Citations

Abstract 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.

Abstract Background The aim of this study was to evaluate the safety and efficacy of fecal microbiota, live-jslm (RBL; REBYOTA)—the first single-dose, broad consortia microbiota-based live biotherapeutic approved by the US Food and Drug Administration for preventing recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care (SOC) antibiotic treatment. Methods PUNCH CD3-OLS was a prospective, phase 3, open-label study, conducted across the US and Canada. Participants were aged ≥18 years with documented rCDI and confirmed use of SOC antibiotics. Participants with comorbidities including inflammatory bowel disease and mild-to-moderate immunocompromising conditions could be enrolled. A single dose of RBL was rectally administered within 24–72 hours of antibiotic completion. The primary endpoint was the number of participants with RBL- or administration-related treatment-emergent adverse events (TEAEs). Secondary endpoints included treatment success and sustained clinical response, at 8 weeks and 6 months after RBL administration, respectively. Results Overall, 793 participants were enrolled, of whom 697 received RBL. TEAEs through 8 weeks after administration were reported by 47.3% of participants; most events were mild or moderate gastrointestinal disorders. Serious TEAEs were reported by 3.9% of participants. The treatment success rate at 8 weeks was 73.8%; in participants who achieved treatment success, the sustained clinical response rate at 6 months was 91.0%. Safety and efficacy rates were similar across demographic and baseline characteristic subgroups. Conclusions RBL was safe and efficacious in participants with rCDI and common comorbidities. This is the largest microbiota-based live biotherapeutic study to date, and findings support use of RBL to prevent rCDI in a broad patient population. Clinical Trials Registration NCT03931941.

The ability to identify individuals in the prodromal phase of Parkinson’s disease has improved in recent years, raising the question of whether and how those affected should be informed about the risk of future disease. Several studies investigated prognostic counselling for individuals with isolated REM sleep behavior disorder and have shown that most patients want to receive information about prognosis, but autonomy and individual preferences must be respected. However, there are still many unanswered questions about risk disclosure or early diagnosis of PD, including the impact on personal circumstances, cultural preferences and specific challenges associated with different profiles of prodromal symptoms, genetic testing or biomarker assessments. This narrative review aims to summarize the current literature on prognostic counselling and risk disclosure in PD, as well as highlight future perspectives that may emerge with the development of new biomarkers and their anticipated impact on the definition of PD.

