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Coagulation and fibrinolysis markers and risk of dementia - The Dutch vascular factors in dementia study
Abstract
We performed a cross-sectional case-control study among 277 subjects with dementia and 298 control subjects drawn from participants of the Rotterdam Study, a population-based cohort study among subjects aged 55 years or over, and from participants of the Rotterdam Stroke Databank, a hospital-based stroke registry, with the objective to evaluate the association of indicators of coagulability, fibrinogen, prothrombin fragments 1+2, thrombin-antithrombin complex (TAI), a nd indicators of fibrinolysis, plasmin-inhibitor complex, D-dimer and tissue-type plasminogen activator (t-PA) with dementia. Increased levels of TAT, D-dimer and t-PA activity were associated with an increased risk of dementia. Additional stratified analyses indicated that an increased TAI level was the primary factor related to dementia. The present study provides evidence that predominantly increased thrombin generation is associated with dementia.
... Seventeen hemostasis or hemorheology biomarkers were described, of which fibrinogen(n = 17 studies) [18][19][20][21][22][23][24][25][26][27]29,30,[32][33][34][35][36][37], D-dimer (n = 9 studies) [19,21,22,26,28,32,35,36,38] and plasma viscosity (n = 7 studies) [24,26,30,31,33,35,36] were most prevalent. Studies varied in methodologies used and potential for bias; no study corrected for all pre-specified covariates (Tables S1 and S2). ...
... Seventeen hemostasis or hemorheology biomarkers were described, of which fibrinogen(n = 17 studies) [18][19][20][21][22][23][24][25][26][27]29,30,[32][33][34][35][36][37], D-dimer (n = 9 studies) [19,21,22,26,28,32,35,36,38] and plasma viscosity (n = 7 studies) [24,26,30,31,33,35,36] were most prevalent. Studies varied in methodologies used and potential for bias; no study corrected for all pre-specified covariates (Tables S1 and S2). ...
... Included studies were heterogeneous in terms of study design, biomarker(s) measured and cognitive domains or diagnoses described. Six case-control studies [19][20][21]28,29,35] and 14 studies describing cross-sectional or cohort data [18,[22][23][24][25][26][27][30][31][32][33][36][37][38] were included. Only the blood marker fibrinogen was described in a sufficient number of studies to allow for funnel plot analysis. ...
Hemostasis and thrombosis may be important contributors to cognitive decline and dementia. Certain blood markers may assist in diagnosis or management.
To collate evidence for the association of circulating hemostatic variables and dementia or cognitive impairment.
A systematic review of studies describing blood markers of hemostatic function and cognition/dementia. Abstracts were reviewed by two independent assessors and studies selected based on pre-specified criteria. We described methodological quality and performed meta-analyzes where data allowed.
From 7103 titles, 485 abstracts and included 21 studies (n = 32,773) were assessed. In two longitudinal studies, the incident of vascular dementia risk was greater for higher D-dimer [hazard ratio (HR): 1.50, 95% confidence interval (CI): 1.15-1.96]. For case-control data, we calculated standardized mean differences (SMD) and 95% CI. Higher levels of: factor (F)VII (SMD: 0.93; 95% CI: 0.60-1.26), fibrinogen (SMD: 1.53; 95% CI: 1.17-1.87), prothrombin fragment 1 and 2 (SMD: 0.64; 95% CI: 0.32-0.96), plasminogen activator inhibitor (SMD: 0.68; 95% CI: 0.26-1.10), D-dimer (SMD: 2.00; 95% CI: 1.59-2.40) and von Willebrand factor (VWF) (SMD: 1.68; 95% CI: 1.30-2.06) showed modest but significant associations with vascular dementia. For patients with any dementia diagnosis, associations were with higher D-dimer (SMD: 0.36; 95% CI: 0.15-0.56) and VWF (SMD: 0.31; 95% CI: 0.11-0.51). For specific cognitive domains, significant (P < 0.001) positive correlations were fibrinogen and speed of processing (0.76; 95% CI: 0.67-0.84), verbal memory (0.69; 95% CI: 0.59-0.79) and non-verbal reasoning (0.57; 95% CI: 0.49-0.65).
The present results suggest a modest association between hemostasis and vascular dementia including increased levels of thrombin generation markers (D-dimer and prothrombin fragment 1 + 2) and endothelial dysfunction (VWF and plasminogen activator inhibitor). Associations are weaker for specific cognitive tests and when all dementias are combined.
... Many recent studies describe D-dimer testing in obstetrics/gynecology, pediatrics, oncology, infectious disease, rheumatology, nephrology/urology, gastroenterology, and neurology. 23,36,44,46,48,53,55,57,[59][60][61]65 However, the majority of research to date has focused on the utility of D-dimer in the identification of thrombogenic conditions or cardiovascular disorders such as PTE, DVT, DIC, ischemic stroke, and myocardial infarction. [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] Several clinical studies have established the value of latex agglutination D-dimer assays as a rapid, easily performed, adjunctive test for the diagnosis of PTE, DVT, myocardial infarction, and DIC. ...
... 29,55,62 It is recently reported that increased thrombin production in the CNS may be associated with development of acute clinical dementia following cerebral infarction. 48 This study showed that markedly with subarachnoid hemorrhage are associated with an increased incidence of delayed cerebral vasospasm following fibrinolytic drug therapy. 65 As thrombi are a major reservoir of the vasoactive substance spasmogen, fibrinolytic agents are administered to patients with subarachnoid hemorrhage to prevent cerebral vasospasm. ...
... Surgical intervention is warranted in cases of rapidly expanding he matomas that cause significant compression of neural tissue. Recent evidence suggests that following the identification of CNS hemorrhage the use of fibrinolytic therapies may reduce the number and/or severity of chronic complications of CNS hemorrhage in humans.36,48,65 If D-dimers prove to facilitate the identification of subdural, subarachnoid, intraparenchymal, or intraventricular hemorrhage, it may allow the institution of beneficial medical therapies prior to the performance of definitive neuroimaging procedures.Besides conflicting results observed in some human studies, other problems with the application and performance of latex agglutination D-dimer assays have been identified since their introduction to clinical medicine. ...
Cerebrospinal fluid analysis (CSF) is commonly performed in clinical neurology, and is a sensitive, but non-specific indicator of central nervous system (CNS) pathology. Blood contaminated CSF samples have the potential to adversely affect results of cytologic, serologic, microbiologic, and molecular biologic diagnostics. A clear consensus of the effects of blood contamination on CSF analysis could not be drawn following a review of the existing veterinary literature. Based on data from earlier reports, it was hypothesized that iatrogenic blood contamination of CSF would result in significant increases in both the CSF total protein (TP) concentration and nucleated cell count (WBC). As hypothesized, in vitro CSF blood contamination resulted in statistically significant (p <0.01) linear increases in both the CSF TP and WBC with increasing RBC concentration in CSF from sixteen normal dogs. Although increases in TP and WBC are statistically significant, their clinical impact is negligible. Results of this study demonstrate that in normal dogs, the mean CSF TP concentration collected from the cerebellomedullary cistern, is lower than previously reported. D-dimers are plasminolytic cleavage products formed by the cross-linkage of fibrin by Factor XIIIa. In humans, D-dimer analysis can be used to differentiate iatrogenic from pathologic CNS hemorrhage. System requirements: PC, World Wide Web browser and PDF reader. Available electronically via Internet. Title from electronic submission form. Thesis (M.S.)--Virginia Polytechnic Institute and State University, 2003. Vita. Abstract. Includes bibliographical references.
