Introduction
Cognitive dysfunction (CD) is a common manifestation of neuropsychiatric lupus (NPSLE) with reported prevalences of 20%–80% and is associated with diminished quality of life.1–4 Discrepancies in prevalence rates reflect the variability and imprecision of available neuropsychological testing, differences in definitions of CD and difficulties with assigning attribution to SLE-associated mechanisms rather than other potentially confounding influences from infection, metabolic disturbances, medication effects, mood disturbances, microvascular insults and neurotoxins. There is a great need for unbiased measures for the assessment and attribution of CD related to SLE (SLE-CD) as these will provide diagnostic and prognostic biomarkers that can also be used as metrics for a clinical trial. Fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) provides non-invasive functional assessments of regional brain metabolism that can be correlated with serology and neuropsychological testing to identify specific SLE-related cognitive deficiencies.5 6
The wide range of clinical manifestations of SLE are unified by the presence of autoreactive cells and antibodies that promote destructive inflammatory responses. Proposed mechanisms for SLE-CD include neurotoxic effects of autoantibodies directed at neuronal antigens such as N-methyl D-aspartate receptors (NMDAR), which affect neuronal function.7–11 In non-autoimmune mice immunised to produce anti-NMDAR antibodies (termed DNRAb), it has been well established that DNRAb, depending on methods used to breach the blood–brain barrier, bind NMDARs on place cells in the CA-1 area of the hippocampus with resulting functional alterations in spatial memory.12–14 Accordingly, studies in SLE participants have demonstrated a significant association between poor performance on a spatial memory task and serum DNRAb titres.12 We have reported previously that SLE participants demonstrate increased resting metabolism in the hippocampus, posterior putamen/globus pallidus/thalamus and orbitofrontal cortex.5 6 Serum DNRAb titres correlated with metabolic increases in the hippocampus and orbitofrontal cortex, decreased microstructural integrity in the parahippocampus, and memory impairment.6
The current study furthers exploration into the relationship between spatial memory and DNRAb in SLE subjects by using a spatial navigation task (SNT) that may be more clinically relevant than the previously used static spatial memory task.12 Spatial navigation is known to rely on the hippocampus and the parahippocampal gyrus in both murine15 and human16 models, with additional input from the caudate nucleus and orbitofrontal cortex. Recruitment of these areas depends on whether an individual is using a more flexible allocentric strategy, which primarily uses the hippocampus,17 18 or a less flexible stimulus-response strategy that uses the caudate.19–21 In addition, the prefrontal cortex is known to vary in activity based on retrieval difficulty for general memory,22 a finding that has been replicated with navigation-specific information.16 23 24 Related to the current study, it has also been shown that better navigational performance without explicit manipulation of retrieval difficulty is directly associated with increased activity in left-lateralised inferior frontal and orbitofrontal cortex.19
The ability of navigation tasks to selectively elicit activity from cortical regions previously shown to be susceptible to damage in SLE (the hippocampus, parahippocampus, putamen and orbitofrontal and prefrontal cortex) makes it ideal as a potential diagnostic tool. We hypothesised that SLE spatial navigation performance would be impaired compared with healthy controls and that high serum DNRAb titres in SLE participants would inversely correlate with performance. FDG-PET imaging was used to explore associations between regional resting metabolism and spatial navigation performance. As in our previous studies, we continue to focus on SLE participants with no known history of NPSLE or other CNS insult in order to avoid confounding influences on our neuropsychological and imaging outcomes that are likely driven by different underlying mechanisms. We employed a dynamic SNT that has been used in a healthy control population to elicit differences in egocentric versus allocentric processing.25 Understanding the relationships between the SNT, serum DNRAb titres, other cognitive testing and resting regional glucose metabolism in the brain will expand our characterisation of SLE-CD and evaluate the potential of these measures as biomarkers for SLE-CD.