Short sleep duration is associated with future cardiovascular disease including hypertension, especially in females, but mechanistic evidence is largely lacking. Experimental sleep restriction has been shown to cause short sleep-mediated tachycardia and reduced heart rate variability, indicative of autonomic cardiac instability, in some but not all studies. Heart rate (HR) response to spontaneous cortical arousals can be regarded as an index of autonomic cardiac control given its characteristic temporal pattern. Whether the HR response to cortical arousals is altered during experimental sleep restriction remains unknown. We hypothesized that sleep restriction would result in augmented HR reactivity to spontaneous arousals, and that this response would be more marked in females. We studied 19 young, healthy subjects (eight females, age: 23.5 ± 5 years, body mass index [BMI]: 24.5 ± 3.6 kg/m2). In a randomized, crossover design, participants were tested during a normal sleep (NS, 9 hr sleep opportunity) or sleep restriction (SR, 4 hr sleep opportunity) study arm. Each 16-day study visit consisted of a 4-day study acclimation phase, 9-day experimental sleep perturbation segment, followed by a 3-day recovery period. An overnight polysomnography (PSG) study was conducted on study days 2, 5 and 11 (at baseline and after 1 and 7 days of restricted versus control sleep). A registered PSG technician provided sleep staging and spontaneous arousal scoring, which was confirmed by an investigator with sleep expertise (IMG). For each identified spontaneous arousal, the HR change was quantified for 30 cardiac cycles post-arousal onset and compared to a pre-arousal baseline (average HR 5 – 10 cardiac cycles prior to arousal). An arousal was considered valid for analysis if at least one minute of stage N2 or rapid eye movement (REM) sleep occurred following sleep stage transition and was at least 30 seconds apart from other sleep disturbance-related events (e.g., limb movement, apneic event, etc.). Given low prevalence of slow wave sleep (SWS) arousals, arousals occurring in that sleep stage were excluded from present analysis. Statistical analysis, including repeated measures ANOVA (RMANOVA, p < 0.05) with condition and time (cardiac cycles) as within-subjects factors and sex as the between-subjects factor, was conducted to compare the beat-to-beat HR response to arousal between study conditions. Additionally, average and peak HR responses to spontaneous arousals were compared via RMANOVA with condition and time (study days) as within-subjects and sex as between-subjects factors. HR response to spontaneous arousal in stage two and REM sleep was similar between NS and SR on study day 5 or day 11 (condition × time: p = 0.943, 0.865). Secondary analysis of average and peak HR responsiveness to spontaneous arousals in stage two and REM sleep between conditions and study days was also not statistically different (condition × time: p = 0.193, 0.185). Last, no significant sex differences were detected across comparisons (condition × time × sex: p > 0.05 for all). These findings suggest that a 9-day sleep restriction paradigm may not alter cardiac autonomic function in otherwise healthy adults. Future work is warranted to determine whether these results extend to individuals with established cardiovascular risk factors or cardiovascular disease. Support: NIH T32-DK007013, R01-114676, and CTSA grant UL1-TR002377. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract Introduction Quantitative rapid eye movement (REM) sleep without atonia (RSWA) recorded during polysomnography (PSG) represents loss of normal REM sleep atonia. RSWA is the neurophysiologic signature of REM sleep behavior disorder (RBD). Visually scored RSWA is a candidate biomarker for synucleinopathies. However, visual RSWA scoring requires expert scoring, limiting widespread application. We comparatively analyzed RSWA in DLB and iRBD using the automated Ferri REM Atonia Index (RAI). Methods We quantitatively analyzed the RAI in 17 DLB and 20 iRBD patients, compared to 20 controls using Hypnolab Software for Sleep Analysis (SWS Soft, Colognola ai Colli, Italy). PSG data were converted to European Data Format (.EDF), and the submentalis surface electromyogram (EMG) signal was notch-filtered at 60 Hertz and rectified. Automatically calculated RAI scores were comparatively analyzed across groups (DLB, iRBD, controls) using Kruskal Wallis H tests for group comparisons, and regression analyses determined relationships between diagnosis, age, and sex. Logistic regression ROC determined optimal RAI for distinguishing iRBD from DLB. When interpreting RAI, lower values represent greater amounts of RSWA, and higher values represent more normal REM atonia. Results Median age was no different between DLB (72.6 years), iRBD (69.4 years), and controls (68.0 years). The DLB group consisted of 16 men and one woman, the iRBD group had 18 men and 2 women, and controls were comprised of 16 men and 4 women. Median RAI was lowest in DLB (0.32), intermediate in iRBD (0.84) and highest in controls (0.96), indicating a gradient in RSWA amounts from DLB patients (highest) to controls (lowest). Regression demonstrated diagnosis independently predicted RAI, controlling for age and sex (adjusted R2=0.64, p=0.0001). The RAI that optimally distinguished iRBD from DLB was 0.48 (specificity 85%, sensitivity 76%, AUC=0.88). Conclusion The RAI demonstrated a clear gradient throughout the Lewy body spectrum; highest (indicating lowest RSWA amounts) in controls, intermediate in iRBD, and lowest (indicating greatest RSWA) in DLB. The RAI is a promising, time efficient and broadly applicable candidate biomarker for DLB and iRBD. Automated quantitative RSWA could be a valuable tool for deep phenotyping throughout the Lewy body disease spectrum. Support (if any) This study was supported by: U01NS100620, R34AG056639, U19AG071754, and P30AG62677.

Abstract Introduction Central sleep apnea (CSA) is associated with several medical conditions (e.g., heart failure, atrial fibrillation) and medications (e.g., opioids, ticagrelor, sodium oxybate and valproic acid). We report a case of a 31-year-old female with bipolar disorder treated with valproic acid diagnosed with central sleep apnea on polysomnography, which revealed an apnea-hypopnea index of 150/hour, central apnea index of 112/hour, nadir oxygen saturation of 78%, and 38.6 minutes with oxygen saturation ≤ 88%. Echocardiogram, electrocardiogram, brain magnetic resonance imaging, serum acylcarnitine and serum ammonia levels were unremarkable. Total and free serum valproic acid level was 33 and &lt; 3 mcg/mL, respectively. Two cases of central sleep apnea associated with valproic acid use, both of which improved upon discontinuation of valproic acid, have been reported in the literature. We started the patient on positive airway pressure and suggested she taper off valproic acid and then repeat polysomnography. Given the possible association between central sleep apnea and valproic acid use, we retrospectively analyzed patients receiving valproic acid at time of polysomnography. Methods We retrospectively identified patients between 2005-2017 who were prescribed valproic acid (n=6,169), and of these 72 received valproic acid within 90 days of polysomnography. After chart review, we were able to confirm that 29 received valproic acid at time of polysomnography via blood levels or clear chart documentation. Results Four patients (13.8 %) demonstrated a central apnea index ≥ 5 per hour (mean apnea-hypopnea index 39.2/hour +/- 32.2/ hour including a central apnea index 11.7 +/- 6.6/hour) during polysomnography. Although one patient (3.4 %), a 2-year-old child with Dravet syndrome and refractory/drug resistant generalized epilepsy, was diagnosed clinically with central sleep apnea, the other three patients were diagnosed with obstructive sleep apnea and had other potential reason(s) for the elevated central apnea index (e.g., opioid use as needed for migraines). Conclusion Our case describes a third report of central sleep apnea possibly associated with valproic acid, and our retrospective study indicates that this association is rare. Prospective sleep studies on patients before and after receiving valproic acid are warranted to determine if valproic acid causes central sleep apnea. Support (if any)