Biochemical and neurochemical sequelae following mild traumatic brain injury: summary of experimental data and clinical implications. Neurosurg Focus 29:E1

Department of Neurosciences Head and Neck Surgery, San Camillo Hospital, Rome, Italy.
Neurosurgical FOCUS (Impact Factor: 2.11). 11/2010; 29(5):E1. DOI: 10.3171/2010.9.FOCUS10183
Source: PubMed


Although numerous studies have been carried out to investigate the pathophysiology of mild traumatic brain injury (mTBI), there are still no standard criteria for the diagnosis and treatment of this peculiar condition. The dominant theory that diffuse axonal injury is the main neuropathological process behind mTBI is being revealed as weak at best or inconclusive, given the current literature and the fact that neuronal injury inherent to mTBI improves, with few lasting clinical sequelae in the vast majority of patients. Clinical and experimental evidence suggests that such a course, rather than being due to cell death, is based on temporal neuronal dysfunction, the inevitable consequence of complex biochemical and neurochemical cascade mechanisms directly and immediately triggered by the traumatic insult. This report is an attempt to summarize data from a long series of experiments conducted in the authors' laboratories and published during the past 12 years, together with an extensive analysis of the available literature, focused on understanding the biochemical damage produced by an mTBI. The overall clinical implications, as well as the metabolic nature of the post-mTBI brain vulnerability, are discussed. Finally, the application of proton MR spectroscopy as a possible tool to monitor the full recovery of brain metabolic functions is emphasized.

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Available from: Giuseppe Lazzarino, Oct 16, 2014
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    • "Of the 1.7 million people diagnosed with TBI, about 75% of them are considered to have experienced mild traumatic brain injury (mTBI) (1). Although most mTBI patients do not have long term impairments (2) approximately 15% may experience symptoms for years, and these persisting deficits are a major contributor to the morbidity associated with the disease (3, 4). Current diagnosis for TBI relies on clinical assessment; (5–7) neuroimaging techniques such as computed axial tomography (CT), magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI) are all used to better detect structural and functional changes in TBI patients (8–10). "
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    ABSTRACT: For the past 25 years, controlled cortical impact (CCI) has been a useful tool in traumatic brain injury (TBI) research, creating injury patterns that includes primary contusion, neuronal loss, and traumatic axonal damage. However, when CCI was first developed, very little was known on the underlying biomechanics of mild TBI. This paper uses information generated from recent computational models of mild TBI in humans to alter CCI and better reflect the biomechanical conditions of mild TBI. Using a finite element model of CCI in the mouse, we adjusted three primary features of CCI: the speed of the impact to achieve strain rates within the range associated with mild TBI, the shape, and material of the impounder to minimize strain concentrations in the brain, and the impact depth to control the peak deformation that occurred in the cortex and hippocampus. For these modified cortical impact conditions, we observed peak strains and strain rates throughout the brain were significantly reduced and consistent with estimated strains and strain rates observed in human mild TBI. We saw breakdown of the blood-brain barrier but no primary hemorrhage. Moreover, neuronal degeneration, axonal injury, and both astrocytic and microglia reactivity were observed up to 8 days after injury. Significant deficits in rotarod performance appeared early after injury, but we observed no impairment in spatial object recognition or contextual fear conditioning response 5 and 8 days after injury, respectively. Together, these data show that simulating the biomechanical conditions of mild TBI with a modified cortical impact technique produces regions of cellular reactivity and neuronal loss that coincide with only a transient behavioral impairment.
    Frontiers in Neurology 06/2014; 5:100. DOI:10.3389/fneur.2014.00100
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    • "N-Acetylaspartate levels are substantially reduced after severe brain injury or stroke, and levels may recover after days or weeks depending on the severity of the injury (Wardlaw et al., 1998; Signoretti et al., 2010, 2011; Vagnozzi et al., 2010). Recovery of NAA to normal levels is typically seen after milder brain injuries, but not in the case of severe injuries, or in the case of multiple milder injuries spaced closely in time as often occurs in contact sports. "
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    ABSTRACT: N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis, and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes, respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate, and acetyl coenzyme A metabolism in response to brain injury.
    Frontiers in Neuroenergetics 12/2013; 5:11. DOI:10.3389/fnene.2013.00011
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    • "Here we report that omega-3 fatty acids support metabolic pathways involved in energy homeostasis, which are fundamental for proper brain function under homeostatic and injury conditions. Patients suffering even mild concussive cerebral injury often exhibit long-term cognitive and emotional disturbances, in spite of minimal neurological damage [4] [5]. In particular, depression and anxiety disorders are the most prevalent sequel in the survivors of TBI [6]. "
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    ABSTRACT: Metabolic dysfunction occurring after traumatic brain injury (TBI) is an important risk factor for the development of psychiatric illness. In the present study, we utilized an omega-3 diet during early life as a metabolic preconditioning to alter the course of TBI during adulthood. TBI animals under omega-3 deficiency were more prone to alterations in energy homeostasis (adenosine monophosphate-activated protein kinase; AMPK phosphorylation and cytochrome C oxidase II; COII levels) and mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGC-1α and mitochondrial transcription factor A; TFAM). A similar response was found for brain-derived neurotrophic factor (BDNF) and its signaling through tropomyosin receptor kinase B (TrkB). The results from in vitro studies showed that 7,8-dihydroxyflavone (7,8-DHF), a TrkB receptor agonist, upregulates the levels of biogenesis activator PGC-1α, and CREB phosphorylation in neuroblastoma cells suggesting that BDNF-TrkB signaling is pivotal for engaging signals related to synaptic plasticity and energy metabolism. The treatment with 7,8-DHF elevated the mitochondrial respiratory capacity, which emphasizes the role of BDNF-TrkB signaling as mitochondrial bioenergetics stimulator. Omega-3 deficiency worsened the effects of TBI on anxiety-like behavior and potentiated a reduction of anxiolytic neuropeptide Y1 receptor (NPY1R). These results highlight the action of metabolic preconditioning for building long-term neuronal resilience against TBI incurred during adulthood. Overall, results emphasize the interactive action of metabolic and plasticity signals for supporting neurological health.
    Biochimica et Biophysica Acta 12/2013; 1842(4). DOI:10.1016/j.bbadis.2013.12.004 · 4.66 Impact Factor
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