Apathy Symptoms, Physical and Cognitive Function, Health-Related Quality of Life, and Mortality in Older Patients With CKD: A Longitudinal Observational Study.

RATIONALE & OBJECTIVE: Apathy reflects diminished motivation, goal-directed behavior, and emotions, as well as less engagement in social interactions. Apathy overlaps with depression and is associated with cognitive decline. In the older individuals with chronic kidney disease (CKD), both depression and cognitive impairments are common, but apathy symptoms have been underreported. We investigated the occurrence of apathy symptoms and their associations with physical and cognitive functioning, health-related quality of life (HRQoL), and mortality in older patients with CKD. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 180 outpatients aged≥65 years with estimated glomerular filtration rate≤20mL/min/1.73m2 from 5 Dutch nephrology centers. EXPOSURE: Apathy symptoms at baseline were considered present when a Geriatric Depression Scale's 3-item apathy subscale score was≥2 points. OUTCOME: Physical and cognitive functioning, HRQoL (assessed in annual geriatric assessments), and 4-year mortality. ANALYTICAL APPROACH: Linear regression for cross-sectional associations, linear regression models for longitudinal associations, and Cox regression models for mortality over 4 years of observation. RESULTS: Apathy symptoms were present in 64 patients (36%; 67% men; median age 75.5 years), of whom 32 (50%) had no depressive symptoms. At baseline, the presence of apathy symptoms was associated with significantly more frailty, more functional dependence, less physical capacity, lower visuoconstructive performance, worse delayed recall, and lower HRQoL scores. The presence of apathy symptoms at baseline was also associated with a higher mortality risk (hazard ratio, 2.3 [95% CI, 1.3-4.2], P=0.005 adjusted for age, sex, and high education level), but not with changes in physical and cognitive functioning or HRQoL during the follow-up period. LIMITATIONS: Risk of selection bias and residual confounding. CONCLUSIONS: Apathy symptoms were highly prevalent and associated with concurrent lower physical and cognitive status, lower HRQoL, and increased mortality. These findings highlight apathy as a potentially important clinical phenotype in older CKD patients. PLAIN-LANGUAGE SUMMARY: We observed that older kidney patients often present apathy symptoms, such as less motivation, fewer goal-directed behaviors, fewer emotions, and less social engagement. Prior research has not extensively described apathy in kidney disease. We investigated the link between apathy symptoms and poor outcomes. We measured physical functioning, cognitive functioning, and quality of life. We learned that one-third of our older kidney patients showed symptoms of apathy, only half of whom had symptoms of depression. Patients with apathy symptoms showed lower quality of life and lower physical and cognitive performance. They also had a higher risk of death. These findings highlight the need for awareness of apathy symptoms in older kidney patients.

Visit-to-visit blood pressure variability and progression of white matter hyperintensities over 14 years.

Purpose: There is evidence that blood pressure variability (BPV) is associated with cerebral small vessel disease (SVD) and may therefore increase the risk of stroke and dementia. It remains unclear if BPV is associated with SVD progression over years. We examined whether visit-to-visit BPV is associated with white matter hyperintensity (WMH) progression over 14 years and MRI markers after 14 years.Materials and methods: We included participants with SVD from the Radboud University Nijmegen Diffusion tensor Magnetic resonance-imaging Cohort (RUNDMC) who underwent baseline assessment in 2006 and follow-up in 2011, 2015 and 2020. BPV was calculated as coefficient of variation (CV) of BP at all visits. Association between WMH progression rates over 14 years and BPV was examined using linear-mixed effects (LME) model. Regression models were used to examine association between BPV and MRI markers at final visit in participants.Results: A total of 199 participants (60.5 SD 6.6 years) who underwent four MRI scans and BP measurements were included, with mean follow-up of 13.7 (SD 0.5) years. Systolic BPV was associated with higher progression of WMH (ß = 0.013, 95% CI 0.005 - 0.022) and higher risk of incident lacunes (OR: 1.10, 95% CI 1.01-1.21). There was no association between systolic BPV and grey and white matter volumes, Peak Skeleton of Mean Diffusivity (PSMD) or microbleed count after 13.7 years.Conclusions: Visit-to-visit systolic BPV is associated with increased progression of WMH volumes and higher risk of incident lacunes over 14 years in participants with SVD. Future studies are needed to examine causality of this association.

