Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus

When systemic lupus erythematosus (SLE) patients exhibit central nervous system (CNS) signs or symptoms, the prognosis is poorer, the mortality higher (1), and the quality of life is reduced (2). The increased mortality and poor quality of life accompanying CNS involvement highlights the importance of detecting SLE-mediated effects on the brain as early as possible. The best estimate for the prevalence rate of SLE in the United States is approximately 350,000 (3) with CNS involvement in as many as 80% (2, 4, 5). Within the first two years of disease, approximately 20% of patients report neuropsychiatric (NP) symptoms that are attributed to SLE (2). However, many patients (28–40%) report at least one neuropsychiatric episode before or within the first year of diagnosis (2). The primary pathophysiology of SLE is inflammation secondary to autoantibody-mediated effects on tissue, degeneration of small vessels and vasculopathy (6). Inflammation is initiated by circulating autoantibodies generating inflammatory mediators and ends with cell dysfunction, apoptosis and tissue loss (1, 6, 7). Neuroimaging studies in SLE have supplied ample evidence of chronic changes indicative of late-stage pathology. PET studies have reported decreased blood flow (hypoperfusion) and decreased glucose metabolism (hypometabolism), chiefly in frontal and parietal grey matter. T1- and T2-weighted MRI studies have reported white matter volume loss and small punctate lesions. Diffusion tensor MRI and magnetization transfer imaging (MTI) studies show reduced myelination, even in SLE patients with no clear structural damage (8). No neuroimaging methods used to date have detected the inciting pathology, i.e., inflammation. Here, we used PET imaging to detect and localize both brain markers of inflammation (incipient pathology) and tissue failure and apoptosis (late-stage pathology) in persons with newly diagnosed, neurologically asymptomatic SLE. This was done using 18F-fluoro-deoxy-glucose (18FDG) PET to index both inflammation (detected as increased 18FDG uptake) and cell failure (detected as decreased 18FDG uptake). 18FDG is commonly used to detect grey matter dysfunction and atrophy, because the glucose metabolic rate decreases as tissue fails. 18FDG, however, can also be used to detect inflammation (e.g., vasculitis (9)) given that inflammatory cells demonstrate increased glucose transporter expression and that cytokines increase the affinity of glucose transporters for deoxyglucose (10). Similar methods to ours have been used to detect early evidence of white matter hypermetabolism in schizophrenia (11) and attention-deficit/hyperactivity disorder (12). PET data can be analyzed either by visual inspection, or more objectively by using regression methods to quantify covariance of regional 18FDG uptake with a clinical measure (13). The Safety of Estrogens in Lupus Erythematosus National Assessment modified version of the SLE Disease Activity Index (SELENA SLEDAI, SS) is a clinical measure used regularly in the evaluation of SLE (14). It is an index of disease activity in multiple organs, including the brain. Its score correlates with the presence of punctate white matter lesions in the brain of SLE patients without CNS signs or neuropsychiatric (NP) symptoms (15). The imaging analysis we utilized allows for the use of SS as a pattern vector to determine covariance of 18FDG uptake with disease activity. We hypothesized that combining the in vivo assessment of inflammation or tissue failure in the brain and the SS would provide a potential window into the CNS pathophysiology in SLE.