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Objectives Cognitive impairment affects up to 80% of systemic lupus erythematosus (SLE) patients within 10 years of diagnosis. Memantine, a seronergic receptor and nicotine acetylcholine receptor antagonist, acts on the glutamatergic system through the NMDA receptor and is used to treat dementia. We investigated whether it had benefit for SLE cognitive impairment. Methods A randomized double-blind, placebo-controlled single-center 12-week trial of memantine titrated to 20 mg/d was performed, using a 2:1 randomization ratio, in 51 SLE patients. The primary outcome measures were change in the Automated Neuropsychological Assessment Metrics throughput scores at 12 weeks. Results There were no statistically significant differences between treatment groups or change from baseline in any of the Automated Neuropsychological Assessment Metrics throughput scores at 6 or 12 weeks. For the American College of Rheumatology cognitive battery, the only statistically significant findings were for the Controlled Oral Word Association Test—S words at 6 and 12 weeks. At 12 weeks, the memantine group exhibited greater improvement compared with the placebo group (3.6 ± 1.8 vs 0.5 ± 3.8 words, P = 0.03). In a subset analysis limited to patients that scored ≥1 standard deviation below normal controls at baseline, no significant differences between treatment groups were found. Conclusions In this first clinical trial of memantine in SLE, patients treated with memantine did not exhibit significant improvement in cognitive performance compared with the placebo group, regardless of the degree of impairment at baseline, with the exception of controlled oral word association.

When systemic lupus erythematosus (SLE) patients exhibit central nervous system (CNS) signs or symptoms, the prognosis is poorer, the mortality higher (1), and the quality of life is reduced (2). The increased mortality and poor quality of life accompanying CNS involvement highlights the importance of detecting SLE-mediated effects on the brain as early as possible. The best estimate for the prevalence rate of SLE in the United States is approximately 350,000 (3) with CNS involvement in as many as 80% (2, 4, 5). Within the first two years of disease, approximately 20% of patients report neuropsychiatric (NP) symptoms that are attributed to SLE (2). However, many patients (28–40%) report at least one neuropsychiatric episode before or within the first year of diagnosis (2). The primary pathophysiology of SLE is inflammation secondary to autoantibody-mediated effects on tissue, degeneration of small vessels and vasculopathy (6). Inflammation is initiated by circulating autoantibodies generating inflammatory mediators and ends with cell dysfunction, apoptosis and tissue loss (1, 6, 7). Neuroimaging studies in SLE have supplied ample evidence of chronic changes indicative of late-stage pathology. PET studies have reported decreased blood flow (hypoperfusion) and decreased glucose metabolism (hypometabolism), chiefly in frontal and parietal grey matter. T1- and T2-weighted MRI studies have reported white matter volume loss and small punctate lesions. Diffusion tensor MRI and magnetization transfer imaging (MTI) studies show reduced myelination, even in SLE patients with no clear structural damage (8). No neuroimaging methods used to date have detected the inciting pathology, i.e., inflammation. Here, we used PET imaging to detect and localize both brain markers of inflammation (incipient pathology) and tissue failure and apoptosis (late-stage pathology) in persons with newly diagnosed, neurologically asymptomatic SLE. This was done using 18F-fluoro-deoxy-glucose (18FDG) PET to index both inflammation (detected as increased 18FDG uptake) and cell failure (detected as decreased 18FDG uptake). 18FDG is commonly used to detect grey matter dysfunction and atrophy, because the glucose metabolic rate decreases as tissue fails. 18FDG, however, can also be used to detect inflammation (e.g., vasculitis (9)) given that inflammatory cells demonstrate increased glucose transporter expression and that cytokines increase the affinity of glucose transporters for deoxyglucose (10). Similar methods to ours have been used to detect early evidence of white matter hypermetabolism in schizophrenia (11) and attention-deficit/hyperactivity disorder (12). PET data can be analyzed either by visual inspection, or more objectively by using regression methods to quantify covariance of regional 18FDG uptake with a clinical measure (13). The Safety of Estrogens in Lupus Erythematosus National Assessment modified version of the SLE Disease Activity Index (SELENA SLEDAI, SS) is a clinical measure used regularly in the evaluation of SLE (14). It is an index of disease activity in multiple organs, including the brain. Its score correlates with the presence of punctate white matter lesions in the brain of SLE patients without CNS signs or neuropsychiatric (NP) symptoms (15). The imaging analysis we utilized allows for the use of SS as a pattern vector to determine covariance of 18FDG uptake with disease activity. We hypothesized that combining the in vivo assessment of inflammation or tissue failure in the brain and the SS would provide a potential window into the CNS pathophysiology in SLE.

