F. van Harskamp

Diabetes mellitus and the risk of dementia The Rotterdam Study

Objective: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. Background: Both dementia and diabetes are frequent disorders in elderly people. Methods: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. Results: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). Conclusion: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.

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

Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study

BACKGROUND Previous studies suggested a protective effect of smoking on Alzheimers disease, but most were case-control studies based on prevalent cases. The findings of prospective studies on the association between smoking and the risk of dementia are inconclusive. METHODS We did a population-based follow-up study of elderly people who were initially free of dementia. 6870 people aged 55 years and older agreed to take part. Smoking history was taken at baseline and participants were classified as never smokers, former smokers, and current smokers. During follow-up, we recorded all incident cases of dementia. We used never smokers as the reference category to calculate relative risks of dementia and Alzheimers disease by Cox proportional hazards regression, after adjustment for age, sex, education, and alcohol intake. We also examined modification of risk by age, sex, and the apolipoprotein E (APOE) genotype. FINDINGS During mean follow-up of 2.1 (range 1.5-3.4) years, 146 incident cases of dementia were detected, of which 105 were Alzheimers disease. Compared with never smokers, smokers had an increased risk of dementia (relative risk 2.2 [95% CI 1.3-3.6]) and Alzheimers disease (2.3 [1.3-4.1]). Smoking was a strong risk factor for Alzheimers disease in individuals without the APOEepsilon4 allele (4.6 [1.5-14.2]), but had no effect in participants with this allele (0.6 [0.1-4.8]). INTERPRETATION Smoking was associated with a doubling of the risk of dementia and Alzheimers disease. Our finding that carriers of the APOEepsilon4 had no increased risk of dementia suggests an interaction between smoking and the APOEepsilon4 genotype in the aetiology of Alzheimers disease.

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.

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation

Abstract Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer’s disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala→Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Aβ amyloid protein. Numerous senile plaques consisted of large Aβ amyloid cores, often measuring more than 30 μm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D.

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.

Education and the incidence of dementia in a large population-based study: The Rotterdam Study

Article abstract We assessed the risk of dementia by educational level in a prospective population-based study. In the Rotterdam Study, 6,827 nondemented participants with known education level were followed for an average of 2.1 years. During this period, 137 new cases of dementia occurred. Low education was associated with higher dementia risk in women but not in men, suggesting that the association is modified by sex. Our data indicate that cross-sectional studies may overrate the association between education and risk of dementia.

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.

Abnormal amino acid metabolism in patients with early stage Alzheimer dementia

Summary. Plasma levels of several amino acids were studied in 14 patients with early stage probable Alzheimers disease (AD) and 17 age-matched controls. In the AD patients a possible relationship between amino acid levels and behavioural symptomatology was also investigated. We found significantly reduced levels of tryptophan and methionine in plasma samples from the AD patients compared to the control subjects. Moreover, plasma tyrosine/large neutral amino acids (LNAA) ratio and the ratio of plasma taurine and the product of the plasma levels of methionine and serine (TSM-ratio) were significantly increased in the AD patients in comparison with the controls. However, no difference was found in plasma tryptophan/LNAA ratio and in homocysteine levels between both groups. Concerning the behavioural symptomatology no significant correlation was found between the Reisberg Behave AD scale and plasma amino acid levels or ratios. The reported findings suggest that abnormal amino acid metabolism is present in the early stages of AD. We hypothesize that this abnormality could play a role in the pathogenesis of behavioural changes occurring in later stages of AD.