Brain white matter extracellular free-water increases are related to reduced neurocognitive function in systemic lupus erythematosus

Abstract

Objectives Brain white matter (WM) microstructural changes evaluated by diffusion MRI were well documented in patients with systemic lupus erythematosus (SLE). Yet, conventional diffusion tensor imaging technique fails to differentiate WM changes that originate from tissue alterations from those due to increased extracellular free water (FW) related to neuroinflammation, microvascular disruption, atrophy, or other extracellular processes. Here, we sought to delineate changes in WM tissue microstructure and extracellular FW volume and examine their relationships with neurocognitive function in SLE patients. Methods Twenty SLE patients (16 females, aged 36.0±10.6) without clinically-overt neuropsychiatric manifestation and 61 healthy controls (HC) (29 females, aged 29.2±9.4) underwent diffusion MRI and computerized neuropsychological assessments cross-sectionally. The FW imaging method was applied to compare microstructural tissue changes and extracellular FW volume of the brain WM between SLE patients and HC. Association between extracellular FW changes and neurocognitive performance was studied. Results SLE patients had higher WM extracellular FW compared to HC (family-wise-error-corrected p < 0.05) while no group difference was found in FW-corrected tissue compartment and structural connectivity metrics. Extracellular FW increases in SLE patients were associated with poorer neurocognitive performance that probed sustained attention (p = 0.022) and higher cumulative glucocorticoid dose (p = 0.0041). Such findings remained robust after controlling for age, gender, IQ, and total WM volume. Conclusions The association between WM extracellular FW increases and reduced neurocognitive performance suggest possible microvascular degradation and/or neuroinflammation in SLE patients with clinically-inactive disease. The mechanistic impact of cumulative glucocorticoids on WM FW deserves further evaluation.

Effects of Systemic Lupus Erythematosus on the Brain: A Systematic Review of Structural MRI Findings and their Relationships with Cognitive Dysfunction

“…A total of 18 articles that evaluated the effect of SLE on brain structure and their links with CD were included in this review (Figure 1) 12,19–21,23–36 . From these studies, eight utilized T1-weighted MRI 12,28,29,31–33,35,36 , nine focused on diffusion MRI 19–21,24–27,30,34 , and one reported brain metrics from both modalities 23 .…”

“…An increasing number of studies are utilizing advanced MRI to investigate NPSLE 10 . Altered tissue microstructure has been reported in several brain regions of patients with and without NPSLE diagnosis when compared to healthy controls 11,19–21 , and they have correlated with higher CD 20 . Overall, the presence of these associations even in the absence of clinical NPSLE diagnosis, suggest that brain involvement could be underdetected in SLE.…”

Long‐term effects of glucocorticoid excess on the brain

“…36 In patients with systemic lupus erythematodus, altered white matter structure correlated with cumulative glucocorticoids dosage and attentional deficits. 37…”

“…In children and adolescents with chronic glucocorticoids treatment, altered white matter microstructure has been observed in the uncinate fasciculus, a structure that regulates emotional processing through connecting the limbic system with prefrontal cortex 36 . In patients with systemic lupus erythematodus, altered white matter structure correlated with cumulative glucocorticoids dosage and attentional deficits 37 …”

Cerebral Microstructure Analysis by Diffusion-Based MRI in Systemic Lupus Erythematosus: Lessons Learned and Research Directions

“…These authors demonstrated a significant reduction in mean kurtosis at the posterior cingulate gyrus level, paired with decreased GM volume and reduction in NAA concentrations (SLE patients versus controls), suggesting a heavy impact on cognitive function of SLE patients, either with or without overt signs of NP involvement. Recently, the quantification of free extracellular water, measured exploiting a free-water (FW) imaging technique derived from DTI, confirmed an increase in the amount of extracellular free water in SLE patients with respect to healthy subjects [ 71 ]. Other researchers, instead, combined MTI with DTI, enrolling active NPSLE subjects, as well as non-NP SLE and controls [ 59 ].…”