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Objective Inflammation plays a role in the pathogenesis of dementia and Alzheimer's disease (AD). Studies examining serum levels of C-reactive protein in relation to dementia yielded conflicting results. Since serum levels of C-reactive protein are partly determined by genetic factors, we examined the association between genetic variation in the C-reactive protein gene with dementia and AD. Methods This study was performed in the Rotterdam Study, a population-based prospective cohort study among elderly. Polymorphisms in the C-reactive protein gene (1184C > T, 2042C > T and 2911C > G) tagging the common haplotypes were genotyped and haplotypes were constructed. During follow-up (mean 9.2 years) 607 dementia cases were identified. We estimated the association between polymorphisms and haplotypes with dementia and AD with Cox’ proportional hazard models. Results The T allele of the C-reactive protein 2042C > T polymorphism, related to lower serum levels of C-reactive protein, was associated with a lower risk of dementia and AD. This association was strongest in APOE ɛ4 allele carriers. Conclusion These findings suggest that C-reactive protein plays a role in development of dementia.

Recently, it was proposed that a combination of the 83,557insA polymorphism in the 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) gene and the R453Q polymorphism in the hexose-6-phosphate dehydrogenase (H6PD) gene interacts to cause cortisone reductase deficiency (CRD) when at least three alleles are affected.The aim was to study the separate and combined effects of these polymorphisms on body composition, adrenal androgen production, blood pressure, glucose metabolism, and the incidence of dementia in the healthy elderly population.The Rotterdam study (n = 6105) and the Frail Old Men study (n = 347) are population-based cohort studies in the elderly.Genotype distributions and influences of (combined) genotypes on body mass index, adrenal androgen production, waist to hip ratio, systolic and diastolic blood pressure, fasting glucose levels, glucose tolerance test, and incidence of dementia were measured.No influence of the HSD11B1 83,557insA (allele frequencies 22.0 and 21.5%) and H6PD R453Q (allele frequencies 22.9 and 20.2%) variants was found for the different outcome measures that were investigated, either separately or when at least three alleles were affected.Two population-based studies among Caucasian elderly showed no evidence for (combined) effects of two polymorphisms in the HSD11B1 and H6PD genes on body composition, adrenal androgen production, blood pressure, glucose metabolism, and incidence of dementia. Moreover, the high frequencies observed for these two polymorphisms do not correspond to the low incidence of CRD observed in the general population. Altogether, it is unlikely that these polymorphisms cause CRD.

Thyroid function has been related to Alzheimer disease (AD) and neuroimaging markers thereof. Whether thyroid dysfunction contributes to or results from developing AD remains unclear. Variations in the deiodinase type 1 (DIO1) and type 2 (DIO2) genes that potentially alter thyroid hormone bioactivity may help in elucidating the role of thyroid function in AD.We investigated the association of recently identified polymorphisms in the DIO1 (D1a-C/T, D1b-A/G) and DIO2 (D2-ORFa-Gly3Asp, D2-Thr92Ala) genes with circulating thyroid parameters and early neuroimaging markers of AD.The Rotterdam Scan Study is a population-based cohort study among 1,077 elderly individuals aged 60-90 yr.DIO1 and DIO2 polymorphisms and serum TSH, free T4, T3, and reverse T3 (rT3) levels were determined in 995 nondemented elderly, including 473 persons with assessments of hippocampal and amygdalar volume on brain magnetic resonance imaging.Carriers of the D1a-T allele had higher serum free T4 and rT3, lower T3, and lower T3/rT3. The D1b-G allele was associated with higher serum T3 and T3/rT3. The DIO2 variants were not associated with serum thyroid parameters. No associations were found with hippocampal or amygdalar volume.This is the first study to report an association of D1a-C/T and D1b-A/G polymorphisms with iodothyronine levels in the elderly. Polymorphisms in the DIO1 and DIO2 genes are not associated with early magnetic resonance imaging markers of AD. This suggests that the previously reported association between iodothyronine levels and brain atrophy reflects comorbidity or nonthyroidal illness rather than thyroid hormones being involved in developing AD.

