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  • Review Article
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Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis

Nature Reviews Neurology volume 15, pages 25–39 (2019)Cite this article

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Abstract

Cerebral autoregulatory dysfunction after traumatic brain injury (TBI) is strongly linked to poor global outcome in patients at 6 months after injury. However, our understanding of the drivers of this dysfunction is limited. Genetic variation among individuals within a population gives rise to single-nucleotide polymorphisms (SNPs) that have the potential to influence a given patient’s cerebrovascular response to an injury. Associations have been reported between a variety of genetic polymorphisms and global outcome in patients with TBI, but few studies have explored the association between genetic variants and cerebrovascular function after injury. In this Review, we explore polymorphisms that might play an important part in cerebral autoregulatory capacity after TBI. We outline a variety of SNPs, their biological substrates and their potential role in mediating cerebrovascular reactivity. A number of candidate polymorphisms exist in genes that are involved in myogenic, endothelial, metabolic and neurogenic vascular responses to injury. Furthermore, polymorphisms in genes involved in inflammation, the central autonomic response and cortical spreading depression might drive cerebrovascular reactivity. Identification of candidate genes involved in cerebral autoregulation after TBI provides a platform and rationale for further prospective investigation of the link between genetic polymorphisms and autoregulatory function.

Key points

  • Impaired cerebral autoregulation after traumatic brain injury (TBI) is linked to poor global outcome; mechanisms involved in the regulation of cerebrovascular reactivity are complex, in both healthy and diseased states.

  • Single-nucleotide polymorphisms (SNPs) related to myogenic, endothelial, neurotransmitter and metabolic mechanisms of cerebrovascular biology are all likely to contribute to cerebral autoregulation and vascular reactivity in the setting of TBI.

  • Polymorphisms related to nitric oxide synthase and the renin–angiotensin system have been studied most extensively in relation to cerebral autoregulatory dysfunction; specific mutations are linked to impaired function.

  • Other polymorphisms related to the inflammatory response to TBI, central autonomic response and cortical spreading depression have the potential to affect cerebral autoregulation.

  • Future prospective multicentre Bayesian analyses of genotype data from TBI populations will be required to fully understand the potential mechanisms involved in impaired vascular reactivity and develop therapeutic targets.

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Fig. 1: Potential role of genetic polymorphisms in the control of cerebral autoregulation.

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Acknowledgements

The authors’ research was made possible through salary support for F.A.Z through the Cambridge Commonwealth Trust Scholarship, the Royal College of Surgeons of Canada – Harry S. Morton Travelling Fellowship in Surgery and the University of Manitoba Clinician Investigator Program. D.K.M. is also supported by National Institute for Healthcare Research (NIHR, UK) through the Acute Brain Injury and Repair theme of the Cambridge NIHR Biomedical Research Centre and an NIHR Senior Investigator Award to E.P.T. received funding support from Swedish Society of Medicine (Grant no. SLS-587221). Authors were also supported by a European Union Framework Program 7 grant (CENTER-TBI; Grant Agreement No. 602150).

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Nature Reviews Neurology thanks R. Diaz-Arrastia and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Division of Anaesthesia, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

    Frederick A. Zeiler, Andrew R. Stevens & David K. Menon

  2. Department of Surgery, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

    Frederick A. Zeiler

  3. Clinician Investigator Program, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

    Frederick A. Zeiler

  4. Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

    Eric P. Thelin, Joseph Donnelly, Peter Smielewski, Marek Czosnyka & Peter J. Hutchinson

  5. Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden

    Eric P. Thelin

  6. Institute of Electronic Systems, Warsaw University of Technology, Warsaw, Poland

    Marek Czosnyka

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Contributions

All authors reviewed and edited the manuscript before submission. F.A.Z, E.T., J.D., P.J.H. and D.K.M. contributed substantially to discussions of the article content. F.A.Z. researched data for the article and wrote the manuscript.

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Correspondence to Frederick A. Zeiler.

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P.S. and M.C. declare that they have financial interests in a part of licensing fee for ICM+ software (Cambridge Enterprise Ltd, UK). D.K.M. declares that he has consultancy agreements and/or research collaborations with GlaxoSmithKline, Ornim Medical, Shire Medical, Calico, Pfizer, Pressura, Glide Pharma and NeuroTraumaSciences.

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Zeiler, F.A., Thelin, E.P., Donnelly, J. et al. Genetic drivers of cerebral blood flow dysfunction in TBI: a speculative synthesis. Nat Rev Neurol 15, 25–39 (2019). https://doi.org/10.1038/s41582-018-0105-9

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