A prospective study of psychiatric disorder and cognitive function in systemic lupus erythematosus.

Hay, Elaine M; Huddy, A.; Black, Douglas; Mbaya, Patrick; Tomenson, Barbara; Bernstein, Robert; Holt, P. J.; Creed, Francis

doi:10.1136/ard.53.5.298

Cited by 97 publications

(83 citation statements)

References 14 publications

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“…Conversely, shortterm, low-dose corticosteroid may enhance memory and learning and augment fear and anxiety responses through effects on the hippocampus and amygdala (46,54,55). Importantly, several studies have not found significant correlations between corticosteroids and cognitive dysfunction or abnormalities in brain volume in SLE (56)(57)(58)(59)(60)(61). Our crosssectional analysis of these two groups is not adequate to address this issue.…”

Section: Figurecontrasting

confidence: 39%

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

Mackay

Bussa

Aranow

et al. 2011

Mol Med

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The mediators of tissue damage in systemic lupus erythematosus (SLE) such as antibodies, cytokines and activated immune cells have direct access to most organs in the body but must penetrate the blood-brain barrier (BBB) to gain access to brain tissue. We hypothesized that compromise of the BBB occurs episodically such that the brain will acquire tissue damage slowly and not at the same rate as other organs. On the basis of these assumptions, we wished to determine if duration of disease correlated with brain injury, as measured with functional magnetic resonance imaging (fMRI), and if this was independent of degree of tissue damage in other organs. We investigated differences in brain activation patterns using fMRI in 13 SLE patients stratified by disease duration of ≤2 years (short-term [ST]) or ≥10 years (long-term [LT]). Two fMRI paradigms were selected to measure working memory and emotional response (fearful faces task). Performance in the working memory task was significantly better in the ST group for one and two shape recall; however, both groups did poorly with three shape recall. Imaging studies demonstrated significantly increased cortical activation in the ST group in regions associated with cognition during the two shape retention phase of the working memory task (P < 0.001) and increased amygdala (P < 0.05) and superior parietal (P < 0.01) activation in response to the fearful faces paradigm. In conclusion, analysis of activation patterns stratified by performance accuracy, differences in comorbid disease, corticosteroid doses or disease activity suggests that these observed differences are attributable to SLE effects on the central nervous system exclusive of vascular disease or other confounding influences. Our hypothesis is further supported by the lack of correlation between regional brain abnormalities on fMRI and the Systemic Lupus International Collaborating Clinics (SLICC) damage index.

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Section: Figurecontrasting

confidence: 39%

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

Mackay

Bussa

Aranow

et al. 2011

Mol Med

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“…There is literature suggesting that inflammatory cytokines are neurotoxic in vitro, although no correlation between cognitive loss and cerebrospinal fluid cytokines has been demonstrated in SLE (40,41). Glucocorticoids may be neurotoxic, especially to hippocampal neurons, and the cytotoxic drugs used to treat lupus flares cause impaired cognition when used at higher doses, such as in cancer chemotherapy (3,5,(42)(43)(44)(45). Yet many SLE patients experience cognitive decline that is not associated with cytotoxic therapy or the use of high doses of corticosteroids.…”

Section: Discussionmentioning

confidence: 99%

Human lupus autoantibodies against NMDA receptors mediate cognitive impairment

Kowal

DeGiorgio²,

Lee³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

367

316

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Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.brain-derived antibodies ͉ neuropsychiatric systemic lupus erythematosus ͉ neurotoxic antibodies N europsychiatric lupus has become a prominent problem in patients with systemic lupus erythematosus (SLE) because they live longer due to improved therapy. Neuropsychiatric lupus is a complex set of syndromes, but cognitive impairment, manifested as a memory deficit, represents one of the most common symptoms (1-5). Certainly, multiple pathogenetic mechanisms underlie cognitive dysfunction in neuropsychiatric lupus, including medication, infarction, hypertension, and accelerated atherosclerosis. Because autoAbs clearly contribute to other organ injuries in SLE, we have been interested in their potential contribution to neuropsychiatric lupus. We have demonstrated that a subset of anti-DNA Abs binds a pentapeptide consensus sequence (D/E W E/D Y S/G, or DWEYS for short) present in the NR2A and NR2B subunits of the NMDA receptor (NMDAR) (6-8) but not in NR2C and NR2D. These Abs cross-react with both murine and human NMDAR, and they mediate neuronal death in vitro when added to cultures of fetal brain cells and in vivo when directly injected into a mouse brain (9). Additionally, NMDAR antagonists can protect neurons from Ab-mediated injury, confirming that the Abs function as receptor agonists. FabЈ2 fragments of a monoclonal crossreacti...

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“…If formal neuropsychological assessment had been included in the study protocol, this would likely have increased the prevalence of cognitive impairment identified in our cohort, although the additional impairment identified would be subtle and subclinical in the majority of cases. However, several cross-sectional and longitudinal studies have indicated that such deficits do not adversely affect HRQOL (19)(20)(21) or lead to long-term, clinically significant neurologic sequelae (19,(30)(31)(32). Also, given that formal neuropsychological assessments are not part of routine followup, we believe our protocol reflects clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: An international inception cohort study

Hanly

Urowitz

Sánchez‐Guerrero

et al. 2007

Arthritis & Rheumatism

281

218

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Objective. To describe the prevalence, characteristics, attribution, and clinical significance of neuropsychiatric (NP) events in an international inception cohort of systemic lupus erythematosus (SLE) patients.Methods. The study was conducted by the Systemic Lupus International Collaborating Clinics (SLICC). Patients were enrolled within 15 months of fulfilling the American College of Rheumatology (ACR) SLE classification criteria. All NP events within a predefined enrollment window were identified using the ACR case definitions of 19 NP syndromes. Decision rules were derived to determine the proportion of NP disease attributable to SLE. Clinical significance was determined using the Short Form 36 (SF-36) Health Survey and the SLICC/ACR Damage Index (SDI).Results. A total of 572 patients (88% female) were recruited, with a mean ؎ SD age of 35 ؎ 14 years. The mean ؎ SD disease duration was 5.2 ؎ 4.2 months. Within the enrollment window, 158 of 572 patients (28%) had at least 1 NP event. In total, there were 242 NP events that encompassed 15 of 19 NP syndromes. The proportion of NP events attributed to SLE varied from 19% to 38% using alternate attribution models and occurred in 6.1-11.7% of patients. Those with NP events, regardless of attribution, had lower scores on the SF-36 and higher SDI scores compared with patients with no NP events.Conclusion. Twenty-eight percent of SLE patients experienced at least 1 NP event around the time of diagnosis of SLE, of which only a minority were attributed to SLE. Regardless of attribution, the occurrence of NP events was associated with reduced quality of life and increased organ damage.Nervous system involvement as part of systemic lupus erythematosus (SLE) is well recognized, although the prevalence is highly variable among studies (1-7). A wide range of neuropsychiatric (NP) manifestations have been described, which span common features such Dr. Hanly

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A prospective study of psychiatric disorder and cognitive function in systemic lupus erythematosus.

Cited by 97 publications

References 14 publications

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

Human lupus autoantibodies against NMDA receptors mediate cognitive impairment

Neuropsychiatric events at the time of diagnosis of systemic lupus erythematosus: An international inception cohort study

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