Publications by authors named "Erik K St Louis"

138 Publications

Effects of Experimental Sleep Restriction on Ambulatory and Sleep Blood Pressure in Healthy Young Adults: A Randomized Crossover Study.

Hypertension 2021 Jul 12:HYPERTENSIONAHA12117622. Epub 2021 Jul 12.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN. (N.C., J.B., P.S., V.K.S.).

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6-3.6], corrected =0.016), endothelial function was attenuated (<0.001), and plasma norepinephrine increased (=0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1-10.8) and 11.3 (5.9-16.7) mm Hg, respectively (both <0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17622DOI Listing
July 2021

An Undifferentiated Spell: The Answer is in The Pillbox.

Mayo Clin Proc 2021 07;96(7):2003-2005

Department of Neurology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1016/j.mayocp.2021.05.003DOI Listing
July 2021

Does testing for sleep-disordered breathing pre-discharge versus post-discharge result in different treatment outcomes?

J Clin Sleep Med 2021 Jun 21. Epub 2021 Jun 21.

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester MN.

Study Objectives: Treatment of sleep-disordered breathing (SDB) may improve health related outcomes post-discharge. However timely definitive sleep testing and provision of ongoing therapy has been a challenge. Little is known about how the time of testing-during hospitalization vs. after discharge-affects important outcomes such as treatment adherence.

Methods: We conducted a 10-year retrospective study of hospitalized adults who received an inpatient sleep medicine consultation for SDB and subsequent sleep testing. We divided them into inpatient and outpatient sleep testing cohorts and studied their clinical characteristics, follow-up and PAP adherence, and hospital readmission.

Results: Of 485 patients, 226 (47%) underwent inpatient sleep testing and 259 (53%) had outpatient sleep testing. The median age was 68 years old (IQR=57-78), and 29.6% were females. The inpatient cohort had a higher Charlson Comorbidity Index (CCI) (4 [3-6] vs 3[2-5], p=<0.0004). A higher CCI (HR=1.14, 95%CI:1.03-1.25, p=0.001), BMI (HR=1.03, 95%CI:1.0-1.05, p=0.008) and stroke (HR=2.22, 95%CI:1.0-4.9, p=0.049) were associated with inpatient sleep testing. The inpatient cohort kept fewer follow-up appointments (39.90% vs 50.62%, p=0.03) however PAP adherence was high among those keeping follow-up appointments (88.9% [inpatient] vs 85.71% [outpatient], p=0.55). The inpatient group had an increased risk for death (HR: 1.82 95%CI 1.28-2.59, p=<0.001) but readmission rates did not differ.

Conclusions: Medically complex patient were more likely to receive inpatient sleep testing but less likely to keep follow-up, which could impact adherence and effectiveness of therapy. Novel therapeutic interventions are needed to increase sleep medicine follow-up post-discharge which may result in improvement in health outcomes in hospitalized patients with SDB.
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http://dx.doi.org/10.5664/jcsm.9450DOI Listing
June 2021

Cardiac Involvement in Facioscapulohumeral Muscular Dystrophy (FSHD).

Front Neurol 2021 24;12:668180. Epub 2021 May 24.

Department of Neurology, Mayo Clinic, Rochester, MN, United States.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and predominantly affects facial and shoulder girdle muscles. Previous case reports and cohort studies identified minor cardiac abnormalities in FSHD patients, but their nature and frequency remain incompletely characterized. We reviewed cardiac, neurological and genetic findings of 104 patients with genetically confirmed FSHD. The most common conduction abnormality was complete (7%) or incomplete (5%) right bundle branch block (RBBB). Bifascicular block, left anterior fascicular block, complete atrioventricular block, and 2:1 atrioventricular block each occurred in 1% of patients. Atrial fibrillation or flutter were seen in 5% of patients. Eight percent of patients had heart failure with reduced ejection fraction and 25% had valvular disease. The latter included aortic stenosis in 6% (severe in 4% and moderate in 2%) and moderate aortic regurgitation in 8%. Mitral valve prolapse (MVP) was present in 9% of patients without significant mitral regurgitation. There were no significant associations between structural or conduction abnormalities and age, degree of muscle weakness, or size of the 4q deletion. Both structural and conduction abnormalities can occur in FSHD. The most common abnormalities are benign (RBBB and MVP), but more significant cardiac involvement was also observed. The presence of cardiac abnormalities cannot be predicted from the severity of the neurological phenotype, nor from the genotype.
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http://dx.doi.org/10.3389/fneur.2021.668180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181417PMC
May 2021

Differential Impact on Isolated REM Sleep without Atonia by Varying Antidepressant Therapies.

