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Objective: 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., Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2013 by the American College of Rheumatology.)