... In recent years, total plasma homocysteine (tHcy) has been proposed as an independent risk factor for dementia and AD [27,50,51]. Hemostasis has been proposed as a possible pathogenetic factor in dementia, especially vascular dementia [52][53][54]. ...
... However, there is a scarcity of publications, probably because the clinical criteria for AD exclude overt vascular disease [19]. The Dutch study, Vascular Factors in Dementia, found an association between increased levels of D-dimer and dementia [53]. Endothelial derived fibrinolytic markers in AD vs VaD has to my knowledge so far only been studied by Mari et al [52], who found that von ...
... 5 Dementia is associated with increased levels of thrombin-antithrombin complexes, D-dimer, and tissue plasminogen activator. 6 Hemostatic activation, including elevated D-dimer, may also be associated with increased risk of disability. 7 However, further research, including prospective longitudinal data, is required to clarify the strength of association of markers of hemostatic function with functional and cognitive decline in older age. ...
... In a nested case-control study from the Rotterdam cohort, D-dimer, thrombin-antithrombin complexes, and tissue plasminogen activator were all associated with increased risk of dementia. 6 We have previously published on community-dwelling subjects with atrial fibrillation, in whom elevated D-dimer is associated with development of dementia. 21 D-dimer is also associated with increased disability in older populations. ...
To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people.
We studied 5804 people (age, 70-82 years) in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Mean follow-up was 3.2 years, including annual measurement of speed of information processing (letter, digit coding, and Stroop), verbal memory (picture-word naming), and basic and instrumental activities of daily living. Raised levels of markers of thrombin generation (d-dimer and prothrombin fragment 1+2) were associated independently with increased rate of cognitive decline (eg, Stroop increased by 4.44 s [SEM, 0.68] in bottom tertile of d-dimer compared to 5.46 [SEM, 0.71] in highest tertile; P<0.05) and deterioration in activities of daily living. This increased rate of decline was attenuated but not removed when subjects with incident nonfatal stroke were omitted from the analysis. It also persisted when adjustments were made for inflammation (C-reactive protein and IL-6).
Older patients with increased markers of thrombin generation (d-dimer and prothrombin fragment 1+2) are at increased risk for cognitive decline and deterioration in ability to perform activities of daily living. This is likely attributable to increased risk of cerebral ischemic damage (including covert disease) associated with prothrombotic states.
... 1 There is limited case-control evidence associating markers of hemostasis and inflammation with dementia. [2][3][4][5][6] Limited prospective data come from the Rotterdam Study, which found that fibrinogen, but not C-reactive protein (CRP), was associated with incident dementia at the age of 6 years. 7 Therefore, further studies of hemostatic and inflammatory markers and risk of dementia (both vascular and nonvascular) are required. ...
... The hypothesis that hemostasis affects vascular dementia was strongly supported. Our findings confirm those of several case-control studies showing that hemostatic markers are related to vascular dementia in particular, 4,6 and dementia in general. 2 Our findings extend this evidence to show prospectively over 17 years that hemostatic markers are associated with vascular dementia but not nonvascular dementia. Previous prospective evidence has shown that fibrinogen, but not CRP, was associated with vascular dementia. ...
Hemostasis and inflammation have been implicated in dementia. This study investigates the role of specific hemostatic and inflammatory pathways with incident vascular and nonvascular dementia.
This was a prospective study of a population sample of men aged 65 to 84 years, with baseline assessment of hemostatic and inflammatory factors and cognition measured 17 years later. The sample included 865 men (59 had dementia and 112 had cognitive impairment, not dementia), free of vascular disease at baseline and for whom hemostatic and inflammatory marker data were available and cognitive status was known. A total of 15 hemostatic and 6 inflammatory markers were assessed. Factor analysis was used to identify hemostatic subsystems. The National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurologie criteria were used to identify vascular dementia. By using standardized (z) scores for hemostatic and inflammatory markers, and after adjustment for age and risk factors, vascular dementia was associated with fibrinogen (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.02-2.76), factor VIII (HR, 1.79; 95% CI, 1.09-3.00), and plasminogen activator inhibitor 1 (HR, 3.13; 95% CI, 1.73-5.70). For vascular dementia, the HR risk from high levels of all three hemostatic variables (fibrinogen, factor VIII, and plasminogen activator inhibitor 1) was 2.97 (P<0.001). Inflammatory factors were not associated with vascular dementia.
The associations of these hemostatic markers with vascular dementia may implicate clot formation as the primary mechanism and are consistent with a microinfarct model of vascular dementia.
... In turn, Factor VII and other coagulation factors, such as Factor V, promote thrombin generation, hence further amplifying the coagulation process ( Figure 3). Interestingly, carriers of the mutant form of Factor V Leiden present thrombotic propensity and higher risk of developing dementia (Bots et al., 1998). Additionally, plasma levels of the coagulation Factor XI (Begic et al., 2020) and Factor XIIa (Zamolodchikov et al., 2015) have been found also significantly increased in AD patients ( Figure 3). ...
Alzheimer's disease (AD) and cardiovascular disease (CVD) are strongly associated. Both are multifactorial disorders with long asymptomatic phases and similar risk factors. Indeed, CVD signatures such as cerebral microbleeds, micro‐infarcts, atherosclerosis, cerebral amyloid angiopathy and a procoagulant state are highly associated with AD. However, AD and CVD co‐development and the molecular mechanisms underlying such associations are not understood. Here, we review the evidence regarding the vascular component of AD and clinical studies using anticoagulants that specifically evaluated the development of AD and other dementias. Most studies reported a markedly decreased incidence of composite dementia in anticoagulated patients with atrial fibrillation, with the highest benefit for direct oral anticoagulants. However, sub‐analyses by differential dementia diagnosis were scarce and inconclusive. We finally discuss whether anticoagulation could be a plausible preventive/therapeutic approach for AD and, if so, which would be the best drug and strategy to maximize clinical benefit and minimize potential risks.
LINKED ARTICLES
This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc
... Although not yet tested directly, we consider it likely that this will also be true for infectious diseases known to be causing similar post-infection syndromes, such as Dengue [218][219][220], Ebola [221][222][223], Lyme [224], Zika and others where viruses persist and can cause microangiopathies [139] that we suspect are also amyloid in character. There is also likely to be a role for molecules raised in pre-existing inflammatory diseases, as well as substances produced by dyregulation microbiomes [225], and Leiden factor V [226,227]. ...
