Cognitive dysfunction and antiphospholipid antibodies in systemic lupus erythematosus.

Nervous system involvement in systemic lupus erythematosus (SLE) is typically diagnosed on the basis of clinical psychiatric and/or neurologic syndromes (NPSLE). Neuropsychological tests can be used to assess nervous system integrity even in the absence of major NP syndromes. Their application has uncovered significant cognitive dysfunction, ranging from mild to severe, in a sizeable proportion of SLE patients irrespective of clinical NP status. Cognitive dysfunction has now been accepted as a bona fide manifestation of NPSLE. The heterogeneity of clinical NPSLE manifestations is paralleled by the diversity of cognitive deficits reported in different studies and within different patients. The success of attempts to explain these deficits on the basis of potential pathogenetic mechanisms, such as antibrain antibodies and proinflammatory cytokines, has been uneven. To date, the most robust findings have emerged in relation to antiphospholipid antibodies, which carry with them important therapeutic implications.

Reduced aggressiveness and low testosterone levels in autoimmune MRL-lpr males.

Autoimmune, lupus-prone MRL-lpr mice float excessively in the forced swim test, explore novel objects and places less, and show blunted responsiveness to palatable stimuli, which is consistent with the hypothesis that the development of chronic autoimmune disease alters emotional reactivity and/or motivation. The present study measures isolation-induced fighting, a model of "affective" aggression, in lupus-prone MRL-lpr and control MRL +/+ males. When compared with controls, autoimmune MRL-lpr mice show reduced aggressiveness, as evidenced by fewer fighting contacts, longer attack latency, shorter fighting episodes and shorter duration of fighting. In addition, reduced testosterone levels accompany serological signs of autoimmunity in the MRL-lpr males. The present results support the hypothesis that affective responsiveness is altered in lupus-prone mice and may suggest limbic system dysfunction during chronic autoimmune/inflammatory disease. The question of whether immune activation alters behavior by a direct effect on the nervous system, or also via the endocrine system, requires further study.

Cognition and mood in systemic lupus erythematosus. Evaluation and pathogenesis.

Cognitive dysfunction is frequent in SLE, probably related to primary underlying immune/inflammatory mechanisms operating in the brain. Longitudinal studies relating patterns of cognitive impairment to putative pathogenetic factors would provide evidence for this hypothesis. Such studies could also lead to more specific therapeutic interventions to ameliorate or reverse brain compromise in SLE.

The relationship of antiphospholipid antibodies to cognitive function in patients with systemic lupus erythematosus.

OBJECTIVE: To examine the relationship between antiphospholipid antibody positivity (expressed as the lupus anticoagulant) and cognitive dysfunction in patients with systemic lupus erythematosus (SLE). METHODS: Cross-sectional comparisons of lupus anticoagulant (LA) positive (N = 39) and negative (N = 79) patients and controls (N = 35) on a cognitive test battery; 22 LA-positive and 53 LA-negative patients who had never experienced neuropsychiatric events (never-NP-SLE) were also compared separately. RESULTS: LA-positive patients were 2 to 3 times more likely than were LA-negative patients to be designated as cognitively impaired. As a group, LA-positive patients, particularly those in the never-NP-SLE group, demonstrated lower performance primarily on tasks of verbal memory, cognitive flexibility, and psychomotor speed. CONCLUSIONS: LA positivity is associated with subclinical nervous system compromise, and a pattern of deficits compatible with subcortical involvement, possibly on the basis of ongoing LA-related microthrombotic events or vasculopathy.

Psychological aspects of systemic lupus erythematosus: cognitive function, mood, and self-report.

Systemic lupus erythematosus (SLE) is a chronic relapsing/remitting autoimmune disorder with both primary and secondary effects on nervous system integrity and psychological functioning. In addition to the occurrence of clinical psychiatric syndromes such as psychosis, depression, and anxiety, other psychological problems documented with increased frequency in SLE include cognitive deficits and emotional distress. We examine issues related to cognitive function, including its assessment and prevalence, and confounding factors in interpreting cognitive problems as reflecting primary central nervous system involvement in SLE. Cognitive data in relation to other facets of the disease such as pain and fatigue, and subjective cognitive complaints are also discussed. Finally, we propose a potential role for cognitive assessment in the identification of SLE related depression.

Blunted sensitivity to sucrose in autoimmune MRL-lpr mice: a curve-shift study.

