Abstract
Considerable strides in medical interventions during the acute phase of traumatic brain injury (TBI) have brought improved overall survival rates. However, following TBI, people often face ongoing, persistent and debilitating long-term complications. Here, we review the recent literature to propose possible mechanisms that lead from TBI to long-term complications, focusing particularly on the involvement of a compromised blood–brain barrier (BBB). We discuss evidence for the role of spreading depolarization as a key pathological mechanism associated with microvascular dysfunction and the transformation of astrocytes to an inflammatory phenotype. Finally, we summarize new predictive and diagnostic biomarkers and explore potential therapeutic targets for treating long-term complications of TBI.
Key points
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Spreading depolarization (SD) is a hallmark of the immediate electrophysiological brain response to traumatic brain injury (TBI).
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SD induces mitochondrial injury preferentially in the cellular elements of the vascular system, leading to breakdown of the blood–brain barrier (BBB).
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BBB dysfunction can last for days to months or even years after TBI and might be associated with oedema, astrocytic and microglial activation, neuroinflammation, extracellular matrix alterations and modification of neuronal networks.
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BBB dysfunction contributes to the long-term neurological complications of TBI, including facilitated brain ageing, cognitive impairments, depression and post-traumatic epilepsy.
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Emerging methods for the assessment of SDs, mitochondrial dysfunction, neuroinflammation and BBB integrity, together with new treatment strategies that aim to facilitate repair of the neurovascular unit, offer new hope for the prevention of TBI-related complications.
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Acknowledgements
The authors thank C. Lemale, S. Mirloo and N. T. Pham for providing their recordings and figures. This work was supported by the Canadian Institutes of Health Research (PJT 180636 and 186067), the Israel Science Foundation (2254/20) and the US–Israel Binational Science Foundation (2021133). In addition, this work was funded by the Citizens United for Research in Epilepsy, doing business as CURE Epilepsy (957373) and the Deanship of the Scientific Research, Al-Balqa Applied University (DSR-2022#484). J.P.D. and A.F. report a grant from the Era-Net Neuron EBio2 with funds from BMBF 01EW2004 and CIHR Award No. NDD 168164. J.P.D. reports a grant from DFG DR 323/10-2.
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van Hameren, G., Aboghazleh, R., Parker, E. et al. From spreading depolarization to blood–brain barrier dysfunction: navigating traumatic brain injury for novel diagnosis and therapy. Nat Rev Neurol 20, 408–425 (2024). https://doi.org/10.1038/s41582-024-00973-9
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DOI: https://doi.org/10.1038/s41582-024-00973-9
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