Biochemical and neurochemical sequelae following mild traumatic brain injury: summary of experimental data and clinical implications

Abstract

<jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p>

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

“…Therefore, as previously reported, 26,27 the present research offers a real time course of NAA, Cr, and Cho following mTBI, demonstrating transient cerebral hypometabolism (decrease in NAA and Cr) corresponding to the window of metabolic brain vulnerability. [1][2][3][5][6][7][8]10,11,35 In light of the data questioning the validity of neuropsychological tests to determine the safe return of athletes to play, 48,49 the present results, besides confirming that recovery of brain metabolism occurs much later than disappearance of postconcussive symptoms, once again indicate that 1 H MRS is a potent, unique tool with which to monitor the closure of the window of metabolic brain vulnerability following mTBI that may involve important brain metabolites such as NAA and Cr. Furthermore, the very recent report carried out in a cohort of 24 symptomfree athletes with concussive head injury (as assessed by clinical self-reported symptom resolution, cognitive and clinical balance testing (SCAT2 and Balance Error Scoring System), and clearance from a medical professional for the first stage of aerobic activity) showing significant alterations in brain metabolism (decrease in NAA in the genu but not in the splenium of the corpus callosum) strongly support the concept that clinical resolution is not coincident with normalization of brain metabolism.…”

“…31,32 To explain their results, these authors concluded that an increase in total Cr (Cr and CrP) levels in the white matter may support a larger pool of high-energy phosphates (CrP and ATP), helping to restore mTBI-induced alteration of cell homeostasis through upregulation of membrane pumps and other processes of cellular repair. 28,29 Notwithstanding, these conclusions are in contrast with the notion of brain vulnerability, [1][2][3][5][6][7][8]10,11,35 which is characterized by a period of metabolic depression (hypometabolism), mainly due to mitochondrial malfunctioning, [36][37][38] particularly affecting NAA homeostasis 39 and ATP supply, [8][9][10][11]31,39 and also causing significant depletion in the total Cr pool. 31,32 Furthermore, given the relative CrP/ATP ratio in the brain tissue, ranging from about 0.8 (from Bryant et al) 32 to about 0.33 (from Signoretti et al), 31 it seems implausible that CrP may efficiently buffer ATP stores in the case of impaired ATP homeostasis.…”

“…However, since these compounds are related to phospholipid metabolism, the Cho peak area is generally considered as a good indicator of the cell membrane turnover, 17,19 that of NAA is used as a marker of energy state and neuronal integrity, 8,10,11,17 and that of Cr is thought to be a marker of cellular energy. 17 Since the period of brain vulnerability following an mTBI is mainly characterized by evident biochemical, metabolic, and molecular changes, 3,5,6,20 it is questionable whether the tests currently adopted in the clinical practice to monitor mTBI patients (neuropsychological tests, balance tests, etc), because of their inability to evaluate cerebral biochemical changes, are of utility to determine the end of brain vulnerability. Although some of them (neuropsychological tests) are largely applied to assess the return of athletes with concussive head injury to play, [21][22][23] it has never been demonstrated that this type of normalization overlaps with the recovery of brain metabolism.…”

“…Supported by the absence of structural lesions on traditional neuroimaging, a general and broadly accepted view is that mild traumatic brain injury (mTBI) is indeed a very frequent entity but is not a very serious injury, leading only to transient disturbances, and that no intervention other than observation is typically required. However, mTBI triggers molecular changes in neuronal cells involving a complex cascade of neurometabolic alterations [1][2][3] that reversibly modify the concentrations of several low-molecular-weight compounds actively involved in functions crucial for cell homeostasis and survival. 3,4 Such a cascade of molecular events is considered as the determinant of the so-called state of metabolic brain vulnerability, 5,6 which transiently exposes cerebral tissue to the cumulative effect of a second mTBI occurring during this particular period.…”

“…However, mTBI triggers molecular changes in neuronal cells involving a complex cascade of neurometabolic alterations [1][2][3] that reversibly modify the concentrations of several low-molecular-weight compounds actively involved in functions crucial for cell homeostasis and survival. 3,4 Such a cascade of molecular events is considered as the determinant of the so-called state of metabolic brain vulnerability, 5,6 which transiently exposes cerebral tissue to the cumulative effect of a second mTBI occurring during this particular period. 7,8 High-energy phosphates, 9,10 coenzyme A metabolites, 11 ATP catabolites, 11 and neurotransmitters, 12,13 are some of the substances whose concentrations are temporarily affected as a result of a traumatic insult.…”