Sleep最新文献

Several dopaminergic compounds, including the clinically used pramipexole, are labeled as preferential dopamine D3 receptor (D3R) agonists based on their moderately higher affinity for the D3R versus other D2-like receptor subtypes. It is therefore generally believed that D3R is the main target for their initial therapeutic response in restless legs syndrome (RLS). Here, we review the results of recent comprehensive pharmacological studies that demonstrate that in addition to the binding affinities of D3R agonists, their functional responses at the different D2-like receptors depend on other pharmacodynamic factors, including intrinsic efficacy, biased agonism, functional efficacy, and receptor heteromerization, and pharmacokinetic factors, including brain penetrability. When considering all these factors, the short isoform of the D2 receptor (D2SR) localized in the dopaminergic neurons and D2SRs and D4Rs localized in corticostriatal glutamatergic terminals become preferential targets of low doses of these D2-like receptor agonists. On the other hand, higher doses are necessary to promote activation of postsynaptic striatal D3Rs forming heteromers with D1Rs, which could be associated with the phenomenon of augmentation, the worsening of RLS symptoms with their chronic use. The putative role of spinal D3Rs, especially with the periodic leg movements of sleep component of RLS, is also discussed. This analysis should provide therapeutic clues for better targeting of the dopamine receptor subtypes involved in the therapeutic and not in the secondary effects of D2-like receptor agonists in RLS. Statement of Significance We discuss recent pharmacological studies demonstrating that the targets of the therapeutic effects of dopamine receptor agonists in restless legs syndrome depend on more than just binding affinities. Several other pharmacodynamic and pharmacokinetic factors also need to be considered when evaluating the main dopamine receptor subtype involved. These studies suggest that striatal presynaptic D2 receptors (D2Rs) and D4Rs are preferentially involved in the therapeutic effects of dopamine receptor agonists, while striatal postsynaptic D1Rs and D3Rs are involved in the worsening of RLS symptoms with their chronic use. The putative role of spinal D3Rs, especially with the periodic leg movements of sleep component of RLS, is also discussed.

Study objectives: Rest-activity rhythm characteristics have been linked to a wide range of health conditions; however, the molecular mechanisms underlying these associations are not well understood. This study is the first of two studies aiming to use an untargeted approach to identify metabolomic markers associated with rest-activity rhythm characteristics and focuses on older men.

Methods: The study included 950 participants from the Osteoporotic Fractures in Men study. Multiple parametric and non-parametric variables of rest-activity rhythms were derived from actigraphy data. A total of 848 metabolites were measured from fasting blood samples using an untargeted approach. Multiple linear regression models and Ingenuity Pathway Analysis (IPA) were used to identify metabolomic profiles associated with rest-activity variables.

Results: We found 65 metabolites, mostly amino acids and lipids, that were significantly associated with at least one of the primary rest-activity variables (i.e. pseudo-F-statistic, intradaily variability, and interdaily stability). These metabolites were from various biochemical pathways, including diacylglycerol, plasmalogen, lysoplasmalogen, and amino sugar metabolism. The IPA suggested that these metabolites may be implicated in various diseases and functions, particularly immune and inflammatory diseases, and identified the PEX2-PEX5 network as a significantly enriched gene-regulation pathway.

Conclusions: Our findings expand the current knowledge about the relationship between diurnal behaviors and human metabolism, and provide new evidence regarding mechanistic pathways that may mediate the adverse health effects of impaired rest-activity rhythms in older men. Statement of Significance In this metabolomics study in older men, we found a large number of metabolites that were associated with rest-activity rhythms. Our findings expand the current knowledge about the relationship between circadian-regulated diurnal behaviors and human metabolism, reinforce the critical role of circadian function in health and diseases, and provide new evidence regarding mechanistic pathways that may mediate the adverse effects of circadian disruptions. Our findings also point to ample future directions for further research to further elucidate the relationships among rest-activity rhythms, metabolomic profiles, and disease risk, which may help identifying intermediate targets for developing disease therapies and developing models for disease risk prediction and management.

Study objectives: Native Americans (NAs) experience higher rates of chronic pain than other U.S. racial/ethnic groups. Sleep and pain share a bidirectional relationship, but sleep impacts pain more than the reverse. NAs experience high rates of sleep problems; thus, sleep may contribute to the NA pain disparity. To date, there have been no intensive longitudinal assessments of sleep and pain to assess whether sleep-pain temporal relationships differ across racial/ethnic groups, including NAs.

Methods: To address this research gap, a secondary analysis of a clinical trial of a mobile health intervention for anxiety and/or depression sample was conducted. NA (n = 199), White (n = 205), Black (n = 198), and Hispanic adults (n = 199) completed ecological momentary assessments of daily sleep quality, sleep duration, and morning and evening pain intensity for 6-months. Dynamic structural equation modeling was used to assess cross-lagged, temporal relationships between sleep and pain, while controlling potential confounds.

