Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study

Mohamed, Mona A.; Barker, Peter B.; Skolasky, Richard L.; Selnes, Ola A.; Moxley, Richard T.; Pomper, Martin G.; Sacktor, Ned

doi:10.1016/j.mri.2010.06.007

Cited by 76 publications

(69 citation statements)

References 31 publications

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“…In a previous report describing CMRs quantified using the LCmodel in HIV disease at a higher magnetic field strength than our study, 24 mean CMRs in the FWM were 1.28, 0.32 and 0.56 for NAA/Cr, Cho/Cr and mI/Cr, respectively. These values are similar to our findings in the FWM utilizing the TARQUIN package (1.25, 0.28 and 0.91 for NAA/Cr, Cho/Cr and mI/Cr, respectively) and differed to our findings utilizing the jMRUI package (1.76, 1.05 and 1.05 for NAA/Cr, Cho/Cr and mI/Cr, respectively).…”

Section: Discussioncontrasting

confidence: 43%

A comparison of two post-processing analysis methods to quantify cerebral metabolites measuredviaproton magnetic resonance spectroscopy in HIV disease

Scott¹,

Underwood²,

Garvey³

et al. 2016

BJR

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Objective: Non-invasive biomarkers to monitor cerebral function in treated human immunodeficiency virus (HIV) disease are required. Cerebral metabolite ratios (CMRs) measured by proton-MR spectroscopy ( 1 H-MRS) are a potential biomarker. Here, we compare two postprocessing software packages to quantify CMRs. Methods: Cerebral 1 H-MRS data from 11 HIV-positive subjects before and after antiretroviral therapy intensification with maraviroc were quantified using a java-based version of the MR user interface package (jMRUI) and the totally automatic robust quantitation in nuclear MR (TARQUIN). 1 H-MRS data included N-acetylaspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) from three cerebral locations. Differences in quantification and clinical associations of CMRs measured by the two packages were evaluated. Results: Mean CMRs were generally lower when measured by TARQUIN than by jMRUI (NAA/Cr, Cho/Cr, mI/ Cr ratios of 1.78, 0.83, 0.81 for jMRUI, and 1.27, 0.25, 0.81 for TARQUIN). Longitudinal changes were observed in CMRs in the basal ganglia voxel although these changes were not statistically significant [17.1% (p 5 0.18), 10.0% (p 5 0.91) and 26.6% (p 5 0.61) and 114.8% (p 5 0.18), 1 17.9% (p 5 0.07) and 134.8% (p 5 0.17) for NAA/Cr, Cho/Cr and mI/Cr ratios measured by TARQUIN and jMRUI, respectively]. Plasma maraviroc concentration was associated with a decrease in mI/Cr ratio measured via TARQUIN (p 5 0.049). Conclusion: Although CMRs differed when quantified by jMRUI vs TARQUIN, these differences were consistently observed across three cerebral locations, and clinical associations were evident by both methods. Advances in knowledge: TARQUIN and jMRUI are viable options to use in the post-processing of cerebral MRS data acquired in HIV disease.

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Section: Discussioncontrasting

confidence: 43%

A comparison of two post-processing analysis methods to quantify cerebral metabolites measuredviaproton magnetic resonance spectroscopy in HIV disease

Scott¹,

Underwood²,

Garvey³

et al. 2016

BJR

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“…NAA was also found to increase after initiation of cART 6, 46 . Previous 3T studies have also reported decreasing Glx concentrations (or Glx/Cr ratios) with increasing symptomatology in HIV infection 17, 18 , and decreased levels compared to HIV− controls 19 . Although some 3T studies have used the technique of TE-averaged PRESS 19 to selectively detect Glu, generally it can be difficult to reliably separate Glu and from Gln using conventional MRS.…”

Section: Discussionmentioning

confidence: 73%

“…MR spectroscopic imaging (MRSI) studies also performed at long TE found progressive declines in NAA from HIV− controls, to asymptomatic and then symptomatic HIV+ patient groups in multiple gray and white matter regions 6, 18, 46 . NAA was also found to increase after initiation of cART 6, 46 .…”

