In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain

Ratai, Eva‐Maria; Pilkenton, Sarah; Greco, Jane B.; Lentz, Margaret R.; Bombardier, Jeffrey P.; Turk, Katherine W.; He, Julian; Joo, Chan-Gyu; Lee, Vallent; Westmoreland, Susan V.; Halpern, Elkan F.; Lackner, Andrew A.; González, R. Gilberto

doi:10.1186/1471-2202-10-63

Cited by 36 publications

(55 citation statements)

References 54 publications

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“…Longitudinal SIV/macaque studies report an initial elevation of Cho/Cr in acute infection that is subsequently reduced during the transition from acute to primary infection. 27,28 Studies with human participants show a similar progression with elevated Cho/Cr at 16-17 days postexposure 10 followed by lower Cho, 15 consistent with our results of lower Cho/Cr and MI/Cr months after exposure. A plausible biological mechanism for the low Cho/Cr and MI/Cr in PHI may be the result of reduced viral load after the acute phase 24 and concomitant reduced membrane turnover and gliosis related to immune stabilization.…”

Section: Magnetic Resonance Spectroscopysupporting

confidence: 80%

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

et al. 2014

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Objective: We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS).Methods: Cerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine 1 phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter.Results: Fifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope 5 0.0012, p 5 0.005) and MI/Cr (slope 5 0.0041, p 5 0.005) in frontal white matter as well as increases in MI/Cr (slope 5 0.0041, p , 0.001) and NAA/Cr (slope 5 0.0024, p 5 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope 5 20.0038, p 5 0.031). Conclusions: Early in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participantssuggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation. Neurology ® 2014;83:1592-1600 GLOSSARY ART 5 antiretroviral therapy; CHI 5 chronic HIV infection; Cho 5 choline-containing metabolites; Cr 5 creatine-containing metabolites; Glu 5 glutamate; 1 H-MRS 5 proton magnetic resonance spectroscopy; IQR 5 interquartile range; MI 5 myoinositol; MPRAGE 5 magnetization-prepared rapid gradient echo; MR 5 magnetic resonance; NAA 5 N-acetylaspartate; PHI 5 primary HIV infection; TCA 5 tricarboxylic acid; TE 5 echo time; VOI 5 volume of interest.Proton magnetic resonance spectroscopy ( 1 H-MRS) can detect dynamic cerebral metabolite changes indicative of inflammation and neuronal injury in individuals with HIV.

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Section: Magnetic Resonance Spectroscopysupporting

confidence: 80%

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

et al. 2014

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“…35,[39][40][41][42] The region-dependent patterns in evolution were seen in the present study as well. Significant reduction of MTR in the centrum semiovale, splenium, and putamen was observed as early as 2 weeks after SIV infection while such alterations lagged behind in genu, thalamus, FWM, caudate, and FGM, revealing regional differences in MTR changes in the cerebral microstructural.…”

supporting

confidence: 66%

A Longitudinal Magnetization Transfer Imaging Evaluation of Brain Injury in a Macaque Model of NeuroAIDS

Herndon

Novembre

et al. 2015

AIDS Research and Human Retroviruses

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Magnetization transfer (MT) imaging has been explored in prior studies of HIV patients and showed the potential capacity to assess brain injury after HIV infection. In the present study, adult pig-tailed macaques were infected with a highly neuropathogenic virus SIVsmmFGb. MT imaging was exploited to examine the monkey brains before simian immunodeficiency virus (SIV) inoculation and 2, 4, 8, 12, 16, and 20 weeks post-SIV inoculation. Blood samples were collected from each animal for monitoring CD4+ and CD8 + T cells before each MRI scan. The MT ratios (MTR) in several brain regions of interest were evaluated longitudinally. Significant reductions of MTR were observed in whole brain and selected regions of interest (genu, splenium, thalamus, caudate, centrum semiovale, frontal white matter, frontal gray matter, and putamen) in the SIV-infected monkeys, consistent with those reported previously in HIV patients. In particular, the longitudinal results indicate that abnormal MTR reduction can be detected as early as in 2 weeks and MTR may be more sensitive to the brain injury in cortical regions than in subcortical regions during acute SIV infection. In addition, MTR reduction in genu, centrum semiovale, and thalamus significantly correlated with the CD4 + T cell percentage decrease. Also, the MTR reduction in thalamus correlated with the CD8 + T cell percentage elevation. Taken together, this study reported the longitudinal evolution of MTR in different brain regions during SIV infection and further validates previous findings in HIV patients. The preliminary results suggest that MT imaging could be a robust and sensitive approach to characterize the neurodegeneration after SIV or HIV infection.

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“…For example, reduced Glx concentrations have been observed in Alzheimer's disease (Antuono et al, 2001;Jones and Waldman, 2004). In HIV, human and animal models have shown decreased levels of cerebral Glx Ratai et al, 2009;Chang et al, 1997), including patients with progressive multifocal leukoencephalopathy. Another study showed decreased frontal Glx concentrations, along with increased white matter integrity on diffusion tensor imaging among patients treated with lithium for HIV-associated cognitive impairment (Schifitto et al, 2009b).…”

Section: Discussionmentioning

confidence: 99%

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

Cohen

Harezlak

Gongvatana

et al. 2010

Journal of NeuroVirology

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Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

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In vivo proton magnetic resonance spectroscopy reveals region specific metabolic responses to SIV infection in the macaque brain

Cited by 36 publications

References 54 publications

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection

A Longitudinal Magnetization Transfer Imaging Evaluation of Brain Injury in a Macaque Model of NeuroAIDS

Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes

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