Cognitive Impairment in SLE: Mechanisms and Therapeutic Approaches

Zarfeshani, Aida; Carroll, Kaitlin; Volpe, Bruce T.; Diamond, Betty

doi:10.1007/s11926-021-00992-1

Cited by 4 publications

(6 citation statements)

References 217 publications

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“…This is supported by recent studies showing abnormalities on dynamic contrast-enhanced MRI scanning. [13][14][15] Knowledge about the associations between cognitive dysfunction and disease activity, organ damage, biomarkers and medications may provide insights into the pathophysiology of cognitive dysfunction in SLE and provide opportunities for preventive intervention. Here, we explored the clinical associations of cognitive dysfunction in a well-characterised SLE patient cohort.…”

Section: What Does This Study Addmentioning

confidence: 99%

Clinical associations of cognitive dysfunction in systemic lupus erythematosus

et al. 2023

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ObjectiveCognitive dysfunction in SLE is common, but clinical risk factors are poorly understood. This study aims to explore the associations of cognitive dysfunction in SLE with disease activity, organ damage, biomarkers and medications.MethodsWe performed cross-sectional cognitive assessment using a conventional neuropsychological test battery, with normative values derived from demographically matched healthy subjects. Endpoints included two binary definitions of cognitive dysfunction and seven individual cognitive domain scores. Clinical parameters included disease activity (SLEDAI-2K) and organ damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We performed regression analyses to determine associations between clinical parameters and cognitive endpoints.Results89 patients with SLE were studied, with median age of 45 and disease duration of 15 years. Organ damage was significantly associated with severe cognitive dysfunction (OR 1.49, CI 1.01–2.22) and worse cognitive test performance in three of the seven individual cognitive domains. In contrast, no significant associations were found between SLEDAI-2K at the time of cognitive assessment and any cognitive endpoints on multivariate analysis. Higher time-adjusted mean SLEDAI-2K was associated with better verbal memory scores but had no significant associations with other cognitive endpoints. The presence of anti-dsDNA antibodies and high IFN gene signature were negatively associated with severe cognitive dysfunction; there were no significant associations with the other autoantibodies studied or any medications. Substance use was significantly associated with lower psychomotor speed. Only 8% of patients who had cognitive dysfunction on testing had been recognised by clinicians on their SDI score.ConclusionsIn SLE, cognitive dysfunction was positively associated with organ damage, but not associated with disease activity, and serological activity and high IFN signature were negatively associated. Cognitive dysfunction was poorly captured by clinicians. These findings have implications for preventative strategies addressing cognitive dysfunction in SLE.

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Section: What Does This Study Addmentioning

confidence: 99%

Clinical associations of cognitive dysfunction in systemic lupus erythematosus

et al. 2023

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“…Nonfocal brain manifestations such as cognitive dysfunction and psychosis remain among the most challenging features of SLE in terms of diagnosis, mechanisms and treatment [69 ▪ ,70,71 ▪▪ ]. Recent advances suggest a targeted therapy at least for patients bearing DNRabs [71 ▪▪ ]. DNRabs are found in 30–50% of SLE patients very likely contributing to cognitive dysfunction [18,72,73].…”

Section: Neuronal Surface P Antigen As a Mediator Of Anti-p Antibodie...mentioning

confidence: 99%

“…Inhibition of GluN2A or angiotensin-converting enzyme-1 (ACE-1) can counteract microglia activity and protects neurons from synaptic pruning [14,74]. Repurposing clinically used ACE-1 inhibitors has been proposed for cognitive dysfunction associated with DNRabs [71 ▪▪ ].…”

Section: Neuronal Surface P Antigen As a Mediator Of Anti-p Antibodie...mentioning

confidence: 99%

“…L-tryptophan (Trp) is also a precursor of quinolinic and kynurenic acids, which have agonist and antagonist effects on NMDAR, respectively, and a quinolinic predominant ratio associates with cognitive dysfunction in several cognitive disorders, including SLE [77 ▪ ]. However, the BBB is frequently opened by a variety of causes in SLE and therefore circulating antibodies can enter into the brain at different locations [71 ▪▪ ,78].…”

Section: Neuronal Surface P Antigen As a Mediator Of Anti-p Antibodie...mentioning

confidence: 99%

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Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease

Barake

Bravo‐Zehnder

González

2022

Current Opinion in Neurology

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Purpose of reviewThe aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE).Recent findingsMice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA.SummaryNSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.

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“…Normally, lupus nephritis (LN) is one of the most common severe organ manifestations of SLE, which is related to high mortality [70]. Neuropsychiatric lupus (NPSLE) occurs in 40-90% of SLE patients, and the damage of microglia may be the major damaged cell [71][72][73]. Actually, NPSLE is a major source of morbidity in the SLE population, and its mortality is second only to that of LN.…”

Section: The Role Of M 6 a In Inflammatory Diseasesmentioning

confidence: 99%

The Role of N6-Methyladenosine in Inflammatory Diseases

Lin

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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N6-Methyladenosine (m6A) is the most abundant epigenetic RNA modification in eukaryotes, regulating RNA metabolism (export, stability, translation, and decay) in cells through changes in the activity of writers, erasers, and readers and ultimately affecting human life or disease processes. Inflammation is a response to infection and injury in various diseases and has therefore attracted significant attention. Currently, extensive evidence indicates that m6A plays an essential role in inflammation. In this review, we focus on the mechanisms of m6A in inflammatory autoimmune diseases, metabolic disorder, cardio-cerebrovascular diseases, cancer, and pathogen-induced inflammation, as well as its possible role as targets for clinical diagnosis and treatment.

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Cognitive Impairment in SLE: Mechanisms and Therapeutic Approaches

Cited by 4 publications

References 217 publications

Clinical associations of cognitive dysfunction in systemic lupus erythematosus

Clinical associations of cognitive dysfunction in systemic lupus erythematosus

Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease

The Role of N6-Methyladenosine in Inflammatory Diseases

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