Effect of kava (Piper methysticum) on peripheral gene expression among individuals with generalized anxiety disorder: A post hoc analysis of a randomized controlled trial.

Kava is a South Pacific plant-based medicine with anxiolytic properties, but little is known about the impact kava has on gene expression or whether gene expression can serve as a marker of kava response. This study aimed to determine whether kava treatment alters the expression of genes with physiological relevance to anxiety pathophysiology and whether the baseline expression of these physiologically relevant genes modifies the efficacy of kava treatment. In this post hoc analysis, we examined the expression of 48 genes relevant to the pathophysiology of anxiety collected from a double-blind randomized controlled trial that assessed the efficacy of kava treatment in generalized anxiety disorder. Peripheral blood gene expression was measured in 71 (34 kava, 37 placebo) adults at baseline and in 40 (19 kava, 21 placebo) after 8 weeks of treatment by reverse transcription polymerase chain reaction (PCR). Results revealed that kava decreased the expression of a subunit of the GABAA -rho receptor gene (GABRR2) and catechol-O-methyltransferase (COMT), a gene related to catecholamine metabolism. Kava efficacy was not found to be modified by baseline (pretreatment) expression of relevant genes. Although these results did not withstand statistical correction for multiple comparisons and require external validation, they support the notion that kava's mechanism of action includes interaction with GABAergic and catecholaminergic systems.

Treatment of refractory obsessive-compulsive disorder with nutraceuticals (TRON): a 20-week, open label pilot study.

BACKGROUND: Obsessive-compulsive disorder (OCD) is often challenging to treat and resistant to psychological interventions and prescribed medications. The adjunctive use of nutraceuticals with potential neuromodulatory effects on underpinning pathways such as the glutamatergic and serotonergic systems is one novel approach. OBJECTIVE: To assess the effectiveness and safety of a purpose-formulated combination of nutraceuticals in treating OCD: N-acetyl cysteine, L-theanine, zinc, magnesium, pyridoxal-5' phosphate, and selenium. METHODS: A 20-week open label proof-of-concept study was undertaken involving 28 participants with treatment-resistant DSM-5-diagnosed OCD, during 2017 to 2020. The primary outcome measure was the Yale-Brown Obsessive-Compulsive Scale (YBOCS), administered every 4 weeks. RESULTS: An intention-to-treat analysis revealed an estimated mean reduction across time (baseline to week-20) on the YBOCS total score of -7.13 (95% confidence interval = -9.24, -5.01), with a mean reduction of -1.21 points per post-baseline visit (P ≤ .001). At 20-weeks, 23% of the participants were considered "responders" (YBOCS ≥35% reduction and "very much" or "much improved" on the Clinical Global Impression-Improvement scale). Statistically significant improvements were also revealed on all secondary outcomes (eg, mood, anxiety, and quality of life). Notably, treatment response on OCD outcome scales (eg, YBOCS) was greatest in those with lower baseline symptom levels, while response was limited in those with relatively more severe OCD. CONCLUSIONS: While this pilot study lacks placebo-control, the significant time effect in this treatment-resistant OCD population is encouraging and suggests potential utility especially for those with lower symptom levels. Our findings need to be confirmed or refuted via a follow-up placebo-controlled study.

Higher habitual dietary flavonoid intake associates with lower central blood pressure and arterial stiffness in healthy older adults.

