What really is nontokenistic fully inclusive patient and public involvement/engagement in research?

Patient and public involvement and engagement (PPIE) is critically important in healthcare research. A useful starting point for researchers to understand the scope of PPIE is to review the definition from the National Institute for Health and Care Research (NIHR) as, 'research being carried out "with" or "by" members of the public rather than "to", "about" or "for" them'. PPIE does not refer to participation in research, but to actively shaping its direction. The 'Effectiveness of a decision support tool to optimise community-based tailored management of sleep for people living with dementia or mild cognitive impairment (TIMES)' study is funded through the NIHR programme grant for applied research. TIMES has thoroughly embraced PPIE by ensuring the person's voice is heard, understood, and valued. This editorial showcases how the TIMES project maximised inclusivity, and we share our experiences and top tips for other researchers. We base our reflections on the six key UK standards for public involvement; Inclusive Opportunities, Working Together, Support and Learning, Communications, Impact and Governance. We present our work, which had been co-led by our PPIE leads, academics and partners including, together in dementia everyday, Innovations in Dementia, The UK Network of Dementia Voices (Dementia Engagement & Empowerment Project) and Liverpool Chinese Wellbeing. We have a Lived Experience Advisory Forum on Sleep, which includes people with dementia, family carers, representatives of the South Asian Community and the Chinese community.

Operationalising the Recovery College model with people living with dementia: a realist review.

OBJECTIVES: Post-diagnostic support is a significant factor in facilitating personal recovery following a diagnosis of dementia, but access is often inconsistent and insufficient. Recovery Colleges offer peer-led, co-produced courses that can support people to have meaningful lives and have been adapted for use in the context of dementia. A realist review was conducted to understand the application and sustainability of Recovery College dementia courses. METHOD: An iterative, five-step process combined literature published to 2023 with knowledge from stakeholders with lived and professional experience of dementia involved with Recovery College dementia courses (PROSPERO registration CRD42021293687). RESULTS: Thirty-five documents and discussions with 19 stakeholders were used to build the initial programme theory comprising of 24 context-mechanism-outcome configurations. Reoccurring factors included: attending to aspects of co-production and course delivery to ensure they promoted inclusion and were not compromised by organisational pressures; how stigma impacted access to course opportunities; and embedding personal recovery principles throughout course development to be relevant for people living with dementia and those who support them. CONCLUSION: People struggling to reconcile their future alongside dementia need practical and emotional support to access and benefit from Recovery College dementia courses, ways to achieve this will be explored through a realist evaluation.

Impact of the iWHELD digital person-centered care program on quality of life, agitation and psychotropic medications in people with dementia living in nursing homes during the COVID-19 pandemic: A randomized controlled trial.

INTRODUCTION: iWHELD is a digital person-centered care program for people with dementia in nursing homes adapted for remote delivery during the COVID-19 pandemic. METHODS: A 16-week two-arm cluster-randomized controlled trial in 149 UK nursing homes compared iWHELD with treatment as usual (TAU). Primary outcome was the overall quality of life with secondary outcomes of agitation and psychotropic use. RESULTS: iWHELD conferred benefit to quality of life on the primary (F = 4.3, p = 0.04) and secondary measures of quality of life (F = 6.45, p = 0.01) and reduced psychotropic medication use (χ2  = 4.08, p = 0.04) with no worsening of agitation. Benefit was seen in participants who contracted COVID-19, those with agitation at baseline, and those taking psychotropic medications. DISCUSSION: iWHELD confers benefits to quality of life and key measures of well-being, can be delivered during the challenging conditions of a pandemic, and should be considered for use alongside any emerging pharmacological treatment for neuropsychiatric symptoms. HIGHLIGHTS: iWHELD is the only remote, digital delivery nursing home training programme for dementia care iWHELD improved quality of life in people with dementia and reduced antipsychotic use without worsening of agitation Residents who contracted Covid-19 during the study also experienced benefits from iWHELD iWHELD offers a valuable, pandemic-safe tool for improving dementia care.

