moderately severe symptoms of RLS, as assessed by survey, occur commonly in individuals undergoing opioid tapering, particularly if exposed to higher doses. In many cases, symptoms appear to be self-limited, although a minority develop persistent symptoms. Our results may have implications for successful opioid tapering, but future confirmatory studies with structured clinician interview are needed to establish that these symptoms truly represent restless legs syndrome given the potential for RLS-mimicking symptoms in individuals with chronic pain syndromes. CITATION: McCarter SJ, Labott JR, Mazumder MK, et al. Emergence of restless legs syndrome during opioid discontinuation. J Clin Sleep Med. 2023;19(4):741-748.

Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment.

This systematic review provides supporting evidence for a clinical practice guideline for the management of rapid eye movement (REM) sleep behavior disorder in adults and children. The American Academy of Sleep Medicine commissioned a task force of 7 experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials and observational studies that addressed interventions for the management of REM sleep behavior disorder in adults and children. Statistical analyses were performed to determine the clinical significance of critical and important outcomes. Finally, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search identified 4,690 studies; 148 studies provided data suitable for statistical analyses; evidence for 45 interventions is presented. The task force provided a detailed summary of the evidence assessing the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2023;19(4):769-810.

Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline.

INTRODUCTION: This guideline establishes clinical practice recommendations for the management of rapid eye movement sleep behavior disorder (RBD) in adults. METHODS: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. GOOD PRACTICE STATEMENT: The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RBD: It is critically important to help patients maintain a safe sleeping environment to prevent potentially injurious nocturnal behaviors. In particular, the removal of bedside weapons, or objects that could inflict injury if thrown or wielded against a bed partner, is of paramount importance. Sharp furniture like nightstands should be moved away or their edges and headboard should be padded. To reduce the risk of injurious falls, a soft carpet, rug, or mat should be placed next to the bed. Patients with severe, uncontrolled RBD should be recommended to sleep separately from their partners, or at the minimum, to place a pillow between themselves and their partners. RECOMMENDATIONS: The following recommendations, with medications listed in alphabetical order, are a guide for clinicians in choosing a specific treatment for RBD in adults. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the patient's values and preferences to determine the best course of action.Adult patients with isolated RBD.1. The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).2. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).3. * The AASM suggests that clinicians use pramipexole (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL).4. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of isolated RBD in adults with mild cognitive impairment. (CONDITIONAL).Adult patients with secondary RBD due to medical condition.5. * The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).6. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).7. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of secondary RBD due to medical condition (Parkinson disease) in adults. (CONDITIONAL).8. * The AASM suggests that clinicians not use deep brain stimulation (DBS; vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL).Adult patients with drug-induced RBD.9. * The AASM suggests that clinicians use drug discontinuation (vs drug continuation) for the treatment of drug-induced RBD in adults. (CONDITIONAL).* The Recommendations section of this paper includes remarks that provide additional context to guide clinicians with implementation of this recommendation. CITATION: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023;19(4):759-768.

Patient values and preferences regarding prognostic counseling in isolated REM sleep behavior disorder.

STUDY OBJECTIVES: Isolated REM sleep behavior disorder (iRBD) carries a high lifetime risk for phenoconversion to a defined neurodegenerative disease (NDD) including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. We aimed to examine iRBD patient values and preferences regarding prognostic counseling. METHODS: One hundred thirteen iRBD patient participants enrolled in the Mayo Clinic iRBD Patient Registry were sent an email survey concerning their values and preferences concerning NDD prognostic counseling and their experiences following diagnosis with iRBD. RESULTS: Of 81 respondents (71.7% response rate), the majority were men (74.0%) with an average age of 65.7 (±9.7) years. Responses indicated a strong preference toward receiving prognostic information about possible future NDD development. 92.5% of respondents felt knowledge concerning personal NDD risk was important, while 87.6% indicated prognostic discussions were important to maintaining trust in their physician. 95.7% indicated a desire for more information, while only 4.3% desired less information regarding their NDD prognostic risk. Most respondents strongly agreed that prognostic information was important to discuss with their family and friends and inform future life planning, and most expressed interest in learning more about future neuroprotective therapies and symptomatic treatments for parkinsonism and dementia. CONCLUSIONS: Most iRBD patients indicated strong preferences for disclosure of NDD prognostic risk and indicated that prognostic information was important for family discussions and future life planning. Future broader surveys and qualitative studies of clinic-based and ultimately community dwelling iRBD patients' values and preferences are needed to guide appropriately tailored and individualized prognostic counseling approaches following iRBD diagnosis.