Flavonoids have shown anti-hypertensive and anti-atherosclerotic properties: the impact of habitual flavonoid intake on vascular function, central haemodynamics and arterial stiffness may be important. We investigated the relationship between habitual flavonoid consumption and measures of central blood pressure and arterial stiffness. We performed cross-sectional analysis of 381 non-smoking healthy older adults (mean age 66·0 (sd 4·1) years; BMI, 26·4 (sd 4·41) kg/m2; 41 % male) recruited as part of the Australian Research Council Longevity Intervention study. Flavonoid intake (i.e. flavonols, flavones, flavanones, anthocyanins, isoflavones, flavan-3-ol monomers, proanthocyanidins, theaflavins/thearubigins and total consumption) was estimated from FFQ using the US Department of Agriculture food composition databases. Measures of central haemodynamics and arterial stiffness included systolic blood pressure (cSBP), diastolic blood pressure (cDBP), mean arterial pressure (cMAP) and augmentation index (cAIx). After adjusting for demographic and lifestyle confounders, each sd/d higher intake of anthocyanins ((sd 44·3) mg/d) was associated with significantly lower cDBP (-1·56 mmHg, 95 % CI -2·65, -0·48) and cMAP (-1·62 mmHg, 95 % CI -2·82, -0·41). Similarly, each sd/d higher intake of flavanones ((sd 19·5) mg/d) was associated with ~1 % lower cAIx (-0·93 %, 95 % CI -1·77, -0·09). These associations remained significant after additional adjustment for (1) a dietary quality score and (2) other major nutrients that may affect blood pressure or arterial stiffness (i.e. Na, K, Ca, Mg, n-3, total protein and fibre). This study suggests a possible benefit of dietary anthocyanin and flavanone intake on central haemodynamics and arterial stiffness; these findings require corroboration in further research.

Nutrient and genetic biomarkers of nutraceutical treatment response in mood and psychotic disorders: a systematic review.

Objective: Nutrient and genetic biomarkers in nutraceutical trials may allow for the personalisation of nutraceutical treatment and assist in predicting treatment response. We aimed to synthesise the findings of trials which have included these biomarkers to determine which may be most useful for predicting nutraceutical response in mood and psychotic disorders.Methods: A systematic review was conducted assessing available literature concerning nutraceutical clinical trials in mood and psychotic disorders (major depression, bipolar disorder, schizophrenia) with baseline and endpoint blood nutrient markers or genetic data available.Results: We identified 35 eligible studies (total n = 3836 participants) examining baseline and endpoint nutrient biomarkers and/or genetic polymorphisms. The key result, as reported in 10 out of 11 omega-3 studies, was a strong association between polyunsaturated fatty acid concentrations (mostly EPA and DHA) and psychiatric outcomes, although the exact nature of the association varied between studies and diagnoses. There was no consistent evidence for levels of other nutrients (including Vitamin D, SAM/SAH ratios, carnitine, folate and vitamin B12) relating to treatment response. The evidence for associations between one-carbon cycle genotypes (e.g. MTHFR C677 T, MTR and FOLH1) and treatment response was also inconsistent.Discussion: The available data tentatively supports omega-3 indices as biomarkers of response to omega-3 treatments in mood disorders. Further research with larger samples examining combinations of polymorphisms is required to determine if any genetic factors influence nutraceutical response in mood and psychotic disorders.

EPA and DHA as markers of nutraceutical treatment response in major depressive disorder.

PURPOSE: Depression clinical trials are increasingly studying biomarkers to predict and monitor response to treatment. Assessment of biomarkers may reveal subsets of patients who are responsive to nutraceutical treatment, which may facilitate a personalized approach to treating depression. METHODS: This is a post hoc analysis of an 8-week, double-blind, randomized, controlled trial (n = 158) investigating a combination nutraceutical comprising Omega-3 (EPA 1 g/DHA 656 mg), SAMe, zinc, 5-HTP, folinic acid, and co-factors versus placebo for the treatment of Major Depressive Disorder. The study explored levels of polyunsaturated fatty acids, folate, vitamin B12, zinc, homocysteine, and BDNF as possible predictors and correlates of response to nutraceutical supplementation. RESULTS: Concentrations of EPA and DHA in red cell membranes increased in response to treatment and were significantly correlated with a decrease in depressive symptoms during active treatment (p = 0.003 and p = 0.029; respectively). Higher baseline levels of omega-6 fatty acid also correlated with depression reduction in the active treatment group ( p = 0.011). No other biomarkers were associated with a lessening of depressive symptoms. CONCLUSION: Changes in fatty acid levels resulting from a nutraceutical combination containing EPA and DHA provide a response biomarker in treating depression.

Kava for generalised anxiety disorder: A 16-week double-blind, randomised, placebo-controlled study.

