Biomarkers following Traumatic Brain Injury

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1		Marco Aurelio M. Freire	--	1605	2023-08-25 15:32:04	\|
2	layout	Camila Xu	-1 word(s)	1604	2023-08-28 03:08:06	\|

This entry is adapted from the peer-reviewed paper 10.3390/biology12081139

Traumatic brain injury (TBI) is one of the leading causes of long-lasting morbidity and mortality worldwide, being a devastating condition related to the impairment of the nervous system after an external traumatic event resulting in transitory or permanent functional disability, with a significant burden to the healthcare system.

traumatic brain injury brain edema inflammation excitotoxicity

1. Introduction

The brain is undoubtedly the most complex and intriguing structure in the human organism. Its organization is characterized by a myriad of cells with distinct morphophysiological characteristics that establish an intricate network of connections that originate and modulate all the individual’s behaviors. Though, despite the ever-increasing range of information about this organ, much remains to be determined, especially concerning tissue and cell responses as a result of disturbances of any nature, either mechanical (traumatic), chemical or physiological.

One of the most common and detrimental events that can generate permanent impacts on brain functioning is traumatic brain injury (TBI), which is a complex and heterogeneous disorder in the brain structure as a result of an external force in the form of mechanical, electrical, thermal or chemical energy, or a set of these, applied on it ^[1], emerging as a serious public health concern globally ^[2]^[3]. TBI corresponds to the third most prevalent cause of death and neurological impairment worldwide, also resulting in serious dysfunctions that severely interfere with the quality of life of affected individuals ^[4]. In the long term, a TBI can, through secondary damage, lead to neurodegenerative pathologies such as Alzheimer’s disease, Parkinson’s disease and dementia ^[5].

Projections from the Global Burden of Disease (GBD) point out that the incidence of TBI tends to increase in the coming years due to the growth in population density and the increasing use of automobiles, motorcycles and bicycles as a way of transport ^[6]. One of the most devastating consequences of a TBI is the cognitive and/or functional impairment observed in surviving patients, which is directly associated to the degree of the injury ^[3], generating not only repercussions on the quality of life of affected individuals but also directly affecting the lives of their relatives and caregivers ^[7], with an important economic burden involved ^[8].

TBI is triggered by a sudden event that elicits morphophysiological disturbances in the brain parenchyma, with variable impact depending on the location and extent of the injury. The deleterious events underlying TBI can be classified into two sequential stages: primary and secondary ^[9]^[10]. The primary injury is a disturbing event that occurs at the time of the initial trauma, causing an irreversible loss of tissue in the core of the lesion. The nature of the insult is highly relevant for a proper characterization of the levels of damage, early diagnosis, and therapeutic interventions.

Depending on whether or not the skull is ruptured, the primary injury can be classified as a penetrating (open-head) or nonpenetrating (closed-head or blunt) lesion ^[9]^[10]. Penetrating injury is mainly defined by an open wound in the head caused by a foreign body, resulting in a focal disturbance that occurs along the path taken by the object through the tissue. It is associated with perforation or fracture of the skull, laceration of the meninges, and structural damage to nervous tissue ^[10]. Conversely, nonpenetrating injury is characterized by tissue damage caused by indirect impact without penetration of a foreign body into the brain. The skull may or may not be injured, but the meninges are not structurally disrupted ^[10].

Concerning the nature of trauma, nonpenetrating lesions can be classified into acceleration and non-acceleration injuries. While the first is associated with whiplash-type injury, resulting in the impact of the brain with the skull due to abrupt incidental acceleration or deceleration of the head, causing a contusion at the site of impact, as seen in blast injury ^[11], the latter is elicited by repeated blows to the head ^[12], resulting in deformation of the skull and causing focal localized damage to both meninges and brain tissue ^[10]. Mechanical tissue deformation, disturbance in the blood flow, osmotic/electrolyte imbalance, necrotic cell death, and the influx of inflammatory cells (neutrophils and monocytes) from bloodstream are hallmarks of the primary lesion in both animal models and humans, which is irreversible and amenable only to preventive measures to reduce the extent of damage ^[13].

The harmful effects following primary injury are not restricted to the site of the lesion. A primary lesion elicits a cascade of pathophysiological events that affects remote brain regions initially not affected, resulting in the so-called secondary injury, referred to as the additional damage that occurs after the primary insult following TBI. While the primary injury is the initial physical impact or event, the secondary injury involves a cascade of complex pathophysiological processes that can exacerbate the initial damage and lead to further neurological dysfunction and tissue loss ^[13]^[14].

Secondary brain injury can result from various mechanisms, including ischemia, excitotoxicity, oxidative stress, inflammation, and mitochondrial dysfunction in both animal models and humans ^[13]^[14]. These processes can cause a myriad of harmful events, such as brain edema, blood–brain barrier (BBB) disruption, increased intracranial pressure, metabolic disfunction, excitotoxicity, oxidative and cellular apoptosis or necrosis, ultimately leading to neurological disfunctions ^[13]^[15]^[16]^[17].

