Annemieke Ruitenberg

Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam study

Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimers disease. It is being debated whether this reflects diminished demand because of advanced neurodegeneration or that cerebral hypoperfusion contributes to dementia. We examined the relation of CBF velocity as measured with transcranial Doppler with dementia and markers of incipient dementia (ie, cognitive decline and hippocampal and amygdalar atrophy on magnetic resonance imaging) in 1,730 participants of the Rotterdam Study aged 55 years and older. Cognitive decline in the 6.5 years preceding CBF velocity measurement was assessed with repeated Mini‐Mental State Examinations in nondemented subjects (n = 1,716). Hippocampal and amygdalar volumes were assessed in a subset of 170 nondemented subjects. Subjects with greater CBF velocity were less likely to have dementia. Furthermore, in nondemented subjects, greater CBF velocity was related to significantly less cognitive decline over the preceding period (odds ratio per standard deviation increase in mean CBF 0.74 [95% confidence interval, 0.58–0.98]) and larger hippocampal and amygdalar volumes. A low CBF is associated with dementia, but also with markers of incipient dementia. Although we cannot exclude that this is caused by preclinical neurodegeneration leading to hypoperfusion, it does suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia. Ann Neurol 2005;57:789–794

Alcohol consumption and risk of dementia: the Rotterdam Study

BACKGROUND Light-to-moderate alcohol consumption reduces the risk of coronary heart disease and stroke. Because vascular disease is associated with cognitive impairment and dementia, we hypothesised that alcohol consumption might also affect the risk of dementia. METHODS We examined the relation between alcohol consumption and risk of dementia in individuals taking part in the Rotterdam Study--a prospective population-based study of 7983 individuals aged 55 years and older. We studied all participants who did not have dementia at baseline (1990-93) and who had complete data on alcohol consumption (n=5395). Through follow-up examinations in 1993-94 and 1997-99 and an extensive monitoring system, we obtained nearly complete follow-up (99.7%) until the end of 1999. We used proportional hazards regression analysis, adjusted for age, sex, systolic blood pressure, education, smoking, and body-mass index, to compare the risk of developing dementia between individuals who regularly consumed alcohol and individuals who did not consume alcohol. FINDINGS The average follow-up was 6.0 years. During this period, 197 individuals developed dementia (146 Alzheimers disease, 29 vascular dementia, 22 other dementia). The median alcohol consumption was 0.29 drinks per day. Light-to-moderate drinking (one to three drinks per day) was significantly associated with a lower risk of any dementia (hazard ratio 0.58 [95% CI 0.38-0.90]) and vascular dementia (hazard ratio 0.29 [0.09-0.93]). We found no evidence that the relation between alcohol and dementia varied by type of alcoholic beverage. INTERPRETATION These findings suggest that light-to-moderate alcohol consumption is associated with a reduced risk of dementia in individuals aged 55 years or older. The effect seems to be unchanged by the source of alcohol.

Diet and risk of dementia: Does fat matter?: The Rotterdam Study

Objective: To examine whether high intake of total fat, saturated fatty acids (saturated fat), trans fatty acids (trans fat), and cholesterol and low intake of monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), n-6 PUFA, and n-3 PUFA are associated with increased risk of dementia and its subtypes. Method: Data from the Rotterdam Study, a prospective cohort study among elderly, were used. At baseline (1990 to 1993), 5,395 subjects had normal cognition, were noninstitutionalized, and underwent complete dietary assessment by a semiquantitative food-frequency questionnaire. The cohort was continuously monitored for incident dementia, and re-examinations were performed in 1993 to 1994 and 1997 to 1999. The association between fat intake and incident dementia was examined by Cox’s proportional hazards models. Results: After a mean follow-up of 6.0 years, 197 subjects developed dementia (146 AD, 29 vascular dementia). High intake of total, saturated, trans fat, and cholesterol and low intake of MUFA, PUFA, n-6 PUFA, and n-3 PUFA were not associated with increased risk of dementia or its subtypes. Rate ratios of dementia per standard deviation increase in intake were for total fat 0.93 (95% CI 0.81 to 1.07), for saturated fat 0.91 (95% CI 0.79 to 1.05), for trans fat 0.90 (95% CI 0.77 to 1.06), for cholesterol 0.93 (95% CI 0.80 to 1.08), for MUFA 0.96 (95% CI 0.84 to 1.10), for PUFA 1.05 (95% CI 0.80 to 1.38), for n-6 PUFA 1.03 (95% CI 0.77 to 1.36), and for n-3 PUFA 1.07 (95% CI 0.94 to 1.22). Conclusion: High intake of total, saturated, and trans fat and cholesterol and low intake of MUFA, PUFA, n-6 PUFA, and n-3 PUFA were not associated with increased risk of dementia or its subtypes.