OBJECTIVE: Previous randomised, double-blind, placebo-controlled studies have shown that Kava (a South Pacific medicinal plant) reduced anxiety during short-term administration. The objective of this randomised, double-blind, placebo-controlled study was to perform a larger, longer-term trial assessing the efficacy and safety of Kava in the treatment of generalised anxiety disorder and to determine whether gamma-aminobutyric acid transporter (SLC6A1) single-nucleotide polymorphisms were moderators of response. METHODS: The trial was a phase III, multi-site, two-arm, 16-week, randomised, double-blind, placebo-controlled study investigating an aqueous extract of dried Kava root administered twice per day in tablet form (standardised to 120 mg of kavalactones twice/day) in 171 currently non-medicated anxious participants with diagnosed generalised anxiety disorder. The trial took place in Australia. RESULTS: An analysis of 171 participants revealed a non-significant difference in anxiety reduction between the Kava and placebo groups (a relative reduction favouring placebo of 1.37 points; p = 0.25). At the conclusion of the controlled phase, 17.4% of the Kava group were classified as remitted (Hamilton Anxiety Rating Scale score < 7) compared to 23.8% of the placebo group (p = 0.46). No SLC6A1 polymorphisms were associated with treatment response, while carriers of the rs2601126 T allele preferentially respond to placebo (p = 0.006). Kava was well tolerated aside from poorer memory (Kava = 36 vs placebo = 23; p = 0.044) and tremor/shakiness (Kava = 36 vs placebo = 23; p = 0.024) occurring more frequently in the Kava group. Liver function test abnormalities were significantly more frequent in the Kava group, although no participant met criteria for herb-induced hepatic injury. CONCLUSION: While research has generally supported Kava in non-clinical populations (potentially for more 'situational' anxiety as a short-term anxiolytic), this particular extract was not effective for diagnosed generalised anxiety disorder.

The relationship between dietary quality, serum brain-derived neurotrophic factor (BDNF) level, and the Val66met polymorphism in predicting depression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of depression, may be influenced by dietary quality. Both dietary quality and serum BDNF have been researched independently in regard to their effect on depression; however, there is limited research investigating the relationship between the two factors and how they interact in depression. Additionally, a single-nucleotide polymorphism (SNP) (Val66Met) in the BDNF gene, which has been implicated in BDNF levels and depression, may contribute to the complex relationship between depression, dietary quality, and BDNF level. METHODS: One hundred and eighty-seven participants with major depressive disorder and 55 non-depressed healthy controls were recruited for this case-control analysis. The relationship between dietary quality and depression was assessed via a novel dietary quality score (the Australian Dietary Quality Score). Serum BDNF levels were measured and the Val66Met SNP was genotyped. RESULTS: Healthy controls had a significantly higher diet quality than depressed participants (t = 2.435, P = 0.016). A logistic regression model investigating age, sex, serum BDNF levels, dietary quality and depression, as well as any interactions, found that lower dietary quality, and surprisingly, higher BDNF levels, were associated with increased depression risk, P = 0.037 and P < 0.001, respectively. Neither seasonality (at the time of recruitment) nor the Val66Met polymorphism was associated with BDNF levels in this sample. Furthermore, there was no evidence of interaction between the Val66Met polymorphism, BDNF levels, dietary quality, and depression. CONCLUSION: Higher dietary quality was associated with both decreased depression incidence and severity in this cross-sectional analysis. The Val66Met polymorphism did not appear to predict BDNF levels, depression incidence, or modify the relationship between dietary quality and BDNF. Further studies utilizing a larger sample size are needed to confirm this finding.

