A critical analysis of the tools to evaluate neuropsychiatric lupus.

Neuropsychiatric symptoms occur commonly in patients with systemic lupus erythematosus, but they are not always due to active disease. It is crucial to identify cases that are due to active systemic lupus erythematosus so that appropriate treatment can be instituted. There is no single serological or imaging test that distinguishes active neuropsychiatric systemic lupus erythematosus from neuropsychiatric manifestations caused by other factors such as infection. Most patients with neuropsychiatric systemic lupus erythematosus have generalised features of disease activity. Raised anti-dsDNA and low C3 complement levels are often seen, but are not an invariable guide. The presence of antiphospholipid antibodies is more suggestive of thrombotic than inflammatory causation. A number of other autoantibody tests have been proposed as biomarkers for neuropsychiatric systemic lupus erythematosus, but results in clinical studies have been inconsistent and none has so far entered routine clinical practice. Cerebrospinal fluid features and magnetic resonance imaging appearances are non-specific in neuropsychiatric systemic lupus erythematosus, but are useful in excluding other causes of neuropsychiatric symptoms. Newer magnetic resonance imaging sequences show promise for distinguishing new neuropsychiatric systemic lupus erythematosus activity from previous damage and recent research suggests these may correlate with changes in cognitive function in patients with systemic lupus erythematosus. However, formal cognitive testing is seldom carried out in the acute setting

Advanced neuroimaging in neuropsychiatric systemic lupus erythematosus

PURPOSE OF REVIEW: Neuropsychiatric lupus (NPSLE) comprises a disparate collection of syndromes affecting the central and peripheral nervous systems. Progress in the attribution of neuropsychiatric syndromes to SLE-related mechanisms and development of targeted treatment strategies has been impeded by a lack of objective imaging biomarkers that reflect specific neuropsychiatric syndromes and/or pathologic mechanisms. The present review addresses recent publications of neuroimaging techniques in NPSLE. RECENT FINDINGS: Imaging studies grouping all NPSLE syndromes together are unable to differentiate between NPSLE and non-NPSLE. In contrast, diffusion tensor imaging, FDG-PET, resting, and functional MRI techniques in patients with stable non-NPSLE demonstrate abnormal network structural and functional connectivity and regional brain activity in multiple cortical areas involving the limbic system, hippocampus, frontal, parietal, and temporal lobes. Some of these changes associate with impaired cognitive performance or mood disturbance, autoantibodies or inflammatory proteins. Longitudinal data suggest progression over time. DCE-MRI demonstrates increased Blood-brain barrier permeability. SUMMARY: Study design issues related to patient selection (non-NPSLE vs. NPSLE syndromes, SLE disease activity, medications) are critical for biomarker development. Regional and network structural and functional changes identified with advanced brain imaging techniques in patients with non-NPSLE may be further developed as biomarkers for cognitive and mood disorders attributable to SLE-related mechanisms

FUNCTIONAL BRAIN IMAGING, COGNITIVE DYSFUNCTION AND ANTI-NR2 ANTIBODIES IN PATIENTS WITH NON-NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS

Ph.DDOCTOR OF PHILOSOPH

Heterogeneity of Antiphospholipid Syndrome (APS) as Characterized by Brain Perfusion Techniques. Towards New Ways of Syndrome Characterization

Antiphospholipid Syndrome (APS) syndrome is an autoimmune condition that affects the way that blood cells in humans bind together. Though the cause of APS is unclear, researchers believe that many factors have an impact on developing this pathological condition. Phospholipids (PLs) play numerous central roles in biological systems, and processes of biological systems regulation act through the liberation of a vast amount of different signalling molecules, which are also involved in the modulation of cell proliferation, inflammation, oxidative stress, neurotransmission and many other processes.A global landmark, holistic, is required to evaluate different phenotypes in APS. All thecriteria validated for the APS diagnosislead to an extremely heterogeneous landmark of the pathology and related to several manifestations in different systems. Heterogeneity also characterizes the SPECT acquisition of the patients and it is connected to several neurological and underestimates symptoms of the pathology. We present some examples to highlight the connection between heterogeneity in SPECT and APS markers of pathology indicating the needs to approach to the Syndrome in a holistic way. At the end of the paper we suggested the multidisciplinary approach that we are tuning for our analysis, approach based on Imaging, Metabolomic and Clinical evaluation, including mental health test for a neuropsychiatric characterization of the pathology

