N‐acetylaspartate is an axon‐specific marker of mature white matter in vivo: A biochemical and immunohistochemical study on the rat optic nerve

Abstract

Axonal pathology is a major cause of neurological disability in multiple sclerosis. Axonal transection begins at disease onset but remains clinically silent because of compensatory brain mechanisms. Noninvasive surrogate markers for axonal injury are therefore essential to monitor cumulative disease burden in vivo. The neuronal compound N-acetylaspartate, as measured by magnetic resonance spectroscopy, is currently the best and most specific noninvasive marker of axonal pathology in multiple sclerosis. The possibility has been raised, however, that N-acetylaspartate is expressed also by oligodendroglial lineage cells. In order to investigate N-acetylaspartate specificity for white matter axons, transected rat optic nerves were analyzed by high-performance liquid chromatography and immunohistochemistry. In transected adult nerves, N-acetylaspartate and N-acetyl aspartylglutamate decreased in concordance with axonal degeneration and were undetectable 24 days posttransection. Nonproliferating oligodendrocyte progenitor cells, oligodendrocytes, and myelin were abundant in these axon-free nerves. At 24 days posttransection, N-acetylaspartate was increased (42%; p = 0.02) in nontransected contralateral nerves. After transection at postnatal day 4, total N-acetylaspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing axon-free nerves, 25 to 33% of oligodendrocyte progenitor cells were proliferating. These data validate magnetic resonance spectroscopy measurements of N-acetylaspartate as an axon-specific monitor of central nervous system white matter in vivo. In addition, the results indicate that neuronal adaptation can increase N-acetylaspartate levels, and that 5 to 20% of the N-acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells.

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…They found the highest levels of NAA in mature oligodendrocytes differentiated with ciliary neurotrophic factor and in oligodendrocyte-type 2 astrocyte progenitor cells. Optic nerve transection studies in rats have shown that NAA levels in the nerves are completely eliminated 24 days post-transection (Bjartmar et al, 2002). In the same study, retinal ablation on postnatal day 4 suggested that approximately 20% of the NAA in the optic nerve at day 14, and 5% of the NAA at day 20 was derived from proliferating oligodendrocyte progenitor cells.…”

“…Axons in many fiber tracts were moderately stained for NAA, including the corpus callosum, corticospinal tracts, optic nerves and tracts, lateral olfactory tracts and stria terminalis (Moffett and Namboodiri, 1995). HPLC studies have confirmed the presence of NAA in optic nerves (Bjartmar et al, 2002). High levels of NAA have also been observed in cerebellar cortex, including the Purkinje cell layer, the granule cell layer and the molecular layer (Simmons et al, 1991).…”

Quantitative Magnetic Resonance Imaging of the Brain : Applications for Tissue Segmentation and Multiple Sclerosis

“…This indicates that the tNA-Aq concentration in these VOIs actually increased as R1 and R2 decreased. Since tNA is considered a marker of neuronal density (138,(172)(173)(174) this result suggests that there was a process of demyelination, indicated by decreased R1 and R2, without neuronal loss in these patients. The neuronal density of the tissue (per volume) may in fact increase as myelin diminishes, caused by a net shrinkage of the tissue, leading to more axons inside the VOI.…”

“…After the initial oedema resolves, lesions which remain elevated in T1 have shown lower levels of N-acetyl-aspartate (NAA), which is considered a marker of neuronal integrity, and increased concentration of cholin, which is considered a marker of cell membrane turnover (138,(171)(172)(173)(174)(175). These correlations suggest that a persisting elevation of T1 may be related to axonal damage in the lesion (138).…”

Imaging of multiple sclerosis: Role in neurotherapeutics

“…Reduced NAA correlates with the extent of histopathologic axonal loss. 99,109 Anatomically, myelin begins to envelop axons close to the neuronal cell body where it is a potential target of the disease process in MS. Purely intracortical and subpial plaques are well documented pathologically 23,110 and are rarely found by conventional MRI. 110,111 Their detection is improved by FLAIR MRI.…”