Inflammatory mechanisms are involved in the pathogenesis of dementia. Inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor β1 (TGFβ1), have been found in association with Alzheimer pathology and there is evidence for direct involvement of these cytokines in formation of amyloid plaques. Polymorphisms in genes encoding for IL-6 and TGFβ1 are associated with plasma levels of IL-6 and TGFβ1. Studies examining the association between polymorphisms in these genes and dementia yielded conflicting results. The purpose of this study was to examine the association between genetic variance in IL-6 and TGFβ1 and risk of dementia. We examined this association in the Rotterdam Study, a prospective population-based cohort study in the elderly. Polymorphisms in the IL-6 (−174G>C) and TGFβ1 gene (−800G>A, −509C>T, +10T>C, +25G>C and 263C>T) were genotyped and haplotypes of the TGFβ1 gene were constructed. In a random subset IL-6 plasma levels were measured. During follow-up (mean 9.2 years), 743 dementia cases were identified. We estimated the association between individual polymorphisms and haplotypes with dementia with Cox’ proportional hazard models. No association was found between the −174G>C polymorphism in the IL-6 gene and risk of dementia. No association was found between polymorphisms and constructed haplotypes in the TGFβ1 gene and risk of dementia or Alzheimer's disease. No association was found between IL-6 genotype and IL-6 plasma levels in the random subset. Associations did not differ across APOE genotypes. Our findings do not suggest involvement of genetic variance in IL-6 and TGFβ1 in the development of dementia.

textabstractPURPOSE: A lower retinal arteriolar-to-venular ratio (AVR) has been suggested to reflect generalized arteriolar narrowing and to predict the risk of cardiovascular diseases. The contribution of the separate arteriolar and venular diameters to this AVR is unknown. Thus, associations between retinal arteriolar and venular diameters, and the AVR on the one hand and blood pressure, atherosclerosis, inflammation markers, and cholesterol levels on the other were examined in the Rotterdam Study. METHODS: In this cross-sectional population-based study, for one eye of each subject (> or =55 years; n = 5674), retinal arteriolar and venular diameters (in micrometers) of the blood columns were summed on digitized images. At baseline blood pressures, cholesterol levels, and markers of atherosclerosis and inflammation were also measured. RESULTS: With increasing blood and pulse pressures, retinal arteriolar and venular diameters and the AVR decreased significantly and linearly. Lower arteriolar diameters were associated with increased carotid intima-media thickness. Larger venular diameters were associated with higher carotid plaque score, more aortic calcifications, lower ankle-arm index, higher leukocyte count, higher erythrocyte sedimentation rate, higher total serum cholesterol, lower HDL, higher waist-to-hip ratio, and smoking. A lower AVR was related to increased carotid intima-media thickness, higher carotid plaque score, higher leukocyte count, lower HDL, higher body mass index, higher waist-to-hip ratio, and smoking. CONCLUSIONS: Because larger venular diameters are associated with atherosclerosis, inflammation, and cholesterol levels, the AVR does not depend only on generalized arteriolar narrowing due to the association between smaller arteriolar diameters and higher blood pressures. These data indicate that retinal venular diameters are variable and may play their own independent role in predicting cardiovascular disorders.

The accumulation of α-synuclein (αSN) is the neuropathologic hallmark of neurodegenerative diseases including dementia with Lewy bodies (DLB), Parkinson disease (PD), and rarer conditions such as multiple system atrophy (MSA) and pure autonomic failure (PAF).1 Symptoms depend on the distribution of αSN, ranging from cognitive dysfunction in DLB with diffuse neocortical localization of αSN to PAF with deposition of αSN in the brainstem.2 The latter condition is characterized by orthostatic hypotension and is associated with other symptoms of autonomic failure, including syncope, urinary or erectile dysfunction, constipation, dysphagia, dysarthria, and apnea syndrome.3

Association FA b MD b FA b MD b FA b MD b FA b MD b ATR -0.26 0.55 -0.21 0.47 -0.07 0.29 -0.05 0.24 IFO -0.35 0.49 -0.33 0.47 -0.16 0.28 -0.12 0.25 ILF -0.27 0.54 -0.25 0.52 -0.16 0.40 -0.11 0.36 PTR -0.32 0.49 -0.31 0.47 -0.18 0.37 -0.15 0.32 SLF -0.18 0.28 -0.19 0.29 -0.10 0.18 -0.11 0.19 UNC -0.30 0.42 -0.25 0.40 -0.25 0.34 -0.19 0.31 Commissural FMA -0.36 0.41 -0.31 0.36 -0.29 0.36 -0.22 0.30 FMI -0.39 0.40 -0.30 0.34 -0.36 0.35 -0.24 0.25 Limbic CGC -0.22 0.24 -0.23 0.24 -0.22 0.23 -0.23 0.23 CGH -0.29 0.36 -0.29 0.35 -0.29 0.36 -0.29 0.35 Sensorimotor CST -0.01 0.09 -0.03 0.12 0.02 0.08 0.00 0.10 MCP 0.05 0.15 -0.01 0.09 0.06 0.16 0.00 0.09 ML 0.01 0.09 0.01 0.11 0.01 0.09 0.01 0.11 STR -0.03 0.02 -0.04 0.02 0.00 0.02 -0.01 0.02

