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

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

[1]  E. Masliah,et al.  In vivo 1H MRS of brain injury and repair during acute SIV infection in the macaque model of neuroAIDS , 2004, Magnetic resonance in medicine.

[2]  Cheuk Y. Tang,et al.  A multi‐center 1H MRS study of the AIDS dementia complex: Validation and preliminary analysis , 2003, Journal of magnetic resonance imaging : JMRI.

[3]  J. Walecki,et al.  Cerebral MR spectroscopy in neurologically asymptomatic HIV-infected patients. , 2003, Acta radiologica.

[4]  S. Strakowski,et al.  Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy. , 2002, Bipolar disorders.

[5]  H. Yamasue,et al.  1H-MR spectroscopy and gray matter volume of the anterior cingulate cortex in schizophrenia , 2002, Neuroreport.

[6]  Leo L. Cheng,et al.  Quantification of neurons in Alzheimer and control brains with ex vivo high resolution magic angle spinning proton magnetic resonance spectroscopy and stereology. , 2002, Magnetic resonance imaging.

[7]  N. Hirokawa,et al.  MAP2 is required for dendrite elongation, PKA anchoring in dendrites, and proper PKA signal transduction , 2002, The Journal of cell biology.

[8]  K. Sakaie,et al.  Magnetic resonance spectroscopy: an in vivo tool for monitoring cerebral injury in SIV‐infected macaques , 2002, Journal of medical primatology.

[9]  Y. Goda,et al.  Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G. E. Alexander,et al.  Brain metabolite concentration and dementia severity in Alzheimer’s disease , 2001, Neurology.

[11]  W M Brooks,et al.  Magnetic resonance spectroscopy in traumatic brain injury. , 2001, The Journal of head trauma rehabilitation.

[12]  P Sachdev,et al.  Magnetic resonance spectroscopy in AD , 2001, Neurology.

[13]  V. Calvez,et al.  Clinical and spectroscopic improvement in HIV-associated cognitive impairment , 2001, Neurology.

[14]  Leo L. Cheng,et al.  Early brain injury in the SIV–macaque model of AIDS , 2000, AIDS.

[15]  A. Blamire,et al.  Early proton magnetic resonance spectroscopy in normal-appearing brain correlates with outcome in patients following traumatic brain injury. , 2000, Brain : a journal of neurology.

[16]  M. Baslow,et al.  Functions of N‐Acetyl‐l‐Aspartate and N‐Acetyl‐l‐Aspartylglutamate in the Vertebrate Brain , 2000, Journal of neurochemistry.

[17]  E G Tangalos,et al.  Regional metabolic patterns in mild cognitive impairment and Alzheimer’s disease , 2000, Neurology.

[18]  H. Fukuzako,et al.  Subtype-associated metabolite differences in the temporal lobe in schizophrenia detected by proton magnetic resonance spectroscopy , 1999, Psychiatry Research: Neuroimaging.

[19]  T. Südhof,et al.  Essential Roles in Synaptic Plasticity for Synaptogyrin I and Synaptophysin I , 1999, Neuron.

[20]  E. Cabanis,et al.  Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis , 1999, Neurology.

[21]  J. McLaughlin,et al.  Calbindin D28K Gene Transfer via Herpes Simplex Virus Amplicon Vector Decreases Hippocampal Damage In Vivo Following Neurotoxic Insults , 1999, Journal of neurochemistry.

[22]  L. Chang,et al.  Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia , 1999, Neurology.

[23]  F. Gao,et al.  Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes , 1999, Nature.

[24]  K O Lim,et al.  In vivo brain concentrations of N-acetyl compounds, creatine, and choline in Alzheimer disease. , 1999, Archives of general psychiatry.

[25]  K. Krishnan,et al.  Metabolic brain mapping in Alzheimer's disease using proton magnetic resonance spectroscopy , 1998, Psychiatry Research: Neuroimaging.

[26]  R. Desrosiers,et al.  Identification of Highly Attenuated Mutants of Simian Immunodeficiency Virus , 1998, Journal of Virology.

[27]  J. Lifson,et al.  Plasma SIV RNA viral load determination by real-time quantification of product generation in reverse transcriptase-polymerase chain reaction. , 1998, AIDS research and human retroviruses.

[28]  E. Masliah,et al.  Comparison of Two Quantitative Methods for the Evaluation of Neuronal Number in the Frontal Cortex in Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[29]  I. Wilkinson,et al.  Proton MRS and quantitative MRI assessment of the short term neurological response to antiretroviral therapy in AIDS , 1997, Journal of neurology, neurosurgery, and psychiatry.

