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<p>Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pathophysiology of these disorders. This study aimed to investigate the association between indicators of glial activation (glial fibrillary acidic protein; GFAP) and axonal injury (neurofilament light chain; NfL) in plasma with functional brain connectivity, and externalizing psychopathology (EXT) in a neurodevelopmental cohort. Towards this, a cross-sectional study was conducted with 144 participants selected from the Indian cVEDA cohort and balanced into EXT and healthy control (HC) groups using Mahalanobis distance matching. Plasma GFAP and NfL were quantified using Simoa technology. Resting-state fMRI data were used to generate between-network connectivity deviation scores via normative modelling. We used Gamma General Linear Models (Gamma GLMs) to test for an age-by-EXT interaction on GFAP/ NfL levels and sparse partial least squares (sPLS) regression to identify connectivity features that correlated with them. We found a significant age-by-EXT interaction for GFAP (p = 0.002), where EXT was associated with higher GFAP levels only in younger participants (&lt;14 years). No significant effects were found for NfL. The sPLS analysis identified a significant five-feature brain connectivity signature that correlated with GFAP levels. This pattern was characterized by atypically strong connectivity between sensorimotor-limbic and attention-default mode networks, and weaker-than-expected connectivity within the default mode network. In conclusion, our findings identify a strong association between plasma GFAP and EXT in youth in an age dependent manner, suggesting a key role for glial activation in the early pathophysiology of these disorders. This process is linked to a specific, multivariate pattern of brain dysconnectivity, providing a potential neurobiological signature that warrants further investigation.</p>

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Plasma Glial Fibrillary Acidic Protein (GFAP) shows age-dependent associations with externalizing psychopathology and atypical brain connectivity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • B. S. Niveditha,
  • Bharath Holla,
  • Sarada Subramanian,
  • N. Gagana,
  • K. M. Bhargavi,
  • Eesha Sharma,
  • Jayant Mahadevan,
  • Meera Purushottam,
  • Biju Viswanath,
  • Vivek Benegal,
  • Gautham Arunachal,
  • Jon Heron,
  • Matthew Hickman,
  • Debasish Basu,
  • B. N. Subodh,
  • Lenin Singh,
  • Roshan Singh,
  • Kalyanaraman Kumaran,
  • Rebecca Kuriyan,
  • Sunita Simon Kurpad,
  • Kamakshi Kartik,
  • Kartik Kalyanram,
  • Sylvane Desrivieres,
  • Gareth Barker,
  • Dimitri Papadopoulos Orfanos,
  • Mireille B. Toledano,
  • Pratima Murthy,
  • Nilakshi Vaidya,
  • Ghattu Krishnaveni,
  • Gunter Schumann,
  • Kuldeep Kumar Sharma,
  • Binukumar Bhaskarapillai,
  • K. Thennarasu,
  • Rajan Kashyap,
  • Rose Dawn Bharath,
  • Amit Chakrabarti,
  • G. K. Chetan,
  • Muchukunte Mukunda Srinivas Bharath

摘要

Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pathophysiology of these disorders. This study aimed to investigate the association between indicators of glial activation (glial fibrillary acidic protein; GFAP) and axonal injury (neurofilament light chain; NfL) in plasma with functional brain connectivity, and externalizing psychopathology (EXT) in a neurodevelopmental cohort. Towards this, a cross-sectional study was conducted with 144 participants selected from the Indian cVEDA cohort and balanced into EXT and healthy control (HC) groups using Mahalanobis distance matching. Plasma GFAP and NfL were quantified using Simoa technology. Resting-state fMRI data were used to generate between-network connectivity deviation scores via normative modelling. We used Gamma General Linear Models (Gamma GLMs) to test for an age-by-EXT interaction on GFAP/ NfL levels and sparse partial least squares (sPLS) regression to identify connectivity features that correlated with them. We found a significant age-by-EXT interaction for GFAP (p = 0.002), where EXT was associated with higher GFAP levels only in younger participants (<14 years). No significant effects were found for NfL. The sPLS analysis identified a significant five-feature brain connectivity signature that correlated with GFAP levels. This pattern was characterized by atypically strong connectivity between sensorimotor-limbic and attention-default mode networks, and weaker-than-expected connectivity within the default mode network. In conclusion, our findings identify a strong association between plasma GFAP and EXT in youth in an age dependent manner, suggesting a key role for glial activation in the early pathophysiology of these disorders. This process is linked to a specific, multivariate pattern of brain dysconnectivity, providing a potential neurobiological signature that warrants further investigation.