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<p>Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts—psychotic experience, cognitive and functional impairment—a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.</p>

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Cerebrospinal fluid biomarkers reveal transdiagnostic synaptic dysfunction across major psychiatric disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Andreas Göteson,
  • Johanna Nilsson,
  • Elena Camporesi,
  • Anna Luisa Klahn,
  • Elin Hörbeck,
  • Robert Sigström,
  • Lina Jonsson,
  • Timea Sparding,
  • Erik Pålsson,
  • Aurimantas Pelanis,
  • Anneli Goulding,
  • Anniella Isgren,
  • Sophie Erhardt,
  • Simon Cervenka,
  • Cynthia M. Bulik,
  • Henrik Zetterberg,
  • Kaj Blennow,
  • Carl M. Sellgren,
  • Ann Brinkmalm,
  • Mikael Landén

摘要

Synaptic dysfunction is increasingly recognized as a core feature of psychiatric disorders, yet fluid biomarkers that reflect such changes in vivo are lacking. Here, we applied targeted mass spectrometry to quantify low-abundant synaptic proteins in cerebrospinal fluid from 672 individuals with anorexia nervosa, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), schizophrenia spectrum disorders (SCZ + ), and healthy controls. Synaptic protein levels were markedly reduced in SCZ + , with intermediate reductions in BD and ADHD. Using a data-driven approach to model transdiagnostic contrasts—psychotic experience, cognitive and functional impairment—a shared two-biomarker signature emerged: elevated LAMP1, a phagolysosomal marker, and reduced NPTX2, a synaptic activity marker which inhibits complement-dependent synapse elimination. Combining this ratio with polygenic scores improved diagnostic classification. Key findings were extended to an independent cohort at first-episode psychosis. These results support synaptic pathology as a measurable and transdiagnostic feature across several psychiatric disorders and highlight the potential of integrating fluid and genetic biomarkers.