The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug.

Background: Evidence suggests that TNF inhibitors (TNFi) used to treat rheumatoid arthritis (RA) may protect against Alzheimer's disease progression by reducing inflammation. Objective: To investigate whether RA patients with mild cognitive impairment (MCI) being treated with a TNFi show slower cognitive decline than those being treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Methods: 251 participants with RA and MCI taking either a csDMARD (N = 157) or a TNFi (N = 94) completed cognitive assessments at baseline and 6-month intervals for 18 months. It was hypothesized that those taking TNFis would show less decline on the primary outcome of Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR) and the secondary outcome of Montreal Cognitive Assessment (MoCA). Results: No significant changes in FCSRT-IR scores were observed in either treatment group. There was no significant difference in FCSRT-IR between treatment groups at 18 months after adjusting for baseline (mean difference = 0.5, 95% CI = -1.3, 2.3). There was also no difference in MoCA score (mean difference = 0.4, 95% CI = -0.4, 1.3). Conclusions: There was no cognitive decline in participants with MCI being treated with TNFis and csDMARDs, raising the possibility both classes of drug may be protective. Future studies should consider whether controlling inflammatory diseases using any approach is more important than a specific therapeutic intervention.

Investigating the prevalence of cognitive impairment and dementia in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA): the Harmonised Cognitive Assessment Protocol (HCAP) cross-sectional substudy.

INTRODUCTION: The Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) study is the largest study of ageing in Northern Ireland (NI). The Harmonised Cognitive Assessment Protocol (HCAP) is a substudy of NICOLA designed to assess cognitive impairment and dementia in individuals aged 65 and over. The NICOLA-HCAP substudy is funded by the National Institute on Aging as part of a network for enhancing cross-national research within a worldwide group of population-based, longitudinal studies of ageing, all of which are centred around the US-based Health and Retirement Study. METHODS AND ANALYSIS: The NICOLA-HCAP study will draw on the main NICOLA cohort (of 8283 participants) and randomly sample 1000 participants aged 65 and over to take part in the substudy. Participants will complete a series of cognitive tests (n=19) via a computer-assisted personal interview administered in their home (or alternatively within the research centre) and will be asked to nominate a family member or friend to complete an additional interview of validated instruments to provide information on respondent's prior and current cognitive and physical functioning and whether the individual requires help with daily activities. The objectives of the study are: to investigate the prevalence of dementia and cognitive impairment in NICOLA; harmonise scoring of the NICOLA-HCAP data to the HCAP studies conducted in Ireland, the USA and England; to explore the validity of dementia estimates; and investigate the risk factors for dementia and cognitive impairment. ETHICS AND DISSEMINATION: The study received ethical approval from the Faculty of Medicine, Health and Life Sciences Research Ethics Committee, Queen's University Belfast. We will provide data from the Northern Irish HCAP to the research community via data repositories such as the Dementias Platform UK and Gateway to Global Aging to complement existing public data resources and support epidemiological research by others. Findings will also be disseminated through peer-reviewed publications and at international conferences.

Effects of PROtein enriched MEDiterranean Diet and EXercise on nutritional status and cognition in adults at risk of undernutrition and cognitive decline: the PROMED-EX Randomised Controlled Trial.

INTRODUCTION: Undernutrition leading to unplanned weight loss is common in older age and has been linked to increased dementia risk in later life. Weight loss can precede dementia by a decade or more, providing a unique opportunity for early intervention to correct undernutrition and potentially prevent or delay cognitive impairment. The combined effects of diet and exercise on undernutrition have not yet been evaluated. The objective of this trial is to determine the effect of a protein-enriched Mediterranean diet, with and without exercise, on nutritional status and cognitive performance in older adults at risk of undernutrition and cognitive decline. METHODS: One hundred and five participants aged 60 years and over at risk of undernutrition and with subjective cognitive decline will be recruited to participate in a 6-month, single-blind, parallel-group randomised controlled trial. Participants will be block randomised into one of three groups: group 1-PROMED-EX (diet+exercise), group 2-PROMED (diet only) and group 3-standard care (control). The primary outcome is nutritional status measured using the Mini Nutritional Assessment. Secondary outcomes include cognitive function, nutritional intake, body composition, physical function and quality of life. Mechanistic pathways for potential diet and exercise-induced change in nutritional status and cognition will be explored by measuring inflammatory, metabolic, nutritional and metabolomic biomarkers. ETHICS AND DISSEMINATION: The study is approved by the UK Office for Research Ethics Committee (ref: 21/NW/0215). Written informed consent will be obtained from participants prior to recruitment. Research results will be disseminated to the public via meetings and media and the scientific community through conference presentations and publication in academic journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05166564).

Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA): health assessment protocol, participant profile and patterns of participation.

BACKGROUND: The Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) is a prospective, longitudinal study of a representative cohort of older adults living in Northern Ireland, United Kingdom. Its aim is to explore the social, behavioural, economic and biological factors of ageing and how these factors change as people age. The study has been designed to maximize comparability with other international studies of ageing thereby facilitating cross-country comparisons. This paper provides an overview of the design and methodology of the health assessment which was carried out as part of Wave 1. METHODS: Three thousand, six hundred and fifty five community dwelling adults, aged 50 years and over participated in the health assessment as part of Wave 1 of NICOLA. The health assessment included a battery of measurements across various domains that addressed key indicators of ageing namely: physical function, vision and hearing, cognitive function, and cardiovascular health. This manuscript describes the scientific rationale for the choice of assessments, provides an overview of the core objective measures carried out in the health assessment and describes the differences in characteristics of participants who took part in the health assessment compared to those who did not take part. RESULTS: The manuscript highlights the importance of incorporating objective measures of health in population based studies as a means of complementing subjective measures and as a way to advance our understanding of the ageing process. The findings contextualize NICOLA as a data resource within Dementias Platform UK (DPUK), the Gateway to Global Ageing (G2G) and other existing networks of population based longitudinal studies of ageing. CONCLUSION: This manuscript can help inform design considerations for other population based studies of ageing and facilitate cross-country comparative analysis of key life-course factors affecting healthy ageing such as educational attainment, diet, the accumulation of chronic conditions (including Alzheimer's disease, dementia and cardiovascular disease) as well as welfare and retirement policies.

Establishing Healthy Eating 'Habits': A Pilot Randomised Controlled Trial of a Habit-Based Dietary Intervention following Oral Rehabilitation for Older Adults.

An ageing population presents significant nutritional challenges, particularly for partially dentate adults. This two-armed pilot randomised controlled trial (RCT) compared habit formation (automaticity) for healthy eating behaviours between control and intervention groups after participation in a habit-based dietary intervention for older adults, following oral rehabilitation in the United Kingdom (UK). n = 54 participants were randomised to receive a habit-based dietary intervention (intervention group n = 27, IG) or standard dietary advice in a leaflet (control group n = 27, CG). The IG attended three sessions over six weeks, which focused on habit formation for three healthy eating behaviours (increasing fruit and vegetables, wholegrains, and healthy proteins). Participants were assessed for habit strength (using the Self-Report Behavioural Automaticity Index (SRBAI)) alongside health and nutrition outcomes at six weeks, four months and eight months. Forty-nine participants completed all follow-up visits. The IG compared to the CG had significant increases in automaticity at six weeks, four months (primary outcome) and eight months for eating ≥3 portions of fruit and vegetables; choosing wholegrain sources over white alternatives, and choosing healthy protein sources over red/processed meat. The mean change in the Mini Nutritional Assessment total score was greater in the IG compared with the CG at six weeks only (p = 0.03). A habit-based dietary intervention following oral rehabilitation increased automaticity for healthy dietary behaviours, which could translate into clinically meaningful benefits in this cohort of older adults.

An Overview of Systematic Reviews and Meta-Analyses on the Effect of Medication Interventions Targeting Polypharmacy for Frail Older Adults.

