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Background Sleep disturbances are increasingly common and associated with adverse health outcomes. Inadequate sleep may also produce daytime symptoms, such as excessive sleepiness. Growing research identifies daytime sleepiness as a risk factor for morbidity and mortality. However, it is unclear whether these associations are independent of the presence of sleep disordered breathing, a primary cause of hypersomnolence. Objective In this study, we sought to assess the relation between daytime sleepiness and established cardiometabolic risk factors, independently of obstructive sleep apnea. Methods We compiled data from 456 individuals (69% male, age 51.3±15.7 years) who participated in research studies performed in the Cardiovascular/Sleep Laboratory at Mayo Clinic and had complete sleepiness data. Height and weight were measured to calculate body mass index (BMI, kg/m 2 ). Obesity was defined as BMI ≥30 kg/m 2 . Hypertension was determined as self‐reported diagnosis or taking antihypertensive medications. Diabetes mellitus was defined as patient‐reported diabetes or usage of insulin or antidiabetic drugs. Obstructive sleep apnea (OSA) was self‐reported or determined from polysomnography. Subjective daytime sleepiness was defined as an affirmative answer to the question “Are you usually sleepy during the daytime?”. Results Daytime sleepiness was reported by 51% of the subjects (n=231). Those with daytime sleepiness were more likely to be male (74.9% vs 62.3%, P=0.005), but the average age was similar between groups (51.6±17.3 years vs 51±14.1 years, P=0.67). BMI was greater among the subjects with perceived daytime sleepiness than in those without (32.2±7 kg/m 2 vs 28.9±6.8 kg/m 2 , P<0.0001), and obesity was more frequent in the former group (62.9% vs 35.4%, P<0.0001). Prevalence of hypertension (37% vs 27.5%, P=0.03), diabetes (14% vs 6.7%, P=0.01), and OSA (18.2% vs 10.4%, P=0.035) was also higher in individuals reporting sleepiness during the day. In multivariable analysis adjusted for age, sex, and OSA, daytime sleepiness was associated with increased risk of obesity (OR=2.88, 95% CI 1.84–4.49, P<0.0001), hypertension (OR=1.73, 95% CI 1.04–2.87, P=0.034), and diabetes (OR=2.58, 95% CI 1.18–5.61, P=0.017). Conclusion Daytime sleepiness is associated with greater risk of obesity, hypertension and diabetes independently of comorbid OSA. Daytime sleepiness may be a novel target for preventative and therapeutic strategies aimed at improving cardiometabolic health. Support or Funding Information NC is supported by American Heart Association grant 16SDG27250156, and Mayo Clinic Center for Clinical and Translational Science grant Marie Ingalls Cardiovascular Research Career Development Fund. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background The prevalence of inadequate sleep in the general population is rising. While the detrimental health consequences of sleep disorders such as sleep‐disordered breathing are well established, little is known on the contributory role of perceived sleep quality on cardiometabolic risk profile. Importantly, poor sleep quality may be reported even in absence of objective findings of suboptimal sleep. We hypothesized that subjective poor sleep quality would be associated with markers of cardiometabolic risk in individuals without sleep disorders. Methods We compiled data from 667 research subjects (446 males, age 36.4±13.8 years) studied in the Cardiovascular/Sleep Laboratory at Mayo Clinic from 2000 to 2017. Subjects with history of sleep disorders and/or overt cardiovascular diseases, as determined from medical record or self‐report, were excluded from this study. Health status was further confirmed by physical exam. Supine systolic and diastolic blood pressure (SBP/DBP), height, weight, and waist and hip circumferences were collected. Body mass index (BMI, kg/m 2 ) was derived from height and weight. Presence of hypertension (SBP and/or DBP ≥140/80 mmHg) and obesity (BMI ≥30 kg/m 2 ) was recorded. Subjective sleep quality was self‐reported as either good or poor. Analysis of variance and Chi‐square tests were performed to examine differences in outcome measures according to sleep quality. Logistic regression models were run to examine the predictive value of poor sleep quality for hypertension and obesity risk. Results Poor subjective sleep quality was reported by 231 individuals out of 667 (34.6%). Subjects with perceived poor sleep were older (poor sleep vs good sleep: 42.3±12.9 years vs 33.2±13.3 years, p<0.0001), with