A.J.M. de Craen

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population

Objective: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. Methods: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. Results: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. Conclusion: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.

A high response is not essential to prevent selection bias: Results from the Leiden 85-plus study

We tested the hypothesis that an additional effort to increase the response rate would diminish selection bias in a community-based cohort study. In the Leiden 85-plus Study, all subjects of the town of Leiden who had reached their 85th birthday were informed of the study by mail and then asked to participate by telephone. In an additional recruitment stage, those subjects who did not participate directly were visited and personally asked to participate. When these subjects refused, some nonresponse questions were asked. In this way we collected data on the whole source population. Of 691 eligible elderly subjects, 511 subjects (74%) participated directly. Of those who did not participate directly, 88 subjects participated after the additional effort. The response rate increased from 74% to 87%. Compared to the 511 subjects who directly participated, the 88 subjects who entered the study after the additional effort had poorer health and lower survival. The subjects who refused were more healthy and had poorer mood. The direct sample did not differ from the source population with respect to socio-demographics, health, and mortality. In conclusion, we showed that given a moderately high direct response the additional effort was effective in increasing the response rate, but was also selective and was not necessary to prevent selection bias.

Inflammation and Stroke The Leiden 85-Plus Study

Background— Experimental evidence indicates that interleukin-10 (IL-10) deficiency is associated with the development of cardiovascular and cerebrovascular disease. We analyzed the relation between low IL-10 production levels, history of stroke, and incident fatal stroke. Summary of Report— All 85-year-old inhabitants of Leiden, Netherlands (n=599) were visited at their place of residence (response rate, 87%). Production levels of the anti-inflammatory cytokine IL-10 were assessed in a whole blood assay whereby lipopolysaccharide was used as a stimulus. Plasma concentrations of C-reactive protein (CRP) were also used as a marker of inflammation. A history of stroke was obtained at baseline (prevalence, 10%). The number of fatal strokes was prospectively obtained for a median follow-up of 2.6 years (incidence, 1.82 per 100 person-years at risk). Subjects with a history of stroke had significantly lower median IL-10 production levels at baseline than subjects without stroke (558 versus 764 pg/mL;P <0.05). They also had significantly higher median CRP concentrations (6 versus 3 mg/L;P <0.05). The odds ratio for a history of stroke increased to 2.30 (95% CI, 1.12 to 4.72) over strata representing decreasing production levels of IL-10. The relative risk for incident fatal stroke was 2.94 (95% CI, 1.01 to 8.53) when we compared subjects with low or intermediate baseline IL-10 production levels to those with high production levels of IL-10. Conclusions— Our data support the hypothesis that subjects with low IL-10 production levels have an increased risk of stroke.

The metabolic syndrome is associated with decelerated cognitive decline in the oldest old

Background: The metabolic syndrome is a cluster of risk factors including hypertension, obesity, dyslipidemia, and impaired glucose metabolism, associated with cardiovascular disease. The metabolic syndrome also appears to predispose to cognitive dysfunction and dementia. In this study the association between the metabolic syndrome and cognitive function was examined in a population of the oldest old. Methods: The Leiden 85-Plus Study is a population-based study of 599 persons from age 85 onward. Cognitive function was assessed annually from age 85 to 90 by means of four neuropsychological tests. The presence (n = 237) or absence (n = 325) of the metabolic syndrome was recorded at baseline. Cross-sectional and prospective associations between the metabolic syndrome and cognitive function were analyzed with linear mixed models, adjusted for sex and level of education. Results: At age 85 the metabolic syndrome was not associated with lower cognitive performance. The metabolic syndrome was associated with a decelerated cognitive decline from age 85 to 90 on the Mini-Mental State Examination (additional annual effect 0.18 [0.07], p = 0.01), the Stroop Test (−1.49 [0.59], p = 0.01), and the Letter Digit Coding Test (0.26 [0.09], p = 0.005). This effect was mainly attributable to glucose, body mass index, and, to a lesser extent, blood pressure. Conclusion: The association between the metabolic syndrome and accelerated cognitive decline, which has been reported in persons up to age 75, is not evident in a population of the oldest old. The concept of the metabolic syndrome may be less valid in this age group.

Heritability estimates of innate immunity: an extended twin study.

