Cognitive Impairment In Systemic Lupus Erythematosus Research Articles

Brain white matter microstructural alterations in patients with systemic lupus erythematosus: an automated fiber quantification study.

This study aimed to identify damaged segments of brain white matter fiber tracts in patients with systemic lupus erythematosus (SLE) using diffusion tensor imaging (DTI)-based automated fiber quantification (AFQ), and analyze their relationship with cognitive impairment. Clinical and imaging data for 39 female patients with SLE and for 44 female healthy controls (HCs) were collected. AFQ was used to track whole-brain white matter tracts in each participant, and each tract was segmented into 100 equally spaced nodes. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated at each node. Correlations were also explored between DTI metrics in the damaged segments of white matter fiber tracts and neuropsychological test scores of patients with SLE. Compared with HCs, SLE patients exhibited significantly lower FA values, and significantly higher MD, AD, RD values in many white matter tracts (all P < 0.05, false discovery rate-corrected). FA values in nodes 97-100 of the left inferior fronto-occipital fasciculus (IFOF) positively correlated with the mini-mental state examination score. AFQ enables precise and accurate identification of damage to white matter fiber tracts in brains of patients with SLE. FA values in the left IFOF correlate with cognitive impairment in SLE.

The Effects of Systemic Lupus-Related Cognitive Impairments on Activities of Daily Living and Life Role Participation: A Qualitative Framework Study.

Cognitive impairment (CI) in systemic lupus erythematosus (SLE) negatively impacts health-related quality of life leading to activity limitations. This qualitative study aimed to (1) explore the effect of SLE-related CI on activities of daily living and life role participation and (2) describe factors influencing activity restriction and life role participation. Semistructured, in-depth interviews of lived experience of CI in SLE were conducted with 24 participants with SLE. Sociodemographic and clinical data, and objective and subjective cognitive function, were collected to characterize participants. A qualitative thematic content analysis was undertaken guided by a framework analytical approach. Participants reported problems in multiple cognitive domains, with multiple perceived causes. CI was felt to impact work, social, domestic, and family life, health, and independence. Five overarching themes were represented in the data: (1) characterization of SLE-reported CI, (2) perceived cause of CI, (3) perceived impact of CI on activities of daily living and life role participation, (4) adaptations for managing CI, and (5) influence of CI adaptations on activities of daily living and life role participation. This study provides a better understanding of the patient experience of CI in SLE, how it impacts their lives, and what coping strategies they employ. It highlights the long-term challenges those with CI in SLE undergo and provides evidence for the urgent need to implement multidisciplinary treatment options. When managing CI, it may be beneficial to evaluate and understand available psychosocial support resources to help identify and reinforce relevant adaptations to improve health-related quality of life.

Screening for cognitive impairment in systemic lupus erythematosus: Application of the Montreal Cognitive Assessment (MoCA) in a Greek patient sample

Cognitive impairment (CI) is one of the most frequent neuropsychiatric manifestations of systemic lupus erythematosus (SLE). Given that extensive neuropsychological testing is not always feasible in routine clinical practice, brief cognitive screening tools are desirable. The aim of this study was to evaluate the Montreal Cognitive Assessment (MoCA) as a screening tool for CI in SLE. Consecutive SLE patients followed at a single centre were evaluated using MoCA and an extensive neuropsychological test battery (NPT), including the Digits Forward and Digits Backwards, Rey Auditory Verbal Learning Memory Test, Trail Making Test, Stroop Colour-Word Test, Semantic and Phonetic Verbal Fluency tests and a 25-problem version of the General Adult Mental Ability test. The criterion validity of MoCA was assessed through receiver operating characteristic (ROC) analyses using three different case definitions: i) against normative population data, ii) and iii) against average performance of a comparison group of rheumatoid arthritis (RA) patients, to adjust for possible confounding effects of chronic illness and inflammatory processes on cognitive performance. The effect of patient-related (age, years of education, anxiety, depression, fatigue and pain) and disease-related (activity, damage, age at diagnosis, disease duration, use of glucocorticoid, psychotropic and pain medication) parameters on the MoCA was examined. A total of 71 SLE patients were evaluated. MoCA significantly correlated with all NPT scores and was affected by education level (p < 0.001), but not by other demographic or clinical variables. The optimal cutoff for detecting CI, as defined on the basis of normative population data, was 23/30 points, demonstrating 73% sensitivity and 75% specificity. A cutoff of 22/30 points, using neuropsychological profiles of the RA group as inflammatory disease controls, exhibited higher sensitivity (100%, based on both definitions) and specificity (87% and 90%, depending on the definition). The standard cutoff of 26/30 points displayed excellent sensitivity (91-100%) with significant expenses in specificity (43-45%). The MoCA is an easily applied tool, which appears to be reliable for identifying CI in SLE patients. The standard cutoff score (26/30) ensures excellent sensitivity while lower cutoff scores (22-23/30) may, also, provide higher specificity.

