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Background: Irregular sleep-wake timing may cause circadian disruption leading to several chronic age-related diseases. We examined the relationship between sleep regularity and risk of all-cause, cardiovascular disease (CVD), and cancer mortality in 88,975 participants from the prospective UK Biobank cohort., Methods: The sleep regularity index (SRI) was calculated as the probability of an individual being in the same state (asleep or awake) at any two time points 24 hr apart, averaged over 7 days of accelerometry (range 0-100, with 100 being perfectly regular). The SRI was related to the risk of mortality in time-to-event models., Results: The mean sample age was 62 years (standard deviation [SD], 8), 56% were women, and the median SRI was 60 (SD, 10). There were 3010 deaths during a mean follow-up of 7.1 years. Following adjustments for demographic and clinical variables, we identified a non-linear relationship between the SRI and all-cause mortality hazard ( p [global test of spline term]<0.001). Hazard ratios, relative to the median SRI, were 1.53 (95% confidence interval [CI]: 1.41, 1.66) for participants with SRI at the 5th percentile (SRI = 41) and 0.90 (95% CI: 0.81, 1.00) for those with SRI at the 95th percentile (SRI = 75), respectively. Findings for CVD mortality and cancer mortality followed a similar pattern., Conclusions: Irregular sleep-wake patterns are associated with higher mortality risk., Funding: National Health and Medical Research Council of Australia (GTN2009264; GTN1158384), National Institute on Aging (AG062531), Alzheimer's Association (2018-AARG-591358), and the Banting Fellowship Program (#454104)., Competing Interests: LC, RS, SY, NG, MC, AB, MP No competing interests declared, (© 2023, Cribb et al.)

Study Objectives: A recent clinical trial demonstrated that melatonin treatment was effective in improving self-perceived sleep quality in patients with traumatic brain injury (TBI); however, it remains unclear which patients benefited from melatonin treatment. To that end, findings from the clinical trial were re-examined to identify possible predictors of treatment response., Methods: Hierarchical multiple regression was used to identify patient characteristics, TBI injury characteristics, and self-report measures assessing sleep, fatigue, mood, and anxiety symptomatology that may uniquely explain a change in self-reported sleep quality scores (follow-up minus baseline score) as assessed by the Pittsburgh Sleep Quality Index (PSQI)., Results: After controlling for patient demographic and TBI injury-related variables, baseline self-report measures of sleep, fatigue, mood, and anxiety explained an additional 32% of the variance in change in PSQI scores. However, only baseline PSQI score made a unique and statistically significant contribution (β = -0.56, P = .006). After controlling for patient and TBI characteristics, baseline PSQI scores further explained 27% of the variance in change in PSQI scores ( R 2 change = .27, F 1, 27 change = 11.79, P = .002). The standardized β for baseline PSQI score revealed a statistically significant negative relationship with change in PSQI score (β = -0.54, P = .002), revealing that higher PSQI score at baseline was associated with better sleep outcomes., Conclusions: In a sample comprising predominantly severe TBI and comorbid insomnia, participants who report poorer sleep quality have the most to gain from melatonin treatment irrespective of time since injury, demographics, fatigue, daytimes sleepiness, mood, and anxiety symptomology., Clinical Trial Registration: Registry: Australian New Zealand Clinical Trials Registry; Name: Efficacy of Melatonin for Sleep Disturbance Following Traumatic Brain Injury; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=343083&showOriginal=true&isReview=true; Identifier: ACTRN12611000734965., Citation: Grima NA, Rajaratnam SMW, Mansfield D, McKenzie D, Ponsford JL. Poorer sleep quality predicts melatonin response in patients with traumatic brain injury: findings from a randomized controlled trial. J Clin Sleep Med. 2021;17(8):1545-1551., (© 2021 American Academy of Sleep Medicine.)

Background: Insomnia is a common condition affecting individuals of various ages. It is diagnosed on the basis of a self-reported complaint of poor sleep quality concomitant with daytime disturbances. If left untreated, insomnia is associated with a number of adverse health outcomes., Objective: The aim of this article is to review key diagnostic criteria, theories and assessment of insomnia., Discussion: Insomnia may be precipitated by stressful events. Unhelpful strategies employed by the individual to remedy sleep can perpetuate insomnia symptoms even after the stressful event subsides. Insomnia is often undiagnosed and undertreated, which is concerning given that untreated insomnia associated with a number of negative health outcomes. Diagnosis and treatment planning can be facilitated using self-report measures.

