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

doi:10.1016/j.mri.2010.06.007

Magnetic Resonance Imaging

Volume 28, Issue 9, November 2010, Pages 1251-1257

https://doi.org/10.1016/j.mri.2010.06.007 Get rights and content

Abstract

Background and Purpose

Human immunodeficiency virus (HIV)-associated dementia (HAD) has been extensively studied using magnetic resonance spectroscopy (MRS) at field strengths of 1.5 T. Higher magnetic field strengths (such as 3 T) allow for more reliable determination of certain compounds, such as glutamate (Glu) and glutamine (Gln). The current study was undertaken to investigate the utility of 3-T MRS for evaluating HIV+ patients with different levels of cognitive impairment with emphasis on the measurement of Glu and Glx (the sum of Glu and Gln).

Methods

Eighty-six HIV+ subjects were evaluated at 3 T using quantitative short echo time single-voxel MRS of frontal white matter (FWM) and basal ganglia (BG). Subjects were divided into three groups according to the Memorial Sloan Kettering (MSK) HIV dementia stage: 21 had normal cognition (NC) (MSK 0), 31 had mild cognitive impairment (MCI) without dementia (clinical MSK stage=0.5), and 34 had dementia (HAD) (MSK≥1). HIV+ subjects had also undergone standardized cognitive testing covering the domains of executive function, verbal memory, attention, information processing speed and motor and psychomotor speed. Between-group differences in metabolite levels in FWM and BG were evaluated using ANOVA. Pearson correlation coefficients were used to explore the associations between the Glu and Glx metabolites and neurocognitive results.

Results

FWM Glx was lower in HAD (8.1±2.1 mM) compared to both the MCI (9.17±2.1 mM) and NC groups (10.0±1.6 mM) (P=.006). FWM myo-inositol (mI) was higher in HAD (4.15±0.75 mM) compared to both MCI (3.86±0.85 mM) and NC status (3.4±0.67 mM) (P=.006). FWM Glx/creatine (Cr) was lower and FWM mI/Cr was significantly higher in the HAD compared to the MCI and NC groups (P=.01 and P=.004, respectively). BG N-acetyl aspartate (NAA) was lower in the HAD group (6.79±1.53 mM), compared to the MCI (7.5±1.06 mM) and NC (7.6±1.01 mM) groups (P=.036). Significant negative correlations were observed between Glu, Glx and NAA concentrations with Trail-Making Test B (P=.006, P=.0001 and P=.007, respectively), and significant positive correlation was found with the Digit symbol test (P=.02, P=.002 and P=.008, respectively). FWM Glx and NAA concentrations showed negative correlation with Grooved Pegboard nondominant hand (P=.02 and P=.04, respectively).

Conclusion

Patients with HAD have lower levels of Glx concentrations and Glx/Cr ratio in FWM, which was associated with impaired performance in specific cognitive domains, including executive functioning, fine motor, attention and working memory performance. Three-Tesla MRS measurements of Glx may be a useful indicator of neuronal loss/dysfunction in patients with HIV infection.

Introduction

Human immunodeficiency virus (HIV) infection is commonly associated with neurological disease that occurs in the absence of extensive infection of neurons by HIV, suggesting that indirect mechanisms account for neuropathogenesis in the CNS. Viral replication occurs primarily in macrophages and microglia, resulting in macrophage/microglial activation and perhaps changing the normal, neuroprotective functions of astrocytes [1]. Histological and neuropathological studies have demonstrated reduced neuronal density in several cortical regions [2], [3], including neuronal loss and damaged neuronal structures in the frontal cortex [4], [5] in patients with HIV encephalitis. Despite frequent detection of the viral genome and proteins in the brains of HIV patients with and without HIV-associated dementia (HAD), only 5–10% of patients develop dementia [6].