[30]  R. Gonzalez,et al.  Quantitative neuropathology by high resolution magic angle spinning proton magnetic resonance spectroscopy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  I. Tracey,et al.  1H magnetic resonance spectroscopy reveals neuronal injury in a simian immunodeficiency virus macaque model. , 1997, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[32]  J. Hennig,et al.  HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times. , 1996, Radiology.

[33]  A. Guimarães,et al.  Brain choline-containing compounds are elevated in HIV-positive patients before the onset of AIDS dementia complex , 1996, Neurology.

[34]  J. Coyle,et al.  Quantitative in vivo 1H nuclear magnetic resonance spectroscopic imaging of neuronal loss in rat brain , 1995, Neuroscience.

[35]  J. Coyle,et al.  N-Acetylaspartate in neuropsychiatric disorders , 1995, Progress in Neurobiology.

[36]  E. Masliah,et al.  Differential Vulnerability of Calbindin‐immunoreactive Neurons in HIV Encephalitis , 1995, Journal of neuropathology and experimental neurology.

[37]  J. Vion-Dury,et al.  Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy , 1995, The Lancet.

[38]  P G Webb,et al.  Automated single‐voxel proton MRS: Technical development and multisite verification , 1994, Magnetic resonance in medicine.

[39]  R. Desrosiers,et al.  Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS , 1993, Journal of virology.

[40]  I. Wilkinson,et al.  Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings. , 1993, Radiology.

[41]  R. Lenkinski,et al.  Proton MR spectroscopy of HIV-infected patients: characterization of abnormalities with imaging and clinical correlation. , 1993, Radiology.

[42]  D. Gadian,et al.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[43]  G. Fein,et al.  Reduced brain N‐acetylaspartate suggests neuronal loss in cognitively impaired human immunodeficiency virus‐seropositive individuals , 1993, Neurology.

[44]  K. Kosik,et al.  Suppression of MAP2 in cultured cerebeller macroneurons inhibits minor neurite formation , 1992, Neuron.

[45]  E. Masliah,et al.  Spectrum of human immunodeficiency virus–associated neocortical damage , 1992, Annals of neurology.

[46]  H. Bruhn,et al.  Multiple sclerosis in children: Cerebral metabolic alterations monitored by localized proton magnetic resonance spectroscopy in vivo , 1992, Annals of neurology.

[47]  M Noble,et al.  Specific Expression of N‐Acetylaspartate in Neurons, Oligodendrocyte‐Type‐2 Astrocyte Progenitors, and Immature Oligodendrocytes In Vitro , 1992, Journal of neurochemistry.

[48]  D. Menon,et al.  Proton MR Spectroscopy of the Brain in AIDS Dementia Complex , 1992, Journal of computer assisted tomography.

[49]  M. Simon,et al.  Pathologic features of SIV-induced disease and the association of macrophage infection with disease evolution. , 1992, AIDS research and human retroviruses.

[50]  J. Coyle,et al.  Immunocytochemical localization of N-acetyl-aspartate with monoclonal antibodies , 1991, Neuroscience.

[51]  J. Olesen,et al.  Localized in vivo proton spectroscopy in the brain of patients with multiple sclerosis , 1991, Magnetic resonance in medicine.

[52]  J. Neale,et al.  Immunohistochemical localization of N-acetylaspartate in rat brain. , 1991, Neuroreport.

[53]  S. Christakos,et al.  Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[54]  P. Bottomley.  Spatial Localization in NMR Spectroscopy in Vivo , 1987, Annals of the New York Academy of Sciences.

[55]  P. Greengard,et al.  Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells , 1986, The Journal of cell biology.

[56]  D Matthaei,et al.  1H NMR chemical shift selective (CHESS) imaging. , 1985, Physics in medicine and biology.

[57]  R. L. Plackett,et al.  The Analysis of Variance , 1960 .

[58]  Jean-Marc Constans,et al.  Proton magnetic resonance spectroscopy (1H MRS) in schizophrenia: investigation of the right and left hippocampus, thalamus, and prefrontal cortex. , 2002, Schizophrenia bulletin.

[59]  H. Fox,et al.  Simian immunodeficiency virus model of HIV-induced central nervous system dysfunction. , 2001, Advances in virus research.

[60]  R. Desrosiers,et al.  Simian immunodeficiency viruses. , 1988, Annual review of microbiology.