A Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury

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Abstract

Multi-modal biomarkers (e.g., imaging, blood-based, physiological) of unique traumatic brain injury (TBI) endophenotypes are necessary to guide the development of personalized and targeted therapies for TBI. Optimal biomarkers will be specific, sensitive, rapidly and easily accessed, minimally invasive, cost effective, and bidirectionally translatable for clinical and research use. For both uses, understanding how TBI biomarkers change over time is critical to reliably identify appropriate time windows for an intervention as the injury evolves. Biomarkers that enable researchers and clinicians to identify cellular injury and monitor clinical improvement, inflection, arrest, or deterioration in a patient's clinical trajectory are needed for precision healthcare. Prognostic biomarkers that reliably predict outcomes and recovery windows to assess neurodegenerative change and guide decisions for return to play or duty are also important. TBI biomarkers that fill these needs will transform clinical practice and could reduce the patient's risk for long-term symptoms and lasting deficits. This article summarizes biomarkers currently under investigation and outlines necessary steps to achieve short- and long-term goals, including how biomarkers can advance TBI treatment and improve care for patients with TBI.

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Most cited references 196

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Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study

Arastoo Vossough, Andy S Jagoda, Tobias Lindner … (2018)

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Research review: Polygenic methods and their application to psychiatric traits.

Naomi R Wray, Sang Hong Lee, Divya Mehta … (2014)

Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors. © 2014 Association for Child and Adolescent Mental Health.

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Inflammation after trauma: microglial activation and traumatic brain injury.

Anil F Ramlackhansingh, David Brooks, Richard Greenwood … (2011)

Patient outcome after traumatic brain injury (TBI) is highly variable. The underlying pathophysiology of this is poorly understood, but inflammation is potentially an important factor. Microglia orchestrate many aspects of this response. Their activation can be studied in vivo using the positron emission tomography (PET) ligand [11C](R)PK11195 (PK). In this study, we investigate whether an inflammatory response to TBI persists, and whether this response relates to structural brain abnormalities and cognitive function. Ten patients, studied at least 11 months after moderate to severe TBI, underwent PK PET and structural magnetic resonance imaging (including diffusion tensor imaging). PK binding potentials were calculated in and around the site of focal brain damage, and in selected distant and subcortical brain regions. Standardized neuropsychological tests were administered. PK binding was significantly raised in the thalami, putamen, occipital cortices, and posterior limb of the internal capsules after TBI. There was no increase in PK binding at the original site of focal brain injury. High PK binding in the thalamus was associated with more severe cognitive impairment, although binding was not correlated with either the time since the injury or the extent of structural brain damage. We demonstrate that increased microglial activation can be present up to 17 years after TBI. This suggests that TBI triggers a chronic inflammatory response particularly in subcortical regions. This highlights the importance of considering the response to TBI as evolving over time and suggests interventions may be beneficial for longer intervals after trauma than previously assumed. Copyright © 2011 American Neurological Association.

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Author and article information

Journal

Journal ID (nlm-ta): J Neurotrauma

Journal ID (iso-abbrev): J Neurotrauma

Journal ID (publisher-id): neu

Title: Journal of Neurotrauma

Publisher: Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd Floor New Rochelle, NY 10801 USA )

ISSN (Print): 0897-7151

ISSN (Electronic): 1557-9042

Publication date (Print): April 2022

Publication date (Electronic): 23 March 2022

Publication date PMC-release: 23 March 2022

Volume: 39

Issue: 7-8

Pages: 436-457

Affiliations

[ ¹ ]TBI and Concussion Center, Department of Neurology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

[ ² ]George E Wahlen Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA.

[ ³ ]H Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, Texas, USA.

[ ⁴ ]Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine University of California, Los Angeles, California, USA.

[ ⁵ ]Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.

[ ⁶ ]National Intrepid Center of Excellence, Walter Reed National Military Medical Center, Bethesda, Maryland, USA.

[ ⁷ ]Department of Nursing and Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

[ ⁸ ]Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.

[ ⁹ ]Minneapolis VA Health Care System, Minneapolis, Minnesota, USA.

[ ¹⁰ ]Department of Psychiatry and Behavioral Sciences, University of Minnesota Medical School, Minneapolis, Minnesota, USA.

[ ¹¹ ]Research Institute, Casa Colina Hospital and Center for Healthcare, Pomona, California, USA.

[ ¹² ]Delix Therapeutics, Inc., Boston, Massachusetts, USA.

[ ¹³ ]Cohen Veterans Bioscience, New York, New York, USA.

Author notes

[*] [ ^* ]Address correspondence to: Andreas Jeromin, PhD, Cohen Veterans Bioscience, 535 8 ^th Avenue, 12 ^th Floor, New York, NY 10018, USA andreasjeromin@ 123456gmail.com

Article

Publisher ID: 10.1089/neu.2021.0099

DOI: 10.1089/neu.2021.0099

PMC ID: 8978568

PubMed ID: 35057637

SO-VID: 598e3885-8187-4a97-bb86-106b12865f47

License:

This Open Access article is distributed under the terms of the Creative Commons License (CC-BY) ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

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Figures: 2, Tables: 2, References: 213, Pages: 22

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A Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury

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Abstract

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Journal of Circulating Biomarkers

Most cited references 196

Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study

Research review: Polygenic methods and their application to psychiatric traits.

Inflammation after trauma: microglial activation and traumatic brain injury.

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