John G Hanly1, Jason W Robertson2, Alexandra Legge3, Lyna Kamintsky4, Guillermo Aristi2, Alon Friedman4,5, Steven D Beyea6, John D Fisk7, Antonina Omisade8, Cynthia Calkin9, Tim Bardouille10, Chris Bowen6, Kara Matheson11, Javeria A Hashmi2. 1. Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia, Canada. 2. Department of Anesthesia, Pain Management and Perioperative Medicine, Dalhousie University, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada. 3. Division of Rheumatology, Department of Medicine, Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia, Canada. 4. Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. 5. Departments of Cognitive and Brain Sciences, Physiology and Cell Biology, Ben-Gurion University of the Negev, Beer Sheva, Israel. 6. Biomedical Translational Imaging Centre (BIOTIC), QEII Health Sciences Centre, and Department of Diagnostic Radiology, Dalhousie University, Halifax, Nova Scotia, Canada. 7. Nova Scotia Health Authority, Halifax, Canada and the Departments of Psychiatry, Psychology & Neuroscience and Medicine, Dalhousie University, Halifax, Nova Scotia, Canada. 8. Acquired Brain Injury (Epilepsy Program), Nova Scotia Health Authority, Halifax Nova Scotia, Canada. 9. Department of Psychiatry and Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada. 10. Department of Physics, Dalhousie University, Halifax, Nova Scotia, Canada. 11. Research Methods Unit, Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
Abstract
OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment (CI) in systemic lupus erythematosus (SLE). This study aimed to examine the associations of brain functional connectivity (FC) with CI and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (DCE-MRI) (n = 61). Differences in rsFC were compared between SLE patients with CI (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (p= 0.030) and healthy controls (p= 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (p= 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and CI in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with CI had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and CI.
OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment (CI) in systemic lupus erythematosus (SLE). This study aimed to examine the associations of brain functional connectivity (FC) with CI and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (DCE-MRI) (n = 61). Differences in rsFC were compared between SLE patients with CI (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (p= 0.030) and healthy controls (p= 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (p= 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and CI in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with CI had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and CI.