J. J. Claus

Cerebral white matter lesions, vascular risk factors, and cognitive function in a population‐based study The Rotterdam Study

Cerebral white matter lesions are a common finding on MRI in elderly persons. We studied the prevalence of white matter lesions and their relation with classic cardiovascular risk factors, thrombogenic factors, and cognitive function in an age- and gender-stratified random sample from the general population that consisted of 111 subjects 65 to 84 years of age. Overall, 27% of subjects had white matter lesions. The prevalence and severity of lesions increased with age. A history of stroke or myocardial infarction, factor VIIc activity, and fibrinogen level were each significantly and independently associated with the presence of white matter lesions. Significant relations with blood pressure level, hypertension, and plasma cholesterol were present only for subjects aged 65 to 74 years. White matter lesions tended to be associated with lower scores on tests of cognitive function and were significantly associated with subjective mental decline. This study suggests that classic cardiovascular risk factors, as well as thrombogenic factors, are associated with white matter lesions in subjects over 65 years of age in the general population, and that these lesions may be related to cognitive function.

Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study

Abstract Objective: To estimate the prevalence of dementia and its subtypes in the general population and examine the relation of the disease to education. Design: Population based cross sectional study. Setting: Ommoord, a suburb of Rotterdam. Subjects: 7528 participants of the Rotterdam study aged 55-106 years. Results: 474 cases of dementia were detected, giving an overall prevalence of 6.3%. Prevalence ranged from 0.4% (5/1181 subjects) at age 55-59 years to 43.2% (19/44) at 95 years and over. Alzheimers disease was the main subdiagnosis (339 cases; 72%); it was also the main cause of the pronounced increase in dementia with age. The relative proportion of vascular dementia (76 cases; 16%), Parkinsons disease dementia (30; 6%), and other dementias (24; 5%) decreased with age. A substantially higher prevalence of dementia was found in subjects with a low level of education. The association with education was not due to confounding by cardiovascular disease. Conclusions: The prevalence of dementia increases exponentially with age. About one third of the population aged 85 and over has dementia. Three quarters of all dementia is due to Alzheimers disease. In this study an inverse dose-response relation was found between education and dementia—in particular, Alzheimers disease. Key messages Key messages Of all cases of dementia, 72% were cases of Alzheimers disease The pronounced increase in prevalence of dementia with age was due to a substantial increase in Alzheimers disease Alzheimers disease was more often diagnosed in less educated people The association between dementia and education could not be explained by cardiovascular disease comorbidity

Cardiovascular disease and distribution of cognitive function in elderly people: the Rotterdam study

abstract Objective: To investigate the distribution of cognitive function in elderly people and to assess the impact of clinical manifestations of atherosclerotic disease on this distribution. Design: Single centre population based cross sectional door to door study. Setting: Ommoord, a suburb of Torrerdam, the Netherlands. Subjects: 4971 subjects aged 55 to 94 years. Main outcome measure: Cognitive function as measured by the mini mental state examination. Results: The overall participation rate in the study was 80%. Cognitive test data were available for 90% of the participants. Increasing age and lower educational level were associated with poorer cognitive function. Previous vascular events, presence of plaques in the carotid arteries, and presence of peripheral arterial atherosclerotic disease were associated with worse cognitive performance independent of the effects of age and education. On average the differences were moderate; however, they reflected the net result of a shift of the total population distribution of cognitive function towards lower values. Thereby, they resulted in a considerable increase in the proportion of subjects with scores indicative of dementia. Conclusions: These findings are compatible with the view that atherosclerotic disease accounts for considerable cognitive impairment in the general population.

Cognitive correlates of ventricular enlargement and cerebral white matter lesions on magnetic resonance imaging. The Rotterdam Study.

Background and Purpose Ventricular enlargement and white matter lesions are frequent findings on cerebral magnetic resonance imaging scans of elderly subjects. In demented subjects they seem related to the severity of the dementia, but in nondemented subjects their clinical significance is less clear. We investigated the relation of size of the lateral ventricles and white matter lesions with cognitive function in a population-based random sample of nondemented elderly persons. Methods The study population consisted of 90 subjects, aged 65 to 84 years, who were randomly selected from the cohort of the Rotterdam Study, and who were not demented. The presence of white matter lesions and the ventricle-to-brain ratio were assessed on magnetic resonance scans. Participants were tested with a neuropsychological battery that covered a broad range of cognitive functions. Results Ventricular enlargement and white matter lesions were both and independently associated with poorer performance on all tests. After adjustment for age and sex, ventricular enlargement was significantly associated with worse scores on tests assessing global cognitive function (Mini-Mental State Examination, P=.02; Groninger Intelligence Test, P=.01), memory (Word List Learning delayed recall, P = .03), and executive control functions (Stroop part II, P=.02; Trail Making Test B, P<.01); for white matter lesions the differences were significant for tests measuring executive control functions and mental speed (Trail Making Test A and B, P=.01 and P<.01, respectively; verbal fluency, P=.01), and memory (Word List Learning delayed recall, P=.04). Conclusions This study suggests that white matter lesions are primarily related to impairment of subcorticofrontal functions, whereas enlargement of the lateral ventricles is associated with disturbances of cortical functions as well.

