Phosphorylated Neurofilament Heavy Chain in the Cerebrospinal Fluid Is a Suitable Biomarker of Acute and Chronic Blast-Induced Traumatic Brain Injury.

Blast-induced traumatic brain injury (bTBI) has been documented as a significant concern for both military and civilian populations in response to the increased use of improvised explosive devices. Identifying biomarkers that could aid in the proper diagnosis and assessment of both acute and chronic bTBI is in urgent need since little progress has been made towards this goal. Addressing this knowledge gap is especially important in military veterans who are receiving assessment and care often years after their last blast exposure. Neuron-specific phosphorylated neurofilament heavy chain protein (pNFH) has been successfully evaluated as a reliable biomarker of different neurological disorders, as well as brain trauma resulting from contact sports and acute stages of brain injury of different origin. In the present study, we have evaluated the utility of pNFH levels measured in the cerebrospinal fluid (CSF) as an acute and chronic biomarker of brain injury resulting from single and tightly coupled repeated blast exposures using experimental rats. The pNFH levels increased at 24 h, returned to normal levels at 1 month, but increased again at 6 months and 1 year post-blast exposures. No significant changes were observed between single and repeated blast-exposed groups. To determine whether the observed increase of pNFH in CSF corresponded with its levels in the brain, we performed fluorescence immunohistochemistry in different brain regions at the four time-points evaluated. We observed decreased pNFH levels in those brain areas at 24 h, 6 months, and 1 year. The results suggest that blast exposure causes axonal degeneration at acute and chronic stages resulting in the release of pNFH, the abundant neuronal cytoskeletal protein. Moreover, the changes in pNFH levels in the CSF negatively correlated with the neurobehavioral functions in the rats, reinforcing suggestions that CSF levels of pNFH can be a suitable biomarker of bTBI.

Experimental Investigation of Cavitation as a Possible Damage Mechanism in Blast-Induced Traumatic Brain Injury in Post-Mortem Human Subject Heads.

The potential of blast-induced traumatic brain injury from the mechanism of localized cavitation of the cerebrospinal fluid (CSF) is investigated. While the mechanism and criteria for non-impact blast-induced traumatic brain injury is still unknown, this study demonstrates that local cavitation in the CSF layer of the cranial volume could contribute to these injuries. The cranial contents of three post-mortem human subject (PMHS) heads were replaced with both a normal saline solution and a ballistic gel mixture with a simulated CSF layer. Each were instrumented with multiple pressure transducers and placed inside identical shock tubes at two different research facilities. Sensor data indicates that cavitation may have occurred in the PMHS models at pressure levels below those for a 50% risk of blast lung injury. This study points to skull flexion, the result of the shock wave on the front of the skull leading to a negative pressure in the contrecoup, as a possible mechanism that contributes to the onset of cavitation. Based on observation of intracranial pressure transducer data from the PMHS model, cavitation onset is thought to occur from approximately a 140 kPa head-on incident blast.

Cerebrospinal Fluid Chemokine (C-C Motif) Ligand 2 Is an Early-Response Biomarker for Blast-Overpressure-Wave-Induced Neurotrauma in Rats.

Chemokines and their receptors are of great interest within the milieu of immune responses elicited in the central nervous system in response to trauma. Chemokine (C-C motif)) ligand 2 (CCL2), which is also known as monocyte chemotactic protein-1, has been implicated in the pathogenesis of traumatic brain injury (TBI), brain ischemia, Alzheimer's disease, and other neurodegenerative diseases. In this study, we investigated the time course of CCL2 accumulation in cerebrospinal fluid (CSF) after exposures to single and repeated blast overpressures of varied intensities along with the neuropathological changes and motor deficits resulting from these blast conditions. Significantly increased concentrations of CCL2 in CSF were evident by 1 h of blast exposure and persisted over 24 h with peak levels measured at 6 h post-injury. The increased levels of CCL2 in CSF corresponded with both the number and intensities of blast overpressure and were also commensurate with the extent of neuromotor impairment and neuropathological abnormalities resulting from these exposures. CCL2 levels in CSF and plasma were tightly correlated with levels of CCL2 messenger RNA in cerebellum, the brain region most consistently neuropathologically disrupted by blast. In view of the roles of CCL2 that have been implicated in multiple neurodegenerative disorders, it is likely that the sustained high levels of CCL2 and the increased expression of its main receptor, CCR2, in the brain after blast may similarly contribute to neurodegenerative processes after blast exposure. In addition, the markedly elevated concentration of CCL2 in CSF might be a candidate early-response biomarker for diagnosis and prognosis of blast-induced TBI.

Computational biomechanics of human brain with and without the inclusion of the body under different blast orientation.

