N‐Acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury

Abstract

To evaluate the contribution of cellular dysfunction and neuronal loss to brain N-acetylaspartate (NAA) depletion, NAA was measured in brain tissue by HPLC and UV detection in rats subjected to cerebral injury, associated or not with cell death. When lesion was induced by intracarotid injection of microspheres, the fall in NAA was related to the degree of embolization and to the severity of brain oedema. When striatal lesion was induced by local injection of malonate, the larger the lesion volume, the higher the NAA depletion. However, reduction of brain oedema and striatal lesion by treatment with the lipophilic iron chelator dipyridyl (20 mg/kg, 1 h before and every 8 h after embolization) and the inducible nitric oxide synthase inhibitor aminoguanidine (100 mg/kg given 1 h before malonate and then every 9 h), respectively, failed to ameliorate the fall in NAA. Moreover, after systemic administration of 3-nitropropionic acid, a marked reversible fall in NAA striatal content was observed despite the lack of tissue necrosis. Overall results show that cellular dysfunction can cause higher reductions in NAA level than neuronal loss, thus making of NAA quanti®cation a potential tool for visualizing the penumbra area in stroke patients.

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…In rats treated with 3NP, NAA decrease was observed selectively in the striatum before any cell loss, but was associated with motor symptoms (Demougeot et al, 2001). Also, a similar selective and early striatal decrease in NAA was observed in 3-NP treated primates (Dautry et al, 2000).…”

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

“…Studies using MRSI in children also showed NAA/Cre reductions early after injury (10) as well as decreased NAA/Cho ratios up to three years post injury (36). Animal models of TBI that demonstrated decreases of NAA, found associations with regions of diffuse axonal injury (37) and neuronal loss (38,39). Therefore, the association of reduced NAA with poor cognitive outcome provides further evidence that NAA functions as a marker for neuronal and axonal injury in the setting of TBI in humans.…”

“…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.…”

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research

“…8,13 For example, although traumatic brain injury (TBI) is associated with immediate reductions in NAA, several studies have reported that these levels appear to recover significantly with time, which could not occur if NAA levels were decreased by cell death alone. 13,14 In fact, research on cerebral injury by Demougeot et al 15 has indicated that cellular dysfunction can actually cause greater measurable reductions in NAA than neuronal loss. Abnormally low ratios of NAA/Cr þ PCr have been observed in patients with a number of mitochondrial encephalomyopathies, 16 and studies using mitochondrial respiratory chain inhibitors have also shown that reductions in NAA are correlated with decreases in O 2 consumption and ATP production.…”