Proton magnetic resonance spectroscopy (MRS) is a noninvasive technique that indirectly gives information on brain pathophysiology through measurement of brain metabolite levels [7]. The most common observations in patients with HIV are increased levels of choline (Cho) [8] and myo-inositol (mI) [9], thought to reflect glial cell proliferation, and decreased levels of N-acetyl aspartate (NAA), believed to be due to neuronal loss or metabolic dysfunction [8], [10], [11], [12]. Metabolic abnormalities may be observed in regions of the brain with normal appearance on conventional MRI, even in subjects who are neurologically asymptomatic, and increase with increasing degrees of neurological involvement [13]. In addition, metabolic abnormalities in mI and Cho have been reported to be reversible following antiretroviral therapy [9]. For these reasons, MRS has been suggested to be a suitable tool of monitoring the degree of HIV involvement in the brain and the effects of therapy [14], [15].

Most published MRS studies of HIV infection have used the conventional clinical MRI magnetic field strength of 1.5 T. At higher magnetic field strengths (such as 3 T or above), and in combination with phased-array receiver coils [16], [17], increased sensitivity and chemical shift dispersion are expected to provide more reliable determination of metabolite concentrations, particularly for coupled spin systems [such as glutamate (Glu) and glutamine (Gln)], which are difficult to quantify at 1.5 T [18]. The current study was therefore undertaken to investigate the utility of 3-T MRS in the evaluation of HIV patients with a range of neurological involvement and to investigate the relationship of brain metabolite signals with neuropsychological (NP) test performance.

Section snippets

Patients

Eighty-six HIV+ subjects (59 male and 27 female; age: mean=46.9±5.8 years, range=31–60 years) who were undergoing highly active antiretroviral therapy (HAART) gave informed consent to participate in the study, which was conducted with the approval of the local institutional human research board. They underwent detailed neurological, neuropsychological, laboratory and functional assessments as described previously [19].

MR spectroscopy

MR imaging and spectroscopy were performed on a 3-T Philips Intera scanner

Results

Based on clinical, functional and neuropsychological assessment, the subjects were stratified into three groups: 21 were HIV+ with normal cognition (NC) [clinical Memorial Sloan Kettering (MSK) HIV dementia stage=0], 31 have mild cognitive impairment (MCI) without dementia (asymptomatic neurocognitive impairment and mild neurocognitive disorder) (clinical MSK stage=0.5) and 34 have HAD (clinical MSK stage) [1]. Patient demographics are given in Table 1; there were no significant differences in

Discussion

The major finding of the current study is that brain MRS performed at 3 T is able to detect decreased levels of Glx in the FWM of patients with HAD compared to those without dementia. Lower Glu and Glx concentrations were associated with worse performance on measures of executive function, measures of motor and psychomotor speed and attention and working memory (Trail-Making Test B, Grooved Pegboard nondominant hand and Digit symbol). To our knowledge, this is the first study correlating Glx

Acknowledgments

This work was supported by NIH grants P41RR015241 and R01MH071150.

References (31)

FineS.M. et al.
Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia
J Biol Chem
(1996)
MeyerhoffD.J. et al.
N-Acetylaspartate reductions measured by 1H MRSI in cognitively impaired HIV-seropositive individuals
Magn Reson Imaging
(1994)
WangZ. et al.
Reduced expression of glutamate transporter EAAT2 and impaired glutamate transport in human primary astrocytes exposed to HIV-1 or gp120
Virology
(2003)
VesceS. et al.
HIV-1 gp120 glycoprotein affects the astrocyte control of extracellular glutamate by both inhibiting the uptake and stimulating the release of the amino acid
FEBS Lett
(1997)
EverallI.P. et al.
Neuronal number and volume alterations in the neocortex of HIV infected individuals
J Neurol Neurosurg Psychiatry
(1993)
NaviaB.A. et al.
The AIDS dementia complex: II. Neuropathology
Ann Neurol
(1986)
MasliahE. et al.
Cortical dendritic pathology in human immunodeficiency virus encephalitis
Lab Invest
(1992)
WileyC.A. et al.
Neocortical damage during HIV infection
Ann Neurol
(1991)
PowerC. et al.
Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients
J Virol
(1998)
Van ZijlP.C. et al.
Magnetic resonance spectroscopy and spectroscopic imaging for the study of brain metabolism
Ann N Y Acad Sci
(1997)

ChongW.K. et al.

Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings

Radiology

(1993)

ChangL. et al.

Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia

Neurology

(1999)

MenonD.K. et al.

Proton MR spectroscopy of the brain in AIDS dementia complex

J Comput Assist Tomogr

(1992)

BarkerP.B. et al.

