Quantitative neuropathologic correlates of changes in ratio of N-acetylaspartate to creatine in macaque brain.
OBJECTIVE
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.


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 ((1)H) magnetic resonance (MR) spectroscopy, and postmortem frontal lobe tissue was investigated by using high-spectral-resolution (1)H 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.


CONCLUSIONS
NAA/Cr is a sensitive marker of neuronal injury, not necessarily neuronal loss, and best correlates with synaptophysin, a marker of synaptodendritic dysfunction.
Lentz
Margaret R
MR
NMR Center and Neuroradiology Division, Massachusetts General Hospital, 55 Fruit St, GRB 285, Boston, MA 02114-2696, USA.
Kim
John P
JP
Westmoreland
Susan V
SV
Greco
Jane B
JB
Fuller
Robert A
RA
Ratai
Eva M
EM
He
Julian
J
Sehgal
Prabhat K
PK
Halpern
Elkan F
EF
Lackner
Andrew A
AA
Masliah
Eliezer
E
González
R Gilberto
RG
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis*; D001921:Brain / Q000473:pathology*; D064026:Calbindins; D002452:Cell Count; D003401:Creatine / Q000032:analysis*; D005625:Frontal Lobe / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008869:Microtubule-Associated Proteins / Q000032:analysis; D009474:Neurons / Q000473:pathology; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D016097:Simian Acquired Immunodeficiency Syndrome / Q000473:pathology*; D013223:Statistics as Topic; D009435:Synaptic Transmission / Q000502:physiology; D016708:Synaptophysin / Q000032:analysis; D019562:Viral Load
D064026:Calbindins; D008869:Microtubule-Associated Proteins; D064030:S100 Calcium Binding Protein G; D016708:Synaptophysin; D001224:Aspartic Acid; C000179:N-acetylaspartate; D003401:Creatine