The diagnostic value of SPECT with Tc 99m HMPAO in Alzheimer's disease: A population‐based study

We studied the diagnostic accuracy of single-photon emission computed tomography (SPECT) with technetium 99m-labeled hexamethylpropylene amine oxime (Tc 99m HMPAO) in 48 patients with probable Alzheimers disease (AD) according to NINCDS-ADRDA criteria and in 60 controls recruited from a population-based study. With logistic regression, we identified decreased temporal regional cerebral blood flow as the best discriminating variable between patients and controls. Receiver-operator characteristic curves showed that the discriminative ability of SPECT improved with increasing dementia severity. With specificity set at 90%, sensitivity figures were 42% in mild, 56% in moderate, and 79% in severe AD. The diagnostic gain as a function of the prior probability of the disease being present was computed for those with mild AD. When the prior probability varied at around 50%, the diagnostic gain for mild AD patients was substantial (a maximum of 34%) for a positive test result but poor for a negative test result. The results suggest that the practical usefulness of SPECT as a diagnostic adjunct in patients suspected of having mild AD is confined to situations in which, on clinical grounds, there is considerable diagnostic doubt.

Regional Cerebral Blood Flow and Cerebrovascular Risk Factors in the Elderly Population

Regional cerebral blood flow (rCBF) was studied in 60 elderly persons (aged 65 to 84 years) recruited from a population-based study, with single photon emission computed tomography using technetium 99m-labeled hexamethylpropylene amine oxime. We investigated whether it is only age that affects rCBF or whether other factors can be indentified that explain this relationship. Using multiple linear regression analysis, increasing age was significantly associated with rCBF decrease in parietal, temporo-parietal, and temporal cortex, but not in frontal cortex. Adjustment with several risk factors for cerebrovascular disease, including hypertension, history of myocardial infarction, factor VIIc, factor VIIIc, cholesterol and HDL cholesterol, smoking, and diabetes mellitus had no influence on these relations. Conversely, the association between age and rCBF was no longer statistically significant after adjustment with fibrinogen and indicators of carotid atherosclerosis, including intima-media wall thickness of the carotid artery and plaques in the carotid artery. Correction with local ratings of cortical atrophy did not affect the relations between age and rCBF. The results suggest that in the elderly population rCBF declines with age in posterior cortical areas and that these changes may well be explained by the presence of atherosclerosis. Reduced contractility of the vascular muscle wall with increasing age resulting from atherosclerosis may be the underlying mechanism.

Vascular risk factors, atherosclerosis, cerebral white matter lesions and cerebral perfusion in a population-based study

We studied risk factors for cerebral vascular disease (blood pressure and hypertension, factor VIIc, factor VIIIc, fibrinogen), indicators of atherosclerosis (intima-media thickness and plaques in the carotid artery) and cerebral white matter lesions in relation to regional cerebral blood flow (rCBF) in 60 persons (aged 65–85 years) recruited from a population-based study. rCBF was assessed with single-photon emission tomography using technetium-99md,l-hexamethylpropylene amine oxime (99mTc-HMPAO). Statistical analysis was performed with multiple linear regression with adjustment for age, sex and ventricle-to-brain ratio. A significant positive association was found between systolic and diastolic blood pressure and temporo-parietal rCBF. In analysis with quartiles of the distribution, we found a threshold effect for the relation of low diastolic blood pressure (≤60 mmHg) and low temporo-parietal rCBF. Levels of plasma fibrinogen were inversely related to parietal rCBF, with a threshold effect of high fibrinogen levels (>3.2 g/1) and low rCBF. Increased atherosclerosis was related to low rCBF in all cortical regions, but these associations were not significant. No consistent relation was observed between severity of cerebral white matter lesions and rCBF. Our results may have implications for blood pressure control in the elderly population.

Assessment of cerebral perfusion with single-photon emission tomography in normal subjects and in patients with Alzheimer's disease: effects of region of interest selection

The shape, size and location of regions of interest (ROls) show considerable variability between single-photon emission tomography (SPET) studies in aging and Alzheimers disease, but the possible influence on study results remains unknown. We compared three different ROIs in a SPET study with 60 controls and in 48 patients with probable Alzheimers disease diagnosed according to the NINCDS-ADRDA criteria. Regional cerebral blood flow (rCBF) was assessed with SPET using technetium-99m d,l-hexamethylpropylene amine oxime (99mTc-HMPAO), normalized to the mean activity in a cerebellar reference slice. The three different ROIs were: a multi-slice and a single-slice ROI with reference to the normal brain anatomy (using an anatomical atlas), and a rectangular (2×4 pixels) ROI in the frontal, temporal, temporoparietal and occipital cortices. No differences were observed for the means of rCBF values between the single-slice and multi-slice ROIs with reference to the normal anatomy, but some variability was present for individual comparisons. In contrast, significantly higher mean rCBF values were obtained with the single-slice rectangular ROls in all four regions for both patients and controls and considerable variability was shown for individual subjects. After analysis with multivariate logistic regression and receiver operator characteristic curves, the ability of SPET to discriminate between controls and Alzheimer patients was similar in the three methods for mild and moderate Alzheimer patients (Global Deterioration Scale = GDS of 3 and 4). However, with increasing dementia severity (GDS>4) the rectangular ROIs showed lower ability to discriminate between groups compared to the singleslice and multi-slice anatomically defined ROIs. This study suggests that results of rCBF assessment with SPET using 99mTc-HMPAO in patients with severe Alzheimers disease are influenced by the shape and size of the ROI.