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BACKGROUND: Understanding how certain factors affect autism incidence can help to identify inequities in diagnostic access. We aimed to investigate the incidence of autism in England as a function of geography and sociodemographics, examining spatial distribution across health service boundaries.METHODS: In this retrospective, longitudinal, school registry study, we sourced data for the years 2014-17 from the summer school census, which is a component of the National Pupil Database, a government registry of pupils under state education in England. Our main outcome was the incidence of autism in the English state-funded education system, defined by the amount of new autism-specific Education, Health and Care Plans or autism-specific special education needs and disability support recorded during each summer school census year since the 2014 baseline. After excluding prevalent cases in 2014, we calculated unadjusted incidence and age-adjusted, sex-adjusted incidence per 100 000 person-years per subsequent school year and by various sociodemographic categories and local authority districts. We report spatial effects using local indicators of spatial association. We used a three-level mixed-effects logistic regression model with two random intercepts (lower-layer super output area [a geographical area in England containing 1000-3000 residents] and pupil identifier) to calculate odds ratios (ORs) for autism incidence, adjusting for age, sex, ethnicity, claimed eligibility for free school meals, ethnic density quintile, Index of Multiple Deprivation quintile, first language spoken at home, and year, with our reference category being White girls without claimed eligibility for free school meals who speak English as their first language.FINDINGS: Between 2014 and 2017, our total sample included 31 580 512 person-years and 102 338 newly diagnosed autistic pupils, corresponding to an unadjusted annual autism incidence of 429·1 cases per 100 000 person-years (95% CI 426·4-431·7) and an age-adjusted, sex-adjusted annual incidence of 426·9 cases per 100 000 person-years (423·5-430·4). The adjusted incidence of autism was slightly higher in 2014-15 than in 2015-16 or 2016-17, and, of the age groups, pupils aged 1-3 years, 4-6 years, and 10-12 years had the highest incidence of autism. Adjusted autism incidence in boys was 3·9-times the incidence in girls (668·6 cases per 100 000 person-years [95% CI 662·5-674·6] vs 173·2 cases per 100 000 person-years [170·1-176·3]). Across ethnic groups, adjusted incidence was highest in pupils who had an unclassified ethnicity (599·4 cases per 100 000 person-years [574·5-624·3]) or were Black (466·9 cases per 100 000 person-years [450·8-483·0]). However, in our fully adjusted mixed-effects logistic regression model, we observed lower odds of autism among Asian (OR 0·65 [0·59-0·71]), Black (0·84 [0·77-0·92]), and Chinese (0·62 [0·42-0·92]) girls compared with White girls when these groups had not claimed free school meals and spoke English as a first language. Boys from all ethnicities irrespective of first language spoken and free school meals status had increased odds of autism compared with White girls with no claimed eligibility for free school meals who spoke English as their first language. We also found that claimed free school meal eligibility, first language spoken, sex, and ethnicity differentially impacted the odds of autism. Our spatial analysis showed significant spatial autocorrelation across lower-layer super output areas in England, with 2338 hotspots (high-incidence areas surrounded by other high-incidence areas).INTERPRETATION: The incidence of autism varies across sex, age, ethnicity, and geographical location. Environmental and social factors might interact with autism aetiology. Speaking a language other than English and economic hardship might increase access barriers to autism diagnostic services, autism-specific Education, Health and Care Plans, and school-level support.FUNDING: The Commonwealth Fund, the Institute for Data Valorization, the Fonds de recherche du Québec-Santé, Calcul Quebec, the Digital Research Alliance of Canada, the Wellcome Trust, the Innovative Medicines Initiative, the Autism Centre of Excellence, the Simons Foundation Autism Research Initiative, the Templeton World Charitable Fund, the Medical Research Council, the National Institute for Health and Care Research Cambridge Biomedical Research Centre, and the National Institute for Health and Care Research Applied Research Collaboration East of England-Population Evidence and Data Science.

Background and Objectives With the emergence of healthy aging as a key societal issue in recent decades, technology has often been proposed as a solution to the challenges faced by aging societies. From a public health perspective, however, aging-related technologies have been inconsistently conceptualized and ill-defined. By examining how relevant concepts in “technology for aging” have been developed to date, we hope to identify gaps and begin clarifying the topic. Research Design and Methods We conducted a scoping review according to PRISMA-ScR, drawing on PubMed and Embase. We selected articles that directly reported concepts of technology for aging, or from which such concepts could be inferred. Results We identified 43 articles, most of which were narrative reviews (n = 31). Concepts of technology for aging were presented in diverse ways with some overlap. Most studies provided some terminology (n = 36), but with little conceptual uniformity. Conceptual discourse was often focused on the aging agenda; while technological aspects were poorly defined. A conceptual framework from a public health perspective was derived from 8 articles—it showed that technology strategies do not take a population approach. Discussion and Implications While the potential of “technology for aging” is vast, its real capacity to deliver a desirable life for older people remains underdeveloped. Clearer concepts and realistic goals at population level are lacking. Efficient investment must be made throughout the social system, and technology needs to be integrated via macro-level practices.

Dementia has been recognised as a key challenge in many ageing societies across the world. Several population-based studies have been developed to investigate dementia and cognitive ageing from perspectives of biology, health, psychology and social sciences. However, there is a need to provide a better understanding of ‘contexts’, the circumstance where these ageing populations existed, and heterogeneity within and across the populations in different time and places. In this article, we summarise some examples of earlier population-based studies undertaken by our research groups in England and Wales and their contribution to the epidemiology of dementia, neuropathology, cognitive and mental health in older age. We also describe how these studies illustrated variation among ageing populations and changes in their health conditions across time and place. These findings highlight the contribution that population-based studies can make, along with the vital to incorporate contexts in ageing research. A lifecourse approach within social context is needed to integrate life experiences, social circumstances, and multiple dimensions of cognition, functioning, physical health and wellbeing over the ageing process. We also discuss how evidence from population-based studies can support various international initiatives on dementia, healthy ageing and Sustainable Development Goals and facilitate tailored approaches for diverse populations across global societies.

