Lisa S. M. Eurelings

Delirium in Elderly Patients and the Risk of Postdischarge Mortality, Institutionalization, and Dementia: A Meta-analysis

CONTEXT Delirium is a common and serious complication in elderly patients. Evidence suggests that delirium is associated with long-term poor outcome but delirium often occurs in individuals with more severe underlying disease. OBJECTIVE To assess the association between delirium in elderly patients and long-term poor outcome, defined as mortality, institutionalization, or dementia, while controlling for important confounders. DATA SOURCES A systematic search of studies published between January 1981 and April 2010 was conducted using the databases of MEDLINE, EMBASE, PsycINFO, and CINAHL. STUDY SELECTION Observational studies of elderly patients with delirium as a study variable and data on mortality, institutionalization, or dementia after a minimum follow-up of 3 months, and published in the English or Dutch language. Titles, abstracts, and articles were reviewed independently by 2 of the authors. Of 2939 references in the original search, 51 relevant articles were identified. DATA EXTRACTION Information on study design, characteristics of the study population, and outcome were extracted. Quality of studies was assessed based on elements of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies. DATA SYNTHESIS The primary analyses included only high-quality studies with statistical control for age, sex, comorbid illness or illness severity, and baseline dementia. Pooled-effect estimates were calculated with random-effects models. The primary analysis with adjusted hazard ratios (HRs) showed that delirium is associated with an increased risk of death compared with controls after an average follow-up of 22.7 months (7 studies; 271/714 patients [38.0%] with delirium, 616/2243 controls [27.5%]; HR, 1.95 [95% confidence interval {CI}, 1.51-2.52]; I(2), 44.0%). Moreover, patients who had experienced delirium were also at increased risk of institutionalization (7 studies; average follow-up, 14.6 months; 176/527 patients [33.4%] with delirium and 219/2052 controls [10.7%]; odds ratio [OR], 2.41 [95% CI, 1.77-3.29]; I(2), 0%) and dementia (2 studies; average follow-up, 4.1 years; 35/56 patients [62.5%] with delirium and 15/185 controls [8.1%]; OR, 12.52 [95% CI, 1.86-84.21]; I(2), 52.4%). The sensitivity, trim-and-fill, and secondary analyses with unadjusted high-quality risk estimates stratified according to the study characteristics confirmed the robustness of these results. CONCLUSION This meta-analysis provides evidence that delirium in elderly patients is associated with poor outcome independent of important confounders, such as age, sex, comorbid illness or illness severity, and baseline dementia.

Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial

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.

Association of Vascular Factors With Apathy in Community-Dwelling Elderly Individuals

CONTEXT Apathy in community-dwelling elderly individuals has been associated with a history of stroke and other cardiovascular disease. OBJECTIVE To assess the relationship between symptoms of apathy and cardiovascular risk factors or disease (stroke or other) in a large sample of elderly people aged 70 to 78 years without depression or dementia. DESIGN Cross-sectional data analysis within an ongoing cluster-randomized, open, multicenter trial. SETTING The Netherlands, general community. PARTICIPANTS We studied 3534 elderly individuals without dementia who were included in the Prevention of Dementia by Intensive Vascular Care trial. MAIN OUTCOME MEASURES Symptoms of apathy, assessed with 3 items from the 15-item Geriatric Depression Scale, in participants with few or no depressive symptoms. RESULTS The median age of participants was 74.3 years. Principal components analysis of the Geriatric Depression Scale confirmed a separate factor for the apathy items (Geriatric Depression Scale-3A). Two or more symptoms of apathy were present in 699 participants (19.9%), of whom 372 (53.2%) were without depressive symptoms (Geriatric Depression Scale-12D score <2). Ordinal regression analysis showed that increasing apathy in the absence of depressive symptoms was associated with a history of stroke (odds ratio, 1.79; 95% CI, 1.38-2.31) and cardiovascular disease other than stroke (1.28; 1.09-1.52). Exploratory analysis among 1889 participants free from stroke and other cardiovascular disease revealed an association between apathy score and the following cardiovascular risk factors: systolic blood pressure (P = .03), body mass index (P = .002), type 2 diabetes mellitus (P = .07), and C-reactive protein (P < .001). CONCLUSIONS Symptoms indicative of apathy are common in community-dwelling nondemented older people who are free from depression. The independent association of stroke, other cardiovascular disease, and cardiovascular risk factors with symptoms of apathy suggests a causal role of vascular factors.

