Post-traumatic epilepsy (PTE) accounts for 10% of all epilepsies and is a serious neurological consequence of TBI that can occur even years after the traumatic event. At present, no diagnostic tools are available for identifying patients at high risk of developing PTE. Together with the Laboratory of Experimental Epilepsy and Therapies, we are conducting a series of studies in animal models and patients to identify a combination of predictive biomarkers of post-traumatic epilepsy, using a combined approach that includes MRI studies, EEG studies, and circulating proteins. Knowing in advance which TBI patients will develop epilepsy could have enormous implications for interventions aimed at preventing the onset or slowing/mitigating the course of the disease. We are also testing in the mouse model the efficacy of therapies aimed at preventing the development of epilepsy.

Repeated exposure to low-energy TBI, as often happens during contact sports, increases the risk of neurodegenerative diseases and dementia later in life. At present, specific treatments able to prevent long-term consequences of sport-related TBI are lacking. Moreover, we need to improve diagnostic tools able to monitor microstructural changes triggered by mild TBI. We have developed a mouse model of repeated mild TBI able to capture key features of the human pathology, such as the development of chronic cognitive deficits associated with neuroinflammation. We recently found that early levels of the axonal protein neurofilament light (NfL), in plasma correlate with the degree of white matter atrophy one year after rmTBI, and can serve to monitor the brain’s susceptibility to a second mTBI, supporting its potential clinical application to guide the return to practice in sport-related TBI.

Subarachnoid hemorrhage (SAH) is a frequent consequence of TBI. SAH induces brain damage through a series of events: the bleeding of the cerebral artery causes a sudden increase in intracranial pressure that induces early brain lesions, responsible for the initial clinical severity. The presence of blood in the subarachnoid space causes a chemical meningitis, persistent inflammatory phenomena and vascular damage, which in 25% of patients leads to delayed chronic ischemia. Understanding the mechanisms leading to the progression of brain damage after SAH and the contribution of the different inflammatory cells in the development of delayed ischemic lesions is a crucial aspect for the development of therapeutic strategies. We have evidence that SAH in patients increases T-cell levels in the cerebrospinal fluid (CSF). Moreover, t-cell levels are further increased in patients who develop delayed ischemia suggesting a pathogenic role in the progression of brain damage after SAH. We are currently investigating the role of t-cell and the inflammatory response, in the progression of brain injury after SAH. We are also evaluating the use of circulating and neuroimaging biomarkers informative of injury severity that can be used to evaluate the efficacy of new therapies for SAH.

Traumatic brain injury (TBI) triggers acute and chronic pathological processes, including inflammatory events and molecular alterations, which contribute to neuronal death and consequent functional loss. Alongside neurotoxic phenomena, traumatic damage also induces a reparative response (neurogenesis, angiogenesis, inflammatory changes and synaptic plasticity) which, however, is short lasting and unable to counteract the evolution of post-traumatic damage. Neuroprotective and reparative strategies are crucial to mitigate/repair the brain damage and mesenchymal stromal cells (MSC) are an ideal candidate. In the animal model we have demonstrated that MSC protects the traumatized brain through pleiotropic effects which determine a functional and structural improvement of the post-traumatic damage. Our research has made it possible to lay the foundations for a first clinical study that will be conducted in collaboration with three Lombard hospitals (IRCCS San Gerardo dei Tintori Foundation in Monza, IRCCS Ca' Granda Policlinico Foundation in Milan, and ASST Papa Giovanni XXIII Hospital in Bergamo). The study will be aimed at verifying the safety and efficacy of treatment with allogeneic MSC, administered intravenously in patients with severe TBI admitted to the intensive care unit, within 48 hours after injury. The success of this study will have far-reaching therapeutic implications. In parallel, at a preclinical level, we are studying the MSC secretome (i.e., the set of soluble bioactive factors released by MSC). We have demonstrated that the administration of the secretome induces an improvement of functional and anatomical damage in mice after TBI. Ongoing studies are aimed at identifying the mediators of protection and repair and in defining the preclinical aspects that could influence the therapeutic response such as TBI heterogeneity, gender and age.

The use of animal models is essential to understand the pathological mechanisms and test new therapeutic strategies. However, simplified preclinical models are needed to reduce the use of animals and to perform a rapid screening of new drugs before in vivo tests. We therefore developed a new in vitro model of TBI, using organotypic cerebral cortical slices subjected to mechanical impact. This model induces a focal tissue damage with pathology spreading to surrounding areas, and increasing over time, with neuronal damage and glial activation similar to human pathology. Tissue damage can be mitigated by treatment with the mesenchymal stromal cell-derived secretome led to a reduction in brain death and neuronal damage, demonstrating the responsiveness of this model to therapeutic treatments. The model of organotypic slices may be used as a preliminary screening tool for therapeutic candidates in order to reduce the use of animals.