Evidence of reduced glutamate in the frontal lobe of HIV‐seropositive patients

Sailasuta, Napapon; Shriner, Kimberly; Ross, Brian D.

doi:10.1002/nbm.1329

Cited by 42 publications

(51 citation statements)

References 44 publications

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“…Since glutamate is required for aspartate synthesis within the neuronal mitochondria, decreased levels of Glx may be an early indicator of neuronal metabolism changes induced by this disease. 35 NAA and Glx levels in the frontal gray matter were found post hoc to have a significant linear correlation (Spearman: R s ϭ 0.56, p Ͻ 0.002), implying that as NAA levels decrease, Glx does as well. 35 However, at lower field strengths, this region of the MR spectrum is complicated by the overlapping resonances from glutamate, glutamine, and NAA.…”

Section: Figurementioning

confidence: 94%

“…35 NAA and Glx levels in the frontal gray matter were found post hoc to have a significant linear correlation (Spearman: R s ϭ 0.56, p Ͻ 0.002), implying that as NAA levels decrease, Glx does as well. 35 However, at lower field strengths, this region of the MR spectrum is complicated by the overlapping resonances from glutamate, glutamine, and NAA. Therefore, it is possible that changes in Glx are indicative of reductions in NAA due to difficulty in peak isolation.…”

Section: Figurementioning

confidence: 94%

“…While evaluations of Glx have become more prevalent, 34,35 results from this measure must be interpreted carefully. Glx is composed of the major excitatory neurotransmitter glutamate, which is found primarily in glutamatergic neurons, and its stored form, glutamine, found within astrocytes.…”

Section: Figurementioning

confidence: 99%

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Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection

Lentz¹,

Kim²,

Lee³

et al. 2009

Neurology

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Objective: To determine if changes in brain metabolites are observed during early HIV infection and correlate these changes with immunologic alterations.Methods: Eight subjects with early HIV infection, 9 HIV-seronegative controls, and 10 chronically HIV-infected subjects without neurologic impairment underwent 1 H magnetic resonance spectroscopy. Subjects with early stage infection were identified near the time of HIV seroconversion and imaged within 60 days of an evolving Western blot, while still having detectable plasma virus. Subjects had blood drawn for viral RNA and T cell quantification.Results: Both N-acetylaspartate (NAA) and Glx (glutamate ϩ glutamine) were decreased in the frontal cortical gray matter of seropositive subjects. NAA levels were found to be decreased in the centrum semiovale white matter of chronically HIV-infected subjects, but not in those with early infection. Both HIV-infected cohorts demonstrated a lower number of CD4 ϩ T lymphocytes and a higher number of CD8 ϩ T lymphocytes in their blood. Lower NAA levels in the frontal cortex of subjects with early infection were associated with an expansion of CD8 ϩ T cells, especially effector CD8 ϩ T cells. Conclusions: These results verify metabolism changes occurring in the brain early during HIVinfection. Lower NAA and Glx levels in the cortical gray matter suggests that HIV causes neuronal dysfunction soon after infection, which correlates to the expansion of CD8 ϩ T cells, specifically to an activated phenotype. Utilizing magnetic resonance spectroscopy to track NAA levels may provide important information on brain metabolic health while allowing better understanding of the virus-host interactions involved in CNS functional deficits. Neurology ® 2009;72:1465-1472 GLOSSARY APC ϭ allophycocyanin; Cho ϭ choline; Cr ϭ creatine; CTL ϭ cytotoxic T lymphocyte; Cy5.5 ϭ cyanin 5.5; FITC ϭ fluorescein isothiocyanate; FOV ϭ field of view; Glx ϭ glutamate ϩ glutamine; MI ϭ myoinositol; MRS ϭ magnetic resonance spectroscopy; NAA ϭ N-acetylaspartate; NRTI ϭ nucleoside reverse transcriptase inhibitors; PE ϭ phycoerythrin; PerCP ϭ peridinium chlorophyll protein; PHI ϭ primary HIV infection; SIV ϭ simian immunodeficiency virus; TE ϭ echo time; TI ϭ inversion time; TR ϭ repetition time.

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Section: Figurementioning

confidence: 94%

Section: Figurementioning

confidence: 94%

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Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection

Lentz¹,

Kim²,

Lee³

et al. 2009

Neurology

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“…The 13 C MR imaging contrast will assist in establishing not only the cellular specificity but the chronology of these events to illuminate novel mechanisms for several different disorders believed to depend on altered glutamatergic neurotransmission: methamphetamine abuse, depression, multiple sclerosis, schizophrenia, hepatic encephalopathy, epilepsy, and human immunodeficiency virusϪencephalopathy. 8 …”