BACKGROUND AND PURPOSE: The roles of blood low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in the development of post-stroke dementia remain uncertain. This study was to investigate their potential associations. METHODS: A retrospective cohort study was conducted using the Clinical Practice Research Datalink. Patients with first-ever stroke but no prior dementia were followed up for 10 years. Cox regression was used to examine the association of baseline LDL-C, HDL-C and triglycerides with post-stroke dementia. RESULTS: Amongst 63,959 stroke patients, 15,879 had complete baseline data and were included in our main analysis. 10.8% developed dementia during a median of 4.6 years of follow-up. The adjusted hazard ratio of dementia for LDL-C (per log mmol/l increase) was 1.29 (95% confidence interval [CI] 1.14-1.47), with a linear increasing trend (p trend

Background Delirium is common, distressing and associated with poor outcomes. Previous studies investigating the impact of delirium on cognitive outcomes have been limited by incomplete ascertainment of baseline cognition or lack of prospective delirium assessments. This study quantified the association between delirium and cognitive function over time by prospectively ascertaining delirium in a cohort aged ≥ 65 years in whom baseline cognition had previously been established. Methods For 12 months, we assessed participants from the Cognitive Function and Ageing Study II-Newcastle for delirium daily during hospital admissions. At 1-year, we assessed cognitive decline and dementia in those with and without delirium. We evaluated the effect of delirium (including its duration and number of episodes) on cognitive function over time, independently of baseline cognition and illness severity. Results Eighty two of 205 participants recruited developed delirium in hospital (40%). One-year outcome data were available for 173 participants: 18 had a new dementia diagnosis, 38 had died. Delirium was associated with cognitive decline (−1.8 Mini-Mental State Examination points [95% CI –3.5 to –0.2]) and an increased risk of new dementia diagnosis at follow up (OR 8.8 [95% CI 1.9–41.4]). More than one episode and more days with delirium (>5 days) were associated with worse cognitive outcomes. Conclusions Delirium increases risk of future cognitive decline and dementia, independent of illness severity and baseline cognition, with more episodes associated with worse cognitive outcomes. Given that delirium has been shown to be preventable in some cases, we propose that delirium is a potentially modifiable risk factor for dementia.

Background:\ud Benzodiazepines and anticholinergic drugs have been implicated in causing cognitive decline and potentially increasing dementia risk. However, evidence for an association with neuropathology is limited.\ud \ud Objective:\ud To estimate the correlation between neuropathology at death and prior use of benzodiazepines and anticholinergic drugs.\ud \ud Methods:\ud We categorized 298 brain donors from the population-based Medical Research Council Cognitive Function and Ageing Study, according to their history of benzodiazepine (including Z-drugs) or anticholinergic medication (drugs scoring 3 on the Anticholinergic Cognitive Burden scale) use. We used logistic regression to compare dichotomized neuropathological features for those with and without history of benzodiazepine and anticholinergic drug use before dementia, adjusted for confounders.\ud \ud Results:\ud Forty-nine (16%) and 51 (17%) participants reported benzodiazepine and anticholinergic drug use. Alzheimer’s disease neuropathologic change was similar whether or not exposed to either drug, for example 46% and 57% had intermediate/high levels among those with and without anticholinergic drug use. Although not significant after multiple testing adjustments, we estimated an odds ratio (OR) of 0.40 (95% confidence interval [95% CI] 0.18–0.87) for anticholinergic use and cortical atrophy. For benzodiazepine use, we estimated ORs of 4.63 (1.11–19.24) and 3.30 (1.02–10.68) for neuronal loss in the nucleus basalis and substantial nigra. There was evidence of neuronal loss in the nucleus basalis with anticholinergic drug use, but the association reduced when adjusted for confounders.\ud \ud Conclusions:\ud We found no evidence that benzodiazepine or anticholinergic drug use is associated with typical pathological features of Alzheimer’s disease; however, we cannot rule out effects owing to small numbers.

BACKGROUND: Previous research has examined the improvements in healthy years if different health conditions are eliminated, but often with cross-sectional data, or for a limited number of conditions. We used longitudinal data to estimate disability-free life expectancy (DFLE) trends for older people with a broad number of health conditions, identify the conditions that would result in the greatest improvement in DFLE, and describe the contribution of the underlying transitions. METHODS AND FINDINGS: The Cognitive Function and Ageing Studies (CFAS I and II) are both large population-based studies of those aged 65 years or over in England with identical sampling strategies (CFAS I response 81.7%, N = 7,635; CFAS II response 54.7%, N = 7,762). CFAS I baseline interviews were conducted in 1991 to 1993 and CFAS II baseline interviews in 2008 to 2011, both with 2 years of follow-up. Disability was measured using the modified Townsend activities of daily living scale. Long-term conditions (LTCs-arthritis, cognitive impairment, coronary heart disease (CHD), diabetes, hearing difficulties, peripheral vascular disease (PVD), respiratory difficulties, stroke, and vision impairment) were self-reported. Multistate models estimated life expectancy (LE) and DFLE, stratified by sex and study and adjusted for age. DFLE was estimated from the transitions between disability-free and disability states at the baseline and 2-year follow-up interviews, and LE was estimated from mortality transitions up to 4.5 years after baseline. In CFAS I, 60.8% were women and average age was 75.6 years; in CFAS II, 56.1% were women and average age was 76.4 years. Cognitive impairment was the only LTC whose prevalence decreased over time (odds ratio: 0.6, 95% confidence interval (CI): 0.5 to 0.6, p < 0.001), and where the percentage of remaining years at age 65 years spent disability-free decreased for men (difference CFAS II-CFAS I: -3.6%, 95% CI: -8.2 to 1.0, p = 0.12) and women (difference CFAS II-CFAS I: -3.9%, 95% CI: -7.6 to 0.0, p = 0.04) with the LTC. For men and women with any other LTC, DFLE improved or remained similar. For women with CHD, years with disability decreased (-0.8 years, 95% CI: -3.1 to 1.6, p = 0.50) and DFLE increased (2.7 years, 95% CI: 0.7 to 4.7, p = 0.008), stemming from a reduction in the risk of incident disability (relative risk ratio: 0.6, 95% CI: 0.4 to 0.8, p = 0.004). The main limitations of the study were the self-report of health conditions and the response rate. However, inverse probability weights for baseline nonresponse and longitudinal attrition were used to ensure population representativeness. CONCLUSIONS: In this study, we observed improvements to DFLE between 1991 and 2011 despite the presence of most health conditions we considered. Attention needs to be paid to support and care for people with cognitive impairment who had different outcomes to those with physical health conditions.

BACKGROUND: Delirium is common, distressing, and associated with poor outcomes. Despite this, delirium remains poorly recognized, resulting in worse outcomes. There is an urgent need for methods to objectively assess for delirium. Physical function has been proposed as a potential surrogate marker, but few studies have monitored physical function in the context of delirium. We examined if trajectories of physical function are affected by the presence and severity of delirium in a representative sample of hospitalized participants older than 65 years. METHOD: During hospital admissions in 2016, we assessed participants from the Delirium and Cognitive Impact in Dementia study daily for delirium and physical function, using the Hierarchical Assessment of Balance and Mobility (HABAM). We used linear mixed models to assess the effect of delirium and delirium severity during admission on HABAM trajectory. RESULTS: Of 178 participants, 58 experienced delirium during admission. Median HABAM scores in those with delirium were significantly higher (indicating worse mobility) than those without delirium. Modeling HABAM trajectories, HABAM scores at first assessment were worse in those with delirium than those without, by 0.76 (95% CI: 0.49-1.04) points. Participants with severe delirium experienced a much greater perturbance in their physical function, with an even lower value at first assessment and slower subsequent improvement. CONCLUSIONS: Physical function was worse in those with delirium compared to without. This supports the assertion that motor disturbances are a core feature of delirium and monitoring physical function, using a tool such as the HABAM, may have clinical utility as a surrogate marker for delirium and its resolution.