Adapted problem adaptation therapy for depression in mild to moderate Alzheimer's disease dementia: A randomized controlled trial.

INTRODUCTION: Trials of effectiveness of treatment options for depression in dementia are an important priority. METHODS: Randomized controlled trial to assess adapted Problem Adaptation Therapy (PATH) for depression in mild/moderate dementia caused by Alzheimer's disease. RESULTS: Three hundred thirty-six participants with mild or moderate dementia, >7 on Cornell Scale for Depression in Dementia (CSDD), randomized to adapted PATH or treatment as usual. Mean age 77.0 years, 39.0% males, mean Mini-Mental State Examination 21.6, mean CSDD 12.9. For primary outcome (CSDD at 6 months), no statistically significant benefit with adapted PATH on the CSDD (6 months: -0.58; 95% CI -1.71 to 0.54). The CSDD at 3 months showed a small benefit with adapted PATH (-1.38; 95% CI -2.54 to -0.21) as did the EQ-5D (-4.97; 95% CI -9.46 to -0.48). DISCUSSION: An eight-session course of adapted PATH plus two booster sessions administered within NHS dementia services was not effective treatment for depression in people with mild and moderate dementia. Future studies should examine the effect of more intensive and longer-term therapy.

Impact of the Covid-19 pandemic on neuropsychiatric symptoms and antipsychotic prescribing for people with dementia in nursing home settings.

OBJECTIVES: This study aimed to determine the impact of the Covid-19 pandemic on neuropsychiatric symptoms and antipsychotic use in people with dementia living in nursing homes. METHODS: This was a comparative analysis of baseline data from two large nursing home studies, one conducted during (COVID-iWHELD study) and one prior (WHELD study) to the pandemic. It involves data from 69 and 149 nursing homes, and 1006 and 666 participants respectively. Participants were people with established dementia (score >1 on Clinical Dementia Rating Scale). Resident data included demographics, antipsychotic prescriptions and neuropsychiatric symptoms using the Neuropsychiatric Inventory Nursing Home version. Nursing home data collected were nursing home size and staffing information. RESULTS: Overall prevalence of neuropsychiatric symptoms was unchanged from pre-pandemic prevalence. Mean antipsychotic use across the sample was 32.0%, increased from 18% pre-pandemic (Fisher's exact test p < 0.0001). At a nursing home level, the medians for the low, medium and high tertiles for antipsychotic use were 7%, 20% and 59% respectively, showing a disproportionate rise in tertile three. Residents in these homes also showed a small but significant increase in agitation. CONCLUSION: There has been a significant increase in antipsychotic prescribing in nursing homes since the COVID-19 pandemic, with a disproportionate rise in one third of homes, where median prescription rates for antipsychotics were almost 60%. Strategies are urgently needed to identify these nursing homes and introduce pro-active support to bring antipsychotic prescription rates back to pre-pandemic levels.

Study of mirtazapine for agitated behaviours in dementia (SYMBAD): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Agitation is common in people with dementia and negatively affects the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this care is not effective. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed the efficacy and safety of mirtazapine, an antidepressant prescribed for agitation in dementia. METHODS: This parallel-group, double-blind, placebo-controlled trial-the Study of Mirtazapine for Agitated Behaviours in Dementia trial (SYMBAD)-was done in 26 UK centres. Participants had probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, and a Cohen-Mansfield Agitation Inventory (CMAI) score of 45 or more. They were randomly assigned (1:1) to receive either mirtazapine (titrated to 45 mg) or placebo. The primary outcome was reduction in CMAI score at 12 weeks. This trial is registered with ClinicalTrials.gov, NCT03031184, and ISRCTN17411897. FINDINGS: Between Jan 26, 2017, and March 6, 2020, 204 participants were recruited and randomised. Mean CMAI scores at 12 weeks were not significantly different between participants receiving mirtazapine and participants receiving placebo (adjusted mean difference -1·74, 95% CI -7·17 to 3·69; p=0·53). The number of controls with adverse events (65 [64%] of 102 controls) was similar to that in the mirtazapine group (67 [66%] of 102 participants receiving mirtazapine). However, there were more deaths in the mirtazapine group (n=7) by week 16 than in the control group (n=1), with post-hoc analysis suggesting this difference was of marginal statistical significance (p=0·065). INTERPRETATION: This trial found no benefit of mirtazapine compared with placebo, and we observed a potentially higher mortality with use of mirtazapine. The data from this study do not support using mirtazapine as a treatment for agitation in dementia. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE-TR mice.