AIDS dementia complex: evaluation with proton MR spectroscopic imaging

Radiology

(1995)

LaubenbergerJ. et al.

HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times

Radiology

(1996)

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Altered metabolism in right basal ganglia associated with asymptomatic neurocognitive impairment in HIV-infected individuals
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Only few studies have focused on the metabolite differences between asymptomatic neurocognitive impairment (ANI) and cognitively normal people living with HIV (PLWH). The current study aims to examine whether brain metabolisms in basal ganglia (BG) by magnetic resonance spectroscopy (MRS) were potential to discriminate ANI from cognitively normal PLWH.
According to neuropsychological (NP) test, 80 PLWH (37.4 ± 10.2 years) were divided into ANI group (HIV-ANI, n = 31) and NP normal group (HIV-normal, n = 49). Brain metabolisms by MRS from right BG were compared between groups, including N-acetylaspartate and N-acetyl aspartylglutamate (tNAA), creatine and phosphocreatine (tCr), and choline-containing compounds (tCho). A total value of three metabolites were introduced. All brain metabolisms were evaluated as its percentage of total. Furthermore, correlations between MRS and NP and clinical measures were evaluated. A logistic regression model was applied, and the AUC values for the model and the continuous factors were compared using receiver operating curve (ROC) analysis.
Compared to HIV-normal group, tNAA/total was lower and tCr/total was higher in the HIV-ANI group (P < 0.05). Both tNAA/total and tCr/total values were correlated with NP score (P < 0.05), especially in verbal fluency, speed of information processing, learning, and recall (P < 0.05). The logistic model included BG-tCr/total, current CD4 and infection years of PLWH. The AUC value for the BG-tCr/total was 0.696 and was not significantly lower than that for logistic model (P < 0.01).
The altered brain metabolites in the right BG were found in the ANI group compared to PLWH with normal cognition, and further associated with NP deficits. The current findings indicated that brain metabolites assessed by MRS has the potential to discriminate ANI from cognitively normal PLWH.
Evolving biomarkers for HIV-associated neurocognitive disorders (HAND)
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This chapter on biomarkers of HIV-associated neurocognitive disorders (HANDs) divides the discussion into the source of the biomarker, namely blood, including monocyte/macrophage markers (M/Mφ), cerebrospinal fluid (CSF), and brain, using neuroimaging. People with HIV are, for the most part, virally suppressed, but a subset continues to have low level chronic inflammation that is driving cognitive impairment. Most of the biomarkers for HAND are activation markers or secreted products of the M/Mφ. On the brain side, the injury comes from migrating M/Mφ plus microglia and their effect on neurons. Damaged neurons can secrete products into the CSF and blood that can be measured. Neurons also secrete extracellular vesicles into the blood that can be captured, and the cargo can be explored for biomarkers of injury. Neuroimaging can give a snapshot of the structural and metabolic changes altered in HAND. Finally, machine learning can combine the abundant biomarkers with epidemiological and clinical parameters to formulate a biomarker profile with a good probability of diagnosing HAND.
Bioenergetic adaptations to HIV infection. Could modulation of energy substrate utilization improve brain health in people living with HIV-1?
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The human brain consumes more energy than any other organ in the body and it relies on an uninterrupted supply of energy in the form of adenosine triphosphate (ATP) to maintain normal cognitive function. This constant supply of energy is made available through an interdependent system of metabolic pathways in neurons, glia and endothelial cells that each have specialized roles in the delivery and metabolism of multiple energetic substrates. Perturbations in brain energy metabolism is associated with a number of different neurodegenerative conditions including impairments in cognition associated with infection by the Human Immunodeficiency Type 1 Virus (HIV-1). Adaptive changes in brain energy metabolism are apparent early following infection, do not fully normalize with the initiation of antiretroviral therapy (ART), and often worsen with length of infection and duration of anti-retroviral therapeutic use. There is now a considerable amount of cumulative evidence that suggests mild forms of cognitive impairments in people living with HIV-1 (PLWH) may be reversible and are associated with specific modifications in brain energy metabolism. In this review we discuss brain energy metabolism with an emphasis on adaptations that occur in response to HIV-1 infection. The potential for interventions that target brain energy metabolism to preserve or restore cognition in PLWH are also discussed.