High blood pressure (BP) is very common, especially among older individuals. BP is not constant but tends to go up and down over time.Earlier studies have shown that when your BP fluctuates more, this can give a higher risk of dementia, stroke, cardiovascular events and even mortality. Large BP fluctuations are likely damaging for your brain, but it remains unknown if it leads to progression of brain damage over a longer period of time.This study examined if fluctuations in BP over 14 years are associated with progression of brain damage in older individuals with a mean age of 60.5 years.The results indicate that markers of brain damage progress more in participants with more variation in BP.This suggests that fluctuations in BP can cause damage in your brain to progress more.However, it is difficult to determine based on these results if BP fluctuations are a cause or a result of brain damage. More research is needed to determine what the temporal order of this association is.If variations in BP can indeed damage the brain, we need to focus not only on lowering BP, but also on keeping BP stable when considering treatments.

General practitioners' views on cardiovascular prevention for ethnic minorities-a qualitative study in the Netherlands.

OBJECTIVES: While ethnic minorities in Europe are disproportionally affected by cardiovascular disease (CVD), little is known about how general practitioners (GPs) perceive differences in risk or care needs across ethnic minority groups. Therefore, we explored GPs' views on whether ethnicity influences cardiovascular risk, whether a culturally sensitive approach is warranted, on potential barriers in the provision of such care, and to find potential opportunities to improve cardiovascular prevention for these groups. METHODS: We conducted a qualitative study by interviewing GPs practising in The Netherlands. The interviews were semistructured, audio-recorded, and analysed by 2 researchers using thematic analysis. RESULTS: We interviewed 24 Dutch GPs (50% male). GPs' views on the impact of ethnicity on CVD risk varied widely, yet it was generally recognized as a relevant factor in cardiovascular prevention for most minority groups, prompting earlier case-finding of high-risk patients. While GPs were aware of sociocultural differences, they emphasized an individualized approach. Perceived limitations were language barriers and unfamiliarity with sociocultural customs, leading to a need for continuing medical education on culturally sensitive care and reimbursement of telephone interpreting services. CONCLUSION: Dutch GPs have differing views on the role of ethnicity in evaluating and treating cardiovascular risk. Despite these differences, they emphasized the importance of a personalized and culturally sensitive approach during patient consultations and expressed a need for continuing medical education. Additional research on how ethnicity influences CVD risk may strengthen cardiovascular prevention in increasingly diverse primary care populations.

The challenge of dementia prevention trials and the role of quasi-experimental studies.

Observational studies have shown consistently that modifiable risk factors during life are associated with increased dementia risk in old age but randomized controlled trials (RCTs) on dementia prevention evaluating the treatment of these risk factors did not find consistent effects on cognitive outcomes. The discrepancy in findings is potentially attributable to inherent differences between the two study designs. Although RCTs are the gold standard for establishing causality, designing and conducting an RCT for dementia prevention is complex. Quasi-experimental studies (QESs) may contribute to investigating causality without randomization. QESs use variation in exposure to a risk factor or intervention in an observational setting to deduct causal effects. Design-specific approaches are used to control for confounding, the main caveat of QESs. In this article we address the challenges, opportunities, and limitations of QESs for research into dementia prevention. HIGHLIGHTS: Despite consistent associations between modifiable risk factors and dementia, the mostly neutral effects of randomized controlled trials (RCTs) challenge the causality of these associations. RCTs in the field of dementia prevention are often problematic due to ethical, practical, or financial constraints, and their results may have limited generalizability. Four quasi-experimental study (QES) designs may be suitable to study causality between risk factors and dementia; we critically appraise these study designs for dementia-prevention studies. We describe how specific QES designs can be used to study the effects of risk-factor modification for 12 known risk factors for dementia.

What would a population-level approach to dementia risk reduction look like, and how would it work?