Peer reviewed: True, Acknowledgements: The authors thank the European Union's Horizon 2020 Research and Innovation Programme and National Key R&D Programme of China for the funding of the trial. The authors thank Kevin Hekert, Louwrens Knulst, Michiel van Dam, Martijn Bos, Jan Eikelenboom, and Mart Hoitink for their substantial contribution in building the platform. The authors thank Jihui Lyu, Wei Zhang, Haifeng Hou, Yixuan Niu, Yueyi Yu, Hui Yuan, Hongmei Liu, Siqi Ge, Mingyue He, Dan Li, Qiang Zeng, Dong Li, Baoliang Sun, Jinxia Zhang, Xiaoyu Zhang, Mingyang Cao, Bin Jiang, Danning Li, Weijiao Zhang, and Cancan Li for their contributions to the trial logistics. The authors thank Ron Handels for his comments on the manuscript. The authors also thank all patient participants and other stakeholders who took part in patient and public involvement groups for their contribution to the platform design., Background: Mobile health (mHealth) has the potential to bring preventive healthcare within reach of populations with limited access to preventive services, by delivering personalized support at low cost. Although numerous mHealth interventions are available, very few have been developed following an evidence-based rationale or have been tested for efficacy. This article describes the systematic development of a coach-supported mHealth application to improve healthy lifestyles for the prevention of dementia and cardiovascular disease in the United Kingdom (UK) and China. Methods: Development of the Prevention of Dementia by Mobile Phone applications (PRODEMOS) platform built upon the experiences with the Healthy Aging Through Internet Counseling in the Elderly (HATICE) eHealth platform. In the conceptualization phase, experiences from the HATICE trial and needs and wishes of the PRODEMOS target population were assessed through semi-structured interviews and focus group sessions. Initial technical development of the platform was based on these findings and took place in consecutive sprint sessions. Finally, during the evaluation and adaptation phase, functionality and usability of the platform were evaluated during pilot studies in UK and China. Results: The PRODEMOS mHealth platform facilitates self-management of a healthy lifestyle by goal setting, progress monitoring, and educational materials on healthy lifestyles. Participants receive remote coaching through a chat functionality. Based on lessons learned from the HATICE study and end-users, we made the intervention easy-to-use and included features to personalize the intervention. Following the pilot studies, in which in total 77 people used the mobile application for 6 weeks, the application was made more intuitive, and we improved its functionalities. Conclusion: Early involvement of end-users in the development process and during evaluation phases improved acceptability of the mHealth intervention. The actual use and usability of the PRODEMOS intervention will be assessed during the ongoing PRODEMOS randomized controlled trial, taking a dual focus on effectiveness and implementation outcomes.

Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones in vitro and in experimental animals in vivo. The neocortical content of serum amyloid P component was immunoassayed in 157 subjects aged 65 or more with known dementia status at death, in the large scale, population-representative, brain donor cohort of the Cognitive Function and Ageing Study, which avoids the biases inherent in studies of predefined clinico-pathological groups. The serum amyloid P component values were significantly higher in individuals with dementia, independent of serum albumin content measured as a control for plasma in the cortex samples. The odds ratio for dementia at death in the high serum amyloid P component tertile was 5.24 (95% confidence interval 1.79-15.29) and was independent of Braak tangle stages and Thal amyloid-β phases of neuropathological severity. The strong and specific association of higher brain content of serum amyloid P component with dementia, independent of neuropathology, is consistent with a pathogenetic role in dementia.

Contains fulltext : 248846.pdf (Publisher’s version ) (Closed access) IMPORTANCE: The optimal systolic blood pressure (SBP) to minimize the risk of dementia in older age is unknown. OBJECTIVE: To investigate whether the association between SBP and dementia risk is U-shaped and whether age and comorbidity play a role in this association. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used an individual participant data approach to analyze 7 prospective, observational, population-based cohort studies that were designed to evaluate incident dementia in older adults. These studies started between 1987 and 2006 in Europe and the US. Participants had no dementia diagnosis and had SBP and/or diastolic blood pressure (BP) data at baseline and incident dementia status during follow-up. Data analysis was conducted from November 7, 2019, to October 3, 2021. EXPOSURES: Baseline systolic BP. MAIN OUTCOMES AND MEASURES: All-cause dementia (defined using Diagnostic and Statistical Manual of Mental Disorders [Third Edition Revised] or Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition] and established at follow-up measurements or in clinical practice), mortality, and combined dementia and mortality were the outcomes. Covariates included baseline antihypertensive medication use, sex, educational level, body mass index, smoking status, diabetes, stroke history, myocardial infarction history, and polypharmacy. Cox proportional hazards regression models were used, and nonlinear associations were explored using natural splines. RESULTS: The study analyzed 7 cohort studies with a total of 17 286 participants, among whom 10 393 were women (60.1%) and the mean (SD) baseline age was 74.5 (7.3) years. Overall, dementia risk was lower for individuals with higher SBP, with the lowest risk associated with an SBP of approximately 185 mm Hg (95% CI, 161-230 mm Hg; P = .001). Stratified by overlapping 10-year baseline age groups, the lowest dementia risk was observed at somewhat lower systolic BP levels in those older than 75 years (158 [95% CI, 152-178] mm Hg to 170 [95% CI, 160-260] mm Hg). For mortality, there was a clear U-shaped association, with the lowest risk at 160 mm Hg (95% CI, 154-181 mm Hg; P

