Blood-brain barrier disruption measured by albumin index correlates with inflammatory fluid biomarkers

Abstract

Introduction: The blood-brain barrier (BBB) is important in vascular cognitive impairment dementia (VCID) and Alzheimer's disease (AD). There are two methods uto measures BBB permeability: 1) the ratio of the concentration of albumin in blood to that in CSF (Albumin index) and 2) dynamic contrast-enhanced MRI (DCEMRI)). Albumin is a large molecule measured in CSF and blood to form the albumin index (Qalb), which is a global measure of BBB permeability, while the smaller Gadolinium molecule measures regional transfer (Ktrans). We have measured BBB permeability using both methods in the same patients, and we now report the results of directly comparing the two methods and correlating the results with biomarkers of inflammation measured as part of the MarkVCID consortium. Methods: The patients were part of the UNM cohort in the MarkVCID study, and underwent complete evaluations as dictated in that study. We used both BBB methods to measure permeability as part of a study of vascular mechanisms of white matter injury in patients with different forms of dementia. In addition, we measured proteases, angiogenic growth factors, and cytokines, and correlated them with the BBB Results: We failed to find a correlation between Qalb and Ktrans. The Qalb was statistically associated with many of the inflammatory biomarkers measured in the MarkVCID study. The biomarkers that correlated with Qalb were three matrix metalloproteinases (MMP-2, MMP-3, and MMP-10), two angiogenic factors, vascular endothelial growth factor-C (VEGF-C), and placental growth factor (PlGF), and three cytokines interleukin-6 (IL-6), IL-8 and tumor necrosis factor-α(TNF-α). On the other hand, Ktrans was associated with two diffusion measures, mean free water and peak width of skeletonized mean diffusion (PSMD), which indicate white matter injury, but not with the inflammatory biomarkers. Discussion: Our results show that the Qalb and Ktrans measure different aspects of BBB permeability, with albumin being a measure of inflammatory BBB opening and Ktrans indicating white matter injury. Pinocytosis is most likely the mechanism for albumin transcytosis, while the smaller gadolinium molecule, could cross through open tight junctions.