Metrics and definitions used in the assessment of cognitive impairment in systemic lupus erythematosus: A systematic review

ObjectiveTo review: 1) degree of conformity to the American College of Rheumatology neuropsychological battery (ACR-NB) among studies that used a NB, 2) review definitions of cognitive impairment (CI) from studies that used a NB, and 3) characterize measurement tools used to assess CI in systemic lupus erythematosus (SLE). MethodsThe literature search was conducted in Ovid Medline, Embase, and PsycINFO for articles on CI in adult SLE patients. We reviewed studies that used a NB and compared their tests to the ACR-NB to assess the degree of conformity. Definitions of CI from studies that used a NB were reviewed when sufficient information was available. We reviewed and categorized CI measurement tools into four broad categories: NB, screening, incomplete/mixed batteries, and computerized batteries. ResultsOf 8727 references, 118 were selected for detailed review and 97 were included in the final analysis. Of 43 studies that used a NB, none of the studies used the ACR-NB exactly as published. Many studies supplemented with other tests. Overall, there was inconsistent use of ACR-NB tests. Definitions for CI varied, with cut-offs ranging from 1 to 3 standard deviations below normative values on domains/tests varying in type and number. The most frequently used measurement tool for assessing CI in SLE was a NB. Use of screening tests and computerized batteries have also increased over the last decade. ConclusionThe assessment and definition of CI in SLE remains heterogeneous. A consensus meeting to address existing inconsistencies should be considered to harmonize the field of CI in SLE.

Cognitive Impairment in SLE: Mechanisms and Therapeutic Approaches.

A wide range of patients with systemic lupus erythematosus (SLE) suffer from cognitive dysfunction (CD) which severely impacts their quality of life. However, CD remains underdiagnosed and poorly understood. Here, we discuss current findings in patients and in animal models. Strong evidence suggests that CD pathogenesis involves known mechanisms of tissue injury in SLE. These mechanisms recruit brain resident cells, in particular microglia, into the pathological process. While systemic immune activation is critical to central nervous system injury, the current focus of therapy is the microglial cell and not the systemic immune perturbation. Further studies are critical to examine additional potential therapeutic targets and more specific treatments based on the cause and progress of the disease.

Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus.

In this 2020 Dunlop-Dottridge Lecture, the authors discuss cognitive impairment (CI), one of the most prevalent neuropsychiatric syndromes in systemic lupus erythematosus (SLE). Patients often report CI as the most bothersome disease-related manifestation, with a great effect on their quality of life. Nevertheless, studies focusing on CI remain scarce and no effective targeted therapy has been identified. We herein present murine models of CI in SLE with insights into the pathogenesis of this condition as well as the role of the renin angiotensin system in microglial activation. We will discuss the role of neuroimaging as a useful objective assessment tool, describing our experience in previous and ongoing clinical trials of CI in patients with SLE.

Accelerated immune aging was correlated with lupus-associated brain fog in reproductive-age systemic lupus erythematosus patients.

Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57+ or loss of CD28 expression), of naïve T cells (CD4+ CD45RA+ and CD8+ CD45RA+ ), memory T cells (CD4+ CD45RO+ and CD8+ CD45RO+ ), and antigen-experienced T cells (CD4+ KLRG1+ and CD8+ KLRG1+ ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P=.005 and P=.000) and MOCA (P=.017 and P=.000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P=.046). There was a negative correlation between memory CD4+ CD45RO+ T cells with recall and visuospatial domain (R=-0.204, P=.039 and R=-0.250, P=.033; respectively), and negative correlation between CD8+ CD28- T cells with recall and attention domain (R=-0.249, P=.027 and R=-0.145, P=.048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.

Screening for cognitive impairment in SLE using the Self-Administered Gerocognitive Exam.

Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can affect the central nervous system in multiple ways, including causing cognitive dysfunction. Cognitive dysfunction is a common complaint of SLE patients yet diagnosis is challenging, time consuming, and costly. This study evaluated the Self-Administered Gerocognitive Exam (SAGE) as a screening test for cognitive impairment in a cohort of SLE patients. Methods A total of 118 SLE patients completed the SAGE. Providers completed the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI). SAGE scores were grouped into normal (>16) and abnormal (≤16) categories. Univariate and multivariate analyses were performed. Results Of the 118 participants, 21(18%) scored ≤16 on the SAGE instrument. In univariate analysis, race, ethnicity, household income, and SLICC-DI scores were associated with the SAGE ( p < 0.05). In multivariable analysis, abnormal SAGE score was independently associated with higher SLICC-DI score (odds ratio (OR) = 1.44, 95% confidence intervals 1.04-1.99, p = 0.03)), Hispanic ethnicity (OR = 43.4, 95% CI 3.1-601, p = 0.005), and lower household income (OR = 11.9 for ≤$15,000 vs >$50,000, 95% CI 2.45-57, p = 0.002). Conclusions In SLE patients, this study demonstrates an independent relationship between neurocognitive impairment (as measured by the SAGE) and higher lupus-related damage, as measured by the SLICC-DI, and lower household income. Abnormal SAGE scores were also associated with Hispanic ethnicity. A language barrier could explain this because the SAGE instrument was conducted in English only. The SAGE was feasible to measure in the clinic setting.

Performance of Screening Tests for Cognitive Impairment in Systemic Lupus Erythematosus.

There is a need for a cognitive function screening test that can be administered to patients with systemic lupus erythematosus (SLE) in clinic. The objectives of this study were to determine (1) prevalence of cognitive impairment (CI) in SLE by the Montreal Cognitive Assessment (MoCA), Mini Mental State Examination (MMSE), in relation to the Hopkins Verbal Learning Test-Revised (HVLT-R), and Perceived Deficits Questionnaire 5-Item (PDQ-5); and (2) associated factors with CI. Consecutive patients followed at a single center were recruited. HVLT-R, MoCA, and MMSE were administered. Sensitivity/specificity, positive (PPV)/negative (NPV) predictive values, and positive likelihood ratio (LR+) of MoCA/MMSE were determined (compared to HVLT-R). A test on intellectual ability and questionnaires on anxiety, depression, and perceived cognitive deficits were completed. Regression analyses determined associations with CI. Of 98 patients, 48% had CI using MoCA and 31% using HVLT-R. Sensitivity was higher for MoCA (73%) compared to MMSE (27%), though MMSE was more specific (90%) than MoCA (63%). PPV and LR+ were similar in MoCA and MMSE (PPV: 47%, 53%; LR+: 2.0, 2.6, respectively), but NPV was higher in MoCA (84%) than MMSE (74%). PDQ-5 predicted objective CI (HVLT-R: sensitivity 100%, specificity 89%). Although CI was associated with depression in univariate analyses, it did not hold in the multivariate analysis, while longer SLE disease duration and more years of education remained significant. CI is highly prevalent and MoCA may be a useful tool to screen for CI in SLE. Patients with more years of education were less likely to have CI.

