Structural and diffusion MRI measures of the hippocampus and memory performance.

Hippocampal atrophy on MRI and changes in diffusion tensor imaging (DTI) measures of the hippocampus have been reported in patients with Alzheimer's disease. We examined the association between hippocampal volumes, DTI measures of the hippocampus and memory performance in 892 non-demented persons (age ≥ 55 years) across different age groups. Hippocampal volume was segmented on 3D volumetric MRI scans. The segmentations were co-registered to mean diffusivity (MD) and fractional anisotropy (FA) maps to yield mean hippocampal MD and FA measurements. Higher MD of the hippocampus was associated with impaired verbal memory performance. In all persons ≥ 55 years, a higher MD of the hippocampus was associated with a worse memory performance. Hippocampal volumes were very weakly positively associated with delayed recall and only in persons > 65 years. FA of the hippocampus was not associated with memory performance. Follow-up studies will be needed to determine whether higher MD of hippocampus at younger ages could be an earlier marker of incident Alzheimer's disease than hippocampal volume.

Genetic risk factors for cerebral small-vessel disease in hypertensive patients from a genetically isolated population.

BACKGROUND: Asymptomatic cerebral lesions on MRI such as white matter lesions (WML), lacunes and microbleeds are commonly seen in older people. We examined the role of a series of candidate genes involved in blood pressure regulation and amyloid metabolism. MATERIALS AND METHODS: The study was embedded in a family-based cohort sampled from a Dutch genetically isolated population. We selected individuals between 55 and 75 years of age with hypertension (N=129). Volumes of WML and presence of lacunes and microbleeds were assessed with MRI. We studied three genes involved in blood pressure regulation (angiotensin, angiotensin II type 1 receptor, α-adducin) and two genes involved in the amyloid pathway (apolipoprotein E (APOE) and sortilin-related receptor gene (SORL1)). RESULTS: All participants had WML (median volume, 3.1 ml; interquartile range, 1.5-6.5 ml); lacunar infarcts were present in 15.5% and microbleeds in 23.3%. Homozygosity for the APOE ε4 allele was associated with lacunes (OR, 4.8; 95% CI, 1.2 to 19.3). Individuals carrying two copies of the variant allele of four single nucleotide polymorphism (SNPs) located at the 3'-end of SORL1 (rs1699102, rs3824968, rs2282649, rs1010159) had significantly more often microbleeds (highest OR, 6.87; 95% CI, 1.78 to 26.44). CONCLUSION: The association of SORL1 with microbleeds suggests that the amyloid cascade is involved in the aetiology of microbleeds in populations with hypertension.

Heart failure and the risk of stroke: the Rotterdam Study.

Patients with heart failure used to have an increased risk of stroke, but this may have changed with current treatment regimens. We assessed the association between heart failure and the risk of stroke in a population-based cohort that was followed since 1990. The study uses the cohort of the Rotterdam Study and is based on 7,546 participants who at baseline (1990­1993) were aged 55 years or over and free from stroke. The associations between heart failure and risk of stroke were assessed using time-dependent Cox proportional hazards models, adjusted for cardiovascular risk factors (smoking, diabetes mellitus, BMI, ankle brachial index, blood pressure, atrial fibrillation, myocardial infarction and relevant medication). At baseline, 233 participants had heart failure. During an average follow-up time of 9.7 years, 1,014 persons developed heart failure, and 827 strokes (470 ischemic, 75 hemorrhagic, 282 unclassified) occurred. The risk of ischemic stroke was more than five-fold increased in the first month after diagnosis of heart failure (age and sex adjusted HR 5.79, 95% CI 2.15­15.62), but attenuated over time (age and sex adjusted HR 3.50 [95% CI 1.96­6.25] after 1­6 months and 0.83 [95% CI 0.53­1.29] after 0.5­6 years). Additional adjustment for cardiovascular risk factors only marginally attenuated these risks. In conclusion, the risk of ischemic stroke is strongly increased shortly after the diagnosis of heart failure but returns to normal within 6 months after onset of heart failure.

Plasma vitamin B12 status and cerebral white-matter lesions.

