Differences in Regional Brain Activation Patterns Assessed by Functional Magnetic Resonance Imaging in Patients with Systemic Lupus Erythematosus Stratified by Disease Duration

Abstract

The mediators of tissue damage in systemic lupus erythematosus (SLE) such as antibodies, cytokines and activated immune cells have direct access to most organs in the body but must penetrate the blood-brain barrier (BBB) to gain access to brain tissue. We hypothesized that compromise of the BBB occurs episodically such that the brain will acquire tissue damage slowly and not at the same rate as other organs. On the basis of these assumptions, we wished to determine if duration of disease correlated with brain injury, as measured with functional magnetic resonance imaging (fMRI), and if this was independent of degree of tissue damage in other organs. We investigated differences in brain activation patterns using fMRI in 13 SLE patients stratified by disease duration of ≤2 years (short-term [ST]) or ≥10 years (long-term [LT]). Two fMRI paradigms were selected to measure working memory and emotional response (fearful faces task). Performance in the working memory task was significantly better in the ST group for one and two shape recall; however, both groups did poorly with three shape recall. Imaging studies demonstrated significantly increased cortical activation in the ST group in regions associated with cognition during the two shape retention phase of the working memory task (P < 0.001) and increased amygdala (P < 0.05) and superior parietal (P < 0.01) activation in response to the fearful faces paradigm. In conclusion, analysis of activation patterns stratified by performance accuracy, differences in comorbid disease, corticosteroid doses or disease activity suggests that these observed differences are attributable to SLE effects on the central nervous system exclusive of vascular disease or other confounding influences. Our hypothesis is further supported by the lack of correlation between regional brain abnormalities on fMRI and the Systemic Lupus International Collaborating Clinics (SLICC) damage index.

Altered functional neuronal activity in neuropsychiatric lupus: A systematic review of the fMRI investigations

“…A summary of the studies (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) is depicted in Table 1. The largest original study contained 31 participants with SLE, whilst the smallest included 9 patients.…”

“…Mackay et al (14) had demonstrated a significant increase in neural activation in cortical areas associated with cognition during working memory task (cingulate gyrus, prefrontal cortex, somatomotor cortex and Brodmann area BA40, as well as the hippocampus, cingulated gyrus and prefrontal cortex in short-term SLE patients (< 2 years duration of SLE disease) in the absence of prior neuropsychiatric events or structural changes on brain MRI as compared to long-term SLE patients (> 10 years duration of disease). Furthermore, there was an increased activation in the amygdale and superior parietal regions in response to stimulation with unmasked neutral and fearful faces in the short-term SLE patients compared with the long-term SLE patients.…”

“…Lin et al (15) reported a significant attenuation of regional brain activity in the bilateral Mackay et al (14) indicated lack of correlation between regional brain activation patterns by fMRI in SLE patients stratified by disease duration and SDI. Such findings suggest that SDI is not a surrogate marker of neurologic damage in SLE.…”

Alterations of white matter structural networks in patients with non-neuropsychiatric systemic lupus erythematosus identified by probabilistic tractography and connectivity-based analyses

“…Although non-NPSLE patients do not manifest neuropsychiatric symptoms, neuroimaging studies have demonstrated some abnormalities in their brains. With regard to brain functions, functional magnetic resonance imaging (fMRI) researches reported some disruptions in several functional systems, such as working memory (Hou et al, 2013, Mackay et al, 2011), attention (Hou et al, 2013), learning memory (Shapira-Lichter et al, 2013), and language processing functional systems (DiFrancesco et al, 2007) in non-NPSLE patient groups. With regard to brain structure, the volume and thickness of gray matter show no abnormality in a non-NPSLE group (Jung et al, 2010b).…”

Integrative neuroscience approach to neuropsychiatric lupus

“…The occurrence of antibodies capable of altering the function of neuronal cells offers a promising avenue to study the diffuse CNS syndromes associated with NPSLE. Indeed, an increasing number of studies have strengthened the idea that some non-focal symptoms can be linked to the presence of DNRABs, a subclass of DNA-reactive antibodies that bind the GluN2A and GluN2B subunits of the n -methyl-d-as-partate receptor (NMDAR) with very high specificity and do not appear to bind any other brain molecule [39–49]. There is now compelling evidence for the pathogenic role of DNRABs in NPSLE [50–55] suggesting that these antibodies can cause more than one manifestation, specifically memory dysfunction and emotional disturbance, depending on the mechanisms by which DNRABs penetrate the blood–brain barrier (BBB) that separates the brain from circulation.…”