J Affect Disord Rep 2020 Dec 25;1. Epub 2020 Sep 25.

Mayo Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota.

Background: REM sleep without atonia (RSWA) is characterized by increased phasic or tonic muscle activity in electromyography channels during polysomnography and usually causes REM sleep behaviour disorder, but RSWA also exists within healthy populations without dream-enactment behaviour, especially in psychiatric populations receiving antidepressant therapies. Evidence for differential impact of antidepressants on RSWA, and whether RSWA persists or resolves following changes in antidepressant therapy, remains limited.

Case: We present a 56-year-old woman with depression undergoing 3 polysomnograms while receiving 3 different distinct antidepressants. Her first polysomnogram demonstrated elevated REM sleep without atonia while receiving a tricyclic antidepressant. Following a switch to fluoxetine, her second polysomnogram showed greater elevation of REM sleep without atonia After a subsequent therapeutic switch to buproprion, a third polysomnogram showed interval decrease in RSWA amounts, lower than the initial levels found during tricyclic antidepressant administration.

Results/outcomes: A switch from fluoxetine to bupropion was associated with markedly reduced RSWA amounts.

Conclusion/interpretation: The polysomnography findings in this case suggest that the type of antidepressant treatment differentially impacts levels of RSWA. The potential importance and implication to practicing psychiatrists is that bupropion, with selective action on dopamine reuptake rather than serotoninergic or acetylcholinergic neurotransmission, may have lesser tendency toward increasing REM sleep muscle activity levels. Additional prospective studies comparing polysomnographic RSWA in psychiatric populations are needed.

Declaration Of Interest/funding: The authors have no financial support, off-label use, or conflict of interest to declare.
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http://dx.doi.org/10.1016/j.jadr.2020.100007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112624PMC
December 2020

Correction to: Sleep Disturbances Associated with Neurological Autoimmunity.

Neurotherapeutics 2021 Jan;18(1):657

Mayo Clinic Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

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http://dx.doi.org/10.1007/s13311-021-01058-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116390PMC
January 2021

Correction to: Sleep Neurology's Toolkit at the Crossroads: Challenges and Opportunities in Neurotherapeutics Lost and Found in Translation.

Neurotherapeutics 2021 Jan;18(1):656

Divisions of Sleep Medicine and Movement Disorders, Department of Neurology, Massachusetts General Hospital, Harvard University, Boston, MA, USA.

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http://dx.doi.org/10.1007/s13311-021-01059-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116468PMC
January 2021

Restless Legs Syndrome: Contemporary Diagnosis and Treatment.

Neurotherapeutics 2021 01 20;18(1):140-155. Epub 2021 Apr 20.

Mayo Center for Sleep Medicine, 200 First Street SW, Rochester, MN, 55905, USA.

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.
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http://dx.doi.org/10.1007/s13311-021-01019-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116476PMC
January 2021

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

Ann Neurol 2021 Jul 7;90(1):62-75. Epub 2021 May 7.

Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

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.
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http://dx.doi.org/10.1002/ana.26085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252762PMC
July 2021

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Neurotherapeutics 2021 01 12;18(1):53-74. Epub 2021 Apr 12.

Mayo Center for Sleep Medicine, Rochester, Minnesota, USA.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.
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http://dx.doi.org/10.1007/s13311-021-01031-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116400PMC
January 2021

Sleep Neurology's Toolkit at the Crossroads: Challenges and Opportunities in Neurotherapeutics Lost and Found in Translation.

Neurotherapeutics 2021 01 5;18(1):1-5. Epub 2021 Apr 5.

Divisions of Sleep Medicine and Movement Disorders, Department of Neurology, Massachusetts General Hospital, Harvard University, Boston, MA, USA.

