Background Cross-reactive, anti-dsDNA/N-methyl D-aspartate receptor antibodies (DNRAb) have been associated with cognitive impairment in SLE. The mouse model demonstrates selective effects of DNRAb on hippocampal neurons following blood brain barrier (BBB) breach.¹ We previously identified abnormal hippocampal glucose hypermetabolism in SLE patients that correlated with serum DNRAb titers and poor performance on neuropsychological (NP) testing.² However, little is known about how antibodies access brain in humans. We evaluated BBB permeability (BBBP) in SLE and healthy control (HC) subjects with DCE-MRI and hypothesized that regions with abnormal hypermetabolism would also demonstrate altered BBBP.

Methods 6 SLE subjects with no history of NP symptoms and 6 age and gender matched HCs underwent NP testing using the Automated Neuropsychological Assessment Metric (ANAM) computerized battery and DCE-MRI on a 3.0 tesla magnet. MRI sequences were acquired according to standard protocols; permeability imaging used DCE technique with axial 3D-SPGR T1-WI sequences and 80 cine phases using TR=25 ms, TE=3.8 ms, FOV=24 mm, and matrix size of 128 × 256. Magnevist Gadolinium contrast, 0.1 mmol/kg IV, was dosed at 5 cc/sec following a 5 sec delay. Post-processing of images into BBBP parameters of K-trans (mL/100 gm/min) and VE (mL/100 gm) was performed using Olea Sphere 2.2 and 2.3 with the Tofts extended permeability model. This technique was standardized with the arterial input function centered in the cavernous ICA segment for all subjects.

Analyses: Regions-of-interest (ROI) from previously identified hypermetabolic regions (hippocampus, orbitofrontal cortex, posterior putamen/globus pallidus/thalamus) were selected. Mirror ROIs were placed in bilateral MRI cerebral hemispheres for sampling at same brain levels. Regional DCE curves were generated to compare permeability phases. T-tests were used to evaluate demographic and NP testing differences.

Results SLE subjects performed significantly worse than HCs on 3 ANAM tests (matching grids, match to sample and continuous processing). Mean DCE curves (figure 1) show perfusion (initial spike) and permeability phases of contrast in the sampled tissues. Compared to HCs, SLE subjects demonstrate significantly increased signal in the permeability phase in the hippocampus, indicating leakage into the extravascular space.

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Abstract TD-05 Figure 1

Dynamic contrast enhanced MRI curves show increased hippocampus permeability in SLE

Conclusion This is the first report of increased BBBP in SLE subjects that is specific to the hippocampus; a region previously reported to have abnormally increased resting metabolism in SLE subjects. These data, including the abnormal NP testing, support the murine model of autoantibody-mediated cognitive impairment following disruption of the BBB. The results also suggest that DCE-MRI is an effective tool to measure BBBP and its role in NPSLE pending confirmatory studies with increased sample size.

References

1. . Kowal C, DeGiorgio LA, Nakaoka T, et al. Cognition and immunity; Antibody impairs memory. Immunity2004;21:179–88.

2. . Mackay M, Tang CC, Volpe BT, et al. Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus. Lupus Sci Med 2015;2:e000074.