G.J. Blauw

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.

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.

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.

Patients with Alzheimer's disease display a pro-inflammatory phenotype

BACKGROUND Inflammation plays a pivotal role in amyloid plaque progression thereby contributing to Alzheimers disease-related neurodegeneration. We hypothesized that patients with Alzheimers disease have an innate pro-inflammatory phenotype, as compared to control subjects without dementia. METHODS Patients with a diagnosis of probable Alzheimers disease (n=12) and control subjects without signs of dementia (n=18) were enrolled. Whole blood samples were stimulated ex vivo with endotoxin under standard conditions. Cytokine levels were assessed by ELISA and compared by Mann-Whitneyll-test after log transformation. RESULTS Patients with Alzheimers disease had seven- to ten-fold higher IL-1beta production relative to the amount of IL-10 both at the low (p=0.006) and high concentration of endotoxin (p=0.007). Subjects who display a pro-inflammatory phenotype as defined by a high IL-1beta/IL-10 ratio had 13.0-fold higher odds (95% CI: 2.1-82) to have dementia. CONCLUSION The data support the hypothesis that a pro-inflammatory phenotype contributes to the development of Alzheimers disease.

Association between apolipoprotein E4 and cognitive decline in elderly adults

OBJECTIVE: To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women.

Effect of pravastatin on cerebral infarcts and white matter lesions

The authors examined the effect of pravastatin 40 mg daily on the progression of ischemic brain lesions using repeated brain MRI. After a mean treatment period of 33 months, there was an increase in total ischemic lesion load of 1.1 cm3 (p < 0.001) in the 270 placebo-treated subjects and 1.1 cm3 (p < 0.001) in the 265 pravastatin-treated subjects. There was no difference between the two treatment groups (p = 0.73).

Favorable Glucose Tolerance and Lower Prevalence of Metabolic Syndrome in Offspring without Diabetes Mellitus of Nonagenarian Siblings: The Leiden Longevity Study

OBJECTIVES: To explore measures of metabolic syndrome and glucose metabolism in families with exceptional longevity.

Interaction of atherosclerosis and inflammation in elderly subjects with poor cognitive function

Objective: To test the hypothesis that a pro-inflammatory response is associated with cognitive impairment among individuals with cardiovascular disease. Method: All 85-year-old inhabitants of Leiden (n = 599) were visited at their place of residence. A history of cardiovascular disease and an EKG were used as indicators of atherosclerosis. Production of the pro-inflammatory cytokine tumor necrosis factor-α and the anti-inflammatory cytokine interleukin-10 was assessed in a whole-blood assay using lipopolysaccharide as a stimulus. Global cognitive functioning was determined with the Mini-Mental State Examination (MMSE); attention, cognitive speed, and memory were determined with four neuropsychological tests; and a history of dementia was obtained. Results: In subjects with cardiovascular disease, median MMSE scores were lower in those with a pro-inflammatory response when compared with those with an anti-inflammatory response (p = 0.02). Similar associations were found for the Stroop Test, measuring attention (p < 0.01), the Coding Test measuring cognitive speed (p = 0.02), the Word Learning Test measuring memory (p < 0.01), and the presence of dementia (p = 0.04). The associations remained unaltered after adjustments for possible confounders such as gender, level of education, use of nonsteroidal anti-inflammatory drugs, use of cardiovascular drugs, and cardiovascular risk factors. In contrast, outcomes of the cognitive tests and presence of dementia were not dependent on the inflammatory response when cardiovascular disease was absent. Conclusion: The combination of cardiovascular disease and a pro-inflammatory cytokine response may be associated with cognitive impairment and dementia.

Different progression rates for deep white matter hyperintensities in elderly men and women

The authors investigated the progression of white matter hyperintensities (WMHs) in a large population of elderly men and women. After 3 years of follow-up, women had accumulated approximately twice as much deep WMH (DWMH) as men. The progression of periventricular WMH was the same for men and women. Gender differences may affect the pathogenesis of DWMH, which in turn may result in different clinical consequences in women.

Atherosclerosis and cognitive impairment are linked in the elderly. The Leiden 85-plus Study

Post-mortem analyses suggest that atherosclerosis more often contributes to late-onset dementia than hitherto expected. We set out to further unravel the relation between atherosclerosis and cognitive impairment. We therefore tested the hypothesis that the number of cardiovascular pathologies is positively associated with cognitive impairment in elderly subjects, and that the smaller number of cardiovascular pathologies in women explains the better cognitive function of elderly women. Within the Leiden 85-plus Study, we assessed the atherosclerotic burden by counting the number of cardiovascular pathologies in the medical histories of a population-based sample of 599 subjects aged 85 years (response 87%). Significantly more men than women had a history of cardiovascular pathologies (67% compared to 59%, P<0.001). In addition, cognitive function was assessed. All subjects completed the Mini-Mental State Examination (MMSE). Cognitive speed and memory were determined with specific neuro-psychological tests in those with a MMSE-score above 18 points. There was a highly significant dose-response relationship between the number of cardiovascular pathologies and cognitive impairment for both men and women. The median MMSE-score was 26 points in subjects without cardiovascular disease and decreased to 25 points for subjects who had two or more cardiovascular pathologies (P for trend =0.003). Similar associations were found for cognitive speed but not for memory. Our data confirm that in old age atherosclerosis significantly contributes to cognitive impairment. Since treatments for atherosclerosis appear to be particularly effective in elderly people, we consider our finding of utmost clinical importance in possibly preventing cognitive impairment and late-onset dementia.