Dementia is a leading global public health challenge. Prevention approaches have traditionally focused on individual-level strategies. However, such approaches have limited potential, particularly for resource-constrained populations in which exposure to risk factors is greatest, and exposure to protective factors is lowest. A population-level approach to dementia risk reduction is therefore essential to meet the scale of the challenge and to tackle global inequalities in risk and incidence of disease. Such approaches can be highly cost effective. In this viewpoint article, we describe what such an approach should look like, barriers and facilitators to success, and how we should go about achieving it. We include 10 strategic goals to achieve population-level dementia risk reduction and protection enhancement, targeted at researchers, professionals, funders, science communicators, governments, businesses, and policy makers. If we are to significantly reduce the prevalence of dementia there must be increased emphasis on population-level approaches. HIGHLIGHTS: Dementia risk reduction is a global public health priority Population-level approaches change societal conditions to make them less conducive to dementia's modifiable risk factors, and increase exposure to protective factors. Urgent development of population-level approaches is required to reduce the prevalence of, and inequalities in, dementia Action is required from researchers, governments and business, funders, public health professionals, and science communicators.

Diagnostic Accuracy of the Telephone Interview for Cognitive Status for the Detection of Dementia in Primary Care.

PURPOSE: Cognitive diagnostic work-up in primary care is not always physically feasible, owing to chronic disabilities and/or travel restrictions. The identification of dementia might be facilitated with diagnostic instruments that are time efficient and easy to perform, as well as useful in the remote setting. We assessed whether the Telephone Interview for Cognitive Status (TICS) might be a simple and accurate alternative for remote diagnostic cognitive screening in primary care. METHODS: We administered the TICS (range, 0-41) for 810 of 1,473 older people aged 84.5 (SD, 2.4) years. We scrutinized electronic health records for participants with TICS scores ≤30 and for a random sample of participants with TICS scores >30 for a dementia diagnosis using all data from the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial for 8-12 years of follow-up. We used multiple imputation to correct for verification bias. RESULTS: Of the 810 participants, 155 (19.1%) had a TICS score ≤30, and 655 (80.9%) had a TICS score >30. Electronic health records yielded 8.4% (13/154) dementia diagnoses for participants with TICS ≤30 vs none with TICS >30. Multiple imputation for TICS >30 yielded a median of 7/655 (1.1%; interquartile range, 5-8) estimated dementia cases. After multiple imputation, the optimal cutoff score was ≤29, with mean sensitivity 65.4%, specificity 87.8%, positive predictive value 11.9%, negative predictive value 99.0%, and area under the curve 77.4% (95% CI, 56.3%-90.0%). CONCLUSIONS: In the present older population, the TICS performed well as a diagnostic screening instrument for excluding dementia and might be particularly useful when face-to-face diagnostic screening is not feasible in family practice or research settings. The potential reach to large numbers of people at low cost could contribute to more efficient medical management in primary care.

Clinical judgement by primary care physicians for the diagnosis of all-cause dementia or cognitive impairment in symptomatic people.