BACKGROUND AND OBJECTIVE: Elevated homocysteine has been associated with a higher prevalence of cerebral white-matter lesions and infarcts, and worse cognitive performance. This raises the question whether factors involved in homocysteine metabolism, such as vitamin B(12), are also related to these outcomes. This study examined the association of several markers of vitamin B(12) status with cerebral white-matter lesions, infarcts and cognition. METHODS: The study evaluated the association of plasma concentrations of vitamin B(12), methylmalonic acid, holotranscobalamin and transcobalamin saturation with cerebral white-matter lesions and infarcts at baseline and cognition at baseline and during follow-up among 1019 non-demented elderly participants of the population-based Rotterdam Scan Study. Analyses were adjusted for several potential confounders, including homocysteine and folate concentration. RESULTS: Poorer vitamin B(12) status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner. Adjustment for common vascular risk factors (including blood pressure, smoking, diabetes and intima media thickness) did not alter the associations. Adjustment for homocysteine and folate modestly weakened the associations. No association was observed for any of the studied markers of vitamin B(12) status with presence of brain infarcts and baseline cognition or cognitive decline during follow-up. CONCLUSIONS: These results indicate that vitamin B(12) status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions. Given the absence of an association with cerebral infarcts, it is hypothesised that this association is explained by effects on myelin integrity in the brain rather than through vascular mechanisms.

Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study.

BACKGROUND: Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipophilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. OBJECTIVES: To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. METHOD: 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. RESULTS: During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). CONCLUSION: In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

[Epidemiology of severe visual impairment and blindness of old people in Germany]. / Epidemiologie hochgradiger Sehbehinderungen und Blindheit älterer Menschen in Deutschland.

Approximately 500,000 blind and 1 million visually impaired persons live in Germany, which lacks a national blind registry. Therefore data from social welfare agencies and population-based studies are used to estimate prevalence and incidence. Main causes for severe visual impairment and blindness are age-related macular degeneration, glaucoma and diabetic eye diseases. We observed a relative decline of the incidence of severe visual impairment and blindness over the last decades, which is primarily due to improved ophthalmic care and better treatment options. However, the absolute number of subjects with severe visual impairment and blindness increases due to population ageing. This will cause significant social and economic challenges in the future.

White matter atrophy and lesion formation explain the loss of structural integrity of white matter in aging.

The importance of macrostructural white matter changes, including white matter lesions and atrophy, in intact brain functioning is increasingly being recognized. Diffusion tensor imaging (DTI) enables measurement of the microstructural integrity of white matter. Loss of white matter integrity in aging has been reported, but whether this is inherent to the aging process itself or results from specific white matter pathology is unknown. In 832 persons aged 60 years and older from the population-based Rotterdam Study, we measured fractional anisotropy (FA) and directional diffusivities in normal-appearing white matter using DTI. All subjects' DTI measures were projected onto a common white matter skeleton to enable robust voxelwise comparison. With increasing age, multiple regions showed significant decreases in FA or increases in axial or radial diffusivity in normal-appearing white matter. However, nearly all of these regional changes were explained by either white matter atrophy or by white matter lesions; each of which related to changes in distinct brain regions. These results indicate that loss of white matter integrity in aging is primarily explained by atrophy and lesion formation and not by the aging process itself. Furthermore, white matter atrophy and white matter lesion formation relate to loss of integrity in distinct brain regions, indicating the two processes are pathophysiologically different.

Interaction between polymorphisms in the renin-angiotensin-system and angiotensin-converting enzyme inhibitor or beta-blocker use and the risk of myocardial infarction and stroke.

This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or beta-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14-0.70). No significant drug-gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44-1.52) or in beta-blocker users. Also, no significant drug-gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.

Depressive symptoms and risk of stroke: the Rotterdam Study.

BACKGROUND: Previous studies that have assessed whether the presence of depressive symptoms predisposes to stroke in the general elderly population have been contradictory. Moreover, they did not distinguish between men and women and did not perform psychiatric workups in those with depressive symptoms. This study examines the association between depressive symptoms, depressive disorder and the risk of stroke in the general population. METHODS: This prospective population based cohort study included 4424 participants from the third Rotterdam Study Survey (1997-1999) who, at that time, were > or =61 years of age and free from stroke. Depressive symptoms were assessed using the Centre for Epidemiological Studies Depression Scale (CESD) and considered present if the CESD score was > or =16. Participants with depressive symptoms had a diagnostic interview for depressive disorder. Follow-up was complete until 1 January 2005. Data were analysed using Cox proportional hazards models with adjustment for relevant confounders. RESULTS: Men with depressive symptoms (n = 73) were at increased risk of stroke (adjusted hazard ratio (HR) 2.17; 95% CI 1.11 to 4.23) and ischaemic stroke (adjusted HR 3.21; 95% CI 1.62 to 6.38). These associations were at least partly attributable to men who reported depressive symptoms but who did not fulfil Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnostic criteria for depressive disorder (n = 32): they had a very high risk of stroke (adjusted HR 2.70; 95% CI 1.15 to 6.33) and ischaemic stroke (adjusted HR 4.01; 95% CI 1.68 to 9.57). In women there was no association between presence of depressive symptoms and risk of stroke. CONCLUSIONS: Presence of depressive symptoms is a strong risk factor for stroke in men but not in women.