Frailty refers to the lack of resilience and a reduction in a person's ability to recover following a health problem, and it is increasingly becoming a challenging aspect of ageing populations. Many older adults are exposed to polypharmacy; i.e., they continue to be on medications without timely re-evaluation. Medication reviews have proven successful in managing polypharmacy in the general population, but there is uncertainty regarding their effect among frail older adults. This overview of published systematic reviews assesses the impact of medication reviews on polypharmacy in frail older adults. Embase was searched from its inception to January 2021 and 28 systematic reviews were identified, out of which 10 were included in the overview. Medication reviews were the most common intervention in 8 out of 10 systematic reviews. The frailty score was reported as an outcome in one systematic review that found no evidence for fundamental pharmacological effects on frailty. Six systematic reviews reported a statistically significant reduction in the number of inappropriately prescribed medications. Four systematic reviews reported on hospital admissions, with two of them reporting a decrease in hospitalisations. The quality assessment was moderate in six and critically low in four of the systematic reviews. We conclude that medication reviews help in reducing the use of inappropriate medications in frail older adults, but that there is insufficient evidence in terms of frailty score and hospital admissions.

Differential methylation in CD44 and SEC23A is associated with time preference in older individuals.

Time preference is a measure used to ascertain the level of which individuals prefer smaller, immediate rewards over larger, delayed rewards. We explored how an individual's time preference associates with their epigenetic profile. Time preferences were ascertained by asking participants of the Northern Ireland COhort for the Longitudinal study of Ageing to make a series of choices between two hypothetical income scenarios. From these, eight 'time preference' categories were derived, ranging from "patient" to "impatient" on an ordinal scale. The Infinium High Density Methylation Assay, MethylationEPIC (Illumina) was used to evaluate the status of 862,927 CpGs. Time preference and DNA methylation data were obtained for 1648 individuals. Four analyses were conducted, assessing the methylation patterns at single site resolution between patient and impatient individuals using two adjustment models. In this discovery cohort analysis, two CpG sites were identified with significantly different levels of methylation (p < 9 × 10-8) between the individuals allocated to the patient group and the remaining population following adjustment for covariates; cg08845621 within CD44 and cg18127619 within SEC23A. Neither of these genes have previously been linked to time preference. Epigenetic modifications have not previously been linked to time preference using a population cohort but they may represent important biomarkers of accumulated, complex determinants of this trait. Further analysis is warranted of both the top-ranked results and of DNA methylation as an important link between measurable biomarkers and health behaviours.

A qualitative study to inform adaptations to a brain health intervention for older adults with type 2 diabetes living in rural regions of Ireland.

AIMS: Type 2 diabetes is a risk factor for late-life dementia, but dementia prevention strategies have yet to be comprehensively evaluated in people with diabetes. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated cognitive benefits of a 2-year multidomain lifestyle intervention. However, given the intensive nature of FINGER, there is uncertainty about whether it can be implemented in other high-risk populations. Our aim was to explore attitudes towards dementia risk, and barriers to an intervention based on the FINGER model in older adults with type 2 diabetes living in rural areas of Ireland. METHODS: Focus groups were conducted with 21 adults (11 men and 10 women) aged 60+ years with type 2 diabetes living in border regions of north and south Ireland. Data were analysed using thematic analysis. RESULTS: There was limited understanding of diabetes as a risk factor for late-life dementia. The main barriers to engagement with the multidomain intervention were eating foods that were not compatible with cultural norms, time and travel constraints, and perceived lack of self-efficacy and self-motivation for adopting the desired diet, exercise and computerised cognitive training (CCT) behaviours. Facilitators for intervention acceptability included the provision of culturally tailored and personalised education, support from a trusted source, and inclusion of goal setting and self-monitoring behavioural strategies. CONCLUSIONS: While there was high acceptability for a brain health intervention, several barriers including cultural food norms and low self-efficacy for adopting the diet, exercise and CCT components would need to be considered in the intervention design. Findings from this study will be used to inform local decisions regarding the adaptation of FINGER for people with type 2 diabetes. The feasibility of the adapted multidomain intervention will then be evaluated in a future pilot trial.

Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study.

