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

Blood-brain barrier (BBB) permeability can be measured by the ratio of albumin in cerebrospinal fluid (CSF) and blood and by 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); few studies have directly compared them in the same patients. We used both methods as part of a study of mechanisms of white matter injury in patients with different forms of dementia. In addition, we also measured biomarkers for inflammation, including proteases, angiogenic growth factors, and cytokines, and correlated them with the BBB results. We found that there was no correlation between Qalb and Ktrans. The Qalb was associated with the matrix metalloproteinases (MMP-2, MMP-3, and MMP-10), the angiogenic factors (VEGF-C and PlGF), and the cytokines (IL-6, IL-8 and TNF-α). On the other hand, Ktrans was associated with the diffusion measures, mean free water and PSMD, which indicate white matter injury. 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.

A double-dichotomy clustering of dual pathology dementia patients.

INTRODUCTION: Subcortical ischemic vascular disease (SIVD) and Alzheimer's disease (AD) related dementia can coexist in older subjects, leading to mixed dementia (MX). Identification of dementia sub-groups is important for designing proper treatment plans and clinical trials. METHOD: An Alzheimer's disease severity (ADS) score and a vascular disease severity (VDS) score are calculated from CSF and MRI biomarkers, respectively. These scores, being sensitive to different Alzheimer's and vascular disease processes are combined orthogonally in a double-dichotomy plot. This formed an objective basis for clustering the subjects into four groups, consisting of AD, SIVD, MX and leukoaraiosis (LA). The relationship of these four groups is examined with respect to cognitive assessments and clinical diagnosis. RESULTS: Cluster analysis had at least 83% agreement with the clinical diagnosis for groups based either on Alzheimer's or on vascular sensitive biomarkers, and a combined agreement of 68.8% for clustering the four groups. The VDS score was correlated to executive function (r = -0.28, p < 0.01) and the ADS score to memory function (r = -0.35, p < 0.002) after adjusting for age, sex, and education. In the subset of patients for which the cluster scores and clinical diagnoses agreed, the correlations were stronger (VDS score-executive function: r = -0.37, p < 0.006 and ADS score-memory function: r = -0.58, p < 0.0001). CONCLUSIONS: The double-dichotomy clustering based on imaging and fluid biomarkers offers an unbiased method for identifying mixed dementia patients and selecting better defined sub-groups. Differential correlations with neuropsychological tests support the hypothesis that the categories of dementia represent different etiologies.