The impact of sex and menopausal status in Alzheimer's disease remains understudied despite increasing evidence of greater female risk, particularly in APOE4 carriers. Utilizing female APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months of age, recognition memory and spatial memory were assessed using object recognition, Y-maze spontaneous alternation, and Barnes maze. A VCD*genotype interaction reduced the recognition memory (P < .05), with APOE4 VCD-treated animals unable to distinguish between novel and familiar objects. APOE4 mice displayed an additional 37% and 12% reduction in Barnes (P < .01) and Y-maze (P < .01) performance, indicative of genotype-specific spatial memory impairment. Molecular analysis indicated both VCD and genotype-related deficits in synaptic plasticity with BDNF, Akt, mTOR, and ERK signaling compromised. Subsequent reductions in the transcription factors Creb1 and Atf4 were also evident. Furthermore, the VCD*genotype interaction specifically diminished Ephb2 expression, while Fos, and Cnr1 expression reduced as a consequence of APOE4 genotype. Brain DHA levels were 13% lower in VCD-treated animals independent of genotype. Consistent with this, we detected alterations in the expression of the DHA transporters Acsl6 and Fatp4. Our results indicate that the combination of ovarian failure and APOE4 leads to an exacerbation of cognitive and neurological deficits.

Higher anticholinergic burden from medications is associated with significant increase in markers of inflammation in the EPIC-Norfolk prospective population-based cohort study.

BACKGROUND: Higher medication anticholinergic burden is associated with increased risk of cardiovascular disease and cognitive decline. A mechanistic pathway has not been established. We aimed to determine whether inflammation may mediate these associations. METHODS: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40-79 years at baseline). Anticholinergic burden score (ACB) was calculated at first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Fibrinogen and C-reactive protein (CRP) were measured during 1HC and tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) during 2HC. Cross-sectional associations between ACB and inflammatory markers were examined for both health checks. Prospective associations were also examined between 1HC ACB and 2HC inflammatory markers. Models were adjusted for age, sex, lifestyle factors, comorbidities and medications. RESULTS: In total, 17 678 and 22 051 participants were included in cross-sectional analyses for CRP, and fibrinogen, respectively. Furthermore, 5101 participants with data on TNF-α and IL-6 were included in the prospective analyses. Cross-sectionally, compared to ACB = 0, ACB ≥ 4 was associated with higher fibrinogen, beta (95% confidence interval) = 0.134 g/L (0.070, 0.199), CRP 1.175 mg/L (0.715, 1.634), IL-6 0.593 pg/mL (0.254, 0.932) and TNF-α 0.137 pg/mL (0.033, 0.241). In addition, a point increase in ACB was associated with higher levels of all markers. Prospectively, compared to ACB = 0, ACB ≥ 4 was associated with higher IL-6(pg/mL) of 0.019 (-0.323, 0.361) and TNF-α (pg/mL) of 0.202% (0.81, 0.323). A unit increase in ACB was associated with a significantly higher TNF-α and IL-6. CONCLUSION: Higher ACB was associated with higher inflammatory markers. Inflammation may mediate the relationship between anticholinergic medications and adverse outcomes.

A novel Artificial Intelligence-based tool to assess anticholinergic burden: a survey.

