Acute brain injury can have severe and long-lasting consequences. Pharmacological neuro-protection, both for traumatic brain injury (TBI) or hemorrhagic lesions, is not available. There is a gap from successful experimental interventions in animal models and failures in clinical applications. Essential for our research, therefore, is alively connection/interplay between the laboratory and the clinical work. Parallel exploration of mechanisms in the clinical setting (through invasive monitoring and neuro-imaging, for instance) and in the laboratory aim:
- at refining experimental models;
- at identifying biomarkers of injury progression/resolution;
- at identifying molecular targets;
- at developing therapeutic approaches.
To understand the mechanisms transforming an initial acute biomechanical injury into a chronic and progressive pathology
Survivors of TBI, are at risk of late neurodegeneration (including chronic traumatic encephalopathy; CTE) and dementia (Alzheimer disease). The cellular drivers and molecular mechanisms of such progressive cognitive deterioration syndromes are unclear. We recently provided first evidence that a single TBI can generate an abnormal form of the dementia associated protein tau that can slowly spread through the brain, resulting in memory deficits and neuronal damage. The observation that a single brain trauma is associated with widespread tau deposition in humans and to the formation of a self-propagating form of tau in a relevant animal model provides the first evidence for how a mechanical brain injury might evolve into chronic degenerative brain disease, including CTE. Together with the Laboratory of Prion Disease, ongoing studies are focused on the development of therapeutic strategies able to interfere with tau propagation.
Biomarkers of acute brain injury and post traumatic epilepsy
Predicting long-term outcome in TBI is extremely challenging. This reflects our incomplete understanding of how traumatic lesions influence neural networks and brain functions. Direct longitudinal brain monitoring of pathophysiological processes would be helpful to understand mechanisms and timing of disease progression. We aim at developing a multimodal device where diagnostic capabilities are integrated. We will combine an electric, fluidic and optical component thus allowing the online investigation of energy derangements, neuronal activity, and molecular events. Together with the Laboratory of Experimental Neurology, we aim at identifying a combination of blood, imaging (MRI) and EcoG biosignature for spontaneous post-traumatic epilepsy (PTE, a condition that represents 10% of all epilepsies) in the mouse model; key drivers identified in the preclinical model will be subjected to clinical validation using archived serum samples from TBI patients with/without PTE. Clinically validated PTE biosignatures could ultimately serve as risk and diagnostic biomarkers as well as lead candidates for novel therapeutic targets.
Traumatic brain injury: cell therapy for brain protection
We aim at assessing neurorestorative strategies with a specific focus on mesenchymal stromal cells (MSC) and their derivatives. We have shown that MSC improve outcome fostering protective and restorative processes after experimental acute brain injury. We have found that MSC released bioactive factors (secretome) mediate plasticity and restorative events, indicating the potential for a cell free approach. We aim at i) capturing the MSC-derived key effectors that induce protection after acute brain injury; ii) providing mechanistic insight onto how MSC derivatives affect systemic and brain cell populations; iii) thoroughly characterizing the therapeutic potential of the secretome by defining a preclinical protocol and by evaluating critical issues related to patients’ selection (i.e. gender issue, aging and TBI heterogeneity). The project will provide new insight onto the therapeutic potential of MSC and their secretome for the traumatized brain and will allow to construct a safe, cell-free and defined therapeutic strategy with direct clinical implications.
International Consensus on Cardiopulmonary Resuscitation.