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Citation Excerpt :
It is notable that mI, also higher in glial cells than neurons, increases with brain inflammation or gliosis. While elevated mI has been reported in the BG, WM and cortical GM of cognitively normal HIV infected patients (Harezlak et al., 2011), greater metabolite differences are associated with greater cognitive impairment (Mohamed et al., 2010). Unlike tNAA/tCr, tCho/tCr and mI ratios did not appear to diminish with calendar year, suggesting that the responsible processes are still at work in patients with early and adequate viral suppression.
Numerous studies have used magnetic resonance spectroscopy (MRS) neurometabolite measurements to study HIV infection effects. While many have reported differences in total N-Acetylaspartate (tNAA), myo-Inositol (mI), and total Choline (tCho), there have been no meta-analyses performed to evaluate concordance across studies.
To evaluate the consistency of HIV serostatus effects on brain metabolites.
The sample included studies conducted between 1993 and 2019 reporting HIV infection effects measured using proton MRS. tNAA/tCr ratios (21 papers), tCho/tCr ratios (21 papers), mI/tCr ratios (17 papers) and quantitative tCr (9 papers), sampling from basal ganglia (BG), gray matter (GM), and white matter (WM) were included.
Random effects meta-analysis using inverse variance weighting and bias corrected standardized mean differences (SMDs) was used. Meta-regression examined effects of publication year and data acquisition technique differences.
BG SMDs related to positive serostatus were −0.10 [−0.39; 0.18] tNAA/tCr, 0.27 [0.05; 0.49] tCho/tCr, 0.60 [0.31; 0.90] mI/tCr, and −0.26 [−0.59; 0.06] tCr. GM SMDs related to serostatus were −0.29 [−0.49; −0.09] tNAA/tCr, 0.37 [0.19; 0.54] tCho/tCr, 0.41 [0.15; 0.68] mI/tCr, and −0.24 [−0.45; −0.03] tCr. WM SMDs related to serostatus were −0.52 [−0.79; −0.25] tNAA/tCr, 0.41 [0.21; 0.61] tCho/tCr, 0.59 [0.24; 0.94] mI/tCr, and −0.03 [−0.25; 0.19] tCr. WM regions showed larger serostatus effect sizes than BG and GM. I² ranged from 52 to 88% for the metabolite ratios. Both GM and WM tNAA/tCr SMDs were lower with increasing calendar year.
Many studies pooled participants with varying treatment, infection, and comorbidity durations.
HIV neurometabolite studies showed consistently lower tNAA/tCr, higher tCho/tCr and higher mI/tCr ratios associated with chronic HIV infection. Substantial between-study variation may have resulted from measurement technique variations, study population differences and HIV treatment changes over time. Higher WM tCho/tCr and mI/tCr may reflect reactive gliosis or myelin turnover. Neurometabolite measurements can reliably detect chronic HIV infection effects and may be useful in understanding the pathophysiology of cognitive and sensorimotor decline following HIV infection.
This study provides Class II evidence of neurometabolite differences in chronic HIV infection.
Increased matrix metalloproteinase levels and perineuronal net proteolysis in the HIV-infected brain; relevance to altered neuronal population dynamics
2020, Experimental Neurology
Citation Excerpt :
Despite these life-saving drugs, infected individuals continue to experience cognitive impairments which are termed HIV-associated neurocognitive deficits (HAND). Up to 50% of infected individuals will develop HAND at some point in their lifetime (Heaton et al., 2010), and HAND symptoms often include deficits in working memory and attention (Mohamed et al., 2010). Although the underlying mechanisms of HAND remain poorly understood, recent attention has focused on altered neuronal population activity in HIV-infected individuals.
HIV-associated neurocognitive disorders (HAND) continue to persist despite effective control of viral replication. Although the mechanisms underlying HAND are poorly understood, recent attention has focused on altered neuronal population activity as a correlate of impaired cognition. However, while alterations in neuronal population activity in the gamma frequency range are noted in the setting of HAND, the underlying mechanisms for these changes is unclear. Perineuronal nets (PNNs) are a specialized extracellular matrix that surrounds a subset of inhibitory neurons important to the expression of neuronal oscillatory activity. In the present study, we observe that levels of PNN-degrading matrix metalloproteinases (MMPs) are elevated in HIV-infected post-mortem human brain tissue. Furthermore, analysis of two PNN components, aggrecan and brevican, reveals increased proteolysis in HIV-infected brains. In addition, local field potential recordings from ex vivo mouse hippocampal slices demonstrate that the power of carbachol-induced gamma activity is increased following PNN degradation. Together, these results provide a possible mechanism whereby increased MMP proteolysis of PNNs may stimulate altered neuronal oscillatory activity and contribute to HAND symptoms.