Background: Insomnia is a common condition affecting individuals of various ages that can be addressed using a range of validated treatments., Objective: The aim of this review is to outline current treatment approaches for insomnia disorder., Discussion: Current guidelines suggest cognitive behavioural therapy is the first-line treatment for insomnia. This may be complemented with short-term pharmacological intervention.

Background: The study aimed to determine the efficacy of melatonin supplementation for sleep disturbances in patients with traumatic brain injury (TBI)., Methods: This is a randomised double-blind placebo-controlled two-period two-treatment (melatonin and placebo) crossover study. Outpatients were recruited from Epworth and Austin Hospitals Melbourne, Australia. They had mild to severe TBI (n = 33) reporting sleep disturbances post-injury (mean age 37 years, standard deviation 11 years; 67% men). They were given prolonged-release melatonin formulation (2 mg; Circadin®) and placebo capsules for 4 weeks each in a counterbalanced fashion separated by a 48-hour washout period. Treatment was taken nightly 2 hours before bedtime. Serious adverse events and side-effects were monitored., Results: Melatonin supplementation significantly reduced global Pittsburgh Sleep Quality Index scores relative to placebo, indicating improved sleep quality [melatonin 7.68 vs. placebo 9.47, original score units; difference -1.79; 95% confidence interval (CI), -2.70 to -0.88; p ≤ 0.0001]. Melatonin had no effect on sleep onset latency (melatonin 1.37 vs. placebo 1.42, log units; difference -0.05; 95% CI, -0.14 to 0.03; p = 0.23). With respect to the secondary outcomes, melatonin supplementation increased sleep efficiency on actigraphy, and vitality and mental health on the SF-36 v1 questionnaire (p ≤ 0.05 for each). Melatonin decreased anxiety on the Hospital Anxiety Depression Scale and fatigue on the Fatigue Severity Scale (p ≤ 0.05 for both), but had no significant effect on daytime sleepiness on the Epworth Sleepiness Scale (p = 0.15). No serious adverse events were reported., Conclusions: Melatonin supplementation over a 4-week period is effective and safe in improving subjective sleep quality as well as some aspects of objective sleep quality in patients with TBI., Trial Registration: Identifier: 12611000734965; Prospectively registered on 13 July 2011.

Purpose of Review: Recent research has provided extensive characterization as to the frequency and nature of sleep disturbances following traumatic brain injury (TBI). This review summarizes the current state of knowledge and proposes future directions for research., Recent Findings: Complaints of sleep disturbance are common following TBI, and objective assessments of sleep largely corroborate these complaints. Sleep is often disturbed in the acute phase postinjury and can persist for decades, with the prevalence of sleep disorders higher in patients with TBI as compared with the general population. The factors causing sleep disturbance appear to involve numerous interrelated primary and secondary factors, including direct damage to vital sleep-regulating regions of the brain, alterations in the circadian system, lowered mood as well as increased anxiety and pain. The complex web of contributing factors implies that combination therapies targeting a number of putative causal mechanisms may yield the greatest success in terms of improving sleep postinjury., Summary: Sleep disturbance is a common consequence of TBI. Research is needed to ascertain the primary drivers of sleep disturbance postinjury to guide the development of targeted interventions. In the absence of a single mechanism, combination therapies may prove most fruitful.

Objective: Sleep disturbance is common in dementia, although it is unclear whether differences in sleep architecture precede dementia onset. We examined the associations between sleep architecture and the prospective risk of incident dementia in the community-based Framingham Heart Study (FHS)., Methods: Our sample comprised a subset of 321 FHS Offspring participants who participated in the Sleep Heart Health Study between 1995 and 1998 and who were aged over 60 years at the time of sleep assessment (mean age 67 ± 5 years, 50% male). Stages of sleep were quantified using home-based polysomnography. Participants were followed for a maximum of 19 years for incident dementia (mean follow-up 12 ± 5 years)., Results: We observed 32 cases of incident dementia; 24 were consistent with Alzheimer disease dementia. After adjustments for age and sex, lower REM sleep percentage and longer REM sleep latency were both associated with a higher risk of incident dementia. Each percentage reduction in REM sleep was associated with approximately a 9% increase in the risk of incident dementia (hazard ratio 0.91; 95% confidence interval 0.86, 0.97). The magnitude of association between REM sleep percentage and dementia was similar following adjustments for multiple covariates including vascular risk factors, depressive symptoms, and medication use, following exclusions for persons with mild cognitive impairment at baseline and following exclusions for early converters to dementia. Stages of non-REM sleep were not associated with dementia risk., Conclusions: Despite contemporary interest in slow-wave sleep and dementia pathology, our findings implicate REM sleep mechanisms as predictors of clinical dementia., (© 2017 American Academy of Neurology.)