Haplotypes of the fibrinogen gene and cerebral small vessel disease: the Rotterdam scan study.

OBJECTIVE: Fibrinogen levels and fibrinogen clot structure have been implicated in the pathogenesis of vascular disease. We examined fibrinogen levels and variation in fibrinogen genes (fibrinogen gamma (FGG), alpha (FGA) and beta (FGB)), which have been associated with fibrin clot structure and fibrinogen levels, in relation to cerebral small vessel disease (SVD). METHODS AND RESULTS: This study was performed as part of the Rotterdam Scan Study, a population based study in 1077 elderly patients undergoing cerebral MRI. Plasma fibrinogen levels and haplotypes were determined. We examined the association between fibrinogen levels and haplotype with silent brain infarcts and white matter lesions using logistic regression models. We constructed seven haplotypes (frequency >0.01) that describe the total common variation in the FGG and FGA genes. Haplotype 2 (GATAGTG) was associated with the presence of silent brain infarcts compared with the most frequent haplotype (GGTGGTA) (OR 1.41, 95% CI 1.03 to 1.94). Haplotype 3 (GGCGATA) was associated with periventricular white matter lesions in the highest tertile of the distribution (OR 1.40, 95% CI 1.01 to 1.92). No association was found between plasma fibrinogen levels and SVD. CONCLUSIONS: Our study provides evidence for an association of common variation in the FGG and FGA genes with cerebral SVD. It is possible that the structure of the fibrin clot rather than plasma fibrinogen levels plays a role in the pathogenesis of cerebral SVD.

Nationwide incidence of first stroke and TIA in the Netherlands.

BACKGROUND: Information on incidence of stroke is important for developing and maintaining public health strategies in primary and secondary prevention. Nationwide data on the incidence of stroke are scarce and absent for the Netherlands. METHODS: New cases of first stroke and stroke subtypes in the Dutch population in 2000 were identified through linkage of national registers and included hospitalized patients for first stroke and out-of-hospital deaths from first stroke. The number of non-fatal, non-hospitalized stroke patients was estimated based on data from the Rotterdam study, a population based cohort. RESULTS: We identified 26,556 patients with a first stroke (20,798 hospitalized patients, 5758 out-of-hospital deaths). The number of non-fatal, non-hospitalized first stroke patients was estimated to be 12,255. Extrapolation of the data to the total Dutch population led to an overall estimate of approximately 41,000 patients with a first stroke. Stroke incidence increased with age and was higher in men than in women, except in the lowest (< 45 years) and highest age group (> 85 years). CONCLUSIONS: The present study provides for the first time incidence estimates of first stroke (hospitalized patients, out-of hospital deaths and non-fatal, non-hospitalized patients) based upon virtually the entire Dutch population.

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Polymorphisms of the renin-angiotensin system are associated with blood pressure, atherosclerosis and cerebral white matter pathology.

BACKGROUND: The renin-angiotensin system is involved in the development of hypertension, atherosclerosis and cardiovascular disease. We studied the association between the M235T polymorphism of the angiotensinogen gene (AGT) and the C573T polymorphism of the angiotensin II type 1 receptor (AT1R) and blood pressure, carotid atherosclerosis and cerebrovascular disease. METHODS: We genotyped over 6000 subjects from the Rotterdam Study and more than 1000 subjects from the Rotterdam Scan Study. We used logistic regression and univariate analyses, adjusting for age and sex with, for AGT, the MM and, for AT1R, the TT genotype as reference. RESULTS: We found that AGT-235T increased systolic (p for trend = 0.03) and diastolic blood pressure (p for trend = 0.04). The prevalence of carotid plaques was increased 1.25-fold (95% CI 1.02-1.52) in AGT-TT carriers. There was a significant increase in mean volume deep subcortical white matter lesions (WML) for AGT-TT carriers (1.78 ml vs 1.09 ml in the reference group; p = 0.008). A significant interaction was found between AGT and AT1R, further increasing the effect on periventricular and subtotal WML (p for interaction = 0.02). We found a non-significant increased risk of silent brain infarction for AGT-TT carriers and AT1R-CC carriers, but no effect on stroke. CONCLUSION: We found an association between AGT and blood pressure, atherosclerosis and WML. Also, we found synergistic effects between AGT and AT1R on the development of WML. These findings raise the question of whether the renin-angiotensin system may be a therapeutic target for the prevention of cerebral white matter pathology.