We find ourselves at our present crossroads with a well-traveled toolkit, perhaps too well worn but with aspirational hopes and dreams for the field of sleep neurotherapeutics. This volume is organized thematically into six topical domains that parallel the major subspecialty areas of contemporary clinical sleep neurology practice, as well as novel directions and opportunities. The issue begins with an overview of the central disorders of hypersomnolence, including narcolepsy, idiopathic hypersomnia and other hypersomnia disorders, and the related use of the entire broad range of stimulant and wake-promoting pharmacotherapies. Next, the range of behavioral therapies, application of light and light restriction and melatonin therapies, and hypnotic pharmacotherapies useful in insomnia and circadian sleep-wake rhythm disorders are reviewed, followed by an overview of treatment options for sleep-related breathing disorders including positive airway pressure and the novel approach of hypoglossal neurostimulation for obstructive sleep apnea. The parasomnias and sleep-related movement disorders, including NREM disorders of arousal, REM parasomnias (nightmares and isolated sleep paralysis and idiopathic/isolated REM sleep behavior disorder, and restless legs syndrome are then discussed, and the applications of sleep neurotherapeutics in sleep and neurological disease are reviewed, including neurodevelopmental, epileptic, autoimmune encephalopathies, and neurodegenerative diseases. Last, the novel directions and opportunities in sleep neurology offered by cannabinoid therapies and machine learning/artificial intelligence methodology conclude this comprehensive survey of contemporary sleep neurology. We hope that you find this volume to be a useful and inspirational support tool for the work that matters most, your care of all our sleep neurology patients in the clinics.
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http://dx.doi.org/10.1007/s13311-021-01032-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020828PMC
January 2021

Proceedings of the Sleep and Epilepsy Workshop: Section 1 Decreasing Seizures-Improving Sleep and Seizures, Themes for Future Research.

Epilepsy Curr 2021 03 31:15357597211004566. Epub 2021 Mar 31.

Department of Neurology and Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

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.
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http://dx.doi.org/10.1177/15357597211004566DOI Listing
March 2021

Sleep and Epilepsy: a Focused Review of Pathophysiology, Clinical Syndromes, Co-morbidities, and Therapy.

Neurotherapeutics 2021 01 30;18(1):170-180. Epub 2021 Mar 30.

Division of Epilepsy and Sleep, Columbia University, New York, NY, USA.

A healthy brain requires balancing of waking and sleeping states. The normal changes in waking and sleeping states result in neurophysiological conditions that either increase or decrease the tendency of seizures and interictal discharges to occur. This article reviews the manifold and complex relationships between sleep and epilepsy and discusses treatment of the sleep-related epilepsies. Several forms of epilepsy predominantly or exclusively manifest during sleep and seizures tend to arise especially from light NREM sleep. Diagnostic interictal epileptiform discharges on the electroencephalogram are also most likely to be activated during deep NREM sleep stage N3. Epileptiform discharges and antiepileptic medications may in turn detrimentally impact sleep. Co-morbid sleep disorders also have the potential to worsen seizure control. Sleep has an important key association with sudden unexpected death in epilepsy (SUDEP). Further research is necessary to understand the complex relationships between sleep and epileptic disorders and their treatments.
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http://dx.doi.org/10.1007/s13311-021-01021-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116418PMC
January 2021

Sleep Disturbances Associated with Neurological Autoimmunity.

Neurotherapeutics 2021 01 30;18(1):181-201. Epub 2021 Mar 30.

Mayo Clinic Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Associations between sleep disorders and neurological autoimmunity have been notably expanding recently. Potential immune-mediated etiopathogenesis has been proposed for various sleep disorders including narcolepsy, Kleine-Levin syndrome, and Morvan syndrome. Sleep manifestations are also common in various autoimmune neurological syndromes, but may be underestimated as overriding presenting (and potentially dangerous) neurological symptoms often require more urgent attention. Even so, sleep dysfunction has been described with various neural-specific antibody biomarkers, including IgLON5; leucine-rich, glioma-inactivated protein 1 (LGI1); contactin-associated protein 2 (CASPR2); N-methyl-D-aspartate (NMDA)-receptor; Ma2; dipeptidyl-peptidase-like protein-6 (DPPX); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R); anti-neuronal nuclear antibody type-1 (ANNA-1, i.e., Hu); anti-neuronal nuclear antibody type-2 (ANNA-2, i.e., Ri); gamma-aminobutyric acid (GABA)-B-receptor (GABA-B-R); metabotropic glutamate receptor 5 (mGluR5); and aquaporin-4 (AQP-4). Given potentially distinctive findings, it is possible that sleep testing could potentially provide objective biomarkers (polysomnography, quantitative muscle activity during REM sleep, cerebrospinal fluid hypocretin-1) to support an autoimmune diagnosis, monitor therapeutic response, or disease progression/relapse. However, more comprehensive characterization of sleep manifestations is needed to better understand the underlying sleep disruption with neurological autoimmunity.
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http://dx.doi.org/10.1007/s13311-021-01020-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116412PMC
January 2021