Background and Purpose— Men, but not women, with unrecognized myocardial infarction (MI) have an increased risk of cardiac events and stroke compared with those without MI or with recognized MI. We investigated whether unrecognized MI is also a risk factor for dementia and cerebral small vessel disease (white matter lesions and brain infarction) in 2 population-based cohort studies. Methods— In the Rotterdam Study, 6347 participants were classified at baseline (1990 to 1993) into those with recognized MI (subdivided into Q-wave and non-Q-wave MI), with unrecognized MI, and without MI based on electrocardiography and interview and were followed for incident dementia (n=613) until January 1, 2005. In the Rotterdam Scan Study, 436 nondemented persons were similarly classified based on electrocardiography and interview and underwent brain MRI for the assessment of white matter lesions and brain infarction. Results— In men, unrecognized MI was associated with an increased risk of dementia (compared with men without MI hazard ratio, 2.14; 95% CI, 1.37 to 3.35) and with more white matter lesions and more often brain infarction on MRI. In women, no associations were found with unrecognized MI. Recognized MI was not associated with the risk of dementia in either sex. Men, but not women, with recognized MI had more often any brain infarction or asymptomatic brain infarction, especially if they had Q-wave MI. No consistent associations were found between recognized Q-wave or non-Q-wave MI and severity of white matter lesions. Additional adjustment for cardiovascular risk factors did not change the results. Conclusions— Men with unrecognized MI have an increased risk of dementia and more cerebral small vessel disease.

Retinal vessel diameters, in particular larger venular diameters, have been associated with cerebrovascular disease. Larger retinal venular diameters may reflect cerebral ischemia. The authors investigated whether arteriolar oxygen saturation (SaO2) and total cerebral blood flow (CBF), indicators of cerebral oxygen supply, are associated with retinal arteriolar or venular diameters.Cross-sectional study performed within the population-based Rotterdam Study.Randomly selected participants aged 55 years or older (n = 696), who underwent both an eye examination and brain magnetic resonance imaging (MRI).Arteriolar oxygen saturation was determined by pulse oximetry on the right index finger. Cerebral blood flow was assessed using a phase-contrast MRI sequence that measured the flow in the basilar and both internal carotid arteries. Brain volume was measured to express CBF per 100 ml brain volume. Retinal arteriolar and venular diameters were measured on digitized fundus color transparencies on 1 eye of each participant. Regression models were used to investigate the association of SaO(2) and CBF with retinal vessel diameters.Mean retinal arteriolar and venular diameters (in micrometers).Lower SaO2 was associated with larger venular diameters. Persons with SaO(2) less than 96% (n = 113) had on average 5 microm larger venular diameters compared with those with SaO(2) of 96% or more (n = 583; age- and gender-adjusted mean difference, 5.6 microm; 95% confidence interval, 1.2-10.0). Cerebral blood flow was not related to venular diameters when analyzed separately. Additional analyses showed that the association between SaO(2) and venular widening was confined to participants within the lowest tertile of CBF. No associations were found between SaO(2) or CBF and arteriolar diameters. Additional adjustment for established cardiovascular risk factors did not change the results.An association of lower SaO(2) with larger retinal venular diameters was observed, in particular in the presence of lower CBF. These findings suggest that venular widening may reflect a lower oxygen supply, especially to the brain.

Retinal vessels may provide a way to study the cerebral microcirculation. In particular, larger retinal venular diameters have been associated with cerebrovascular disease. An inflammatory response may underlie this association. In a population-based cohort study among 5,279 participants aged 55 years or older with graded retinal vessel diameters, we observed that greater serum levels of C-reactive protein and fibrinogen and greater lipoprotein-associated phospholipase A(2) activity were strongly associated with larger venular diameters. Weaker associations were found with arteriolar diameters. Our findings support the hypothesis that larger retinal venular diameters reflect systemic inflammation and suggest that inflammation is involved in cerebrovascular disease.

