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Quantitative Neuropathologic Correlates of Changes in Ratio of N-acetylaspartate to Creatine in Macaque Brain¹

¹ From the NMR Center and Neuroradiology Division, Massachusetts General Hospital, 55 Fruit St, GRB 285, Boston, MA 02114-2696 (M.R.L., J.P.K., J.B.G., R.A.F., E.M.R., J.H., E.F.H., R.G.G.); New England Primate Research Center, Southborough, Mass (S.V.W., P.K.S.); Department of Neurosciences, University of California, San Diego, La Jolla, Calif (E.M.); and Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, La (A.A.L.). Received January 2, 2004; revision requested March 3; final revision received July 8; accepted July 28. Supported by NIH grants RR13213 (R.G.G.), NS34626 (R.G.G.), NS30769 (A.A.L.), MH61192 (A.A.L.), MH45294 (E.M.), RR00168–39 (New England Primate Research Center), and P41RR00995 (Massachusetts Institute of Technology); National Center for Research Resources grant P41RR14075; and the Mental Illness and Neuroscience Discovery Institute. Address correspondence to R.G.G. (e-mail: rggonzalez@partners.org).

PURPOSE: To elucidate the neuropathologic basis of transient changes in the ratio of N-acetylaspartate (NAA) to creatine (Cr) in the primate brain by using a simian immunodeficiency virus (SIV)–infected macaque model of the neurologic manifestation of acquired immune deficiency syndrome.

MATERIALS AND METHODS: This study was approved by the Massachusetts General Hospital Subcommittee on Research and Animal Care and the Institutional Animal Care and Use Committee of Harvard University. Rhesus macaques infected with SIV were evaluated during the 1st month of infection. A total of 11 animals were studied, including four control animals, three animals sacrificed 12 days after infection, three animals sacrificed 14 days after infection, and one animal sacrificed 28 days after infection. All animals underwent in vivo proton (¹H) magnetic resonance (MR) spectroscopy, and postmortem frontal lobe tissue was investigated by using high-spectral-resolution ¹H MR spectroscopy of brain extracts. In addition, quantitative neuropathologic analyses were performed. Stereologic analysis was performed to determine neuronal counts, and immunohistochemical analysis was performed to analyze three neuronal markers: synaptophysin, microtubule-associated protein 2 (MAP2), and calbindin. Analysis of variance (ANOVA) was used to determine substantial changes in neuropathologic and MR spectroscopic markers. Spearman rank correlations were calculated between plasma viral load and neuropathologic and spectroscopic markers.

RESULTS: During acute infection with SIV, the macaque brain exhibited significant changes in NAA/Cr (P < .02, ANOVA) and synaptophysin (P < .013, ANOVA). There was no significant change in the concentration of Cr. No significant changes were found in neuronal counts or other immunohistochemical neuronal markers. With the Spearman rank test, a significant direct correlation was detected between synaptophysin and ex vivo NAA/Cr (r_s = 0.72, P < .013). No correlation between NAA/Cr and neuronal counts, calbindin, or MAP2 was found.

CONCLUSION: NAA/Cr is a sensitive marker of neuronal injury, not necessarily neuronal loss, and best correlates with synaptophysin, a marker of synaptodendritic dysfunction.

© RSNA, 2005

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