The relationships between multidimensional sleep health and work productivity in individuals with neurological conditions

Numerous studies have reported the negative impacts of poor sleep on work productivity in the general population. However, despite the known sleep issues that individuals living with neurological conditions experience, no study has explored its impact on their work productivity. Sleep health is a concept that includes multiple domains of sleep, measured with a combination of objective and subjective measures. Therefore, this study aimed to ascertain the associations between sleep health and its domains and work productivity in individuals with neurological conditions. Sleep health domains were determined through actigraphy data collected over 1 week and sleep questionnaires. Work productivity was assessed via the Work Productivity and Activity Impairment Questionnaire. A comparison of sleep health scores between demographic variables was performed using Mann–Whitney U and Kruskal–Wallis tests. Associations between the sleep health domains and work productivity were performed using linear regression models. There were no significant differences in sleep health scores between sex, smoking status, education level, employment status or any work productivity domain. Individuals with non-optimal sleep timing had greater absenteeism (22.99%) than the optimal group. Individuals with non-optimal sleep quality had an increase in presenteeism (30.85%), work productivity loss (26.44%) and activity impairment (25.81%) compared to those in the optimal group. The findings from this study highlight that self-reported sleep quality has the largest impact on work productivity. Improving individuals’ sleep quality through triage for potential sleep disorders or improving their sleep hygiene (sleep behaviour and environment) may positively impact work productivity

Utility of DNA methylation as a biomarker in ageing and Alzheimer’s disease

Epigenetic mechanisms such as DNA methylation have been implicated in a number of diseases including cancer, heart disease, autoimmune disorders, and neurodegenerative diseases. While it is recognized that DNA methylation is tissue-specific, a limitation for many studies is the ability to sample the tissue of interest, which is why there is a need for a proxy tissue such as blood, that is reflective of the methylation state of the target tissue. In the last decade, DNA methylation has been utilized in the design of epigenetic clocks, which aim to predict an individual’s biological age based on an algorithmically defined set of CpGs. A number of studies have found associations between disease and/or disease risk with increased biological age, adding weight to the theory of increased biological age being linked with disease processes. Hence, this review takes a closer look at the utility of DNA methylation as a biomarker in aging and disease, with a particular focus on Alzheimer’s disease

Hair and salivary cortisol and their relationship with lifestyle, mood and cognitive outcomes in premanifest Huntington’s disease

Salivary cortisol dysrhythmias have been reported in some, but not all studies assessing hypothalamic–pituitary–adrenal (HPA) axis function in Huntington’s disease (HD). These differences are presumed to be due to environmental influences on temporal salivary cortisol measurement. Further exploration of HPA-axis function using a more stable and longer-term measure, such as hair cortisol, is needed to confirm earlier findings. This study aimed to evaluate hair and salivary cortisol concentrations and their associations with clinical and lifestyle outcomes in individuals with premanifest HD (n = 26) compared to healthy controls (n = 14). Participants provided saliva and hair samples and data were collected on clinical disease outcomes, mood, cognition, physical activity, cognitive reserve, sleep quality and social network size to investigate relationships between clinical and lifestyle outcomes and cortisol concentrations. Hair and salivary cortisol concentrations did not significantly differ between the premanifest HD and control groups. No significant associations were observed between hair or salivary cortisol concentrations and cognitive, mood or lifestyle outcomes. However, hair cortisol concentrations were significantly associated with disease outcomes in individuals with premanifest HD. Significant associations between hair cortisol concentrations and measures of disease burden and onset may suggest a potential disease marker and should be explored longitudinally in a larger sample of individuals with HD

Relationship of cognition and Alzheimer’s disease with gastrointestinal tract disorders: A large-scale genetic overlap and mendelian randomisation analysis

