Background/Purpose: Cognitive impairment is the most frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), yet the mechanisms underlying it remain poorly understood. The purpose of our study was to examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE).

Methods: A total of 65 ambulatory SLE patients and 9 healthy controls underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning, for quantitative assessment of blood-brain barrier (BBB) permeability. Volumetric data was extracted using the VolBrain pipeline. Global cognitive function and performance in five individual cognitive domains was compared between patients with normal versus extensive BBB leakage.

Results: Patients were predominantly female (87.7%) and Caucasian (89%) with a mean±SD age of 48.9 ± 13.3 years and disease duration of 15.1 ± 10.5 years. All patients had quiescent SLE and prior NP events attributable to SLE were present in 23% of patients. Impairment in at least one of five cognitive domains was found in 47.7% of patients. SLE patients had significantly higher levels of BBB leakage compared to controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in SLE patients (16/65; 24.6%), who also had smaller right and left cerebral gray matter volumes compared to controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment in one or more cognitive domains (p=0.01).

Conclusion: Our findings provide evidence for an association between extensive BBB leakage and changes in both brain structure and cognitive function in SLE patients. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, the diagnostic utility of BBB imaging, and the potential of targeting the BBB as a therapeutic strategy in SLE patients.

Figure 1. A sub-group of SLE patients have extensive BBB leakage. A. The rate of BBB leakage was quantified for every brain voxel. Shades of blue represent tissue with non-permeable BBB and shades of red represent contrast agent accumulation due to BBB leakage. A qualitative review of leakage maps in these selected cases illustrates that some SLE patients are visually comparable to controls, while others exhibit visibly higher number of voxels with BBB leakage. B. The percent of brain volume with BBB leakage was quantified for each subject, revealing a significant difference between SLE patients and controls (p=0.04). Outlier analysis of all 74 participants identified a group with “extensive BBB leakage”, consisting of 16 SLE patients; and a group termed “normal BBB leakage”, consisting of 9 controls and 49 SLE patients.

Figure 2. Extensive BBB leakage in SLE patients is associated with smaller gray matter volume. A. Depiction of the nine largest brain structures (of the 23 regions compared between the groups) illustrates the reduced right- and left- gray matter volumes in patients with extensive BBB leakage compared to controls (p=0.04, corrected for multiple comparisons). There were no volumetric differences in any other regions. B. Comparison of BBB leakage in the same 23 brain structures revealed that the ‘extensive BBB leakage group’ had higher levels of leakage in all regions (the same nine regions are depicted in B and A), compared to patients with normal BBB leakage and controls (p≤0.001, corrected for multiple comparisons). The Wilcoxon rank sum test was used to compare between the groups, and the false discovery rate algorithm was used to correct for multiple comparisons. Error bars denote standard error of the mean. Asterisks denote level of significance, with ***p≤0.001. GM, gray matter; WM, white matter; CE, cerebellum.

Figure 3. Extensive BBB leakage in SLE patients is associated with cognitive impairment. A. SLE patients with extensive BBB leakage had worse delayed recall and lower mean cognitive scores (averaged Z-scores of the five examined cognitive domains) compared to patients with normal BBB leakage (p=0.02, Wilcoxon rank sum test). B. The extensive BBB leakage group also had a significantly higher percent of subjects failing at least one cognitive test (p=0.01, chi-square test). Error bars denote standard error of the mean.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blood-brain-barrier-leakage-in-systemic-lupus-erythematosus-is-associated-with-gray-matter-loss-and-cognitive-impairment/