Incidence of dementia: Does gender make a difference?

Several studies suggested that women are at higher risk of dementia than men. However, that was based on rather limited data. We investigated possible gender differences in the incidence of dementia, Alzheimers disease and vascular dementia, in the Rotterdam Study, a large population based prospective cohort study in the Netherlands of 7,046 persons aged 55 years and older, free of dementia at baseline. In 40,441 person-years of follow-up (mean 5.7 years) we identified 395 new cases of dementia (overall incidence: 9.8 per 1,000 person-years). Alzheimers disease was the most frequent subtype of dementia (293 cases; 7.2 per 1,000). Vascular dementia was diagnosed in 57 participants (1.5 per 1,000). Overall, dementia incidence was similar for men and women (rate ratio women versus men: 1.00, 95% CI: 0.80-1.24). However, after 90 years of age dementia incidence declined in men but not in women (rate ratio 2.61, 95% CI: 1.04-6.56), in particular for Alzheimers disease (rate ratio 5.79, 95% CI: 1.40-23.90). The overall incidence of vascular dementia was lower in women than in men (rate ratio 0.57, 95% CI: 0.34-0.97). This large population-based study suggests no gender differences in the incidence of dementia up to high age. After 90 years of age the incidence of Alzheimers disease is higher for women than for men. The incidence of vascular dementia is higher for men than for women in all age groups.

Antihypertensive drugs and incidence of dementia: the Rotterdam Study

There is increasing evidence that hypertension may contribute to the development of dementia. We investigated the relation of antihypertensive drug use and the risk of dementia in the cohort of the population based Rotterdam Study. The study cohort included 7046 elderly, free of dementia at baseline. Dementia was diagnosed in a stepwise procedure. Participants were first screened. Screen positives were further tested. Those suspected of dementia underwent a diagnostic work-up. Dementia and its subtypes were diagnosed according to prevailing criteria. A Cox proportional hazards model was used to estimate relative risks. After a mean follow-up of 2.2 years, subjects taking antihypertensive medication at baseline (n = 2015) had a reduced incidence of dementia (adjusted relative risk, 0.76; 95% confidence interval 0.52-1.12). This risk reduction was most pronounced for vascular dementia, (adjusted relative risk, 0.30; 95% confidence interval 0.11-0.99). For Alzheimers disease the relative risk was 0.87, not significant. Dementia may be prevented by antihypertensive treatment. In order to confirm any relation in Alzheimers disease larger observational studies with longer follow-up are needed.

Blood Pressure and Risk of Dementia: Results from the Rotterdam Study and the Gothenburg H-70 Study

The association between blood pressure and dementia is debated. Results from population-based studies on blood pressure and dementia are inconclusive, and most are performed in subjects younger than 80 years of age. We examined the relation between blood pressure and dementia and the possible effect modification of this relation by age in a pooled dataset based on two prospective population-based studies. Subjects came from the Rotterdam study (n = 6,668), a longitudinal population-based study among subjects aged 55 years and over, and from the Gothenburg H-70 Study (n = 317), a study on subjects aged 85 years at baseline. Screening and diagnostic procedures for assessment of dementia were similar at baseline and follow-up and comparable between studies. We estimated relative risks of dementia using Cox proportional hazards regression analysis, adjusted for age, gender and study location. The average follow-up was 2.1 years. During this period, 196 subjects developed dementia. The risk of dementia decreased with increasing blood pressure level (per 10 mm Hg systolic blood pressure: RR = 0.93, 95% CI = 0.88–0.99; per 10 mm Hg diastolic blood pressure: RR = 0.89, 95% CI = 0.79–1.00). This association was confined to subjects who used anthypertensive medication. Persons who were demented at baseline had a stronger blood pressure decline during follow-up than those who were non-demented. This study suggests an inverse association between blood pressure and dementia risk in elderly persons on antihypertensive medication. Possibly, they may need higher blood pressure levels to maintain an adequate cerebral perfusion. Alternatively, lower blood pressure may be secondary to brain lesions in preclinical stages of dementia.

