Blood-based candidate biomarkers of the presence of neuropsychiatric systemic lupus erythematosus in children

Abstract

ObjectiveTo examine select brain-reactive proteins for their usefulness to serve as blood-based biomarkers in the screening for neurocognitive deficits in childhood-onset systemic lupus erythematosus (cSLE-NCD).MethodsPatients withcSLE (n=40) were studied longitudinally (month 1; month 18): working memory, psychomotor speed and visuoconstructional ability were assessed using formal neurocognitive testing to determine the presence of cSLE-NCD. Patients also completed the computerised Paediatric Automated Neuropsychological Assessment Metrics. The following brain-reactive proteins were measured in the blood: neutrophil gelatinase associated lipocalin (NGAL), S100B, S100A8/9, antibodies to NR2 glutamate receptor (aNR2-AB), ribosomal-P (aP-AB), glycoprotein-1 (aGP1-AB), and lupus anticoagulant.ResultscSLE-NCD was present in 6 of 40 patients at baseline and 4 of 27 patients with 18-month information. aP-AB positivity was more commonly present with cSLE-NCD than without (p=0.05). aP-ABs were negatively associated with performance on tests assessing working memory, psychomotor speed and visuoconstructional ability in using formal neurocognitive testing. There were also significant negative associations between aP-AB, S100A8/9, aNR2-AB, aGP1-AB, and lupus anticoagulant and accuracy rates on select Paediatric Automated Neuropsychological Assessment Metrics subtests (p<0.05). Over time, decline in cognitive performance was more pronounced among patients with higher NGAL and aNR2-AB levels. Combinations of serum levels of S100A8/9, S100B, NGAL, aNR2-AB and aP-AB were able to identify cSLE-NCD (sensitivity: 100%; specificity 76%) in exploratory analysis.ConclusionsSelect brain-reactive proteins in the blood are associated with cognitive performance and the presence of cSLE-NCD, cross-sectionally and over time. This raises the possibility that testing of these proteins may assist with the screening of cSLE-NCD.

Challenges of Diagnosing Cognitive Dysfunction With Neuropsychiatric Systemic Lupus Erythematosus in Childhood

“…Anti–ribosomal P antibodies have been linked to psychosis and depression and might be involved in cognitive decline in cSLE . Other brain‐reactive antibodies are likely involved in the development of NPSLE, possibly contributing to the diverse clinical and imaging features of NPSLE.…”

Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus

“…As of April 2015, eight human studies with specific analyses performed for associations between a priori defined cognitive dysfunction as a NPSLE manifestation and serum anti-NR2A/B antibodies were published [ 9 , 19 , 31 , 43 , 44 , 45 , 46 , 47 ]. Table 1 summarizes the characteristics and findings of the studies.…”

“…All eight studies synthesized DWEYSVWLSN or DWEYS peptides for ELISA testing and reported presence of anti-NR2A/B antibodies in comparison to the optical density values of the controls, each using slightly different definitions and cut-offs [ 9 , 19 , 31 , 43 , 44 , 45 , 46 , 47 ]. Six of the studies were cross-sectional and two studies were longitudinal [ 9 , 19 , 31 , 43 , 44 , 45 , 46 , 47 ]. Between 14% and 35% of the SLE patients were anti-NR2A/B antibody positive [ 9 , 19 , 43 , 44 , 45 , 46 , 47 ].…”

“…In a longitudinal study by Hanly, anti-NR2A/B antibodies levels fluctuated over time and some patients had persistently elevated levels; there was no association between a rise in or persistently elevated anti-NR2A/B antibody levels and change in cognitive function in 65 female SLE patients over a follow-up period of five years [ 44 ]. However, the longitudinal study by Brunner revealed an association between decline in working memory and an increase in anti-NR2A/B antibodies from baseline in pediatric SLE patients followed up for 18 months [ 31 ]. Studies with other a priori defined NPSLE manifestations have also yielded inconsistent results in correlating serum levels of anti-NR2A/B antibodies [ 6 ].…”

“…The choice of mechanisms considered in this review has been driven by earlier, albeit controversial, reports from the medical literature [ 16 ]. However, affirmatively, a recent study screening a multimarker panel for cognitive dysfunction in childhood-onset SLE identified anti-NR2A/B antibodies and elements of blood-brain barrier (BBB) disruption and neutrophil activation as potential biomarkers [ 31 ]. Hence, key to this discussion is the idea that when considered individually, the impact of these mechanisms might be muted but they likely function together, as an ensemble, to contribute to disease pathogenesis of lupus-related cognitive dysfunction.…”