Erythrocyte polyunsaturated fatty acid composition is associated with depression and FADS genotype in Caucasians.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) play an important role in the pathophysiology of major depressive disorder (MDD), related, in part, to their role in inflammatory systems. The enzymes δ-5 and δ-6 desaturase are the rate-limiting steps in the metabolism of PUFAs and are encoded in the genes fatty acid desaturase (FADS) 1 and 2, respectively. Single nucleotide polymorphisms (SNPs) and haplotypes within the FADS gene cluster have been shown to influence PUFA composition. AIM: The objective of this study was to determine whether key omega-3 (n-3) and omega-6 (n-6) fatty acids may be associated with depression, and to explore the role of FADS genotype in PUFA variation. METHODS: Four erythrocyte long chain (LC) fatty acids (linoleic acid [LA], α-linolenic acid [ALA], arachidonic acid [AA] and Eicosapentaenoic acid [EPA]), as well as six SNPs (rs174537, rs174547, rs174570, rs174575, rs498793 and rs3834458) within the FADS gene cluster were measured in a sample of 207 participants (154 with MDD versus 53 non-depressed controls). RESULTS: The precursor LC-PUFAs LA and ALA appeared to be negatively associated with depression (P < 0.001 and P < 0.01, respectively), while AA:LA (surrogate measure of desaturase activity) was positively associated with depression (P < 0.01). No significant differences were noted in erythrocyte EPA, AA or AA:EPA between groups. Minor alleles of each SNP (excluding rs498793) were associated with variation in desaturase activity and LA. Both rs174537 and rs174547 were associated with ALA. No genotype was associated with EPA or AA. Minor alleles of rs174537 and rs174547 were significantly associated with lower odds of MDD (although significance was lost after correction for multiple comparisons). CONCLUSION: Precursor LC-PUFAs, LA and ALA, appear to be associated with MDD and potentially modulated by genetic variation in the FADS gene cluster. These results provide support for the consideration of PUFA composition, diet and FADS genetic variation in the pathophysiology of MDD.

Dietary factors and DNA methylation-based markers of ageing in 5310 middle-aged and older Australian adults.

The role of nutrition in healthy ageing is acknowledged but details of optimal dietary composition are still uncertain. We aimed to investigate the cross-sectional associations between dietary exposures, including macronutrient composition, food groups, specific foods, and overall diet quality, with methylation-based markers of ageing. Blood DNA methylation data from 5310 participants (mean age 59 years) in the Melbourne Collaborative Cohort Study were used to calculate five methylation-based measures of ageing: PCGrimAge, PCPhenoAge, DunedinPACE, ZhangAge, TelomereAge. For a range of dietary exposures, we estimated (i) the 'equal-mass substitution effect', which quantifies the effect of adding the component of interest to the diet while keeping overall food mass constant, and (ii) the 'total effect', which quantifies the effect of adding the component of interest to the current diet. For 'equal-mass substitution effects', the strongest association for macronutrients was for fibre intake (e.g. DunedinPACE, per 12 g/day - 0.10 [standard deviations]; 95%CI - 0.15, - 0.05, p < 0.001). Associations were positive for protein (e.g. PCGrimAge, per 33 g/day 0.04; 95%CI 0.01-0.08, p = 0.005). For food groups, the evidence tended to be weak, though sugar-sweetened drinks showed positive associations, as did artificially-sweetened drinks (e.g. DunedinPACE, per 91 g/day 0.06, 95%CI 0.03-0.08, p < 0.001). 'Total effect' estimates were generally very similar. Scores reflecting overall diet quality suggested that healthier diets were associated with lower levels of ageing markers. High intakes of fibre and low intakes of protein and sweetened drinks, as well as overall healthy diets, showed the most consistent associations with lower methylation-based ageing in our study.

Interleukin 10 (IL10) promoter region polymorphism is associated with IL10 serum concentrations and processing speed in healthy community-dwelling older adults.

Inflammation is repressed by interleukin 10 (IL10), a potent anti-inflammatory cytokine, and unchecked inflammation can have detrimental effects on cognition. In healthy older adults enrolled in the Australian Research Council Longevity Intervention (ARCLI) cohort we explored whether a known functional single nucleotide polymorphism (SNP) in the promoter region of IL10, -1082 G/A (rs1800896), was associated with reaction times on computerized cognitive testing that included elements of processing speed (i.e., reaction time). Participants were aged 60-75 years (240 females, 158 males), free of dementia and psychiatric disorders, and provide a blood sample. Processing speed was measured using the Swinburne University Computerized Cognitive Assessment Battery (SUCCAB), which includes measures of reaction time (in milliseconds, ms) on six tasks. Blood-derived DNA was genotyped for the IL10 rs1800896 SNP and presence of the APOE E4 allele. General linear models for each SUCCAB subtest were fitted, with age, sex, education (years), APOE E4 carrier status, and IL10 genotype as independent variables. Carriers of the IL10 AA genotype had significantly slower reaction times on multiple tests compared to carriers of the minor allele (AG, GG) and lower IL10 serum levels. Although IL10 SNPs have not been detected in Alzheimer's disease genome-wide associated studies, these results support further exploration of IL10 mechanisms as a possible resilience factor.

