Cognitive dysfunction in lupus is 'very real'
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A mounting body of evidence is showing that cognitive dysfunction in lupus is a legitimate complaint, according to a presenter at the 2021 Congress of Clinical Rheumatology-East.
However, understanding the true etiology of those complaints has proven challenging, according to Meggan Mackay, MD, MS, professor at the Institute of Molecular Medicine at the Feinstein Institutes for Medical Research and associate professor of molecular medicine and medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.
Mackay described factors ranging from pain and anxiety to socioeconomic or environmental factors as potential causes of cognitive dysfunction in lupus. “There are multiple confounders,” she said.
Even measuring cognitive dysfunction is difficult, according to Mackay. Autopsy reports have shown various biomarkers and vascular abnormalities in many lupus patients. These include disruption of the blood brain barrier; autoantibodies ranging from phospholipid, N-methyl-D-aspartate receptor (NMDAR), ribosomal P, neuronal surface p antigen, aquaporin-4, endothelial cell, MAP2, Sm and Ro; cytokines such as TNF, B-cell activating factor (BAFF), interferon alpha and gamma, TNF-like weak inducer of apoptosis (TWEAK), interleukin-6 and IL-8; microglia cells; and the complement system, according to Mackay.
“There is a lot of work to be done, because we don’t understand the biologic basis for all of these abnormalities,” Mackay said.
Mackay noted that interferon-alpha “deserves a special mention” because of its prevalence in lupus. Specifically, interferon alpha correlates strongly with lupus manifestations found in the central nervous system.
As for the blood brain barrier, Mackay highlighted the fact that many, if not most, patients with lupus have some brain involvement.
“Once these molecules get into the brain, they can stimulate microglial cells,” she said. “They can then transform into this very aggressive-looking cell that secretes these active inflammatory mediators that can then also act from the inside out perhaps to disturb the blood brain barrier.”
Use of advanced imaging techniques has allowed clinicians and researchers to identify some of these phenomena, according to Mackay. Another important step is to identify lupus patients with cognitive disease who have no previous history or family history of such disorders.
Looking deeper, data have shown that hypermetabolism in the hippocampus has correlated with poor performance in memory testing in lupus patients, as did high antibody titers. “If you had both antibody titer and hypermetabolism, there was even poorer performance on memory testing,” Mackay said.
That said, this is just one step to getting a handle on these cognitive difficulties. “Grouping all of the neuropsychiatric disorders in lupus is difficult because there are 19 syndromes,” Mackay said. “Each syndrome is different. Trying to get at the mechanism is difficult.”
If there is a bright side, it pertains to the duration of brain fog that lupus patients experience, according to Mackay. “We tend to think of it as steadily progressing,” she said. “But a lot of this fog that our patients describe is transient.”
Perhaps because of this transience, Mackay believes that certain functional impairments associated with cognitive disorders in lupus may be reversible. “However, the microstructural changes may not be reversible,” she said
As confounding as much of this research has been, what is clearly understood by both patients and the rheumatologists treating them is that brain fog and cognitive complaints are “very real,” according to Mackay. “Cognitive impairment is one of the most common symptoms in SLE,” she said. “It is not surprising that our patients complain from this.”
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Mackay M. Cognitive Dysfunction and Brain Fog in SLE. Is It Real? Presented at: Congress of Clinical Rheumatology-East annual symposium; August 12-15, 2021 (hybrid meeting).
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