C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study.

BACKGROUND: Inflammatory processes are involved in the development and consequences of atherosclerosis. Whether these processes are also involved in cerebral small-vessel disease is unknown. Cerebral white matter lesions and lacunar brain infarcts are caused by small-vessel disease and are commonly observed on MRI scans in elderly people. These lesions are associated with an increased risk of stroke and dementia. We assessed whether higher C-reactive protein (CRP) levels were related to white matter lesion and lacunar infarcts. METHODS AND RESULTS: We based our study on 1033 participants of the population-based Rotterdam Scan Study for whom complete data on CRP levels were available and who underwent brain MRI scanning. Subjects were 60 to 90 years of age and free of dementia at baseline. Six hundred thirty-six subjects had a second MRI scan on average 3.3 years later. We used multivariate regression models to assess the associations between CRP levels and markers of small-vessel disease. Higher CRP levels were associated with presence and progression of white matter lesions, particularly with marked lesion progression (ORs for highest versus lowest quartile of CRP 3.1 [95% CI 1.3 to 7.2] and 2.5 [95% CI 1.1 to 5.6] for periventricular and subcortical white matter lesion progression, respectively). These associations persisted after adjustment for cardiovascular risk factors and carotid atherosclerosis. Persons with higher CRP levels tended to have more prevalent and incident lacunar infarcts. CONCLUSIONS: Inflammatory processes may be involved in the pathogenesis of cerebral small-vessel disease, in particular, the development of white matter lesions.

A longitudinal population-based study of prothrombotic factors in elderly subjects with atrial fibrillation: the Rotterdam Study 1990-1999.

BACKGROUND: A prothrombotic or hypercoagulable state in atrial fibrillation may contribute to stroke and thromboembolism. Results of longitudinal population-based studies in elderly people with atrial fibrillation are not yet available. METHODS: In the Rotterdam Study, a population-based prospective cohort study, 162 participants with atrial fibrillation at baseline, aged 55 years and over, were matched for age and gender with 324 people in sinus rhythm. Associations were examined between three coagulation factors and the risk of total and cardiac mortality and stroke. Hazard rate ratios were calculated with 95% confidence intervals using Cox's proportional hazards model, adjusted for potential confounders. RESULTS: Plasma von Willebrand factor was, age- and gender-adjusted, associated with cardiac mortality in the total population (relative risk 1.16; 1.06-1.27, per 10 IU dL(-1) increase), but statistical significance was lost after additional adjustments. A strong association (1.27; 1.08-1.50, per 5-unit increase) was found between soluble P-selectin (sP-sel) and cardiac mortality in atrial fibrillation patients but not in participants in sinus rhythm. Furthermore, the expected association between fibrinogen and cardiac mortality was observed only in those in sinus rhythm (2.60; 1.69-4.01, per unit increase), and not in atrial fibrillation. No associations were found between coagulation factors and stroke. CONCLUSIONS: In this population-based study, plasma levels of sP-sel predicted clinical adverse outcomes in atrial fibrillation, suggesting a role of platelets in the prothrombotic state associated with atrial fibrillation. Fibrinogen was a risk factor of cardiac and all-cause mortality in sinus rhythm, but not in atrial fibrillation.

Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: the Rotterdam study.

