We recently proposed dopamine D3 receptor (D3R) antagonists as a potential therapy for restless legs syndrome (RLS). To test this hypothesis, we evaluated two selective D3R ligands, PG01042 and PG01037, in a brain iron-deficient rat model of RLS. Their biochemical properties were also characterized and compared with pramipexole, a commonly used D2-like receptor agonist for RLS. Periodic leg movements (PLM) during sleep and wake and sleep fragmentation were analyzed in rats with an iron deficient diet during the postweaning period. Go protein activation and β-arrestin1 and β-arrestin2 recruitment were analyzed with BRET methodology in HEK-293T cells expressing D3Rs and in cells co-transfected with D3R and D1R. Molecular dynamic simulations were additionally performed to define the distinct molecular profiles of PG01042 and PG01037. In iron-deficient rats, PG01042 and PG01037 produced opposite behavioral effects, with PG01042 dose-dependently reducing motor symptoms and improving sleep quality, whereas PG01037 dose-dependently exacerbated motor symptoms without improving sleep. Compared with pramipexole, PG01042 behaved as a D3R partial agonist at both G protein activation and β-arrestin recruitment. In contrast, PG01037 behaved as a partial agonist for β-arrestin recruitment while exhibiting inverse agonism at G protein activation. Co-transfection with the D1R abrogated the partial efficacy of both compounds at β-arrestin recruitment. The differences in G protein activation between both ligands were attributed to subtle variations in the positioning of the chloro substituents on their 2,3-dichlorophenyl moiety. These findings highlight the therapeutic potential of D3R ligands with the distinct pharmacological profile of PG01042 in RLS.

Sleep duration is a key component of overall sleep health, but prior population-level studies characterizing this have relied on brief self-report questions (often one item) or used different objective devices within the same study. We examined the normal variation of sleep duration in an adult population using a single consumer-grade wearable device with a unified algorithm. Retrospective cohort study conducted in the United States. Data were analyzed from 274,128 U.S.-based adults aged 20 to 69 who used a Samsung Galaxy Watch between February 2023 and April 2023; participants were included if they had ≥20 valid weekdays and ≥8 valid weekend days of data. Sleep duration was the primary outcome, defined as the longest continuous nighttime sleep period between 6:00 p.m. and 6:00 a.m. averaged over a three-month period. Sleep duration and weekday-weekend variability were examined across age groups and by sex using descriptive statistics and independent t-tests. Overall, average sleep duration was 7.57 hours, with a 10th-90th percentile range of 6.5 to 8.9 hours. Sleep duration was shortest in the 40-49 year old group (7.54 hours) and longest in the 60-69 year old group (7.75 hours; p < .001). Overall, 23.0% of adults slept less than 7 hours, more commonly among those aged 40-49 (25.1%) and 50-59 (24.7%). Across all age groups, weekend sleep was longer than weekday sleep by an average of 28 minutes, with the largest gap in the 40-49 year old group (34 minutes), and the smallest in the 60-69 year old group (20 minutes). Women consistently slept longer than men (+18 minutes on average), and exhibited greater between-subject variability in total sleep duration (SD = 1.61 hours for women vs. 1.54 hours for men). This study demonstrates considerable variability in objectively measured sleep duration across adulthood, spanning a broad range and differing by age groups and sex. These findings provide reference distributions that may inform clinical expectations and public health messaging regarding sleep duration.

Large long-term assessments of opioid effectiveness and dose stability for those with dopamine agonist augmentation of restless legs syndrome (RLS) are lacking. We present 5-year longitudinal findings from the National RLS Opioid Registry. Five-hundred participants taking opioids for RLS were interviewed at baseline about RLS symptoms, opioid medications and doses, sleep, and mental health. Participants subsequently completed online surveys every 6months. Changes from baseline to 5-year follow-up in morphine milligram equivalents (MMEs), excluding those taking buprenorphine, were evaluated by group-based trajectory modeling. Independent associations with opioid dose changes were determined using multiple logistic regression. At 5 years of follow-up, 410 (364 excluding any taking buprenorphine) participants remained for this analysis. Most participants are female (57.1 per cent) and white (98.3 per cent), with an average age of 64.7 (±10.6) and 88.8 per cent had a history of dopamine agonist augmentation. The median daily MME at 5 years was 37.5 (equivalent to methadone 8.0mg or oxycodone 25.0mg), an increase of 7.5 MME from baseline. Opioid doses increased from baseline to 5 years in 49.5 per cent of participants and decreased in 20.0 per cent of participants. Group-based trajectory analysis identified four distinct groups: decrease (3.4 per cent of participants; average MME change = -15.7 ± 12.4), no/little change (66.1 per cent of participants; average MME change = 1.5 ± 8.0), small increase (23.9 per cent of participants; average MME change = 22.0 ± 11.6), and large increase (3.4 per cent of participants; average MME change = 49.2 ± 18.7). RLS severity was stable from baseline (13.3 ± 9.6) to 5 years (13.1 ± 9.0) according to the International Restless Legs Syndrome Study Group Severity Scale. Opioid doses in augmented RLS remain largely stable over 5 years of follow-up. Low-dose opioids provide an effective long-term option for augmented RLS.

