Traumatic Brain Injury (TBI)

Traumatic brain injury is defined as damage to the brain due to sudden trauma, either by closed or penetrating head injury. TBI can be either focal or diffuse. Focal TBI can be caused by contusion, haemorrhage, or haematoma, and diffuse TBI by brain oedema, ischemic injury, or diffuse axonal injury caused by intraventricular haemorrhage. Moderate and severe TBI leads to impairments in cognition, attention, memory and motor function, but even mild TBI (mTBI) can lead to lasting effects such as fatigue, headache, dizziness, insomnia, mood disturbances, and concentration difficulties. 5-15% of mTBI patients have persistent neurocognitive symptoms 1 year after the primary trauma. TBI may lead to late-appearing Alzheimer’s-like neurodegeneration.

Minor failures in microvessels and tissue organization can cause failures in metabolic homeostasis, and lead to neurotoxicity cascade involving glutamate, aspartate, and glutamatergic system, and axonal damage can cause further defects in autoregulation of the vasculature. In mild case, microglia is able to restore glutamate homeostasis, but if not, overstimulation of glutamate receptors will lead to Ca2+ influx and death of neurons and oligodendrocytes (excitotoxicity) as secondary brain injury.

Primary injury to the brain compromises the blood-brain barrier (BBB), and secondary injury exacerbates the BBB breakdown. This leads to release of proteins and protein fragments from the brain to the circulation, and attracts peripheral leukocytes in to the brain. Tissue break-down products are also released via glymphatic system to the lymphatics, where those can be identified as antigens by T and B lymphocytes leading to production of autoantibodies and accelerated inflammatory response. CB2 receptor agonists dampen inflammation and improve outcome in mouse model of TBI (Magid et al., 2019).

Intracerebral haemorrhage (ICH) in stroke can be classified as primary or secondary. Primary ICH is associated with arterial hypertension, and usually affects small artery deep inside the brain, while secondary ICH is caused by an existing vascular malformation or tumour. Epidural haematoma is often seen in patients with skull fracture. Subdural haematomas can develop slowly without no initial evidence of brain damage. Contusions can cause subarachnoid haemorrhage. The rupture of an arterial vessel causes bleeding into brain parenchyma, which provokes mechanical damage to surrounding blood vessels and secondary bleeds. The shear stress and mass effect of expanding haematoma leads to instant necrosis of neurons and glial cells, and destruction of BBB and extracellular matrix (ECM).

In a rat model of TBI, the uptake of NMDA receptor radioligand was increased, while binding of GABAA receptor targeting radioligand was decreased outside of the lesion core (López-Picón et al., 2016).

Inflammation may persist in the brain long after the brain trauma (Donat et al., 2017). TSPO-radioligand [11C]PK11195 has shown chronic neuroinflammation especially in subcortical regions (Ramlackhansingh et al., 2011). In a mouse model of focal brain injury, another TSPO-radioligand [18F]DPA-714 had shown chronic neuroinflammation in regions remote from the initial site of injury (Hosomi et al., 2018).

Amyloid β plaques are increased in TBI survivors. [11C]PIB PET has shown that the plaques are regionally more widely distributed than in AD, including the cerebellum (Scott et al., 2016).

The defective brain functions in TBI are at least partially mediated by cholinergic system, and acetylcholinesterase inhibitors can be used in the treatment of chronic TBI (Tenovuo, 2005; Shin & Dixon, 2015). Nicotinic acetylcholine receptors (nAChRs) have a major role in cognitive functions. While nAchRs are upregulated in smokers, smoking does not affect the outcome of TBI (Östberg & Tenovuo, 2014). Several PET tracers are available for assessing the cholinergic system. [11C]MP4A PET has been used to show the cholinergic perturbation in TBI (Östberg et al., 2011); and that in TBI patients with treatment response to rivastigmine the baseline AChE activity is lower than in non-responders (Östberg et al., 2018).


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References:

Amyot F, Arciniegas DB, Brazaitis MP, Curley KC, Diaz-Arrastia R, Gandjbakhche A, Herscovitch P, Hinds SR 2nd, Manley GT, Pacifico A, Razumovsky A, Riley J, Salzer W, Shih R, Smirniotopoulos JG, Stocker D. A review of the effectiveness of neuroimaging modalities for the detection of traumatic brain injury. J Neurotrauma 2015; 32(22): 1693-1721. doi: 10.1089/neu.2013.3306.

Dambinova SA, Hayes RL, Wang KKW (eds.): Biomarkers for Traumatic Brain Injury. RSC Publishing, 2012. ISBN: 978-1-84973-389-2.

Donat CK, Scott G, Gentleman SM, Sastre M. Microglial activation in traumatic brain injury. Front Aging Neurosci. 2017; 9:208. doi: 10.3389/fnagi.2017.00208.

Granagher RP (ed.): Traumatic Brain Injury - Methods for Clinical and Forensic Neuropsychiatric Assessment. CRC Press, 2003. ISBN: 0-8493-1429-1.

Maas AIR, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017; 16(12): 987-1048. doi: 10.1016/S1474-4422(17)30371-X.

Van Horn JD, Bhattrai A, Irimia A. Multimodal imaging of neurometabolic pathology due to traumatic brain injury. Trends Neurosci. 2017; 40(1): 39-59. doi: 10.1016/j.tins.2016.10.007.



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Updated at: 2019-03-21
Created at: 2017-11-16
Written by: Vesa Oikonen