BACKGROUND: In primary care, general practitioners (GPs) unavoidably reach a clinical judgement about a patient as part of their encounter with patients, and so clinical judgement can be an important part of the diagnostic evaluation. Typically clinical decision making about what to do next for a patient incorporates clinical judgement about the diagnosis with severity of symptoms and patient factors, such as their ideas and expectations for treatment. When evaluating patients for dementia, many GPs report using their own judgement to evaluate cognition, using information that is immediately available at the point of care, to decide whether someone has or does not have dementia, rather than more formal tests. OBJECTIVES: To determine the diagnostic accuracy of GPs' clinical judgement for diagnosing cognitive impairment and dementia in symptomatic people presenting to primary care. To investigate the heterogeneity of test accuracy in the included studies. SEARCH METHODS: We searched MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), Web of Science Core Collection (ISI Web of Science), and LILACs (BIREME) on 16 September 2021. SELECTION CRITERIA: We selected cross-sectional and cohort studies from primary care where clinical judgement was determined by a GP either prospectively (after consulting with a patient who has presented to a specific encounter with the doctor) or retrospectively (based on knowledge of the patient and review of the medical notes, but not relating to a specific encounter with the patient). The target conditions were dementia and cognitive impairment (mild cognitive impairment and dementia) and we included studies with any appropriate reference standard such as the Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD), aetiological definitions, or expert clinical diagnosis. DATA COLLECTION AND ANALYSIS: Two review authors screened titles and abstracts for relevant articles and extracted data separately with differences resolved by consensus discussion. We used QUADAS-2 to evaluate the risk of bias and concerns about applicability in each study using anchoring statements. We performed meta-analysis using the bivariate method. MAIN RESULTS: We identified 18,202 potentially relevant articles, of which 12,427 remained after de-duplication. We assessed 57 full-text articles and extracted data on 11 studies (17 papers), of which 10 studies had quantitative data. We included eight studies in the meta-analysis for the target condition dementia and four studies for the target condition cognitive impairment. Most studies were at low risk of bias as assessed with the QUADAS-2 tool, except for the flow and timing domain where four studies were at high risk of bias, and the reference standard domain where two studies were at high risk of bias. Most studies had low concern about applicability to the review question in all QUADAS-2 domains. Average age ranged from 73 years to 83 years (weighted average 77 years). The percentage of female participants in studies ranged from 47% to 100%. The percentage of people with a final diagnosis of dementia was between 2% and 56% across studies (a weighted average of 21%). For the target condition dementia, in individual studies sensitivity ranged from 34% to 91% and specificity ranged from 58% to 99%. In the meta-analysis for dementia as the target condition, in eight studies in which a total of 826 of 2790 participants had dementia, the summary diagnostic accuracy of clinical judgement of general practitioners was sensitivity 58% (95% confidence interval (CI) 43% to 72%), specificity 89% (95% CI 79% to 95%), positive likelihood ratio 5.3 (95% CI 2.4 to 8.2), and negative likelihood ratio 0.47 (95% CI 0.33 to 0.61). For the target condition cognitive impairment, in individual studies sensitivity ranged from 58% to 97% and specificity ranged from 40% to 88%. The summary diagnostic accuracy of clinical judgement of general practitioners in four studies in which a total of 594 of 1497 participants had cognitive impairment was sensitivity 84% (95% CI 60% to 95%), specificity 73% (95% CI 50% to 88%), positive likelihood ratio 3.1 (95% CI 1.4 to 4.7), and negative likelihood ratio 0.23 (95% CI 0.06 to 0.40). It was impossible to draw firm conclusions in the analysis of heterogeneity because there were small numbers of studies. For specificity we found the data were compatible with studies that used ICD-10, or applied retrospective judgement, had higher reported specificity compared to studies with DSM definitions or using prospective judgement. In contrast for sensitivity, we found studies that used a prospective index test may have had higher sensitivity than studies that used a retrospective index test. AUTHORS' CONCLUSIONS: Clinical judgement of GPs is more specific than sensitive for the diagnosis of dementia. It would be necessary to use additional tests to confirm the diagnosis for either target condition, or to confirm the absence of the target conditions, but clinical judgement may inform the choice of further testing. Many people who a GP judges as having dementia will have the condition. People with false negative diagnoses are likely to have less severe disease and some could be identified by using more formal testing in people who GPs judge as not having dementia. Some false positives may require similar practical support to those with dementia, but some - such as some people with depression - may suffer delayed intervention for an alternative treatable pathology.

Factors Predicting Engagement of Older Adults With a Coach-Supported eHealth Intervention Promoting Lifestyle Change and Associations Between Engagement and Changes in Cardiovascular and Dementia Risk: Secondary Analysis of an 18-Month Multinational Randomized Controlled Trial.

BACKGROUND: Digital health interventions could help to prevent age-related diseases, but little is known about how older adults engage with such interventions, especially in the long term, or whether engagement is associated with changes in clinical, behavioral, or biological outcomes in this population. Disparities in engagement levels with digital health interventions may exist among older people and be associated with health inequalities. OBJECTIVE: This study aimed to describe older adults' engagement with an eHealth intervention, identify factors associated with engagement, and examine associations between engagement and changes in cardiovascular and dementia risk factors (blood pressure, cholesterol, BMI, physical activity, diet, and cardiovascular and dementia risk scores). METHODS: This was a secondary analysis of the 18-month randomized controlled Healthy Ageing Through Internet Counselling in the Elderly trial of a tailored internet-based intervention encouraging behavior changes, with remote support from a lifestyle coach, to reduce cardiovascular and cognitive decline risk in 2724 individuals aged ≥65 years, recruited offline in the Netherlands, Finland, and France. Engagement was assessed via log-in frequency, number of lifestyle goals set, measurements entered and messages sent to coaches, and percentage of education materials read. Clinical and biological data were collected during in-person visits at baseline and 18 months. Lifestyle data were self-reported on a web-based platform. RESULTS: Of the 1389 intervention group participants, 1194 (85.96%) sent at least one message. They logged in a median of 29 times, and set a median of 1 goal. Higher engagement was associated with significantly greater improvement in biological and behavioral risk factors, with evidence of a dose-response effect. Compared with the control group, the adjusted mean difference (95% CI) in 18-month change in the primary outcome, a composite z-score comprising blood pressure, BMI, and cholesterol, was -0.08 (-0.12 to -0.03), -0.04 (-0.08 to 0.00), and 0.00 (-0.08 to 0.08) in the high, moderate, and low engagement groups, respectively. Low engagers showed no improvement in any outcome measures compared with the control group. Participants not using a computer regularly before the study engaged much less with the intervention than those using a computer up to 7 (adjusted odds ratio 5.39, 95% CI 2.66-10.95) or ≥7 hours per week (adjusted odds ratio 6.58, 95% CI 3.21-13.49). Those already working on or with short-term plans for lifestyle improvement at baseline, and with better cognition, engaged more. CONCLUSIONS: Greater engagement with an eHealth lifestyle intervention was associated with greater improvement in risk factors in older adults. However, those with limited computer experience, who tended to have a lower level of education, or who had poorer cognition engaged less. Additional support or forms of intervention delivery for such individuals could help minimize potential health inequalities associated with the use of digital health interventions in older people.

