Cognitive Dysfunction in Systemic Lupus Erythematosus: Immunopathology, Clinical Manifestations, Neuroimaging and Management

Abstract

Cognitive dysfunction (CD) is a common yet often clinically subtle manifestation that considerably impacts the health-related quality of life in patients with systemic lupus erythaematosus (SLE). Given the inconsistencies in CD assessment and challenges in its attribution to SLE, the reported prevalence of CD differs widely, ranging from 3 to 88%. The clinical presentation of CD in SLE is non-specific and may manifest concurrently with overt neuropsychiatric illness such as psychosis or mood disorders or as isolated impairment of attention, working memory, executive dysfunction or processing speed. Despite the lack of standardized and sensitive neuropsychological tests and validated diagnostic biomarkers of CD in SLE, significant progress has been made in identifying pathogenic neural pathways and neuroimaging. Furthermore, several autoantibodies, cytokines, pro-inflammatory mediators and metabolic factors have been implicated in the pathogenesis of CD in SLE. Abrogation of the integrity of the blood-brain barrier (BBB) and ensuing autoantibody-mediated neurotoxicity, complement and microglial activation remains the widely accepted mechanism of SLE-related CD. Although several functional neuroimaging modalities have consistently demonstrated abnormalities that correlate with CD in SLE patients, a consensus remains to be reached as to their clinical utility in diagnosing CD. Given the multifactorial aetiology of CD, a multi-domain interventional approach that addresses the risk factors and disease mechanisms of CD in a concurrent fashion is the favourable therapeutic direction. While cognitive rehabilitation and exercise training remain important, specific pharmacological agents that target microglial activation and maintain the BBB integrity are potential candidates for the treatment of SLE-related CD.

Keywords: Cognitive; Glucocorticoids; Imaging; Lupus; Neuropsychiatric; Systemic lupus erythematosus.

Fig. 1

Immunopathology of CD in SLE. SLE-related factors like autoantibodies, complement, proinflammatory cytokines and MMP-9 work in concert, leading to a breach in the BBB integrity. SLE-independent factors are equally important in regulating the BBB permeability. Autoantibodies that are produced extrathecally cross the impaired BBB into the CSF to influence cognitive function. 25(OH)D₃ crosses the blood-brain barrier to reach VDRs which are present on neurons and glial cells. NMDARs harbouring NR2A and NR2B subunits are most dense in the hippocampus CA1 region, which is important for memory and learning. Anti-NR2A/B antibodies bind to the NMDARs, inducing apoptotic cell death. Microglial cells activated by type I IFNs lead to engulfment of synaptic material from neurons, leading to reduced synaptic diversity. BBB blood-brain barrier, CD cognitive dysfunction, IFN interferon, MMP-9 matrix metalloproteinase-9, NET neutrophil extracellular trap, NMDAR N-methyl-d-aspartate receptor, SLE systemic lupus erythematosus, VDR vitamin D receptor

Fig. 2

Summary of different magnetic resonance imaging techniques for investigation of cognitive function in patients with SLE. See texts for details. Numbers in brackets denote references. fMRI functional magnetic resonance imaging, BOLD blood oxygen level dependent, SLE systemic lupus erythematosus, MRS magnetic resonance spectroscopy, PET positron emission tomography, Ch/Cr choline/creatine, TSPO 18-kD translocator protein, CD cognitive dysfunction, MR magnetic resonance, DCE-MRI dynamic contrast-enhanced MRI, BBB blood-brain barrier, WM white matter, DTI/MTI diffusion tensor imaging and magnetization transfer imaging

Fig. 3

Approach to cognitive dysfunction in SLE. Approach to cognitive dysfunction in SLE. ANAM Automated Neuropsychological Assessment Metrics, CANTAB Cambridge Neuropsychological Test Automated Battery, COWAT Controlled Oral Word Association Test, DCE-MRI dynamic contrast-enhanced magnetic resonance imaging, DTI diffusion tensor imaging, fMRI functional magnetic resonance imaging, HIV human immunodeficiency virus, HVLT-R Hopkins Verbal Learning Test-Revised, MMSE mini-mental state examination, MRI magnetic resonance imaging, MRS magnetic resonance spectroscopy, MTI magnetization transfer imaging, PET positron emission tomography, SLE systemic lupus erythematosus