PURPOSE: To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland. STUDY DESIGN: Population-based longitudinal cohort study. METHODS: Retinal imaging at the Norther Ireland Cohort for the Longitudinal Aging Study health assessment included stereo Colour Fundus Photography (CFP) (Canon CX-1, Tokyo, Japan) and Spectral-Domain Optical Coherence Tomography (SD-OCT) ((Heidelberg Retinal Angopgraph (HRA)+OCT; Heidelberg Engineering, Heidelberg, Germany). Medical history and demographic information was obtained during a home interview. Descriptive statistics were used to describe the prevalence of AMD and individual AMD features. Multiple imputation followed by multiple regression modelling was used to explore risk factor associations including relationships with AMD genetic risk score. RESULTS: Retinal images from 3386 participants were available for analysis. Mean age of the sample was 63.4 (SD 9.01, range: 36-99). Population weighted prevalence of AMD using colour grading in those over 55 years was: no drusen: 6 0.4%; drusen <63 µm: 15.9%; drusen 63-125 µm: 13.7%; drusen >125 µm or pigmentary changes: 8.3%; late AMD: 1.6%. Prevalence of AMD features in those over 55 years was: OCT drusen 27.5%, complete outer retinal pigment epithelium and outer retinal atrophy (cRORA) on OCT was 4.3%, reticular drusen 3.2% and subretinal drusenoid deposits 25.7%. The genetic risk score was significantly associated with drusen and cRORA but less so for SDD alone and non-significant for hyperpigmentation or vitelliform lesions. CONCLUSIONS: Multimodal imaging-based classification has provided evidence of some divergence of genetic risk associations between classical drusen and SDD. Our findings support an urgent review of current AMD severity classification systems.

Plasma metabolites distinguish dementia with Lewy bodies from Alzheimer's disease: a cross-sectional metabolomic analysis.

Background: In multifactorial diseases, alterations in the concentration of metabolites can identify novel pathological mechanisms at the intersection between genetic and environmental influences. This study aimed to profile the plasma metabolome of patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), two neurodegenerative disorders for which our understanding of the pathophysiology is incomplete. In the clinical setting, DLB is often mistaken for AD, highlighting a need for accurate diagnostic biomarkers. We therefore also aimed to determine the overlapping and differentiating metabolite patterns associated with each and establish whether identification of these patterns could be leveraged as biomarkers to support clinical diagnosis. Methods: A panel of 630 metabolites (Biocrates MxP Quant 500) and a further 232 metabolism indicators (biologically informative sums and ratios calculated from measured metabolites, each indicative for a specific pathway or synthesis; MetaboINDICATOR) were analyzed in plasma from patients with probable DLB (n = 15; age 77.6 ± 8.2 years), probable AD (n = 15; 76.1 ± 6.4 years), and age-matched cognitively healthy controls (HC; n = 15; 75.2 ± 6.9 years). Metabolites were quantified using a reversed-phase ultra-performance liquid chromatography column and triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode, or by using flow injection analysis in MRM mode. Data underwent multivariate (PCA analysis), univariate and receiving operator characteristic (ROC) analysis. Metabolite data were also correlated (Spearman r) with the collected clinical neuroimaging and protein biomarker data. Results: The PCA plot separated DLB, AD and HC groups (R2 = 0.518, Q2 = 0.348). Significant alterations in 17 detected metabolite parameters were identified (q ≤ 0.05), including neurotransmitters, amino acids and glycerophospholipids. Glutamine (Glu; q = 0.045) concentrations and indicators of sphingomyelin hydroxylation (q = 0.039) distinguished AD and DLB, and these significantly correlated with semi-quantitative measurement of cardiac sympathetic denervation. The most promising biomarker differentiating AD from DLB was Glu:lysophosphatidylcholine (lysoPC a 24:0) ratio (AUC = 0.92; 95%CI 0.809-0.996; sensitivity = 0.90; specificity = 0.90). Discussion: Several plasma metabolomic aberrations are shared by both DLB and AD, but a rise in plasma glutamine was specific to DLB. When measured against plasma lysoPC a C24:0, glutamine could differentiate DLB from AD, and the reproducibility of this biomarker should be investigated in larger cohorts.

Prevalence of cognitive impairment in patients with rheumatoid arthritis: a cross sectional study.