Hypertension and Alzheimer's disease pathology at autopsy: A systematic review.

Hypertension is an important risk factor for Alzheimer's disease (AD) and all-cause dementia. The mechanisms underlying this association are unclear. Hypertension may be associated with AD neuropathological changes (ADNC), but reports are sparse and inconsistent. This systematic review included 15 autopsy studies (n = 5879) from observational cohorts. Studies were highly heterogeneous regarding populations, follow-up duration, hypertension operationalization, neuropathological methods, and statistical analyses. Hypertension seems associated with higher plaque and tangle burden, but results are inconsistent. Four studies (n = 3993/5879; 68%), reported clear associations between hypertension and ADNC. Another four suggested that antihypertensive medication may protect against ADNC. Larger studies with longer follow-up reported the strongest relationships. Our findings suggest a positive association between hypertension and ADNC, but effects may be modest, and possibly attenuate with higher hypertension age and antihypertensive medication use. Investigating interactions among plaques, tangles, cerebrovascular pathology, and dementia may be key in better understanding hypertension's role in dementia development.

European Stroke Organisation and European Academy of Neurology joint guidelines on post-stroke cognitive impairment.

BACKGROUND AND PURPOSE: The optimal management of post-stroke cognitive impairment (PSCI) remains controversial. These joint European Stroke Organisation (ESO) and European Academy of Neurology (EAN) guidelines provide evidence-based recommendations to assist clinicians in decision making regarding prevention, diagnosis, treatment and prognosis. METHODS: Guidelines were developed according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations. RESULTS: There was limited randomized controlled trial (RCT) evidence regarding single or multicomponent interventions to prevent post-stroke cognitive decline. Lifestyle interventions and treating vascular risk factors have many health benefits, but a cognitive effect is not proven. We found no evidence regarding routine cognitive screening following stroke, but recognize the importance of targeted cognitive assessment. We describe the accuracy of various cognitive screening tests, but found no clearly superior approach to testing. There was insufficient evidence to make a recommendation for use of cholinesterase inhibitors, memantine nootropics or cognitive rehabilitation. There was limited evidence on the use of prediction tools for post-stroke cognition. The association between PSCI and acute structural brain imaging features was unclear, although the presence of substantial white matter hyperintensities of presumed vascular origin on brain magnetic resonance imaging may help predict cognitive outcomes. CONCLUSIONS: These guidelines highlight fundamental areas where robust evidence is lacking. Further definitive RCTs are needed, and we suggest priority areas for future research.

Multi-domain interventions for the prevention of dementia and cognitive decline.