Background: Sleep-wake disturbances are highly prevalent following traumatic brain injury (TBI), impeding rehabilitaion and quality of life. However, the mechanisms underlying these sleep disturnbances are unclear, and efficacious treatments are lacking. To investigate possible mechanisms underlying sleep disturbance in TBI, we examined characteristics of the circadian rhythm of melatonin, a hormone involved in sleep-wake regulation. We compared TBI patients reporting sleep disturbance with age- and gender-matched healthy volunteers., Methods: We conducted an overnight observational study with salivary melatonin samples collected hourly in 9 patients with severe TBI and 9 controls. Salivary dim light melatonin onset (DLMO) as well as melatonin synthesis onset (SynOn) and offset (SynOff) were used to determine circadian timing. Total overnight salivary melatonin production was calculated as the area under the curve from melatonin synthesis onset to offset., Results: Compared with healthy individuals, TBI patients showed 42% less melatonin production overnight (d = 0.87; P = .034). The timing of DLMO was delayed by approximately 1.5 hours in patients with TBI compared with controls (d = 1.23; P = .003)., Conclusions: In patients with TBI, melatonin production was attenuated overnight, and the timing of melatonin secretion was delayed. We suggest that disruption to the circadian regulation of melatonin synthesis is a feature of severe TBI, possibly contributing to the sleep difficulties that are commonly reported in this population., (© The Author(s) 2016.)

Low cerebral blood flow velocity is associated with cognitive decline. However, the association between pulsatile brain blood flow velocity and cognition has not been investigated. High pulsatile hemodynamic stress in the brain may impair cognitive function through damage to small cerebral vessels. The current objective was to examine the cross-sectional association of pulsatile and mean cerebral blood flow velocity with age and neuropsychological performance. We also examined whether cerebral blood flow velocity was associated with aortic pulse pressure, a measure of arterial ageing and aortic stiffness. Cerebral blood flow velocity was measured in the middle cerebral artery using Transcranial Doppler Ultrasonography (TDU) while neuropsychological performance was measured using a computerized cognitive test battery. Aortic pulse pressure was non-invasively derived from applanation tonometry of the radial artery. The sample comprised 160 healthy adults aged 50-70 years. Results indicated that increasing age correlated with lower mean (r=-0.23, p<0.01) and higher pulsatile (r=0.27, p<0.01) brain blood flow velocity. In multivariate adjusted models, both peripheral (β=0.28, p<0.05) and aortic (β=0.24, p<0.05) pulse pressure were associated with higher pulsatile flow velocity through the middle cerebral artery. In adjusted models, neither mean nor pulsatile cerebral blood flow velocity was associated with performance on any cognitive task. In conclusion, arterial ageing was associated with increased pulsatile hemodynamic stress in the brain. However, this was not associated with impaired neuropsychological performance., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Central (aortic) blood pressures differ from brachial pressures and may be more relevant to the study of cognitive function, given that blood is delivered to the brain through the central large arteries. Pulse-pressure amplification reflects the augmentation of blood pressure between the central and peripheral arteries, which diminishes with aging. We aimed to determine the association between central blood pressure and cognitive function in independently living adults aged 20 to 82 years (N = 493). In adjusted regression models, higher central systolic pressure and higher central pulse pressure were each associated with poorer processing speed, Stroop processing, and recognition memory. Lower amplification was associated with poorer Stroop processing, working memory, and recognition memory. Higher brachial systolic pressure and brachial pulse pressure were both associated with poorer Stroop processing. In summary, central pressures and amplification were sensitive indicators of cognitive aging, predicting aspects of cognitive performance not predicted by brachial blood pressure.

