Summary Background Cardiovascular risk factors are associated with an increased risk of dementia. We assessed whether a multidomain intervention targeting these factors can prevent dementia in a ...population of community-dwelling older people. Methods In this open-label, cluster-randomised controlled trial, we recruited individuals aged 70–78 years through participating general practices in the Netherlands. General practices within each health-care centre were randomly assigned (1:1), via a computer-generated randomisation sequence, to either a 6-year nurse-led, multidomain cardiovascular intervention or control (usual care). The primary outcomes were cumulative incidence of dementia and disability score (Academic Medical Center Linear Disability Score ALDS) at 6 years of follow-up. The main secondary outcomes were incident cardiovascular disease and mortality. Outcome assessors were masked to group assignment. Analyses included all participants with available outcome data. This trial is registered with ISRCTN, number ISRCTN29711771. Findings Between June 7, 2006, and March 12, 2009, 116 general practices (3526 participants) within 26 health-care centres were recruited and randomly assigned: 63 (1890 participants) were assigned to the intervention group and 53 (1636 participants) to the control group. Primary outcome data were obtained for 3454 (98%) participants; median follow-up was 6·7 years (21 341 person-years). Dementia developed in 121 (7%) of 1853 participants in the intervention group and in 112 (7%) of 1601 participants in the control group (hazard ratio HR 0·92, 95% CI 0·71–1·19; p=0·54). Mean ALDS scores measured during follow-up did not differ between groups (85·7 SD 6·8 in the intervention group and 85·7 7·1 in the control group; adjusted mean difference −0·02, 95% CI −0·38 to 0·42; p=0·93). 309 (16%) of 1885 participants died in the intervention group, compared with 269 (16%) of 1634 participants in the control group (HR 0·98, 95% CI 0·80–1·18; p=0·81). Incident cardiovascular disease did not differ between groups (273 19% of 1469 participants in the intervention group and 228 17% of 1307 participants in the control group; HR 1·06, 95% CI 0·86–1·31; p=0·57). Interpretation A nurse-led, multidomain intervention did not result in a reduced incidence of all-cause dementia in an unselected population of older people. This absence of effect might have been caused by modest baseline cardiovascular risks and high standards of usual care. Future studies should assess the efficacy of such interventions in selected populations. Funding Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund of Collaborative Health Insurances; and Netherlands Organisation for Health Research and Development.
Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically ...reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain.
We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions.
Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels.
Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.
Summary Systemic infection and drugs with anticholinergic effects are well-recognised and prevalent risk factors for delirium in elderly people. Experimental findings and neuropathological ...observations suggest that activation of microglia is pivotal for mediation of the behavioural effects of systemic infections. The microglial response is usually regulated tightly, but defensive features could turn neurotoxic once microglial cells escape from cholinergic inhibition. A self-propelling neuroinflammatory reaction might follow, and this cascade could account for the strong association between delirium and long-term cognitive impairment and even dementia. Here, we propose a hypothetical model, suggesting that poor outcome after delirium can be averted in vulnerable elderly people by use of readily available drugs. Agents that either restore cholinergic control of microglia or directly inhibit neuroinflammation warrant testing in clinical trials.
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.
Numerous clinical trials of anti‐amyloid beta (Aβ) 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 Aβ from the brain may be probed to slow progression of Alzheimer's disease.
Objectives: To study the effectiveness of haloperidol prophylaxis on incidence, severity, and duration of postoperative delirium in elderly hip‐surgery patients at risk for delirium.
Design: ...Randomized, double‐blind, placebo‐controlled trial.
Setting: Large medical school–affiliated general hospital in Alkmaar, the Netherlands.
Participants: A total of 430 hip‐surgery patients aged 70 and older at risk for postoperative delirium.
Intervention: Haloperidol 1.5 mg/d or placebo was started preoperatively and continued for up to 3 days postoperatively. Proactive geriatric consultation was provided for all randomized patients.
Measurements: The primary outcome was the incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and Confusion Assessment Method criteria). Secondary outcomes were the severity of delirium (Delirium Rating Scale, revised version‐98 (DRS‐R‐98)), the duration of delirium, and the length of hospital stay.
Results: The overall incidence of postoperative delirium was 15.8%. The percentage of patients with postoperative delirium in the haloperidol and placebo treatment condition was 15.1% and 16.5%, respectively (relative risk=0.91, 95% confidence interval (CI)=0.6–1.3); the mean highest DRS‐R‐98 score±standard deviation was 14.4±3.4 and 18.4±4.3, respectively (mean difference 4.0, 95% CI=2.0–5.8; P<.001); delirium duration was 5.4 versus 11.8 days, respectively (mean difference 6.4 days, 95% CI=4.0–8.0; P<.001); and the mean number of days in the hospital was 17.1±11.1 and 22.6±16.7, respectively (mean difference 5.5 days, 95% CI=1.4–2.3; P<.001). No haloperidol‐related side effects were noted.
Conclusion: Low‐dose haloperidol prophylactic treatment demonstrated no efficacy in reducing the incidence of postoperative delirium. It did have a positive effect on the severity and duration of delirium. Moreover, haloperidol reduced the number of days patients stayed in the hospital, and the therapy was well tolerated.