BACKGROUND: many medications possess anticholinergic activity. Their use is associated with a number of serious adverse effects including cognitive effects. The cumulative anticholinergic effect of medications as assessed by tools such as the anticholinergic burden scale (AchB) can identify people particularly at risk of anticholinergic side-effects. Currently, >20 tools are available for clinicians to use, but there is no consensus on the most appropriate tool. METHODS: a newly created online tool-International Anticholinergic Cognitive Burden Tool (IACT)-based on natural language processing and chemical structure analysis, was developed and made available for clinicians to test its functions. We carried out a survey (between 8th of February and 31st of March 2021) to assess the overall need for an assessment tool as well as the usability of the IACT. RESULTS: a total of 110 responses were received from different countries and practitioners' groups. The majority of the participants (86.11%) stated they would use a tool for AchB assessment if available and when they were asked to rate the IACT against other tools, amongst 34 responders, 20.59% rated it better and 8.82% rated it significantly better, 44.12% rated it neither better, nor worse, 14.71% rated it worse and 11.76% somewhat worse. CONCLUSION: there is a need for an anticholinergic burden calculator to assess the anticholinergicity of medications. Tools such as the IACT potentially could meet this demand due to its ability to assign scores to current and new medications appearing on the market based both on their chemical structure and reported adverse pharmacological effects.

A realist evaluation of a multifactorial falls prevention programme in care homes.

BACKGROUND: falls in care homes are common, costly and hard to prevent.Multifactorial falls programmes demonstrate clinical and cost-effectiveness, but the heterogeneity of the care home sector is a barrier to their implementation. A fuller appreciation of the relationship between care home context and falls programme delivery will guide development and support implementation. METHODS: this is a multi-method process evaluation informed by a realist approach.Data include fidelity observations, stakeholder interviews, focus groups, documentary review and falls-rate data. Thematic analysis of qualitative data and descriptive statistics are synthesised to generate care home case studies. RESULTS: data were collected in six care homes where a falls programme was trialled. Forty-four interviews and 11 focus groups complemented observations and document review.The impact of the programme varied. Five factors were identified: (i) prior practice and (ii) training may inhibit new ways of working; (iii) some staff may be reluctant to take responsibility for falls; (iv) some may feel that residents living with dementia cannot be prevented from falling; and, (v) changes to management may disturb local innovation.In some care homes, training and improved awareness generated a reduction in falls without formal assessments being carried out. CONCLUSIONS: different aspects of the falls programme sparked different mechanisms in different settings, with differing impact upon falls.The evaluation has shown that elements of a multifactorial falls programme can work independently of each other and that it is the local context (and local challenges faced), which should shape how a falls programme is implemented.

Cost-effectiveness of mirtazapine for agitated behaviors in dementia: findings from a randomized controlled trial.

OBJECTIVES: To examine the costs and cost-effectiveness of mirtazapine compared to placebo over 12-week follow-up. DESIGN: Economic evaluation in a double-blind randomized controlled trial of mirtazapine vs. placebo. SETTING: Community settings and care homes in 26 UK centers. PARTICIPANTS: People with probable or possible Alzheimer's disease and agitation. MEASUREMENTS: Primary outcome included incremental cost of participants' health and social care per 6-point difference in CMAI score at 12 weeks. Secondary cost-utility analyses examined participants' and unpaid carers' gain in quality-adjusted life years (derived from EQ-5D-5L, DEMQOL-Proxy-U, and DEMQOL-U) from the health and social care and societal perspectives. RESULTS: One hundred and two participants were allocated to each group; 81 mirtazapine and 90 placebo participants completed a 12-week assessment (87 and 95, respectively, completed a 6-week assessment). Mirtazapine and placebo groups did not differ on mean CMAI scores or health and social care costs over the study period, before or after adjustment for center and living arrangement (independent living/care home). On the primary outcome, neither mirtazapine nor placebo could be considered a cost-effective strategy with a high level of confidence. Groups did not differ in terms of participant self- or proxy-rated or carer self-rated quality of life scores, health and social care or societal costs, before or after adjustment. CONCLUSIONS: On cost-effectiveness grounds, the use of mirtazapine cannot be recommended for agitated behaviors in people living with dementia. Effective and cost-effective medications for agitation in dementia remain to be identified in cases where non-pharmacological strategies for managing agitation have been unsuccessful.

