Longitudinal evaluation of diffusion tensor imaging and cognition in systemic lupus erythematosus.

Objective This pilot study aimed to examine longitudinal changes in brain structure and function in patients with systemic lupus erythematosus (SLE) using diffusion tensor imaging (DTI) and neuropsychological testing. Methods Fifteen female SLE patients with no history of major neuropsychiatric (NP) manifestations had brain magnetic resonance imaging (MRI) with DTI at baseline and approximately 1.5 years later. At the same time points, a standardized battery of cognitive tests yielding a global cognitive impairment index (CII) was administered. At baseline, the SLE patients had mean age of 34.0 years (SD = 11.4), mean education of 14.9 years (SD = 2.1), and mean disease duration of 121.5 months (SD = 106.5). The MRI images were acquired with a 3T GE MRI scanner. A DTI sequence with 33 diffusion directions and b-value of 800 s/mm2 was used. Image acquisition time was about 10 minutes. Results No significant change in cognitive dysfunction (from the CII) was detected. Clinically evaluated MRI scans remained essentially unchanged, with 62% considered normal at both times, and the remainder showing white matter (WM) hyperintensities that remained stable or resolved. DTI showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in bilateral cerebral WM and gray matter (GM) with no major change in NP status, medical symptoms, or medications over time. Lower FA was found in the following regions: left and right cerebral WM, and in GM areas including the parahippocampal gyrus, thalamus, precentral gyrus, postcentral gyrus, angular gyrus, parietal lobe, and cerebellum. Greater MD was found in the following regions: left and right cerebral WM, frontal cortex, left cerebral cortex, and the putamen. Conclusions This is the first longitudinal study of DTI and cognition in SLE, and results disclosed changes in both WM and GM without cognitive decline over an 18-month period. DTI abnormalities in our participants were not associated with emergent NP activity, medical decline, or medication changes, and the microstructural changes developed in the absence of macrostructural abnormalities on standard MRI. Microstructural changes may relate to ongoing inflammation, and the stability of cognitive function may be explained by medical treatment, the variability of NP progression in SLE, or the impact of cognitive reserve.

Cardiopulmonary correlates of cognition in systemic lupus erythematosus.

OBJECTIVE: We aimed to evaluate the relationship between cognitive dysfunction and lung function, exercise endurance, and self-reported activity levels in patients with systemic lupus erythematosus (SLE). BACKGROUND: Cognitive dysfunction is present in 20%-60% of SLE patients. No studies to date have investigated the inter-relationships between cardiopulmonary factors and cognition in this population. METHODS: Thirty-seven SLE patients without overt neuropsychiatric histories and 16 healthy controls completed neuropsychological testing, measures of lung function, exercise capacity (distance walked during a timed walk test,(1) maximal oxygen uptake(2)), and exercise questionnaires. RESULTS: Thirty-two percent of SLE patients demonstrated cognitive impairment. Cognitive impairment was correlated with Six-Minute Walk Distance (6MWD) (r = 0.37, p = 0.02) and certain measures of lung function. Also, in SLE patients, self-reported physical activity was correlated with 6MWD (p = 0.012), but none of the more complex measures of physical activity (VO2max). CONCLUSIONS: Patients with mild SLE disease activity have cognitive dysfunction associated with certain objective markers of exercise capacity and activity levels. The lack of associations between self-report activity and VO2max suggests the possibility that multiple factors mediate the relationships between perceived and actual physical ability. Additional studies are needed to better understand the relationship between cognition and physical activity in patients with SLE.

Site differences in mild cognitive dysfunction (MCD) among patients with systemic lupus erythematosus (SLE).

BACKGROUND: Mild cognitive dysfunction (MCD) is common in patients with systemic lupus erythematosus (MCD-SLE) but few studies have investigated potential site differences. METHODS: SLE patients from Denver, CO, and New York, NY, were enrolled in two different cognition studies employing similar screening methods. Using the resulting neuropsychological scores, cognitive impairment was calculated using a cognitive impairment index (CII). RESULTS: The rate of MCD-SLE was 24% at the Denver, CO, site and 60% at the New York, NY, site. The mean CII was 2.6 ± 2.3 versus 4.4 ± 2.7, respectively (p = 0.005). The NY participants had a significantly longer disease duration (p = 0.13) and higher American College of Rheumatology SLE criteria scores (p > 0.001). NY participants had a higher frequency of impairment in semantic verbal fluency (p = 0.005), visuomotor speed (p = 0.013), and motor sequencing (p = 0.001). A correlation was found between cognitive impairment and SLE disease duration (p = 0.03). CONCLUSIONS: The rate of MCD-SLE was greater in SLE patients from New York, NY, compared to patients in the Denver, CO, area. The greater duration of disease and higher prevalence of medical complications in the NY group might contribute to this difference. Findings suggest that MCD-SLE may differ by site, but future studies that better evaluate site or selection bias are recommended.