The secondary injury cascade typically unfolds over time, evolving from minutes to days after the initial insult. It can be influenced by factors such as systemic hypotension, hypoxemia, increased intracranial pressure, and metabolic imbalances ^[18]. The severity of the secondary injury and its impact on the patient’s outcome depend on various factors, including the nature and extent of the primary injury as well as the effectiveness of medical interventions to mitigate its progression ^[14].

2. Biomarkers following TBI

According to the Food and Drug Administration (FDA), biomarkers can be defined as a “characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions”. Recent advances in its characterization have been obtained in both humans and animal models ^[19]^[20]^[21]^[22].

Among the biomarkers reported in the literature in recent decades, there are neurodegeneration markers (tau and amyloid-beta 12), autophagy and cell destruction markers (Beclin-1 and LC3B), and inflammatory markers (GFAP, TNF-α, IL-6, NO) with special attention paid to the S100B, which is a calcium-binding protein found in astrocytes that has a number of studies in both experimental and human models ^[23]^[24]. From this perspective, it is a hard task to summarize all the most prominent biomarkers and those commonly found in animals and clinical studies. Despite that, it is possible to highlight a few of them, grouping them in three major categories: trophic factors, enzymes and epigenetic markers.

The first category involves both neurotrophic and gliotrophic factors. S100B is present in physiological conditions in the CNS due to its gliotrophic and neurotrophic roles. Initially, it was discovered that this marker plays a fundamental role in the differentiation and development of astrocytes but also in the neurite outgrowth. However, as well as the dual face of glial scar, the S100B overexpression also possess two contradictory activities: On one hand, its overexpression is often associated with injury events, such as spinal cord injury, brain traumas and stroke, and it displays a deleterious activity ^[25]^[26]. On the other hand, this protein also negatively modulates the neuroinflammation by the TNF-α pathway and other pro-inflammatory mediators and also the reduction of microgliosis, depending on the S100B extracellular concentration ^[26]^[27]^[28]. Insulin-like growth factor (IGF) has several biological activities in the CNS related to the brain development and the synaptoplasticity. Corne et al. ^[29] have detected reduced levels of IGF-1 and IGF-2 in the early chronic phase of TBI and an upregulation in the acute phase after TBI, indicating that the IGF system is differentially deregulated in the both acute and early chronic stages of TBI.

Glial fibrillary acidic protein (GFAP), a constitutive protein associated with astroglial damage and released after injury-induced impairment of the astroglial cytoskeleton, emerges as a biomarker following TBI, and it has been suggested that it may serve as a marker of focal lesions ^[30]. In addition, the protease ubiquitin C-terminal hydrolase-L1 (UCH-L1) has also been investigated as a biomarker following TBI. In an observational study, Diaz-Arrastia et al. ^[31] showed a relationship between GFAP and UCH-L1 markers, providing an indication that an analysis of both biomarkers together would be more effective than an analysis of each alone for the diagnosis and prognosis of TBI.

Although the CNS presents a high density of cell bodies, the extracellular matrix is present and composed mainly by glycosaminoglycans and proteoglycans, performing the classical roles of extracellular matrix but also providing a suitable microenvironment for BBB maintenance, neuroplasticity, synaptic transmission and microglial activity ^[32]. From this perspective, considering the morphological alteration triggered by TBI, would there be a biochemical and morphological alteration on the matrix? In order to shed some light on this question, Minta et al. ^[33] have investigated the behavior of matrix metalloproteinases (MMPs) after TBI, and have showed an increase of MMP-1, MMP-3 and MMP-10 in TBI patients, while MMP-2, MMP-9 and MMP-12 did not differ between both TBI and control patients. Such results indicate a differential role in the pathophysiology following human TBI.

The third category regards the epigenetic mechanisms involved in TBI events. Epigenetic markers are involved in gene expression mechanisms, such as histone methylation and miRNA, that modulate the status of regulation of genes by increasing or decreasing the susceptibility to translation processes ^[34]. Particularly in stroke events, some miRNA are enrolled in inflammatory functions, such as miR-424, which lead to microglial activation inhibition, and miR-155, which is associated with the TNF-α pathway ^[35]. These are only two examples from a broad range of miRNA that have already been associated with stroke events; however, most of them are also found in cardiovascular and metabolic diseases, such as arterial hypertension and diabetes ^[36].

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Subjects: Neurosciences

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Marco Aurelio M. Freire

Gabriel Sousa Rocha

Leonardo Oliveira Bittencourt

Daniel Falcao

Rafael Rodrigues Lima

Jose Rodolfo Lopes P. Cavalcanti

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Update Date: 28 Aug 2023

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1. Introduction

2. Biomarkers following TBI

References