IMPORTANCE: Fear of dementia is pervasive in older people with cognitive concerns. Much research is devoted to finding prognostic markers for dementia risk. Studies suggest apathy in older people may ...be prodromal to dementia and could be a relevant, easily measurable predictor of increased dementia risk. However, evidence is fragmented and methods vary greatly between studies. OBJECTIVE: To systematically review and quantitatively synthesize the evidence for an association between apathy in dementia-free older individuals and incident dementia. DATA SOURCES: Two reviewers conducted a systematic search of Medline, Embase, and PsychINFO databases. STUDY SELECTION: Inclusion criteria were (1) prospective cohort studies, (2) in general populations or memory clinic patients without dementia, (3) with clear definitions of apathy and dementia, and (4) reporting on the association between apathy and incident dementia. DATA EXTRACTION AND SYNTHESIS: PRISMA and MOOSE guidelines were followed. Data were extracted by 1 reviewer and checked by a second. MAIN OUTCOMES AND MEASURES: Main outcomes were pooled crude risk ratios, maximally adjusted reported hazard ratios (HR), and odds ratios (OR) using DerSimonian-Laird random effects models. RESULTS: The mean age of the study populations ranged from 69.2 to 81.9 years (median, 71.6 years) and the percentage of women ranged from 35% to 70% (median, 53%). After screening 2031 titles and abstracts, 16 studies comprising 7365 participants were included. Apathy status was available for 7299 participants. Studies included populations with subjective cognitive concerns (n = 2), mild cognitive impairment (n = 11), cognitive impairment no dementia (n = 1), or mixed cognitive and no cognitive impairment (n = 2). Apathy was present in 1470 of 7299 participants (20.1%). Follow-up ranged from 1.2 to 5.4 years. In studies using validated apathy definitions (n = 12), the combined risk ratio of dementia for patients with apathy was 1.81 (95% CI, 1.32-2.50; I2 = 76%; n = 12), the hazard ratio was 2.39 (95% CI, 1.27-4.51; I2 = 90%; n = 7), and the odds ratio was 17.14 (95% CI, 1.91-154.0; I2 = 60%; n = 2). Subgroup analyses, meta-regression, and individual study results suggested the association between apathy and dementia weakened with increasing follow-up time, age, and cognitive impairment. Meta-regression adjusting for apathy definition and follow-up time explained 95% of heterogeneity in mild cognitive impairment. CONCLUSIONS AND RELEVANCE: Apathy was associated with an approximately 2-fold increased risk of dementia in memory clinic patients. Moderate publication bias may have inflated some of these estimates. Apathy deserves more attention as a relevant, cheap, noninvasive, and easily measureable marker of increased risk of incident dementia with high clinical relevance, particularly because these vulnerable patients may forgo health care.
IMPORTANCE: The optimal systolic blood pressure (SBP) to minimize the risk of dementia in older age is unknown. OBJECTIVE: To investigate whether the association between SBP and dementia risk is ...U-shaped and whether age and comorbidity play a role in this association. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used an individual participant data approach to analyze 7 prospective, observational, population-based cohort studies that were designed to evaluate incident dementia in older adults. These studies started between 1987 and 2006 in Europe and the US. Participants had no dementia diagnosis and had SBP and/or diastolic blood pressure (BP) data at baseline and incident dementia status during follow-up. Data analysis was conducted from November 7, 2019, to October 3, 2021. EXPOSURES: Baseline systolic BP. MAIN OUTCOMES AND MEASURES: All-cause dementia (defined using Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised or Diagnostic and Statistical Manual of Mental Disorders Fourth Edition and established at follow-up measurements or in clinical practice), mortality, and combined dementia and mortality were the outcomes. Covariates included baseline antihypertensive medication use, sex, educational level, body mass index, smoking status, diabetes, stroke history, myocardial infarction history, and polypharmacy. Cox proportional hazards regression models were used, and nonlinear associations were explored using natural splines. RESULTS: The study analyzed 7 cohort studies with a total of 17 286 participants, among whom 10 393 were women (60.1%) and the mean (SD) baseline age was 74.5 (7.3) years. Overall, dementia risk was lower for individuals with higher SBP, with the lowest risk associated with an SBP of approximately 185 mm Hg (95% CI, 161-230 mm Hg; P = .001). Stratified by overlapping 10-year baseline age groups, the lowest dementia risk was observed at somewhat lower systolic BP levels in those older than 75 years (158 95% CI, 152-178 mm Hg to 170 95% CI, 160-260 mm Hg). For mortality, there was a clear U-shaped association, with the lowest risk at 160 mm Hg (95% CI, 154-181 mm Hg; P < .001). This U-shape occurred across all age groups, with the lowest dementia risk associated with an SBP of 134 mm Hg (95% CI, 102-149 mm Hg; P = .03) in those aged 60 to 70 years and increasing to between 155 mm Hg (95% CI, 150-166 mm Hg; P < .001) and 166 mm Hg (95% CI, 154-260 mm Hg; P = .02) for age groups between 70 and 95 years. Combined dementia and mortality risk curves closely resembled those for mortality. Associations of diastolic BP with dementia risk were generally similar but were less distinct. CONCLUSIONS AND RELEVANCE: This cohort study found that dementia risk was lower for older individuals with higher SBP levels and that more distinctly U-shaped associations appeared for those older than 75 years, but these associations cannot be explained by SBP-associated changes in mortality risk. The findings may warrant future trials on tailored BP management in older age groups that take life expectancy and health context into consideration.
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