Female patients with classical galactosemia (galactose-1-phosphate uridyltransferase [GALT] deficiency) frequently suffer from premature ovarian failure, despite treatment with a galactose-restricted diet. Earlier research has suggested an association between heterozygosity for GALT mutations and early menopause. This study evaluates the effect of carriership for classical galactosemia on ovarian reserve and menopausal age. Proven female carriers of classical galactosemia were recruited via the Dutch Galactosemia Society. All 58 participants underwent a structured interview regarding fertility, smoking status, and menopause. To determine ovarian reserve, 42 premenopausal GALT carriers underwent ovarian antral follicle count (AFC) by transvaginal ultrasound and early follicular phase blood sampling for hormonal measurement of follicle-stimulating hormone (FSH), inhibin B, and anti-Mullerian hormone (AMH). These ovarian reserve parameters were compared with a cohort of proven fertile women (n = 166). The mean age at menopause in GALT carriers was 49.7 years, which is not different from the mean age at menopause in the general population in the Netherlands. There was no difference in FSH, inhibin B, and AMH levels or in the AFC (when corrected for age and smoking status) between 42 premenopausal GALT carriers and controls. The authors conclude that there is no evidence that GALT mutation carriership affects ovarian reserve or menopausal age.

PURPOSE. Retinal venular dilatation is associated with systemic inflammation. The hypothesis for the current study was that larger retinal venular diameters are related to the His allele of the Tyr402His polymorphism in the complement factor H (CFH) gene, a major inhibitor of the complement pathway. Possible effect modification by smoking and inflammatory markers was examined. METHODS. This cross-sectional study was performed within the Rotterdam Study, a population-based study among elderly persons aged 55 years and older. The Tyr402His polymorphism of the CFH gene was genotyped in 5066 participants and retinal arteriolar and venular diameters were graded on digitized fundus transparencies. RESULTS. Genotype frequencies were 41% in TyrTyr, 45% in TyrHis, and 14% in HisHis carriers. The His 402 allele was associated with smaller rather than larger venular diameters (ageand sex-adjusted means and standard errors [in micrometers] were 222.5 0.45 for TyrTyr, 221.9 0.43 for TyrHis, and 220.6 0.78 for HisHis carriers; P-trend 0.03). This association was apparent only in never-smokers and was not modified by the inflammatory markers erythrocyte sedimentation rate, leukocyte count, C-reactive protein, or fibrinogen. Adjustment for cardiovascular risk factors did not change results. No associations were found with arteriolar diameters. CONCLUSIONS. The findings do not support the hypothesis that the His 402 allele is related to larger retinal venular diameters. The association with smaller retinal venular diameters most likely is a chance finding, because it was present only among never-smokers and was not modified by inflammatory mediators of complement. These results suggest that the Tyr402His variant is not related to retinal venular diameters. (Invest Ophthalmol Vis Sci. 2007;48:3014‐3018) DOI:10.1167/iovs.061460

Objective: Atherosclerosis has been implicated in the development of dementia and its major subtypes, Alzheimer's disease and vascular dementia. However, support for this association mainly comes from cross-sectional studies. We investigated the association of atherosclerosis with dementia and subtypes of dementia during long follow-up, with various noninvasive measures of atherosclerosis. Methods: This study was based on 6,647 participants in the Rotterdam Study, a population-based prospective cohort study among 7,983 elderly subjects. At baseline (1990-1993) and at the third survey (1997-1999), common carotid intima media thickness, carotid plaques, and peripheral arterial disease (measured as ankle-brachial index) were measured. During follow-up (mean, 9.0 years), 678 subjects developed dementia. We estimated the associations of different measures of atherosclerosis with risk for dementia and subtypes of dementia by means of Cox proportional hazard models. Analyses were repeated and stratified on duration of follow-up. To evaluate competing risk for mortality, we examined the association between measures of atherosclerosis and risk for dementia or mortality by combining the two in a single outcome measure. Results: We found that atherosclerosis, predominantly carotid atherosclerosis, was associated with an increased risk for dementia during short follow-up. This association attenuated with longer follow-up, likely because of the strong association between atherosclerosis and mortality. The associations did not differ across apolipoprotein E genotypes. Interpretation: Our findings suggest that atherosclerosis is associated with an increased risk for dementia. Stronger associations between atherosclerosis and mortality may attenuate the association between atherosclerosis and dementia in prospective cohort studies with long follow-up periods.

