Arjen J. C. Slooter

Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study

BACKGROUND Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimers disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimers disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimers disease. We investigated the frequency of dementia and its subtypes in relation to atherosclerosis and apolipoprotein E. METHODS We did a population-based study of 284 patients with dementia, 207 of whom had Alzheimers disease, and 1698 individuals who were not demented. Indicators of atherosclerosis included vessel wall thickness and plaques of the carotid arteries, assessed by ultrasonography, and the ratio of ankle-to-brachial systolic blood pressure as a measure of generalised atherosclerosis. Based on these indicators participants were scored from 0 (no atherosclerosis) to 3 (severe atherosclerosis) for degree of atherosclerosis. Apolipoprotein-E polymorphisms were assessed in 246 patients and in 928 controls. FINDINGS All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1.3 to 1.9) and its major subtypes Alzheimers disease (odds ratios 1.3-1.8) and vascular dementia (odds ratios 1.9-3.2). The frequencies of all dementia. Alzheimers disease, and vascular dementia increased with the degree of atherosclerosis. The odds ratio for Alzheimers disease in those with severe atherosclerosis compared with those without atherosclerosis was 3.0 (95% CI 1.5-6.0; p = 0.001). In participants with the apolipoprotein-E epsilon 4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4.5 (2.0-10.1; p < 0.001), for Alzheimers disease was 3.9 (1.6-9.6; p = 0.002), and for vascular dementia was 19.8 (4.1-95.0; p < 0.001). INTERPRETATION These findings suggest that dementia and its two major subtypes Alzheimers disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimers disease.

Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study

BACKGROUND Previous studies suggested a protective effect of smoking on Alzheimers disease, but most were case-control studies based on prevalent cases. The findings of prospective studies on the association between smoking and the risk of dementia are inconclusive. METHODS We did a population-based follow-up study of elderly people who were initially free of dementia. 6870 people aged 55 years and older agreed to take part. Smoking history was taken at baseline and participants were classified as never smokers, former smokers, and current smokers. During follow-up, we recorded all incident cases of dementia. We used never smokers as the reference category to calculate relative risks of dementia and Alzheimers disease by Cox proportional hazards regression, after adjustment for age, sex, education, and alcohol intake. We also examined modification of risk by age, sex, and the apolipoprotein E (APOE) genotype. FINDINGS During mean follow-up of 2.1 (range 1.5-3.4) years, 146 incident cases of dementia were detected, of which 105 were Alzheimers disease. Compared with never smokers, smokers had an increased risk of dementia (relative risk 2.2 [95% CI 1.3-3.6]) and Alzheimers disease (2.3 [1.3-4.1]). Smoking was a strong risk factor for Alzheimers disease in individuals without the APOEepsilon4 allele (4.6 [1.5-14.2]), but had no effect in participants with this allele (0.6 [0.1-4.8]). INTERPRETATION Smoking was associated with a doubling of the risk of dementia and Alzheimers disease. Our finding that carriers of the APOEepsilon4 had no increased risk of dementia suggests an interaction between smoking and the APOEepsilon4 genotype in the aetiology of Alzheimers disease.

Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients : a multicentre, double-blind, placebo-controlled randomised trial

BACKGROUND Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. FUNDING ZonMw, the Netherlands Brain Foundation, and Novartis.

