Diffuse+Axonal+Injury

toc Diffuse axonal injury is one of the most common pathologies of traumatic brain injury, occurring in both mild and severe cases. It is also one of the major causes of TBI patients going into a [|coma] following their injury. This pathology occurs most often in car accidents, falls, or assault. Under these conditions, strong inertial forces cause axons to lose their normal elasticity and become brittle. Subsequently, damage occurs to the cytoskeleton of myelinated white matter tracts, transport proteins accumulate in axonal swellings, and communication between neurons is lost. Unlike focal injury, diffuse axonal injury has widespread effects in brain regions including cortical and subcortical white matter, the corpus callosum, and brainstem. Although widespread, these changes are microscopic and are often very difficult to detect under conventional brain imaging techniques. As such, many patients with diffuse axonal injury often go undiagnosed as their brains appear normal under [|neuroimaging] examination. Currently scientists are developing treatments for this injury through either hindering progression of the axonal injury, or through regenerative medicine approaches using embryonic, pre-differentiated, and bone marrow stem cells.

=1.1 Epidemiology=

Diffuse (as opposed to focal) axonal injury, is one of the most common pathological features of TBI, which affects over 2 million patients in the USA each year. DAI occurs in 40-50% of all patients admitted with to the hospital with TBI. Furthermore, it accounts for a high degree of morbidity and mortality in both developing and industrialized nations. The most common cause of diffuse axonal injury is car accidents, but it has also been seen in cases of falls, assault, or other incidents involving strong inertial forces on the brain

=2.1. Pathogenesis & Mechanism=

2.1.a. Biomechanics of Damage
Diffuse axonal injury occurs when unrestricted head movement causes rotational acceleration of the brain. During this acceleration, the brain is subject to forces that shear, pull, and compress the white matter tissue. Normally brain white matter tissue is compliant and responsive to stress, however under these strong mechanical forces, axons become stiff and brittle, making the axon far more susceptible to damage and deformation. Immediately following the injury, a small subpopulation of axons is completely disconnected by shear inertial force.Diffuse axonal injury subsequently develops over a progressive pathophysiological process which occurs over the course of several hours, days, and weeks. First, damage to sodium channels found along axons causes an influx of sodium, and fluids, leading to axonal swelling. Secondly, calcium also enters the axon through damaged voltage gated calcium channels, activating a cellular and molecular cascade ultimately activating proteolytic enzymes such as cysteine proteases, calpain, and caspase. These enzymes degrade spectrin, an essential component of the axon cytoskeletal network. This disruption in the integrity of the cytoskeleton causes a buildup of axonal transport proteins within axonal varicosity swellings called “retraction balls” such that neuron communication is disrupted. The proteolytic enzymes also promote apoptosis by destroying the mitochondria which releases pro-apoptotic factors such as AAF, cytochrome c, and caspase enzymes. The combination of these processes disrupts neuronal communication with their targets. These pathological changes are commonly found in areas where brain tissue density changes, such as the white matter of the hemispheres, corpus callosum, and the brainstem. Figure 1 shows a some characteristic features of DAI pathology.

2.1.b. Progression to Coma
Often individuals progress into a comatose state in severe cases of diffuse axonal injury. Diffuse axonal injury can be the sole cause of posttraumatic coma, unlike focal brain injuries which cause coma in a secondary fashion following hemorrhagic contusion, hematoma, or brainstem compression,. Gennarelli and colleagues found that even in the absence of mass lesions, nonimpact rotational acceleration could cause an immediate and sustained posttraumatic coma //.//Furthermore, Smith and colleagues demonstrate that the primary determinant to developing a coma is axonal pathology in the brainstem //.//

media type="youtube" key="2RgzIjeKbXo" height="219" width="294" media type="youtube" key="qiC2Efbxa3Q" height="219" width="294" = = =3.1 Models of DAI=
 * A visualization of the pathogenesis of DAI :

Both //in vivo// and //in vitro// models of diffuse axonal injury are essential to cast light on the pathological mechanisms of injury, biomechanical analysis of TAI, and to develop more effective treatments.

3.1.a. //In vivo// Animal models and limitations
Three main experimental models of traumatic axonal injury have been used on various animal models. These include the instant rotational injury model, the impact acceleration injury model, and the lateral fluid percussion injury model. These //in vivo// models have limitations in their reproducibility in humans, biomechanical accuracy; have a high degree of experimental variability and applicability to clinical studies.

3.1.b. //In vitro// models and limitations
//In vitro// models are used to complement the in vivo models. They offer a quantitative assessment of pathologies at multiple time points which provides a better understanding of the chronology of diffuse axonal injury. //In vitro// models include transection, compressed trauma, hydrostatic pressure, acceleration, and cell stretch. These have been used to study the axonal microalterations seen in DAI such as changes in ion homeostasis, membrane permeability changes, electrophysiological responses, and axonal swelling. //In vitro// models also allow cost-efficient and timely screening of potential therapeutic molecules .These models are still not reliable reproduction of human diffuse axonal injury and thus more precise physiological and biomechanical experimental models are needed to transition from the lab to the clinic.

