19 research outputs found
Biomarkers and Risk Factors of Dementia
Dementia is a devastating disease that is common in elderly people. The prevalence increases from almost 1% at age 65 to over 40% of people older than 90 years.1 Because the population is aging, the number of people living with dementia world- wide is expected to double every 20 years with an expected number of 81 million people with dementia in 2040.2 Currently, dementia is still a clinical diagnosis of disturbances in cognitive functions that interfere with normal daily functioning.3,4 The major subtype of dementia is Alzheimer disease, which based on a clinical diag- nosis, accounts for around 70% of all dementia. The second most common subtype is vascular dementia, which is diagnosed in about 15% of dementia cases.1 Nowadays, however, we know that most patients with dementia have a mix of the neurodegen- erative changes that typically occur in Alzheimer disease, vascular pathology and other pathological signs, like Lewy bodies.5,6 In addition, vascular risk factors have repeatedly been associated with not only vascular dementia, but also with Alzheim- er disease,7 supporting the neuropathological findings of mixed brain pathologies. Although many risk factors for dementia have been identified in the past decades, the exact mechanisms that lead to dementia are still unclear. When the clinical di- agnosis of dementia is made, the actual neuropathological processes that have lead to dementia have already been ongoing for many years. Biomarkers that can detect these processes before a clinical diagnosis can be made are strongly needed in order to identify persons who will develop dementia, to gain more insight in the pathogen- esis of dementia and ultimately to help find new therapeutic agents that may alter or stop the disease. Currently, the most explored biomarkers are imaging markers and the proteins β-Amyloid (Aβ)-42 and tau that are altered in the cerebrospinal fluid of patients with Alzheimer disease early in the disease process.8,9 A lumbar puncture, required to obtain cerebrospinal fluid, is a relative invasive procedure that is not easily performed on large numbers of patients or in the general population, and imaging methods such as PET are not routinely available in all clinical settings. Less invasive biomarkers of dementia are therefore wanted
Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease
Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD
Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease
Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction
Routine thrombolysis with intravenous tissue plasminogen activator in acute ischaemic stroke patients aged 80 years or older: a single centre experience
Associations of Serum Cortisol with Cognitive Function and Dementia: The Rotterdam Study
Higher levels of cortisol have been observed in persons with cognitive decline and dementia. It is unknown whether these higher levels are a cause or a consequence of disease. We investigated whether morning levels of serum cortisol were associated with cognitive function, cognitive decline, and the risk of dementia and Alzheimer's disease in the Rotterdam Study, a large prospective population based cohort study. Cortisol levels were assessed in fasting blood serum in 3341 participants, who were free of dementia at baseline (1997-1999). Cognitive function was assessed with a dedicated neuropsychological test battery at baseline and at follow-up examination (2002-2004). In addition, the cohort was continuously monitored for incident dementia until January 1, 2007. After a mean follow-up of 7.1 years, 243 participants had developed dementia, of whom 210 were diagnosed with Alzheimer's disease. Morning serum levels of cortisol were neither related to cognitive function at baseline, nor to annual cognitive decline. There was no relation between serum levels of cortisol and the risk of developing dementia or Alzheimer's disease. These results suggest that that morning serum cortisol is not a causal factor in the development of dementia
Insulin metabolism and the risk of Alzheimer disease: The Rotterdam Study
Objective: Diabetes mellitus has been associated with an increased risk of Alzheimer disease (AD), but how it exerts its effect remains controversial. Possible pathophysiologic mechanisms are glucose toxicity and a direct effect of insulin on amyloid metabolism. Most studies had short follow-up, and longer-term effects of diabetes on AD risk are unknown. We investigated whether fasting glucose and insulin levels and insulin resistance are associated with the risk of AD and whether this risk is constant over time. Methods: The study was based on 3,139 participants of the Rotterdam Study, a population-based cohort study. All subjects were free from dementia, did not have a history of diabetes, and had fasting levels of glucose and insulin measured at baseline. Insulin resistance was estimated with the homeostasis model assessment. We investigated how fasting glucose, insulin, and insulin resistance are related to the risk of AD in 3 different strata according to time-to-event, using Cox proportional hazards models. Results: During follow-up, 211 participants developed AD, 71 of them within 3 years of baseline. Levels of insulin and insulin resistance were associated with a higher risk of AD within 3 years of baseline. After 3 years, the risk was no longer increased. Glucose was not associated with a higher risk of AD. There was no interaction of APOE ε4 carriership and insulin metabolism on the risk of AD. ConclusionS: Our findings suggest that insulin metabolism influences the clinical manifestation of AD only within 3 years. Copyrigh
Retinopathy and risk of dementia: the Rotterdam Study.