A 19-month-old boy with decreased sleep and a distinctive EEG pattern.

J Clin Sleep Med 2021 Mar 29. Epub 2021 Mar 29.

Mayo Center for Sleep Medicine, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.5664/jcsm.9274DOI Listing
March 2021

Specialist approaches to prognostic counseling in isolated REM sleep behavior disorder.

Sleep Med 2021 03 24;79:107-112. Epub 2020 Dec 24.

Mayo Center for Sleep Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, USA; Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA; Biomedical Ethics Research Program, Mayo Clinic College of Medicine and Science, Rochester, MN, USA. Electronic address:

Objectives/background: Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling.

Patients/methods: We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics.

Results: Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient's and family's mental health.

Conclusions: Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients' values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling.
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http://dx.doi.org/10.1016/j.sleep.2020.12.014DOI Listing
March 2021

Quantitative REM Sleep without Atonia in Parkinson's Disease and Essential Tremor.

Mov Disord Clin Pract 2021 Jan 26;8(1):37-43. Epub 2020 Nov 26.

Division of Pulmonary and Critical Care Medicine Mayo Center for Sleep Medicine Scottsdale Arizona USA.

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) occurs occasionally in essential tremor (ET), but polysomnographic REM sleep without atonia (RSWA) analyses have been sparse.

Objective: To characterize the amount and distribution of polysomnographic RSWA, the electrophysiologic substrate of RBD, in patients with Parkinson's disease (PD) and ET.

Methods: We analyzed quantitative RSWA in 73 patients: PD (23), ET (23), and age-sex-matched controls (27). None had dream-enactment behavior history or received antidepressants. Phasic, tonic, "any," and phasic-burst duration RSWA measures were calculated in the submentalis (SM) and anterior tibialis (AT) muscles. The automated REM atonia index (RAI) was also determined. Statistical analysis was performed by Kruskal-Wallis rank-sum and Mann-Whitney tests.

Results: SM phasic RSWA was significantly greater for PD than ET patients and controls (12.5% ± 12.8% vs. 4.9% ± 6.7%, 3.9% ± 2.6%), as was SM "any" (13.54% ± 14.30% vs. 5.2% ± 7.6%, 4.2% ± 2.6%). RAI was significantly lower in PD than in ET and controls (0.78 ± 0.23 vs. 0.92 ± 0.09 vs. 0.90 ± 0.17,  ≤ 0.005), but no different between ET and controls. AT phasic and "any" RSWA was similar between the 3 groups. ET and control RSWA was similar in all measures. Two ET patients (8.7%) had SM RSWA similar to PD patients.

Conclusions: Elevated SM RSWA distinguished PD from ET in patients without dream-enactment symptoms and occurs frequently in PD patients, and in isolated tremor suggests underlying synucleinopathy. Prospective studies will further validate these findings.
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http://dx.doi.org/10.1002/mdc3.13112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780943PMC
January 2021

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

Ann Neurol 2021 02 20;89(2):293-303. Epub 2020 Nov 20.

Department of Neurology, Mayo Clinic, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1002/ana.25952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080353PMC
February 2021

Expanded genetic insight and clinical experience of DNMT1-complex disorder.

Neurol Genet 2020 Aug 12;6(4):e456. Epub 2020 Jun 12.

