N-Acetylaspartate Reduction as a Measure of Injury Severity and Mitochondrial Dysfunction Following Diffuse Traumatic Brain Injury

Abstract

N-Acetylaspartate (NAA) is considered a neuron-specific metabolite and its reduction a marker of neuronal loss. The objective of this study was to evaluate the time course of NAA changes in varying grades of traumatic brain injury (TBI), in concert with the disturbance of energy metabolites (ATP). Since NAA is synthesized by the mitochondria, it was hypothesized that changes in NAA would follow ATP. The impact acceleration model was used to produce three grades of TBI. Sprague-Dawley rats were divided into the following four groups: sham control (n = 12); moderate TBI (n = 36); severe TBI (n = 36); and severe TBI coupled with hypoxia-hypotension (n = 16). Animals were sacrificed at different time points ranging from 1 min to 120 h postinjury, and the brain was processed for high-performance liquid chromatography (HPLC) analysis of NAA and ATP. After moderate TBI, NAA reduced gradually by 35% at 6 h and 46% at 15 h, accompanied by a 57% and 45% reduction in ATP. A spontaneous recovery of NAA to 86% of baseline at 120 h was paralleled by a restoration in ATP. In severe TBI, NAA fell suddenly and did not recover, showing critical reduction (60%) at 48 h. ATP was reduced by 70% and also did not recover. Maximum NAA and ATP decrease occurred with secondary insult (80% and 90%, respectively, at 48 h). These data show that, at 48 h post diffuse TBI, reduction of NAA is graded according to the severity of insult. NAA recovers if the degree of injury is moderate and not accompanied by secondary insult. The highly similar time course and correlation between NAA and ATP supports the notion that NAA reduction is related to energetic impairment.

MR spectroscopy: Predicting long‐term neuropsychological outcome following pediatric TBI

“…In this study, patients were imaged on average 6 Ϯ 4 days following injury, with some as long as 16 days after injury. Animal models have shown that metabolites such as Cho and mI increase soon after injury (38) whereas, NAA associated with neuronal dysfunction may remain depressed for days to weeks depending on the severity of injury (41) and may be permanent if neuronal loss has occurred (39). The time course for metabolic changes following TBI is not well established in humans and may vary by age as well as injury severity.…”

Severity of experimental traumatic brain injury modulates changes in concentrations of cerebral free amino acids

“…After anaesthesia, a metal disk was fixed onto the central portion of the skull, between the coronal and lambdoid sutures, to prevent skull fracture and to homogenously distribute the force acting at the time of impact. Mild or severe TBI were induced by dropping a cumulative weight of 450 g from 1 or 2 m height and knowing to cause, respectively, a mTBI or a sTBI either histopathologically or biochemically 34, 35, 36, 37, 38. At 6, 12, 24, 48 and 120 hrs from injury, rats were again anaesthetized ( n = 6 for each time‐point in both groups of injured animals) and then immediately killed.…”

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…However, animal studies of moderate to severe TBI have shown more rapid declines in NAA levels which were paralleled by decreases in ATP levels. Using HPLC analyses of brain extracts, Signoretti and colleagues reported significant and concomitant drops in NAA and ATP within 10 minutes of injury, and partial recovery of both compounds by 5 days in less severe injuries (Signoretti et al, 2001). In more severe TBI injuries, and those exacerbated by hypoxia-hypotension, recovery of NAA and ATP levels was not observed.…”