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

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.

Neurofilament light is a biomarker of brain involvement in lupus and primary Sjögren's syndrome.

BACKGROUND: To test the hypothesis that neurofilament light (NfL) in CSF is a biomarker of CNS involvement in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS), we measured NfL in CSF from 52 patients with lupus and 54 with pSS and explored associations with clinical, structural, immunological and biochemical abnormalities. METHODS: In CSF, we measured NfL, anti-P antibodies, protein S100B and TWEAK by ELISA and anti-NR2 antibodies by electrochemiluminescence. Anti-phospholipid antibodies and routine immunological tests were performed in blood. IgG and albumin were measured in CSF and serum for assessment of the blood-brain barrier function (Q-albumin) and intrathecal IgG production (IgG index). Cerebral MRI and neuropsychological testing were performed. RESULTS: A multivariable regression model showed that increasing CSF anti-NR2 antibody levels were associated with increasing NfL levels in patients with SLE (B 1.27, 95% CI 0.88-1.65, p < 0.001). Age contributed significantly in the model (B 0.04, 95% CI 0.03-0.05, p < 0.001). Similar findings were observed in the pSS group. Adjusted for age and sex, no associations were found between NfL levels and any MRI data. In SLE patients, higher NfL concentrations were associated with impairments in psychomotor speed and motor function, and in pSS with motor dysfunction. These associations remained in multivariable regression models. CONCLUSIONS: Increased concentration of NfL in CSF is a marker of cerebral involvement in patients with SLE and pSS, is strongly associated with the presence of anti-NR2 antibodies, and correlates with cognitive impairment in several domains.

No structural cerebral MRI changes related to fatigue in patients with primary Sjögren's syndrome.

OBJECTIVE: Whether or not chronic fatigue is reflected in structural changes in the brain is a matter of debate. Primary SS (pSS) is characterized by dryness of the mouth and eyes, migrating muscle and joint pain and prominent fatigue. We aimed to investigate whether the severity of fatigue in pSS was associated with cerebral MRI findings. METHODS: Fatigue was measured with the fatigue visual analog scale in 65 patients with pSS. Global grey matter (GM) and white matter volumes were estimated from magnetic resonance T1 images, and associations between fatigue and brain volumes were assessed in regression models. Voxel-based morphometric analyses of GM were performed to investigate possible associations between fatigue and GM volume changes in particular brain regions. RESULTS: The fatigue scores in the patient group were spread across a wide range. Global volume analyses showed no significant effect of GM volumes and white matter volumes on fatigue. Voxel-wise analyses of GM did not identify any particular brain region associated with fatigue. CONCLUSION: Fatigue is a dominant phenomenon in pSS patients but is not reflected in structural abnormalities in the brain as visualized by conventional MRI. Our findings support the hypothesis of fatigue as a physiological phenomenon that does not lead to vascular changes or neuronal or glial death or damage.

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.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Systemic lupus erythematosus, the brain, and anti-NR2 antibodies.

Neurological and psychiatric disorders are common in patients with systemic lupus erythematosus (SLE). While several pathogenetic mechanisms are thought to be involved, among of the most challenging and best investigated are antibodies against the N-methyl-D: -aspartate (NMDA) receptor subtypes 2a and 2b (anti-NR2 antibodies). This review summarizes the most relevant mechanisms for neuropsychiatric (NP) involvement in SLE (NPSLE) with special emphasis on the role of anti-NR2 antibodies and provides an overview of published articles on anti-NR2 antibodies and brain involvement as of May 2011. In mice, neuronal cell death occurs when anti-NR2 antibodies gain access to the brain, either by injection directly into the brain, or by systemic immunization and abrogation of the blood-brain barrier. Either impaired memory and hippocampal atrophy, or emotional disturbances and atrophy of the amygdala follow, seemingly dependent on the method used for disruption of the blood-brain barrier. Recent studies indicate that the effect of anti-NR2 antibodies is dose dependent; at low concentrations they alter synaptic function; at higher concentrations they can cause neuronal cell death by apoptosis. An association between anti-NR2 antibodies and NPSLE has been confirmed in 6 out of 13 human studies; the manifestations are primarily of diffuse cerebral character.