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

Abstract

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.

Figure 1:. Proposed mechanism of SLE mediated CD.

Neuroimaging studies support a mechanism of CD beginning with hippocampal injury and altered microstructural integrity in the parahippocampus leading to decreased integrity of white matter outflow tracts and resulting in impaired cognition.

Figure 2:. Proposed two stage model for DNRAb mediated neurotoxicity, and the contribution of IFNα to neurotoxicity.

Exposure to DNRAb mediates immediate excitotoxic death of some neurons (acute stage). The surviving neurons experience strong NMDAR stimulation that induces HMGB1 secretion. Microglia are activated following DNRAb penetration of the BBB. There are at least three possible mechanisms for microglial activation in the DNRAb model: binding of secreted HMGB1 to receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4), engagement of activating Fc receptors (FcR) by DNRAb-immune complexes, and/or exposure to damage-associated molecular patterns (DAMPs) from apoptotic neurons. Activated microglia contribute to the loss of dendrites and synapses, which are “tagged” for destruction by a NMDAR-HMGB1-C1q complex (chronic stage). Interferon-alpha (IFNα) penetrates the BBB, or is produced centrally, and activates microglia, resulting in the loss of neuronal dendrites and synapses. Another mechanism of IFNα-induced neurotoxicity may be through stimulation of the KYN/TRP metabolic pathway in microglia, causing excessive production of QA that results in neuronal excitotoxicity.

Figure 3:. Proposed mechanism of ACE-inhibitor (ACE-I) treatment of SLE mediated CD.

Treatment with a BBB permeable ACE-I (captopril), but not with a BBB impermeable ACE-I (enalapril) or saline, suppresses microglial activation and preserves dendritic complexity and spatial memory in DNRAb+ mice. Importantly, captopril treatment after the onset of microglial activation can restore dendritic complexity, suggesting damaged neurons can recover following treatment.