Lupus-prone MRL-lpr mice show an autoimmunity-associated behavioral syndrome that has many features similar to the effects of chronic stress. The present study evaluated whether autoimmune MRL-lpr mice show reduced responsiveness to sucrose, as observed in normal animals exposed to chronic mild stress. Sixteen-week old MRL-lpr mice and their age-matched congenic MRL +/+ controls were given 0%, 0.5%, 1%, 2%, 4%, 8%, or 16% sucrose solution to drink every 48 h in a one-bottle test. The MRL-lpr mice drank less than controls at all concentrations, except at 16%. The amount of sucrose consumed vs. solution concentration followed a saturation curve. Estimates were obtained for the concentration yielding the half-maximum response (X50) and the response at saturating concentration of sucrose (Rmax). The X50 was significantly higher in MRL-lpr than in MRL +/+ mice, indicating a shift to the right of the concentration-intake curve. The Rmax did not differ significantly between substrains, suggesting that the autoimmune process did not affect performance capacity. Pretreatment with the immunosuppressant cyclophosphamide diminished the substrain difference in X50, suggesting that reduced sensitivity to sucrose is related to autoimmune/inflammatory factors. These results support the similarity between autoimmunity-associated behavioral syndrome and behavioral changes produced by chronic stress, and suggest common neuroendocrine mechanisms. Because reduced sensitivity to palatable stimulus may reflect blunted hedonic responsiveness ("anhedonia"), it is hypothesized that an autoimmune/inflammatory factor(s) produces the depression found in human lupus, and some cases of affective disorder.

Immunosuppressive treatment prevents behavioral deficit in autoimmune MRL-lpr mice.

MRL-lpr mice, which develop severe autoimmune disease, explore novel objects less well than do their congenic MRL(-)+/+ controls, in which symptoms of the disease are relatively mild. Moreover, diminished exploration in MRL-lpr mice correlates with the elevated titers of antinuclear antibodies (ANA) in their sera, suggesting that this behavioral deficit is caused by the autoimmune process. To test the hypothesis that autoimmunity affects behavior, in this study we examine whether treatment of the autoimmune process will reduce the difference in performance between the two MRL substrains in the novel-object test. Forty mice in each substrain were treated from 4 to 10 wk of age with the immunosuppressive drug, cyclophosphamide (100 mg/kg/wk, IP) or a saline vehicle. The immunosuppressive treatment reduced ANA titers to low levels and eliminated ANA production completely in 55% of MRL-lpr mice, suggesting an attenuation of the autoimmune process. In addition, treatment with cyclophosphamide, but not saline, abolished significant differences in exploration between the MRL-lpr and MRL +/+ groups, as measured by the latency to touch a novel object and the time spent exploring it. Thus, the present results suggest that a treatment which ameliorates autoimmune symptoms can concurrently remove the substrain difference in behavior. The effect of cyclophosphamide in the MRL-lpr group is believed to reflect the suppression of pathogenic immune factor(s) that alter behavior during the onset of autoimmune disease.

Cognitive dysfunction in systemic lupus erythematosus is independent of active disease.

OBJECTIVE: To determine whether disease activity in organ systems other than the central nervous system (CNS) contributes to impaired neurocognitive functioning in patients with systemic lupus erythematosus (SLE) without current major neuropsychiatric problems. METHODS: A cross sectional study of 90 consecutive female patients with SLE. Neuropsychological status was evaluated with a comprehensive 2.5 h battery of tests. Disease activity was evaluated by the Lupus Activity Criteria Count (LACC) in all patients and the SLE Disease Activity Index (SLEDAI) in a subset of 20. Involvement of particular organ systems was identified with reference to American Rheumatism Association criteria. RESULTS: Sixty-eight of the 90 patients showed no active CNS involvement at the time of testing. Of these 68, 36 (53%) were impaired according to quantitative criteria alone. However, the association between cognitive impairment and disease activity was not significant using either LACC or SLEDAI as the measure of disease activity. Further, the group with active disease did not show generally poorer performance in specific areas of cognitive function than the group with inactive disease at the time of testing. The likelihood of significant cognitive impairment was not increased in the presence of involvement of any of the organ systems reviewed by the LACC. CONCLUSION: These findings substantiate our working hypothesis that cognitive impairment in SLE reflects an immune mediated compromise of an underlying neural substrate, rather than the non-specific effects of chronic illness or its treatment.

Evaluating the empirical support for the role of testosterone in the Geschwind-Behan-Galaburda model of cerebral lateralization: commentary on Bryden, McManus, and Bulman-Fleming.

The main tenet of the GBG model relates to the prenatal action of testosterone. Anomalies in cerebral dominance, immune functioning, abilities, and neural crest development are hypothesized to correlate with each other because all result from high levels of prenatal testosterone. Studies directly evaluating the effect of testosterone on these traits do not validate the model: sex ratios and animal studies suggest that testosterone has a protective, rather than facilitatory, effect on autoimmune diseases; individuals with high levels of early testosterone do not have elevated rates of left-handedness or learning disabilities. These findings reinforce Bryden et al.'s conclusions that there is little empirical support for the GBG model, and that it is wise to consider other theories in evaluating data derived from the model.