Head trauma and risk of dementia and Alzheimer’s disease The Rotterdam Study

Objective: To investigate the relation between head trauma and incidence of dementia in a prospective population-based study. Background: Whether head trauma increases the risk of dementia and AD remains controversial. It has been suggested that the risk might be particularly increased for carriers of the APOE-ε4 allele. Methods: The study population included 6645 participants of the prospective population-based Rotterdam Study, aged 55 years or older, who were free of dementia at baseline. Head trauma with loss of consciousness was measured at baseline by a self-report to a physician and detailed the number of head traumas, time since head trauma, and duration of loss of consciousness. The cohort was followed for incident dementia that was diagnosed according to international criteria. Logistic regression was used to calculate the risk of dementia after adjusting for age, gender, and education. Results: No increased risk of dementia or AD was found for persons with a history of head trauma with loss of consciousness (relative risk [RR] for dementia = 1.0, 95% CI, 0.5–2.0; RR for AD = 0.8, 95% CI, 0.4–1.9). Multiple head traumas, time since head trauma, and duration of unconsciousness did not significantly influence the risk of dementia. In addition, the APOE-ε4 allele did not modify the relationship. Conclusions: This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly. In addition, this study does not concur with previous cross-sectional studies suggesting an interaction with the APOE genotype.

Routine use of the confusion assessment method for the intensive care unit : a multicenter study

RATIONALE Delirium is often unrecognized in ICU patients and associated with poor outcome. Screening for ICU delirium is recommended by several medical organizations to improve early diagnosis and treatment. The Confusion Assessment Method for the ICU (CAM-ICU) has high sensitivity and specificity for delirium when administered by research nurses. However, test characteristics of the CAM-ICU as performed in routine practice are unclear. OBJECTIVES To investigate the diagnostic value of the CAM-ICU in daily practice. METHODS Teams of three delirium experts including psychiatrists, geriatricians, and neurologists visited 10 ICUs twice. Based on cognitive examination, inspection of medical files, and Diagnostic and Statistic Manual of Mental Disorders, 4th edition, Text Revision criteria for delirium, the expert teams classified patients as awake and not delirious, delirious, or comatose. This served as a gold standard to which the CAM-ICU as performed by the bedside ICU-nurses was compared. Assessors were unaware of each others conclusions. MEASUREMENTS AND MAIN RESULTS Fifteen delirium experts assessed 282 patients of whom 101 (36%) were comatose and excluded. In the remaining 181 (64%) patients, the CAM-ICU had a sensitivity of 47% (95% confidence interval [CI], 35%-58%); specificity of 98% (95% CI, 93%-100%); positive predictive value of 95% (95% CI, 80%-99%); and negative predictive value of 72% (95% CI, 64%-79%). The positive likelihood ratio was 24.7 (95% CI, 6.1-100) and the negative likelihood ratio was 0.5 (95% CI, 0.4-0.8). CONCLUSIONS Specificity of the CAM-ICU as performed in routine practice seems to be high but sensitivity is low. This hampers early detection of delirium by the CAM-ICU.

A systematic review of risk factors for delirium in the ICU.

Objective:Although numerous risk factors for delirium in the ICU have been proposed, the strength of evidence supporting each risk factor remains unclear. This study systematically identifies risk factors for delirium in critically ill adults where current evidence is strongest. Data Sources:CINAHL, EMBASE, MEDLINE, the Cochrane Central Register for Controlled Trials, and the Cochrane Database of Systematic Reviews. Study Selection:Studies published from 2000 to February 2013 that evaluated critically ill adults, not undergoing cardiac surgery, for delirium, and used either multivariable analysis or randomization to evaluate variables as potential risk factors for delirium. Data Extraction:Data were abstracted in duplicate, and quality was scored using Scottish Intercollegiate Guidelines Network checklists (i.e., high, acceptable, and low). Using a best-evidence synthesis each variable was evaluated using 3 criteria: the number of studies investigating it, the quality of these studies, and whether the direction of association was consistent across the studies. Strengths of association were not summarized. Strength of evidence was defined as strong (consistent findings in ≥2 high quality studies), moderate (consistent findings in 1 high quality study and ≥1 acceptable quality studies), inconclusive (inconsistent findings or 1 high quality study or consistent findings in only acceptable quality/low quality studies) or no evidence available. Data Synthesis:Among 33 studies included, 70% were high quality. There was strong evidence that age, dementia, hypertension, pre-ICU emergency surgery or trauma, Acute Physiology and Chronic Health Evaluation II score, mechanical ventilation, metabolic acidosis, delirium on the prior day, and coma are risk factors for delirium, that gender is not associated with delirium, and that use of dexmedetomidine is associated with a lower delirium prevalence. There is moderate evidence that multiple organ failure is a risk factor for delirium. Conclusions:Only 11 putative risk factors for delirium are supported by either strong or moderate level of evidence. These factors should be considered when designing delirium prevention strategies or controlling for confounding in future etiologic studies.