Post-acute sequelae of COVID (PASC), usually referred to as 'Long COVID' (a phenotype of COVID-19), is a relatively frequent consequence of SARS-CoV-2 infection, in which symptoms such as breathlessness, fatigue, 'brain fog', tissue damage, inflammation, and coagulopathies (dysfunctions of the blood coagulation system) persist long after the initial infection. It bears similarities to other post-viral syndromes, and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Many regulatory health bodies still do not recognize this syndrome as a separate disease entity, and refer to it under the broad terminology of 'COVID', although its demographics are quite different from those of acute COVID-19. A few years ago, we discovered that fibrinogen in blood can clot into an anomalous 'amyloid' form of fibrin that (like other β-rich amyloids and prions) is relatively resistant to proteolysis (fibrinolysis). The result, as is strongly manifested in platelet-poor plasma (PPP) of individuals with Long COVID, is extensive fibrin amyloid microclots that can persist, can entrap other proteins, and that may lead to the production of various autoantibodies. These microclots are more-or-less easily measured in PPP with the stain thioflavin T and a simple fluorescence microscope. Although the symptoms of Long COVID are multifarious, we here argue that the ability of these fibrin amyloid microclots (fibrinaloids) to block up capillaries, and thus to limit the passage of red blood cells and hence O2 exchange, can actually underpin the majority of these symptoms. Consistent with this, in a preliminary report, it has been shown that suitable and closely monitored 'triple' anticoagulant therapy that leads to the removal of the microclots also removes the other symptoms. Fibrin amyloid microclots represent a novel and potentially important target for both the understanding and treatment of Long COVID and related disorders.
... In a study including elderly participants (>65 years old), the risk of VaD was found to increase with increasing plasma D-Dimer levels [11]. Another study identified elevated plasma D-Dimer and other coagulation and inflammatory serum markers in VaD patients [55]. Hemostasis abnormalities such as increased plasma plasminogen activator inhibitor type 1 (PAI-1), D-Dimer, fibrinogen, and von Willebrand factor (vWF, a marker of endothelial disturbance) were more frequently and significantly observed in patients with VaD than with AD [56,57]. ...
Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA-/-) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA-/- mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA-/- mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA-/- mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.
... Various cohort and case-control-based studies have described an apparent association between higher levels of blood markers of thrombosis and haemostasis and incident dementia or cognitive decline (Bots et al. 1998;Gallacher et al. 2010;Stott et al. 2010). Recent systematic review and meta-analysis have confirmed this link with blood markers; observed associations were strongest for Bvascular^dementia but also apparent for Ball-cause^(undifferentiated) dementias (Quinn et al. 2011). ...
An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.
... With regard to alcohol intake, the outcomes are also controversial, but suggest that light to moderate consumption may decrease the risk of dementia, when compared to abstinence or heavy drinking, in a J-shaped relationship (Xu et al., 2009). Additional risk factors have been suggested, including migraine (Tyas et al., 2001), high intake of saturated fat (Luchsinger and Mayeux, 2004), high serum homocysteine (Kalmijn et al., 1999) and fibrinogen concentrations (Bots et al., 1998), peripheral inflammation (Engelhart et al., 2004), atrial fibrillation (Duron and Hanon, 2010) and head injury (Guo et al., 2000). In the elderly population, studies show a strong inverse association between the levels of mental, social and physical activity and the dementia risk (Wang et al., 2002;Rovio et al., 2005). ...
Investigation in the field of Alzheimer’s disease (AD), the commonest cause of dementia, has been very active in recent years and it may be difficult for the clinician to keep up with all the innovations and to be aware of the implications they have in clinical practice. The authors, thus, reviewed recent literature on the theme in order to provide the clinician with an updated overview, intended to support decision-making on aspects of diagnosis and management. This article begins to focus on the concept of AD and on its pathogenesis. Afterward, epidemiology and non-genetic risk factors are approached. Genetics, including genetic risk factors and guidelines for genetic testing, are mentioned next. Recommendations for diagnosis of AD, including recently proposed criteria, are then reviewed. Data on the variants of AD is presented. First approach to the patient is dealt with next, followed by neuropsychological evaluation. Biomarkers, namely magnetic resonance imaging, single photon emission tomography, FDG PET, PiB PET, CSF tau, and Aβ analysis, as well as available data on their diagnostic accuracy, are also discussed. Factors predicting rate of disease progression are briefly mentioned. Finally, non-pharmacological and pharmacological treatments, including established and emerging drugs, are addressed.
... A longitudinal study with 5.7-year follow-up. Increased fibrinogen was associated with an increased risk of incident dementia This has been independently replicated in other studies [96] [97] D-dimer, TAT and t-PA activity Cross-sectional, case–control study demonstrating increased concentrations associated with a higher prevalence of dementia D-dimer finding was replicated in a longitudinal study against incident dementia [98] [99] Inflammation α1-antichymotrypsin, IL-6 and CRP Increased concentration at baseline was associated with a risk of incident AD. Longitudinal study with 6713 subjects of whom a subcohort of 727 randomly selected individuals were studied along with 188 subjects with dementia at follow-up The CRP finding has been replicated against prevalent MCI and prevalent dementia Low levels of CRP in patients with established AD are associated with a more rapid cognitive and functional decline [52] [53,56] [39] Homocysteine Increased baseline plasma concentration is associated with higher risk of incident AD in longitudinal studies This was independently replicated but not consistently observed ...
Blood-based biomarkers present a considerable challenge: technically, as blood is a complex tissue and conceptually, as blood lacks direct contact with brain. Nonetheless, increasing evidence suggests that there is a blood protein signature, and possibly a transcript signature, that might act to increase confidence in diagnosis, be used to predict progression in either disease or prodromal states, and that may also be used to monitor disease progression. Evidence for this optimism comes partly from candidate protein studies, including those suggesting that amyloid-beta measures might have value in prediction and those studies of inflammatory markers that consistently show change in Alzheimer's disease, and partly from true proteomics studies that are beginning to identify markers in blood that replicate across studies and populations.
... Hemostasis has been proposed as a possible pathogenetic factor in dementia, especially vascular dementia123. To our knowledge there is only one study by Mari et al [1] plasminogen activation potential and thereby a decreased level of proteolytic and fibrinolytic activity. ...
Introduction: The importance of vascular risk factors for Alzheimer’s disease (AD) is not settled. Our aim was to compare patients with AD or vascular dementia (VaD) with non-demented subjects with regard to endothelial derived fibrinolytic and hemostatic factors.
Materials and methods: In a cross-sectional mono-center case-referent study in Örebro, Sweden, we consecutively included 95 patients with AD and 55 with VaD and 154 non-demented active seniors (AS). Plasma biomarkers including the endothelial derived fibrinolytic factors: mass concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA/PAI-1 complex and von Willebrand factor (vWF), as well as clinical data were analyzed.
Results: None of the endothelial derived fibrinolytic markers or vWF differed between AD vs. VaD. In comparison with the AS group, tPA was higher in AD (p=0.001) and VaD (p=0.023) but its inhibitor, PAI-1 mass concentration did not differ significantly; tPA/PAI-1 complex was higher in both VaD (p=0.038) and AD (p=0.005). vWF concentration was lower in the AS group (p<0.001) than in both dementia groups.
