Blood-brain barrier permeability abnormalities in vascular cognitive impairment

Abstract

Background and purpose: Disruption of the blood-brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood-brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood-brain barrier permeability in vascular cognitive impairment. Method- We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems.

Results: Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood-brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. K(i) values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts.

Conclusions: There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood-brain barrier damage and development of white matter hyperintensities.

Figure 1

Density distribution of permeability values for white matter (WM) voxels of a control and a VCI patient. A) The color-coded permeability map shows normal permeability, which is below the threshold of 3×10⁻⁴ ml/gm-min, which was established in 17 control subjects. C) The histogram of permeability values for the control subject shown in A. B) The permeability map of a VCI patient showing the regions of increased permeability in yellow and red. D) Permeability histogram shows the shift to the right of permeability values for patient in B.

Figure 2

A) FLAIR MRI shows WMHs in the centrum semiovale (arrowhead) without involvement of the cortex. B) The corresponding permeability map has regions of moderately increased permeability (light blue) and high permeability (red). C) FLAIR image from another SIVD patient with larger white matter lesions (arrowhead). D) Permeability map shows increased permeability is limited to two small regions within the WMHs.

Figure 3

Effect of age on white matter BBB permeability in VCI and controls. A) Q_alb for the VCI group plotted against age failed to show a correlation. B) BBB permeability of WM as a function of age. No correlation was found between Q_alb or DCEMRI values and age.

Figure 4

A) Q_alb for the different diagnostic categories are shown; SIVD was significantly increased over MI/LAC and CON (p<0.05). B) Mean white matter permeability, K_i, was significantly higher for the SIVD and MI/LAC groups than the controls (CON), but no differences were seen between SIVD and MI/LAC. Asterisks indicate a significant difference by nonparametric ANOVA (p<0.05).

Figure 5

ROC curve used for analyzing mean BBB permeability performance for classification of SIVD patients from controls. Evaluation of the discrimination of SIVD based on mean BBB permeability shows an ROC cut-point of 0.0018, which discriminates SIVD from controls with a reasonable balance in sensitivity and specificity. Area under the curve (AUC) and significance are shown.