Blood biomarkers are substances found in the bloodstream that provide information about a person's health status. They can indicate disease presence, organ function, or response to medical treatment. Common examples include glucose for diabetes and cholesterol for cardiovascular risk. Blood biomarkers are essential tools for understanding TBI pathophysiology and developing new therapies. Proteins such as neurofilament light chain (released by neurons after injury) can indicate disease progression and can be analyzed non-invasively, making them crucial for research. However, their integration into preclinical animal studies remains limited. To bridge this gap, our laboratory characterizes circulating protein variations at different post-trauma stages. Recently, we conducted and published a systematic review of preclinical TBI biomarkers, highlighting that rodent models exhibit biomarker trends similar to humans. This allows for better calibration of preclinical models to enhance clinical relevance. Moreover, understanding how biomarkers respond to therapies—decreasing with effective treatments and increasing with toxic agents—will enable their incorporation as indicators of therapeutic response in drug development for TBI patients. To further improve the translation from preclinical research to clinical practice, we aim to study biomarker trends in the subacute and chronic phases of TBI. TBI is a known risk factor for dementia and Alzheimer’s disease; however, we lack acute predictive tools to identify patients at risk of cognitive decline. We are conducting parallel analyses on blood samples from TBI patients and individuals with clinically and neuroimaging-characterized cognitive decline. The goal is to profile plasma biomarkers of neuronal damage, synaptic dysfunction, and blood-brain barrier impairment to identify a biological "fingerprint" associated with cognitive decline. This will improve patient prognosis and predict the risk of progression from mild cognitive impairment to advanced deterioration and dementia. The findings could significantly impact new strategies for diagnosing and mitigating disease progression in TBI and dementia patients, ultimately improving quality of life and reducing healthcare burdens.

Post-traumatic epilepsy (PTE) accounts for 10% of all epilepsies and is a severe neurological consequence of TBI. PTE can develop years after the traumatic event, yet no diagnostic tools exist to identify high-risk patients. In collaboration with the Laboratory of Epilepsy and Therapeutic Strategies, we conduct studies in animal models and patients to identify a combination of predictive biomarkers for PTE, using an integrated approach that includes MRI, EEG, and circulating protein analysis. Early identification of TBI patients at risk of epilepsy could have significant implications for preventive interventions. In a murine model, we identified an EEG pattern at seven days post-trauma that stratifies subjects based on PTE risk. Ongoing studies aim to validate its relevance in a patient cohort. We are also investigating the role of neuroinflammation in PTE onset and progression and evaluating targeted therapies to prevent epilepsy development.

A key predictor of poor outcomes after TBI is the presence of blood in the subarachnoid space. Traumatic subarachnoid hemorrhage (SAH) causes brain damage through multiple mechanisms, including increased intracranial pressure leading to early brain injury and persistent inflammation contributing to secondary damage. Our preliminary studies showed that SAH patients have high cerebrospinal fluid T-cell levels, which are further elevated in cases of delayed ischemia. We are currently investigating the role of inflammatory responses—particularly T-cell populations—in early and late brain injuries. Moreover, we are evaluating circulating and neuroimaging biomarkers to inform on the severity of brain injury and evaluate therapeutic strategies.

Emerging evidence suggests a bidirectional communication axis between the brain and the gut microbiota. TBI triggers an acute inflammatory response, which in turn alters gut microbiota composition (dysbiosis). Dysbiosis can amplify neuroinflammation via pro-inflammatory mediators. Although these mechanisms have been characterized in the acute phase after TBI, their contribution to chronic TBI outcomes is currently unknown. We are conducting parallel analyses in animal models and patients (in collaboration with IRCCS San Gerardo dei Tintori, Monza, and IRCCS Ospedale Policlinico San Martino, Genoa) to longitudinally characterize intestinal dysfunction and dysbiosis and correlate them with long-term neurological outcomes. Additionally, we are testing pharmacological treatments to restore gut functionality and evaluate their impact on neurological recovery. If effective, this study could identify the gut as a novel therapeutic target for TBI.

Neurophysiological changes in acute brain injury models, such as stroke and TBI, are key to understanding long-term effects. High-density electrode neural interfaces developed by Corticale Srl allow precise monitoring of brain activity. Our aim is to understand how neural activity modifies following injury and how this influences recovery. The project is built around three main objectives: identifying neuroelectric signal indicating maladaptive processes following stroke or TBI, understanding how these alterations contribute to chronic injury outcomes, such as the development of epilepsy, neurodegeneration and dementia, and evaluating the efficacy of different therapeutic strategies by monitoring the response to treatment of neuroelectric signals.

TBI triggers acute and chronic pathological processes, including inflammation and molecular changes that contribute to neuronal death and functional impairment. Together with maladaptive processes, TBI induces adaptive events (as neurogenesis, angiogenesis, inflammatory modulations and synaptic plasticity), aimed at injury repair. Mesenchymal stromal cells (MSC) have demonstrated neuroprotective, reparative, and regenerative effects in animal models, improving functional and structural outcomes. These findings led to an ongoing clinical trial in collaboration with four hospitals in Lombardy, Italy (Fondazione IRCCS San Gerardo dei Tintori di Monza, Fondazione IRCCS Ca’ Granda Policlinico di Milano, e ASST Ospedale Papa Giovanni XXIII di Bergamo, Niguarda, Ca’ Granda), to assess the safety and efficacy of intravenous MSC therapy in severe TBI patients admitted to intensive care within 48 hours of injury. This could potentially pave the way for positive findings that would have significant therapeutic implications. In parallel, at the preclinical level, we are studying the secretome of MSCs, which consists of the soluble factors released by the cells that are involved in neurorepair and regeneration processes. We have demonstrated that the administration of the secretome leads to an improvement in both functional and anatomical damage following experimental traumatic brain injury. Ongoing studies aim to identify the protective mediators and define factors that may influence the therapeutic response, such as TBI heterogeneity, sex, and age.

Repeated mild TBI, common in contact sports, increases the risk of neurodegeneration and predisposes individuals to dementia. Currently, no treatments exist to prevent long-term effects of sports-related TBI, and better diagnostic tools are needed to monitor microscopic brain damage. Using a murine model of repeated mild TBI, we identified plasma neurofilament light (NfL) as an acute indicator of white matter damage, predicting long-term cognitive impairment. New biomarker identification could have major implications for assessing the long-term consequences of sports-related TBI and evaluating novel therapeutic approaches.