Plasma and cerebrospinal fluid neurofilament light concentrations reflect neuronal damage in systemic lupus Erythematosus.

BACKGROUND: Neuronal damage in systemic lupus erythematosus (SLE) is common, but the extent and mechanisms are unclear. Neurofilament light (NfL) concentrations rise in plasma and cerebrospinal fluid (CSF) during neuronal damage in various neurological disorders. In this cross-sectional study, plasma and CSF concentrations of NfL were explored as a marker of neuronal damage in SLE. METHODS: Seventy-two consecutive SLE out-patients and 26 healthy controls, all female, aged < 55 years, underwent magnetic resonance imaging (MRI) and neurocognitive testing. NfL concentrations in plasma from all individuals and in CSF from 32 patients were measured with single-molecule array technology. Patients were assessed by a rheumatologist and neurologist to define neuropsychiatric involvement (NPSLE) according to three attribution models: SLICC A, SLICC B and ACR. RESULTS: Plasma and CSF NfL concentrations correlated strongly (r = 0.72, p < 0.001). Both NPSLE and non-NPSLE patients in all attribution models had higher plasma NfL concentrations compared with healthy controls (log-NfL, pg/ml, mean (SD); healthy controls (0.71 (0.17)); SLICC A model: NPSLE (0.87 (0.13), p = 0.003), non-NPSLE (0.83 (0.18), p = 0.005); SLICC B model: NPSLE (0.87 (0.14), p = 0.001), non-NPSLE (0.83 (0.18), p = 0.008); ACR model: NPSLE (0.86 (0.16), p < 0.001), non-NPSLE (0.81 (0.17), p = 0.044)). Plasma and CSF NfL concentrations did not differ between NPSLE and non-NPSLE patients. Higher plasma NfL concentrations correlated with larger CSF volumes on MRI (r = 0.34, p = 0.005), and was associated with poorer cognitive performance in the domains of simple attention, psychomotor speed and verbal memory. SLICC/ACR-Damage Index ≥1 was independently associated with higher plasma NfL concentrations (ß = 0.074, p = 0.038). Higher plasma creatinine concentrations, anti-dsDNA-positivity, low complement C3 levels, or a history of renal involvement were associated with higher plasma NfL concentrations (ß = 0.003, p = 0.009; ß = 0.072, p = 0.031; ß = 0.077, p = 0.027; ß = 0.069, p = 0.047, respectively). CONCLUSIONS: Higher plasma NfL concentrations in NPSLE and non-NPSLE patients may indicate a higher degree of neuronal damage in SLE in general, corresponding to cognitive impairment and organ damage development. Furthermore, our results may indicate a higher degree of neuronal breakdown in patients with active SLE, also without overt clinical symptoms. NfL may serve as an indicator of neuronal damage in SLE in further studies.

Serum S100A8/A9 concentrations are associated with neuropsychiatric involvement in systemic lupus erythematosus: a cross-sectional study.

BACKGROUND: Neuropsychiatric (NP) involvement and fatigue are major problems in systemic lupus erythematosus (SLE). S100A8/A9 is a marker of inflammation and responds to therapy in SLE patients. S100A8/A9 has an immunopathogenic role in various neurological diseases. We investigated S100A8/A9 in relation to NP-involvement and fatigue in SLE. METHODS: 72 consecutive SLE outpatients at a tertiary centre and 26 healthy controls were included in this cross-sectional study. NPSLE was determined by specialists in rheumatology and neurology and defined according to three attribution models: "ACR", "SLICC A" and "SLICC B". Cerebral MRI was assessed by a neuroradiologist and neurocognitive testing by a neuropsychologist. The individuals were assessed by scores of pain (VAS), fatigue (VAS and FSS), and depression (MADRS-S). Concentrations of S100A8/A9 in serum and cerebrospinal fluid were measured with ELISA. Statistical calculations were performed using non-parametric methods. RESULTS: Serum concentrations of S100A8/A9 were higher in SLE patients compared with controls (medians 1230 ng/ml; 790 ng/ml, p = 0.023). The concentrations were higher in NPSLE patients compared with non-NPSLE patients when applying the SLICC A and ACR models, but not significant when applying the SLICC B model (medians 1400 ng/ml; 920 ng/ml, p = 0.011; 1560 ng/ml; 1090 ng/ml, p = 0.050; 1460 ng/ml; 1090 ng/ml, p = 0.083, respectively). No differences of CSF S100A8/A9 concentrations were observed between NPSLE and non-NPSLE patients. SLE patients with depression or cognitive dysfunction as an ACR NPSLE manifestation had higher serum S100A8/A9 concentrations than non-NPSLE patients (median 1460 ng/ml, p = 0.007 and 1380 ng/ml, p = 0.013, respectively). Higher serum S100A8/A9 correlated with higher VAS fatigue (r = 0.31; p = 0.008) and VAS pain (r = 0.27, p = 0.021) in SLE patients. Serum S100A8/A9 was not independently associated with NPSLE when adjusting for scores of fatigue (FSS) and pain (VAS) (OR 1.86, 95% CI 0.93-3.73, p = 0.08). CONCLUSIONS: Serum S100A8/A9 concentrations may be associated with NPSLE and fatigue. S100A8/A9 may be of interest in evaluating NPSLE, although further investigations are needed.

Structural Changes on MRI Demonstrate Specific Cerebellar Involvement in SLE Patients-A VBM Study.

