Coregistration of quantitative proton magnetic resonance spectroscopic imaging with neuropathological and neurophysiological analyses defines the extent of neuronal impairments in murine human immunodeficiency virus type-1 encephalitis.
Relatively few immune-activated and virus-infected mononuclear phagocytes (MP; perivascular macrophages and microglia) may affect widespread neuronal dysfunction during human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD). Indeed, histopathological evidence of neuronal dropout often belies the extent of cognitive impairment. To define relationships between neuronal function and histopathology, proton magnetic resonance spectroscopic imaging (1H MRSI) and hippocampal long-term potentiation (LTP) were compared with neuronal and glial immunohistology in a murine model of HIV-1 encephalitis (HIVE). HIV-1(ADA)-infected human monocyte-derived macrophages (MDM) were stereotactically injected into the subcortex of severe combined immunodeficient (SCID) mice. Sham-operated and unmanipulated mice served as controls. Seven days after cell injection, brain histological analyses revealed a focal giant cell encephalitis, with reactive astrocytes, microgliosis, and neuronal dropout. Strikingly, significant reductions in N-acetyl aspartate concentration ([NAA]) and LTP levels in HIVE mice were in both injected and contralateral hemispheres and in brain subregions, including the hippocampus, where neuropathology was limited or absent. The data support the importance of 1H MRSI as a tool for assessing neuronal function for HAD. The data also demonstrate that a highly focal encephalitis can produce global deficits for neuronal function and metabolism.
Nelson
J A
JA
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, Nebraska 68198-1045, USA. jnelsona@unmc.edu
Dou
H
H
Ellison
B
B
Uberti
M
M
Xiong
H
H
Anderson
E
E
Mellon
M
M
Gelbard
H A
HA
Boska
M
M
Gendelman
H E
HE
D015526:AIDS Dementia Complex / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D001931:Brain Mapping; D002135:Calcium-Binding Proteins / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology* / Q000821:virology; D003401:Creatine / Q000378:metabolism; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D015658:HIV Infections / Q000473:pathology; D015497:HIV-1; D006624:Hippocampus / Q000503:physiopathology / Q000821:virology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000502:physiology / Q000528:radiation effects; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011522:Protons; D013997:Time Factors; D014746:Vimentin / Q000378:metabolism
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D036022:Capsid Proteins; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D011522:Protons; C116449:RH24 protein, HIV-1; D014746:Vimentin; D001224:Aspartic Acid; C000179:N-acetylaspartate; C516724:PTPN11 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; D010751:Phosphopyruvate Hydratase; D003401:Creatine; D002794:Choline