Characteristics of Dyshoric Capillary Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) affects brain parenchymal and leptomeningeal arteries and arterioles but sometimes involves capillaries (capCAA) with spread of the amyloid into the surrounding neuropil, that is, dyshoric changes. We determined the relationship between capCAA and larger vessel CAA, &bgr; amyloid (A&bgr;) plaques, neurofibrillary changes, inflammation, and apolipoprotein E (APOE) in 22 cases of dyshoric capCAA using immunohistochemistry. The dyshoric changes contained predominantly A&bgr;1-40, whereas dense bulblike deposits adjacent to the capillary wall contained mostly A&bgr;1-42. There was an inverse local correlation between A&bgr; plaque load and capCAA severity (p = 0.01), suggesting that A&bgr; transport between the neuropil and the circulation may be mechanistically involved. Deposits of hyperphosphorylated tau and ubiquitin and clusters of activated microglia, resembling the changes around A&bgr; plaques, were found around capCAA but were absent around larger vessel CAA. In 14 cases for which APOE genotype was available, there was a high APOE-ϵ4 allele frequency (54%; 43% homozygous). The severity of CapCAA increased with the number of ϵ4-alleles; and APOE4 seemed to colocalize with capCAA by immunohistochemistry. These results suggest that capCAA is pathologically and possibly pathogenetically distinct from larger vessel CAA, and that it is associated with a high APOE-ϵ4 allele frequency.

Apathy is an independent risk factor for incident cardiovascular disease in the older individual: a population-based cohort study.

Although depression is considered to be associated with cardiovascular disease (CVD), specifically symptoms of apathy have been strongly associated with a history of CVD in recent studies. In this study, we prospectively assess whether symptoms of apathy and depression are independent risk factors for incident CVD and stroke.

Low-grade inflammation differentiates between symptoms of apathy and depression in community-dwelling older individuals.

BACKGROUND Systemic low-grade inflammation has repeatedly been associated with depression in old age, but the relationship with apathy is less clear. The present study assessed whether C-reactive protein (CRP) is differentially associated with symptoms of apathy and depression. METHODS A population-based cohort study was carried-out. At baseline and after two and four years of follow-up, CRP levels were assessed and symptoms of apathy and depression were measured using the 15-item Geriatric Depression Scale. Logistic regression analysis was used to investigate the cross-sectional and longitudinal associations of CRP with symptoms of apathy and depression. RESULTS Two thousand forty-seven community-dwelling participants (70-78 years) without a history of cardiovascular disease or stroke were studied. A cross-sectional association was found between CRP and apathy symptoms at three time points (odds ratio (OR) per natural log unit increase in CRP: baseline visit = 1.40, 95% CI = 1.12-1.75; two-year follow-up visit = 1.62, 95% CI = 1.17-2.25; four-year follow-up visit = 1.51, 95% CI = 1.03-2.21). This did not change after adjustment for demographics and depressive symptoms, and was slightly attenuated after adjustment for cardiovascular risk factors. No cross-sectional association was found with depressive symptoms. Baseline CRP did not predict incident apathy or depressive symptoms during four years of follow-up. CONCLUSIONS Increased CRP levels are associated with apathy symptoms but not with depressive symptoms. This suggests a differential effect of inflammation on apathy and depression. In older persons, symptoms of apathy may be a behavioral manifestation of concurrent low-grade inflammation.

Apathy and depressive symptoms in older people and incident myocardial infarction, stroke, and mortality: a systematic review and meta-analysis of individual participant data

Background Previous findings suggest that apathy symptoms independently of depressive symptoms measured using the Geriatric Depression Scale (GDS) are associated with cardiovascular disease (CVD) in older individuals. Aims To study whether apathy and depressive symptoms in older people are associated with future CVD, stroke, and mortality using individual patient-data meta-analysis. Methods Medline, Embase, and PsycInfo databases up to September 3, 2013, were systematically searched without language restrictions. We sought prospective studies with older (mean age ≥65 years) community-dwelling populations in which the GDS was employed and subsequent stroke and/or CVD were recorded to provide individual participant data. Apathy symptoms were defined as the three apathy-related subitems of the GDS, with depressive symptoms the remaining items. We used myocardial infarction (MI), stroke, and all-cause mortality as main outcomes. Analyses were adjusted for age, sex, and MI/stroke history. An adaptation of the Newcastle–Ottawa scale was used to evaluate bias. Hazard ratios were calculated using one-stage random-effect Cox regression models. Results Of the 52 eligible studies, 21 (40.4%) were included, comprising 47,625 older people (mean age [standard deviation] 74 [7.4] years), over a median follow-up of 8.8 years. Participants with apathy symptoms had a 21% higher risk of MI (95% confidence interval [CI] 1.08–1.36), a 37% higher risk of stroke (95% CI 1.18–1.59), and a 47% higher risk of all-cause mortality (95% CI 1.38–1.56). Participants with depressive symptoms had a comparably higher risk of stroke (HR 1.36, 95% CI 1.18–1.56) and all-cause mortality (HR 1.44, 95% CI 1.35–1.53), but not of MI (HR 1.08, 95% CI 0.91–1.29). Associations for isolated apathy and isolated depressive symptoms were comparable. Sensitivity analyses according to risk of bias yielded similar results. Conclusion Our findings stress the clinical importance of recognizing apathy independently of depressive symptoms, and could help physicians identify persons at increased risk of vascular disease.