To investigate the relation between retinopathy and the risk of dementia. We investigated the associations between retinopathy and dementia and its subtypes Alzheimer disease (AD) and vascular dementia both cross-sectionally and prospectively in the Rotterdam Study, a large population-based cohort study. Digitized retinal images were available for 195 participants with prevalent dementia and 6,078 participants without dementia at baseline (1990-1993). Participants were reexamined in 1993-1994, 1997-1999, and 2002-2004 and were continuously monitored for development of dementia until January 1, 2007. Retinopathy was graded on fundus photographs and was defined as the presence of one or more dot/blot hemorrhages, microaneurysms, cotton wool spots, or evidence of laser treatment for retinopathy. Retinopathy was associated with prevalent dementia (age and sex-adjusted odds ratio 2.04, 95% confidence interval [CI] 1.34-3.09). Results were similar for AD and vascular dementia. During a mean follow-up of 11.4 years, 735 participants developed incident dementia, of whom 583 had AD and 80 had vascular dementia. There was no association of retinopathy at baseline with the risk of incident dementia during follow-up (age- and sex-adjusted hazard ratio 1.15, 95% CI 0.88-1.48) or the risk of incident AD or vascular dementia. Retinopathy is more prevalent in persons with dementia but is not associated with an increased risk of dementia over time. AD: Alzheimer disease ARIC: Atherosclerosis Risk in Communities CI: confidence interval CRP: C-reactive protein DSM-III-TR: Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised GMS: Geriatric Mental State schedule MMSE: Mini-Mental State Examination OR: odds ratio
Plasma amyloid β, depression, and dementia in community-dwelling elderly
Plasma amyloid β (Aβ) levels have been associated with an increased risk of Alzheimer's disease (AD). As depression is common before the onset of AD, a few clinical studies tested the cross-sectional association of Aβ levels with depression in elderly and showed incongruous findings. Hence, we tested the longitudinal association between Aβ levels and depressive symptoms in community-dwelling elderly. The study is embedded in a population-based cohort of 980 participants aged 60 years or older from the Rotterdam Study with Aβ levels. Participants were evaluated for depressive symptoms with the Centre for Epidemiological Studies-Depression scale at baseline and repeatedly over the mean follow-up of 11 years. We first performed cross-sectional analyses. Then, we tested the longitudinal association between Aβ levels and depressive symptoms after excluding participants with dementia during follow-up. In cross-sectional analyses, persons with high Aβ1-40 levels had more clinically relevant depressive symptoms. However, this association was accounted for by persons with clinically relevant depressive symptoms who developed dementia within the next 11 years. In longitudinal analyses, persons with low levels of Aβ1-40 and Aβ1-42 without dementia had a higher risk of clinically relevant depressive symptoms during the follow-up. These findings suggest that the cross-sectional association between high plasma Aβ levels and clinically relevant depressive symptoms in the elderly is due to prodromal dementia. In contrast, the longitudinal association between low plasma Aβ levels and depressive symptoms could not be explained by dementia during follow-up suggesting that Aβ peptides may play a distinct role on depression etiology
Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation
We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P <5 x 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P <.05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (Blood. 2012;120(24):4873-4881