Structural brain changes and cognition in relation to markers of vascular dysfunction

Abstract

The aim was to investigate the relationship between blood markers of vascular dysfunction with brain microstructural changes and cognition. Eighty-six participants from the Barcelona-Asymptomatic Intracranial Atherosclerosis (AsIA) neuropsychology study were included. Subjects were 50–65 years old, free from dementia and without history of vascular disease. We assessed correlations of blood levels of inflammatory biomarkers (C-reactive protein [CRP] and resistin) and fibrinolysis inhibitors (plasminogen activator inhibitor-1 [PAI-1] and A-lipoprotein (Lp (a)) with fractional anisotropy (FA) measurements of diffusion tensor images (DTI), regional gray matter (GM) volumes and performance in several cognitive domains. Increasing levels of C-reactive protein and PAI-1 levels were associated with white matter (WM) integrity loss in corticosubcortical pathways and association fibers of frontal and temporal lobes, independently of age, sex and vascular risk factors. PAI-1 was also related to lower speed and visuomotor/coordination. None of the biomarkers were related to gray matter volume changes. Our findings suggest that inflammation and dysregulation of the fibrynolitic system may be involved in the pathological mechanisms underlying the WM damage seen in cerebrovascular disease and subsequent cognitive impairment.

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.