The mediating role of cardiovascular risk factors in the relationship between symptoms of apathy and incident cardiovascular disease in community-dwelling older individuals

BACKGROUND In old age, both apathy and depression have been associated with an increased cardiovascular disease (CVD) risk. This study evaluated the mediating role of cardiovascular risk factors in the relationship of apathy and mood symptoms with incident CVD. METHODS Prospective cohort study of 1,790 community-dwelling older individuals (70-78 years) without a history of CVD or stroke. At baseline, apathy and mood symptoms were assessed with the 15-item Geriatric Depression Scale (GDS-15), of which three items represent apathy symptoms. The mediational risk factors included were diabetes mellitus (DM), body mass index (BMI), current smoking, physical inactivity, systolic blood pressure, and total cholesterol. Incident CVD was evaluated after two years of follow-up. Data were analyzed using structural equation modeling (SEM). RESULTS Incident CVD occurred in 59 (3.3%) participants. Apathy symptoms had a significant estimated total effect on incident CVD, with increases of 2.2% for each unit increase in apathy score. Of this total effect, 22.7% was due to the mediational effects of physical inactivity (13.6%), current smoking (4.5%), and DM (4.5%). The remaining 77.3% was due to direct effects reflecting other mediational dynamics. No significant (in)direct effects of mood symptoms on incident CVD were found. CONCLUSIONS Physical inactivity, smoking, and DM account for nearly one-fourth of the variation reflecting the link between apathy symptoms and incident CVD. This illustrates the relevance of unfavorable health behaviors and assessment of DM in older individuals with apathy. The majority of the effect of apathy symptoms on incident CVD is caused by other, yet unknown, factors.

Improving Prediction of Dementia in Primary Care

PURPOSE The Mini-Mental State Examination (MMSE) is one of the most widely used instruments to screen for cognitive deficits; however, this instrument alone is not sensitive enough to detect early symptoms of dementia. We aimed to investigate whether additionally using the Visual Association Test (VAT) improves the predictive value of the MMSE score for development of dementia. METHODS Analyses were based on data from 2,690 primary care patients aged 70 to 78 years who participated in the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial. We assessed change in the 30-point MMSE score over 2 years and the VAT score at 2 years—dichotomized as perfect (6 points) or imperfect (≤5 points)—and evaluated the predictive values of these tests for a diagnosis of dementia in the subsequent 4 to 6 years. Data were analyzed with logistic regression analysis. RESULTS Patients having a decline of 2 points or more in total MMSE score over 2 years had an odds ratio of 3.55 (95% CI, 2.51–5.00) for developing dementia. Patients having the same decline in MMSE score plus an imperfect VAT score had an odds ratio of 9.55 (95% CI, 5.89–15.41) for developing dementia. A 1-point decline in MMSE score increased odds of dementia only when the VAT score was imperfect. Dementia risk for patients with a 2- or 3-point decrease in MMSE score and a perfect VAT score did not differ significantly from the average risk of the cohort as a whole. CONCLUSIONS Administering the VAT in patients with a small decline on the MMSE over a 2-year period has substantial incremental value for identifying those at elevated risk for developing dementia. This simple test may help distinguish older adults who need further cognitive examination from those in whom a watchful waiting policy is justified.

PREVENTION OF DEMENTIA BY INTENSIVE VASCULAR CARE (PREDIVA): A CLUSTER-RANDOMIZED TRIAL

O4-05-01 PREVENTION OF DEMENTIA BY INTENSIVE VASCULAR CARE (PREDIVA): A CLUSTERRANDOMIZED TRIAL Edo Richard, Eric P. Moll van Charante, Lisa S. Eurelings, JanWillem van Dalen, Suzanne A. Ligthart, Emma F. van Bussel, Marieke P. Hoevenaar, Marinus Vermeulen, Willem A. van Gool, 1 Academic Medical Center, Amsterdam, Netherlands; 2 Radboud University Medical Center, Nijmegen, Netherlands. Contact e-mail: e.richard@amc. uva.nl