Three different human head models in a free space are exposed to blast waves coming from four different directions. The four head-neck-body models composed of model a, with the neck free in space; model b, with neck fixed at the bottom; and model c, with the neck attached to the body. The results show that the effect of the body can be ignored for the first milliseconds of the head-blast wave interactions. Also one can see that although most biomechanical responses of the brain have similar patterns in all models, the shear stresses are heavily increased after a few milliseconds in model b in which the head motion is obstructed by the fixed-neck boundary conditions. The free-floating head model results are closer to the attached-body model.

Time-dependent changes of protein biomarker levels in the cerebrospinal fluid after blast traumatic brain injury.

Time-dependent changes of protein biomarkers in the cerebrospinal fluid (CSF) can be used to identify the pathological processes in traumatic brain injury (TBI) as well as to follow the progression of the disease. We obtained CSF from a large animal model (swine) of blast-induced traumatic brain injury prior to and at 6, 24, 72 h, and 2 wk after a single exposure to blast overpressure, and determined changes in the CSF levels of neurofilament-heavy chain, neuron-specific enolase, brain-specific creatine kinase, glial fibrillary acidic protein, calcium-binding protein ß (S100ß), Claudin-5, vascular endothelial growth factor, and von Willebrand factor using reverse phase protein microarray. We detected biphasic temporal patterns in the CSF concentrations of all tested protein markers except S100ß. The CSF levels of all markers were significantly increased 6 h after the injury compared to preinjury levels. Values were then decreased at 24 h, prior to a second increase in all markers but S100ß at 72 h. At 2 wk postinjury, the CSF concentrations of all biomarkers were decreased once again; brain-specific creatine kinase, Claudin-5, von Willebrand factor, and S100ß levels were no longer significantly higher than their preinjury values while neurofilament-heavy chain, neuron-specific enolase, vascular endothelial growth factor, and glial fibrillary acidic protein levels remained significantly elevated compared to baseline. Our findings implicate neuronal and glial cell damage, compromised vascular permeability, and inflammation in blast-induced traumatic brain injury, as well as demonstrate the value of determining the temporal pattern of biomarker changes that may be of diagnostic value.

No neurochemical evidence of brain injury after blast overpressure by repeated explosions or firing heavy weapons.

BACKGROUND: Psychiatric and neurological symptoms are common among soldiers exposed to blast without suffering a direct head injury. It is not known whether such symptoms are direct consequences of blast overpressure. OBJECTIVE: To examine if repeated detonating explosions or firing if of heavy weapons is associated with neurochemical evidence of brain damage. MATERIALS AND METHODS: Three controlled experimental studies. In the first, army officers were exposed to repeated firing of a FH77B howitzer or a bazooka. Cerebrospinal fluid (CSF) was taken post-exposure to measure biomarkers for brain damage. In the second, officers were exposed for up to 150 blasts by firing a bazooka, and in the third to 100 charges of detonating explosives of 180 dB. Serial serum samples were taken after exposure. Results were compared with a control group consisting of 19 unexposed age-matched healthy volunteers. RESULTS: The CSF biomarkers for neuronal/axonal damage (tau and neurofilament protein), glial cell injury (GFAP and S-100b), blood-brain barrier damage (CSF/serum albumin ratio) and hemorrhages (hemoglobin and bilirubin) and the serum GFAP and S-100b showed normal and stable levels in all exposed officers. DISCUSSION: Repeated exposure to high-impact blast does not result in any neurochemical evidence of brain damage. These findings are of importance for soldiers regularly exposed to high-impact blast when firing artillery shells or other types of heavy weapons.

[The immunological and biochemical reactions of the cerebrospinal fluid in victims of blast injuries of the skull and brain]. / Immunologicheskie i biokhimicheskie reaktsii tserebrospinal'noi zhidkosti u postradavshikh s vzryvnymi porazheniiami cherepa i golovnogo mozga.

An analysis of immunobiochemical indices of the cerebrospinal fluid has shown possibilities to establish objective mechanisms of injuries of the brain by explosions. Biochemical manifestations of the cytolysis syndrome can be taken as symptoms of primary injury of the brain under conditions of burst polytrauma since increased activity of cytoplasmic and mitochondrial enzymes in the liquor is directly proportional to the brain trauma degree. The primary injury of the brain is characterized by a specific immune response: increased concentration of IgG, IgA in the liquor with the increased circulation of immune complexes.

[The adaptation of the human central nervous system to ecological job factors]. / Adaptatsiia tsentral'noi nervnoi sistemy cheloveka k ékologo-professional'nym faktoram.

The EEG, quantity of cation proteins in neutrophils, the opioid peptides concentration in the CSF, were analysed in military personnel after a prolonged climatic and specific stress complicated by traumas, at the Kabul military hospital in Afghanistan. The brain functional reserve was significantly lower in the control subjects. A positive correlation between the brain functional reserve and the average cytochemical coefficient, was found in certain phases of traumatic disease alone. Accumulation of opioid peptides occurred under the adaptation to stress, being more evident in wounded soldiers.