Metabolic and microstructural alterations in the SLE brain correlate with cognitive impairment

Mackay, Meggan; Vo, An; Tang, Chris C.; Small, M.; Anderson, Erik; Ploran, Elisabeth J.; Storbeck, Justin; Bascetta, Brittany; Kang, Simran; Aranow, Cynthia; Sartori, Carl; Watson, Phillip; Volpe, Bruce T.; Diamond, Betty; Eidelberg, David

doi:10.1172/jci.insight.124002

Cited by 65 publications

(81 citation statements)

References 70 publications

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“…We found that these SLE patients demonstrate hypermetabolism on 18 F-fluorodeoxyglucose (FDG)-PET in the hippocampus, among other brain regions, and hippocampal hypermetabolism correlates with poor working memory (69), demonstrating that SLE patients with no other NPSLE symptoms may exhibit CD that correlates with clear abnormalities in brain function. Further, DNRAb antibody positivity was shown to correlate with hippocampal hypermetabolism (69) and decreased white matter microstructural integrity in the parahippocampal gyrus on DTI (67). This decreased microstructural integrity correlated with increased serum DNRAb and poor spatial memory performance.…”

Section: Spatial Memory Spatialflexibilitymentioning

confidence: 88%

“…Although it may be difficult to extrapolate results from mice to humans, the mouse model informed our choice of applying tasks related to spatial memory in humans with SLE. Using a 2 × 2 array of objects that assessed both object recognition and memory for spatial relations, we found that DNRAb is associated with a spatial memory deficit in humans with SLE . Additionally, we used a desktop, 3‐dimensional spatial navigation task that may be more clinically relevant than the 2 × 2 array and found that DNRAb‐positive SLE patients performed poorly compared to DNRAb‐negative SLE patients, who performed similarly to healthy controls .…”

Section: Introductionmentioning

confidence: 90%

“…| 1421 spatial memory deficit in humans with SLE (66,67). Additionally, we used a desktop, 3-dimensional spatial navigation task that may be more clinically relevant than the 2 × 2 array and found that DNRAb-positive SLE patients performed poorly compared to DNRAb-negative SLE patients, who performed similarly to healthy controls (68).…”

Section: Spatial Memory Spatialflexibilitymentioning

confidence: 99%

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Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Kello

Anderson

Diamond

2019

Arthritis & Rheumatology

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Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE‐related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody‐ and cytokine‐mediated neuronal injury include the abrogation of blood–brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE‐mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin‐converting enzyme inhibitors, or that protect blood–brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.

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Section: Spatial Memory Spatialflexibilitymentioning

confidence: 88%

Section: Introductionmentioning

confidence: 90%

Section: Spatial Memory Spatialflexibilitymentioning

confidence: 99%

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Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Kello

Anderson

Diamond

2019

Arthritis & Rheumatology

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“…Functional MRI studies have shown increased functional connectivity in core resting-state networks in SLE patients that correlate with reduced cognitive performance compared with healthy controls [37]. FDG-PET imaging highlighted hypermetabolic regions that corresponded with increased serum anti-NMDAR antibodies in SLE patients with CD and did not correlate with disease duration, activity, medications or comorbidities [26,27]. These studies highlight a potential role for these imaging techniques in objectively diagnosing and monitoring CD in SLE patients.…”

Section: Advanced Imaging Studiesmentioning

confidence: 94%

“…In fact, there is evidence for the involvement of multiple aspects of the immune system in NPSLE, including neurotoxic autoantibodies, pro-inflammatory cytokines and cell-mediated effects, in conjunction with abnormalities in neuroimmune interfaces including the choroid plexus and blood-brain barrier which allow systemic autoimmune drivers into the central nervous system [21,24]. Specifically, several studies have pointed to increased systemic levels of cytokines such as interleukin 6 (IL-6) and neurotoxic anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in SLE patients with CD [25][26][27]. In addition, type I interferon (IFN-I) and anti-NMDAR antibodies were shown to enhance microglia activation, leading to aberrant synaptic pruning with subsequent CD [28,29].…”

Section: Pathogenesismentioning

confidence: 99%

Cognitive dysfunction in autoimmune rheumatic diseases

Oláh¹,

Schwartz

Denton

et al. 2020

Arthritis Res Ther

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For people with chronic autoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis (SSc), normal cognitive functions are essential for performing daily activities. These diseases may be associated with cognitive dysfunction (CD). In RA, CD has been associated with age, lower education and disease duration and activity. Great advances have been achieved in neuropsychiatric SLE in the identification of pathogenic pathways, assessment and possible treatment strategies. SSc rarely exerts direct effects on the brain and cognitive function. However, the psychological burden that includes depression, anxiety and social impact may be high. AIRD patients with sustained disease activity, organ damage or lower education should be evaluated for CD. The control of systemic inflammation together with tailored behavioural cognitive therapies may benefit these patients.

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Aptamer‐Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome

Vanarsa

Sasidharan

Duran

et al. 2022

Arthritis & Rheumatology

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Objective As no gold‐standard diagnostic test exists for neuropsychiatric systemic lupus erythematosus (NPSLE), we undertook this study to execute a broad screen of NPSLE cerebrospinal fluid (CSF) using an aptamer‐based platform. Methods CSF was obtained from NPSLE patients and subjected to proteomic assay using the aptamer‐based screen. Potential biomarkers were identified and validated in independent NPSLE cohorts in comparison to other neurologic diseases. Results Forty proteins out of the 1,129 screened were found to be elevated in NPSLE CSF. Based on enzyme‐linked immunosorbent assay validation, CSF levels of angiostatin, α2‐macroglobulin, DAN, fibronectin, hepatocellular carcinoma clone 1, IgM, lipocalin 2, macrophage colony‐stimulating factor (M‐CSF), and serine protease inhibitor G1 were significantly elevated in a predominantly White NPSLE cohort (n = 24), compared to patients with other neurologic diseases (n = 54), with CSF IgM (area under the curve [AUC] 0.95) and M‐CSF (AUC 0.91) being the most discriminatory proteins. In a second Hong Kong–based NPSLE cohort, CSF IgM (AUC 0.78) and lipocalin 2 (AUC 0.85) were the most discriminatory proteins. Several CSF proteins exhibited high diagnostic specificity for NPSLE in both cohorts. Elevated CSF complement C3 was associated with an acute confusional state. Eleven molecules elevated in NPSLE CSF exhibited concordant elevation in the choroid plexus, suggesting shared origins. Conclusion Lipocalin 2, M‐CSF, IgM, and complement C3 emerge as promising CSF biomarkers of NPSLE with diagnostic potential.

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Metabolic and microstructural alterations in the SLE brain correlate with cognitive impairment

Cited by 65 publications

References 70 publications

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Cognitive dysfunction in autoimmune rheumatic diseases

Aptamer‐Based Screen of Neuropsychiatric Lupus Cerebrospinal Fluid Reveals Potential Biomarkers That Overlap With the Choroid Plexus Transcriptome

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