Nervous system lupus: pathogenesis and rationale for therapy.

Several different pathogenic mechanisms appear to be involved in CNS lupus. These include: B-cell/autoantibody-mediated nervous system compromise; immune complex deposition and vasculitis; microthrombosis and vasculopathy; aberrant MHC Class II antigen expression with T-cell mediated disease (multiple-sclerosis model); and, cytokine-induced brain inflammation. These processes are not mutually exclusive: there exist in vitro and in vivo models for each of these. A number of autoantibodies, especially those with specificities for shared neuronal/lymphocyte antigens, are associated with certain forms of cognitive dysfunction or overt nervous system manifestations. In MRL/lpr mice, lymphoid infiltrates in the brain parenchyma are related to a neurobehavioural dysfunction which develops very early in the course of autoimmune disease. Recent results, both in animal models and in human studies on the therapeutic effects of corticosteroids, immunosuppressive drugs or anticoagulants on clinical and subclinical manifestations of CNS lupus are highlighted in an attempt to develop a rationale for intervention based upon presumed pathogenesis.

Disturbed emotionality in autoimmune MRL-lpr mice.

MRL-lpr mice develop symptoms of autoimmune lupus-like disease early in the life and MRL(-)+/+ mice develop it substantially later. The present study examines our previous suggestion that autoimmune MRL-lpr mice show altered emotional reactivity. In addition, it aims to identify the set of measures which best discriminate the behavior of MRL-lpr mice from their congenic controls (MRL +/+). Behavior of males from these two substrains (n = 40/substrain; 3-4 mo of age) was compared on a battery of tests presumed to be reflective of emotional reactivity. MRL-lpr mice explored the open field less, spent more time at home-base, and defecated less in comparison to congenic MRL +/+ controls. Moreover, MRL-lpr mice hesitated to step down from an elevated platform and to make contact with a novel object. They also visited open-arms of a plus-maze less often and showed extensive floating in the Porsolt's swim test. Discriminant analysis revealed that the performance of the MRL-lpr and MRL +/+ mice differed most profoundly on measures taken in the Porsolt's swim and step-down tests. In addition, in the MRL-lpr group high titers of serum antinuclear antibodies were associated with impaired exploration of a novel object. These results are consistent with the previously proposed notion of increased "timidity" in autoimmune MRL-lpr mice and of an immune factor contribution to altered emotional reactivity. Considering that behavior of autoimmune MRL-lpr mice resembles behavior of stressed animals, it is speculated that disturbed emotional reactivity reflects the effect of autoimmunity on the hypothalamic-pituitary-adrenal axis.

Corticosteroids and neuropsychological functioning in patients with systemic lupus erythematosus.

OBJECTIVE: This study was designed to assess the effects of corticosteroids on select aspects of nervous system functioning, specifically, cognition and mood, as well as disease-related symptoms in individual patients with mild systemic lupus erythematosus (SLE) and mild neuropsychiatric (NP) symptoms. METHODS: Ten women who had not been taking corticosteroids for at least 6 months were selected from a referral-based lupus clinic to participate in an N of 1 double-blind, controlled trial consisting of 3 randomly assigned drug/placebo pairings, with a drug dose of 0.5 mg/kg of prednisone daily. RESULTS: Analysis of variance on the group data yielded significant positive drug effects for cognition (P = 0.02), mood (P = 0.003), and SLE symptom ratings (P = 0.0002). Drug efficacy was also evaluated by an objective decision rule, which yielded evidence of overall drug benefit in 5 of the 8 patients who completed the trial, and a deleterious drug effect in 1 patient. Posttrial clinical results indicated that for the 8 women who completed the trial, "acceptable" decisions, leading to remission of SLE symptoms or appropriate withholding of steroids, were made on the basis of this rule. CONCLUSION: Improvement in cognition, mood, and/or SLE symptom ratings can be observed following brief exposure to relatively low doses of corticosteroids in individual women with mild SLE; these persist over repeated drug exposure. The current application of N of 1 methodology represents the first systematic study of steroid efficacy in central nervous system (CNS)-related problems in SLE. The results can now be applied to the design of randomized, controlled trials of the effects of corticosteroids on CNS function in SLE.

Lymphocyte antigens in neuropsychiatric systemic lupus erythematosus. Relationship of lymphocyte antibody specificities to clinical disease.