Estrogen use and early onset Alzheimer's disease: a population-based study

Estrogen use may be protective for Alzheimers disease with late onset. However, the effects on early onset Alzheimers disease are unclear. This issue was studied in a population based setting. For each female patient, a female control was matched on age (within 5 years) and place of residence. Information on estrogen use and other risk factors were, for cases (n=109) and controls (n=119), collected from the next of kin by structured interview. The strength of the association between estrogen use and early onset Alzheimers disease was studied using conditional logistic regression with adjustment for age and education level. There was an inverse association between estrogen use and early onset Alzheimers disease (adjusted odds ratio 0.34; 95% confidence interval 0.12–0.94). The study therefore suggests that estrogen use is beneficial to Alzheimers disease with early onset.

Apolipoprotein E genotype, atherosclerosis, and cognitive decline: the Rotterdam study

The apolipoprotein E4 allele (APOE epsilon 4) and atherosclerosis are risk factors for cognitive decline. We investigated whether the effects of APOE epsilon 4 and atherosclerosis on cognitive decline are independent. A population-based follow-up study was performed on 838 subjects who were non-demented at baseline. The Mini Mental State Examination (MMSE) score at follow-up was studied as a function of APOE epsilon 4 and atherosclerosis. Mild, non-significant effects on the MMSE score were found for atherosclerosis in the absence of APOE epsilon 4 and for APOE epsilon 4 in the absence of atherosclerosis. APOE epsilon 4 carriers with two or more indicators of atherosclerosis positive, had a significantly lower MMSE score at follow-up (mean difference -0.7 points; 95% confidence interval -1.1 to -0.2) relative to non-APOE epsilon 4 carriers with no evidence of atherosclerosis. Our findings suggest that the consequences of APOE epsilon 4 and atherosclerosis are not independent, and that particularly APOE epsilon 4 carriers with atherosclerosis are at increased risk of cognitive decline.

Serum apolipoprotein e level is not increased in Alzheimer's disease: The Rotterdam study

The APOE*4 allele of the apolipoprotein E gene (APOE) is an important risk factor for Alzheimers disease. It has been suggested that levels of apolipoprotein E (apoE) in plasma are increased in Alzheimers disease. In this population-based study, we found that serum apoE levels were lower in Alzheimer patients compared to non-demented controls (0.75 micromol/l (SD 0.35), vs. 0.83 micromol/l (SD 0.40), P < 0.05). This finding is in accordance with lower serum apoE levels as observed in carriers of the APOE*4 allele, who are over-represented in Alzheimers disease. After adjustment for age, sex, total protein, albumin level, body mass index and the APOE genotype, the difference in serum apoE levels largely disappeared. Our population-based study suggests that the differences in serum apoE level between Alzheimer patients and controls are mainly the result of differences in the distribution of the APOE genotype.

Apolipoprotein E genotype and progression of Alzheimer’s disease: the Rotterdam Study

Abstract The APOE*4 allele of the apolipoprotein E gene increases the risk of Alzheimer’s disease (AD), but whether it also affects the course of the disease is controversial. However, all studies on this issue until now have been based on patients at various stages of disease. In the present population-based study, 97 patients were included at a similar stage, i.e., before the onset of symptoms, and followed for up to 5 years. We found that the APOE*4 allele is not a strong determinant of survival in AD. As change in cognitive function and severity of dementia are similar for AD patients with and without APOE*4, our study suggests that progression of AD is not related to the APOE*4 allele.