Section: Discussionmentioning

confidence: 99%

“…MRS at field strengths of 1.5, 3.0 and 4.0 Tesla (T) 6, 18, 26–28 has been extensively used to investigate neurological involvement in HIV+ subjects. Higher magnetic field strengths (such as 7.0T) allow increased sensitivity and chemical shift dispersion and more reliable determination of brain metabolites, particularly for some of the smaller and overlapping signals in the spectrum, such as glutamate and glutamine 29, 30 .…”

Section: Introductionmentioning

confidence: 99%

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7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests

Mohamed¹,

Barker

Skolasky

et al. 2018

AJNR Am J Neuroradiol

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Background and Purpose The purpose of this study was to explore the relationship between cognitive impairment and brain metabolism in older subjects with HIV infection. It was hypothesized that MRS measurements related to neuronal health and function (particularly N-acetylaspartate (NAA) and glutamate (Glu)) would be lower in HIV+ subjects with worse cognitive performance. Materials and Methods 45 HIV+ patients [58.9 ± 5.3 years; 33 male] underwent detailed neuropsychological (NP) testing and brain MRS at 7 Tesla. 24 subjects were classified as having asymptomatic cognitive impairment and 21 were classified as symptomatic cognitive impairment. Single voxel proton MR spectra were acquired from 5 brain regions and quantified using ‘LCModel’ software. Brain metabolites and NP test results were compared using non-parametric statistics and Pearson correlation coefficients. Results Significant differences in brain metabolites were found between symptomatic and asymptomatic subjects, with the main findings being lower measures of N-acetyl aspartate (NAA) in the frontal white matter (FWM), posterior cingulate cortex (PCC), and precuneus (PC). In the PC, glutamate (Glu) was also lower in the symptomatic group. In the FWM, PC and PCC, NAA and Glu measurements showed significant positive correlation with better performance on NP tests. Conclusion Compared to asymptomatic, symptomatic HIV+ subjects had lower levels of NAA and Glu, most notably in frontal white matter, which also correlated with performance on neuropsychological tests. High field MRS offers insights into the pathophysiology associated with cognitive impairment in HIV, and may be useful as a quantitative outcome measure in future treatment trials.

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“…Magnetic Resonance Spectroscopy. MR imaging and spectroscopy were performed on a 3-T Philips Intera scanner with a six-channel SENSE head coil as previously described (53). Spectra were analyzed using the LCModel algorithm (54) and quantified in millimolar concentrations using the unsuppressed water signal as an internal intensity reference.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.G lutamate carboxypeptidase II (GCPII), previously called Nacetylated-α-linked acidic dipeptidase (NAALADase), is a membrane-bound enzyme expressed on the surface of astrocytes that catalyzes the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate ( Fig. 1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1, 2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1, 2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.Cognitive impairment is a frequent comorbidity of many neurological diseases, including multiple sclerosis (MS). MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5-7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8). Global brain atrophy, candidate genetic risk factors, accelerated inflammatory processes (7), and dysregulated signaling pathways (9) have been implicated as contributing factors, but an incomplete understanding of the molecular mechanisms behind cognitive impairment in MS has prevented the development and Food and Drug Administration (FDA) approval of drug therapies.The most widely used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a valuable tool for developing treatments for MS. Three FDA-approved disease-modifying agents were deve...

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Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study

Cited by 76 publications

References 31 publications

A comparison of two post-processing analysis methods to quantify cerebral metabolites measuredviaproton magnetic resonance spectroscopy in HIV disease

A comparison of two post-processing analysis methods to quantify cerebral metabolites measuredviaproton magnetic resonance spectroscopy in HIV disease

7T Brain MRS in HIV Infection: Correlation with Cognitive Impairment and Performance on Neuropsychological Tests

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

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