greater BMI (31.4±7 kg/m 2 vs 26.5±6.3 kg/m 2 , p<0.0001), waist (104.6±17.8 kg/m 2 vs 89.7±14.8 kg/m 2 , p<0.0001) and hip (111.8±14.8 kg/m 2 vs 102.3±11.5 kg/m 2 , p<0.0001) circumference than good sleepers. Compared to the latter group, SBP and DBP values were also higher in self‐evaluated poor sleepers (poor sleep vs good sleep, SBP: 128.8±15.5 mmHg vs 122.9±14.4 mmHg, p<0.0001; DBP: 74.5±10.6 mmHg vs 71.8±11.4 mmHg, p=0.012). Obesity was more prevalent in those with subjective poor sleep quality than in good sleepers (53.3% vs 19.7%, p<0.0001). Similarly, 72.5% of patients with hypertension reported poor sleep quality while only 27.5% of them were good sleepers (p<0.0001). In comparison to good sleep quality, perceived poor sleep was associated with 3.6 times greater risk of obesity (95% CI 2.5, 5.2, p<0.0001) and 3.5 times greater risk of hypertension (95% CI 1.7, 6.9, p=0.0004) after correcting for conventional covariates. Significance was retained after further adjustment for reported snoring and witnessed apneas. Conclusions Poor perceived sleep quality is independently associated with elevated risk of high blood pressure and excess body weight in individuals without sleep disorders. These findings favor the concept that promoting adequate sleep quality, even subjectively, may benefit cardiometabolic health. Support or Funding Information American Heart Association grant 16SDG27250156; National Institutes of Health grants RO1 HL 065176 and HL 134808. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Background Increasing evidence suggests that insufficient sleep is associated with increased morbidity and mortality. Studies linking short sleep with metabolic derangements such as obesity, insulin resistance and dyslipidemia, are especially persuasive. Nevertheless, the vast majority of these data have been obtained from observational studies. We sought to evaluate the effects of 9 days of partial sleep deprivation compared to normal sleep on lipid profile in healthy subjects undergoing an in‐laboratory, experimental protocol. Methods Eight healthy, nonobese, normolipidemic subjects (4 males, age 25.4±6.8 years, body mass index 25.2±3.9 kg/m 2 ) completed a randomized, controlled, crossover, 16‐day in‐patient study. Each sequence consisted of a 4‐day acclimation period, followed by 9 days of experimental partial sleep deprivation (4 hours of sleep opportunity; 00:30 AM – 4:30 AM); or normal sleep (9 hours of sleep opportunity; 10:00 PM – 7:00 AM), and a subsequent 3‐day recovery segment. Subjects consumed a controlled, weight maintenance diet (15% protein, 55% carbohydrates, and 30% fat) during the study. Fasting blood samples for measures of total cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, and triglycerides were obtained in both study sequences on Days 4, 7, 10, 13, and 16. Results Compared to normal sleep, experimental partial sleep deprivation did not cause significant changes in total cholesterol (partial sleep deprivation vs normal sleep: 160.1±21.8 mg/dL vs 164.9±23.7 mg/dL, P=0.724), HDL cholesterol (54.1±14.7 mg/dL vs 52±12.8 mg/dL, P=0.75), LDL cholesterol (86.5±18.9 mg/dL vs 89.5±19.7 mg/dL, P=0.329), or triglycerides (97.7±26.6 mg/dL vs 96.6±38.3 mg/dL, P=0.633). Analysis of time course of lipid values across study days did not reveal appreciable patterns (all P>0.295). Likewise, body weight was similar during both study sequences (partial sleep deprivation vs normal sleep: 69.6±14.2 kg vs 69.2±13.5 kg, P=0.459). Conclusions Experimental sleep restriction does not alter circulating lipids or weight in healthy subjects. Aberrant metabolic effects of insufficient sleep may be mediated by dietary intake and occur when access to food is unrestricted, or may emerge only after longer exposure to sleep curtailment. Support or Funding Information American Heart Association grant 16SDG27250156; National Institutes of Health R01 grants HL114676 and HL114024; European Union project FNUSA‐ICRC no. CZ.1.05/1.1.00/02.0123. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

AbstractPatients with early‐onset Alzheimer's disease (EOAD) are commonly excluded from large‐scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial‐ready network. LEADS will follow 400 amyloid beta (Aβ)‐positive EOAD, 200 Aβ‐negative EOnonAD that meet National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age‐matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [18F]Florbetaben and [18F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post‐mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.