Quantitative identification of functional connectivity disturbances in neuropsychiatric lupus based on resting-state fMRI: a robust machine learning approach

Neuropsychiatric systemic lupus erythematosus (NPSLE) is an autoimmune entity comprised of heterogenous syndromes affecting both the peripheral and central nervous system. Research on the pathophysiological substrate of NPSLE manifestations, including functional neuroimaging studies, is extremely limited. The present study examined person-specific patterns of whole-brain functional connectivity in NPSLE patients (n = 44) and age-matched healthy control participants (n = 39). Static functional connectivity graphs were calculated comprised of connection strengths between 90 brain regions. These connections were subsequently filtered through rigorous surrogate analysis, a technique borrowed from physics, novel to neuroimaging. Next, global as well as nodal network metrics were estimated for each individual functional brain network and were input to a robust machine learning algorithm consisting of a random forest feature selection and nested cross-validation strategy. The proposed pipeline is data-driven in its entirety, and several tests were performed in order to ensure model robustness. The best-fitting model utilizing nodal graph metrics for 11 brain regions was associated with 73.5% accuracy (74.5% sensitivity and 73% specificity) in discriminating NPSLE from healthy individuals with adequate statistical power. Closer inspection of graph metric values suggested an increased role within the functional brain network in NSPLE (indicated by higher nodal degree, local efficiency, betweenness centrality, or eigenvalue efficiency) as compared to healthy controls for seven brain regions and a reduced role for four areas. These findings corroborate earlier work regarding hemodynamic disturbances in these brain regions in NPSLE. The validity of the results is further supported by significant associations of certain selected graph metrics with accumulated organ damage incurred by lupus, with visuomotor performance and mental flexibility scores obtained independently from NPSLE patients. View Full-Text Keywords: neuropsychiatric systemic lupus erythematosus; rs-fMRI; graph theory; functional connectivity; surrogate data; machine learning; visuomotor ability; mental flexibilit

A Conscious Resting State fMRI Study in SLE Patients Without Major Neuropsychiatric Manifestations

Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the main causes of death in patients with systemic lupus erythematosus (SLE). Signs and symptoms of NPSLE are heterogeneous, and it is hard to diagnose, and treat NPSLE patients in the early stage. We conducted this study to explore the possible brain activity changes using resting state functional magnetic resonance imaging (rs-fMRI) in SLE patients without major neuropsychiatric manifestations (non-NPSLE patients). We also tried to investigate the possible associations among brain activity, disease activity, depression, and anxiety. In our study, 118 non-NPSLE patients and 81 healthy controls (HC) were recruited. Rs-fMRI data were used to calculate the regional homogeneity (ReHo) in all participants. We found decreased ReHo values in the fusiform gyrus and thalamus and increased ReHo values in the parahippocampal gyrus and uncus. The disease activity was positively correlated with ReHo values of the cerebellum and negatively correlated with values in the frontal gyrus. Several brain areas showed correlations with depressive and anxiety statuses. These results suggested that abnormal brain activities might occur before NPSLE and might be the foundation of anxiety and depression symptoms. Early detection and proper treatment of brain dysfunction might prevent the progression to NPSLE. More studies are needed to understand the complicated underlying mechanisms

Cortical Thickness and Subcortical Gray Matter Reductions in Neuropsychiatric Systemic Lupus Erythematosus

Within systemic lupus erythematosus (SLE) patients can be divided into groups with and without central nervous system involvement, the latter being subcategorized as neuropsychiatric systemic lupus erythematosus (NPSLE). While a number of research groups have investigated NPSLE, there remains a lack of consistent application of this diagnostic criteria within neuroimaging studies. Previous neuroimaging research suggests that SLE patients have reduced subcortical and regional gray matter volumes when compared to controls, and that these group differences may be driven by SLE patients with neuropsychiatric symptoms. The current study sought to compare measures of cortical thickness and subcortical structure volume between NPSLE, SLE, and healthy controls. We hypothesized that patients with NPSLE (N = 21) would have thinner cortex and reduced subcortical gray matter volumes when compared to SLE (N = 16) and control subjects (N = 21). All subjects underwent MRI examinations on a 1.5 Tesla Siemens Sonata scanner. Anatomical reconstruction and segmentation were performed using the FreeSurfer image analysis suite. Cortical and subcortical volumes were extracted from FreeSurfer and analyzed for group differences, controlling for age. The NPSLE group exhibited decreased cortical thickness in clusters of the left frontal and parietal lobes as well as in the right parietal and occipital lobes compared to control subjects. Compared to the SLE group, the NPSLE group exhibited comparable thinning in clusters of the frontal and temporal lobes. Controlling for age, we found that between group effects for subcortical gray matter structures were significant for the thalamus (F = 3.06, p = .04), caudate nucleus (F = 3.19, p = .03), and putamen (F = 4.82, p = .005). These results clarify previous imaging work identifying cortical atrophy in a mixed SLE and NPSLE group, and suggest that neuroanatomical abnormalities are specific to SLE patients diagnosed with neuropsychiatric symptoms. Future work should help elucidate the underlying mechanisms underlying the emerging neurobiological profile seen in NPSLE, as well as clarify the apparent lack of overlap between cortical thinning and functional activation results and other findings pointing to increased functional activation during cognitive tasks