Conclusion: Thus, endothelial derived fibrinolytic factors, tPA/PAI-1 complex and vWF, discriminated between the reference group of non-demented elderly and the AD and VaD groups, but not between AD and VaD. This suggests similar disturbances for endothelial derived fibrinolytic and hemostatic factors among AD and VaD patients and may reflect shared vascular pathophysiological mechanisms in the dementias.
... Our finding regarding the association of high level of D-dimer with vascular dementia is consistent with previous reports from case-control studies [21][22][23][24]. Nonetheless, this is the first report where the level of D-dimer is being associated with the incidence of VaD in a large cohort of older subjects. ...
Hemostatic biomarkers have been associated with coronary heart disease (CHD) and stroke. However, few studies have investigated these associations in the elderly. Moreover, vascular factors may be involved in dementia. Data on the relationship between hemostatic biomarkers and dementia remain scarce.
Our study aimed to investigate the relationship between hemostatic biomarkers and the risk of CHD, stroke and dementia in an elderly population.
In the Three-City cohort study including men and women aged > or = 65, we investigated the association of fibrinogen, D-dimer and von Willebrand factor with the 4-year incidence of arterial disease (CHD, n = 199; and stroke, n = 111) and dementia (n = 218). Measurements were performed for all cases and for a random sample of the entire cohort (n = 1254). Hazards ratios (HR) compared the last quintile with the first of each parameter's distribution and P-values refer to the test for linear trend across quintiles.
Elevated fibrinogen was associated with the risk of CHD and myocardial infarction (HR = 2.20, P < 0.05 and 2.45 P < 0.05, respectively). Moreover, high D-dimer was associated with the risk of CHD among younger subjects (aged < 75, HR = 3.64, P < 0.01) but not older subjects (P for interaction = 0.01). Furthermore, the risk of vascular dementia (VaD) increased with D-dimer level (HR = 3.05, P < 0.01).
In the elderly, elevated fibrinogen and D-dimer levels were associated with incident arterial disease. In addition, high D-dimer level could represent a new risk factor for VaD.
... 13 The dementia group was further divided into vascular and Alzheimer's dementia with the use of accepted neurological, neuroimaging, and psychological screening techniques. 13,14 On the basis of the collective data gathered by the Rotterdam Study, it was concluded that vascular risk factors and indicators of vascular disease, particularly in elderly subjects, have an established association with AD. 15,16 The risk factors for AD reported thus far in the Rotterdam Study, many of which have been confirmed by other independent studies, include the following: (1) diabetes mellitus, 17 (2) thrombotic episodes, 18 (3) high fibrinogen concentrations, 19 (4) high serum homocysteine, 20 (5) atrial fibrillation, 16,21 (6) smoking, 22,23 (7) alcoholism, 24 (8) low level of education, 25 and (9) atherosclerosis 26 (Table). All these conditions have a vascular involvement and are known to reduce cerebral perfusion. ...
... Within the pathways of coagulation and fibrinolysis, fibrinogen represents an important marker. Elevated levels of fibrinogen are associated with increased risks of cardiovascular disease and ischaemic stroke [39,40] but the results are less conclusive for vascular dementia [41,42]. Lowe and Haverkate [43] believe that because vascular dementia is only one phenotype of the systemic atherothrombosis disease, associations between haemostatic variables and any given phenotype should be interpreted with caution. ...
Chronic inflammation appears to play a role in the pathogenesis of vascular dementia. Given the association between Chlamydia pneumoniae and stroke, the possibility exists that previous exposure to C. pneumoniae may play a role in vascular dementia. The objective of this study was to determine if there was an association between serological evidence of C. pneumoniae infection or inflammatory markers with vascular dementia.
28 case-patients with vascular dementia at a geriatric clinic and 24 caregiver-controls were tested for C. pneumoniae IgG and IgA antibodies. The association between vascular dementia and C. pneumoniae titres as well as inflammatory markers was estimated by using both conditional logistic regression and stratified logistic regression.
When matched cases were compared to controls, there was no significant difference in elevated C. pneumoniae specific IgG antibodies (titre >or= 1:32), odds ratio [OR] 1.3 (95% confidence intervals [CI] 0.3 to 6.0), p = 0.71, or in elevated C. pneumoniae specific IgA antibodies (titre >or= 1:16), OR 2.0 (95%CI 0.5 to 8.0), p = 0.33 indicative of past or persistent C. pneumoniae infection. Similarly, no difference in high IgG or IgA antibody levels (IgG titre >or= 1:512 or IgA titre >or= 1:64) between the two groups, indicative of recent C. pneumoniae infection, was found, OR 0.4 (95%CI 0.1 to 2.1), p = 0.27. For C-reactive protein (CRP), the mean difference between 18 matched pairs (case - control) was - 3.33 mg/L. There was no significant difference between cases and controls when comparing log transformed values, OR 0.03 (95%CI 0.00 to 2.89), p = 0.13 or comparing CRP values above or below the median, OR 0.8 (95%CI 0.2 to 3.4), p = 0.71. For fibrinogen, the mean difference between pairs (case - control) was -0.07 g/L. There was no statistical difference between cases and controls when comparing log transformed values, OR 0.6 (95%CI 0.0 to 31.2), p = 0.79 or between fibrinogen values above and below the median, OR = 0.5 (95%CI 0.1 to 2.0), p = 0.50.
We found no evidence for a significant association between C. pneumoniae infection, inflammatory markers such as CRP and fibrinogen, and vascular dementia.
Measures of cardiovascular health (CVH) assessed by a combination of behavioral and biological factors has shown protective associations with all-cause mortality. The mechanisms underlying these associations have not been fully elucidated. In this study, we characterized the plasma proteomics profile of CVH and tested whether specific proteins mediated the associations between CVH and all-cause mortality in participants of the InCHIANTI study. Of the 1301 proteins tested, 92 proteins were associated with CVH (22 positively, 70 negatively). Proteins most strongly associated with CVH included leptin (LEP), fatty acid binding protein 3 (FABP3), Angiopoietin-2 (ANGPT2), and growth-differential factor 15 (GDF15). Of the 92 CVH-associated proteins, 33 proteins significantly mediated the associations between CVH and all-cause mortality, with percent mediation ranging from 5 to 30%. The most significant mediating proteins were GDF15 and insulin-like growth factor 2 (IGFBP2). Proteins associated with better CVH were enriched for proteins that reflect the suppression of the complement coagulation and GH/IGF pathways.
Background Transcatheter aortic valve implantation (TAVI) is an evolving treatment of severe aortic valve stenosis. However, thromboembolic events such as stroke are common, predominantly early after TAVI. Optimal periprocedural antithrombotic regime is unknown. Especially, as antithrombotic medication enhances bleeding risk, thrombin generation and platelet function are crucial in the pathogenesis of ischemic events. However, the impact of the TAVI procedure on thrombin formation and platelet reactivity is not known by now.
Methods We evaluated thrombin levels using thrombin–antithrombin (TAT) complexes and prothrombin fragments (PTFs) using enzyme-linked immunosorbent assay. Furthermore, platelet reactivity was measured via light transmission aggregometry before and 2 hours after TAVI in 198 patients.