BACKGROUND: Dementia is a worldwide concern. Its global prevalence is increasing. Currently, no effective medical treatment exists to cure or to delay the onset of cognitive decline or dementia. Up to 40% of dementia is attributable to potentially modifiable risk factors, which has led to the notion that targeting these risk factors might reduce the incidence of cognitive decline and dementia. Since sporadic dementia is a multifactorial condition, thought to derive from multiple causes and risk factors, multi-domain interventions may be more effective for the prevention of dementia than those targeting single risk factors. OBJECTIVES: To assess the effects of multi-domain interventions for the prevention of cognitive decline and dementia in older adults, including both unselected populations and populations at increased risk of cognitive decline and dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid SP), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), and ClinicalTrials.gov on 28 April 2021. We also reviewed citations of reference lists of included studies, landmark papers, and review papers to identify additional studies and assessed their suitability for inclusion in the review. SELECTION CRITERIA: We defined a multi-domain intervention as an intervention with more than one component, pharmacological or non-pharmacological, but not consisting only of two or more drugs with the same therapeutic target. We included randomised controlled trials (RCTs) evaluating the effect of such an intervention on cognitive functioning and/or incident dementia. We accepted as control conditions any sham intervention or usual care, but not single-domain interventions intended to reduce dementia risk. We required studies to have a minimum of 400 participants and an intervention and follow-up duration of at least 12 months. DATA COLLECTION AND ANALYSIS: We initially screened search results using a 'crowdsourcing' method in which members of Cochrane's citizen science platform identify RCTs. We screened the identified citations against inclusion criteria by two review authors working independently. At least two review authors also independently extracted data, assessed the risk of bias and applied the GRADE approach to assess the certainty of evidence. We defined high-certainty reviews as trials with a low risk of bias across all domains other than blinding of participants and personnel involved in administering the intervention (because lifestyle interventions are difficult to blind). Critical outcomes were incident dementia, incident mild cognitive impairment (MCI), cognitive decline measured with any validated measure, and mortality. Important outcomes included adverse events (e.g. cardiovascular events), quality of life, and activities of daily living (ADL).  Where appropriate, we synthesised data in random-effects meta-analyses. We expressed treatment effects as risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). MAIN RESULTS: We included nine RCTs (18.452 participants) in this review. Two studies reported incident dementia as an outcome; all nine studies reported a measure for cognitive functioning. Assessment of cognitive functioning was very heterogeneous across studies, ranging from complete neuropsychological assessments to short screening tests such as the mini-mental state examination (MMSE). The duration of the interventions varied from 12 months to 10 years. We compared multi-domain interventions against usual care or a sham intervention. Positive MDs and RRs <1 favour multi-domain interventions over control interventions. For incident dementia, there was no evidence of a difference between the multi-domain intervention group and the control group (RR 0.94, 95% CI 0.76 to 1.18; 2 studies; 7256 participants; high-certainty evidence). There was a small difference in composite Z-score for cognitive function measured with a neuropsychological test battery (NTB) (MD 0.03, 95% CI 0.01 to 0.06; 3 studies; 4617 participants; high-certainty evidence) and with the Montreal Cognitive Assessment (MoCA) scale (MD 0.76 point, 95% CI 0.05 to 1.46; 2 studies; 1554 participants), but the certainty of evidence for the MoCA was very low (due to serious risk of bias, inconsistency and indirectness) and there was no evidence of an effect on the MMSE (MD 0.02 point, 95% CI -0.06 to 0.09; 6 studies; 8697participants; moderate-certainty evidence). There was no evidence of an effect on mortality (RR 0.93, 95% CI 0.84 to 1.04; 4 studies; 11,487 participants; high-certainty evidence). There was high-certainty evidence for an interaction of the multi-domain intervention with ApoE4 status on the outcome of cognitive function measured with an NTB (carriers MD 0.14, 95% CI 0.04 to 0.25, noncarriers MD 0.04, 95% CI -0.02 to 0.10, P for interaction 0.09). There was no clear evidence for an interaction with baseline cognitive status (defined by MMSE-score) on cognitive function measured with an NTB (low baseline MMSE group MD 0.06, 95% CI 0.01 to 0.11, high baseline MMSE group MD 0.01, 95% CI -0.01 to 0.04, P for interaction 0.12), nor was there clear evidence for an effect in participants with a Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score > 6 points (MD 0.07, 95%CI -0.00 to 0.15). AUTHORS' CONCLUSIONS: We found no evidence that multi-domain interventions can prevent incident dementia based on two trials. There was a small improvement in cognitive function assessed by a NTB in the group of participants receiving a multi-domain intervention, although this effect was strongest in trials offering cognitive training within the multi-domain intervention, making it difficult to rule out a potential learning effect. Interventions were diverse in terms of their components and intensity.

Bayes analysis supports null hypothesis of anti-amyloid beta therapy in Alzheimer's disease.