OBJECTIVE: To explore the role of chronic inflammation in rheumatoid arthritis (RA) on cognition. METHODS AND ANALYSIS: Six hundred sixty-one men and women aged ≥55 years who fulfilled the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for RA were recruited from three healthcare trusts in the United Kingdom (UK) between May 2018 and March 2020. Study participants took part in interviews which captured sociodemographic information, followed by an assessment of cognition. RA specific clinical characteristics were obtained from hospital medical records. Participants were cognitively assessed using the Montreal Cognitive Assessment (MoCA) and were classified as cognitively impaired if they scored ≤27/30 points. Linear regression analyses were conducted to identify which demographic and clinical variables were potential predictors of cognitive impairment. RESULTS: The average age of participants was 67.6 years and 67% (444/661) were women. 72% (458/634; 95% CI 0.69 to 0.76) of participants were classified as cognitively impaired (MoCA≤27). Greater cognitive impairment was associated with older age (p = .006), being male (p = .041) and higher disease activity score (DAS28) (with moderate (DAS28 > 3.1) (p = 0.008) and high (DAS28 > 5.1) (p = 0.008)) compared to those in remission (DAS28 ≤ 2.6). There was no association between MoCA score and education, disease duration, RF status, anti-cyclic citrullinated peptide (anti-CCP) status, RA medication type or use of glucocorticoids or non-steroidal anti-inflammatory drugs (p > 0.05). CONCLUSION: This study suggests that cognitive impairment is highly prevalent in older adults with RA. This impairment appears to be associated with higher RA disease activity and supports the concept that chronic systemic inflammation might accelerate cognitive decline. This underlines the importance of controlling the inflammatory response.

Exposure to the troubles in Northern Ireland, memory functioning, and social activity engagement: results from NICOLA.

We investigated the potential impact of a cohort traumatic exposure, the Troubles in Northern Ireland, on memory functioning in later life, and the potential moderating effect of social activity engagement. Using data from 6571 participants aged 60 + in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) cohort, we used a structural equation modelling framework to explore associations between traumatic exposure during the Troubles and memory functioning. As expected, social activity engagement was positively associated with memory functioning, ß = .102. Traumatic exposure was also positively associated with memory functioning, ß = .053. This association was stronger at low levels of social activity engagement; among those with higher levels, there was little association, interaction ß = - 0.054. The positive association between traumatic exposure during the Troubles and memory functioning was not moderated by the age at which the exposures occurred (based on analysis of a subsample with available data), interaction ß = - 0.015. We conclude that superior memory functioning was associated with higher levels of traumatic exposure during the Troubles, particularly among those with lower levels of social activity engagement, and regardless of the age at which the exposures occurred. Future longitudinal analyses are required to build on these results, which potentially have implications for life-course epidemiology, in relation to critical periods for traumatising experiences. Supplementary Information: The online version contains supplementary material available at 10.1007/s10433-022-00683-5.

Dementia with Lewy bodies post-mortem brains reveal differentially methylated CpG sites with biomarker potential.

Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. Herein, we measure genome-wide DNA methylation profiles of post-mortem brain tissue (Broadmann area 7) from 15 pathologically confirmed DLB brains and compare them with 16 cognitively normal controls using Illumina MethylationEPIC arrays. We identify 17 significantly differentially methylated CpGs (DMCs) and 17 differentially methylated regions (DMRs) between the groups. The DMCs are mainly located at the CpG islands, promoter and first exon regions. Genes associated with the DMCs are linked to "Parkinson's disease" and "metabolic pathway", as well as the diseases of "severe intellectual disability" and "mood disorders". Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future.

A blood DNA methylation biomarker for predicting short-term risk of cardiovascular events.

BACKGROUND: Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the 'next-generation' epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2. RESULTS: Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant). CONCLUSIONS: We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

PROtein enriched MEDiterranean diet to combat undernutrition and promote healthy neuroCOGnitive ageing in older adults: The PROMED-COG consortium project.

