Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients

Abstract

The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon β1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P ≤ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event.

Keywords: apolipoproteins; cholesterol; clinically isolated syndrome; high density lipoprotein.

Fig. 1.

Associations of HDL-C quartiles with albumin quotient (A), IgG index (B), IgM index (C), and CSF leukocytes (D). The quartile boundaries were: the lowest quartile corresponds to HDL-C ≤ 56.27 mg/dl, 56.27 mg/dl < quartile 2 (Q2) ≤ 66.25 mg/dl, 66.25 mg/dl < quartile 3 (Q3) ≤ 80.69 mg/dl, and the highest quartile > 80.69 mg/dl. The bars compare mean values of the CSF measures shown on the y axis for the quartiles of HDL-C shown on the x axis. The error bars indicate the standard error of the mean.

Fig. 2.

Associations of ApoA-I quartiles with albumin quotient (A), IgG index (B), IgM index (C), and CSF leukocytes (D). The ApoA-I quartile boundaries were: the lowest quartile corresponds to ApoA-I ≤ 128.3 mg/dl, 128.3 mg/dl < quartile 2 (Q2) ≤ 151.1 mg/dl, 151.1 mg/dl < quartile 3 (Q3) ≤ 175.8 mg/dl, and the highest quartile > 175.8 mg/dl. The bars compare mean values of the CSF measures shown on the y axis to the quartiles of ApoA-I shown on the x axis. The error bars indicate the standard error of the mean.

Fig. 3.

Associations of mean CSF CD80+ (A–C) and CSF CD80+CD19+ (D–F) cell frequencies in percent with HDL-C quartiles, ApoA-I quartiles, and ApoB quartiles. A, D: The HDL-C quartile boundaries were: the lowest quartile corresponds to HDL-C ≤ 56.27 mg/dl, 56.27 mg/dl < quartile 2 (Q2) ≤ 66.25 mg/dl, 66.25 mg/dl < quartile 3 (Q3) ≤ 80.69 mg/dl, and the highest quartile > 80.69 mg/dl. B, E: The ApoA-I quartile boundaries were: the lowest quartile corresponds to ApoA-I ≤ 128.3 mg/dl, 128.3 mg/dl < quartile 2 ≤ 151.1 mg/dl, 151.1 mg/dl < quartile 3 ≤ 175.8 mg/dl, and the highest quartile > 175.8 mg/dl. C, F: The ApoB quartile boundaries were: the lowest quartile corresponds to ApoB ≤ 54.0 mg/dl, 54.0 mg/dl < quartile 2 ≤ 70.75 mg/dl, 70.75 mg/dl < quartile 3 ≤ 87.0 mg/dl, and the highest quartile > 87.0 mg/dl. The bars compare mean values of the CSF cell frequencies in percent shown on the y axis to the quartiles of HDL-C, ApoA-I, or ApoB on the x axis. The error bars indicate the standard error of the mean.

Fig. 4.

Associations of albumin quotient (A, B) and CSF leukocytes (C, D) with CEL number and T2-LV MRI measures. The bars compare mean values of the MRI measures shown on the y axis for the quartiles of the CSF variable shown on the x axis. A, B: The albumin quotient quartile boundaries were: the lowest quartile corresponds to albumin quotient ≤ 3.36 mg/g, 3.36 mg/g < quartile 2 (Q2) ≤ 4.25 mg/g, 4.25 mg/g < quartile 3 (Q3) ≤ 5.58 mg/g, and the highest quartile > 5.58 mg/g. C, D: The CSF leukocytes quartile boundaries were: the lowest quartile corresponds to CSF leukocytes ≤ 9.0/3 μl, 10.0/3 μl ≤ quartile 2 ≤ 17.0/3 μl, 18.0/3 μl ≤ quartile 3 ≤ 33.5/3 μl, and the highest quartile > 33.5/3 μl. The error bars indicate the standard error of the mean.