Results: As expected, there was a reciprocal sleep-pain relationship; lower sleep quality was associated with higher next-morning pain and higher pain was associated with lower next-day sleep quality. The sleep to pain path was stronger than the reverse. Evening pain was also associated with next-night sleep quality. Sleep duration was not temporally related to pain. There was a stronger sleep quality-pain association in NAs compared to Black participants, but no other racial/ethnic difference was significant.

Conclusions: This is the first study to show that sleep-pain relationships extend to NAs and other minoritized groups, but poor sleep may not fully account for NA pain disparities.

Clinical trial: Mobile Health and COVID-19, https://clinicaltrials.gov/study/NCT05074693, NCT05074693 Statement of Significance This is the first study to examine sleep-pain relationships in Native Americans (NAs), a group that experiences significant pain disparities. Sleep quality was related to morning pain and morning pain was related to sleep quality, but the effect of sleep quality on pain was stronger than the reverse. Similar relationships were found in other racial/ethnic groups (Black, Hispanic, White), except that the sleep-pain path was stronger in NAs than Black participants. Together, these findings suggest that poor sleep contributes to pain and that pain contributes to poor sleep in all groups and does not fully account for the NA pain disparity.

Study objectives: This study investigated the associations between changes in sleep dimensions, cognitive transition, and incident dementia.

Methods: Using data from the UK Biobank (UKB) and the China Health and Retirement Longitudinal Study (CHARLS), we systematically investigated longitudinal changes in eight distinct sleep dimensions, including sleep duration, chronotype, and napping, etc. Cognitive transitions were assessed through changes in standardized cognitive test scores in the UKB and categorized cognitive states (normal cognition, mild cognitive impairment [MCI], and probable dementia) in CHARLS. We used generalized linear models for cognitive scores, logistic regression for cognitive status transitions, and Cox models for dementia risk associated with changes in sleep dimensions.

Results: A total of 8994 and 14 720 participants were involved in the change-to-change analyses and change-to-dementia analyses, respectively. Compared to individuals who maintained their original sleep dimensions, those who changed their sleep duration to the optimal range (7-8 h/day) or shifted chronotype to morningness exhibited higher overall cognitive scores (β = 0.15, p = .037; β = 0.23, p = .011). Conversely, transitioning to non-optimal sleep duration (OR = 1.07, p = .034) or declining overall sleep quality (OR = 1.06, p = .006) increased the risk of cognitive decline from normal baseline. Napping cessation increased the risk of MCI progression to dementia (OR = 1.16, p = .001). Transitioning to non-optimal sleep duration (HR = 1.82, p = .005) and discontinuing napping (HR = 2.13, p = .015) were associated with a higher incident of all-cause dementia.

Conclusions: Maintaining optimal or optimizing sleep duration, preserving napping habits, and transitioning to a morning chronotype are essential for dementia prevention.

Study objectives: Insomnia is highly prevalent among postmenopausal women and is associated with adverse health outcomes, highlighting the need to identify modifiable determinants of sleep. Diet and sleep are interrelated; however, few studies have evaluated longitudinal associations of complete dietary patterns with incident insomnia in postmenopausal women. This study evaluates prospective associations of established diet quality metrics with insomnia in the Women's Health Initiative Observational Study (WHI-OS).

Methods: The WHI-OS enrolled 93 676 postmenopausal women from across the United States. Alternate Mediterranean (aMed) diet and Dietary Approaches to Stop Hypertension (DASH) diet quality scores were quantified from a Food Frequency Questionnaire at baseline and dichotomized scores using a data-driven approach. Insomnia was assessed at baseline and Year 3 using the WHI Insomnia Rating Scale. Multivariable logistic regression models adjusted for sociodemographic, lifestyle, and health factors evaluated associations of baseline diet quality with incident insomnia and longitudinal insomnia status (stable/new onset insomnia vs. stable absence/remission of insomnia).

Results: Among women without insomnia at baseline (n = 50 644), good vs. poor diet quality at baseline was associated with lower risk for incident insomnia at 3-year follow-up (OR [95% CI], aMed: 0.925 [0.879-0.974], p=.003; DASH: 0.937 [0.891-0.985], p=.01]). In longitudinal analyses (n = 74 513), greater baseline adherence to aMed and DASH diets related to 6.3% (0.903-0.971) and 8.5% (0.883-0.948) lower odds, respectively, of having stable or new onset insomnia over 3 years (both p<.005).

Conclusions: Better diet quality predicts lower insomnia risk in postmenopausal women. Clinical trials are needed to determine whether strategies to enhance diet quality improve insomnia symptoms.

Clinical trial information: The Women's Health Initiative Observational Study is registered on Clinicaltrials.gov #NCT00000611: https://clinicaltrials.gov/study/NCT00000611.