Omega-3 and polyunsaturated fat for prevention of depression and anxiety symptoms: systematic review and meta-analysis of randomised trials.

BACKGROUND: There is strong public belief that polyunsaturated fats protect against and ameliorate depression and anxiety. AIMS: To assess effects of increasing omega-3, omega-6 or total polyunsaturated fat on prevention and treatment of depression and anxiety symptoms. METHOD: We searched widely (Central, Medline and EMBASE to April 2017, trial registers to September 2016, ongoing trials updated to August 2019), including trials of adults with or without depression or anxiety, randomised to increased omega-3, omega-6 or total polyunsaturated fat for ≥24 weeks, excluding multifactorial interventions. Inclusion, data extraction and risk of bias were assessed independently in duplicate, and authors contacted for further data. We used random-effects meta-analysis, sensitivity analyses, subgrouping and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment. RESULTS: We included 31 trials assessing effects of long-chain omega-3 (n = 41 470), one of alpha-linolenic acid (n = 4837), one of total polyunsaturated fat (n = 4997) and none of omega-6. Meta-analysis suggested that increasing long-chain omega-3 probably has little or no effect on risk of depression symptoms (risk ratio 1.01, 95% CI 0.92-1.10, I2 = 0%, median dose 0.95 g/d, duration 12 months) or anxiety symptoms (standardised mean difference 0.15, 95% CI 0.05-0.26, I2 = 0%, median dose 1.1 g/d, duration 6 months; both moderate-quality evidence). Evidence of effects on depression severity and remission in existing depression were unclear (very-low-quality evidence). Results did not differ by risk of bias, omega-3 dose, duration or nutrients replaced. Increasing alpha-linolenic acid by 2 g/d may increase risk of depression symptoms very slightly over 40 months (number needed to harm, 1000). CONCLUSIONS: Long-chain omega-3 supplementation probably has little or no effect in preventing depression or anxiety symptoms. DECLARATION OF INTEREST: L.H. and A.A. were funded to attend the World Health Organization Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health meetings and present review results. The authors report no other conflicts of interest.

Cognitive decline associated with anticholinergics, benzodiazepines and Z-drugs: Findings from The Irish Longitudinal Study on Ageing (TILDA).

AIMS: To estimate the association between patterns of anticholinergic, benzodiazepine and Z-drug medication use and change in cognitive function in middle-aged and older adults. METHODS: This prospective cohort study used data from the first three waves of The Irish Longitudinal Study on Ageing (TILDA), including community-dwelling adults aged ≥50 years followed for up to 4 years (n = 7027). Cognitive function was assessed using the Mini Mental State Examination, animal naming test and word recall tests. Regular medication use was self-reported at baseline and follow-up interviews at 2 and 4 years. Pharmacy dispensing claims for a subset (n = 2905) allowed assessment of medication use between interviews and cumulative dosage. Medication use at consecutive waves of TILDA was analysed in relation to change in cognitive function between waves. RESULTS: Strongly anticholinergic medications (Anticholinergic Cognitive Burden scale 3), benzodiazepines and Z-drugs were reported by 7.3%, 5.8% and 5.1% of participants, respectively, at any time during the study. Adjusting for potential confounders, new anticholinergic use between interviews was associated with change in recall score (-1.09, 95% confidence interval -1.64, -0.53) over 2 years compared to non-use, but not with MMSE (0.07; 95% CI -0.21, 0.34) or animal naming (-0.70; 95% CI -1.43, 0.03). The pharmacy claims analysis was consistent with this finding. Other hypothesised associations were not supported. CONCLUSIONS: Except for new use of anticholinergic medications, no other findings supported a risk of cognitive decline over 2-year periods in this middle-aged and older cohort. Patients and prescribers should weigh this potential risk against potential benefits of commencing anticholinergic medications.

