The presence of antibodies against the NR2 subtype of N-methyl-d-aspartate receptor in cerebrospinal fluid had a significantly negative effect on the gray matter volume of the hippocampus of patients with systemic lupus erythematosus or primary Sjögren’s syndrome in a single-center, prospective, cross-sectional study.
Anti-NR2 antibodies have been found, albeit inconsistently, to be associated with cognitive dysfunction and memory impairment in previous studies of both patients with systemic lupus erythematosus (SLE) and those with primary Sjögren’s syndrome (pSS). The NR2 subtype of N-methyl-d-aspartate (NMDA) receptor is widespread in the brain, but it occurs at a high density in the hippocampus, the brain’s vital structure for memory formation and learning.
Dr. Maria Boge Lauvsnes
Dr. Maria B. Lauvsnes of Stavanger (Norway) University Hospital and her associates recruited 50 patients (mean age, 44 years) who had had SLE for an average of 12.5 years; 8 (16%) had anti-NR2 antibodies in cerebrospinal fluid. A separate group of 50 patients (mean age, 57 years) had had pSS for an average of 6.6 years; 6 (12%) had anti-NR2 antibodies.
Although anti-NR2 antibodies were associated with smaller hippocampal gray matter volume on 1.5 T MRI, there was no significant effect on this volume according to disease group (SLE or pSS), the presence of antiphospholipid antibodies, disease duration, or present use of corticosteroids. Disease group also did not act as a confounder of the association between anti-NR2 antibodies and hippocampal gray matter volume (Arthritis Rheumatol. 2014 Aug. 22 [doi: 10.1002/art.38852]).
A whole-brain analysis showed that no regions outside the hippocampus had significant gray matter loss in association with the presence of anti-NR2 antibodies.
"The reason for this localized loss of gray matter could be due to the high density in the hippocampus of NR2 receptors, allowing only atrophy of these structures to reach statistical significance. Another explanation could be that other disease factors not tested for in this study, such as anti-ribosomal P protein (anti-P) antibodies, might have an additive effect with anti-NR2 antibodies in the hippocampus," the investigators wrote.
They noted that in vitro studies have shown that anti-NR2 antibodies enhance the normal influx of calcium through the receptor’s ion channel and thereby cause cytotoxic intracellular levels of calcium that leads to neuronal apoptosis.
Studies in a mouse model of SLE have demonstrated that anti-NR2 antibodies cause cognitive impairment and altered emotional behavior. In both SLE and pSS patients, anti-NR2 antibodies have been linked to memory impairment, Dr. Lauvsnes and her associates said.
The authors acknowledged that the study did not track if anti-NR2 levels fluctuated over time, and could not determine an origin for the antibodies.
None of the authors had relevant conflicts of interest to report. Dr. Lauvsnes received funding support as a doctoral research fellow from the Western Norway Regional Health Authority.