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Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

Background/aims: Knowledge and research about research participation in the context of care homes is sparse. This article describes the level of research engagement for care homes in Scotland, and the facilitators and barriers to this. Methods: A short survey was distributed to care homes in Scotland. A total of 130 care homes returned completed surveys. Results: As of 2014, only 7' of care homes had past or present experience of research. Lack of time and workplace pressures were key obstacles to increasing research within care homes. Respondents recognised that residents could benefit from research but there were also concerns about the risks of research involvement. Conclusions: The survey provides much needed evidence that care homes are being overlooked in research, leading to exclusion of staff and residents. More work is needed to help integrate research into care homes without adding to the demands and pressures of the workplace.

BACKGROUND: Drugs modifying angiotensin II signalling could reduce Alzheimer's disease pathology, thus decreasing the rate of disease progression. We investigated whether the angiotensin II receptor antagonist losartan, compared with placebo, could reduce brain volume loss, as a measure of disease progression, in clinically diagnosed mild-to-moderate Alzheimer's disease.METHODS: In this double-blind, multicentre, randomised controlled trial, eligible patients aged 55 years or older, previously untreated with angiotensin II drugs and diagnosed (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria) with mild-to-moderate Alzheimer's disease, and who had capacity to consent, were recruited from 23 UK National Health Service hospital trusts. After undergoing a 4-week, open-label phase of active treatment then washout, participants were randomly assigned (1:1) oral over-encapsulated preparations of either 100 mg losartan (after an initial two-dose titration stage) or matched placebo daily for 12 months. Randomisation, minimised by age and baseline medial temporal lobe atrophy score, was undertaken online or via pin-access service by telephone. Participants, their study companions, and study personnel were masked to group assignment. The primary outcome, analysed by the intention-to-treat principle (ie, participants analysed in the group to which they were randomised, without imputation for missing data), was change in whole brain volume between baseline and 12 months, measured using volumetric MRI and determined by boundary shift interval (BSI) analysis. The trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN93682878) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2012-003641-15), and is completed.FINDINGS: Between July 22, 2014, and May 17, 2018, 261 participants entered the open-label phase. 211 were randomly assigned losartan (n=105) or placebo (n=106). Of 197 (93%) participants who completed the study, 171 (81%) had complete primary outcome data. The mean brain volume (BSI) reduction was 19·1 mL (SD 10·3) in the losartan group and 20·0 mL (10·8) in the placebo group. The difference in total volume reduction between groups was -2·29 mL (95% CI -6·46 to 0·89; p=0·14). The number of adverse events was low (22 in the losartan group and 20 in the placebo group) with no differences between treatment groups. There was one treatment-related death per treatment group.INTERPRETATION: 12 months of treatment with losartan was well tolerated but was not effective in reducing the rate of brain atrophy in individuals with clinically diagnosed mild-to-moderate Alzheimer's disease. Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods.FUNDING: Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

OBJECTIVE To investigate the impact of type 2 diabetes on incidence of major dementia subtypes, Alzheimer and vascular dementia, using electronic medical records (EMR) in the GoDARTS bioresource. RESEARCH DESIGN AND METHODS GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) comprises a large case-control study of type 2 diabetes with longitudinal follow-up in EMR. Dementia case subjects after recruitment were passively identified in the EMR, and using a combination of case note review, an Alzheimer-specific weighted genetic risk score (wGRS), and APOE4 genotype, we validated major dementia subtypes. We undertook a retrospective matched cohort study to determine the risk of type 2 diabetes status for incident dementia accounting for competing risk of death. RESULTS Type 2 diabetes status was associated with a significant risk of any dementia (cause-specific hazard ratio [csHR] 1.46, 95% CI 1.31–1.64), which was attenuated, but still significant, when competing risk of death was accounted for (subdistribution [sd]HR 1.26, 95% CI 1.13–1.41). The accuracy of EMR-defined cases of Alzheimer or vascular dementia was high—positive predictive value (PPV) 86.4% and PPV 72.8%, respectively—and wGRS significantly predicted Alzheimer dementia (HR 1.23, 95% CI 1.12–1.34) but not vascular dementia (HR 1.02, 95% CI 0.91–1.15). Conversely, type 2 diabetes was strongly associated with vascular dementia (csHR 2.47, 95% C 1.92–3.18) but not Alzheimer dementia, particularly after competing risk of death was accounted for (sdHR 1.02, 95% CI 0.87–1.18). CONCLUSIONS Our study indicates that type 2 diabetes is associated with an increased risk of vascular dementia but not with an increased risk of Alzheimer dementia and highlights the potential value of bioresources linked to EMR to study dementia.