This individual participant data analysis assesses the cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia., Key Points Question Is thyroid dysfunction associated with cognitive decline? Findings In this individual participant data analysis of 23 cohorts including 74 565 participants with cognitive function and/or dementia measurements, subclinical thyroid dysfunction was not associated with global cognitive function at baseline (standardized mean difference, −0.02 for subclinical hyperthyroidism and 0.05 for subclinical hypothyroidism) or annual decline (standardized mean difference, −0.02 for subclinical hyperthyroidism and −0.00 for subclinical hypothyroidism). Meaning These findings do not support the need for screening for subclinical thyroid dysfunction for prevention of cognitive decline or dementia., Importance In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism—cross-sectionally (−0.06 standardized mean difference in score; 95% CI, –0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, –0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Current evidence is inconclusive on cognitive benefits or harms of statins among stroke patients, who have high risk of dementia. This observational cohort study investigated the association between statin use and post-stroke dementia using data from the Clinical Practice Research Datalink. Patients without prior dementia who had an incident stroke but received no statins in the preceding year were followed for up to 10 years. We used inverse probability weighted marginal structural models to estimate observational analogues of intention-to-treat (ITT, statin initiation versus no initiation) and per-protocol (PP, sustained statin use versus no use) effects on the risk of dementia. To explore potential impact of unmeasured confounding, we examined the risks of coronary heart disease (CHD, positive control outcome), fracture and peptic ulcer (negative control outcomes). In 18,577 statin initiators and 14,613 non-initiators (mean follow-up of 4.2 years), the adjusted hazard ratio (aHR) for dementia was 0.70 (95% confidence interval [CI] 0.64-0.75) in ITT analysis and 0.55 (95%CI 0.50-0.62) in PP analysis. The corresponding aHRITT and aHRPP were 0.87 (95%CI 0.79-0.95) and 0.70 (95%CI 0.620.80) for CHD, 1.03 (95%CI 0.82-1.29) and 1.09 (95%CI 0.77-1.54) for peptic ulcer, and 0.88 (95%CI 0.80-0.96) and 0.86 (95%CI 0.75-0.98) for fracture. Statin initiation after stroke was associated with lower risk of dementia, with a potentially greater benefit in patients who persisted with statins over time. The observed association of statin use with post-stroke dementia may in part be overestimated due to unmeasured confounding shared with the association between statin use and fracture., NIHR

Patients and families need hope, not false hope

Background Disability-free life expectancy (DFLE) inequalities by socioeconomic deprivation are widening, alongside rising prevalence of multiple long-term conditions (MLTCs). We use longitudinal data to assess whether MLTCs contribute to the widening DFLE inequalities by socioeconomic deprivation. Methods The Cognitive Function and Ageing Studies (CFAS I and II) are large population-based studies of those ≥65 years, conducted in three areas in England. Baseline occurred in 1991 (CFAS I, n=7635) and 2011 (CFAS II, n=7762) with two-year follow-up. We defined disability as difficulty in activities of daily living, MLTCs as the presence of at least two of nine health conditions, and socioeconomic deprivation by area-level deprivation tertiles. DFLE and transitions between disability states and death were estimated from multistate models. Findings For people with MLTCs, inequalities in DFLE at age 65 between the most and least affluent widened to around 2.5 years (men:2.4 years, 95% confidence interval (95%CI) 0.4–4.4; women:2.6 years, 95%CI 0.7–4.5) by 2011. Incident disability reduced for the most affluent women (Relative Risk Ratio (RRR):0.6, 95%CI 0.4–0.9), and mortality with disability reduced for least affluent men (RRR:0.6, 95%CI 0.5–0.8). MLTCs prevalence increased only for least affluent men (1991: 58.8%, 2011: 66.9%) and women (1991: 60.9%, 2011: 69.1%). However, DFLE inequalities were as large in people without MLTCs (men:2.4 years, 95%CI 0.3–4.5; women:3.1 years, 95% CI 0.8–5.4). Interpretation Widening DFLE inequalities were not solely due to MLTCs. Reduced disability incidence with MLTCs is possible but was only achieved in the most affluent. Funding This work was supported by the Dunhill Medical Trust. CFAS II was supported by the UK Medical Research Council (MRC; research grant G0601022), Alzheimer's Society Grant Ref: 294, and received support from the UK National Institute for Health Research (NIHR) comprehensive clinical research networks in West Anglia and Trent, and the Dementias and Neurodegenerative Disease Research Network in Newcastle. HB is supported by the Dunhill Medical Trust (grant number RPGF1806\44), and AK by a Newcastle University Research Fellowship. This research was undertaken within the UK NIHR collaboration for leadership in applied health research and care for Cambridgeshire and Peterborough and the Cambridge Biomedical Research Centre infrastructures, Nottingham city and Nottinghamshire county NHS primary care trusts, and UK NIHR Policy Research Programme, conducted through the NIHR Older People and Frailty Policy Research Unit, PR-PRU-1217-21502.

Never before in history have we had the data to track such a rapid increase in inequalities. With changes imminent in healthcare and public health organisational landscape in England and health inequalities high on the policy agenda, we have an opportunity to redouble efforts to reduce inequalities. In this article, we argue that health inequalities need re-framing to encompass the breadth of disadvantage and difference between healthcare and health outcome inequalities. Second, there needs to be a focus on long-term organisational change to ensure equity is considered in all decisions. Third, actions need to prioritise the fundamental redistribution of resources, funding, workforce, services and power. Reducing inequalities can involve unpopular and difficult decisions. Physicians have a particular role in society and can support evidenced-based change across practice and the system at large. If we do not act now, then when?

Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes., We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer’s-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom’s Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4–20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.

Context The risk for dementia among subjects who are obese with normal metabolic profiles, or called metabolically healthy obese (MHO), remains uninvestigated. Objective To determine the association between late-life metabolic health and obesity status and risk of incident dementia. Design Retrospective cohort study. Setting The National Health Insurance System, Republic of Korea. Patients A total of 12,296,863 adults >50 years old who underwent health examinations from 2009 to 2012 without baseline history of dementia. Main outcome measure Incident overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Results Among subjects ≥60 years old, 363,932 (6.4%) developed dementia during a median follow-up of 65 months (interquartile range 51 to 74 months). The MHO group showed the lowest incidence of overall dementia [hazard ratio (HR) 0.85; 95% CI, 0.84 to 0.86] and AD (HR 0.87; 95% CI, 0.86 to 0.88), but not VaD, compared with the metabolically healthy nonobese group. All components of metabolic syndrome except obesity significantly elevated the risk of dementia, and these associations were more pronounced in VaD. In particular, being underweight dramatically increased the risk of dementia. Conclusions The MHO phenotype in late life demonstrated lower risk of overall dementia and AD but not VaD. Additional studies in other populations are warranted to elucidate current results and may predict individuals most at risk for developing dementia.

Dementia is a public health and socioeconomic concern that is widely predicted to worsen as the proportion of older adults making up our global population increases.1 By 2050, 152 million people worldwide are expected to experience dementia, along with its associated impact. In an ambitious act to galvanise a global response, the 2013 G8 Dementia Summit was convened with a primary aim to identify a cure or disease-modifying therapy for dementia by 2025.2 New evidence has since deepened our understanding of the potential for disease-modifying therapies, making this target even more unrealistic. In parallel, rapidly accumulating evidence has emphasised the importance of broader societal policies for dementia prevention across the lifecourse.3 Here, we review the goals, progress, and challenges of the Summit activities, and propose potential ways forward to align policy with the public health evidence for dementia prevention.

