Ramona M. Carbotte

Prevalence of cognitive impairment in systemic lupus erythematosus

We administered a battery of neuropsychological tests to 62 female patients with systemic lupus erythematosus (SLE), 12 female patients with rheumatoid arthritis (RA), and 35 normal control subjects. By applying objective decision rules to individual test protocols, an overall prevalence of cognitive impairment of 66% was obtained in the SLE patient sample. Independent clinical, radiological, and laboratory data were used to determine neuropsychiatric (NP) symptomatology and to group SLE patients as 1) “active” (N=21), 2) “inactive” (N=15), and 3) “never” (N=26) NP-SLE. More than 80% of the patients in groups 1 and 2 and 42% in group 3 showed significant cognitive impairment as compared with 17% of the RA patients and 14% of the normal control subjects. Neither steroid medication nor psychological distress could account for these findings. The unexpectedly high prevalence of cognitive impairment in SLE patients with either inactive or absent neuropsychiatric symptomatology provides evidence for subclinical nervous system involvement in SLE.

Does treatment with L-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism?

OBJECTIVE: To determine if health-related quality of life (HRQL) in patients of middle age and older with elevated thyroid-stimulating hormone (TSH) and normal total thyroid hormone levels—subclinical hypothyroidism—improves withl-thyroxine replacement therapy.DESIGN: Randomized, double-blind, placebo-controlled trial.SETTING: Outpatient clinic.PATIENTS: Thirty-seven patients with subclinical hypothyroidism, most with symptoms consistent with hypothyroidism, over 55 years of age.INTERVEJVTIOJVS: Placebo or L-thyroxine replacement therapy to achieve normal TSH level.MEASUREMENTS AND MAIN RESULTS: Disease-specific and general HRQL, cognitive function, bone mineral density, lipid levels. The mean daily dose of L-thyroxine replacement in the active group was 68±21 µg. TSH decreased by 8.6 mIU/L (95% confidence interval [CI] 4.1 to 13.1) and T4 increased by 27.9 nmol/L (95% CI 14.8 to 41.2). There was a statistically significant improvement in a composite psychometric memory score in treated versus control patients; all other outcomes showed similar findings in the two groups. Although confidence intervals for most measures did not exclude an important improvement in HRQL with thyroid replacement, no measure of symptoms or HRQL either showed clinically important trends in favor of treatment, or approached conventional levels of statistical significance.CONCLUSIONS: In middle-aged and older patients with elevated TSH and normal T4, it may not be harmful to follow biochemical and clinical status even in the presence of nonspecific symptoms potentially associated with hypothyroidism.

Neuronal antibodies and cognitive function in systemic lupus erythematosus.

The pathogenesis of neuropsychiatric lupus (NP-SLE) is unclear, but may involve vasculopathy, antibodies against nervous system tissue, or both. A major difficulty in determining the significance of antineuronal antibodies in NP-SLE has been lack of consistent clinical diagnostic approaches. By utilizing a new clinical classification of NP-SLE, neuropsychological assessments, and an assay for IgG antineuronal antibodies, we have found a significant association between antibody-positivity and cognitive impairment or nonfocal NP-SLE. These observations indicate that antineuronal antibodies may play a role in NP-SLE and emphasize the clinical importance of cognitive function in patients with SLE.

Cognitive impairment in systemic lupus erythematosus: A neuropsychological study of individual and group deficits

Eighty-six females with systemic lupus erythematosus (SLE) were grouped according to present or past history of neuropsychiatric (NP) symptomatology (Active, Inactive, or Never). Performance of these three groups was compared to that of 35 normal women on an extensive battery of neuropsychological tests sampling a wide range of cognitive functions. In addition to making group comparisons, we also devised a system for identifying individual impairment using decision rules for both quantitative and qualitative data. Our results indicate that a variety of cognitive deficits are present in SLE patients taken together as a group; there is no significant association between cognitive impairment and emotional disturbance; patients with resolved NP symptomatology are as impaired as patients with active NP symptoms, suggesting residual CNS involvement; in spite of no significant difference emerging on direct group comparisons, significantly more Never NP-SLE patients are impaired than are controls on several summary scores, suggesting subclinical CNS involvement in these patients.