Immune function and brain abnormalities in patients with systemic lupus erythematosus without overt neuropsychiatric manifestations.

OBJECTIVE: This study examined the relationship between immune, cognitive and neuroimaging assessments in subjects with systemic lupus erythematosus (SLE) without histories of overt neuropsychiatric (NP) disorders. METHODS: In total, 84 subjects with nonNPSLE and 37 healthy controls completed neuropsychological testing from the American College of Rheumatology SLE battery. Serum autoantibody and cytokine measures, volumetric magnetic resonance imaging, and magnetic resonance spectroscopy data were collected on a subset of subjects. RESULTS: NonNPSLE subjects had lower scores on measures of visual/complex attention, visuomotor speed and verbal memory compared with controls. No clinically significant differences between nonNPSLE patients and controls were found on serum measures of lupus anticoagulant, anticardiolipin antibodies, beta 2-glycoproteins, or pro-inflammatory cytokines (interleukin (IL)-1, IL-6, interferon alpha (IFN-alpha), and interferon gamma (IFN-gamma)). Higher scores on a global cognitive impairment index and a memory impairment index were correlated with lower IFN-alpha. Few associations between immune functions and neuroimaging parameters were found. CONCLUSIONS: Results indicated that nonNPSLE patients demonstrated cognitive impairment but not immune differences compared with controls. In these subjects, who were relatively young and with mild disease, no relationship between cognitive dysfunction, immune parameters, or previously documented neuroimaging abnormalities were noted. Immune measures acquired from cerebrospinal fluid instead of serum may yield stronger associations.

Memory impairment associated with neurometabolic abnormalities of the hippocampus in patients with non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Memory impairment is common in patients with systemic lupus erythematosus (SLE). This study examined hippocampal volumes and neurometabolic alterations in relation to memory function in SLE patients without a history of neuropsychiatric syndromes (nonNPSLE). METHODS: Subjects included 81 nonNPSLE patients and 34 healthy controls. Volumetric magnetic resonance imaging and magnetic resonance spectroscopy of the right and left hippocampal areas (RH, LH) were performed. Verbal and visual memory tests were administered and a memory impairment index (MII) was derived from standardized tests. RESULTS: Higher memory impairment (MII) was correlated with lower RH glutamate + glutamine/creatine (p = 0.009) and lower RH N-acetylaspartic acid/creatine (p = 0.012) in nonNPSLE patients. A trend for a negative correlation between RH and LH volumes and MII was evident for absolute hippocampal volumes. Lower RH glutamate + glutamine/creatine was also correlated with worse performance in a mean visual memory index (p = 0.017). CONCLUSIONS: An association between reduced memory and lower N-acetylaspartic acid/creatine in the RH suggests neuronal damage in nonNPSLE patients with very mild and early disease. Alterations in glutamate + glutamine/creatine further indicate early metabolic changes in nonNPSLE are related to memory impairment, a finding that might suggest that memory impairment relates to presynaptic glutamatergic dysfunction in the hippocampus.

Functional Magnetic Resonance Imaging of Working Memory and Executive Dysfunction in Systemic Lupus Erythematosus and Antiphospholipid Antibody-Positive Patients.

OBJECTIVE: Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. METHODS: Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL-positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. RESULTS: Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. CONCLUSION: Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders.

Neuropsychological test performance and MEG-based brain lateralization: sex differences.

Magnetoencephalographic (MEG) auditory evoked fields (EF) were recorded from left and right hemispheres of 9 normal males and 12 normal females. Source location of the 100 ms latency component (M100) was localized to superior temporal lobes bilaterally using an inverse solution algorithm. All subjects also were administered the Wechsler block design and visual reproduction subtests, and the California Verbal Learning Test (CVLT). M100 source locations demonstrated significant sex differences in interhemispheric asymmetry. Males had source locations further anterior than females, with the differences most pronounced in the right hemisphere. Expected sex differences were found in neuropsychological test performance, with males performing better on block design ad visual reproduction, and females performing better on the CVLT. Across both sexes, block design scores correlated significantly with right hemisphere M100 location, with more anterior source locations associated with better performance. CVLT scores were negatively correlated with right hemisphere M100 source locations. These findings suggest MEG-based measures of interhemispheric asymmetry may be related to specific neuropsychological test performance measures.