The purpose of this study is to investigate possible differences in brain structure, as measured by T1-weighted MRI, between patients with systemic lupus erythematosus (SLE) and healthy controls (HC), and whether any observed differences were in turn more severe in SLE patients with neuropsychiatric manifestations (NPSLE) than those without (non-NPSLE). Structural T1-weighted MRI was performed on 69 female SLE patients (mean age = 35.8 years, range = 18-51 years) and 24 age-matched female HC (mean age = 36.8 years, range = 23-52 years) in conjunction with neuropsychological assessment using the CNS Vital Signs test battery. T1-weighted images were preprocessed and analyzed by FSL-VBM. The results show that SLE patients had lower grey matter probability values than the control group in the VIIIa of the cerebellum bilaterally, a region that has previously been implied in sensorimotor processing in human and non-human primates. No structural differences for this region were found between NPSLE and non-NPSLE patients. VBM values from the VIIIa region showed a weak positive correlation with the psychomotor speed domain from CNS Vital Signs (p = 0.05, r = 0.21), which is in line with its presumed role as a sensorimotor processing area.

Functional connectivity changes in core resting state networks are associated with cognitive performance in systemic lupus erythematosus.

To investigate core resting state networks in SLE patients with and without neuropsychiatric symptoms by examining functional connectivity changes correlating with results of cognitive testing. Structural MRI and resting state-fMRI (rs-fMRI) were performed in 61 female SLE patients (mean age: 36.8 years, range 18.2-52.0 years) and 20 healthy controls (HC) (mean age 36.2 years, range 23.3-52.2 years) in conjunction with clinical examination and cognitive testing. Alterations in core resting state networks, not found in our healthy controls sample, correlated with cognitive performance gauged by neuropsychological tests in non-neuropsychiatric SLE (nNP) as well as in neuropsychiatric SLE patients (NP). The observed pattern of increased functional connectivity in core resting state networks correlated with reduced cognitive performance on all cognitive domains tested and with a heavy focus on DM, CE, and DM-CE in the NP subgroup. Furthermore, we found that the observed alterations in memory and psychomotor speed correlated with disease duration. In SLE patients both with and without clinically overt neuropsychiatric manifestations, we found changes in the functional connectivity of core resting state networks essential to cognitive functions. These findings may represent a rewiring of functional architecture in response to neuronal damage and could indicate suboptimal compensatory mechanisms at play.

Functional Connectivity Changes in Systemic Lupus Erythematosus: A Resting-State Study.

To investigate resting-state functional connectivity of lupus patients and associated subgroups according to the ACR NPSLE case definitions (ACR ad hoc). In addition, we investigated whether or not the observed alterations correlated with disease duration, the systemic lupus erythematosus (SLE)-Disease Activity Index-2000 (SLEDAI-2k), and Systemic Lupus International Collaborating Clinical/ACR organ damage index (SDI)-scores. Anatomical 3T magnetic resonance imaging (MRI) and resting-state functional MRI were performed in 61 female lupus patients (mean age = 37.0 years, range = 18.2-52.0 years) and 20 gender- and age-matched controls (mean age = 36.2 years, range = 23.3-52.2 years) in conjunction with clinical examination and laboratory testing. Whole-brain voxelwise functional connectivity analysis with permutation testing was performed to extract network components that differed in lupus patients relative to healthy controls (HCs). Lupus patients exhibited both inter- and intranetwork hypo- and hyperconnectivity involving several crucial networks. We found reduced connectivity within the default mode network (DMN), the central executive network (CEN), and in-between the DMN and CEN in lupus patients. Increased connectivity was primarily observed within and between the sensory motor network in lupus patients when compared to HCs. Comparing lupus patients with and without neuropsychiatric symptoms, hypoconnectivity was more pronounced in the group with neuropsychiatric complaints. The functional connectivity of SLE patients was both positively and negatively correlated to duration of disease. We conclude that SLE patients in general and neuropsychiatric SLE patients in particular experience altered brain connectivity. These patterns may be due both to direct neuronal damage and compensatory mechanisms through neuronal rewiring and recruitment and may partly explain neuropsychiatric symptoms in SLE patients.

Altered white matter microstructure in lupus patients: a diffusion tensor imaging study.

BACKGROUND: The purpose of this study was to investigate whether white matter microstructure is altered in patients suffering from systemic lupus erythematosus (SLE), and if so, whether such alterations differed between patients with and without neuropsychiatric symptoms. METHODS: Structural MRI and diffusion tensor imaging (DTI) were performed in 64 female SLE patients (mean age 36.9 years, range 18.2-52.2 years) and 21 healthy controls (mean age 36.7 years, range 23.3-51.2 years) in conjunction with clinical examination, laboratory tests, cognitive evaluation, and self-assessment questionnaires. The patients were subgrouped according to the American College of Rheumatology Neuropsychiatric Systemic Lupus Erythematosus case definitions into non-neuropsychiatric SLE (nonNPSLE) and neuropsychiatric SLE (NPSLE). RESULTS: Comparisons between the SLE group and healthy controls showed that the mean fractional anisotropy (FA) was significantly reduced in the right rostral cingulum (p = 0.038), the mid-sagittal corpus callosum (CC) (p = 0.050), and the forceps minor of the CC (p = 0.015). The mean diffusivity (MD) was significantly increased in the left hippocampal cingulum (p = 0.017). No significant differences in MD or FA values were identified between NPSLE and nonNPSLE patients. Disease duration among all SLE patients correlated significantly with reduced FA in the CC (p < 0.05). No correlations were found between DTI parameters and white matter hyperintensities, SLE Disease Activity Index-2000, Systemic Lupus International Collaborating Clinical/ACR Organ Damage Index, or Montgomery Asberg Depression Rate Score Self-report. CONCLUSIONS: We found alterations of white matter microstructure in SLE patients that were related to disease duration and fatigue. Our results indicate that cerebral involvement in SLE is not isolated to the NPSLE subgroup.