Results TAT complexes and PTF F1 + 2 substantially increased during TAVI. Postprocedurally, TAT complexes and PTF were significantly higher after TAVI compared with percutaneous coronary intervention due to acute myocardial infarction, while preprocedural TAT complexes and PTF F1 + 2 did not differ. In contrast, platelet reactivity was not altered early after TAVI. Only adenosine diphosphate-induced aggregation was reduced, reflecting preprocedural loading with clopidogrel.
Conclusion In this pilot study, we were able to demonstrate that thrombin generation is significantly increased early after TAVI, while platelet function is not affected. Increased thrombin concentrations may contribute to the high risk of postprocedural thromboembolic events. This leads to the hypothesis that extended peri-interventional anticoagulation early after TAVI may be an approach to reduce thromboembolic events.
Background:
The aim of this meta-analysis is to evaluate the association of fibrinogen with risk of dementia and its subtypes.
Methods:
Embase, Pubmed and Web of Science were retrieved systematically up to February 2019. Standard mean difference (SMD) with 95% confidence intervals was estimated using random-effects models.
Results:
Sixteen studies involving 3,649 participants were summarized. Patients with all-cause dementia exhibited higher fibrinogen levels than those in non-dementia controls (SMD = 0.90 [0.43;1.36] p < 0.01). Further subgroup analysis revealed a positive association of fibrinogen with vascular dementia (VaD) (SMD=1.11 [0.45;1.78] p < 0.01) rather than Alzheimer's disease (AD) (SMD=0.01 [-0.17;0.19]) p = 0.92) and Parkinson's disease dementia (PDD) (SMD=0.35 [-0.23;0.93] p = 0.24). This correlation was significant in Europeans (SMD=0.92 [0.34;1.49] p < 0.01), but probably not in Asian based populations (SMD=1.04 [-0.09;2.17] p = 0.07), and gradually declined with advancing age (60≤age<70: SMD=1.22 [0.38;2.06] p < 0.01; 70≤age<80: SMD=0.29 [0.04;0.53] p = 0.02; age≥80: SMD=0.01 [-0.12;0.15] p = 0.84).
Conclusions:
Plasma fibrinogen is a potential risk factor for all-cause dementia and VaD under the age of 80, and is more obvious in cohorts with people of European descent.
Die vorliegende Übersicht zu den Demenzerkrankungen versucht, klinisch besonders relevante Aspekte von Diagnostik und Therapie in den Vordergrund zu stellen, dabei aber gleichzeitig wichtige molekular-pathophysiologische Grundlagen zu vermitteln, die vielfach für das tiefere Verständnis diagnostischer Verfahren und therapeutischer Behandlungsansätze unverzichtbar sind. Dabei werden aktuelle Entwicklungen in Diagnostik und Therapie berücksichtigt, aber es wird mit Bezug auf die aktualisierten S3-Leitlinien „Demenzen“ (Langversion, Januar 2016) differenziert, ob diese bereits Eingang in die klinische Praxis genommen haben oder sich noch in der Phase der Validierung befinden. Die vorliegende Übersicht macht deutlich, dass Demenz bei mehr als 70 Demenzerkrankungen ein ausgesprochen heterogenes Syndrom ist, wobei zwischen primär degenerativen und den zu einem geringen Anteil sekundären Demenzen unterschieden werden kann. Neben der bisher weiltweit weiter verbindlichen ICD-10-Klassifikation stellen wir auch die konzeptionell tiefgreifend modifizierte neue DSM-5-Klassifikation neurokognitiver Störungen vor, die den klassischen Demenzbegriff auflöst. Weiterhin macht die aktuelle klinische Forschung und internationale Leitlinienentwicklung deutlich, dass diagnostische Biomarker für eine „State of the art“ Früh- und Differenzialdiagnostik demenzieller Erkrankungen auch für die klinische Praxis einen wichtigen Beitrag leisten. Biomarkergestützt konnte zwischenzeitlich auch eine molekular-prädiktive Diagnostik der drohenden Demenz etabliert werden, die zwar für die klinische Praxis zur Zeit noch keinen hohen Stellenwert einnimmt, aber innerhalb der klinischen Therapieforschung zu dringend benötigten ersten präventiven Behandlungsansätzen bereits unverzichtbar geworden ist. In diesem Zusammenhang werden auch neuere diagnostische Klassifikationen vorgestellt, die zwar noch nicht Eingang in die ICD-10 genommen haben, aber bereits international validiert wurden und bereits für zulassungsrelevante Medikamentenstudien eingesetzt werden. In kaum einem anderen Bereich der Psychiatrie hat die biomarkerunterstützte Diagnostik einen so hohen Stellenwert eingenommen wie im Bereich demenzieller Erkrankungen und hier zeichnet sich ab, dass über diesem Ansatz neue Subphänotypen von Demenzerkrankungen beschrieben werden können, die wahrscheinlich zukünftig auch für subphänotypspezifische Therapieansätze relevant werden.
Die vorliegende Übersicht zu den Demenzerkrankungen versucht, klinisch besonders relevante Aspekte von Diagnostik und Therapie in den Vordergrund zu stellen, dabei aber gleichzeitig wichtige molekular-pathophysiologische Grundlagen zu vermitteln, die vielfach für das tiefere Verständnis diagnostischer Verfahren und therapeutischer Behandlungsansätze unverzichtbar sind. Dabei werden aktuelle Entwicklungen in Diagnostik und Therapie berücksichtigt, aber es wird mit Bezug auf die aktualisierten S3-Leitlinien „Demenzen“ (Langversion, Januar 2016) differenziert, ob diese bereits Eingang in die klinische Praxis genommen haben oder sich noch in der Phase der Validierung befinden. Die vorliegende Übersicht macht deutlich, dass Demenz bei mehr als 70 Demenzerkrankungen ein ausgesprochen heterogenes Syndrom ist, wobei zwischen primär degenerativen und den zu einem geringen Anteil sekundären Demenzen unterschieden werden kann. Neben der bisher weiltweit weiter verbindlichen ICD-10-Klassifikation stellen wir auch die konzeptionell tiefgreifend modifizierte neue DSM-5-Klassifikation neurokognitiver Störungen vor, die den klassischen Demenzbegriff auflöst. Weiterhin macht die aktuelle klinische Forschung und internationale Leitlinienentwicklung deutlich, dass diagnostische Biomarker für eine „State of the art“ Früh- und Differenzialdiagnostik demenzieller Erkrankungen auch für die klinische Praxis einen wichtigen Beitrag leisten. Biomarkergestützt konnte zwischenzeitlich auch eine molekular-prädiktive Diagnostik der drohenden Demenz etabliert werden, die zwar für die klinische Praxis zur Zeit noch keinen hohen Stellenwert einnimmt, aber innerhalb der klinischen Therapieforschung zu dringend benötigten ersten präventiven Behandlungsansätzen bereits unverzichtbar geworden ist. In diesem Zusammenhang werden auch neuere diagnostische Klassifikationen vorgestellt, die zwar noch nicht Eingang in die ICD-10 genommen haben, aber bereits international validiert wurden und bereits für zulassungsrelevante Medikamentenstudien eingesetzt werden. In kaum einem anderen Bereich der Psychiatrie hat die biomarkerunterstützte Diagnostik einen so hohen Stellenwert eingenommen wie im Bereich demenzieller Erkrankungen und hier zeichnet sich ab, dass über diesem Ansatz neue Subphänotypen von Demenzerkrankungen beschrieben werden können, die wahrscheinlich zukünftig auch für subphänotypspezifische Therapieansätze relevant werden.
