Association of hippocampal atrophy with cerebrospinal fluid antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor in patients with systemic lupus erythematosus and patients with primary Sjögren's syndrome.

Cognitive dysfunction is common in both systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (SS). Antibodies against the NR2 subtype of the N-methyl-D-aspartate receptor (anti-NR2 antibodies) cause hippocampal atrophy and cognitive impairment in mice and have been associated with memory impairment in both patients with SLE and patients with primary SS. In addition, a reduced volume of hippocampal gray matter has been demonstrated in both SLE and primary SS. This study was undertaken to investigate whether there is a connection between the presence of anti-NR2 antibodies and hippocampal atrophy in human diseases. Fifty patients with SLE and 50 patients with primary SS underwent clinical examination and cerebral magnetic resonance imaging. Anti-NR2 antibodies in cerebrospinal fluid (CSF) were measured, and hippocampal gray matter volumes were compared between patients who were positive for and those who were negative for anti-NR2 antibodies. Patients with anti-NR2 antibodies in CSF had less hippocampal gray matter than patients without these antibodies. No other differences regarding gray matter volumes in other parts of the brain were identified. The present findings indicate that anti-NR2 antibodies in patients with SLE and primary SS cause neuronal death manifested as reduced hippocampal gray matter, as has been previously demonstrated in mice with autoimmune disease.

Lauvsnes MB ，Beyer MK ，Kvaløy JT ，Greve OJ ，Appenzeller S ，Kvivik I ，Harboe E ，Tjensvoll AB ，Gøransson LG ，Omdal R ... -  《-》

Memory dysfunction in primary Sjögren's syndrome is associated with anti-NR2 antibodies.

Our understanding of the etiology and pathogenesis of neuropsychiatric involvement in primary Sjögren's syndrome (SS) is incomplete. In systemic lupus erythematosus, it has been reported that antibodies directed against N-methyl-D-aspartate receptor subtype NR2 (anti-NR2) interfere with memory and learning function, as well as mood. This has not been investigated in primary SS; however, the present study was undertaken to advance our understanding of neuropsychiatric involvement in this disease. Sixty-six patients with primary SS and 66 age- and sex-matched healthy control subjects underwent clinical examination and neuropsychological evaluation. Anti-NR2 antibodies were measured in serum and cerebrospinal fluid. Hippocampus volume was estimated using software extensions to SPM5. Patients with primary SS had smaller hippocampi than healthy subjects (mean ± SD 8.15 ± 0.98 cm(3) versus 8.49 ± 0.88 cm(3); P = 0.01). In patients with primary SS, anti-NR2 antibodies in cerebrospinal fluid were associated with a worse performance in 8 of 10 memory and learning tests, and anti-NR2 antibodies in serum were associated with a worse performance in 6 of those same tests. In addition, a higher proportion of patients with depression than patients without depression had serum anti-NR2 antibody levels above the cutoff value. Results of this study indicate that anti-NR2 antibodies may represent one of the pathogenetic mechanisms for cognitive disturbances and mood disorders in patients with primary SS.

Lauvsnes MB ，Maroni SS ，Appenzeller S ，Beyer MK ，Greve OJ ，Kvaløy JT ，Harboe E ，Gøransson LG ，Tjensvoll AB ，Omdal R ... -  《-》

Migraine in patients with systemic lupus erythematosus is associated with reduced cerebral grey matter volume but not with measures of glial activation or anti-NR2 or anti-P antibodies.

Migraine is frequent in patients with systemic lupus erythematosus (SLE), but the pathogenesis and pathophysiology are poorly understood. Migraine is assumed to be a consequence of abnormal neuronal excitability. Based on the hypothesis that the threshold for migraine is lower in SLE patients due to cerebral disturbances, whether structural abnormalities of the brain or relevant biomarkers are associated with headaches in SLE was investigated. Sixty-seven SLE patients and age- and gender-matched healthy subjects participated. Volumes of grey matter (GM) and white matter (WM) were estimated from cerebral magnetic resonance images with SPM8 software. Anti-NR2 and anti-P antibodies and protein S100B were measured in cerebrospinal fluid. In regression analyses, larger GM volumes in SLE patients reduced the odds for headache in general [odds ratio (OR) 0.98, P = 0.048] and for migraine in particular (OR 0.95, P = 0.004). No localized loss of GM was observed. Larger WM volumes in patients increased the odds for migraine (OR 1.04, P = 0.007). These findings could not be confirmed in healthy subjects. Neither anti-NR2 and anti-P antibodies nor S100B were associated with headaches in SLE patients. Systemic lupus erythematosus patients with migraine have a diffuse reduction in GM compared to patients without migraine. This finding was not observed in healthy subjects with migraine, and selected biomarkers did not indicate specific pathophysiological processes in the brain. These findings indicate that unknown pathogenic processes are responsible for the increased frequency of migraine in SLE patients.

Tjensvoll AB ，Lauvsnes MB ，Hirohata S ，Beyer MK ，Greve OJ ，Kvivik I ，Kvaløy JT ，Harboe E ，Gøransson LG ，Omdal R ... -  《-》

Association between autoantibodies and neuropsychiatric manifestations of autoimmune disease: comment on the article by Lauvsnes et al.

Kivity S ，Shoenfeld Y 《-》

Reply: To PMID 25156222.

Lauvsnes MB ，Greve OJ ，Kvivik I ，Harboe E ，Tjensvoll AB ，Beyer MK ，Kvaløy JT ，Gøransson LG ，Appenzeller S ，Omdal R ... -  《-》