Endogenous estradiol and risk of dementia in women and men: The Rotterdam Study

We determined whether higher endogenous estradiol levels were associated with lower risk of dementia in older men and women not using hormonal replacement therapy, using a case‐cohort design within the Rotterdam Study, a population‐based follow‐up study on chronic diseases, including dementia, in 7,983 subjects aged 55 years or older, and ongoing since 1990. The analyses were based on a random subcohort of 508 women and 438 men, and on 76 women and 53 men with incident dementia. Cox proportional hazards models with robustly estimated standard errors showed that in women higher levels of total estradiol were associated with higher risk of dementia (age‐adjusted hazard ratio per standard deviation increase 1.38; 95% CI 1.04–1.84). Age‐adjusted HRs of Alzheimers disease and vascular dementia associated with higher levels of total estradiol (per SD increase) were 1.24 (95% CI 0.87–1.76) and 2.19 (95% CI 1.22–3.92), respectively. Similar results were observed for bioavailable estradiol. Additional adjustments for potential confounders did not change the results substantially. In men, no clear association was observed between estradiol levels and risk of dementia or its subtypes. The findings do not support the hypothesis that higher levels of endogenous estradiol reduce risk of dementia, neither in women nor in men. Ann Neurol 2003

Plasma Levels of Antioxidants Are Not Associated with Alzheimer’s Disease or Cognitive Decline

Antioxidants prevent oxidative stress that possibly causes neuronal loss in Alzheimer’s disease (AD). We examined whether high plasma levels of the antioxidant vitamins A and E were associated with lower prevalence of AD or cognitive decline (CD). We performed a cross-sectional study within the Rotterdam Study. In an univariate model, higher levels of vitamins A and E were significantly associated with lower prevalence of AD. However, when additional adjustments were made for important confounders, such as age, gender and total cholesterol, the relation substantially weakened – odds ratios per standard deviation increase were 0.87 (95% CI 0.64–1.19) for vitamin A and 0.94 (95% CI 0.60–1.48) for vitamin E. Antioxidants were not related to CD in non-demented subjects. Our findings suggest no association between plasma levels of vitamin A and E and AD or CD.

Prognosis of Alzheimer’s Disease: The Rotterdam Study

The aim of this study was to construct a prognostic model to predict the progression of Alzheimer’s disease (AD). Prevalent and incident cases with AD came from the Rotterdam Study, a population-based prospective cohort study of persons aged 55 years and older, including those living in institutions. Rate of cognitive decline, as measured by the Mini Mental State Examination (MMSE score), was predicted by a random effects model. Risk of institutionalization and death were estimated with polytomous logistic regression analysis. At baseline, 306 subjects were diagnosed with prevalent AD and had complete data on living conditions and cognitive function. After a mean follow-up of 2.1 years, 95 subjects with incident AD had been diagnosed. Prevalent patients showed a slower decline in cognitive function than incident patients (p = 0.004). For prevalent and incident AD patients, high age and low cognitive performance were the strongest predictors for institutionalization and death. These prognostic risk functions can provide information on the decline of Alzheimer patients and might be used to better evaluate the effect of treatments for AD.

The electrophysiological muscle scan.

This study aims to assess the potential of the electrophysiological muscle scan or stimulus–response curve as a diagnostic instrument. If stimulus intensity is gradually increased from subthreshold to supramaximal values, all motor units in a muscle are successively activated. Thus, by plotting response size versus stimulus intensity, an impression (scan) of the entire muscle can be obtained. We recorded 54 detailed scans from 34 patients and 11 healthy subjects, and analyzed them visually and quantitatively. The scan summarized much diagnostic information in a single picture. Specific patterns in or properties of the scan (steps, maximum, variability, decrements, stimulus intensities used) provide clinically relevant information regarding motor unit number, size, and stability, and neuromuscular transmission and axonal excitability. The scan can be recorded noninvasively in about 5 minutes and is fairly easy to interpret. Because it is built up from contributions of all functioning motor units, the scan shows if and how many large motor units are present. There is no sample bias. For these reasons, further exploration and exploitation of this tool in the clinical setting are warranted. Muscle Nerve, 2007