Background: Although arterial stiffness has recently been confirmed as a predictor of cardiovascular disease, the association between arterial stiffness and cognitive decline is less clear., Aim: We performed a systematic review and meta-analysis to examine the evidence for large artery stiffness as a cause of cognitive decline and dementia., Method: Electronic databases were systematically searched until September 2011 for studies reporting on the longitudinal relationship between any validated measure of large artery stiffness and cognitive decline or dementia. Meta-analysis was performed on four studies investigating the association between aortic pulse wave velocity and a decline in Mini-Mental State Examination scores., Results: Six relevant longitudinal studies were located, conducted over an average of 5 years follow up. Arterial stiffness was predictive of cognitive decline in five/six studies. In meta-analysis, higher aortic stiffness predicted lower Mini-Mental State Examination scores within the sample (β=-0.03, 95% confidence interval (CI): -0.06 to 0.01, n= 3947), although studies were not all homogeneous, and statistical heterogeneity was present (I(2) = 71.9%, P= 0.01). Removal of one study with a relatively younger cohort and lower median aortic stiffness found higher aortic stiffness to significantly predict cognitive decline (β=-0.04, 95% CI: -0.07 to -0.01, n= 3687) without evidence of heterogeneity (I(2) = 9.5%, P= 0.33). There was little research investigating the effects of aortic stiffness on the development of dementia., Conclusion: Aortic stiffness was found to predict cognitive decline in both qualitative review and quantitative analysis., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Fish oils, rich in long-chain n-3 PUFA, are known to reduce various risk factors for CVD. However, conclusive evidence regarding the benefits of n-3 on arterial stiffness, a risk factor for CVD, has not yet been established. Consequently, we conducted the first study aimed to quantify the effects of n-3 supplementation on arterial stiffness through meta-analysis. Multiple databases and clinical trial registries were systematically searched up until September 2010 for randomised and controlled adult human clinical trials to investigate the effects of long-chain n-3 fatty acids on arterial stiffness. No limits were set on dosage sizes or sample characteristics. A total of ten n-3 trials met the final inclusion criteria; four using pulse wave velocity (PWV) and six using arterial compliance, measured as capacitive compliance or systemic arterial compliance, as respective outcome measures. Meta-analysis revealed that n-3 was statistically significant in effectively improving both PWV (g = 0·33; 95 % CI 0·12, 0·56; P < 0·01) and arterial compliance (g = 0·48; 95 % CI 0·24, 0·72; P < 0·001). There was no evidence of heterogeneity or publication bias. Results were not influenced by changes in blood pressure, heart rate or BMI. The findings of the present study reveal that supplementation with n-3 offers a scientifically supported means of reducing arterial stiffness. Reduction in arterial stiffness by n-3 may account for some of its purported cardioprotective effects.

Background: Although dietary and nutrient interventions have been extensively studied as a means of improving arterial stiffness, to our knowledge no systematic analysis of the data has been conducted., Objective: The aim of the current study was to systematically review the human clinical trial data and qualitatively examine the efficacy of dietary and nutrient interventions in the treatment of arterial stiffness., Design: We systematically searched multiple databases until July 2010 for relevant randomized controlled human clinical trials of common dietary and nutrient interventions in the treatment of arterial stiffness. Located studies were subject to strict inclusion criteria and objectively assessed for scientific quality., Results: Of the 75 relevant studies located, we considered 38 studies to be appropriate for review. Results revealed support for intakes of omega-3 (n-3) fish oils (Cohen's d = 0.21-0.81) and soy isoflavones (Cohen's d = 0.35-0.39) in the treatment of arterial stiffness. There was limited but consistent evidence to suggest that salt restriction (Cohen's d = 0.28-0.37) as well as consumption of fermented-milk products (Cohen's d = 0.15-0.33) that contain bioactive peptides improved arterial stiffness. The evidentiary support for intakes of vitamins, micronutrients, and herbal medicines was insufficient. Limited but consistent evidence suggested that caffeine intake acutely increased arterial stiffness (Cohen's d = 0.34-0.51)., Conclusions: Current evidence from several small studies suggests that omega-3 and soy isoflavone supplementation provides an effective means of reducing arterial stiffness. There was little research that explored intakes of herbal medicines or micronutrients in the treatment of arterial stiffness, and this remains an area of potential research.