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Tryptophan and tyrosine metabolism has a major effect on human health, and disorders have been associated with the development of several pathologies. Recently, gut microbial metabolism was found to be important for maintaining correct physiology. Here, we describe the development and validation of a UHPLC-ESI-MS/MS method for targeted quantification of 39 metabolites related to tryptophan and tyrosine metabolism, branched chain amino acids and gut-derived metabolites in human plasma and urine. Extraction from plasma was optimised using 96-well plates, shown to be effective in removing phospholipids. Urine was filtered and diluted ten-fold. Metabolites were separated with reverse phase chromatography and detected using triple quadrupole MS. Linear ranges (from ppb to ppm) and correlation coefficients (r2 &gt, 0.990) were established for both matrices independently and the method was shown to be linear for all tested metabolites. At medium spiked concentration, recovery was over 80% in both matrices, while analytical precision was excellent (CV &lt, 15%). Matrix effects were minimal and retention time stability was excellent. The applicability of the methods was tested on biological samples, and metabolite concentrations were found to be in agreement with available data. The method allows the analysis of up to 96 samples per day and was demonstrated to be stable for up to three weeks from acquisition.

The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995-1996, we measured blood pressure and performed MRI in 1077 nondemented elderly (age 60-90 years). For 513 of these, we had information on a blood pressure level 20 years before. The degree of cortical atrophy was semi-quantitatively scored (range 0-15). In late life, a high (greater than or equal to 90 mmHg) and low (

White matter lesions are frequently found on cerebral MRI scans of elderly people and are thought to be important in the pathogenesis of dementia. Hypertension has been associated with the presence of white matter lesions but this has been investigated almost exclusively in cross-sectional studies. We studied prospectively the association of these lesions with the duration and treatment of hypertension. We randomly sampled 1077 subjects aged between 60 and 90 years from two prospective population-based studies. One-half of the study subjects had their blood pressure measured between 1975 and 1978 and the other half between 1990 and 1993. All subjects underwent 1.5 T MRI scanning; white matter lesions in the subcortical and periventricular regions were rated separately. Subjects with hypertension had increased rates of both types of white matter lesion. Duration of hypertension was associated with both periventricular and subcortical white matter lesions. This relationship was influenced strongly by age. For participants with >20 years of hypertension and aged between 60 and 70 years at the time of follow-up, the relative risks for subcortical and periventricular white matter lesions were 24.3 [95% confidence interval (CI) 5.1-114.8] and 15.8 (95% CI 3.4-73.5), respectively, compared with normotensive subjects. Subjects with successfully treated hypertension had only moderately increased rates of subcortical white matter lesions and periventricular white matter lesions (relative risk 3.3, 95% CI 1.3-8.4 and 2.6, 95% CI 1.0-6.8, respectively) compared with normotensive subjects. For poorly controlled hypertensives, these relative risks were 8.4 (95% CI 3.1-22.6) and 5.8 (95% CI 2.1-16.0), respectively. In conclusion, we found a relationship between long-standing hypertension and the presence of white matter lesions. Our findings are consistent with the view that effective treatment may reduce the rates of both types of white matter lesion. Adequate treatment of hypertension may therefore prevent white matter lesions and the associated cognitive decline.

Background and Purpose-Coronary calcification as detected by electron-beam CT measure the atherosclerotic plaque burden and has been reported to predict coronary events. Because atherosclerosis is a generalized process, coronary calcification may also be associated with manifest atherosclerotic disease at other sites of the vascular tree. We examined whether coronary calcification as detected by electron-beam CT is related to the presence of stroke. Methods-From 1997 onward, subjects were invited to participate in the prospective Rotterdam Coronary Calcification Study and undergo electron-beam CT to detect coronary calcification. The study was embedded in the population-based Rotterdam Study. Calcifications were quantified in a calcium score according to Agatston's method. Calcium scores were available for 2013 subjects (mean age [SD], 71 [5.7] years). Fifty subjects had experienced stroke before scanning. Results-Subjects were 2 times more likely to have experienced stroke when their calcium score was between 101 and 500 (odds ratio [OR], 2.1; 95% CI, 0.9 to 4.7) and 3 times more likely when their calcium score was above 500 (OR, 3.3; 95% CI, 1.5 to 7.2), compared with subjects in the lowest calcium score category (0 to 100). Additional adjustment for cardiovascular risk factors did not materially alter the risk estimates. Conclusions-In this population-based study, a markedly graded association was found between coronary calcification and stroke. The results suggest that coronary calcification as detected by electron-beam CT may he useful to identify subjects at high risk of stroke.

Background and Purpose-Silent brain infarcts are commonly seen on magnetic resonance imaging (MRI) both in patients with a first stroke and in healthy elderly persons. These infarcts seem associated with an increased risk of stroke. It is unclear whether risk factors for silent infarcts differ from those for symptomatic stroke. We investigated the prevalence of, and cardiovascular risk factors for, silent brain infarcts. Methods-The Rotterdam Scan Study is a population-based cohort study among 1077 participants 60 to 90 years of age. Participants underwent cerebral MRI. We assessed cardiovascular risk factors by interview and physical examination. Associations between risk factors and presence of infarcts were analyzed by logistic regression and adjusted for age, sex, and relevant confounders. Results-For 259 participants (24%) 1 or more infarcts on MRI were seen; 217 persons had only silent and 42 had symptomatic infarcts. The prevalence odds ratio (OR) of both silent and symptomatic infarcts increased with age by 8% per year (95% CI, 1.06 to 1.10 and 1.04 to 1.13, respectively). Silent infarcts were more frequent in women (age-adjusted OR, 1.4; 95% CI, 1.0 to 1.8). Hypertension was associated with silent infarcts (age- and sex-adjusted OR, 2.4; 95% CI, 1.7 to 3.3), but diabetes mellitus and smoking were not. Conclusions-Silent brain infarcts are 5 times as prevalent as symptomatic brain infarcts in the general population. Their prevalence increases with age and seems higher in women. Hypertension is associated with silent infarcts, but other cardiovascular risk factors are not.

OBJECTIVE - To examine the association between insulin and cognitive function in the population-based Rotterdam Study. RESEARCH DESIGN AND METHODS - Serum insulin was measured 2 h after an oral glucose load, while global cognitive function was assessed by the Mini Mental State Examination in 5,510 subjects, aged 55 years and over. RESULTS - An increase in postload insulin only in women was associated with a decrease in cognitive function (age-adjusted regression coefficient -0.10 per 50 mU/l insulin; 95% CI -0.16 to -0.04). The association between insulin resistance, assessed by the ratio of postload insulin over glucose, and cognitive function was not statistically significant. Further adjustment for the individual risk factors of serum glucose, BMI, HDL, systolic blood pressure, smoking, or use of estrogen did not change the results. The association was present in women with and without cardiovascular disease and present after excluding subjects with diabetes. Women with dementia, the extreme of cognitive dysfunction, had increased age-adjusted insulin levels (76.3 +/- 4.9 vs. 66.8 +/- 1.0 mU/l [means +/- SE], P = 0.06). CONCLUSIONS - The results of this study suggest that increased serum insulin may be associated with decreased cognitive function and dementia in women. These findings are more compatible with a direct effect of insulin on the brain than with an effect through an increase in cardiovascular risk factors.

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinson's disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.