OBJECTIVES High levels of life course intellectually-stimulating activity are hypothesised to produce a cognitive reserve that mitigates against overt cognitive impairment in the face of neuropathology. Leisure-time musical instrument playing could be a viable source of that stimulation, but to date no systematic review has been undertaken to investigate the effect of musical instrument playing on the incidence of cognitive impairment and dementia. METHODS A systematic review and meta-analysis including any study with musical instrument playing as the exposure, and cognitive impairment and/or dementia as the outcome. RESULTS 1211 unduplicated articles were identified from literature searching, of which three articles were included: two cohort studies and one twin study. All studies were of good methodological quality, and reported large protective effects of musical instrument playing. The twin study reported that musicians were 64% less likely to develop mild cognitive impairment or dementia, after additionally adjusting for sex, education and physical activity. A meta-analysis of the cohort studies found a 59% reduction in the risk of developing dementia within the study follow up. The evidence base is limited by size, small sample sizes and the risk of reverse causality. CONCLUSION The three identified studies that investigated the specific relationship of musical instrument playing and subsequent incidence of cognitive impairment and dementia all reported a large protective association. The results are encouraging but should be interpreted with caution. Larger, more focussed studies are required to further explore this association, with a particular need to consider the cumulative lifetime quantity of music playing.

Background Universal health coverage (UHC), which is embedded within the United Nations Sustainable Development Goals, is defined by the World Health Organization as all individuals having access to required health services, of sufficient quality, without suffering financial hardship. Effective strategies for financing healthcare are critical in achieving this goal yet remain a challenge in Sub-Saharan Africa (SSA). This systematic review aims to determine reported health financing mechanisms in SSA within the published literature and summarize potential learnings. Methods A systematic review was conducted aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. On 19 to 30 July 2019, MEDLINE, EMBASE, Web of Science, Global Health Database, the Cochrane Library, Scopus and JSTOR were searched for literature published from 2005. Studies describing health financing approaches for UHC in SSA were included. Evidence was synthesised in form of a table and thematic analysis. Results Of all records, 39 papers were selected for inclusion. Among the included studies, most studies were conducted in Kenya (n=7), followed by SSA as a whole (n=6) and Nigeria (n=5). More than two thirds of the selected studies reported the importance of equitable national health insurance schemes for UHC. The results indicate that a majority of health care revenue in SSA is from direct out-of-pocket payments. Another common financing mechanism was donor funding, which was reported by most of the studies. The average quality score of all studies was 81.6%, indicating a high appraisal score. The interrater reliability Cohen’s kappa score, κ=0.43 (p=0.002), showed a moderate level of agreement. Conclusions Appropriate health financing strategies that safeguard financial risk protection underpin sustainable health services and the attainment of UHC. It is evident from the review that innovative health financing strategies in SSA are needed. Some limitations of this review include potentially skewed interpretations due to publication bias and a higher frequency of publications included from two countries in SSA. Establishing evidence-based and multi-sectoral strategies tailored to country contexts remains imperative.

Background: Children with special education needs (SEN), such as autistic children, benefit from being included in education along with typical peers. However, development and implementation of inclusive education (IE) is considered difficult. This paper identifies conditions that facilitate IE development for autistic children in the European Union and benchmarks to track IE policy development. Methods: Education policy data from thirty legislative regions in the European Union were analyzed through a qualitative comparative analysis using eight conditions: a definition of SEN, the right to education for children with SEN, support for teaching staff, support services for children with SEN, individualized learning outcomes, parental involvement, and mixed mainstream classes.Results: The right to education for children with SEN is implemented in all regions under study. Seven of the examined conditions were associated with an environment of IE in the European Union from an autism perspective: an established definition of SEN, support for teaching staff, general availability of support services for children with SEN, individualized learning outcomes, parental involvement, IE policies, and mixed mainstream classrooms. Mixed classrooms and support services for children with SEN were identified as necessary for IE. IE policies and support for teaching staff were present in all scenarios that facilitated IE. Even though the analysis was initially focused on autism, the policies consisted predominantly of general SEN policies. As such, the results can be interpreted in a wider context, beyond autism.Conclusion: Mixed mainstream classrooms and support services for children with special needs were found essential for consistent IE development. Support for teaching staff and IE policies facilitate IE and should be further explored and implemented.

Background: Exploring the domains of cognitive function which are most strongly associated with future dementia may help with understanding risk factors for, and the natural history of dementia. Objective: To examine the association of performance on a range of cognitive tests (both global and domain specific) with subsequent diagnosis of dementia through health services in a population of relatively healthy men and women and risk of future dementia. Methods: We examined the association between performance on different cognitive tests as well as a global score and future dementia risk ascertained through health record linkage in a cohort of 8,581 individuals (aged 48–92 years) between 2004–2019 with almost 15 years follow-up (average of 10 years) before and after adjustment for socio-demographic, lifestyle, and health characteristics. Results: Those with poor performance for global cognition (bottom 10%) were almost four times as likely to receive a dementia diagnosis from health services over the next 15 years than those who performed well HR = 3.51 (95% CI 2.61, 4.71 p

Purpose of review The paper applies recent conceptualisations of predictive processing to the understanding of inequalities in mental health. Recent findings Social neuroscience has developed important ideas about the way the brain models the external world, and how the interface between cognitive and cultural processes interacts. These resonate with earlier concepts from cybernetics and sociology. These approaches could be applied to understanding some of the dynamics leading to the patterning of mental health problems in populations. Summary The implications for practice are the way such thinking might help illuminate how we think and act, and how these are anchored in the social world.

Introduction Musical instrument playing provides intellectual stimulation, which is hypothesised to generate cognitive reserve that protects against cognitive impairment. Studies to date have classified musicianship as a binary entity. This investigation draws on the dataset of the European Prospective Investigation of Cancer Norfolk study to examine the effect of frequency of playing on later-life cognition. Methods We compared three categorisations of self-reported musical playing frequency in late mid-life (12-month period) against cognitive performance measured after a 4–11 year delay, adjusted for relevant health and social confounders. Logistic regression models estimated the adjusted association between frequency of musical playing and the likelihood of being in the top and bottom cognitive deciles. Results A total of 5,693 participants (745 musicians) provided data on music playing, cognition and all co-variables. Classification of musicianship by frequency of playing demonstrated key differences in socio-demographic factors. Musicians outperformed non-musicians in cognition generally. Compared with non-musicians, frequent musicians had 80% higher odds of being in the top cognitive decile (OR 1.80 [95% CI 1.19–2.73]), whereas musicians playing at any frequency had 29% higher odds (95% CI 1.03–1.62). There was evidence of a threshold effect, rather than a linear dose–response relationship. Discussion This study supports a positive association between late mid-life musical instrument playing and later-life cognition, although causation cannot be assumed. Musicians playing frequently demonstrated the best cognition. ‘Musicians’ are a heterogeneous group and frequency of music playing seems a more informative measure than binary classification. Ideally, this more nuanced measure would be collected for different life course phases.

Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272, Background: Poor performance in the 5‐chair stand test (5‐CST) indicates reduced lower limb muscle strength. The 5‐CST has been recommended for use in the initial assessment of sarcopenia, the accelerated loss of muscle strength and mass. In order to facilitate the use of the 5‐CST in sarcopenia assessment, our aims were to (i) describe the prevalence and factors associated with poor performance in the 5‐CST, (ii) examine the relationship between the 5‐CST and gait speed, and (iii) propose a protocol for using the 5‐CST. Methods: The population‐based study Cognitive Function and Ageing Study II recruited people aged 65 years and over from defined geographical localities in Cambridgeshire, Newcastle, and Nottingham. The study collected data for assessment of functional ability during home visits, including the 5‐CST and gait speed. We used multinomial logistic regression to assess the associations between factors including the SARC‐F questionnaire and the category of 5‐CST performance: fast (15 s), or unable, with slow/unable classed as poor performance. We reviewed previous studies on the protocol used to carry out the 5‐CST. Results: A total of 7190 participants aged 65+ from the three diverse localities of Cognitive Function and Ageing Study II were included (54.1% female). The proportion of those with poor performance in the 5‐CST increased with age, from 34.3% at age 65–69 to 89.7% at age 90+. Factors independently associated with poor performance included positive responses to the SARC‐F questionnaire, physical inactivity, depression, impaired cognition, and multimorbidity (all P < 0.005). Most people with poor performance also had slow gait speed (57.8%) or were unable to complete the gait speed test (18.4%). We found variation in the 5‐CST protocol used, for example, timing until a participant stood up for the fifth time or until they sat down afterwards. Conclusions: Poor performance in the 5‐CST is increasingly common with age and is associated with a cluster of other factors that characterize risk for poor ageing such as physical inactivity, impaired cognition, and multimorbidity. We recommend a low threshold for performing the 5‐CST in clinical settings and provide a protocol for its use.

In the last two decades, there has been in-depth investigation into understanding the pathogenesis, epidemiological profiling, and clinical characterization of dementia. However, these investigations have not led to successful interventions to prevent, delay, or reverse the pathological processes underlying dementia. Recent findings of a decrease in dementia risk in high-income countries such as the UK, USA and the Netherlands highlight that dementia, at least in some cases, is preventable. This article includes a synthesis of current knowledge on dementia epidemiology, biological underpinnings, risk factors, and current prevention programs, with the aim to set the path for research, funding, and policy initiatives to address the global public health challenge of how to prevent dementia or reduce risk within the framework of population-based studies. We advocate for development of novel approaches for intelligent data synthesis that go well beyond single approaches to enable powerful risk stratification analyses. An integrated approach is needed where researchers, funders, policymakers, and stakeholders contribute to and work together to formulate effective strategies for the global monitoring and development of population-based risk reduction, treatment, and prevention programs for dementia.

Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aβ phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p

The Soviet occupation of the Baltic States followed by joining the United Nations (UN) and European Union make these countries an interesting point of comparison in the development of autism and education policy. This study investigates how policies changed following the transition and how the right and access to education are facilitated for autistic children by performing a path dependence analysis. All Baltic States created new education policies following the transition out of the Soviet era, with their accession to the UN and their appetite to follow internationally available guidance. The right to education for all children in was adopted in all education systems. Education facilities for children with disabilities were implemented in all countries. Afterward, all countries started toward the development of more inclusive systems. Nevertheless, the majority of policies did not specify for autism, yet covered special education needs in general. A development in Latvia should be noted, where various special education needs are outlined in national policy, along with provisions and professional assistance required to address them in mainstream or special classrooms. Ultimately, education policy flourished after the transition. Their development caught up to other European Union countries and they are currently working on implementing inclusive education.

Background: Prior atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD) and peripheral artery disease (PAD), are common among patients with stroke, a known risk factor for dementia. However, whether these conditions further increase the risk of post-stroke dementia remains uncertain. Objective: To examine whether prior ASCVD is associated with increased risk of dementia among stroke patients. Methods: A retrospective cohort study was conducted using the Clinical Practice Research Datalink with linkage to hospital data. Patients with first-ever stroke between 2006 and 2017 were followed up to 10 years. We used multi-variable Cox regression models to examine the associations of prior ASCVD with dementia and the impact of prior ASCVD onset and duration. Results: Among 63,959 patients, 7,265 cases (11.4%) developed post-stroke dementia during a median of 3.6-year follow-up. The hazard ratio (HR) of dementia adjusted for demographics and lifestyle was 1.18 (95% CI: 1.12–1.25) for ASCVD, 1.16 (1.10–1.23) for CHD, and 1.25 (1.13–1.37) for PAD. The HRs additionally adjusted for multimorbidity and medications were 1.07 (1.00–1.13), 1.04 (0.98–1.11), and 1.11 (1.00–1.22), respectively. Based on the fully adjusted estimates, there was no linear relationship between the age of ASCVD onset and post-stroke dementia (all p-trend >0.05). The adjusted risk of dementia was not increased with the duration of pre-stroke ASCVD (all p-trend >0.05). Conclusion: Stroke patients with prior ASCVD are more likely to develop subsequent dementia. After full adjustment for confounding, however, the risk of post-stroke dementia is attenuated, with only a slight increase with prior ASCVD.

BackgroundNeurotrauma is an important global health problem. The largest cause of neurotrauma worldwide is road traffic collisions (RTCs), particularly in low- and middle-income countries (LMICs). Neurotrauma and RTCs are preventable, and many preventative interventions have been implemented over the last decades, especially in high-income countries (HICs). However, it is uncertain if these strategies are applicable globally due to variations in environment, resources, population, culture and infrastructure. Given this issue, this scoping review aims to identify, quantify and describe the evidence on approaches in neurotrauma and RTCs prevention, and ascertain contextual factors that influence their implementation in LMICs and HICs.MethodsA systematic search was conducted using five electronic databases (MEDLINE, EMBASE, CINAHL, Global Health on EBSCO host, Cochrane Database of Systematic Reviews), grey literature databases, government and non-government websites, as well as bibliographic and citation searching of selected articles. The extracted data were presented using figures, tables, and accompanying narrative summaries. The results of this review were reported using the PRISMA Extension for Scoping Reviews (PRISMA-ScR).ResultsA total of 411 publications met the inclusion criteria, including 349 primary studies and 62 reviews. More than 80% of the primary studies were from HICs and described all levels of neurotrauma prevention. Only 65 papers came from LMICs, which mostly described primary prevention, focussing on road safety. For the reviews, 41 papers (66.1%) reviewed primary, 18 tertiary (29.1%), and three secondary preventative approaches. Most of the primary papers in the reviews came from HICs (67.7%) with 5 reviews on only LMIC papers. Fifteen reviews (24.1%) included papers from both HICs and LMICs. Intervention settings ranged from nationwide to community-based but were not reported in 44 papers (10.8%), most of which were reviews. Contextual factors were described in 62 papers and varied depending on the interventions.ConclusionsThere is a large quantity of global evidence on strategies and interventions for neurotrauma and RTCs prevention. However, fewer papers were from LMICs, especially on secondary and tertiary prevention. More primary research needs to be done in these countries to determine what strategies and interventions exist and the applicability of HIC interventions in LMICs.