Emerging observational evidence suggests links between cognitive impairment and a range of gastrointestinal tract (GIT) disorders; however, the mechanisms underlying their relationships remain unclear. Leveraging large-scale genome-wide association studies’ summary statistics, we comprehensively assessed genetic overlap and potential causality of cognitive traits and Alzheimer’s disease (AD) with several GIT disorders. We demonstrate a strong and highly significant inverse global genetic correlation between cognitive traits and GIT disorders — peptic ulcer disease (PUD), gastritis-duodenitis, diverticulosis, irritable bowel syndrome, and gastroesophageal reflux disease (GERD), but not inflammatory bowel disease (IBD). Further analysis detects 35 significant (p \u3c 4.37 × 10 − 5) bivariate local genetic correlations between cognitive traits, AD, and GIT disorders (including IBD). Mendelian randomisation analysis suggests a risk-decreasing causality of educational attainment, intelligence, and other cognitive traits on PUD and GERD, but not IBD, and a putative association of GERD with cognitive function decline. Gene-based analysis reveals a significant gene-level genetic overlap of cognitive traits with AD and GIT disorders (IBD inclusive, pbinomial-test = 1.18 × 10 − 3 – 2.20 × 10 − 16). Our study supports the protective roles of genetically-influenced educational attainments and other cognitive traits on the risk of GIT disorders and highlights a putative association of GERD with cognitive function decline. Findings from local genetic correlation analysis provide novel insights, indicating that the relationship of IBD with cognitive traits (and AD) will depend largely on their local effects across the genome

A potential role for sirtuin-1 in Alzheimer\u27s disease: Reviewing the biological and environmental evidence

Sirtuin-1 (Sirt1), encoded by the SIRT1 gene, is a conserved Nicotinamide adenine dinucleotide (NAD+) dependent deacetylase enzyme, considered as the master regulator of metabolism in humans. Sirt1 contributes to a wide range of biological pathways via several mechanisms influenced by lifestyle, such as diet and exercise. The importance of a healthy lifestyle is of relevance to highly prevalent modern chronic diseases, such as Alzheimer\u27s disease (AD). There is growing evidence at multiple levels for a role of Sirt1/SIRT1 in AD pathological mechanisms. As such, this review will explore the relevance of Sirt1 to AD pathological mechanisms, by describing the involvement of Sirt1/SIRT1 in the development of AD pathological hallmarks, through its impact on the metabolism of amyloid- and degradation of phosphorylated tau. We then explore the involvement of Sirt1/SIRT1 across different AD-relevant biological processes, including cholesterol metabolism, inflammation, circadian rhythm, and gut microbiome, before discussing the interplay between Sirt1 and AD-related lifestyle factors, such as diet, physical activity, and smoking, as well as depression, a common comorbidity. Genome-wide association studies have explored potential associations between SIRT1 and AD, as well as AD risk factors and co-morbidities. We summarize this evidence at the genetic level to highlight links between SIRT1 and AD, particularly associations with AD-related risk factors, such as heart disease. Finally, we review the current literature of potential interactions between SIRT1 genetic variants and lifestyle factors and how this evidence supports the need for further research to determine the relevance of these interactions with respect to AD and dementia

The acceleration of aging and Alzheimer’s disease through the biological mechanisms behind obesity and type II diabetes

The incidence of diabetes is predicted to increase to 21% by 2050. Currently, one third of US adults are obese and over 11% of these individuals have diabetes. Due to the growing need for therapeutic intervention to control and/or stabilize this increase in the incidence of diabetes in Western communities, gaining a comprehensive understanding of the association between obesity and Type 2 diabetes has become increasingly important to diabetes research. The increased cell senescence associated with diabetes has been associated with the limited ability of cells to divide, with indication of telomere shortening and genomic instability of the cells. Obese individuals have shorter telomeres suggesting an inverse relationship between adiposity and telomere length. The implication that Type 2 diabetes has on biological aging is of particular interest since telomere shortening in obesity and diabetes has been associated with an early risk for dementia and even progression to Alzheimer’s disease (AD). Lifestyle, nutrition and longevity are closely related and cellular senescence has been associated with telomere shortening and connected to longevity. Diet, cholesterol lowering drugs and exercise that control food intake and glucose tolerance in aging and diabetic individuals, via connections between liver circadian clocks and the suprachiasmatic nucleus in the brain, also have been shown to alter telomere lengths. Lifestyle interventions, such as diets low in fat and exercise, target the rise in obesity and associated telomere shortening by delaying or preventing the onset of Type 2 diabetes. The implementation of these anti-aging therapies early in life may prevent calorie overload and activation of calorie sensitive genes such as Sirtuin 1 (Sirt1). This may maintain telomere length and the control of obesity, which is linked to cardiovascular disease, diabetes and accelerates aging and AD

Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators

Background/Objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE 4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE 4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE 4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE 4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE 4 carriers show a greater decline in stress as a result of exercise relative to non-APOE 4 carriers

Exploring discordant low amyloid beta and high neocortical tau positron emission tomography cases

Introduction: Neocortical 3R4R (3-repeat/4-repeat) tau aggregates are rarely observed in the absence of amyloid beta (Aβ). 18F-MK6240 binds specifically to the 3R4R form of tau that is characteristic of Alzheimer\u27s disease (AD). We report four cases with negative Aβ, but positive tau positron emission tomography (PET) findings. Methods: All Australian Imaging, Biomarkers and Lifestyle study of aging (AIBL) study participants with Aβ (18F-NAV4694) and tau (18F-MK6240) PET scans were included. Centiloid \u3c 25 defined negative Aβ PET (Aβ–). The presence of neocortical tau was defined quantitatively and visually. Results: Aβ– PET was observed in 276 participants. Four of these participants (one cognitively unimpaired [CU], two mild cognitive impairment [MCI], one AD) had tau tracer retention in a pattern consistent with Braak tau stages V to VI. Fluid biomarkers supported a diagnosis of AD. In silico analysis of APP, PSEN1, PSEN2, and MAPT genes did not identify relevant functional mutations. Discussion: Discordant cases were infrequent (1.4% of all Aβ– participants). In these cases, the Aβ PET ligand may not be detecting the Aβ that is present

Discovery of a missense mutation (Q222K) of the APOE gene from the Australian imaging, biomarker and lifestyle study

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer\u27s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ϵ2, ϵ3, and ϵ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ϵ4 (Q222K) mutation did not form dimers or complexes observed for apoE ϵ2 ϵ3 proteins

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline in Preclinical Alzheimer's Disease

Studies of Alzheimer's disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory was determined individually for 27 genetic variants in a reference sample (n = 151). These were then summed to generate a emPRS either including APOE (emPRSc̅APOE) or excluding APOE (emPRSs̅APOE ). Resultant emPRS were then evaluated, in a test sample (n = 75), against decline in global cognition, verbal episodic memory and a pre-Alzheimer's cognitive composite (AIBL-PACC) over 7.5 years. The mean (SD) age of the 226 participants was 72.2 (6.6) years and 116 (51.3%) were female. Reference and test samples did not differ significantly demographically. Whilst no association of emPRSs were observed with baseline cognition, the emPRSc̅ APOE was associated with longitudinal global cognition (-0.237, P = 0.0002), verbal episodic memory (-0.259, P = 0.00003) and the AIBL-PACC (-0.381, P = 0.02). The emPRSs̅ APOE was also associated with global cognition (-0.169, P = 0.021) and verbal episodic memory (-0.208, P = 0.004). Stratification by APOE ε4 revealed that the association between the emPRS and verbal episodic memory was limited to carriage of no ε4 or one ε4 allele. This was also observed for global cognition. The emPRS and rates of decline in AIBL-PACC were associated in those carrying one ε4 allele. Overall, the described novel emPRS has utility for the prediction of decline in cognition in preclinical AD. This study provides evidence to support the further use and evaluation of phenotype weightings in PRS development