Cytokines are key players in numerous inflammatory processes. Demonstration of a heritable component in the variation of cytokine production would indicate that simultaneous occurrence of conditions might be caused by a heritable inflammatory characteristic. We applied an extended twin study approach to assess heritability estimates of interleukin (IL)-1β, IL-1ra, IL-10, IL-6, and TNF-α production capacity after ex vivo stimulation with lipopolysaccharide. Cytokine production capacity was assessed in 42 monozygotic pairs, 52 dizygotic pairs, one trizygotic triplet, 33 single twins, and 83 additional siblings. Heritability estimates were derived from variance decomposition models using maximum likelihood estimation. For all cytokines, over 50% of the variance was genetically determined. IL-1ra and TNF-α had the lowest heritability estimate of 53%. Estimates for IL-6 and IL-10 were 57 and 62%, respectively. IL-1β had the highest estimate of 86%. We conclude that the production of cytokines is under tight genetic control.

Progression of brain atrophy and cognitive decline in diabetes mellitus A 3-year follow-up

Objective: To investigate progression of MRI-assessed manifestations of cerebral degeneration related to cognitive changes in a population of elderly patients with diabetes mellitus (DM) compared to age-matched control subjects. Methods: From a randomized controlled trial (PROSPER study), a study sample of 89 patients with DM and 438 control subjects without DM aged 70–82 years were included for brain MRI scanning and cognitive function testing at baseline and reexamination after 3 years. Changes in brain atrophy, white matter hyperintensities (WMHs), number of infarctions, and cognitive function test results were determined in patients with DM and subjects without DM. Linear regression analysis was performed with correction for age, gender, hypertension, pravastatin treatment, educational level, and baseline test results. In patients with DM, baseline MRI parameters were correlated with change in cognitive function test result using linear regression analysis with covariates age and gender. Results: Patients with DM showed increased progression of brain atrophy (p < 0.01) after follow-up compared to control subjects. No difference in progression of WMH volume or infarctions was found. Patients with DM showed increased decline in cognitive performance on Stroop Test (p = 0.04) and Picture Learning Test (p = 0.03). Furthermore, in patients with DM, change in Picture Learning Test was associated with baseline brain atrophy (p < 0.02). Conclusion: Our data show that elderly patients with DM without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without DM. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity.

Increase in hospital admission rates for heart failure in The Netherlands, 1980-1993.

OBJECTIVE: To study the trend in hospital admission rates for heart failure in the Netherlands from 1980 to 1993. DESIGN: All hospital admissions in the Netherlands with a principal discharge diagnosis of heart failure were analysed. In addition, individual records of heart failure patients from a subset of 7 hospitals were analysed to estimate the frequency and timing of readmissions. RESULTS: The total number of discharges for men increased from 7377 in 1980 to 13 022 in 1993, and for women from 7064 to 12 944. From 1980 through 1993 age adjusted discharge rates rose 48% for men and 40% for women. Age adjusted in-hospital mortality for heart failure decreased from 19% in 1980 to 15% in 1993. For all age groups in-hospital mortality for men was higher than for women. The mean length of hospital admissions in 1993 was 14.0 days for men and 16.4 days for women. A review of individual patient records from a 6.3% sample of all hospital admissions in the Netherlands indicated that within a 2 year period 18% of the heart failure patients were admitted more than once and 5% more than twice. CONCLUSIONS: For both men and women a pronounced increase in age adjusted discharge rates for heart failure was observed in the Netherlands from 1980 to 1993. Readmissions were a prominent feature among heart failure patients. Higher survival rates after acute myocardial infarction and the longer survival of patients with heart disease, including heart failure may have contributed to the observed increase. The importance of advances in diagnostic tools and of possible changes in admission policy remain uncertain.

