Abstracts of online articleStructural brain changes and cognition in relation to markers of vascular dysfunction
Introduction
Vascular dysfunction is an important contributor to cognitive decline and dementia (Gorelick et al., 2011). Brain vascular-related changes (i.e., brain atrophy, small vessel disease [SVD] and clinical stroke) represent the link between vascular risk factors (VRF) and cognition (Bowler and Gorelick, 2009, Knopman and Roberts, 2010). In addition, biological aging of the brain is partly attributable to aging of the cerbrovascular circulation and the effects of these vascular changes on the brain (Kennedy and Raz, 2009).
Because VRF are treatable, it is possible to prevent, postpone, and/or mitigate cerebrovascular disease (CVD) and subsequent vascular cognitive impairment (VCI). Therefore, identification of individuals at higher risk of VCI is of utmost importance. Biomarkers reflect core elements of the disease process and have been proposed as potential tools for early diagnosis of CVD and VCI (Gorelick et al., 2011).
Imaging biomarkers, especially magnetic resonance imaging (MRI)-based measures of gray matter (GM) atrophy and white matter (WM) integrity, are regarded as possible indicators of disease state and progression (Bowler and Gorelick, 2009).
Blood markers of vascular dysfunction reflect the underlying pathology and provide an independent measure of pathology based on biology. Their association with subclinical brain changes is still unclear. Whereas some studies have linked them with silent brain infarcts (Fornage et al., 2008, Hoshi et al., 2005), WM abnormalities (Fornage et al., 2008, van Dijk et al., 2005, Wersching et al., 2010), and cognition (Laurin et al., 2009, Noble et al., 2010, Wersching et al., 2010) others failed to do so (Schmidt et al., 2006, van Dijk et al., 2005, Weuve et al., 2006).
We will focus on markers of inflammation, insulin resistance, and impaired endogenous fibrinolysis. These mechanisms might play a relevant role in the pathogenesis and progression of CVD (Arenillas et al., 2004, Arenillas et al., 2008) and proved to increase the risk for vascular dementia and Alzheimer's disease (AD) (Schmidt et al., 2002). The markers are representative of molecular pathways known to be involved in vascular dysfunction and damage affecting intracranial circulation and subsequent impairment of the neurovascular unit. The resulting progressive vascular damage may lead to WM integrity loss, brain atrophy, and cognitive impairment (Arenillas et al., 2008, Iadecola, 2010).
When combined, blood markers and MRI measures together can improve early detection of subjects with VCI and evaluation of disease progression (Gorelick et al., 2011). A previous study using diffusion tensor images (DTI) found an association between inflammation, WM integrity loss in frontal pathways, and impaired executive functions (Wersching et al., 2010). However, no other biomarkers were considered in this study. Furthermore, the relationship between markers of endothelial dysfunction and brain structural and functional changes remains largely unknown.
Our aim is to investigate possible associations between inflammatory molecules and fibrinolysis inhibitors with brain changes and cognition in individuals without history of symptomatic CVD. Our hypothesis is that increased levels of these biomarkers would be related to brain microstructural changes and cognitive impairment.
Section snippets
Participants
The Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) study is an ongoing collaborative research project that includes 28 primary healthcare centers, a tertiary stroke center and the University of Barcelona. The study protocol included clinical and neurological examinations, duplex ultrasound exploration, and laboratory testing with blood cell count and a complete blood chemistry panel. Complete details for the Barcelona-AsIA protocol have been described elsewhere (López-Cancio et al.,
Sample characteristics
The demographic and clinical characteristics of the study population are summarized in Table 2. The mean age of participants was 59.7 years, 59% were women. Their intelligence, general cognitive function, and depressive symptoms were normal. Their cardiovascular risk according the Registre Gironí del Cor (REGICOR) score was low.
Associations between biomarkers and demographic and clinical variables
CRP was related to resistin (r = 0.223; p = 0.013) and PAI-1 (r = 0.279; p = 0.009). No other significant correlations were found between biomarkers. Table 1 shows the
Discussion
This study investigated the relationship of biomarkers of vascular dysfunction with brain structure and cognition. The main finding is that increases in blood levels of CRP and PAI-1 are independently associated with WM integrity loss in stroke-free individuals with low cardiovascular risk and normal cognitive functioning.
We also found an association of PAI-1 with lower performance in speed/visuomotor coordination. This is in agreement with previous studies that described slower processing
Disclosure statement
There are no actual or potential conflicts of interest.
The local ethics committee of the University of Barcelona and the Germans Trias i Pujol Hospital approved the use of human subjects for this study. All patients gave their written consent to participate in the study, which was conducted according to the provisions of the Helsinki declaration.
Acknowledgements
This research has made use of the SMILE medical imaging laboratory at Karolinska University Hospital, Stockholm, Sweden. This work was supported by the grants 2009FI_B00285 from the Generalitat of Catalunya to J. Miralbell, AP2006-00311 to J.J. Soriano, SEJ2006-15399/PSIC to Dr. M. Mataró, and FIS PI-070393 to Dr. J.F. Arenillas from Ministerio de Ciencia de Innovación. The authors thank all the participants from the Barcelona-AsIA study, who voluntarily accepted to enroll in this project.
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