Effects of examiner error on neuropsychological test results in a multi-site study.

This study compared the difference between original and "corrected" neuropsychological test scores at baseline and following 1 year of experience in 17 non-psychology trained examiners. Test protocols were reviewed for errors in instruction, administration, recording, and scoring. Fewer than 3% of the test scaled scores showed a correction of greater than 1 SD. At baseline, individual test scores that changed T-score classification occurred on Digit Symbol, Trails B, and Logical Memory I and II. At one year, significant classification changes remained for Logical Memory I and II (25% and 15%). Scoring of subjective tests remains problematic and centralized re-scoring is recommended.

Training and management of a multisite neuropsychological testing protocol for the Department of Veterans Affairs cooperative study evaluating on- and off-pump coronary artery bypass graft procedures.

Research study coordinators from 17 sites participating in a cardiac surgery study were trained to administer and score a brief neuropsychological test battery. Results were sent to the study's centralized laboratory for review and feedback. The average examiner errors on the first six protocols were compared with the average errors on the last six protocols over 12 months for each site. Overall, errors for the first six protocols were 4.42, and errors for the last six protocols were 1.83, representing a significant overall decline. Errors for instruction, administration, and recording showed a significant decrease over time. Despite ongoing feedback to examiners, scoring errors did not decline significantly overall; this suggests that a review of all protocols is necessary to achieve reliable scoring. However, when examiners' number of protocols completed was compared with number of scoring errors per protocol, there was a trend for examiners who had completed more protocols to show more improvement in scoring.

Major life stress, coping styles, and social support in relation to psychological distress in patients with systemic lupus erythematosus.

The objective of this study was to examine psychological processes in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients in relation to measures of life stress, coping styles, social support and cognitive ability. Fifty-two SLE patients without overt neuropsychiatric symptoms, 29 RA patients and 27 healthy controls completed measures of depression, mood, disease activity, perceived health, stressful life events, coping, and social support. Variables entered into the multiple regression analysis following principal component analysis were: group, major difficult event, major life threatening event, disengaging coping, emotional coping, social support, and cognitive impairment. Depressive symptoms were associated with SLE group status (P < 0.001), major life-threatening events (P < 0.01), disengage coping (P < 0.001) and emotional coping (P < 0.05). SLE group status (P < 0.05), disengage coping (P < 0.05) and emotional coping (P < 0.05) were associated with current distressed mood. SLE patients without overt, major neuropsychiatric symptoms had greater psychological distress compared to RA and control subjects. Increased depressive symptoms and distressed mood state in SLE patients were related to use of disengaging and emotional coping styles. These findings are limited to SLE patients with no overt neuropsychiatric illness and low disease activity, suggesting the need for future studies with a greater variety of SLE patients. Interventions aimed at improving active coping and minimizing emotional response to stress may lower psychological distress in SLE patients with mild disease.

Life stress and clinically elevated MMPI scales: gender differences in the moderating influence of coping.

Coping styles were evaluated as moderators of life stress-psychopathology relationships. Five hundred twenty-one undergraduates (271 females and 250 males) completed the Life Experiences Survey, the Coping Strategies Inventory, and the MMPI. To assess maladaptive coping styles, groups were constructed for each of 8 clinical scales (Hs, D, Hy, Pd, Pa, Pt, Sc, and Ma) composed of all subjects with a clinically significant elevation on that scale. The coping styles of these "clinical" groups were compared to the coping styles of "normal" groups, made up of subjects whose life stress scores were approximately the same but whose corresponding MMPI scale scores were within normal limits. To assess adaptive coping styles, a group of effective copers (with high life stress but normal MMPI profiles) was compared to a group of less effective copers (with high life stress but with at least one scale outside of normal limits). All groups were constructed separately for gender. The predicted gender differences and specific coping style-psychopathology relationships were, by and large, found. Coping style differences between the effective and less effective copers were also found. These findings suggest that several coping styles are important moderators of life event stress-psychopathology relationships.

Towards patient collaboration in cognitive assessment: Specificity, sensitivity, and incremental validity of self-report.

The present work addressed the specificity and sensitivity of patient-reported cognitive ability using both cross-sectional and longitudinal data, and the incremental validity of patient self-report in addition to knowledge gained through neuropsychological tests. We examined a sample of individuals with multiple sclerosis (N=130) as a model of chronic illness where neuropsychological deficits are relatively common. Results revealed that 64% of the sample reported noticing some problems with memory or confusion. Very high levels of reported problems were not consistent with objective testing, whereas moderate levels of noticing problems were congruent with test results. This pattern suggests a curvilinear relationship between self-reported and objective assessment. The moderate reporters seem to be attending to subtle increases in deficits over time. Results also supported the incremental validity of combining subjective and objective indices, but only when the high reporters were excluded. We conclude that patients can provide important complementary data which may promote preventive care.