Department of Neurology (H.B., J.G.-R., E.K.S.L., E.P.F., S.N., D.T.J., M.C.P., S.K., C.J.K.), Mayo Clinic, Rochester, MN; Department of Neurology (H.B.), Beijing Friendship Hospital, China; Division of Neuropsychiatry (K.H.), Harima Sanatorium, Hyogo, Japan; Department of Neurology (M.W.), Ehime Prefectural Central Hospital, Matsuyama, Japan; Harvard Medical School (C.Y., K.M.), Boston Children's Hospital, MA; Center for Molecular Medicine and Genetics (S.S.), School of Medicine, Wayne State University, Detroit, MI; Department of Psychology (M.M.M.), Mayo Clinic, Rochester, MN; Atrium Health (I.S.H.), Neurosciences Institute, Concord, NC; Deapartment of Head and Neck Surgery (Y.R.), Oregon Health and Science University, Portland; Department of Laboratory Medicine and Pathology (Z.N., C.J.K.), Mayo Clinic, Rochester, MN; and Department of Neurology and Translational Neuroscience Initiative (J.L.), School of Medicine. Wayne State University, Detroit, MI.

Objective: To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder.

Methods: Neurophysiologic testing, imaging, and genetic findings were summarized in clinical context for 5 cases with DNMT1-complex disorder.

Results: We identified 2 novel DNMT1 mutations (p.E510K and p.P1546A) by whole-exome sequencing (WES). Case 1 (p.E510K) presented with childhood ataxia, treatment-refractory seizures, and rapid cognitive decline in his 50s. Case 2 also had childhood onset and presented with seizures, language regression, hearing loss, narcolepsy with cataplexy symptoms, optic atrophy, sensory neuropathy, and hypogammaglobulinemia requiring IV immunoglobulin. Case 2 (p.P1546A) was identified with a de novo and the first mutation residing outside the targeting sequence domain. Case 3 (p.A570V) had paralytic asymmetric onset attacks triggered by emotionality and lasting sometimes for weeks. Neuropsychological testing showed executive dysfunction localizing to frontosubcortical and frontoparietal structures. He gradually developed left predominant brain atrophy. MRI showed T2 hyperintense lesions that enhanced on T1 postgadolinium images, and brain PET showed hypometabolism in atrophied regions. Case 4 (p.T497P) underwent left cochlear implant, resulting in significant hearing improvements at all tested frequencies (250-6,000 Hz). Case 5 (p.Y511H) had profound gait ataxia with posterior column atrophy of the spinal cord and abnormal evoked potentials primarily affecting the fasciculus gracilis.

Conclusions: Broader application of WES further expands genotype-phenotype correlations of DNMT1-complex disorder. Two mutations are identified with early childhood onsets. The expanded new phenotypes include asymmetric brain hemiatrophy with parenchymal gadolinium enhancement, spinal cord atrophy, prolonged cataplectic spells, and hypogammaglobulinemia. Hearing loss treatment by cochlear implantation is helpful and should be considered.
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http://dx.doi.org/10.1212/NXG.0000000000000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357420PMC
August 2020

Hypoglossal Nerve Stimulator Implantable Pulse Generator Exchange for Battery Depletion.

Otolaryngol Head Neck Surg 2020 08 19;163(2):389-390. Epub 2020 May 19.

Department of Otolaryngology-Head & Neck Surgery, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1177/0194599820925767DOI Listing
August 2020

Frequency of sleep-disordered breathing in a referral population of Somali-Americans.

J Clin Sleep Med 2020 08;16(8):1343-1347

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Study Objectives: To study the frequency of obstructive sleep apnea (OSA) in individuals of Somali ancestry referred to a clinical sleep laboratory.

Methods: This was a retrospective study using a large registry of patients who underwent diagnostic polysomnography between 17 November 2009 and 15 April 2017. Adult patients self-reporting as being of Somali origin were confirmed using the electronic medical record.

Results: Somali-American patients comprised approximately 0.2% of all patients undergoing polysomnography at the Mayo Clinic Center for Sleep Medicine. The median (interquartile range) age was 52.6 (35, 64) years with 66% males and a median (interquartile range) body mass index of 31.2 (27, 34) kg/m². OSA was diagnosed in 77% of patients, with approximately 50% having moderate to severe OSA. OSA was more frequent in older patients and similar between men and women, and only age predicted an OSA diagnosis while sex and body mass index did not. All patients with diabetes mellitus type 2 (n = 7) and all but one of the hypertensive patients (n = 11) had significant OSA.

