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<p>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, <i>p</i> = 0.55). In the longitudinal arm, natalizumab did not significantly alter ACC glutamate levels (mean difference = 0.227 i.u., t = 1.52, <i>p</i> = 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.</p>

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Does a monoclonal antibody targeting immune cells affect glutamatergic level in schizophrenia? A multimodal PET/MRS brain imaging study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Guy Hindley,
  • Yuya Mizuno,
  • Katherine Beck,
  • Ines Carreira Figueiredo,
  • Toby Pillinger,
  • Sami Jeljeli,
  • Joel Dunn,
  • Alexander Hammers,
  • Ramla Awais,
  • Kerstin Sander,
  • Erik Årstad,
  • David J. Lythgoe,
  • Julia J. Schubert,
  • Mattia Veronese,
  • Federico Turkheimer,
  • Oliver D. Howes,
  • Tiago Reis Marques

摘要

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.