Interest in NAA was stimulated by the fact that it represents the largest peak on proton nuclear magnetic resonance spectroscopy,8 and alterations in its levels have been demonstrated in a wide range of disorders including Alzheimer's Disease, epilepsy and schizophrenia. Thus, it would be essential to know the precise cellular localization of NAA in order to interpret its role in disease processes. Simmons et al.9 used NAA linked to bovine serum albumin by carbodiimide to develop a highly specific monoclonal antibody against with only 1% cross reactivity with NAAG-BSA. Immunocytochemical staining with avidin-biotin-peroxidase demonstrated that the NAA-like immunoreactivity was localized to neurons distributed throughout the brain. Immunoreactive neurons exhibited intense staining of the perikaraya, proximal dendrites and axons, although no consistent pattern of distribution of immunoreactivity was observed with regard to primary neurotransmitter characteristics of neurons. Neurons with long projections or extensive axonal arbors, such as the cortical pyramidal cells, the locus ceruleus, motor neurons, and Purkinje cells, stained much more intensely than local circuit neurons. These findings have been independently corroborated10.
Perikaryal specific excitotoxin lesions of the rat striatum substantially reduced NAA levels at the lesion site.11 The NAA decrements were mirrored by a comparable reduction in the NAA signal as measured by magnetic resonance spectroscopy (MRS), thereby validating the inference that NAA measured by MRS was a reasonable surrogate for neuronal integrity. However, NAA reductions can not be simply equated with neuronal degeneration, because such reductions have been observed in conditions such as HIV encephalopathy, in which neuronal loss has not been documented.12 Furthermore, Yurgelun-Todd et al. (in press) has found that the reductions in NAA levels in frontal cortex in schizophrenia may be an artifact of a change in relaxation time, which can be mimicked in vitro by adding increased concentrations of albumin to fixed concentrations of NAA. Thus, changes in intracellular environment associated with atrophy could also affect the apparent levels of NAA measured with MRS
Major questions concerning the role of NAA remain open and need to be addressed. First, the function of NAA within neurons remains unclear. Second, if NAA is involved in myelin synthesis how does its neuronal localization comport with oliogodendrogliocyte function? Third, how are the alterations in NAA signal in human MRS studies to be interpreted with regard to specific neurologic and psychiatric disorders. It is hoped that this conference will shed light on these important questions.
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