Vascular disease and Alzheimer’s disease are both common disorders, in particularly among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemiological studies have suggested that the risk factors for vascular disease and stroke are associated with cognitive impairment and Alzheimer’s disease, and that the presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer’s disease. In this chapter, current knowledge on the relation between vascular risk factors and Alzheimer’s disease is reviewed.
Das Demenzsyndrom ist durch die progrediente Entwicklung vielfältiger kognitiver und psychopathologischer Defizite charakterisiert, wobei neben einer Merkfähigkeits - und Gedächtnisstörung weitere kognitive Einbußen (»Werkzeugstörungen «) vorhanden sein müssen: Hierzu zählen z. B. Orien tierungs-, Aufmerksamkeits- und Konzentrationsstörungen, Aphasie, Apraxie, Agnosie, Alexie, Akalkulie, Visuo - konstruktion oder eine Beeinträchtigung der Exekutivfunktionen (Planen, Organi sieren, Abstrahieren). Im Vergleich zur noch z. T. verbreiteten deutschsprachigen Tradition, in der der Demenzbegriff ausschließlich auf schwere fortgeschrittene Zustände intellektuellen Abbaus angewendet wurde, ist die moderne Definition erheblich weiter gefasst (American Psychiatric Association 1994). Die Störung kann reversibel oder irreversibel sein, muss aber das Gedächtnis betreffen und darf nicht mit einer qualitativen Bewusstseinsstörung einhergehen. Das Ausmaß der kognitiven Defizite muss zu einer individuell bedeutsamen Beeinträchtigung der Alltagsbewältigung führen und eine Verschlechterung gegenüber einem zuvor höheren Leistungsniveau darstellen.
Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer's disease (AD) at an early stage in the disease process.
In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment).
The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP) were consistently increased in all groups with dementia but only in some of their incipient states.
In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration.
Advances in epidemiological, clinical, imaging, and neuropathological studies have undermined the clear distinction between vascular and Alzheimer-type dementia, which has characterized the last two decades of research in dementia. A significant degree of overlap between the two entities was demonstrated in terms of clinical expression, risk factors, and postmortem brain autopsy. In this article, we propose mechanisms by which cardiovascular risk factors might affect the manifestation of Alzheimer's disease, suggest possible explanations for the overlap with vascular dementia, and discuss the implications this might have on future differential diagnosis and treatment strategies.
This review discusses the experimental and clinical data which indicate that chronic cerebral hypoperfusion can affect metabolic, anatomic, and cognitive function adversely. In aged but not young animals, chronic brain hypoperfusion results in regional pre- and post-synaptic changes, protein synthesis abnormalities, energy metabolic dysregulation, reduced glucose utilization, cholinergic receptor loss, and visuo-spatial memory deficits. Additionally, aging animals that are kept for prolonged periods of time after chronic brain hypoperfusion, also develop brain capillary degeneration in CA1 hippocampus and neuronal damage extending from the hippocampal region to the temporo-parietal cortex where neurodegenerative tissue atrophy eventually forms. All these pathologic events occur in rodents in the absence of senile plaques and neurofibrillary tangles. Alzheimer brains reveal similar biochemical and structural changes as those experimentally induced in aging animals. Moreover, regional cerebral hypoperfusion is one of the earlier (if not the earliest) clinical manifestations in both the sporadic and familial forms of Alzheimer's disease. In addition, therapy that improves or increases cerebral perfusion is generally of some benefit to Alzheimer patients. Conversely, a variety of disorders with different etiologies that impair or diminish cerebral perfusion are reported to be risk factors for this dementia. These findings have prompted us to propose the concept that advanced aging in the presence of a vascular risk factor can converge to create a critically attained threshold of cerebral hypoperfusion (CATCH) that triggers regional brain microcirculatory disturbances and impairs optimal delivery of energy substrates needed for normal brain cell function. The outcome of this defect generates a chain of events leading to the progressive evolution of brain metabolic, cognitive and tissue pathology that characterize Alzheimer's disease. The possible role of CATCH in familial and early onset Alzheimer's disease is briefly discussed from a theoretical vantagepoint. The growing and most recent evidence in support of the CATCH concept is the focus of this review.
Vascular disease and Alzheimer's disease are both common disorders, in particular among elderly subjects. Therefore, it can be expected that the joint occurrence of these two disorders is not a rare phenomenon. In recent years, evidence is increasing that the two may be more closely linked than just by chance. Epidemiological studies have suggested that risk factors for vascular disease and stroke are associated with cognitive impairment and Alzheimer's disease, and that the presence of cerebrovascular disease intensifies the presence and severity of the clinical symptoms of Alzheimer's disease. In this paper, current knowledge on the relation between vascular risk factors and risk indicators and Alzheimer's disease will be reviewed.
The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now.
Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease.
Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings.
Although Alzheimer s disease is classified as a neurodegenerative dementia, in Alzheimer s dementia there is increasing evidence of an association with vascular risk factors and vascular pathology. These observations are supported by epidemiological and pathological studies. Vascular factors may play a significant role in the pathogenesis of Alzheimer s dementia. Further research is needed to explore this relationship. Modification of vascular risk factors could make a significant impact towards prevention and treatment of Alzheimer s disease, which is a distressing and prevalent condition in the community. This article considers the relationship of these vascular risk factors and potential mechanisms associated with the aetiopathogenesis of Alzheimer s dementia.
Considerable evidence now indicates that Alzheimer's disease (AD) is primarily a vascular disorder. This conclusion is supported by the following evidence: (1) epidemiologic studies linking vascular risk factors to cerebrovascular pathology that can set in motion metabolic, neurodegenerative, and cognitive changes in Alzheimer brains; (2) evidence that AD and vascular dementia (VaD) share many similar risk factors; (3) evidence that pharmacotherapy that improves cerebrovascular insufficiency also improves AD symptoms; (4) evidence that preclinical detection of potential AD is possible from direct or indirect regional cerebral perfusion measurements; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathology in AD and VaD; (7) evidence that cerebral hypoperfusion can trigger hypometabolic, cognitive, and degenerative changes; and (8) evidence that AD clinical symptoms arise from cerebromicrovascular pathology. The collective data presented in this review strongly indicate that the present classification of AD is incorrect and should be changed to that of a vascular disorder. Such a change in classification would accelerate the development of better treatment targets, patient management, diagnosis, and prevention of this disorder by focusing on the root of the problem. In addition, a theoretical capsule summary is presented detailing how AD may develop from chronic cerebral hypoperfusion and the role of critically attained threshold of cerebral hypoperfusion (CATCH) and of vascular nitric oxide derived from endothelial nitric oxide synthase in triggering the cataclysmic cerebromicrovascular pathology.
