Coagulation and Fibrinolysis Markers and Risk of Dementia

Bots, Michiel L.; Breteler, Monique M.B.; Kooten, Fop van; Haverkate, F.; Meijer, Piet; Koudstaal, Peter J.; Grobbee, Diederick E.; Kluft, C.

doi:10.1159/000022433

Cited by 35 publications

(42 citation statements)

References 15 publications

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“…DISCUSSION In the present study, we promote the hypothesis that the complex pathologies of AD and DLB are reflected in concentrations of plasma and CSF inflammatory markers. [38][39][40][41][42] To * Associations between the levels of measured variables and Alzheimer disease (AD) vs controls. † Associations between the levels of measured variables and dementia with Lewy bodies (DLB) vs controls.…”

Section: Results Patient Characteristicsmentioning

confidence: 99%

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Nielsen¹,

Minthon²,

Londos³

et al. 2007

Neurology

110

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Objective: 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.Methods: Using rocket immunoelectrophoresis, ELISA, and Luminex xMAP technology, we analyzed plasma levels of ␣ 1 -antichymotrypsin and ␣ 1 -antitrypsin, and CSF levels of ␣ 1 -antichymotrypsin, ␣ 1 -antitrypsin, and neuroserpin along with three standard biomarkers (total tau, tau phosphorylated at threonine-181, and the A␤ 1-42 ) in patients with AD (n ϭ 258), patients with dementia with Lewy bodies (DLB; n ϭ 38), and age-matched controls (n ϭ 37). Results:The level of CSF neuroserpin was significantly higher in AD compared with controls and DLB, whereas CSF ␣ 1 -antichymotrypsin and ␣ 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 ␣ 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 ␣ 1 -antichymotrypsin, neuroserpin, and A␤ 1-42 enabled us to discriminate between AD patients and controls with a sensitivity of 94.7% and a specificity of 77.8%. Conclusions:Higher CSF levels of neuroserpin and ␣ 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. Neurology ® 2007;69:1-1 GLOSSARY AAT ϭ ␣1-antitrypsin; ACT ϭ ␣1-antichymotrypsin; AD ϭ Alzheimer disease; ApoE ϭ apolipoprotein E; AUC ϭ area under the curve; BBB ϭ blood-brain barrier; COPD ϭ chronic obstructive pulmonary disease; %CV ϭ coefficients of variation percentage; DLB ϭ dementia with Lewy bodies; IL ϭ interleukin; MMSE ϭ Mini-Mental State Examination; NSAIDs ϭ nonsteroidal anti-inflammatory drugs; OR ϭ odds ratio; P-tau ϭ tau phosphorylated at threonine-181; ROC ϭ receiver operating characteristic; T-tau ϭ total tau.In addition to ␤-amyloid plaques and neurofibrillary tangles, the pathology of Alzheimer disease (AD) is characterized by excessive inflammation.1 Inflammation is driven by cytokines (particularly interleukin [IL]-1) that are released from activated microglia and astrocytes, 2 and this in turn drives the expression of IL-6 3 and inducible nitric oxide synthase. 4 Neuronal proteases that are released as part of the inflammatory response are controlled by a variety of inhibitors including members of the serine protease inhibitor (serpin) superfamily.5 These include ␣ 1 -antichymotrypsin, ␣ 1 -antitrypsin, and neuroserpin. The important role of ␣ 1 -antichymotrypsin in the pathogenesis of AD was demone-Pub ahead of print at www.neurology.org.

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Section: Results Patient Characteristicsmentioning

confidence: 99%

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Nielsen¹,

Minthon²,

Londos³

et al. 2007

Neurology

110

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

Activation of Hemostasis and Decline in Cognitive Function in Older People

Stott

Robertson²,

Rumley³

et al. 2010

ATVB

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Objective-To determine whether activation of hemostatic function (thrombosis and fibrinolysis) is associated with cognitive decline in older people. Methods and Results-We studied 5804 people (age, 70 -82 years) Key Words: aging Ⅲ cognition Ⅲ fibrinolysis Ⅲ stroke Ⅲ thrombosis V ascular disease is an important and potentially preventable contributor to cognitive decline and dementia in older people. 1 Postmortem studies have shown that Alzheimer pathology is important; however, on its own it is often not sufficient to cause major cognitive impairment. However the combination of Alzheimer pathology and ischemic cerebrovascular disease (particularly small-vessel ischemia) has particular risk for dementia. 2 Longitudinal population studies have shown that traditional vascular risk factors, particularly hypertension, diabetes mellitus, and cigarette smoking, are associated with increased risk of dementia. 3,4

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“…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 Ballcause^(undifferentiated) dementias (Quinn et al 2011).…”

Section: Introductionmentioning

confidence: 98%

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

Quinn

Alghamdi

Padmanabhan

et al. 2015

AGE

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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.

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Coagulation and Fibrinolysis Markers and Risk of Dementia

Cited by 35 publications

References 15 publications

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies

Activation of Hemostasis and Decline in Cognitive Function in Older People

Association between cognition and gene polymorphisms involved in thrombosis and haemostasis

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