BACKGROUND: Few studies have quantified the relation between carotid plaques and stroke in asymptomatic patients, and limited data exist on the importance of location of plaques or the association with subtypes of cerebral infarction. We investigated the relationship between carotid plaques, measured at different locations, and risk of stroke and subtypes of cerebral infarction in a population-based study. Methods and Results- The study was based on the Rotterdam Study and included 4217 neurologically asymptomatic subjects aged 55 years or older. Presence of carotid plaques at 6 locations in the carotid arteries was assessed at baseline. Severity was categorized according to the number of affected sites. After a mean follow-up of 5.2 years, 160 strokes had occurred. Data were analyzed using Cox proportional hazards regression. Plaques increased the risk of stroke and cerebral infarction approximately 1.5-fold, irrespective of plaque location. Severe carotid plaques increased the risk of nonlacunar infarction in anterior (RR 3.2 [95% CI, 1.1 to 9.7]) but not in posterior circulation (RR 0.6 [95% CI, 0.1 to 4.9]). A >10-fold increased risk of lacunar infarction was found in subjects with severe plaques (RR 10.8 [95% CI, 1.7 to 69.7]). No clear difference in risk estimates was seen between ipsilateral and contralateral infarction. CONCLUSIONS: Carotid plaques increase the risk of stroke and cerebral infarction, irrespective of their location. Plaques increase the risk of infarctions in the anterior but not in the posterior circulation. It is likely that carotid plaques in neurologically asymptomatic subjects are both markers of generalized atherosclerosis and sources of thromboemboli.

Cerebral white matter lesions and depressive symptoms in elderly adults.

BACKGROUND: There is evidence for a vascular cause of late-life depression. Cerebral white matter lesions are thought to represent vascular abnormalities. White matter lesions have been related to affective disorders and a history of late-onset depression in psychiatric patients. Their relation with mood disturbances in the general population is not known. We investigated the relation between white matter lesions and the presence of depressive symptoms or a history of depression in a population-based study. METHODS: In a sample of 1077 nondemented elderly adults, we assessed the presence and severity of subcortical and periventricular white matter lesions using magnetic resonance imaging, presence of depressive symptoms, and history of depression. Using multiple regression analysis, we examined the relation among white matter lesions, depressive symptoms, and history of depression. RESULTS: Most of the subjects had white matter lesions. Persons with severe white matter lesions (upper quintile) were 3 to 5 times more likely to have depressive symptoms as compared with persons with only mild or no white matter lesions (lowest quintile) (periventricular odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.2-9.5; subcortical OR = 5.4; 95% CI, 1.8-16.5). In addition, persons with severe subcortical but not periventricular white matter lesions were more likely to have had a history of depression with an onset after age 60 years (OR = 3.4; 95% CI, 1.1-10.7) compared with persons with only mild or no white matter lesions. CONCLUSION: The severity of subcortical white matter lesions is related to the presence of depressive symptoms and to a history of late-onset depression.

Genome-wide scan linkage analysis for Parkinson's disease: the European genetic study of Parkinson's disease.

OBJECTIVE: To undertake a full genome-wide screen for Parkinson's disease susceptibility loci. METHODS: A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at approximately 10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test. RESULTS: There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11-q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11-q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (approximately 17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance. CONCLUSIONS: These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11-q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.

Insulin and cognitive function in an elderly population. The Rotterdam Study.

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.

Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study.

BACKGROUND AND PURPOSE: Several measures of atherosclerosis predict the risk of stroke. However, a comparison between various measures of atherosclerosis is lacking, and limited information exists on the added value of individual measures of atherosclerosis to cardiovascular risk factors. We compared different measures of atherosclerosis in relation to stroke. METHODS: The study was based on the prospective cohort of the Rotterdam Study and included 6913 participants who did not suffer from previous stroke. At baseline, carotid intima-media thickness and plaques, ankle-arm index, and aortic calcifications were assessed; 3996 participants (53%) had measures of all studied markers of atherosclerosis. After a mean follow-up of 6.1 years, 378 strokes occurred. Data were analyzed with Cox proportional-hazards regression and Akaike information criteria scores. RESULTS: Carotid intima-media thickness and aortic calcifications were related most strongly to the risk of stroke (relative risk, 2.23 and 1.89; 95% confidence interval, 1.48 to 3.36 and 1.28 to 2.80 for highest versus lowest tertile, respectively). The relations between intima-media thickness, aortic calcifications, and carotid plaques and stroke remained after adjustment for cardiovascular risk factors. Intima-media thickness and aortic calcifications were related to the risk of stroke independently of each other. The relation between ankle-arm index and stroke disappeared after adjustment for cardiovascular risk factors. CONCLUSIONS: Carotid intima-media thickness and aortic calcifications are stronger predictors of incident stroke than carotid plaque or ankle-arm indexes. They have additional value to each other and to classic risk factors and may reflect different processes.