## 2 Mechanisms of Cognitive Dysfunction
### Anti-N-methyl-d-aspartate Receptor Subunit NR2A/B Antibodies
This might imply that low titers of anti-NR2A/B antibodies in the CSF cause synaptic alteration with transient dysfunction (_i.e._, activity), while high titers result in mitochondrial stress, causing apoptosis (_i.e._, damage) [2]. 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]. A cross-sectional study by [PERSON] demonstrated an association with anti-NR2A/B antibodies and cognitive impairment in 7 out of the 31 neuropsychological tests in 57 SLE patients [43]. The cross-sectional study by [PERSON] showed an association with anti-NR2A/B antibodies and impaired attention and executive function assessed using a computerized system in 133 women with SLE [47]. In a longitudinal study by [PERSON], 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 [PERSON] 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]. For example, two studies demonstrated an association with mood disorder (depressed mood measured using Beck Depression Inventory) and serum anti-NR2A/B antibodies, but four other studies found no such correlation [9, 19, 43, 45, 46, 48]. In contrast, an association with diffuse and central NPSLE manifestations has been demonstrated in all four studies in which CSF anti-NR2A/B antibodies were measured [49, 50, 51, 52]. Levels of CSF anti-NR2A/B antibodies were elevated in patients with diffuse and central manifestations of NPSLE compared to controls [49, 50, 51, 52]. Titers of CSF anti-NR2A/B antibodies correlated with the severity of NPSLE manifestations [51, 52]. CSF anti-NR2A/B titers were highest in SLE patients with acute confusional state (the severest form of diffuse NPSLE), followed by SLE patients with other diffuse and central NPSLE manifestations (including cognitive dysfunction and mood disorder) and lastly NPSLE manifestations involving the peripheral nervous system [52]. Q albumin, an indicator of BBB dysfunction, was highest in SLE patients with acute confusional state, followed by other diffuse and central NPSLE manifestations and lastly NPSLE manifestations involving the peripheral nervous system [52]. Further, CSF anti-NR2A/B titers correlated with Q albumin, indicating that BBB dysfunction plays an important role in the pathogenesis of NPSLE, allowing the entry of greater amounts of anti-NR2A/B antibodies from the systemic circulation into the CNS in the more severe forms of NPSLE [52]. Up to 8% of the healthy controls were classified as serum anti-NR2A/B antibody positive in four cross-sectional studies [43, 46, 50, 53]. Interestingly, serum anti-NR2A/B antibodies have been demonstrated in patients with transient ischemic attacks and strokes using peptide-based ELISA [54, 55]. Peptide fragments of NR2A and NR2B subunits have been observed in plasma of patients with acute cerebral ischemia [54].