N-Acetylaspartate as a Marker of Neuronal Injury in Neurodegenerative Disease

Abstract

Considerable evidence suggests that normal aging is associated with gradual impairment of memory functioning [1]. The medial temporal lobe, especially the hippocampus, plays a central role in declarative memory processing [2]. However, magnetic resonance imaging (MRI) studies have produced controversial results concerning the age-related hippocampal volume loss, which could be due in part to the non-specificity of volume shrinkage as an indicator for neuron loss. In contrast to volume, NAA is generally considered a marker for viable neurons, because NAA reaches detectable concentrations only in neuronal tissue but not in other brain tissues, including glial cells. Using proton magnetic resonance spectroscopic imaging ( 1 H MRSI) and MRI together, we studied hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of age. Our goals were to test whether NAA levels vary in the hippocampus as a function of normal aging and 2) to determine the relationship between hippocampal NAA and volume changes. We found NAA/Cho ratios decreased by 24% (r = −0.53, p = 0.01) and NAA/Cr ratios decreased by 26% (r = −0.61, p < 0.005) over the age range studied, while Cho/Cr remained stable, implying diminished NAA levels. In the same population, hippocampal volume shrank by 20% (r = −0.64, p < 0.05). The relationships of these measures with aging are depicted in Figure 1. Since NAA is considered a marker of neurons, these results provide stronger support for neuron loss in the aging hippocampus than volume measurements by MRI alone.Since contributions to the NAA signal may arise from both gray and white matter tissue, it is critical to differentiate between metabolite changes of gray and white matter, and other tissue types. One approach for differentiation is the use of linear regressions to predict the relationship between metabolite intensity changes and gray/white matter variations in MRSI voxels (4,(8)(9)(10)(11)(12). However, most previous MRSI studies that used linear regression averaged metabolite concentrations over different lobes of the brain, ignoring regional variations. In addition, tissues other than gray and white matter were ignored or not determined, such as white matter lesions, which occur frequently in the aged brain. We developed an approach for obtaining metabolite concentrations of gray, white matter, as well as of white matter lesions in different lobes of the brain using linear regression. We applied the new technique to measure NAA concentrations in the frontal and the parietal lobe in 40 normal elderly subjects (56 to 89 years, mean age 74 ± 8, 22 female, 18 male). NAA was about 15% lower in cortical gray matter and 23% lower in white matter lesions when compared to normal white matter. Cr was 11% higher in cortical gray than in white matter, and also about 15% higher in the parietal cortex compared to the frontal cortex. Cho was 28% lower in cortical gray matter than in white matter. Furthermore, NAA and Cr changes correlated with age. The results suggest that in addition to the hippo...

Imaging Biomarkers of the Neuroimmune System among Substance Use Disorders: A Systematic Review

“…As stated above, myo- inositol is involved in cell volume regulation, and thus, may be directly influenced by edema and/or osmotic changes [36, 43-47, 54-56]. Further, as described below, normalization to NAA may be susceptible to bias due to neurodegeneration [60], which may or may not be attributed to chronic neuroinflammation [35]. Conversely, normalization to creatine, often considered a stable metabolite, may be less susceptible to bias than NAA.…”

“…Similarly, brain choline levels are influenced by dietary choline consumption [72] and psychiatric comorbidities [73, 74]. NAA is a putative neuronal marker [35], and abnormally low levels may reflect neuronal degeneration [60], but it is not necessarily specific to neuroimmune signaling. In addition to MRS, several other imaging markers exist.…”

Biomarkers for the Diagnosis, Prognosis, and Evaluation of Treatment Efficacy for Traumatic Brain Injury

“…135 Reductions of hippocampal NAA, a marker for viable neurons, have been shown in temporal lobe epilepsy and mesial temporal lobe sclerosis. 136 Collapsin response-mediated protein-2, and proteins involved in axonal outgrowth, path finding, and maintaining neuronal polarity have been demonstrated to be down-regulated in hippocampal tissue of patients with mesial temporal lobe epilepsy. 137 All of these have also been associated with other neurodegenerative disorders, such as Alzheimer's disease.…”

Neurotoxic profiles of HIV, psychostimulant drugs of abuse, and their concerted effect on the brain: Current status of dopamine system vulnerability in NeuroAIDS

“…Chang and colleagues (2005) recently discovered a concerted effect of METH abuse and HIV on the amount of brain metabolites and cellular byproducts, specifically the neuronal marker NAA. NAA is a reliable neuronal marker as it has been shown to be detectable almost exclusively in neurons (Moffet et al, 1991;Simmons et al, 1991), and reductions in NAA often correlate with neuronal loss (for review, see Schuff et al, 2006). Chang et al (2005) found the lowest amount of NAA in frontal gray matter (-5.7%), frontal white matter (-6.1%), and the basal ganglia (-9%) relative to HIV seropositive non-drug abusers and HIV seronegative METH abusers.…”