Objective.Cognitive impairment is present in 80% of patients with systemic lupus erythematosus (SLE) 10 years after diagnosis. The natural history of cognitive dysfunction in newly diagnosed SLE is unknown. We examined the association of depression and cognitive performance in newly diagnosed SLE.Methods.A multicenter cohort of 111 patients newly diagnosed (within 9 months) with SLE underwent cognitive function testing using an automated battery [Automated Neuropsychological Assessment Metrics (ANAM)] with 9 subtests. Depression was measured using the Calgary Depression Scale (CDS).Results.The patient cohort was 97.3% female, 55.9% white, 15.3% African American, 20.7% Hispanic, mean age 37.8 years, mean education 15.2 years. CDS score ranged from 0 to 18 (mean 5.0 ± 4.6). CDS score did not differ by age, sex, ethnicity, or prednisone dose. Higher Krupp Fatigue Severity Scale scores and presence of fibromyalgia were significantly associated with higher CDS score (p < 0.001; p = 0.006, respectively). Depressed patients, defined by a CDS score > 6, had significantly poorer performance on 5 ANAM throughput measures: code substitution (p = 0.03), continuous performance (p = 0.02), matching-to-sample (p = 0.04), simple reaction time (p = 0.02), and the Sternberg memory test (p = 0.04). Adjusting for age, sex, ethnicity, education, and prednisone dose, a higher CDS score remained significantly associated with poorer performance on 3 measures, but the association was slightly attenuated for code substitution and matching-to-sample. Depression was not associated with mathematical or spatial processing.Conclusion.Depression, a modifiable risk factor, is associated with significantly poorer function in several cognitive domains in patients newly diagnosed with SLE. Treatment of depression when the CDS score is greater than 6 may improve cognitive functioning and should be further studied.

ObjectiveWe wished to determine the prevalence of cerebral atrophy and focal lesions in a cohort of patients with newly diagnosed systemic lupus erythematosus (SLE) and the association of these brain abnormalities with clinical characteristics.MethodsA total of 97 patients with SLE, within 9 months of diagnosis, with 4 or more American College of Rheumatology classification criteria, were enrolled. Brain magnetic resonance imaging was performed.ResultsThe patients were 97% female, mean age 38.1 (SD 12.2) years, education 15.1 (2.8) years; 59 Caucasian, 11 African American, 19 Hispanic, 5 Asian, and 3 other ethnicity. Cerebral atrophy was prevalent in 18% (95% CI 11%–27%): mild in 12%, moderate in 5%. Focal lesions were prevalent in 8% (95% CI 4%–16%): mild in 2%, moderate in 5%, severe in 1%. Patients with cerebral atrophy were more likely to have anxiety disorder (p = 0.04). Patients with focal lesions were more likely to be African American (p = 0.045) and had higher Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI scores (p = 0.02) and anti-dsDNA (p = 0.05).ConclusionIn this population with newly diagnosed SLE, brain abnormalities were prevalent in 25% of patients. These findings suggest that the brain may be affected extremely early in the course of SLE, even before the clinical diagnosis of SLE is made. Followup of these patients is planned, to determine the reversibility or progression of these abnormalities and their association with and potential predictive value for subsequent neuropsychiatric SLE manifestations.

Measurable cognitive impairment occurs in 30-75% of patients with systemic lupus erythematosus (SLE). We compared cognitive functioning in recently-diagnosed SLE patients and normal controls.The Automated Neuropsychological Assessment Metrics (ANAM), a repeatable computerized cognitive battery assessing cognitive processing speed and efficiency, was administered to 111 recently diagnosed SLE patients and 79 normal controls. Throughput scores on ANAM subtests were compared using linear regression.After adjusting for age, gender, ethnicity, and education, SLE patients scored significantly lower than controls on throughput measures of 4 ANAM subtests: code substitution immediate recall (p = 0.02), continuous performance (p = 0.02), matching to sample (p = 0.02), and Sternberg subtest (p = 0.0002).Recently diagnosed SLE patients performed significantly worse than normal controls on 4 of 9 ANAM subtests. ANAM subtests of cognitive efficiency requiring sustained attention/vigilance, visuospatial span of attention/working memory, and simple reaction time showed the greatest impairment. These cognitive deficits were particularly striking, because the SLE patients in this sample were not selected for the presence of neuropsychiatric manifestations, had mild SLE-related disease/damage, and were recently diagnosed with SLE. This suggests that deficits in cognitive efficiency and sustained attention are present early in the course of SLE and in the absence of other significant neuropsychiatric manifestations.