Imaging studies of the HIV-infected brain
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Citation Excerpt :
The lower Glu levels in these HIV patients also correlated with poorer cognitive performance on tasks that required motor function (Fig. 18.3D), attention, working memory, and verbal memory (Ernst et al., 2010). Similarly, lower levels of Glu + glutamine (Glx) level and Glx/tCr ratio in frontal white matter were also observed (Harezlak et al., 2011), and those with lower Glx/tCr had impaired performance in executive functioning, fine motor, attention, and working memory leading to HIV-associated dementia (Mohamed et al. 2010). In addition, higher Glu concentration in CSF (extracellular compartment) and plasma of patients with HIV-associated dementia were reported, which further supports the view that neurocognitive impairment resulted from greater Glu-mediated excitotoxicity (Ferrarese et al., 2001).
Human immunodeficiency virus (HIV) enters the brain early after infecting humans and may remain in the central nervous system despite successful antiretroviral treatment. Many neuroimaging techniques were used to study HIV + patients with or without opportunistic infections. These techniques assessed abnormalities in brain structures (using computed tomography, structural magnetic resonance imaging (MRI), diffusion MRI) and function (using functional MRI at rest or during a task, and perfusion MRI with or without a contrast agent). In addition, single-photon emission computed tomography with various tracers (e.g., thallium-201, Tc99-HMPAO) and positron emission tomography with various agents (e.g., [18F]-dexoyglucose, [11C]-PiB, and [11C]-TSPO tracers), were applied to study opportunistic infections or HIV-associated neurocognitive disorders. Neuroimaging provides diagnoses and biomarkers to quantitate the severity of brain injury or to monitor treatment effects, and may yield insights into the pathophysiology of HIV infection. As the majority of antiretroviral-stable HIV + patients are living longer, age-related comorbid disorders (e.g., additional neuroinflammation, cerebrovascular disorders, or other dementias) will need to be considered. Other highly prevalent conditions, such as substance use disorders, psychiatric illnesses, and the long-term effects of combined antiretroviral therapy, all may lead to additional brain injury. Neuroimaging studies could provide knowledge regarding how these comorbid conditions impact the HIV-infected brain. Lastly, specific molecular imaging agents may be needed to assess the central nervous system viral reservoir.

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^☆: Disclosure: The authors report no conflict of interest.

¹: Affiliated with the Orthopedic Surgery Department of the Johns Hopkins University School of Medicine and conducted the statistical analysis.

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

Abstract

Background and Purpose

Methods

Results

Conclusion

Introduction

Section snippets

Patients

MR spectroscopy

Results

Discussion

Acknowledgments

J Biol Chem

Magn Reson Imaging

Virology

FEBS Lett

Neuronal number and volume alterations in the neocortex of HIV infected individuals

J Neurol Neurosurg Psychiatry

The AIDS dementia complex: II. Neuropathology

Ann Neurol

Cortical dendritic pathology in human immunodeficiency virus encephalitis

Lab Invest

Neocortical damage during HIV infection

Ann Neurol

Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients

J Virol

Magnetic resonance spectroscopy and spectroscopic imaging for the study of brain metabolism

Ann N Y Acad Sci

Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings

Radiology

Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia

Neurology

Proton MR spectroscopy of the brain in AIDS dementia complex

J Comput Assist Tomogr

AIDS dementia complex: evaluation with proton MR spectroscopic imaging

Radiology

HIV-related metabolic abnormalities in the brain: depiction with proton MR spectroscopy with short echo times

Radiology

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