Section: Imaging the 2-hit Hypothesis Of Clinical Glutamate Neurotranmentioning

confidence: 99%

Hyperpolarized MR Imaging: Neurologic Applications of Hyperpolarized Metabolism

Ross

Bhattacharya²,

Wagner³

et al. 2009

AJNR Am J Neuroradiol

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SUMMARY:Hyperpolarization is the general term for a method of enhancing the spin-polarization difference of populations of nuclei in a magnetic field. No less than 5 distinct techniques (dynamic nuclear polarization [DNP]; parahydrogen-induced polarizationϪparahydrogen and synthesis allow dramatically enhanced nuclear alignment [PHIP-PASADENA]; xenon/helium polarization transfer; Brute Force; 1 H hyperpolarized water) are currently under exhaustive investigation as means of amplifying the intrinsically (a few parts per million) weak signal intensity used in conventional MR neuroimaging and spectroscopy. HD-MR imaging in vivo is a metabolic imaging tool causing much of the interest in HD-MR imaging. The most successful to date has been DNP, in which carbon-13 ( 13 C) pyruvic acid has shown many. PHIP-PASADENA with 13 C succinate has shown HD-MR metabolism in vivo in tumorbearing mice of several types, entering the KrebsϪtricarboxylic acid cycle for ultrafast detection with 13 C MR imaging, MR spectroscopy, and chemical shift imaging. We will discuss 5 promising preclinical studies:13 C succinate PHIP in brain tumor; 13 C ethylpyruvate DNP and 13 C acetate; DNP in rodent brain;13 C succinate PHIP versus gadolinium imaging of stroke; and 1 H hyperpolarized imaging. Recent developments in clinical 13 C neurospectroscopy encourage us to overcome the remaining barriers to clinical HD-MR imaging.T he symposium 1 dealt with the topic of novel contrast agents "that enhance your image." If the definition of contrast is the addition of any new dimension, then a reasonable theme for this review-which asks whether hyperpolarized (HD)-MR imaging and spectroscopy of the brain are both feasible and contributory-would be to discuss the novel contrast that is enhanced by chemistry. Chemical ContrastMore than 80 brain metabolites can be distinguished and displayed (as a spectrum) by using MR spectroscopy. However, a quick glance at the metabolic diagram provided as a guide to the human single-voxel proton brain examination (the conventional and automated PROBE/SV; GE Healthcare, Milwaukee, Wisconsin) shows that we do not directly observe any metabolites of the KrebsϪtricarboxylic acid (TCA-the centerpiece of cerebral mitochondrial energy metabolism) cycle and do not draw any conclusions about it or several other important aspects of brain chemistry, except by inference. Under special circumstances, the TCA cycle intermediates do appear in a human brain spectrum. As an example, succinate, at an estimated concentration of 25 mmol/L, appears at a chemical shift of 2.42 ppm. The concentration has been estimated on the basis of the reference creatine (Cr) peak at 3.02 ppm, which is generally present at a 10-mmol/L concentration (an "amount" of succinate, for the 8-cm 3 result, equivalent to 200 mol). For future reference, for the proton spectrum, 4 minutes' accumulation detected 200 mol of succinate, approximately 50 mol/min. Spatial ContrastChemical shift imaging, so-called because multiple spectra are acquired during a single MR spec...

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“…One group observed reduced Glu in FWM of HIV1 patients. 31 However, Glu in plasma and CSF is elevated in HIV dementia, with CSF Glu correlating to brain atrophy and dementia severity. 32 Glutamate regulation by HIV is poorly understood.…”

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confidence: 99%

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter

et al. 2013

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Objective: We evaluated regional brain volumes and cerebral metabolite levels as correlates of HIV DNA in peripheral blood mononuclear cells (PBMCs). Methods:In this cross-sectional study, 35 HIV1 subjects aged $40 years (25 with detectable PBMC HIV DNA; 10 with HIV DNA ,10 copies/10 6 cells, the threshold of detection) and 12 seronegative controls underwent structural brain MRI and magnetic resonance spectroscopy at 3 T. HIV1 subjects were on combination antiretroviral therapy $1 year; all but 1 had plasma HIV RNA ,50 copies/mL. We used logistic regression to evaluate relationships of likely predictor variables to the outcome of PBMC HIV DNA detectability in the HIV1 subjects. Effects of serostatus and HIV DNA on regional brain volumes (normalized to intracranial volume) and on metabolite ratios over creatine were evaluated by analyses of covariance, controlling for age.Results: Relative to the HIV1 group with undetectable HIV DNA, subjects with detectable HIV DNA demonstrated decreased volumes of cerebellar (214%, p 5 0.020) and total subcortical (210%, p 5 0.024) gray matter. Compared to healthy controls, only the detectable HIV DNA group showed significant (p , 0.05) enlargement of lateral ventricles and volumetric reductions of caudate, putamen, thalamus, hippocampus, nucleus accumbens, brainstem, total cortical gray matter, and cerebral white matter. Detectable HIV DNA was not associated with significantly altered cerebral metabolite levels. Glu 5 glutamate; HAND 5 HIV-associated neurocognitive disorders; ICV 5 intracranial volume; MI 5 myo-inositol; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetylaspartate; PBMC 5 peripheral blood mononuclear cell; PLSD 5 protected least significant difference; SN 5 seronegative; U-HIV 5 HIV1 infected subjects with undetectable peripheral blood mononuclear cells HIV DNA; VRS 5 Virchow-Robin spaces. Conclusion:

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Evidence of reduced glutamate in the frontal lobe of HIV‐seropositive patients

Cited by 42 publications

References 44 publications

Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection

Changes in MRS neuronal markers and T cell phenotypes observed during early HIV infection

Hyperpolarized MR Imaging: Neurologic Applications of Hyperpolarized Metabolism

Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter

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