Antiglutamate Receptor Antibodies and Cognitive Impairment in Primary Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome have an increased risk to develop cognitive impairment. A possible role for antiphospholipid antibodies (aPL) and antiglutamate receptor (anti-NMDA) antibodies in the pathogenesis of neurological manifestations of these two conditions, have been suggested. In particular, the role of anti-NMDA antibodies in the pathogenesis of neuropsychiatric SLE is supported by several experimental studies in animal models and by the finding of a correlation between anti-NMDA positivity in cerebrospinal fluid and neurological manifestations of SLE. However, data from the literature are controversial, as several studies have reported a correlation of these antibodies with mild cognitive impairment in SLE, but more recent studies have not confirmed this finding. The synergism between anti-NMDA and other concomitant autoantibodies, such as aPL, can be hypothesized to play a role in inducing the tissue damage and eventually the functional abnormalities. In line with this hypothesis, we have found a high incidence of at least one impaired cognitive domain in a small cohort of patients with primary APS (PAPS) and SLE. Interestingly, aPL were associated with low scoring for language ability and attention while anti-NMDA titers and mini-mental state examination scoring were inversely correlated. However, when patients were stratified according to the presence/absence of aPL, the correlation was confirmed in aPL positive patients only. Should those findings be confirmed, the etiology of the prevalent defects found in PAPS patients as well as the synergism between aPL and anti-NMDA antibodies would need to be explored.

Non-criteria anti-phospholipid antibodies and cognitive impairment in SLE.

The pathogenesis of cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) is unknown. Anti-phospholipid antibodies (APL) have been implicated. The APL which have been evaluated have variably included anti-cardiolipin (ACL) antibodies, lupus anticoagulant (LAC), and antibodies to beta-2 glycoprotein I (β2GPI). Few studies have examined other APL (so-called non-criteria APL). We evaluated the association of CI with a broad spectrum of non-criteria APL. Subjects meeting SLE classification criteria were recruited from three different patient populations. Cognitive function was assessed with the Automated Neuropsychologic Assessment Metrics (ANAM), a validated computer-based assessment tool. The total throughput score (TTS = number of correct responses/time) was used as the primary outcome measure. The following APL of all three isotypes were assessed by ELISA using standardized techniques: anti-β2GPI, anti-phosphatidyl ethanolamine (aPE), anti-phosphatidyl choline (aPC), anti-phosphatidyl inositol (aPI), anti-phosphatidyl serine (aPS), anti-phosphatidyl glycerol (aPG), anti-phosphatidic acid (aPA). Fifty-seven (57) patients were evaluated. Of the 57, 12 had definite CI (>1.5 SD below the mean of an age-, sex-, and race-matched RA population). The two groups were significantly different with regard to age, ethnicity, and family income. There was no significant difference between groups with regard to the presence of any non-criteria APL. When titers of specific non-criteria APL were compared with TTS, no significant correlations were found. Using multiple linear regression and adjusting for relevant covariates including age, ethnicity, and family income, neither the presence nor the titer of any non-criteria APL significantly influenced TTS. In this cross-sectional study, non-criteria APL were not associated with CI.

Systemic lupus erythematosus impairs memory cognitive tests not affected by depression.

Our aim was to assess the contribution of depression to cognitive impairment in patients with systemic lupus erythematosus (SLE). Clinical features, education, age, and Hospital Anxiety and Depression Scale (HADS) were evaluated in 82 patients with SLE and 22 healthy controls, all Chilean women. The Cambridge Neuropsychological Test Automated Battery (CANTAB eclipseTM) assessing attention, spatial memory, and learning and executive function domains was applied. Cognitive deficit definition: a cut-off for definite impairment was defined as a score below -2 standard deviations in at least one outcome measure in two or more domains. ANCOVA with stepwise selection evaluated influences of health status (SLE or control), age, education, and HADS depression and anxiety scores on cognitive outcomes. To avoid overfitting, a shrinkage method was performed. Also, adjusted p-values for multiple comparisons were obtained. Cognitive deficit affected 16 (20%) patients, and no controls (p=0.039). Median HADS depression score in SLE patients was 6 (range 0-19) and in controls was 0 (0-19), p<0.001). ANCOVA and shrinkage models showed that worse cognitive performance in sustained attention and spatial working memory tests was explained by the presence of SLE but not depression, whereas depression only affected a measure of executive function (I/ED Stages completed). Depression has a limited role in cognitive impairment in SLE. Impairments in sustained attention and spatial working memory are distinctly influenced by yet-unknown disease-intrinsic factors.

