Traumatic brain injury (TBI) is a leading cause of long-term disability, but the mechanisms driving chronic sequelae remain incompletely defined. Beyond persistent neuroinflammation, emerging evidence implicates dysregulation of the gut microbiota in influencing brain recovery. The OVERCOME-TBI study is designed to investigate long-term functional, cognitive, imaging, biochemical and gastrointestinal outcomes after TBI of all severities. The principal aims are to identify biomarkers and microbiome signatures associated with progressive neurodegeneration and poor recovery, and to link these biological signals with longitudinal clinical outcomes.
OVERCOME-TBI leverages two previously established TBI cohorts. The Evidence-based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries (TBIcare) cohort was recruited between 2011 and 2013. The Pathophysiological Characterisation of Severe TBI (PACoS-TBI) cohort was recruited from 2020 to 2023. The study combines prospectively collected acute and subacute data from those original cohorts with newly performed cross-sectional assessments at chronic time points. Chronic-phase assessments are scheduled at two windows: 2–5 years and 12–15 years post-injury. Participants from the original cohorts are re-contacted and re-consented for these additional evaluations.
The protocol plans to include up to 160 patients with TBI across the recruited cohorts. In addition, up to 30 orthopaedic injury controls will be enrolled for comparison. A small positive control group of 10 patients with multiple sclerosis will undergo select imaging and biomarker sampling to provide a reference for neuroinflammatory imaging and blood biomarkers.
Participants will undergo comprehensive multimodal examinations that span clinical, imaging and molecular domains. Clinical assessments include neurological and neuropsychological testing to characterize cognitive and functional status.
Advanced neuroimaging modalities are incorporated: multishell diffusion MRI and resting-state functional MRI are planned to assess structural connectivity and functional networks. Positron emission tomography (PET) imaging will be performed using the radioligand [11C]PK11195 to quantify neuroinflammatory burden.
Molecular and microbiome investigations include blood-based analyses — proteomics, lipidomics and metabolomics — alongside faecal and intestinal microbiome profiling. Colonoscopy biopsies will be collected to provide intestinal tissue for further analysis, linking mucosal findings with faecal microbiota and systemic markers.
The multiple sclerosis group will undergo PET imaging and blood biomarker sampling as a positive control for neuroinflammatory measures.
Primary outcomes specified in the protocol are:
These endpoints are intended to capture the interplay between brain inflammation, systemic molecular signatures and gastrointestinal microbial states, and how these relate to long-term recovery trajectories.
The protocol describes application of statistical modelling to identify predictors of outcome and disease progression. Analytic methods will include regression models to test associations between imaging, molecular and microbiome measures and clinical endpoints. The study will also employ machine learning approaches to detect complex, multivariable patterns and potential biomarker signatures predictive of poor recovery or progressive neurodegeneration.
Details about specific modelling algorithms, validation strategies, or power calculations were not reported in the source summary.
Ethical approval for the study has been obtained from the Ethical Committee of the Wellbeing Services County of Southwest Finland. Written informed consent will be obtained from all participants prior to inclusion in the chronic-phase assessments. The investigators plan to disseminate findings through peer-reviewed publications, conference presentations and stakeholder engagement. The stated translational goal is to support development of personalised diagnostics and novel therapeutic targets to address chronic consequences of TBI.
The study is registered under trial number NCT06927063. Participant groups include up to 160 TBI cases, 30 orthopaedic injury controls and 10 multiple sclerosis positive controls for selected imaging and biomarker measures.