Inflammatory and hormonal measures predict neuropsychological functioning in systemic lupus erythematosus and rheumatoid arthritis patients.

Abnormalities of inflammatory and hormonal measures are common in SLE patients. Although cognitive dysfunction has been documented in SLE patients, the biological mechanism of these deficits has not been clarified. The goal of this study was to explore the relationship between inflammatory and hormonal activity and measures of learning, fluency, and attention in systemic lupus erythematosus patients without neuropsychiatric symptoms (non-CNS-SLE), patients with rheumatoid arthritis (RA), and healthy controls (HC). Fifteen non-CNS-SLE patients, 15 RA patients and 15 HC participants similar in age, education, and gender (female) were compared on tests of cognition, depression, and plasma levels of interleukin-6 (IL-6), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol. Non-CNS-SLE patients demonstrated lower learning and poorer attention. Furthermore, non-CNS-SLE and RA patients had significantly lower levels of DHEA and DHEA-S than HC participants. Hierarchical regression analysis demonstrates that DHEA-S and IL-6 accounts for a unique portion of the variance in subject performance on measures of learning and attention after controlling for depression and corticosteroid treatment. This data highlights the value of hierarchical analyses with covariates, and provides evidence in humans of a relationship between peripheral cytokine levels and cognitive function.

Episodic memory function in advanced aging and early Alzheimer's disease.

Despite some well-documented differences, normal aging and Alzheimer's disease (AD) share a number of common neuropathological and neuropsychological features. Many of the reported differences are largely quantitative in nature and there is often overlap between the respective distributions of these populations. To assess the issue of overlap and distinguishing features in memory functions between these groups, and to minimize aging effects per se, samples of older individuals in good health (ages 75-95 yr) and younger patients in the early stages of AD (age < 75 yr) were selected to be similar in global cognitive functioning. Despite comparable language and visuospatial scores, these preliminary results suggest important qualitative differences in episodic memory functions between these conditions, even when "low-functioning" or "at-risk" controls are compared with early AD patients. These findings furthermore highlight some of the challenges in defining "normality" among the oldest segment of our population.

Qualitative Features of Clock Drawings in Normal Aging and Alzheimer's Disease

Two investigations examined qualitative features of clock drawings in normal aging and Alzheimer's disease (AD), using standard 3-point and 10-point scales and an expanded 16-point scoring system. In the first study, clock drawings by healthy adults aged 50-70 were found to be significantly better than those of adults aged 70-95 using all three scoring systems. Results based on the 16-point system were strongly associated with those of other scoring systems, but correlations with two other visuospatial measures were low. Older adults demonstrated more difficulty in terms of numerical position, time-setting, and addition of irrelevant details. In Study II, using the same scoring systems, AD patients were significantly impaired on clock drawings compared to matched controls. AD patients showed particular deficits in the following domains: numerical position, time setting, proportions, spatial accuracy, and omission of details. The 16-point clock scoring system was equivalent to other scoring procedures in differentiating groups and showed modest reliability coefficients. Results suggest that alterations in visuospatial relations in aging and dementia share some features with conceptual declines in the two groups, although there are qualitative differences that may be of utility in understanding the underlying processes involved in aging and dementia.

Magnetic resonance imaging abnormalities and cognitive deficits in systemic lupus erythematosus patients without overt central nervous system disease.

OBJECTIVE: To investigate cerebral magnetic resonance imaging (MRI) abnormalities in relation to cognitive functioning in systemic lupus erythematosus (SLE) patients without a history of central nervous system (CNS) disease. METHODS: Ventricle-to-brain ratios (VBRs) and the total number of white matter hyperintensities (WMHIs) were computed in 20 female patients with non-CNS SLE using established MRI computer-generated quantification procedures. Comprehensive neuropsychological test scores across 8 domains were also obtained. RESULTS: A mean VBR of 2.83% (SD = 0.7) occurred in the non-CNS SLE patients compared with a VBR of 1.36% in a normative sample. The average number of WMHIs was 4.95 (SD = 6.0). Using a combined rating scale (VBR > 2.25%, WMHIs > 5), 7 of 20 MRI scans (35%) were classified as abnormal. Increased VBRs and larger numbers of WMHIs showed a trend association with longer duration of SLE. Thirty-five percent of the non-CNS SLE patients demonstrated neuropsychological deficits. No significant correlations were found between the VBR, total WMHIs, and cognitive scores. Comparisons of cognitively impaired and nonimpaired patients with non-CNS SLE revealed no significant differences across clinical characteristics or MRI values. CONCLUSION: Quantified MRI analyses indicated atypical brain structure and an increased number of WMHIs in a subset of non-CNS SLE patients. However, these MRI abnormalities were not associated with functional abnormalities determined by comprehensive neuropsychological testing. Therefore, MRI analyses are not likely to provide additional clinical information on cognitively impaired SLE patients who have no other evidence of CNS involvement.

