Association between angiogenic factors and vascular risk, white matter hyperintensities and CSF amyloid beta

Abstract

Introduction: Angiogenic mediators like placental growth factor (PlGF) and vascular endothelial growth factors (VEFG-C and VEFG-A) in cerebrospinal fluid (CSF) are suggested markers of cerebral small vessel disease (SVD). SVD is a cause of vascular cognitive impairment and dementia (VCID), but studies have shown that both non-amyloid SVD related to vascular risk factors and cerebral amyloid angiopathy (CAA) often exist in patients with Alzheimer's Disease (AD). CSF amyloid beta (Abeta) 42 is reduced in AD due to trapping in parenchymal plaques. Abeta40 is mainly deposited in the vasculature, and low CSF concentrations are seen in CAA. In this cross-sectional study, we examine the associations between these angiogenic factors, vascular risk and white matter hyperintensities (WMH) on MRI, as well as Abeta peptides in CSF. Methods: We recruited non-demented participants from the Norwegian Dementia Disease Initiation cohort. We measured PlGF, VEGF-C and VEGF-A in CSF. Vascular risk was assessed with the Framingham Risk Score (FRS) for cardiovascular disease. WMH volumes were calculated by an automated algorithm. We used linear regression to examine associations between angiogenic markers and FRS, CSF levels of Abeta42 and Abeta40. Associations with WMH load were assessed in models without (Model 1) and with (Model 2) correction for amyloid status. Continuous variables were standardized. Age and sex were covariates. Results: In total, 240 individuals (mean age 63.4 years, 128 female/112 male, 124 cognitively normal/116 cognitively impaired) were included. Reduced VEGF-C was associated with higher FRS (B=-0.292, p<0.001) and reduced Abeta42 (B=0.261, p<0.001) and Abeta40 (B=0.574, p<0.001). We also found a negative association between WMH load and VEGF-C (B=-0.233, p<0.001), that remained significant after correction for amyloid status. Increased PlGF was associated with higher FRS (B=0.186, p<0.001), lower Abeta40 (B=-0.111, p=0.029) and increased WMH load (B=0.188, p=0.026), the latter remaining significant after correction for amyloid status. Discussion: Both angiogenic factors VEGF-C and PlGF are associated with vascular risk, Abeta40 and WMH load, suggesting a role in both SVD and AD pathogenesis. These factors should be included in longitudinal studies to further confirm their impact on disease processes and elucidate mechanisms involved in the interaction between SVD and AD.