Numerous clinical trials of anti-amyloid beta (Aß) immunotherapy in Alzheimer's disease have been performed. None of these have provided convincing evidence for beneficial effects. Using traditional frequentist meta-analysis, the conclusion is that there is absence of evidence for a therapeutic effect, with a point estimate effect size of 0.05 (95% confidence interval -0.00 to 0.10, P = .055). In addition, this non-significant effect equates to 0.4 points per year on the cognitive subscale of the Alzheimer's Disease Assessment Scale. This is well below the minimally clinically important difference. Bayesian meta-analysis of these trial data provides strong evidence of absence of a therapeutic effect, with a Bayes factor of 11.27 in favor of the null hypothesis, opposed to a Bayes factor of 0.09 in favor of a treatment effect. Bayesian analysis is particularly valuable in this context of repeatedly reported small, non-significant effect sizes in individual trials. Mechanisms other than removal of Aß from the brain may be probed to slow progression of Alzheimer's disease.

ExploreASL: An image processing pipeline for multi-center ASL perfusion MRI studies.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

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.

Dementia risk scores as surrogate outcomes for lifestyle-based multidomain prevention trials-rationale, preliminary evidence and challenges.

INTRODUCTION: Although not designed as such, dementia risk scores might be useful surrogate outcomes for dementia prevention trials. Their suitability may be improved by using continuous scoring systems, taking into account all changes in risk factors, not only those crossing cut-off values. METHODS: In three large multidomain dementia prevention trials with 1.5 to 2 years of follow-up (Multidomain Alzheimer Preventive Trial, Prevention of Dementia by Intensive Vascular Care and Healthy Ageing Through Internet Counselling in the Elderly) we assessed (1) responsiveness (sensitivity to change) and (2) actual and simulated intervention effects of the original and crude/weighted z-score versions of the cardiovascular risk factors, aging and incidence of dementia, and Lifestyle for Brain Health scores. RESULTS: All versions of the risk scores were generally responsive, and able to detect small though statistically significant between-group differences after multidomain interventions. Simulated intervention effects were well detected in z-score versions as well as in the original scores. DISCUSSION: Dementia risk scores and their z-score versions show potential as surrogate outcomes. How changes in risk scores affect dementia remains to be determined.

Associations of Subjective Memory Complaints and Simple Memory Task Scores With Future Dementia in the Primary Care Setting.

PURPOSE: Family physicians need simple yet comprehensive algorithms to discriminate between community-dwelling older persons who are at increased risk of dementia and those who are not. We aimed to investigate associations between incident dementia and responses to a single question regarding subjective memory complaints (SMC) combined with scores on 2 simple memory tests that are easy to use in the primary care setting. METHODS: Analyses were based on data from 3,454 community-dwelling older persons who participated in the 6- to 8-year Prevention of Dementia by Intensive Vascular Care (preDIVA) trial, yielding 21,341 person-years of observation. Participants were considered a single cohort. We used Cox models to assess separate and combined associations of SMC, an imperfect score on the Mini-Mental State Examination delayed recall item (MMSE-5), and an imperfect score on the Visual Association Test (VAT) with future dementia. RESULTS: Subjective memory complaints alone were associated with future dementia (hazard ratio [HR] = 3.01; 95% CI, 2.31-3.94; P <.001), as were the MMSE-5 (HR = 2.14; 95% CI, 1.59-2.87; P <.001) and VAT (HR = 3.19; 95% CI, 2.46-4.13; P <.001) scores. After a median follow-up of 6.7 years, the occurrence of dementia ranged from 4% to 30% among persons with SMC, depending on the MMSE-5 and VAT scores. These test scores did not substantially alter the association with future dementia for persons without SMC. CONCLUSIONS: In persons with SMC, the strength of the association between future dementia and an imperfect MMSE-5 score depends substantially on the VAT score.

When is Alzheimer's not dementia-Cochrane commentary on The National Institute on Ageing and Alzheimer's Association Research Framework for Alzheimer's Disease.

Early 2018 saw the release of new diagnostic guidance on Alzheimer's disease from the National Institute on Ageing and the Alzheimer's Association (NIA-AA). This proposed research framework represents a fundamental change in how we think about Alzheimer's disease, moving from diagnosis based on clinical features to diagnosis based solely on biomarkers. These recommendations are contentious and have important implications for patients, clinicians, policy makers and the pharmaceutical industry. In this commentary, we offer a summary of the NIA-AA research framework. We then focus on five key areas: divorcing neuropathology from the clinical syndrome; the emphasis placed on one dementia subtype; validity of available biomarkers; the changing meaning of the term 'Alzheimer's disease'; and the potential for a research framework to influence clinical practice.