Neurofilament light in plasma is a potential biomarker of central nervous system involvement in systemic lupus erythematosus

BACKGROUND: Neuropsychiatric manifestations (NP) are common in systemic lupus erythematosus (SLE). However, the pathophysiological mechanisms are not completely understood. Neurofilament light protein (NfL) is part of the neuronal cytoskeleton. Increased NfL concentrations, reflecting neurodegeneration, is observed in cerebrospinal fluid (CSF) in several neurodegenerative and neuroinflammatory conditions. We aimed to explore if plasma NfL could serve as a biomarker for central nervous system (CNS) involvement in SLE. METHODS: Sixty-seven patients with SLE underwent neurological examination; 52 underwent lumbar puncture, while 62 underwent cerebral magnetic resonance imaging (MRI). We measured selected auto-antibodies and other laboratory variables postulated to have roles in NP pathophysiology in the blood and/or CSF. We used SPM12 software for MRI voxel-based morphometry. RESULTS: Age-adjusted linear regression analyses revealed increased plasma NfL concentrations with increasing creatinine (β = 0.01, p < 0.001) and Q-albumin (β = 0.07, p = 0.008). We observed higher plasma NfL concentrations in patients with a history of seizures (β = 0.57, p = 0.014), impaired motor function (β = 0.36, p = 0.008), increasing disease activity (β = 0.04, p = 0.008), and organ damage (β = 0.10, p = 0.002). Voxel-based morphometry suggested an association between increasing plasma NfL concentrations and the loss of cerebral white matter in the corpus callosum and hippocampal gray matter. CONCLUSION: Increased plasma NfL concentrations were associated with some abnormal neurological, cognitive, and neuroimaging findings. However, plasma NfL was also influenced by other factors, such as damage accrual, creatinine, and Q-albumin, thereby obscuring the interpretation of how plasma NfL reflects CNS involvement. Taken together, NfL in CSF seems a better marker of neuronal injury than plasma NfL in patients with SLE

Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus

OBJECTIVE: We investigated whether systemic lupus erythematosus (SLE) disease duration or serology associate with abnormal regional glucose metabolism as measured with [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and deficits on neuropsychological testing. METHODS: Subjects with SLE with stable disease activity, without brain damage or clinical symptoms of neuropsychiatric (NP) SLE, stratified by disease duration (short-term (ST)-SLE=disease/=10 years), underwent clinical assessments, neuropsychological testing, resting FDG-PET scan imaging and measurement of serum titres of antibody to N-methyl-d-aspartate receptor (DNRAb). FDG-PET scans were compared with age-matched and gender-matched healthy controls. RESULTS: Subjects with LT-SLE demonstrated hypometabolism in the prefrontal and premotor cortices that correlated with accrued SLE-related damage, but not with DNRAb titre or performance on NP testing. Independent of disease duration, subjects with SLE demonstrated hypermetabolism in the hippocampus and orbitofrontal cortex that correlated with impaired memory performance and mood alterations (depression, anxiety, fatigue). Serum DNRAb also correlated independently with impaired memory performance and increased anxiety. Together, serum DNRAb titre and regional hypermetabolism were more powerful predictors of performance than either alone. INTERPRETATION: The presence of serum DNRAbs can account for some aspects of brain dysfunction in patients with SLE, and the addition of regional measurements of resting brain metabolism improves the assessment and precise attribution of central nervous system manifestations related to SLE