=4.1. Clinical Assessment and Diagnosis=

The severity of DAI is the best indicator of clinical outcome in traumatic brain injuries. The severity of DAI can be classified into different grades. In Grade I,diffuse axonal damage occurs in absence of focal abnormalities. An individual is upgraded to Grade II when there are focal abnormalities, generally in the corpus callosum. In Grade III, both characteristics of Grade I and II are present in addition to rostral brain stem damage and tears in the tissue.

4.1. Neuroimaging Limitations
The different grades of DAI can be accurately detected in post-mortem sections of the brain using immunohistochemical markers. However, diagnosis of DAI in live patients is difficult because conventional neuroimaging techniques are not sensitive enough to pick up the microscopic changes. This means that brain scans of patients with DAI often appear normal and that DAI is clinically underdiagnosed. About 50-70% of patients eventually shown to have DAI displayed a normal [|CT scan] upon presentation. This has lead clinicians to adopt the “diagnosis of exclusion” model where DAI is diagnosed in patients who have no abnormal brain imaging findings, yet display distinct symptoms such as prolonged unconsciousness or cognitive dysfunction after brain trauma. Figure 2 shows the need for more sensitive imaging technologies for diagnosis

4.2. a. Neuroimaging
Specialized MRI techniques can be used to address the need of more sensitive and accurate neuroimaging to detect axonal abnormalities in white matter tracts. Specifically, [|susceptibility weighted MRI imaging] has been shown to demonstrate superior image enhancement of primary lesion sites and axonal damage sites compared to conventional MRI. Similarly [|magnetization transfer imaging] and [|magnetic resonance spectroscopy] showed improved sensitivity for detection of DAI and axonal pathology in swine traumatic brain injuries.

4.2. b. Biomarkers
An emerging field of research focuses on using biomarkers as a different non-invasive clinical approach for diagnosis of DAI. These markers could be detected in CSFsamples due to the breakdown products of neurons and diffusion through the damaged blood brain barrier of traumatic brain injury patients. Possible biomarkers could include proteins associated with primary structural damage or with the cellular and molecular cascade involved in secondary axonomy. Axonal and glial biomarkers include neurofilaments (NF), microtubule-associated protein tau, and α-II Spectrin, and myelin basic protein. These are all critical components of the cytoskeleton or myelin that are dephosphorylated, degraded, depolymerized, and form protein bundles upon injury due to the action of proteolytic enzymes. Biomarkers associated with the molecular cascade during secondary axonomy include β-Amyloid precursor protein, an axoplasmic transport protein that accumulates in the retraction balls, amyloid β, FE65, and Neuron-Specific Enolase (NSE), a slow axoplasmic transport protein released into the ECF upon injury.

=5.1. Therapeutic Approaches for DAI=

Currently, there is no specific treatment available for DAI and instead clinicians take general approaches for a typical head injury; stabilizing and limiting increases in intracranial pressure. There are two active areas of research in therapeutic approaches to DA. Unfortunately, none of these have progressed past phase III of human clinical trials.

5.1. a. Drugs that limit the progression of DAI
One therapeutic approach is to limit the extent of axonal injury by using drugs to target the molecular cascade of events that occurs during secondary axonomy. [|Cyclosporine A] has protective effects on axons by reducing the number of axonal retraction balls, inhibiting the calcium-mediated destruction of the mitochondria, and preventing destruction of the axonal cytoskeleton. Similarly, [|FK506] impairs secondary axonomy by inhibiting the activity of the serine/threonine protein phosphatase 2B, calcineurin.

5.1.b. Regenerative Medicine Approaches for DAI
Myelinated axons have a limited ability to regenerate, due to cytoskeletal outgrowth inhibitors such as Nogo-A, oligodendrocyte-myelin glycoprotein (Omgp) and myelin associated protein (MAP). When these inhibition molecules are blocked, axonal regeneration can take place. This has been demonstrated in several //in vivo and invitro// models of CNS injury. Stem cells offer a different avenue for possible therapeutics due to their ability to proliferate, differentiate, and migrate into target tissue areas. [|Embryonic stem cells], which have unlimited differentiation potential, have been shown to have functional improvement in several behavioral tasks when injected into mouse models of DAI. Predifferentiated [|lineage-restricted cell lines] have a reduced risk of developing tumors, and can successfully migrate into brain injury sites, differentiate into neurons, improve cognitive tasks, and improve motor recovery in animal models. [|Bone marrow] derived cells injected intrarterially or intravenously into mouse models survived, migrated to injury site, and expressed neural cell markers. The advantage of using marrow cells is that they can be removed relatively non-invasively and could be harvested from and transplanted into the same individual.

Despite its promise, these regenerative medicine strategies are still preliminary and much more research is still necessary to meet clinical and safety standards. =See also=

> =External Links=
 * Traumatic Brain Injury
 * Intracranial Hematoma
 * Concussions
 * Shaken Baby Syndrome
 * EPO and TBI


 * 1) [|A Guide to Neuroimaging DAI]
 * 2) [|Can you spot the DAI?]