This study assessed trends in personal financial issues among physical medicine and rehabilitation resident physicians and their impact on resident well-being.A 25-question cross-sectional survey was sent to 18 physical medicine and rehabilitation residents.A total of 17 residents completed the survey (94% response rate), with 82% (14 of 17) endorsing personal finances as a contributor to their personal health. Residents also endorsed minimal previous financial education and an interest in more formal education on related topics.This study revealed personal financial issues are a factor in resident well-being and garner high levels of interest. Despite this, residents have received little financial education. These results have motivated us to address this deficit in our education program.

Aims and methodTo provide a picture of availability and equality of access to mental health services for older people prior to the Equality Act. In 2010, a questionnaire was sent to health commissioners in England, Scotland and Wales under a Freedom of Information request.ResultsOverall, 132 (76%) replied. Of 11 services, 7 were either unavailable or did not provide equality of access to older people in more than a third of commissioning areas. When provided by specialist older people's mental health, services were more often considered to ensure equality.Clinical implicationsIncreasing need resulting from an ageing population is unlikely to be met in the face of current inequality. Inequality on the basis of age is the result of government policy and not the existence of specialist services for older people. Single age-inclusive services may create indirect age discrimination. Availability alone is insufficient to demonstrate equality of access. Monitoring the effects of legislation must take this into account.

AIM To demonstrate the benefits of collecting family history systematically to enhance the care provided to families living with dementia. In addition, to identify the contribution nurses can make in responding to relatives' concerns about dementia and its risk factors. METHOD An individual case study was derived from a larger observational study of the psycho-educational needs of families affected by dementia. This case study presents extracts from one anonymised interview with an adult son whose father has dementia. FINDINGS The family of the patient with dementia did not feel they had a positive experience of care delivery. Although they had a high level of knowledge and personal experience of dementia, their beliefs and concerns appear to have been overlooked by healthcare staff. This may have led to a delay in the diagnosis of dementia and missed opportunities for earlier treatment. CONCLUSION Healthcare staff should consider the concerns expressed by people with dementia and their families. Knowledge of the risk factors for dementia and risk-reduction strategies can improve the care nurses provide. This should include an increased awareness of the complex interaction between genes, environment and lifestyle.

OBJECTIVE: To investigate concussion rates and reporting frequencies in high school and collegiate athletes in 2013, compare results to those obtained from 1999 to 2002, and examine to what extent the 2012 Wisconsin state concussion law affected reporting in 2013. DESIGN: Retrospective 2013 survey compared with prior survey. SETTING: High schools and colleges in the Milwaukee, Wisconsin, area. PARTICIPANTS: Athletes (N = 784) from multiple sports were surveyed in 2013. Football players (N = 1532) from 1999 to 2002 completed the same measure. MAIN OUTCOME MEASURES: Both surveys assessed concussion history, concussion incidence during the current season, whether incident concussions were reported, who concussions were reported to, and reasons for not reporting. The 2013 survey also assessed awareness of the Wisconsin state law and its effect on reporting. RESULTS: Rates of concussion in the surveyed season were comparable to previous findings from 1999 to 2002 (16.6% vs 15.3%, P = 0.558). Notably, athletes were significantly more likely to report their concussions in 2013 (70.6% vs 47.3% previously, P = 0.011). Among high school athletes surveyed, 59.5% were aware of the Wisconsin state law, with 55.1% stating it would make them more likely to report a concussion. CONCLUSIONS: Rates of concussion for 1 sport season have not changed significantly over the past 14 years. The percentage of concussions that are reported to someone has increased significantly. Awareness of the Wisconsin state law does not fully account for the increase in concussion reporting. CLINICAL RELEVANCE: Given the finite amount of knowledge regarding the influence of concussion-related cultural and legal changes, these findings will help to inform clinicians of the current concussion milieu from the perspective of athletes. It will inform practitioners involved in concussion management to what extent athletes are aware of and report concussions. Language: en

Over the past five to ten years, neuroimaging capability for neurodegenerative diseases has made remarkable progress. However, debate remains as to the true clinical utility of these advanced and costly investigations. Not only is the place of these tests in diagnostic algorithms unclear, but the access to them varies both within and between countries. We sought to gather informed opinion from recognized leaders in the field who can combine both an academic and a clinical perspective on the use of neuroimaging in their own countries. Opinion is presented from Scotland, Argentina, the Czech Republic, France, the USA and Australia. The emerging consensus was one of ongoing caution. While in most countries there was a sense that the use of more advanced imaging techniques was growing, their hour has not yet cometh. However, these techniques, rather than falling from the Ivory Tower, should descend slowly step by step onto fertile and receptive clinics from where better clinical guidelines will emerge.

Owing to a miscommunication at proof stage, the words “with dementia” were omitted from this article in paragraph 4 line 7 on p S62 where they should have been placed between the words “people” and “in”. The correct wording of the clause is “. . . the number with dementia in the second most populous state (Victoria) will exceed the total number of people with dementia in Australia today”.