OBJECTIVE: To examine the relationships among specific lymphocyte antigenic reactivities of lupus sera and central nervous system complications of systemic lupus erythematosus (SLE), lymphocytotoxic antibody (LCA) positivity, and specific cognitive impairment. METHODS: Sera from 115 patients with SLE were examined for the presence of IgM- and IgG-class autoantibodies binding to surface target antigens on lymphocytes, by immunoblotting and microdroplet lymphocytotoxicity studies. Seventy-three of these patients also underwent detailed neuropsychological testing within the same time period. RESULTS: Significant associations were found between reactivities to several lymphocyte antigenic moieties and neuropsychiatric SLE (NPSLE) or cognitive impairment. Specifically, immunoblot reactivities to 31-32-kd, 50-52-kd, 54-56-kd, and 97-98-kd targets were associated with clinical NPSLE; there was a significant association between reactivity to the 50-52-kd moiety in particular and cognitive impairment. There were also associations between LCA and immunoblot reactivity. Furthermore, the previously reported association between LCA positivity and specific visuospatial cognitive impairment was confirmed with data obtained from 2 different batteries of neuropsychological tests. CONCLUSION: In some cases, specific antigenic targets of LCA-containing sera may be implicated in the pathogenesis of NPSLE:

Cognitive deficits in systemic lupus erythematosus.

Several independent studies have now demonstrated the presence of significant cognitive impairment in SLE patients. Such impairment, whether it precedes or follows overt NP events, suggests compromise of the neural substrate, irrespective of overt clinical NP symptomatology. The association between cognitive impairment and brain cross-reactive autoantibodies suggests one mechanism for CNS involvement in SLE that warrants further study; the data relating specific cognitive deficits to the presence of specific antibodies raise the intriguing possibility of system- or structure-specific immune-mediated involvement in the CNS. Whatever the mechanism, cognitive impairment in SLE may have significant implications for daily functioning of some lupus patients and requires the selection of appropriate psychosocial and somatic treatment strategies.

Fluctuating cognitive abnormalities and cerebral glucose metabolism in neuropsychiatric systemic lupus erythematosus.

Brain imaging techniques such as MRI and PET have the potential for identifying central nervous system involvement in SLE. They may also help elucidate the mechanisms giving rise to the widely diverging manifestations of CNS involvement in SLE. This report documents an intensive longitudinal study of three women with neuropsychiatric SLE. PET and neuropsychological evaluation were both used to examine the co-occurrence of behavioural/cognitive deficits with alterations in regional brain glucose metabolism. In all three patients, FDG uptake indicated abnormalities which were not identified on CT scan, but corresponded well with localisable cognitive deficits. Changes in each patient's cognitive profile on reassessment paralleled changes on PET. These findings support the suggestion that cognitive deficits in SLE patients reflect primary CNS involvement.

Serum lymphocytotoxic antibodies and neurocognitive function in systemic lupus erythematosus.

The hypothesis that lymphocytotoxic antibodies are associated with neuropsychiatric involvement in systemic lupus erythematosus (NP-SLE) is re-evaluated in this study. In an unselected cohort of 98 women with SLE a cross-sectional study has been performed to analyse associations among standardised clinical, neurological, and neuropsychological assessments and lymphocytotoxic antibodies measured by microcytotoxicity assay. Fifty patients showed objective clinical evidence of continuing or past NP-SLE and 54 patients had cognitive impairment. In accordance with previous observations 44% (24/54) of the cognitively impaired group did not have clinically detectable evidence of NP-SLE. Although lymphocytotoxic antibodies were found to be only marginally more prevalent in those patients with a clinical diagnosis of NP-SLE than in those without (32% v 23%), these antibodies were significantly associated with cognitive impairment (chi 2 = 5.42; p less than 0.02). No association was detected between lymphocytotoxic antibodies and either overall systemic disease activity or other organ system involvement, suggesting that the association between lymphocytotoxic antibodies and cognitive dysfunction in SLE is specific.

The association between sequential changes in serum antineuronal antibodies and neuropsychiatric systemic lupus erythematosus.

To determine the significance of changes in serum antineuronal antibody levels in systemic lupus erythematosus, 9 patients who had a rise and 11 patients who had a fall in neuronal antibody titre over a mean duration of 2.1 years (range 0.25-5.2) were identified. These changes were examined in the light of concurrent changes in other serological variables, overall disease activity, neuropsychiatric disease and neuropsychological tests. Changes in antineuronal antibodies were frequently associated with concurrent changes in anti-DNA antibodies and overall disease activity. When neuropsychiatric disease or cognitive dysfunction were present, their course showed a close correlation with changes in antineuronal antibody levels. The results support the association between antineuronal antibodies and neuropsychiatric-systemic lupus erythematosus, but suggest that their measurement will provide useful information of disease status in only a subpopulation of patients.