To investigate the effect of coagulation and inflammatory pathway activation on future cognitive decline in older persons.
Prospective cohort study.
Rural and urban communities in North Carolina.
Community-dwelling older people enrolled in the Duke Established Populations for Epidemiologic Studies of the Elderly in 1986.
In 1992, blood was drawn for assay of D-dimer (1,723 subjects), Interleukin-6 (1,726 subjects), and other cytokines (1,551 subjects). Cognitive and functional assessments were performed in 1986, 1989, 1992, and 1996. Cognition was measured using the Short Portable Mental Status Questionnaire.
Cognitive decline over a 4-year period was significantly correlated (P<.001) with D-dimer, age, race, and physical performance status as measured using the Rosow-Breslau and Nagi instruments. After controlling for demographics, functional status, and comorbidities, D-dimer remained predictive of cognitive decline. Proinflammatory cytokines were not associated with current cognitive status in cross-sectional analyses or with incident cognitive decline in prospective analyses.
In a large sample of community-dwelling elders, higher levels of D-dimer were predictive of cognitive decline over a 4-year period. No clinically significant associations were found between age-related peripheral cytokine dysregulation and cognition.
The distinction between Alzheimer's disease and vascular dementia, the two most common types of dementia, has been undermined by recent advances in epidemiologic, clinical, imaging, and neuropathological studies. Cardiovascular risk factors, traditionally regarded as distinguishing criteria between the two entities, have been shown to be associated with both AD and vascular dementia. In this article, we propose mechanisms of action of cardiovascular risk factors in AD, suggest possible explanations for the overlap with vascular dementia and discuss the implications this might have on future differential diagnosis, research, and treatment strategies.
Considerable evidence now indicates that Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences. As a result, AD and vascular dementia (VaD) can each be described as a 'vasocognopathy'. The term better describes the origin of the disease (vaso: vessel/blood flow), its primary effect on a system (-cogno: relating to cognition) and its clinical course (-pathy: disorder). Evidence that AD is a vasocognopathy is partly supported by the following multidisciplinary findings: (1) epidemiologic studies linking AD and vascular risk factors to cerebral hypoperfusion; (2) evidence that AD and vascular dementia (VaD) share practically all reported risk factors; (3) evidence that pharmacotherapy which increases or improves cerebral perfusion lowers AD symptoms; (4) evidence of preclinical detection of AD candidates using regional cerebral perfusion and glucose uptake studies; (5) evidence of overlapping clinical symptoms in AD and VaD; (6) evidence of parallel cerebrovascular and neurodegenerative pathologic markers (including plaques and tangles) in AD and VaD; (7) evidence that cerebral infarction increases AD incidence by 50%; (8) evidence that chronic brain hypoperfusion can trigger hypometabolic, cognitive and neurodegenerative changes typical of AD; (9) evidence that most autopsied AD brains contain cerebrovascular pathology; (10) evidence that mild cognitive impairment (a transition stage for AD) converts to AD or VaD in 48% and 56% of cases, respectively, within several years. The collective evidence presented here poses a powerful argument for the re-classification of AD as a vascular disorder. Re-classification would allow a new strategy that could result in the tactical development and application of genuinely effective treatments, provide earlier diagnosis and reduce AD prevalence by focusing on the root of the problem.
Cigarette smoking is a major risk factor for clinical cardiovascular disease and may also be associated with poorer cognitive functioning in older age. We measured lifetime cigarette smoking, smoking status and cognitive function in over 2,000 men and women from the general population aged over 50 years with subclinical atherosclerosis (ankle brachial pressure index<or=0.95 but no history of clinical cardiovascular disease). In this population, an association was found between greater lifetime smoking and poorer cognitive function in men and between smoking cessation and better cognitive function in women. The former relationship appeared to reflect an association between smoking habit and prior cognitive function (in early life), whereas the latter remained significant after adjustment for tests of crystallised cognitive function, suggesting a relationship between continuing to smoke (as opposed to quitting) and age-related cognitive decline. Both relationships were independent of the degree of atherosclerosis (as measured using the ankle brachial pressure index), suggesting alternative underlying mechanisms for the association between smoking and human adult cognitive function.
There is now sizable literature on the association between traditional cardiovascular risk factors and Alzheimer's disease (AD). Based on epidemiologic studies, both cross-sectional and longitudinal, there are statistically significant correlations between the prevalence of AD and diabetes, hypercholesterolemia, hypertension, hyperhomocysteinemia, dietary saturated fats, cholesterol, antioxidants, alcohol consumption, smoking, physical activity, the presence of atrial fibrillation, atherosclerotic disease, and the plasma concentration of some hemostatic factors. Most of the cardiovascular risk factors found to be associated with AD are age-dependent, and the prevalence of AD increases with age. Therefore, the association could simply be attributed to aging. On the other hand, the common pathogenetic mechanisms for the generation of both atherosclerotic disease and AD, such as inflammation and the generation of free radicals, suggest a causal link. If this is the case, the identification of modifiable risk factors for dementia becomes a research priority and early intervention aimed at reducing those cardiovascular risk factors a therapeutic imperative.
Serine protease inhibitors (serpins), the acute phase reactants and regulators of the proteolytic processing of proteins, have been recognized as potential contributors to the pathogenesis of Alzheimer disease (AD). We measured plasma and CSF levels of serpins in controls and patients with dementia.
Using rocket immunoelectrophoresis, ELISA, and Luminex xMAP technology, we analyzed plasma levels of alpha(1)-antichymotrypsin and alpha(1)-antitrypsin, and CSF levels of alpha(1)-antichymotrypsin, alpha(1)-antitrypsin, and neuroserpin along with three standard biomarkers (total tau, tau phosphorylated at threonine-181, and the A beta(1-42)) in patients with AD (n = 258), patients with dementia with Lewy bodies (DLB; n = 38), and age-matched controls (n = 37).
The level of CSF neuroserpin was significantly higher in AD compared with controls and DLB, whereas CSF alpha(1)-antichymotrypsin and alpha(1)-antitrypsin were significantly higher in both AD and DLB groups than in controls. Results from logistic regression analyses demonstrate a relationship between higher CSF levels of alpha(1)-antichymotrypsin and neuroserpin and increased predicted probability and odds ratios (ORs) of AD (OR 5.3, 95% CI 1.3 to 20.8 and OR 3.3, CI 1.3 to 8.8). Furthermore, a logistic regression model based on CSF alpha(1)-antichymotrypsin, neuroserpin, and A beta(1-42) enabled us to discriminate between AD patients and controls with a sensitivity of 94.7% and a specificity of 77.8%.
Higher CSF levels of neuroserpin and alpha(1)-antichymotrypsin were associated with the clinical diagnosis of Alzheimer disease (AD) and facilitated the diagnostic classification of AD vs controls. CSF serpin levels did not improve the diagnostic classification of AD vs dementia with Lewy bodies.