Abstract Introduction Rapid Eye Movement (REM) Sleep Behavior Disorder (RBD) is characterized by a lack of muscle atonia during REM sleep with dream enactment. RBD is regarded as a prodromal synucleinopathy as a high proportion of patients eventually phenoconvert to Parkinson’s Disease and related synucleinopathies, suggesting RBD may be an early non-motor symptom of disease. Accordingly, patients with RBD are ideally situated to test potential therapeutic interventions to prevent phenoconversion to synucleinopathy. However, RBD itself, and associated patient registries, are rare. The North American Prodromal Synucleinopathy Consortium (formed in 2018) establishes a multisite registry of RBD patients with standardized neurological, neuropsychiatric, and neuropsychological assessments and biomarker collection. The present work reports baseline characteristics of this RBD patient database at its current state. Methods Seven participating sites have contributed n=170 polysomnographically-confirmed RBD patients. Data includes past medical and family history, self-report questionnaires, and neuropsychological, motor, sensory, and autonomic function testing. Additionally, all subjects have contributed blood, and a subset of subjects have contributed cerebrospinal fluid samples to the National Centralized Repository for Alzheimer’s Disease and Related Dementias for future analysis. A final diagnosis for each subject was determined through an adjudication process by NAPS Consortium PIs; subjects were categorized as ether: 1) isolated RBD, 2) RBD+, 3) Early Symptomatic, or 4) Phenoconverted. Results Of the n=170 subjects, there were n=39 isolated RBD, n=81 RBD+, n=45 Early Symptomatic, and n=4 Phenoconverted. Isolated RBD subjects have no other early neurodegeneration signs/symptoms, those with RBD+ have at least one other identifiable early/mild symptom. The early symptomatic group includes those with mild or subjective cognitive impairment, pure autonomic failure, or possible multiple systems atrophy. The Phenoconverted group consists of those with Dementia with Lew Bodies, Dementia NOS, Parkinson’s Disease, or Parkinson’s NOS. The distribution of impairment across the 5 major domains (motor, cognitive, autonomic, sensory, and psychiatric) for each of the 4 groups will be described. Conclusion This interim analysis presents data on n=170 subjects. The target enrollment is n=360 across the 7 original sites plus 3 new sites. Future work will follow these subjects longitudinally to assess rates and predictors of phenoconversion. Support (if any) NIH NIA R34 AG056639 (YJ, BB)

Abstract Introduction REM sleep behavior disorder (RBD) is characterized by disruptive, violent dream enactment behaviors (DEB), necessitating symptomatic treatment to prevent injury and reduce DEB frequency and severity. Melatonin and clonazepam are regarded as RBD therapeutic mainstays, although outcomes data remains limited. We surveyed RBD patients to determine their outcomes following melatonin, clonazepam, and melatonin-clonazepam combination therapy. Methods Mayo Clinic RBD Patient Registry participants received an electronic survey concerning treatment type(s) and dose(s), efficacy, and adverse effects. The primary outcome was treatment efficacy, determined by comparing DEB frequency/severity ratings on a visual analog scale (VAS). Adverse effects severity was assessed by Likert scales. We comparatively analyzed VAS before and after treatment and adverse effects between treatments using non-parametric statistical tests. Results Sixty-eight of 109 patients responded (62.3%; 64 had analyzable data) with a mean age of 67.7 years. Fifty-seven (85%) were men, with mean RBD symptom duration of 13.9 years. Patients receiving each treatment were: melatonin=30, clonazepam=8, and combination=12; 14 received other or no treatment. Baseline VAS ratings were similar between groups. Only melatonin (p=0.003) and combination therapy (p=0.039) improved VAS ratings; clonazepam monotherapy did not improve VAS. Only melatonin monotherapy was reported to lower VAS compared to untreated patients (p=0.02). Optimally effective mean dosages were melatonin 9.95±5.06 mg and clonazepam 0.81±0.48 mg. Patient frequencies reporting one or more moderately-severe side effect(s) were similar between melatonin (15%), clonazepam (7%), and combination therapies (9%). Twenty-five (36.8%) patients had received only one medication trial, while 41.2% required more than one medication. Of these, 15 (22.1%) tried 2 and 13 (19.1%) tried 3 or more treatments. Conclusion Melatonin therapy at an approximate mean 10 mg dosage improved patient-reported DEB frequency/severity on VAS, compared between both previous intraindividual baseline ratings and with untreated patients, while clonazepam monotherapy did not, without differential adverse effects. Clonazepam monotherapy data were limited. These data inform future prospective melatonin symptomatic therapy trials for RBD. Additionally, 41.2% required more than one RBD pharmacological treatment, suggesting a current therapeutic gap and unmet need for future development of biologically-informed, evidence-based symptomatic RBD therapeutics. Support (if any):

Abstract Introduction Idiopathic/isolated REM sleep behavior disorder (iRBD) is a prodromal alpha-synucleinopathy characterized by dream enactment behavior and REM sleep without atonia (RSWA). We sought to define quantitative RSWA diagnostic thresholds in the North American Prodromal Synucleinopathy (NAPS) Consortium cohort. We analyzed RSWA between iRBD patients across participating NAPS sleep centers, compared to normative controls, and hypothesized that previous diagnostic RSWA thresholds were overestimates. Methods All digital polysomnography files were converted to European Data Format and scored at a central laboratory (Mayo Clinic) which standardized display scoring montages, channel sensitivities, and filtering, and scripted computational analyses for visual scoring. RSWA was quantitatively analyzed in the submentalis (SM) and anterior tibialis (AT) muscles in iRBD (n=86) patients and controls (n=118) utilizing well validated visual (Mayo) and automated (RAI) methods. Parametric statistics were used to compare RSWA metrics, and RSWA thresholds were developed using receiver operating characteristic curves. Results RSWA was significantly higher for the RAI and all visual individual and combined muscle activity metrics in iRBD compared to controls (all p&lt;0.001). Average SM phasic measures were: 14.2% (Mayo), 17.9% (McGill), 18.5% (UCLA), and 9.4% (Washington University). Average AT phasic measures at each site were: 26.7% (Mayo), 17.1% (McGill), 23.3% (UCLA), and 17.4% (Washington University). Average SM/AT ‘any’ measures at each site were: 45.4% (Mayo), 35.9% (McGill), 53.4% (UCLA), and 23.5% (Washington University). Overall cohort RBD diagnostic thresholds (AUC, specificity/sensitivity) were: SM phasic 4.9% (90.0, 82.2%/83.7%); AT phasic 7.6% (88.7%, 82.2%/81.4%) and combined SM/AT ‘any’ 13% (94.6, 83.9%/96.5%). Conclusion RSWA thresholds in the NAPS cohort were substantially lower than previously reported, suggesting previously overestimated diagnostic RSWA thresholds due to smaller, enriched patient samples and overfit statistical modeling. Confirmation of these findings in the complete NAPS cohort (n=300 iRBD patients across all 10 NAPS centers) is planned. Support (if any):

ObjectiveThis 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).MethodsWe 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.ResultsNo 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.InterpretationAutomated 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

Epileptic seizures, sleep, and circadian timing share bilateral interactions, but concerted work to characterize these interactions and to leverage them to the advantage of patients with epilepsy remains in beginning stages. To further the field, a multidisciplinary group of sleep physicians, epileptologists, circadian timing experts, and others met to outline the state of the art, gaps of knowledge, and suggest ways forward in clinical, translational, and basic research. A multidisciplinary panel of experts discussed these interactions, centered on whether improvements in sleep or circadian rhythms improve decrease seizure frequency. In addition, education about sleep was lacking in among patients, their families, and physicians, and that focus on education was an extremely important “low hanging fruit” to harvest. Improvements in monitoring technology, experimental designs sensitive to the rigor required to dissect sleep versus circadian influences, and clinical trials in seizure reduction with sleep improvements were appropriate.