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Does a monoclonal antibody targeting immune cells affect glutamatergic level in schizophrenia? A multimodal PET/MRS
Guy Hindley1,2,3, Yuya Mizuno4,5,6, Katherine Beck4,7
1Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, 0407, Oslo, Norway. g.f.l.hindley@medisin.uio.no.
Abstract:
Microglial dysfunction and glutamatergic dysregulation are implicated in the neurobiology of schizophrenia. Microglia regulate brain glutamate levels through mechanisms including the cysteine-glutamate antiporter, raising the possibility that microglial dysfunction could underlie glutamatergic dysregulation in schizophrenia. We tested this using a combined cross-sectional/longitudinal study of individuals with first episode psychosis and healthy controls. We investigated two hypotheses: (1) increase in a positron emission tomography (PET) imaging marker of microglia is associated with increased anterior cingulate (ACC) glutamate levels; and (2) reducing immune trafficking into the CNS using the monoclonal antibody natalizumab would reduce ACC glutamate levels in people with first-episode psychosis. A total of 108 participants (68 patients and 40 healthy controls) underwent simultaneous proton magnetic resonance spectroscopy to quantify ACC glutamate and glutamate/glutamine (glx) levels and PET imaging with [18 F]DPA-714 to quantify translocator protein (TSPO) levels, a protein highly expressed by microglia in neuroinflammatory conditions. In the longitudinal arm, 50 first-episode psychosis patients were included and either randomised to receive natalizumab or placebo double-blind, or received open-label natalizumab. At baseline, there was no significant association between ACC glutamate concentration and ACC TSPO binding in the entire sample (β = -0.003, SE = 0.006, p = 0.55). In the longitudinal arm, natalizumab did not significantly alter ACC glutamate levels (mean difference = 0.227 i.u., t = 1.52, p = 0.139). These findings do not support the hypothesis that microglial dysfunction drives ACC glutamatergic dysregulation in early psychosis. Microglial dysfunction and glutamatergic dysregulation may therefore represent distinct mechanisms within the neurobiology of schizophrenia.
Insights
This study found no link between microglial activity and glutamate levels in early psychosis, suggesting these may be separate issues in schizophrenia. Natalizumab treatment did not alter glutamate levels.
Area of Science:
- Neurobiology
- Psychiatry
- Neuroimmunology
Background:
- Microglial dysfunction and altered glutamate signaling are key in schizophrenia.
- Microglia influence brain glutamate levels, suggesting a potential link to schizophrenia pathology.
Purpose of the Study:
- To investigate if microglial activation correlates with anterior cingulate cortex (ACC) glutamate levels in first-episode psychosis.
- To determine if natalizumab, an immune-modulating drug, can reduce ACC glutamate levels in early psychosis.
Main Methods:
- Combined cross-sectional and longitudinal study involving 108 participants (68 patients, 40 controls).
- Used positron emission tomography (PET) with [18F]DPA-714 to measure translocator protein (TSPO) as a marker of microglial activity.
- Quantified ACC glutamate and glutamate/glutamine (glx) levels using proton magnetic resonance spectroscopy (MRS).
- Longitudinal arm involved 50 patients randomized to natalizumab or placebo, or open-label natalizumab.
Main Results:
- No significant association was found between ACC glutamate concentration and ACC TSPO binding at baseline.
- Natalizumab treatment did not significantly alter ACC glutamate levels in the longitudinal arm.
Conclusions:
- The findings do not support the hypothesis that microglial dysfunction drives ACC glutamatergic dysregulation in early psychosis.
- Microglial dysfunction and glutamatergic dysregulation may represent distinct pathophysiological mechanisms in schizophrenia.