Conclusions: Less than 0.2% of all patients undergoing polysomnography at Mayo Clinic were of Somali origin. Moderate-to-severe OSA was frequent in this select sample of individuals who underwent polysomnography. Hypertension and diabetes were present in most Somali-Americans with OSA. Given the rising prevalence of diabetes and hypertension in Somali-Americans, and the likely high prevalence of undiagnosed OSA, screening Somali-Americans for sleep disorders may contribute importantly to prevention, early detection, and reduction of cardiovascular and metabolic diseases in this population.
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http://dx.doi.org/10.5664/jcsm.8544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446069PMC
August 2020

Lower Vitamin B12 Level at Multiple System Atrophy Diagnosis Is Associated With Shorter Survival.

Mov Disord 2020 08 22;35(8):1462-1466. Epub 2020 Apr 22.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Multiple system atrophy (MSA) is a neurodegenerative disorder from α-synuclein aggregation. in vitro studies suggest vitamin B12 may interrupt α-synuclein-mediated neurodegeneration. The objective of this study was to determine whether serum vitamin B12 level at MSA diagnosis is associated with survival.

Methods: One hundred eighty-two MSA patients evaluated at Mayo Clinic with vitamin B12 testing were studied. We determined the risk of death in relationship to serum vitamin B12 levels at MSA diagnosis, adjusting for predictors of poor survival.

Results: Predictors of shorter survival included vitamin B12 < 367 ng/L (HR, 1.8; 95% CI, 1.3-2.7), falls within 3 years of MSA diagnosis (HR, 1.6; 95% CI, 1.1-2.3), bladder symptoms (HR, 1.6; 95% CI, 1.0-2.6), urinary catheter requirement (HR, 1.7; 95% CI, 1.0-2.8), male sex (HR, 1.4; 95% CI, 1.0-2.0), and MSA-P subtype (HR, 1.5; 95% CI, 1.0-2.0).

Conclusions: Low vitamin B12 levels are associated with shorter survival in MSA. Additional studies to explore this observation and assess the potential role of vitamin B12 as a modifiable survival factor are needed. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729983PMC
August 2020

Witnessed apneas are associated with elevated tau-PET levels in cognitively unimpaired elderly.

Neurology 2020 04 26;94(17):e1793-e1802. Epub 2020 Mar 26.

From the Departments of Neurology (D.Z.C., E.K.S.L., B.F.B., M.M.M., D.S.K., R.C.P.), Radiology (C.G.S., V.J.L., A.R., C.R.J., P.V.), and Health Sciences Research (S.A.P., M.M.M.), Mayo Clinic, Rochester, MN.

Objective: To assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau.

Methods: From the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB.

Results: Forty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs: 0.049 SUVR (95% confidence interval [CI] 0.010-0.087, = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006-0.067, = 0.019) in the inferior temporal cortex after controlling for confounders.

Conclusion: We identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality.
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http://dx.doi.org/10.1212/WNL.0000000000009315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274847PMC
April 2020

Autonomic dysfunction and phenoconversion in idiopathic REM sleep behavior disorder.

Clin Auton Res 2020 06 19;30(3):207-213. Epub 2020 Mar 19.

Department of Neurology, Mayo Clinic, 200 First Street Southwest, Rochester, MN, 55905, USA.

Background: REM sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients presenting with idiopathic RBD (iRBD), and the predictive value of autonomic dysfunction for phenoconversion to a defined neurodegenerative disease.

Methods: We searched our electronic medical record for patients diagnosed with iRBD who also underwent standardized autonomic function testing within 6 months of iRBD diagnosis, and who had clinical follow-up of at least 3 years following iRBD diagnosis. The composite autonomic severity score (CASS) was derived and compared between phenoconverters and non-converters using chi-square and Wilcoxon rank-sum tests.

Results: We identified 18 patients who fulfilled inclusion and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; six developed Parkinson's disease (PD), and the other six, dementia with Lewy bodies (DLB). Fifteen (83%) patients had at least mild autonomic dysfunction. There were no significant differences between overall converters and non-converters in total CASS or CASS subscores. However, iRBD patients who developed DLB had significantly higher total and cardiovagal CASS scores compared with those who developed PD (p < 0.05), and a trend for higher adrenergic CASS scores compared to those who developed PD and those who did not phenoconvert.