Analysis of cognitive and psychological deficits in systemic lupus erythematosus patients without overt central nervous system disease.

OBJECTIVE: To examine cognitive and psychological functioning in relation to antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE) who had no previous history of central nervous system disease (non-CNS SLE). METHODS: Comprehensive neuropsychological and psychological tests were administered to 51 non-CNS SLE patients, 29 rheumatoid arthritis (RA) patients, and 27 healthy controls. RESULTS: Twenty-nine percent of the non-CNS SLE patients, 31% of the RA patients, and 11% of the control subjects were classified as cognitively impaired. Similar reductions in intelligence, attention, and fluency were detected in the non-CNS SLE and RA patients compared with controls. The non-CNS SLE patients showed a distinct deficit in learning compared with the RA and control groups. Forty-two percent of the non-CNS SLE patients demonstrated psychological distress, compared with 7% of the RA patients and 6% of the controls. In the patient groups, neither cognitive dysfunction nor psychological distress was associated with disease activity or prednisone dosage. Elevated serum levels of autoantibodies to ribosomal P protein were not associated with either psychological or cognitive abnormalities. CONCLUSION: These results suggest that certain cognitive deficits in non-CNS SLE patients may not be specific to the immunopathology of SLE. In contrast, it is possible that deficits in learning, as well as psychological distress without major psychiatric pathology, may be subtle manifestations of CNS lupus.

Cognitive functioning in patients with chronic obstructive pulmonary disease and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls.

OBJECTIVE: To examine neuropsychologic functions in patients with chronic obstructive pulmonary disease (COPD) and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls. BACKGROUND: Cognitive deficits have been documented in patients with COPD, but few studies have compared the neuropsychologic status of these patients with that of other neurologic groups. METHOD: Cognitive test results from 32 patients with COPD and mild hypoxemia (mean age, 70.3 years; mean education, 13.2 years; mean partial arterial oxygen pressure, 68.8 mm Hg) who had no neurologic symptoms were compared with 31 subjects with mild Alzheimer disease (AD) and 31 normal controls similar in age, education, and sex. Seventy-three percent of the patients with COPD were receiving supplementary oxygen. RESULTS: Significant group differences across 11 cognitive scores were found using analysis of variance, and post hoc analyses indicated that patients with mild AD performed significantly worse than normal controls and patients with COPD on most tests. The group with COPD and the group with AD demonstrated lower letter fluency compared with controls. Although the patients with COPD performed significantly worse than controls on verbal fluency tasks, they were not in the clinically impaired range, and, overall, the group with COPD was similar to the controls on most cognitive tests. CONCLUSIONS: These findings suggest that many patients with COPD and mild hypoxemia who don't have neuropsychiatric histories may perform normally on cognitive measures. Oxygen therapy may partially account for preservation of cognitive function in these patients. Results also suggest that patients with COPD and normal controls can be readily distinguished from patients with mild AD based on levels and patterns of neuropsychologic test results. Any significant cognitive deficits in patients with mildly hypoxemic COPD may warrant continued neurologic evaluation.

Assessing depression in systemic lupus erythematosus: determining reliable change.

Systemic lupus erythematosus (SLE) can follow an unpredictable course. Clinicians and researchers use various self-report inventories to track aspects of the patient's functioning during the course of the illness (e.g. health status, pain, fatigue, quality of life and psychological status). These self-report inventories are used to measure improvement or deterioration as a function of the natural history of the disease process, or as a function of response to treatment. Proper interpretation of scores derived from these inventories requires an understanding of their psychometric properties, in particular, their reliability. It is important to calculate reliable change difference scores for tests commonly used in rheumatology so clinicians can determine if a change score is a reliable indicator of improvement or deterioration in individual patients (i.e. the change score is not likely to be due to measurement error). The purpose of this article is to illustrate the use of the reliable change difference scores when assessing depression in patients with SLE using the Beck Depression Inventory (BDI).