Body Size, Diet Quality, and Epigenetic Aging: Cross-Sectional and Longitudinal Analyses.

Epigenetic age is an emerging marker of health that is highly predictive of disease and mortality risk. There is a lack of evidence on whether lifestyle changes are associated with changes in epigenetic aging. We used data from 1 041 participants in the Melbourne Collaborative Cohort Study with blood DNA methylation measures at baseline (1990-1994, mean age: 57.4 years) and follow-up (2003-2007, mean age: 68.8 years). The Alternative Healthy Eating Index-2010 (AHEI-2010), the Mediterranean Dietary Score, and the Dietary Inflammatory Index were used as measures of diet quality, and weight, waist circumference, and waist-to-hip ratio as measures of body size. Five age-adjusted epigenetic aging measures were considered: GrimAge, PhenoAge, PCGrimAge, PCPhenoAge, and DunedinPACE. Multivariable linear regression models including restricted cubic splines were used to assess the cross-sectional and longitudinal associations of body size and diet quality with epigenetic aging. Associations between weight and epigenetic aging cross-sectionally at both time points were positive and appeared greater for DunedinPACE (per SD: ß ~0.24) than for GrimAge and PhenoAge (ß ~0.10). The longitudinal associations with weight change were markedly nonlinear (U-shaped) with stable weight being associated with the lowest epigenetic aging at follow-up, except for DunedinPACE, for which only weight gain showed a positive association. We found negative, linear associations for AHEI-2010 both cross-sectionally and longitudinally. Other adiposity measures and dietary scores showed similar results. In middle-aged to older adults, declining diet quality and weight gain may increase epigenetic age, while the association for weight loss may require further investigation. Our study sheds light on the potential of weight management and dietary improvement in slowing aging processes.

Cross-sectional associations between neighborhood characteristics, cognition and dementia risk factor burden in middle-aged and older Australians.

Dementia disproportionately affects individuals from disadvantaged backgrounds, including those living in areas of lower neighborhood-level socioeconomic status. It is important to understand whether there are specific neighborhood characteristics associated with dementia risk factors and cognition which may inform dementia risk reduction interventions. We sought to examine whether greenspace, walkability, and crime associated with the cumulative burden of modifiable dementia risk factors and cognition. This was a cross-sectional analysis of 2016-2020 data from the Healthy Brain Project, a population-based cohort of community-dwelling individuals across Australia. Participants were aged 40-70 and free of dementia. Measures included greenspace (greenspace % in the local area, and distance to greenspace, n = 2,181); and intersection density (n = 1,159), and crime (rate of recorded offences; n = 1,159). Outcomes included a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score to index the burden of modifiable vascular dementia risk factors; and composite scores of both memory and attention, derived from the Cogstate Brief Battery. Linear regressions adjusted for age, sex, education, and personal socio-economic status, demonstrated distance to greenspace (b ± SE per 2-fold increase = 0.09 ± 0.03, p =.005) and crime rate (b ± SE per 2-fold increase = 0.07 ± 0.03, p =.018) were associated with higher modified CAIDE. Higher crime was associated with lower memory performance (b ± SE = -0.03 ± 0.01, p =.018). The association between distance to greenspace and modified CAIDE was only present in low-moderate socioeconomic status neighborhoods (p interaction = 0.004). Dementia prevention programs that address modifiable risk factors in midlife should consider the possible role of neighborhood characteristics.

Association of the Sleep Regularity Index With Incident Dementia and Brain Volume.

