Immune alterations in schizophrenia and the effects of a therapeutic antibody: a neuroimaging study

Abstract

Immune dysfunction is implicated in the pathophysiology of schizophrenia. The 18-kDa translocator protein (TSPO), expressed by various cell types including microglia and astrocytes, is widely used as a marker for neuroinflammation and can be quantified in vivo using positron emission tomography (PET). However, findings from TSPO PET studies in recent-onset psychosis have been inconsistent, and it remains unknown whether TSPO levels can be modified in schizophrenia. We addressed these questions with a baseline case-control comparison of patients with a first-episode psychotic disorder who were symptomatic despite antipsychotic treatment and healthy volunteers, and a longitudinal study testing the effects of natalizumab (a monoclonal antibody previously shown to reduce TSPO levels in neuroinflammatory conditions) on TSPO levels and symptoms in patients. Baseline and three-month follow-up brain imaging was carried out using [18F]DPA-714 TSPO PET, quantified as distribution volume ratio (DVR) in total, frontal lobe, and temporal lobe grey matter. A total of 103 volunteers (62 patients, 41 healthy controls) received baseline brain imaging, and 47 patients completed follow-up imaging after receiving natalizumab (n = 31) or placebo (n = 16) infusions. Natalizumab was well tolerated with no serious treatment-related adverse events. The patient group also received clinical assessments with the Positive and Negative Syndrome Scale (PANSS) at baseline and follow-up. At baseline, DVR was significantly higher in patients relative to controls in total (η2 = 0.04) and temporal lobe (η2 = 0.06) grey matter. However, there was no significant change in DVR across these regions following natalizumab or placebo treatment. Mean ± SD cerebrospinal fluid levels of natalizumab after treatment were 10.7 ± 27.2 ng/mL; indicating that the monoclonal antibody crossed the blood brain barrier. Patients receiving natalizumab showed a modest but statistically significant improvement in PANSS total scores (mean ± SD change: -3.7 ± 9.1, Cohen's d = 0.40, P = 0.017), though there was no relationship between change in DVR and change in symptom severity (P > 0.05). These findings are consistent with elevated grey matter TSPO levels in first-episode psychosis relative to healthy controls. Although natalizumab treatment was associated with a modest reduction in symptoms, the absence of corresponding changes in DVR suggests that higher grey matter TSPO may reflect expression by non-microglial cells. The lack of significant changes in the placebo group indicate it is a stable trait biomarker. Further work is needed to clarify the functional relevance and cellular specificity of TSPO alterations in psychosis. ClinicalTrials.gov: NCT03093064.

Keywords: TSPO; first episode-psychosis; longitudinal; microglia; natalizumab; positron emission tomography.