Neurocognitive dysfunction in systemic lupus erythematosus: association with antiphospholipid antibodies, disease activity and chronic damage.

IntroductionSystemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage.MethodsFifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs).ResultsNineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment.ConclusionsAnti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients.

General and specific factors associated with severity of cognitive impairment in systemic lupus erythematosus

To determine factors affecting the severity of cognitive impairment in systemic lupus erythematosus (SLE) and to analyze its anatomic location. Fifteen cognitive functions grouped into 8 domains were evaluated in 52 patients with SLE and 20 with rheumatoid arthritis. Patients were classified according to severity of impairment as normal, mild, or moderate/severe. Multivariate analysis was performed to identify the main factors affecting severity of cognitive deficits. The most likely anatomic site of damage according to neuropsychological performance was compared with the lesion's location on magnetic resonance imaging (MRI). In SLE patients, a stepwise regression analysis showed that the number of impaired functions (dependent variable) was associated with antiphospholipid antibody positivity (aPL+; P = 0.04), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; P = 0.001), hypertension (P = 0.032), and was inversely related to educational level (P = 0.021). Including MRI, the number of impaired functions was associated with severity of MRI (P < 0.001), the SDI (P = 0.013), and the presence of Raynaud's phenomenon (P = 0.04). The contemporary presence of aPL+ and Raynaud's phenomenon resulted in a higher probability to develop moderate/severe cognitive deficits (P = 0.015). Two logistic multiple regression analyses identified hypertension (P < 0.05), the SDI (P < 0.01), and moderate/severe MRI findings as main predictors of moderate/severe impairment (dependent variable). The damage site hypothesized through neuropsychological testing corresponded with MRI findings in 71.7% of SLE patients K = 0.42, P = 0.005). Hypertension, aPL+, accumulated damage, and MRI lesions are the main factors affecting severity of cognitive impairment in SLE. The hypothesized sites of central nervous system involvement according to neuropsychological testing correlated with MRI findings in most patients.

Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials

The objective of this study was to identify reliable and valid instruments to measure cognitive impairment in systemic lupus erythematosus (SLE), and to define minimally important change of cognitive impairment in SLE for clinical trials. Neurocognitive measures used in randomized clinical trials in SLE were reviewed, and response criteria were developed using consensus expert opinion. The definition of cognitive impairment in the ACR nomenclature for neuropsychiatric lupus syndrome was adopted. Cognitive impairment is a deficit of 2.0 or more standard deviations (SD) below the mean, compared to normative data, in the key domains of attention, memory and psychomotor speed. Cognitive decline is defined as a deficit of 1.5-1.9 SD below the mean. Focal decline is defined if impairment exists in one or more measures within one domain, and multifocal decline if impairment exists on measures spanning two or more domains. The combination of ACR neuropsychological battery and the Cognitive Symptoms Inventory (CSI) is recommended to quantitate cognitive function. A clinically important response is defined as an improvement of > or = 1.0 SD with an effect size of 1.0 in the key domains of the ACR neuropsychological testing, and an improvement of > or = 1.0 SD with an effect size of 1.0 in functional performance of the CSI.

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

To investigate change in psychiatric disorder and change in cognitive function in patients with systemic lupus erythematosus (SLE) assessed on two occasions two years apart. A prospective cohort study of 49 patients with SLE using standardised psychiatric and clinical research methods. The point prevalence of psychiatric disorder (20% and 24%), and of cognitive impairment (23% and 18%), was similar at first and second interview for the whole group. There was, however, considerable change in individual patient's psychiatric status and cognitive function: only 1/9 patients with impairment on two or more cognitive tests at first interview was still impaired at second interview. Change in cognitive function appeared to mirror change in psychiatric status. These findings suggest that the previously reported high prevalence of cognitive impairment in SLE may be explained by coexisting psychiatric disorder, rather than reflecting subclinical central nervous system (CNS) involvement.