A comparative study of the effect of the Time for Dementia programme on medical students.

BACKGROUND: Traditional healthcare education typically focuses on short block clinical placements based on acute care, investigations and technical aspects of diagnosis and treatment. It may therefore fail to build the understanding, compassion and person-centred empathy needed to help those with long-term conditions, like dementia. Time for Dementia was developed to address this. METHOD: Parallel group comparison of two cohorts of UK medical students from universities, one participating in Time for Dementia (intervention group) and one not (control group). In Time for Dementia students visit a person with dementia and their family in pairs for 2 hours three times a year for 2 years, the control group received their normal curriculum. RESULTS: In an adjusted multilevel model (intervention group n = 274, control n = 112), there was strong evidence supporting improvements for Time for Dementia participants in: total Approaches to Dementia Questionnaire score (coefficient: 2.19, p = 0.003) and its person-centredness subscale (1.32, p = 0.006) and weaker evidence in its hopefulness subscale (0.78, p = 0.070). There was also strong evidence of improvement in the Dementia Knowledge Questionnaire (1.63, p < 0.001) and Dementia Attitudes Scale (total score: 6.55, p < 0.001; social comfort subscale: 4.15, p < 0.001; dementia knowledge subscale: 3.38, p = 0.001) scores. No differences were observed on the Alzheimer's Disease Knowledge Scale, the Medical Condition Regard Scale or the Jefferson Scale of Empathy. DISCUSSION: Time for Dementia may help improve the attitudes of medical students towards dementia promoting a person-centred approach and increasing social comfort. Such patient-focused programmes may be a useful complement to traditional medical education.

The effectiveness and cost-effectiveness of assistive technology and telecare for independent living in dementia: a randomised controlled trial.

OBJECTIVES: The use of assistive technology and telecare (ATT) has been promoted to manage risks associated with independent living in people with dementia but with little evidence for effectiveness. METHODS: Participants were randomly assigned to receive an ATT assessment followed by installation of all appropriate ATT devices or limited control of appropriate ATT. The primary outcomes were time to institutionalisation and cost-effectiveness. Key secondary outcomes were number of incidents involving risks to safety, burden and stress in family caregivers and quality of life. RESULTS: Participants were assigned to receive full ATT (248 participants) or the limited control (247 participants). After adjusting for baseline imbalance of activities of daily living score, HR for median pre-institutionalisation survival was 0.84; 95% CI, 0.63 to 1.12; P = 0.20. There were no significant differences between arms in health and social care (mean -£909; 95% CI, -£5,336 to £3,345, P = 0.678) and societal costs (mean -£3,545; 95% CI, -£13,914 to £6,581, P = 0.499). ATT group members had reduced participant-rated quality-adjusted life years (QALYs) at 104 weeks (mean - 0.105; 95% CI, -0.204 to -0.007, P = 0.037) but did not differ in QALYs derived from proxy-reported EQ-5D. DISCUSSION: Fidelity of the intervention was low in terms of matching ATT assessment, recommendations and installation. This, however, reflects current practice within adult social care in England. CONCLUSIONS: Time living independently outside a care home was not significantly longer in participants who received full ATT and ATT was not cost-effective. Participants with full ATT attained fewer QALYs based on participant-reported EQ-5D than controls at 104 weeks.

Placing assistive technology and telecare in everyday practices of people with dementia and their caregivers: findings from an embedded ethnography of a national dementia trial.