Objective: The platelet specific protein, β-thromboglobulin has been suggested to be a sensitive marker of in vivo platelet activation. The aim of the present study was to evaluate β-thromboglobulin levels in an elderly population and to determine to which extent β-thromboglobulin levels are associated with blood sampling procedures. Methods: This report presents baseline findings on β-thromboglobulin of the first 2,831 participants of the Rotterdam Study, a population based prospective cohort study among persons aged 55 years and over. Nonfasting blood samples were taken at varying times during the day. β-Thromboglobulin was assayed by an ELISA method. Applied stasis and quality of blood flow during sampling were registered on three grade scales. Results: The overall mean level of β-thromboglobulin was 69.2 (SD 75.5) IU/ml (range 6–612 IU/ml). In women and to a lesser extent in men, β-thromboglobulin was positively associated with age. According to increasing stasis applied during sampling mean β-thromboglobulin levels were 65.3 (SE 2.31), 74.1 (3.18), 77.6 (8.66) IU/ml. Mean β-thromboglobulin in three grades of decreasing quality of blood flow were 69.0 (1.73), 104.0 (11.5), 86.0 (23.7) IU/ml. Mean levels of β-thromboglobulin differed slightly, but significantly between the 14 laboratory technicians who collected the blood. Conclusion: In elderly women and to a lesser extent in elderly men, β-thromboglobulin is positively associated with age. A wide range in β-thromboglobulin is found in elderly subjects which is determined to a limited extent by quality of blood sampling.
Thrombin was detected immunohistochemically in brain tissue of Alzheimer's disease (AD) patients and age-matched controls. Positive staining was restricted to vessels and residual plasma in controls but was also present in senile plaques, some diffuse amyloid deposits and neurofibrillary tangles in AD. Positive staining was abolished by absorption of antibody with purified human thrombin but not by absorption with prothrombin. The data suggest that thrombin formation from prothrombin probably takes place in AD brain.
Broad spectrum assays which measure a range of fibrinogen/fibrin derivatives (FDPs) in serum have become an established means of identifying activation of blood coagulation and/or fibrinolysis, such as occurs in disseminated intravascular coagulation (DIC). There is considerable interest in the application of these assays to the diagnosis of other hypercoagulable states, such as recurrent deep venous thrombosis and myocardial infarction. In recent years, more sensitive and specific FDP assays (e.g. for fragment E, fragment E neoantigen, D-dimer, fragment D neoantigen, fibrinopeptide A and fibrin fragment beta 15-42) have been devised, some of which allow measurement in plasma of FDPs without interference from fibrinogen or certain of its derivatives. It was predicted that these assays would both avoid the possibility of artifacts introduced as a consequence of serum preparation and improve detection of hypercoagulable states. In the light of these expectations we have reviewed data published on the use of assays to detect clinical hypercoagulability, giving prominence to assays of crosslinked fibrin derivatives and nothing particularly certain studies that have compared the performance of different assays on the same samples. The accumulating evidence indicates that all of the assays are adequate for detection of DIC. The same cannot be said for other hypercoagulable states. Here much variation is evident between different studies of similar patients in the ability of a particular marker to discriminate between a normal control group and patients determined to be hypercoagulable by an independent method. This variability would seem to be a function of patient group heterogeneity and selection, as assays that detect different antigenic determinants produce results on the same plasma samples that are well correlated. It appears that the precise antigenic determinant does not critically affect detection of hypercoagulability. Additionally, some studies have indicated that use of serum need not introduce artifacts. Despite there being no other obvious advantage, the convenience of some of the plasma assays may well encourage their widespread use. Assays have also been developed for measuring activation fragments of coagulation proteins (e.g. prothrombin fragment F1 + 2 and protein C activation peptide) and for proteinase inhibitor complexes (e.g. thrombin-antithrombin complex) generated during activation of coagulation. The latter assays have been useful in providing a biochemical definition of a 'prethrombotic state'.
In recent years, interest in vascular causes of dementia has increased and it has been proposed that vascular dementia (VAD) may be more common than previously supposed. This may have important implications, because VAD at present may be more amenable to prevention and treatment than Alzheimer's disease (AD). Several vascular factors have been related to cognitive decline and dementia in the elderly, including stroke and white matter disease. However, while numerous case-control studies have been concerned with the risk factors for AD, studies on risk factors for VADs are rare. The problems inherent in the diagnostic criteria make it difficult to interpret the results from the few studies that have been performed. Generally, risk factors for multi-infarct dementia are supposed to be the same as those for stroke, and include hypertension, diabetes mellitus, advanced age, male sex, smoking and cardiac diseases. White matter dementia has mainly been related to hypertension. Recent research suggests that vascular factors may also be important in AD, especially in the late-onset type. In stroke patients, dementia has been associated with higher age, less formal education, cerebral atrophy, left-sided or bilateral infarcts, volume of macroscopic infarcts, bilateral symptoms, previous stroke and white matter lesions. The pathogenetic mechanism through which these factors cause dementia is still not clear. Furthermore, it is not known if risk factors for VAD differ from those found in stroke patients. There is now an urgent need for further research on risk factors for VAD and on factors related to dementia in subjects with cerebrovascular disorders.
Vascular disorders have been implicated in dementia, but whether atherosclerosis is related to the most frequent type of dementia, Alzheimer's disease, is not known. The apolipoprotein-E genotype has been associated with Alzheimer's disease, and we postulate that it plays a part, together with atherosclerosis, in the aetiology of Alzheimer's disease. We investigated the frequency of dementia and its subtypes in relation to atherosclerosis and apolipoprotein E.
We did a population-based study of 284 patients with dementia, 207 of whom had Alzheimer's disease, and 1698 individuals who were not demented. Indicators of atherosclerosis included vessel wall thickness and plaques of the carotid arteries, assessed by ultrasonography, and the ratio of ankle-to-brachial systolic blood pressure as a measure of generalised atherosclerosis. Based on these indicators participants were scored from 0 (no atherosclerosis) to 3 (severe atherosclerosis) for degree of atherosclerosis. Apolipoprotein-E polymorphisms were assessed in 246 patients and in 928 controls.
All indicators of atherosclerosis were associated with dementia (odds ratios ranging from 1.3 to 1.9) and its major subtypes Alzheimer's disease (odds ratios 1.3-1.8) and vascular dementia (odds ratios 1.9-3.2). The frequencies of all dementia. Alzheimer's disease, and vascular dementia increased with the degree of atherosclerosis. The odds ratio for Alzheimer's disease in those with severe atherosclerosis compared with those without atherosclerosis was 3.0 (95% CI 1.5-6.0; p = 0.001). In participants with the apolipoprotein-E epsilon 4 genotype and an atherosclerosis score of 2 or 3 the odds ratio for all dementia was 4.5 (2.0-10.1; p < 0.001), for Alzheimer's disease was 3.9 (1.6-9.6; p = 0.002), and for vascular dementia was 19.8 (4.1-95.0; p < 0.001).
These findings suggest that dementia and its two major subtypes Alzheimer's disease and vascular dementia are associated with atherosclerosis and that there is an interaction between apolipoprotein E and atherosclerosis in the aetiology of Alzheimer's disease.