R.G.J. Westendorp

Strongly reduced volumes of putamen and thalamus in Alzheimer's disease: an MRI study

Atrophy is regarded a sensitive marker of neurodegenerative pathology. In addition to confirming the well-known presence of decreased global grey matter and hippocampal volumes in Alzheimers disease, this study investigated whether deep grey matter structure also suffer degeneration in Alzheimers disease, and whether such degeneration is associated with cognitive deterioration. In this cross-sectional correlation study, two groups were compared on volumes of seven subcortical regions: 70 memory complainers (MCs) and 69 subjects diagnosed with probable Alzheimers disease. Using 3T 3D T1 MR images, volumes of nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus were automatically calculated by the FMRIBs Integrated Registration and Segmentation Tool (FIRST)—algorithm FMRIBs Software Library (FSL). Subsequently, the volumes of the different regions were correlated with cognitive test results. In addition to finding the expected association between hippocampal atrophy and cognitive decline in Alzheimers disease, volumes of putamen and thalamus were significantly reduced in patients diagnosed with probable Alzheimers disease. We also found that the decrease in volume correlated linearly with impaired global cognitive performance. These findings strongly suggest that, beside neo-cortical atrophy, deep grey matter structures in Alzheimers disease suffer atrophy as well and that degenerative processes in the putamen and thalamus, like the hippocampus, may contribute to cognitive decline in Alzheimers disease.

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.

In a population-based prospective study, no association between high blood pressure and mortality after age 85 years.

Objective To study the impact of a history of hypertension and current blood pressure on mortality in the oldest old. Design An observational population-based cohort study. Setting Community city of Leiden, The Netherlands. Participants Five hundred and ninety-nine inhabitants of the birth-cohort 1912–1914 were enrolled on their 85th birthday. There were no selection criteria related to health or demographic characteristics. Interventions The mean follow-up was 4.2 years. Medical histories were obtained from general practitioners. Medication histories were obtained from the participants pharmacist. Blood pressure was measured twice at baseline. Main outcome measures All cause and cardiovascular mortality. Results Five hundred and seventy-one participants were included, 39.2% had a history of hypertension. During follow-up 290 participants died, 119 due to cardiovascular causes. Compared to participants without a history of hypertension, those with a history of hypertension had increased mortality from cardiovascular causes [relative risk (RR) 1.60, confidence interval (CI) 1.06–2.40] but equal mortality from all causes (RR 1.19, CI 0.91–1.55). High blood pressure at baseline (age 85) was not a risk factor for mortality. Baseline blood pressure values below 140/70 mmHg (n = 48) were associated with excess mortality, predominantly in participants with a history of hypertension. Conclusion In the oldest old, high blood pressure is not a risk factor for mortality, irrespective of a history of hypertension. Blood pressure values below 140/70 mmHg are associated with excess mortality.

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.

Prevalence, correlates and recognition of depression in the oldest old: the Leiden 85-plus study

BACKGROUND Various studies support the notion that the clinical picture of depression in the oldest old differs from that in younger elderly. Moreover, withstanding the serious negative effects of depression on well being and functioning, the detection rate of depression in several medical settings is low. METHODS Prevalence of depression, correlates and the rate of recognition by general practitioners were assessed in an 85-year-old community-based population. The GDS-S was applied in 500 participants with a MMSE >18, from a representative sample of 599 community based 85-year-old subjects. Demographic data, daily functioning, health correlates, use of medication and recognition of depression were recorded in home visits and from the general practitioner and pharmacists registers. RESULTS The prevalence of depression, as measured with a GDS-S score of 5 points or more, was 15.4%, which is comparable to previous studies. No demographic factors were correlated with depression. Perceived health, loneliness, impaired mobility, cognitive decline and functional disability were major correlates of depression. From the participants who were seen by their general practitioner, 25% were recognised as depressed. Antidepressive pharmacotherapy was almost nonexistent. LIMITATIONS Formal diagnosis of depression was not available. The data were collected cross-sectionally. CONCLUSIONS Depression is highly prevalent in the oldest old and strongly associated with functional disability and cognitive impairment. It is important to enhance recognition of depression in community based oldest old as a first step to possible interventions.

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.

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.