BACKGROUND: Policy makers and care providers see assistive technology and telecare as potential products to support people with dementia to live independently in their homes and communities. Previous research rarely examined how people with dementia and their caregivers actually use such technology. The study examined how and why people living with dementia and their caregivers used assistive technology and telecare in their own homes. METHODS: This study used an ethnographic design embedded within the NIHR-funded Assistive Technology and Telecare to maintain Independent Living At home for people with dementia (ATTILA) randomised controlled trial. We collected 208 h of observational data on situated practices of ten people with dementia and their ten caregivers. We used this data to construct extended cases to explain how technologies supported people with dementia in home and community settings. RESULTS: We identified three themes: placing technology in care, which illustrates how people with dementia and caregivers 'fit' technology into their homes and routines; replacing care with technology, which shows how caregivers replaced normal care practices with ones mediated through technologies; and technology displacing care and everyday life, which highlights how technologies disrupted the everyday lives of people with dementia. DISCUSSION: This study exemplifies unintended and unanticipated consequences for assistive technology and telecare uptake in 'real world' community-based dementia care. It underlines the need to identify and map the context of technological provision over time within the changing lives of people with dementia and their caregivers.

Putting primary prevention of dementia on everybody's agenda.

Many publications on dementia start by outlining the current estimated number of people with dementia and how that figure is going to double (in Western societies) or even quadruple (in developing countries) in the coming decades as a result of increasing life expectancy (in itself a good development). Dementia is therefore a huge challenge to society, both in terms of providing good care for persons living with dementia and their family caregivers, as well as in searching for curative solutions. Both these challenges are complex. Fortunately, recent research indicates primary prevention to be a promising additional strategy in the dementia quest. Now that epidemiological research robustly shows the link between lifestyle and risk of dementia, new challenges emerge, such as how to increase public awareness about brain health, how to develop and implement strategies to promote brain healthy lifestyles and how to avoid increasing health inequalities. Interdem, the pan-European network of researchers on Psychosocial Interventions in Dementia, strongly welcomes this new strategy and consequently established a taskforce on primary prevention. In this position paper, we outline what we see as main building blocks of primary prevention of dementia.

Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study.

BACKGROUND: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. METHODS: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. RESULTS: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]). CONCLUSIONS: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. TRIAL REGISTRATION: ENCePP e-register of studies, EUPAS18006.

Dementia Research Fit for the Planet: Reflections on Population Studies of Dementia for Researchers and Policy Makers Alike.

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.

Anticholinergic drugs and incident dementia, mild cognitive impairment and cognitive decline: a meta-analysis.

BACKGROUND: the long-term effect of the use of drugs with anticholinergic activity on cognitive function remains unclear. METHODS: we conducted a systematic review and meta-analysis of the relationship between anticholinergic drugs and risk of dementia, mild cognitive impairment (MCI) and cognitive decline in the older population. We identified studies published between January 2002 and April 2018 with ≥12 weeks follow-up between strongly anticholinergic drug exposure and the study outcome measurement. We pooled adjusted odds ratios (OR) for studies reporting any, and at least short-term (90+ days) or long-term (365+ days) anticholinergic use for dementia and MCI outcomes, and standardised mean differences (SMD) in global cognition test scores for cognitive decline outcomes. Statistical heterogeneity was measured using the I2 statistic and risk of bias using ROBINS-I. RESULTS: twenty-six studies (including 621,548 participants) met our inclusion criteria. 'Any' anticholinergic use was associated with incident dementia (OR 1.20, 95% confidence interval [CI] 1.09-1.32, I2 = 86%). Short-term and long-term use were also associated with incident dementia (OR 1.23, 95% CI 1.17-1.29, I2 = 2%; and OR 1.50, 95% CI 1.22-1.85, I2 = 90%). 'Any' anticholinergic use was associated with cognitive decline (SMD 0.15; 95% CI 0.09-0.21, I2 = 3%) but showed no statistically significant difference for MCI (OR 1.24, 95% CI 0.97-1.59, I2 = 0%). CONCLUSIONS: anticholinergic drug use is associated with increased dementia incidence and cognitive decline in observational studies. However, a causal link cannot yet be inferred, as studies were observational with considerable risk of bias. Stronger evidence from high-quality studies is needed to guide the management of long-term use.