Discussion: Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal autonomic dysfunction in iRBD was associated with phenoconversion to DLB but not PD. Prospective studies are needed to confirm the value of autonomic testing for predicting phenoconversion and disease phenotype in iRBD.
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http://dx.doi.org/10.1007/s10286-020-00674-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255960PMC
June 2020

Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.

J Am Heart Assoc 2020 01 21;9(1):e012264. Epub 2019 Dec 21.

Mayo Clinic College of Medicine Mayo Clinic Rochester MN.

Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death. SUDEP shares many features with sudden cardiac death and sudden unexplained death in the young and may have a similar genetic contribution. We aim to systematically review the literature on the genetics of SUDEP. Methods and Results PubMed, MEDLINE Epub Ahead of Print, Ovid Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus were searched through April 4, 2017. English language human studies analyzing SUDEP for known sudden death, ion channel and arrhythmia-related pathogenic variants, novel variant discovery, and copy number variant analyses were included. Aggregate descriptive statistics were generated; data were insufficient for meta-analysis. A total of 8 studies with 161 unique individuals were included; mean was age 29.0 (±SD 14.2) years; 61% males; ECG data were reported in 7.5% of cases; 50.7% were found prone and 58% of deaths were nocturnal. Cause included all types of epilepsy. Antemortem diagnosis of Dravet syndrome and autism (with duplication of chromosome 15) was associated with 11% and 9% of cases. The most frequently detected known pathogenic variants at postmortem were in Na and K ion channel subunits, as were novel potentially pathogenic variants (11%). Overall, the majority of variants were of unknown significance. Analysis of copy number variant was insignificant. Conclusions SUDEP case adjudication and evaluation remains limited largely because of crucial missing data such as ECGs. The most frequent pathogenic/likely pathogenic variants identified by molecular autopsy are in ion channel or arrhythmia-related genes, with an ≈11% discovery rate. Comprehensive postmortem examination should include examination of the heart and brain by specialized pathologists and blood storage.
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http://dx.doi.org/10.1161/JAHA.119.012264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988156PMC
January 2020

Rationale, design, and development of SleepWell24: A smartphone application to promote adherence to positive airway pressure therapy among patients with obstructive sleep apnea.

Contemp Clin Trials 2020 02 14;89:105908. Epub 2019 Dec 14.

College of Health Solutions, Arizona State University, United States of America. Electronic address:

Background: Positive airway pressure (PAP) therapy is the gold standard treatment for obstructive sleep apnea (OSA), a chronic disorder that affects 6-13% of the adult population. However, adherence to PAP therapy is challenging, and current approaches to improve adherence have limited efficacy and scalability.

Methods/design: To promote PAP adherence, we developed SleepWell24, a multicomponent, evidence-based smartphone application that delivers objective biofeedback concerning PAP use and sleep/physical activity patterns via cloud-based PAP machine and wearable sensor data, and behavior change strategies and troubleshooting of PAP therapy interface use. This randomized controlled trial will evaluate the feasibility, acceptability, and initial efficacy of SleepWell24 compared to a usual care control condition during the first 60 days of PAP therapy among patients newly diagnosed with OSA.

Discussion: SleepWell24 is an innovative, multi-component behavior change intervention, designed as a self-management approach to addressing the psychosocial determinants of adherence to PAP therapy among new users. The results will guide lengthier future trials that assess numerous patient-centered and clinical outcomes.
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http://dx.doi.org/10.1016/j.cct.2019.105908DOI Listing
February 2020

REM sleep atonia loss distinguishes synucleinopathy in older adults with cognitive impairment.

Neurology 2020 01 12;94(1):e15-e29. Epub 2019 Dec 12.