Genetic susceptibility to Alzheimer's disease (ad) may influence the extent to which environmental factors shape cognition, with individuals at higher genetic risk potentially exhibiting greater sensitivity to environmental exposures. Sleep, an important factor for both cognitive function and ad risk, may further moderate genetic influences (A), including both measured (AP) and latent (AL) components, as well as shared (C) and non-shared environmental (E) contributions to cognition. This study leveraged data from the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium (N = 3894; 1947 complete twin pairs, 842 monozygotic (MZ) pairs and 1105 dizygotic (DZ); Average age = 62.36years, 38.75% female). Across six cognitive abilities, we examined whether an ad polygenic score (ad-PGS) moderated environmental influences on cognitive performance. We also examined whether sleep moderated genetic and environmental contributions on cognitive performance. Although the ad-PGS accounted for a negligible proportion of genetic variance as a main effect (B's = -0.004 to 0.02), we observed environment-by-PGS interactions. Increasing genetic risk for ad was associated with lower contributions from environmental experiences unique to each individual, on episodic memory, working memory, and verbal ability (B's = -0.03 to -0.05). These interaction effects, albeit small, were primarily observed with the ad-PGS including the APOE region. Hence, the role of person-specific environments on cognitive functioning was boosted for those at lower genetic risk for ad but reduced at greater genetic risk for ad. Although sleep moderation was minimal, results suggest that poorer sleep influences genetic influences on cognitive functioning.

The emergence of potent and durable obesity pharmacotherapies has the potential to drastically alter the treatment landscape for comorbid obesity and OSA. Recent clinical trials examining the impact of weight loss on OSA have demonstrated marked improvements in both weight and OSA severity, leading to the first FDA approval of a weight loss medication for OSA. However, several questions remain unanswered regarding which trial and management strategies will best optimize real-world outcomes for patients with comorbid obesity and OSA in an equitable manner.

High night-to-night variability in obstructive sleep apnea (OSA) severity is associated with cardiovascular risk factors such as high blood pressure and pulse wave velocity, yet associations with cardiovascular events remains unknown. This study investigates the association of multi-night OSA severity and night-to-night variability with the prevalence of non-fatal major adverse cardiovascular and cerebrovascular events (MACCEs). Multi-night data were collected from people who purchased and used an FDA-cleared under- mattress sensor to track nightly OSA severity (apnoea-hypopnea index-AHI) and completed questionnaires on physician-diagnosed health conditions between 10/2022-12/2024. Mean OSA severity and variability (AHI standard deviation) were calculated over 6-months preceding questionnaire data collection. The primary outcome was a composite of non-fatal MACCEs, including myocardial infarction or heart attack, stroke, angina pectoris or coronary artery disease, and congestive heart failure. Logistic models assessed associations between OSA severity and variability with MACCE prevalence. Among 3,159 participants (19% female, aged 49±13 years, BMI of 29±6 kg/m2), 142 (4.5%) MACCE cases were reported. Participants with moderate-severe OSA had a higher odds of MACCEs versus those without OSA (OR [95%CI]; 1.45[0.93, 2.25]). High night-to-night OSA variability (75th vs. 25th; 8.0 vs. 2.8 events/h) was associated with 34% higher odds of having a MACCE, independent of OSA severity and other confounders (1.34[1.04, 1.72]). High night-to-night variability in OSA severity is associated with higher odds of non-fatal MACCEs. These novel findings underscore the need for prospective trials to investigate the potential causal mechanisms between variability in OSA severity and incident cardiovascular events.