Background: The current evidence for higher physical activity and better cognitive function and lower risk of dementia is strong but not conclusive. More robust evidence is needed to inform public health policy. We provide further insight to discrepancies observed across studies, reporting on habitual inactivity including that during work. Methods: We examined cross-sectional and prospective relationships of physical inactivity during leisure and occupation time, with cognitive performance using a validated physical activity index in a cohort of 8585 men and women aged 40-79 years at baseline (1993-1997) for different domains using a range of cognitive measures. Cognitive testing was conducted between 2006-2011 (including pilot phase 2004-2006). Associations were examined using multinomial logistic regression adjusting for socio-demographic and health variables as well total habitual physical activity. Results: Inactivity during work was inversely associated with poor cognitive performance (bottom tenth percentile of a composite cognition score); Odds Ratio (OR) = 0·68 (95% Confidence Interval (CI) 0.54, 0·86) P=0·001. Results were similar cross-sectionally; OR = 0·65 (95% CI 0·45, 0·93) P=0·02. Manual workers had increased risk of poor performance compared to those with an occupation classified as inactive. Inactivity during leisure time was associated with increased risk of poor performance in the cross-sectional analyses only. Conclusions: The relationship between inactivity and cognition is strongly confounded by education, social class and occupation. Physical activity during leisure may be protective for cognition, but work related physical activity is not protective. A greater understanding of the mechanisms and confounding underlying these paradoxical findings is needed., This work was supported by the Medical Research Council, UK (MRC) http://www.mrc.ac.uk/ (Ref: MR/N003284/1, MC-UU_12015/1 to N.W.); Cancer Research UK, http://www.cancerresearchuk.org/ (CRUK, Ref: C864/A8257) and NIHR, https://www.nihr.ac.uk (Ref: NF-SI-0616–10090 to C.B.). The clinic for EPIC- orfolk 3HC was funded by Research into Ageing, now known as Age UK, http://www.ageuk.org.uk/ (Grant Ref: 262). The pilot phase was supported by MRC (Ref: G9502233) and CRUK (Ref: C864/A2883)

Although people are living longer, there is no discernible pattern about the quality of life in an increasing lifespan. This restricts our capacity to predict and prepare for the consequences of population ageing. Accordingly, we propose a population ageing indicator that combines demographic and disability prevalence data through a characteristics approach and explore different scenarios to account for uncertainty in life quality projections. Our results, available for 186 countries, show that countries that rank older under conventional chronological ageing measures may rank younger under our qualitative measure. Additionally, we find substantial differences in our projections depending on different health assumptions, demonstrating the risk of using ageing indicators that make implicit assumptions about health characteristics., This work is the result of a 2018 Ignacio H. Larramendi Research Grant of Fundación MAPFRE. AR-U' work received funding from the Gillings Fellowship in Global Public Health and Autism Research, Grant Award YOG054. JO acknowledges the financial support of Spanish Ministry of Science, Innovation and Universities (formerly, Ministry of Economy and Competitiveness), Project ECO2016-76506-C4-3-R.

BACKGROUND: This study aims to determine whether older adults reporting back pain (BP) are at increased risk of premature mortality, specifically, to examine the association with disabling/non-disabling pain separately. METHODS: Participants aged ≥75 years were recruited to the Cambridge City over-75s Cohort (CC75C) study. Participants answered interviewer-administered questions on BP and were followed up until death. The relationship between BP and mortality was examined using Cox regression, adjusted for potential confounding factors. Separate models were computed for men and women. RESULTS: From 1174 individuals with BP data, the date of death was known for 1158 (99%). A significant association was found between disabling BP and mortality (hazard ratio: 1.4; 95% confidence interval: 1.1-1.8) and this remained, albeit of borderline significance, following adjustment for socio-demographic variables and potential disease markers (1.3; 0.99-1.7). Further, this association was found to vary with sex: women experienced a 40% increase in the risk of mortality associated with disabling BP (1.4; 1.1-1.9), whereas no such increase was observed for men (1.0; 0.5-1.9). Participants with non-disabling BP were not at increased risk of mortality. CONCLUSIONS: This study confirmed previous findings regarding the relationship between pain and excess mortality. Further, we have shown that, among older adults, this association is specific to disabling pain and to women. Clinicians should be aware not only of the short-term implications of disabling BP but also the longer-term effects. Future research should attempt to understand the mechanisms underpinning this relationship to avoid excess mortality and should aim to determine why the relationship differs in men and women.

BACKGROUND: Previous imaging studies have suggested links between brain pathologies and factors that are associated with falls such as gait, balance and daily function. Possible neuropathological correlates of older people's falls have been suggested based on brain imaging studies, but to date none have been examined in brain tissue. METHODS: Falls data collected from repeated surveys of a population-based cohort of individuals aged at least 75 years old at baseline were related to neuropathological data collected from post-mortem examination of the study's associated brain donor collection (n=212). RESULTS: Amongst people without dementia, most cerebrovascular neuropathological features examined, particularly white matter pallor, microinfarcts and microscopic atherosclerosis, were increasingly common across the subgroups categorised by no reports of falling, only one or at least two reports of falling. The overall burden of pathology was greater in those with dementia, but only microinfarcts showed a similar increase with respect to reported falling status. CONCLUSIONS: Subclinical pathologies sharing a common vascular origin are associated with increased falling amongst people with no dementia, as are microinfarcts in those with dementia. Although further research is needed to address the mechanisms of falls and their neuropathological correlates, the findings from the current study would suggest that if cerebrovascular disease prevention reduces vascular neuropathology changes this may have direct benefits in reducing falls amongst older people with or without dementia.

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response.