Spatial learning during the course of autoimmune disease in MRL mice

The present study examines whether autoimmune MRL-lpr mice develop impairments in learning and memory that correlate with changing severity of lupus-like disease. MRL-lpr mice (n = 20) were tested in the Morris water-maze at 12, 14, 16 and 18 weeks of age. Age-matched controls were congenic MRL +/+ mice (n = 20) that develop the disease much later. Immune status was assessed by the presence of anti-nuclear antibodies (ANA), brain-reactive antibodies, proteinuria, and haematocrit. Learning rates and memory retention did not differ between the substrains, and did not correlate or deteriorate with advancing age and autoimmunity. However, the baseline performance level in autoimmune MRL-lpr mice was shifted, as evidenced by a consistently longer task-solving latencies. Thigmotaxic swimming (along the pool wall) was pronounced in the MRL-lpr group, and was associated with the observed difference in performance. The present study does not support the notion that learning/memory abilities of autoimmune MRL-lpr mice are impaired per se, but may support the hypothesis that the rapid progress of humoral autoimmunity affects the emotionality of lupus-prone mice.

Neurobehavioral outcomes among farm and nonfarm rural Ecuadorians.

International researchers have urged greater use of simple neurobehavioral batteries in developing country settings where higher levels of exposure and a variety of cultural and demographic factors may both occur. We conducted a cross-sectional survey of 144 farm members and 72 age and education frequency-matched controls from rural Ecuador, using an amplified Neurobehavioral Core Test Battery. Farm members ranged from those with only indirect pesticide contact to applicators regularly applying organophosphate and carbamate insecticides by backpack sprayer. The distributors of scores showed those with less than 4 years of formal education and at the extremes of age (< 16 or > 65 years old) contributed sufficiently to nonnormality that they had to be excluded from subsequent analyses (resultant n = 170). After adjustment for age and education, language-based IQ test scores and farm membership were the most consistent determinants of neurobehavioral outcomes. Visual-spatial tasks were the most sensitive to the effects of farm membership. Gender (women better than men), alcohol problems, and solvent use were also important for some neurobehavioral tests.

Brain-reactive antibodies and behavior of autoimmune MRL-lpr mice

The hypothesis that brain-reactive autoantibodies (BRA) impair behavior was examined in MRL-lpr mice, which develop spontaneous autoimmune disease. Circulating BRA were measured as in vitro serum reactivity to Neuro-2A neuroblastoma cell line, and behavioral competence was assessed in activity monitors, open field, beam walking, and Morris water maze task. Mice with BRA in serum (BRA positive) exhibited slower spontaneous locomotion in a novel environment, shorter grooming episodes, and less exploration of the open field centre when compared to age-matched 7-11-week-old BRA-negative cagemates. Moreover, when initially exposed to the large swimming pool, BRA-positive mice showed increased swimming along the wall, but had no difficulty in learning the water maze task or in traversing a narrow beam. Brain-reactive autoantibodies titre and behavioral measures were not correlated, suggesting that the concentration of serum BRA is not reflective of the magnitude of behavioral impairment. Nevertheless, the present study suggests that the presence of circulating BRA is associated with impaired exploration and/or enhanced emotional reactivity in MRL-lpr mice. It also supports the hypothesis of a pathogenic role of BRA in various mental disorders.

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.

Cognition and Mood in Systemic Lupus Erythematosu

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.

On energy-dependent cues in duration discrimination

We consider the possibility that, in a duration discrimination task involving very short empty time intervals, T and T + ‡T, bounded by brief auditory pulses, there may be a critical value of the base duration T within the range 50–300 msec below which duration is coded on the basis of sensory interactions between the markers which bound the interval. With ‡T fixed at 10 msec, the functional relation between performance and base duration was determined under three levels of marker intensity. Changing the intensity by 37 dB resulted in the same small change in performance at the shortest base duration (50 msec), where it is most likely that an intensity-dependent interaction could be present, as was obtained at the longest base duration (250 msec), where such an interaction should be minimally effective as a cue for duration discrimination. The code for the duration of an empty auditory interval greater than 50 msee probably is not dorived from energy-dependent processes.