Background Subjective memory complaints are common in the elderly. Although memory complaints are associated with an increased risk of Alzheimer's disease in persons with cognitive impairment as well as in persons with normal cognition, they are commonly considered of less importance than objective cognitive measures. We hypothesized that the clinical relevance of subjective memory complaints might vary with educational background. Methods The study was performed within the Rotterdam Study, a prospective population-based cohort study among 7983 persons 55 years and older. Subjective memory complaints and level of education were assessed in the baseline interview (1990 to 1993). During a mean follow-up of 9.0 years we identified 568 incident Alzheimer's disease patients. We estimated the association between subjective memory complaints and risk of dementia by means of Cox proportional hazard models. Results The association between subjective memory complaints and risk of Alzheimer's disease varied across levels of education. The risk of Alzheimer's disease associated with subjective memory complaints was higher in highly educated persons (age- and sex-adjusted hazard ratio, 2.33; 95% confidence interval [CI], 1.00–5.49) than in persons with a low education (age- and sex-adjusted hazard ratio, 1.53; 95% CI, 1.15–2.05) ( P value for interaction, .02). In highly educated persons without objective cognitive impairment (Mini-Mental State Examination score, 29 or 30) the risk of Alzheimer's disease was highest (age- and sex-adjusted hazard ratio, 2.98; 95% CI, 1.76–5.02). Conclusions Especially in persons with a high level of education who still perform well on formal cognitive tests, subjective memory complaints might be an important first sign of imminent Alzheimer's disease.

Inflammatory mechanisms are involved in the pathogenesis of dementia. Inflammatory cytokines, including interleukin-6 (IL-6) and transforming growth factor beta1 (TGFbeta1), have been found in association with Alzheimer pathology and there is evidence for direct involvement of these cytokines in formation of amyloid plaques. Polymorphisms in genes encoding for IL-6 and TGFbeta1 are associated with plasma levels of IL-6 and TGFbeta1. Studies examining the association between polymorphisms in these genes and dementia yielded conflicting results. The purpose of this study was to examine the association between genetic variance in IL-6 and TGFbeta1 and risk of dementia. We examined this association in the Rotterdam Study, a prospective population-based cohort study in the elderly. Polymorphisms in the IL-6 (-174GC) and TGFbeta1 gene (-800GA, -509CT, +10TC, +25GC and 263CT) were genotyped and haplotypes of the TGFbeta1 gene were constructed. In a random subset IL-6 plasma levels were measured. During follow-up (mean 9.2 years), 743 dementia cases were identified. We estimated the association between individual polymorphisms and haplotypes with dementia with Cox' proportional hazard models. No association was found between the -174GC polymorphism in the IL-6 gene and risk of dementia. No association was found between polymorphisms and constructed haplotypes in the TGFbeta1 gene and risk of dementia or Alzheimer's disease. No association was found between IL-6 genotype and IL-6 plasma levels in the random subset. Associations did not differ across APOE genotypes. Our findings do not suggest involvement of genetic variance in IL-6 and TGFbeta1 in the development of dementia.

The direct visualization of retinal vessels provides a unique opportunity to study cerebral small vessel disease, because these vessels share many features. It was reported that persons with smaller retinal arteriolar-to-venular ratio tended to have more white matter lesions on MRI. It is unclear whether this is due to arteriolar narrowing or venular dilatation. We investigated whether smaller arteriolar or larger venular diameters or both were related to severity and progression of cerebral small vessel disease. We studied 490 persons (60-90 years) without dementia from a population-based cohort study. At baseline (1990-1993), retinal arteriolar and venular diameters were measured on digitized images of one eye of each participant. In 1995-1996, participants underwent cerebral MRI scanning. We rated the severity of periventricular white matter lesions on a 9-point scale, approximated a total subcortical white matter lesion volume (range: 0-29.5 ml) and rated the presence of lacunar infarcts. On average 3.3 years later, 279 persons had a second MRI. Changes in periventricular and subcortical white matter lesions were rated with a semi-quantitative scale, and progression was classified as no, minor and marked. An incident infarct was a new infarct on the follow-up MRI. Neither venular nor arteriolar diameters were related to the severity of cerebral small vessel disease. Larger venular diameters were, however, associated with a marked progression of cerebral small vessel disease. Age and gender adjusted odds ratios (ORs) per standard deviation increase were 1.71 [95% confidence interval (CI): 1.11-2.61] for periventricular, 1.72 (95% CI: 1.09-2.71) for subcortical white matter lesion progression and 1.59 (95% CI: 1.06-2.39) for incident lacunar infarcts. These associations were independent of other cardiovascular risk factors. Only the OR for incident lacunar infarcts was attenuated (1.24; 95% CI: 0.72-2.12). No association was observed between arteriolar diameters and progression of cerebral small vessel disease. In conclusion, retinal venular dilatation was related to progression of cerebral small vessel disease. The mechanisms underlying venular dilatation deserve more attention, as they may provide new clues into the pathophysiology of cerebral small vessel disease.