Plasma Glial Fibrillary Acidic Protein (GFAP) shows age-dependent associations with externalizing psychopathology and atypical brain connectivity
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.
Authors
- Matthew Hickman (ORCID: https://orcid.org/0000-0001-9864-459X)
- Amit Chakrabarti (ORCID: https://orcid.org/0000-0003-4342-6581)
- Rose Dawn Bharath (ORCID: https://orcid.org/0000-0002-7464-4250)
- Sunita Simon Kurpad
- Jon Heron (ORCID: https://orcid.org/0000-0001-6199-5644)
- Jayant Mahadevan (ORCID: https://orcid.org/0000-0001-7494-9380)
- Biju Viswanath (ORCID: https://orcid.org/0000-0002-7317-1789)
- Gautham Arunachal (ORCID: https://orcid.org/0000-0001-9985-7028)
- K Thennarasu
- Mireille B. Toledano (ORCID: https://orcid.org/0000-0001-5695-6210)
- Vivek Benegal (ORCID: https://orcid.org/0000-0002-8896-9689)
- G. K. Chetan
- Kalyanaraman Kumaran (ORCID: https://orcid.org/0000-0002-6107-8608)
- Meera Purushottam (ORCID: https://orcid.org/0000-0002-4000-268X)
- Kartik Kalyanram (ORCID: https://orcid.org/0000-0002-6837-0062)
- B.S. Niveditha
- Eesha Sharma (ORCID: https://orcid.org/0000-0001-7681-9563)
- Sarada Subramanian
- Lenin Singh
- N. Gagana
- B N Subodh
- Gareth Barker
- K. M. Bhargavi
- Roshan Singh
- Rebecca Kuriyan
- Binukumar Bhaskarapillai
- Gunter Schumann (ORCID: https://orcid.org/0000-0002-7740-6469)
- Sylvane Desrivieres (ORCID: https://orcid.org/0000-0002-9120-7060)
- Pratima Murthy
- Dimitri Papadopoulos Orfanos (ORCID: https://orcid.org/0000-0002-1242-8990)
- Rajan Kashyap (ORCID: https://orcid.org/0000-0002-5967-2173)
- Kuldeep Kumar Sharma
- Muchukunte Mukunda Srinivas Bharath (ORCID: https://orcid.org/0000-0003-0221-9228)
- Debasish Basu
- Nilakshi Vaidya (ORCID: https://orcid.org/0000-0002-4600-7158)
- Bharath Holla (ORCID: https://orcid.org/0000-0003-0999-1237)
- Kamakshi Kartik
- Ghattu Krishnaveni
Institutions
- Wellcome Centre for Human Neuroimaging (GB)
- St. John's College of Nursing (US)
- King's College London (GB)
- Fudan University (CN)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- University of Bristol (GB)
- Indian Council of Medical Research (IN)
- CEA Paris-Saclay (FR)
- St.John's Medical College Hospital (IN)
- CSI Holdsworth Memorial Hospital (IN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Southampton (GB)
- Regional Institute of Medical Sciences (IN)
- Post Graduate Institute of Medical Education and Research (IN)
- Imperial College London (GB)
- National Institute of Mental Health and Neurosciences (IN)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Translational Psychiatry
- Published
- 2026-05-29
- DOI
- https://doi.org/10.1038/s41398-026-04114-2
- Primary Topic
- Functional Brain Connectivity Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Indian Council of Medical Research
- Medical Research Council