A network approach on the relation between apathy and depression symptoms with dementia and functional disability.

BACKGROUND: Studies on the association between depression and dementia risk mostly use sum scores on depression questionnaires to model symptomatology severity. Since individual items may contribute differently to this association, this approach has limited validity. METHODS: We used network analysis to investigate the functioning of individual Geriatric Depression Scale (GDS-15) items, of which, based on studies that used factor analysis, 3 are generally considered to measure apathy (GDS-3A) and 12 depression (GDS-12D). Functional disability and future dementia were also included in our analysis. Data were extracted from 3229 participants of the Prevention of Dementia by Intensive Vascular care trial (preDIVA), analyzed as a single cohort, yielding 20,542 person-years of observation. We estimated a sparse network by only including connections between variables that could not be accounted for by variance in other variables. For this, we used a repeated L1 regularized regression procedure. RESULTS: This procedure resulted in a selection of 59/136 possible connections. GDS-3A items were strongly connected to each other and with varying strength to several GDS-12D items. Functional disability was connected to all three GDS-3A items and the GDS-12D items "helplessness" and "worthlessness". Future dementia was only connected to the GDS-12D item "memory problems", which was in turn connected to the GDS-12D items "unhappiness" and "helplessness" and all three GDS-3A items. CONCLUSION: Network analysis reveals interesting relationships between GDS items, functional disability and dementia risk. We discuss what implications our results may have for (future) research on the associations between depression and/or apathy with dementia.

On the reconceptualization of Alzheimer's disease.

In the hope of future treatments to prevent or slow down the disease, there is a strong movement towards an ever-earlier detection of Alzheimer's disease (AD). In conjunction with scientific developments, this has prompted a reconceptualization of AD, as a slowly progressive pathological process with a long asymptomatic phase. New concepts such as 'preclinical' and 'prodromal' AD have been introduced, raising a number of conceptual and ethical questions. We evaluate whether these new concepts are theoretically defensible, in light of theories of health and disease, and whether they should be understood as disease or as an at-risk state. We introduce a pragmatic view on disease concepts and argue that an evaluation of the reconceptualization of AD should also take its aims and effects into account, and assess their ethical acceptability. The reconceptualization of AD is useful to coordinate research into preventive strategies, and may potentially benefit future patients. However, in the short term, early detection and labelling of 'preclinical AD' can potentially harm people. Since there is no treatment available and the predictive value is unclear, it may only create a group of 'patients-in-waiting' who may suffer from anxiety, uncertainty and stigmatization, but will never actually develop dementia. We conclude that only if the promise of preventive medication materializes, will the reconceptualization of AD turn out unequivocally to be for the better. Otherwise, the reconceptualization may do more harm than good.

Adherence to multidomain interventions for dementia prevention: Data from the FINGER and MAPT trials.

INTRODUCTION: Multidomain interventions, targeting multiple risk factors simultaneously, could be effective dementia prevention strategies, but may be burdensome and not universally acceptable. METHODS: We studied adherence rates and predictors in the Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability and Multidomain Alzheimer Preventive Trial prevention trials, for all intervention components (separately and simultaneously). Finnish Geriatric Intervevntion Study to Prevent Cognitive Impairment and Disability participants received a 2-year multidomain lifestyle intervention (physical training, cognitive training, nutritional counseling, and cardiovascular monitoring). Multidomain Alzheimer Preventive Trial participants received a 3-year multidomain lifestyle intervention (cognitive training, physical activity counseling, and nutritional counseling) with either an omega-3 supplement or placebo. RESULTS: Adherence decreased with increasing intervention complexity and intensity: it was highest for cardiovascular monitoring, nutritional counseling, and the omega-3 supplement, and lowest for unsupervised computer-based cognitive training. The most consistent baseline predictors of adherence were smoking and depressive symptoms. DISCUSSION: Reducing participant burden, while ensuring that technological tools are suitable for older individuals, maintaining face-to-face contacts, and taking into account participant characteristics may increase adherence in future trials.