Use of Aspirin postdiagnosis improves survival for colon cancer patients

Background:The preventive role of non-steroid anti-inflammatory drugs (NSAIDs) and aspirin, in particular, on colorectal cancer is well established. More recently, it has been suggested that aspirin may also have a therapeutic role. Aim of the present observational population-based study was to assess the therapeutic effect on overall survival of aspirin/NSAIDs as adjuvant treatment used after the diagnosis of colorectal cancer patients.Methods:Data concerning prescriptions were obtained from PHARMO record linkage systems and all patients diagnosed with colorectal cancer (1998–2007) were selected from the Eindhoven Cancer Registry (population-based cancer registry). Aspirin/NSAID use was classified as none, prediagnosis and postdiagnosis and only postdiagnosis. Patients were defined as non-user of aspirin/NSAIDs from the date of diagnosis of the colorectal cancer to the date of first use of aspirin or NSAIDs and user from first use to the end of follow-up. Poisson regression was performed with user status as time-varying exposure.Results:In total, 1176 (26%) patients were non-users, 2086 (47%) were prediagnosis and postdiagnosis users and 1219 (27%) were only postdiagnosis users (total n=4481). Compared with non-users, a survival gain was observed for aspirin users; the adjusted rate ratio (RR) was 0.77 (95% confidence interval (CI) 0.63–0.95; P=0.015). Stratified for colon and rectal, the survival gain was only present in colon cancer (adjusted RR 0.65 (95%CI 0.50–0.84; P=0.001)). For frequent users survival gain was larger (adjusted RR 0.61 (95%CI 0.46–0.81; P=0.001). In rectal cancer, aspirin use was not associated with survival (adjusted RR 1.10 (95%CI 0.79–1.54; P=0.6). The NSAIDs use was associated with decreased survival (adjusted RR 1.93 (95%CI 1.70–2.20; P<0.001).Conclusion:Aspirin use initiated or continued after diagnosis of colon cancer is associated with a lower risk of overall mortality. These findings strongly support initiation of a placebo-controlled trial that investigates the role of aspirin as adjuvant treatment in colon cancer patients.

Living with epilepsy: Long-term prognosis and psychosocial outcomes

Objective: To analyze the impact of seizures on everyday life and the long-term effects of epilepsy on health status and psychosocial outcomes. Methods: Follow-up study was conducted of a cohort of consecutive patients newly diagnosed with epilepsy between 1953 and 1967. In 1995 (mean follow-up 34 years), a random sample of 333 patients received a questionnaire asking clinical and demographic information and validated measures for psychosocial outcomes. Comparisons were made with the general Dutch population. Results: The response rate was 73% (116 men and 127 women); mean age was 49.9 years (SD 11.2 years). Mean age at epilepsy onset was 15 years (SD 11 years); mean duration was 24.4 years (SD 13.1 years). In total, 134 (55%; 72 men and 62 women) patients were seizure-free for the previous 5 years, and 81 patients still had seizures in the last year. One hundred twenty-seven patients were taking antiepileptic drugs, of which 51 were on monotherapy. Epilepsy patients have a positive health evaluation, comparable with the general Dutch population. Fewer epilepsy patients married or had children than the general Dutch population; more patients live at home with their parents or in foster homes or institutions (p < 0.001). Having epilepsy at school age has a significant negative effect on learning achievement (p < 0.01). Employment status is affected less, though more epilepsy patients are unfit to work than individuals from the general population (p < 0.05). Conclusions: Epilepsy has a marked negative impact on education and achievement in later life. Despite worse psychosocial outcomes than the Dutch population, patients with epilepsy cope well with their epilepsy, regardless of their handicaps.

Generalized atherosclerosis, cognitive decline, and depressive symptoms in old age

Background: Atherosclerosis may be linked to cognitive decline and depression in old age. Methods: The Leiden 85-Plus Study is a prospective population-based study of 599 subjects from age 85 onward. The generalized atherosclerotic burden was rated by the number of cardiovascular pathologies at baseline, as assessed by history taking from treating physicians and EKG. Cardiovascular pathologies included myocardial infarction, angina pectoris or myocardial ischemia, claudicatio intermittens, and arterial surgery. Global cognitive function (Mini-Mental State Examination), attention (Stroop Test), processing speed (Letter Digit Coding Test), immediate recall memory (Word Learning Test-Immediate Recall), delayed recall memory (Word Learning Test-Delayed Recall), and depressive symptoms (15-item Geriatric Depression Scale) were assessed each year from ages 85 through 90. The prospective associations between both the generalized atherosclerosis rating and stroke with cognitive function and depressive symptoms were analyzed by linear mixed models adjusted for sex and level of education. Results: During follow-up, there was a significant cognitive decline and a significant increase of depressive symptoms. At baseline, a history of stroke was correlated with lower global cognitive function, slower processing speed, impaired immediate and delayed recall memory, and more depressive symptoms. In addition, a higher generalized atherosclerosis rating was correlated with impaired global cognitive function, lower attention, and a slower processing speed at baseline. During follow-up, a higher generalized atherosclerosis rating was associated with an accelerated decline of immediate recall memory and delayed recall memory. In contrast, there was no relation between the generalized atherosclerosis rating and depressive symptoms, either in the cross-sectional analysis or in the prospective analysis. Conclusion: In the population at large, generalized atherosclerosis contributes to cognitive decline in old age but not to depression.