BACKGROUND AND OBJECTIVES: Irregular sleep may increase the risk of cardiometabolic conditions, but its association with incident dementia is unclear. The aim of this study was to assess the association between sleep regularity, that is, the day-to-day consistency in sleep-wake patterns and the risk of incident dementia and related brain MRI endophenotypes. METHODS: We used Cox proportional hazard models to investigate the relationships between sleep regularity and incident dementia in 88,094 UK Biobank participants. The sleep regularity index (SRI) was calculated as the probability of being in the same state (asleep/awake) at any 2 time points 24 hours apart, averaged over 7 days of accelerometry. RESULTS: The mean age of the sample was 62 years (SD = 8), 56% were women, and the median SRI was 60 (SD = 10). There were 480 cases of incident dementia over a median 7.2 years of follow-up. Following adjustments for demographic, clinical, and genetic confounders (APOE ε4), there was a nonlinear association between the SRI and dementia hazard (p [global test of spline term] < 0.001) with hazard ratios (HRs) following a U-shape pattern. HRs, relative to the median SRI, were 1.53 (95% CI 1.24-1.89) for participants with SRI at the 5th percentile (SRI = 41) and 1.16 (95% CI 0.89-1.50) for those with SRI at the 95th percentile (SRI = 71). In a subset with brain MRI (n = 15,263), gray matter and hippocampal volume tended to be lowest at the extremes of the SRI. DISCUSSION: Sleep regularity displayed a U-shaped association with risk of incident dementia. Irregular sleep may represent a novel dementia risk factor.

Associations of body habitus and its changes with incident dementia in older adults.

BACKGROUND: This study examined the associations of body mass index (BMI) and waist circumference (WC), as well as their short- and long-term changes over time, with incident dementia in older individuals. METHODS: Data came from 18,837 community-dwelling individuals aged 65+ years from Australia and the United States, who were relatively healthy without major cognitive impairment at enrolment. Anthropometric measures were prospectively assessed at baseline, as well as change and variability from baseline to year two (three time-points). In a subgroup (n = 11,176), self-reported weight at age 18 and 70+ years was investigated. Dementia cases satisfied DSM-IV criteria. Cox regression was used to examine the associations between anthropometric measures and incident risk of dementia. RESULTS: Compared to normal weight, an overweight (HR: 0.67, 95%CI: 0.57-0.79, p < 0.001) or obese BMI (HR: 0.73, 95%CI: 0.60-0.89, p = 0.002), or a larger WC (elevated, HR: 0.71, 95%CI: 0.58-0.86, p < 0.001; highly elevated, HR: 0.65, 95%CI: 0.55-0.78, p < 0.001; relative to low) at baseline was associated with lower dementia risk. In contrast, substantial increases in BMI (>5%) over 2 years after baseline were associated with higher dementia risk (HR: 1.49, 95% CI: 1.17-1.91, p = 0.001). Increased dementia risk was also seen with an underweight BMI at baseline and a 2-year BMI decrease (>5%), but these associations appeared only in the first 4 years of follow-up. Compared to normal weight at both age 18 and 70+ years, being obese at both times was associated with increased dementia risk (HR: 2.27, 95%CI: 1.22-4.24, p = 0.01), while obesity only at age 70+ years was associated with decreased risk (HR: 0.70, 95%CI: 0.51-0.95, p = 0.02). CONCLUSIONS: Our findings suggest that long-term obesity and weight gain in later life may be risk factors for dementia. Being underweight or having substantial weight loss in old age may be early markers of pre-clinical dementia.

Exploring the Potential Association Between Self-Reported Psychological Stress and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Midlife: A Cross-Sectional Study.

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-ß42, phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f2 effect sizes were small in magnitude (f2≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress.

Sleep regularity and mortality: a prospective analysis in the UK Biobank.

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).

Associations of Perceived Stress and Psychological Resilience With Cognition and a Modifiable Dementia Risk Score in Middle-Aged Adults.

OBJECTIVES: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined. METHODS: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors. RESULTS: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score. DISCUSSION: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk.

Sleep Regularity and Mortality: A Prospective Analysis in the UK Biobank.

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 hours 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. Findings: The mean sample age was 62 years (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).

Insomnia Symptoms and Biomarkers of Alzheimer's Disease in the Community.

BACKGROUND: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal. OBJECTIVE: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample. METHODS: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aß42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype. RESULTS: Higher ISI score was associated with greater average levels of CSF Aß42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aß42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels. CONCLUSION: Insomnia symptoms were associated with higher CSF Aß42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.