Louis, Erik K. St.

ABSTRACTBackgroundRapid eye movement (REM) sleep behavior disorder (RBD) occurs occasionally in essential tremor (ET), but polysomnographic REM sleep without atonia (RSWA) analyses have been sparse.ObjectiveTo characterize the amount and distribution of polysomnographic RSWA, the electrophysiologic substrate of RBD, in patients with Parkinson's disease (PD) and ET.MethodsWe 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.ResultsSM 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, P ≤ 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.ConclusionsElevated 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.

Abstract Introduction Sleepiness has been associated with functional and cognitive decline, and may present with excessive daytime sleepiness (EDS) and/or increased sleep duration. We investigated whether sleepiness and changes in sleep patterns are associated with FDG-PET levels in wake-promoting regions. Methods From the Mayo Clinic Study of Aging cohort, we identified 373 cognitively-unimpaired middle-aged and older adults (mean +/- s.d. 66.1 +/- 13.2 yo) who underwent FDG-PET. EDS was defined as ESS score >=10. Changes in sleep patterns (sleeping more, less, or no change) were assessed using question #16 of the Beck Depression Inventory-2. We used probabilistic maps to create regions of interest (ROIs): the locus coeruleus (LC), posterior lateral hypothalamus (PLH), and the basal forebrain divided in 1) medial septum/diagonal band of Broca (MS/DB) and 2) nucleus basalis of Meynert (nbM). FDG-PET levels were referenced to the pons (SUVR). In this cross-sectional analysis, we fit linear models to assess the association between EDS and changes in sleeping patterns with FDG SUVR in in each ROI, while controlling for age, sex, education, BMI, witnessed apneas, and cardiovascular risk factors. Results 10.5% had EDS, 15% reported sleeping more and 21% reported sleeping less than usual. 30.7% of participants with EDS reported sleeping more, 25.6% less, and 43.5% the same. EDS was associated with an elevation in FDG-PET SUVR in the MS/DB region (.035 [95% CI .008; .063], p=.012), while sleeping more was associated with a decrease in FDG-PET SUVR in the same region (-.027 [95%CI -.052; -.002], p=.036). Sleeping less was associated with an increase in FDG-PET SUVR in the PLH (.021 [95% CI .005; .03], p=.019). No associations were found in other ROIs. Conclusion Our results suggest that sleepiness and changes in sleep patterns in cognitively-unimpaired middle-aged and older adults were associated with measurable metabolic changes in areas of the brain involved in sleep and wakefulness. Further research should clarify whether these findings could represent different phenotypes of sleepiness with potential diagnostic and prognostic implications. Support NIA/NIH

Abstract Introduction Voluntary sleep curtailment decreases insulin sensitivity. However, molecular mechanisms underlying impaired insulin signaling are not completely understood. To gain molecular insights, we examined the transcription of known cellular insulin-signaling regulators in adipose tissue obtained from subjects undergoing experimental sleep restriction. Methods Nineteen healthy subjects (males: 11; age: 19 - 36 years; BMI: 24.5 ± 3.6 kg/m2) underwent a normal (9 hours/night) and a restricted sleep (4 hours/night) sequence in a random order. Each inpatient stay included a screen visit followed by 4 days of acclimation and 9 days of experimental phase consisting of a controlled sleep opportunity. Eucaloric diet was provided to ensure weight maintenance. Abdominal fat sample was obtained at the screen and end of the experimental phase. mRNA was quantified by RT-PCR. Fasting morning blood draws were obtained at the end of acclimation and experimental phases. Mixed models were used for analysis. Results mRNA expression did not differ in normal and restricted sleep condition for SOCS3 [changes in normal Vs. restricted sleep, 0.02 (0.11, -0.01) Vs. 0.01 (0.12, -0.07), p=0.33], PTEN [-0.22 (0.18, -0.39) Vs. -0.10 (0.21, -0.20), p=0.22], PTB1B [-0.003 (0.04, -0.07) Vs. -0.01 (0.06, -0.06), p=0.74] and Cav-1 [-2.45 (0.78, -8.39) Vs. -6.31 (1.68, -8.29), p=0.34]. Further, transcription of insulin-receptor also did not change [0.01 (0.07, -0.06) Vs. -0.03 (0.09, -0.07), p=0.92]. However, within group analysis show significant decreases in Cav-1 mRNA only during sleep restriction (normal: p=0.09; restricted: p=0.003). Importantly, restricting sleep duration was associated with lowering of insulin (0.6 ± 1.9 Vs. -1.6 ± 1.7 uIU/ml; p=0.003), no change in glucose (-1.5 ± 3.8 Vs. -3.7 ± 4.12 mg/dl, p=0.06) and improvement in HOMA-IR index (0.12 ± 0.44 Vs -0.42 ± 0.43, p=0.002). Conclusion Chronic sleep restriction does not alter the transcription of cell-signaling regulators in abdominal adipose tissue. Moreover, restricting sleep duration without increasing calorie intake did not seem to decrease insulin sensitivity as determined by HOMA-IR. Support NIH grants HL114676, Mayo Clinic CCaTS UL1 TR002377; AHA grant 13POST16420009 to NC