Dementia is a major public health challenge owing to its increasing prevalence and recognised impact on disability among older adults. Observational data indicate that weight loss is associated with increased dementia risk of 30%-40% and precedes a diagnosis of cognitive impairment or dementia by at least one decade. Although relatively little is known about the mechanisms of unintentional weight loss in dementia, this provides a window of opportunity to intervene with strategies to counteract undernutrition and delay, or prevent, the onset of dementia. This article provides an overview of the PROMED-COG project and associated work packages. The project aimes to (1) strengthen the epidemiologic evidence to better understand the potential benefits of combating undernutrition for healthy neurocognitive ageing; (2) increase scientific knowledge on the balance between a protein enriched Mediterranean diet (PROMED) and physical exercise to prevent undernutrition and promote healthy neurocognitive ageing, and generate data on mechanistic pathways; (3) stimulate collaboration and capacity building for nutrition and neurocognitive ageing research in Europe; and (4) develop public and practice recommendations to combat undernutrition and promote healthy neurocognitive ageing in older adults. Findings will provide new and critical insights into the role of undernutrition in neurocognitive ageing, how this role can differ by sex, genetic risk and timing of undernutrition exposure, and how modifications of dietary and physical activity behaviour can reduce the burden of undernutrition and neurodegeneration. The research outcomes will be useful to inform policy and practice about the dietary guidelines of older people and provide insight to industry for the development of food-based solutions to prevent undernutrition.

The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and their Associations with the Incidence of Postoperative Delirium.

The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were ≥65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 ± 5.2) or delirium (n = 28, aged: 76.2 ± 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.

A systematic review of interventions to reduce anticholinergic burden in older people with dementia in primary care.

OBJECTIVE: This systematic review aimed to assess the types and effectiveness of interventions that sought to reduce anticholinergic burden (ACB) in people with dementia (PwD) in primary care. METHODS: One trial registry and eight electronic databases were systematically searched to identify eligible English language studies from inception until December 2021. To be eligible for inclusion, studies had to be randomised controlled trials (RCTs) or non-randomised studies (NRS), including controlled before-and-after studies and interrupted time-series studies, of interventions to reduce ACB in PwD aged ≥65 years (either community-dwelling or care home residents). All outcomes were to be considered. Quality was to be assessed using the Cochrane Risk of Bias tool for RCTs and ROBINS-I tool for NRS. If data could not be pooled for meta-analysis, a narrative synthesis was to be conducted. RESULTS: In total, 1880 records were found, with 1594 records remaining after removal of duplicates. Following title/abstract screening, 13 full-text articles were assessed for eligibility. None of these studies met the inclusion criteria for this review. Reasons for exclusion were incorrect study design, ineligible study population, lack of focus on reducing ACB, and studies conducted outside the primary care setting. CONCLUSIONS: This 'empty' systematic review highlights the lack of interventions to reduce ACB in PwD within primary care, despite this being highlighted as a priority area for research in recent clinical guidance. Future research should focus on development and testing of interventions to reduce ACB in this patient population through high-quality clinical trials.

The Role of Epigenetic Clocks in Explaining Educational Inequalities in Mortality: A Multicohort Study and Meta-analysis.

Educational inequalities in all-cause mortality have been observed for decades. However, the underlying biological mechanisms are not well known. We aimed to assess the role of DNA methylation changes in blood captured by epigenetic clocks in explaining these inequalities. Data were from 8 prospective population-based cohort studies, representing 13 021 participants. First, educational inequalities and their portion explained by Horvath DNAmAge, Hannum DNAmAge, DNAmPhenoAge, and DNAmGrimAge epigenetic clocks were assessed in each cohort via counterfactual-based mediation models, on both absolute (hazard difference) and relative (hazard ratio) scales, and by sex. Second, estimates from each cohort were pooled through a random effect meta-analysis model. Men with low education had excess mortality from all causes of 57 deaths per 10 000 person-years (95% confidence interval [CI]: 38, 76) compared with their more advantaged counterparts. For women, the excess mortality was 4 deaths per 10 000 person-years (95% CI: -11, 19). On the relative scale, educational inequalities corresponded to hazard ratios of 1.33 (95% CI: 1.12, 1.57) for men and 1.15 (95% CI: 0.96, 1.37) for women. DNAmGrimAge accounted for the largest proportion, approximately 50%, of the educational inequalities for men, while the proportion was negligible for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the World Health Organization (WHO) risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.