In recent years, a rapidly increasing collection of investigative methods in addition to changes in diagnostic criteria for dementia have followed “high-tech” trends in medicine, with the aim to better define the dementia syndrome and its biological substrates, mainly in order to predict risk prior to clinical expression. These approaches are not without challenge. A set of guidelines have been developed by a group of European experts in population-based cohort research through a series of workshops, funded by the Joint Program for Neurodegenerative Disorders (JPND). The aims of the guidelines are to assist policy makers and researchers to understand (1) What population studies for ageing populations should encompass and (2) How to interpret the findings from population studies. Such studies are essential to provide evidence relevant to the understanding of healthy and frail brain ageing, including the dementia syndrome for contemporary and future societies by drawing on the past.

Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.

Background Special education provides an array of support that can advantageously meet special education needs (SEN) of children with autism. This report maps autism and SEN policies, and tension of international legislation in Malta, Cyprus, Luxembourg and Slovenia. Methods A policy path analysis was performed using a scoping review as fundamental methodological framework. Results Education for children with SEN developed from limited education towards segregation, and further to integration, and inclusion in mainstream education. International policy has greatly influenced the education systems under study. The rights to education and to have SEN addressed have been adopted in all countries. Inclusion is seen to be gradually incorporated by Malta, Cyprus and Luxembourg—closely following values of international documents through concise SEN policies. Slovenia’s education system remains segregated, indicating potential tension. Conclusions It appears that mainstream schools offer SEN services until no longer feasible for the child in the majority of investigated countries. Inclusion has become a guiding principle for most education systems under study. Finally, small states either commit to the implementation of inclusion or delay it and attempt to improve the education system for children with SEN in different ways.

Background A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). Objectives To update the evidence and reassess the accuracy of 18F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease (AD) dementia at follow-up. Methods A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. Results When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56-100%, specificity 24-100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. Conclusion Systematic and comprehensive assessment of studies of 18FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18F-FDG PET in people with MCI is needed.

Background death certification data are routinely collected in most developed countries. Coded causes of death are a readily accessible source and have the potential advantage of providing complete follow-up, but with limitations. Objective to investigate the reliability of using death certificates for surveillance of dementia, the time trend of recording dementia on death certificates and predictive factors of recording of dementia. Subjects individuals aged 65 and over in six areas across England and Wales were randomly selected for the Medical Research Council Cognitive Function and Ageing Study (CFAS) and CFAS II with mortality follow-up. Methods prevalence of dementia recorded on death certificates were calculated by year. Reporting of dementia on death certificates compared with the study diagnosis of dementia, with sensitivity, specificity and Cohen’s κ were estimated. Multivariable logistic regression models explored the impact of potential factors on the reporting of dementia on the death certificate. Results the overall unadjusted prevalence of dementia on death certificates rose from 5.3% to 25.9% over the last 26 years. Dementia reported on death certificates was poor with sensitivity 21.0% in earlier cohort CFAS, but it had increased to 45.2% in CFAS II. Dementia was more likely to be recorded on death certificates in individuals with severe dementia, or those living in an institution, yet less likely reported if individuals died in hospital. Conclusion recording dementia on death certificate has improved significantly in the England and Wales. However, such information is still an underestimate and should be used alongside epidemiological estimations.

Contains fulltext : 191185.pdf (Publisher’s version ) (Open Access) In clinical trials which target pathophysiological mechanisms associated with Alzheimer's disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer's dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants' experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer's disease biomarkers.

BACKGROUND: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. OBJECTIVE: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. METHODS: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. RESULTS: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. CONCLUSION: Despite differences in CVR management within the countries considered, it was possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally., The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 305374. The study has also been funded by the “Multimodal preventive trials for Alzheimer’s Disease: towards multinational strategies-programme: MIND-AD”, Academy of Finland (291803) and VTR, Kuopio University Hospital (5772815), Swedish Research Council (529-2014-7503), The Stockholms Sjukhem foundation, the Netherlands Organization for Health Research and Development, (733051041), and the French National Research Agency (ANR-14-JPPS-0001-02).

SummaryThe Prime Minister's challenge on dementia called for improved dementia diagnosis rates, based on assumptions of benefit to individuals and those who care for them. Subsequent policies have led to increased target drives for clinical practice to achieve early diagnosis of dementia through intense case identification. However, the current evidence base and treatment options do not support screening for dementia, and there is little empirical evidence that such intensive case identification and early diagnosis for dementia is justified without a better understanding of the benefits, costs and potential harms to individuals and services.Declaration of interestNone.

International audience; Several studies have reported a decline in incidence of dementia which may have large implications for the projected burden of disease, and provide important guidance to preventive efforts. However, reports are conflicting or inconclusive with regard to the impact of gender and education with underlying causes of a presumed declining trend remaining largely unidentified. The Alzheimer Cohorts Consortium aggregates data from nine international population-based cohorts to determine changes in the incidence of dementia since 1990. We will employ Poisson regression models to calculate incidence rates in each cohort and Cox proportional hazard regression to compare 5-year cumulative hazards across study-specific epochs. Finally, we will meta-analyse changes per decade across cohorts, and repeat all analysis stratified by sex, education and APOE genotype. In all cohorts combined, there are data on almost 69,000 people at risk of dementia with the range of follow-up years between 2 and 27. The average age at baseline is similar across cohorts ranging between 72 and 77. Uniting a wide range of disease-specific and methodological expertise in research teams, the first analyses within the Alzheimer Cohorts Consortium are underway to tackle outstanding challenges in the assessment of time-trends in dementia occurrence.

Background Delirium is common, affecting at least 20% of older hospital inpatients. It is widely accepted that delirium is associated with dementia but the degree of causation within this relationship is unclear. Previous studies have been limited by incomplete ascertainment of baseline cognition or a lack of prospective delirium assessments. There is an urgent need for an improved understanding of the relationship between delirium and dementia given that delirium prevention may plausibly impact upon dementia prevention. A well-designed, observational study could also answer fundamental questions of major importance to patients and their families regarding outcomes after delirium. The Delirium and Cognitive Impact in Dementia (DECIDE) study aims to explore the association between delirium and cognitive function over time in older participants. In an existing population based cohort aged 65 years and older, the effect on cognition of an episode of delirium will be measured, independent of baseline cognition and illness severity. The predictive value of clinical parameters including delirium severity, baseline cognition and delirium subtype on cognitive outcomes following an episode of delirium will also be explored. Methods Over a 12 month period, surviving participants from the Cognitive Function and Ageing Study II-Newcastle will be screened for delirium on admission to hospital. At the point of presentation, baseline characteristics along with a number of disease relevant clinical parameters will be recorded. The progression/resolution of delirium will be monitored. In those with and without delirium, cognitive decline and dementia will be assessed at one year follow-up. We will evaluate the effect of delirium on cognitive function over time along with the predictive value of clinical parameters. Discussion This study will be the first to prospectively elucidate the size of the effect of delirium upon cognitive decline and incident dementia. The results will be used to inform future dementia prevention trials that focus on delirium intervention.

Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.