Abstract Introduction Sleep disturbances, including rapid eye movement (REM) behavior disorder (RBD), are known manifestations of voltage-gated-potassium-channel-complex VGKC-IgG seropositivity (VGKC+). Discovery of leucine-rich, glioma inactivated protein 1 (LGI1) and contactin-associated protein 2 (CASPR2) have refined our understanding of VGKC+. VGKC+ without LGI1/CASPR2-IgG (“double-negative”) has lost its clinical significance. Previous detailed sleep analysis of these subtypes has been limited. Methods We performed a retrospective study to characterize clinical and polysomnographic features of LGI1/CASPR2 seropositive (LGI1+/CASPR2+) and VGKC double-negative patients, including quantitative REM sleep without atonia (RSWA). Quantified RSWA was compared to matched controls and normative RSWA percentiles. Results Eleven LGI1+/CASPR2+ (LGI1+, 9) and twelve VGKC double-negative patients were analyzed. Insomnia was seen in 55% of LGI1+/CASPR2+ and 8% of VGKC double-negative patients (p=0.05). The LGI1+/CASPR2+ group had reduced slow wave sleep compared to the VGKC double-negative group. Five LGI1+ patients had clinical dream enactment behavior (DEB). Eight LGI1+ patients met quantitative diagnostic levels of RSWA. Higher RSWA levels were seen in the LGI1+/CASPR2+ group. Ten LGI1+/CASPR2+ patients received immunotherapy; all ten neurologically benefited with sleep benefits in 6/10. Conclusion Sleep disorders such as insomnia and RBD are part of the LGI1/CASPR2 autoimmune phenotype. Objective sleep manifestations can be seen on polysomnogram in the form of reduced N3 and elevated RSWA as compared to controls. Quantitative RSWA analysis identified RBD in more LGI1+ patients than clinical report or qualitative RSWA. In this study, RBD was only seen with LGI1+, not CASPR2+. The intermediate RSWA levels of the VGKC double-negative patients may suggest a spectrum of abnormal motor activity in these related antibodies. Additional studies are needed to further explore the biomarker potential of quantitative RSWA in autoimmune neurological conditions. Support This project was supported by the National Center forResearch Resources, National Institutes of Health, through Grant Number 1 UL1 RR024150- 01.

Abstract Introduction 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. Patients who received a diagnosis of phenoconversion within 3 months of autonomic testing were excluded. 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 in- and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; 6 developed PD, the other 6 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 (p=0.08 for each). Conclusion Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal and adrenergic 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. Support

Abstract Introduction Post-traumatic stress disorder (PTSD) is characterized by persistent mental and emotional stress following one or more significant physical or psychological traumatic incidents earlier in life. Vivid recall of the events, including traumatic nightmares, and prominent sleep disturbance are usual in PTSD. Previous studies have suggested that PTSD may share some clinical features with idiopathic REM sleep behavior disorder (iRBD) including altered REM sleep without atonia (RSWA) levels. Our group has previously found evidence for altered RSWA control in patients with psychiatric disease, including a pilot sample of PTSD patients with iRBD. We aimed to comparatively analyze RSWA levels between patients with PTSD, PTSD and RBD (PTSD+RBD), iRBD, and controls. Methods We selected 18 PTSD, 18 PTSD+RBD, 15 iRBD, and 51 healthy control patients matched for age and sex from the Mayo Clinic Center for Sleep Medicine’s polysomnography database for RSWA quantification. RSWA amounts in the submentalis (SM) and anterior tibialis (AT) were quantitatively analyzed as a percentage of REM sleep duration, in accordance with previously published methods. Non-parametric analyses were performed to compare RSWA, patient demographics, and PSG data across groups. Significance was set at p < 0.016. Results Patients with PTSD had significantly higher RSWA than controls in all RSWA density measures (p < 0.016 for all). All measures of RSWA, excluding average SM duration, were significantly greater in PTSD+RBD patients compared with controls (p < 0.016 for all). Within the PTSD group, patients on antidepressants did not have significantly higher RSWA in any of the measures. PTSD+RBD patients had significantly higher SM Phasic, AT Any, SM+AT Any, and Tonic RSWA measures than PTSD patients (p < 0.016 for all). Conclusion PTSD patients have significantly higher RSWA than controls, with PTSD+RBD patients having higher RSWA levels than PTSD patients. These data provide the first evidence for abnormal RSWA control in patients with chronic PTSD. This provides evidence of a unique biology in PTSD that could imply a future risk for neurodegenerative disease in PTSD similar to RBD patients. Further prospective studying will need to be performed on patients with PTSD to understand the unique biology. Support

Abstract 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