Blood-Brain Barrier Leakage Linked to Cognitive Impairment in SLE

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25% of patients presented with extensive blood-brain barrier leakage, which was linked to both cognitive impairment and shorter disease duration.

Although cognitive impairment is common among patients with systemic lupus erythematosus (SLE), the causes are relatively unknown. However, according to a study published in Lupus Science & Medicine,1 extensive blood-brain barrier (BBB) leakage alone was associated with cognitive impairment in patients with SLE, regardless of circulating SLE-related autoantibodies.

“Neuropsychiatric (NP) events are frequent in patients with SLE and are associated with lower self-reported health-related quality of life and with increased mortality,” investigators explained. “Cognitive impairment is one of the most frequent manifestations of neuropsychiatric SLE (NPSLE)… Clinically overt NP events, mood disorders, vascular risk factors, and medications may contribute but do not appear to be the predominant cause of cognitive difficulties in most patients.”

In the cross-sectional study, patients with SLE were recruited from a single academic medical center, Dalhousie Lupus Clinic, Division of Rheumatology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, to examine the association between serological biomarkers, SLE-related autoantibodies, and BBB leakage. Cognitive function was assessed via formal neuropsychological testing and BBB permeability was determined using dynamic contrast-enhanced MRI (DCE-MRI) scanning. Information regarding SLE disease activity, organ damage, anxiety and depression symptoms, SLE-related medications, lifestyle habits, and comorbidities was collected. Laboratory variables, such as a complete blood count, antiphospholipid antibodies, serum creatinine, urinalysis, and C3 and C4 levels were evaluated. Regression modelling determined impairment, BBB leakage, and biomarkers/autoantibodies.

In total, 102 patients with SLE were observed (88% White; 90% female; mean age 48.9 years). The mean disease duration was 14.8 years. Impairment was present in nearly half of patients (n = 47/101; 47%), which included issues with attention span (21%), executive abilities (21%), delayed recall (15%), information processing speed (9%), and new learning (8%). Prior NP evens occurred in roughly half of patients with SLE (n = 57/102; 56%).

One quarter (n = 20/79) of patients presented with extensive BBB leakage, which was linked to cognitive impairment (15 of 20 [75%] vs 24 of 59 [41%]; p=0.01) and shorter disease duration (median [IQR]: 7 [8–24 years] vs 15 [2–16 years]; p=0.02) when compared with patients without leakage. Extensive BBB leakage was not linked to serological parameters. No statistically significant link was discovered between impairment and circulating autoantibodies, regardless of BBB leakage.

Most patients had quiescent SLE without severe NP manifestations, which limited the study. However, the patients observed generally reflected a typical ambulatory SLE population, including the frequency and characteristics of cognitive impairment. Additionally, investigators were not able to obtain cerebrospinal fluid (CSF) samples, which may have provided more insight into clinical-laboratory associations, including the detection of intrathecal autoantibody production. The study was strengthened by performing neuroimaging, cognitive assessments, and bloodwork on the same day and in the same sequence, which minimized temporal disconnect between the variables of interest.

“Although causality cannot be inferred from our cross-sectional study, the findings suggest that perturbation of normal BBB function is related to cognitive impairment in a proportion of patients with SLE,” investigators concluded. “Further work addressing the clinical and pathogenic bases for extensive BBB leakage is required as is further investigation aimed at understanding the mechanisms underlying cognitive impairment following BBB dysfunction in patients with SLE.”


Hanly JG, Legge A, Kamintsky L, et al. Role of autoantibodies and blood-brain barrier leakage in cognitive impairment in systemic lupus erythematosus. Lupus Sci Med. 2022;9(1):e000668. doi:10.1136/lupus-2022-000668