From the Mayo Center for Sleep Medicine (S.J.M., G.M.T., D.J.S., P.C.T., K.L.J., A.R.M., R.S., M.M.M., B.F.B., M.H.B., E.K.S.L.) and Departments of Neurology (S.J.M., P.V., B.F.B., M.H.S., E.K.S.L.), Health Science Research (R.S., M.M.M.), Psychology (M.M.M.), Radiology (K.K.), and Medicine (E.K.S.L.), Mayo Clinic and Foundation, Rochester, MN; Department of Neurology (H.-Y.J.), Providence Neurological Specialties-West, Portland, OR; and University of Minnesota Duluth (A.R.M.).

Objective: To determine whether quantitative polysomnographic REM sleep without atonia (RSWA) distinguishes between cognitive impairment phenotypes.

Background: Neurodegenerative cognitive impairment in older adults predominantly correlates with tauopathy or synucleinopathy. Accurate antemortem phenotypic diagnosis has important prognostic and treatment implications; additional clinical tools might distinguish between dementia syndromes.

Methods: We quantitatively analyzed RSWA in 61 older adults who underwent polysomnography including 46 with cognitive impairment (20 probable synucleinopathy), 26 probable non-synucleinopathy (15 probable Alzheimer disease, 11 frontotemporal lobar dementia), and 15 age- and sex-matched controls. Submentalis and anterior tibialis RSWA metrics and automated REM atonia index were calculated. Group statistical comparisons and regression were performed, and receiver operating characteristic curves determined diagnostic RSWA thresholds that best distinguished synucleinopathy phenotype.

Results: Submentalis-but not anterior tibialis RSWA-was greater in synucleinopathy than nonsynucleinopathy; several RSWA diagnostic thresholds distinguished synucleinopathy with excellent specificity including submentalis tonic, 5.6% (area under the curve [AUC] 0.791); submentalis any, 15.0% (AUC 0.871); submentalis phasic, 10.8% (AUC 0.863); and anterior tibialis phasic, 31.4% (AUC 0.694). In the subset of patients without dream enactment behaviors, submentalis RSWA was also greater in patients with synucleinopathy than in those without synucleinopathy. RSWA was detected more frequently by quantitative than qualitative methods ( = 0.0001).

Conclusion: Elevated submentalis RSWA distinguishes probable synucleinopathy from probable nonsynucleinopathy in cognitively impaired older adults, even in the absence of clinical dream enactment symptoms.

Classification Of Evidence: This study provides Class III evidence that quantitative RSWA analysis is useful for distinguishing cognitive impairment phenotypes. Further studies with pathologic confirmation of dementia diagnoses are needed to confirm the diagnostic utility of RSWA in dementia.
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http://dx.doi.org/10.1212/WNL.0000000000008694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011690PMC
January 2020

Prognostic Counseling for Patients With Idiopathic/Isolated REM Sleep Behavior Disorder: Should We Tell Them What's Coming? Yes.

Authors:
Erik K St Louis

Mov Disord Clin Pract 2019 Nov 1;6(8):667-668. Epub 2019 Oct 1.

Mayo Center for Sleep Medicine, and Sleep Behavior and Neurophysiology Laboratory, Departments of Neurology and Medicine, Division of Pulmonary and Critical Care Medicine Mayo Clinic College of Medicine and Science Rochester Minnesota USA.

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http://dx.doi.org/10.1002/mdc3.12814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856446PMC
November 2019

Submentalis Rapid Eye Movement Sleep Muscle Activity: A Potential Biomarker for Synucleinopathy.

Ann Neurol 2019 12;86(6):969-974

Mayo Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN.

Accurate antemortem diagnosis of parkinsonism is primarily based on clinical evaluation with limited biomarkers. We evaluated the diagnostic utility of quantitative rapid eye movement (REM) sleep without atonia analysis in the submentalis and anterior tibialis muscles in parkinsonian patients (53 synucleinopathy, 24 tauopathy). Receiver operating characteristic curves determined REM sleep without atonia cutoffs distinguishing synucleinopathies from tauopathies. Elevated submentalis muscle activity was highly sensitive (70-77%) and specific (95-100%) in distinguishing synucleinopathy from tauopathy. In contrast, anterior tibialis synucleinopathy discrimination was poor. Our results suggest that elevated submentalis REM sleep without atonia appears to be a potentially useful biomarker for presumed synucleinopathy etiologies in parkinsonism. ANN NEUROL 2019;86:969-974.
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http://dx.doi.org/10.1002/ana.25622DOI Listing
December 2019