Treatment with the novel TAAR1 agonist ulotaront is associated with reductions in quantitative polysomnographic REM sleep without atonia in healthy human subjects: Results of a post-hoc analysis.

BACKGROUND: Isolated REM sleep behavior disorder (RBD) is a potentially injurious parasomnia lacking an established treatment. Ulotaront is a trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity that has demonstrated efficacy in patients with schizophrenia. In a single dose challenge study in humans, ulotaront 50 mg demonstrated significant REM suppressant effects. We now report post-hoc exploratory analyses designed to evaluate the effect of ulotaront on quantitative REM sleep without atonia (RSWA). METHODS: Young healthy adult men (ages 19-35) were randomized to double-blind, cross-over treatment (after 7-day wash-out) with single doses of ulotaront (50 mg or 10 mg) versus placebo followed by polysomnography (PSG) on each of the nights following treatment. Quantitative RSWA was analyzed in a blinded fashion using established visual and automated methods. RESULTS: Subjects received 50 mg (n = 11) or 10 mg (n = 9) of ulotaront. Treatment with ulotaront 50 mg was associated with lower RSWA (p < 0.05), with greatest RSWA reduction (vs. placebo) observed in subjects with RSWA levels above the mean on the baseline night. RSWA levels were similar between treatment with ulotaront 10 mg and placebo. CONCLUSION: Treatment with ulotaront 50 mg (but not 10 mg) was associated with reductions in RSWA levels in healthy subjects, especially in subjects with higher baseline RSWA levels, providing proof-of-concept for ulotaront efficacy in reducing RSWA levels. However, whether ulotaront might have efficacy as a treatment for human RBD awaits double-blind trials with ulotaront in clinical RBD populations.

Nocturnal Pulse Event Frequency Is Reduced in Multiple System Atrophy.

Risk of sudden death in multiple system atrophy (MSA) is greatest during sleep with unknown mechanisms. We compared nocturnal pulse event frequency in 46 MSA patients and age-/sex-matched controls undergoing overnight pulse oximetry. Nocturnal oxyhemoglobin desaturation indices and pulse event indices (PEIs) were recorded, and relationships between pulse oximetry variables and survival were analyzed. MSA patients had lower PEI (3.1 ± 5.3 vs. 12.8 ± 10.8, p < 0.001) despite greater hypoxic burden and similar frequency of respiratory events. Nocturnal pulse events were not associated with severity of daytime autonomic failure. Two MSA patients had suspected sudden death, both with severely reduced PEI. MSA patients have fewer nocturnal pulse events compared with controls, despite similar respiratory event frequency, suggesting abnormal cardiac responses to sleep-disordered breathing. Whether this contributes to sudden death in MSA requires further study. ANN NEUROL 2023;93:205-212.

Autopallidotomy: From Colloquial Term to Scientific Theory.

Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In atypical parkinsonism, LID occurs less frequently than in PD. Lower frequency of LID in atypical parkinsonism has traditionally been attributed to lower amounts of levodopa used by these patients; however, recent studies have shown lower frequency of LID in atypical parkinsonism compared with PD when adjusting for levodopa dose. The mechanism of LID is complex but requires pulsatile levodopa stimulation, progressive presynaptic dopaminergic degeneration, and a relatively intact postsynaptic dopaminergic system. The globus pallidus internus (GPi), the main inhibitory nucleus of the basal ganglia, may play a major role in the development and treatment of LID. Surgical lesioning of the posteroventral GPi is directly antidyskinetic; animal models showing GPi-associated striatal neurons are directly responsible for the development of LID. However, other cortical areas, particularly the primary sensory and motor cortices may also play a role in LID. In some cases of atypical parkinsonism, particularly progressive supranuclear palsy and corticobasal degeneration, severe degeneration of the GPi, a so-called "autopallidotomy," may explain the absence of LID in these patients. In other atypical parkinsonisms, such as PD dementia and dementia with Lewy bodies, the lower incidence of LID may partly be attributed to more striatal degeneration but likely also relates to the degeneration of the motor cortex and resultant network dysfunction. Overall, atypical parkinsonism serves as a natural model that may ultimately reveal more effective therapies for LID.