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

Abstract

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.

Introduction

Human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) is characterized by cognitive, behavioral, and motor dysfunction which impacts daily functioning^1–3 and is predictive of poor survival in patients⁴. Combination antiretroviral therapy (cART) can improve cognitive performance and brain metabolism in some patients with HAND^{2, 5, 6}. However, many antiretroviral drugs do not penetrate well into the central nervous system⁷, and neurocognitive deficits are reversed in many but not all patients^{8, 9}. The prevalence of HAND in HIV positive (HIV+) individuals with advanced infection remains around 45-50%, and patients are now surviving for years with HIV infection and HAND as chronic conditions^{10, 11}. Advanced age is an important risk factor for HAND; for instance, in the Hawaii Aging with HIV cohort, HIV+ individuals greater than age 50 were twice as likely to have dementia compared to HIV+ individuals who were 20-39 years of age^{12, 13}. As HIV+ individuals are now living longer as a result of cART, the proportion of HIV+ individuals older than 50 years of age has increased. There is some evidence that HIV+ subjects may develop cognitive decline earlier than the HIV− population (i.e. more rapid aging). For the quantitative assessment of neurological involvement in older HIV+ individuals, it is important to develop and validate non-invasive imaging tools that are sensitive to changes in cognitive and behavioral status, which, for instance, may be of use as quantitative measures in future treatment trials. Measurements of regional brain metabolism may also shed some light on the neurobiology of brain aging and cognitive decline in the older HIV+ population.

Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that gives information on brain pathophysiology through measurement of brain metabolite levels¹⁴. The most common observations in HIV+ subjects are increased levels of choline (Cho)¹⁵ and myo-inositol (mI)¹⁶, thought to reflect inflammation and microglial proliferation, and decreased levels of N-acetyl aspartate (NAA) and glutamate^17–19, believed to be due to neuronal injury or dysfunction^{15, 20–22}. 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 involvement²³. For these reasons, MRS has been proposed to be a suitable tool of monitoring the degree of HIV involvement in the brain, and the effects of therapy^{24, 25}.

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}.

The current study was undertaken to investigate the utility of 7.0T MRS in evaluating a cohort of older HIV⁺ patients with varying degrees of neurocognitive impairment. It was hypothesized that differences in brain metabolites reflecting neuronal and glial cell populations will be observed between older HIV+ individuals with and without cognitive impairment. For analysis, patients were classified either as ‘asymptomatic’ (i.e. either cognitively normal, or asymptomatic neurocognitive impairment (ANI) or ‘symptomatic’ (HAND, including those with either mild neurocognitive disorder (MND) or HIV associated dementia (HAD).

Materials and Methods

Participants and clinical testing

The study was approved the local institutional review board (IRB), and all subjects gave written informed consent. HIV+ individuals were recruited at the Institute for Clinical and Translational Research at Johns Hopkins Hospital in Baltimore, Maryland from 2013 to 2016. Inclusion criteria included adults who were HIV positive, older than 50 years, who had the ability to provide written informed consent and to ambulate at first clinic visit. Patients were excluded if they had a history of or current opportunistic central nervous system infection, schizophrenia, affective disorder or psychiatric diseases which could be a confounder for cognitive impairment, or chronic neurological disorders such as brain infarction, hemorrhage, epilepsy, and multiple sclerosis. Active substance abusers or opiate users were excluded, defined as any history of illicit drug use within 3 months preceding the baseline visit, established by subject history and urine toxicology screens. Any contraindication for 7T MRI (metal in body, claustrophobia, inner ear disorder) was also an exclusion criterion.

As described above, subjects were stratified by neurocognitive disorder status using the revised American Academy of Neurology (AAN) ‘Frascati’ criteria³¹. All subjects underwent detailed neurological, neuropsychological, laboratory and functional assessments. Clinical assessments included standardized questionnaires which assessed demographic information including primary language, reading abilities, medical, psychiatric, and neurological history, as well as a neurological examination. Serum CD4 T-cell counts and HIV RNA levels via quantitative polymerase chain reaction (PCR) in the plasma and cerebrospinal fluid were obtained. Depression symptomatology was rated using the Center for epidemiological studies depression score (CES-D)³². Hepatitis C viral status was obtained via clinical history and evaluation of laboratory findings for hepatitis C virus antibodies.

Measures of functional performance included Karnofsky Performance Scale, a questionnaire for instrumental activities of daily living (IADLs), and a questionnaire for role and physical quality of life (QOL) measures^{1–3, 33–35}. Neuropsychological (NP) testing include the Trail Making Test, Color Trail, Grooved Pegboard Test, Digit Symbol, Stroop Test, Rey Complex Figure Test, and Hopkins Verbal Learning Test^36–38. Raw scores on each neuropsychological test were converted to z-scores using published normative data³¹.

MR Imaging and Spectroscopy

All studies were performed on a 7T scanner (Philips ‘Achieva’, Best, The Netherlands) equipped with a 32-channel receive head coil and quadrature transmit coil (Nova Medical Inc., Wilmington, MA, USA). Brain MRI consisted of localizer images and a 3D T₁-weighted MPRAGE scan with 1.2 mm isotropic voxel size. Single voxel STEAM spectra (TR/TE/TM=3000/14/25 msec) were acquired from the left frontal white matter (FWM), left basal ganglia (BG), mesial precuneus (PC), mesial posterior cingulate cortex (PCC) and left hippocampus (hippo) with and without VAPOR water suppression. These regions were chosen based on prior studies which have indicated that they are involved in HIV infection and aging^{10, 39–41}. The voxel sizes ranged from 8 to 15 cc (Figure 1). The hippocampal voxel was carefully angulated parallel to the long axis of the hippocampus and had dimensions were 1.5×1.5×3.5cm to minimize partial volume contributions from surrounding tissues. 80 acquisitions were acquired with water suppression, and 2 unsuppressed, to give a total scan time per region of 4 min 6 sec. Prior to the acquisition of each region, field inhomogeneity was corrected up to 2^nd order using the ‘FASTMAP’ localized shimming technique⁴² and localized power optimization⁴³ was also performed (transmit B₁ = 15 μT).

Figure 1.

Examples of the 5 voxel locations used for brain MRS in the left frontal white matter (FWM), left hippocampus (Hippo), left basal ganglia (BG), mesial posterior cingulate cortex (PCC) and mesial precuneus (PC). An example of a spectrum from the PC in a 55 year old HIV+ subject is shown, including results from the LCModel analysis (red curve). Signals are assigned to lipids (Lip), N-acetyl aspartate (NAA), N-acetyl aspartate glutamate (NAAG), glutamate (Glu), glutamine (Gln), creatine (Cr), choline (Cho) myo-inositol (mI), and Glx (the sum of Glu and Gln). The top trace is the difference between the original data and the results of the curve-fit.

Spectra were analyzed using a basis set designed for 7T STEAM sequence incorporated in the ‘LCModel’ software package⁴⁴ and quantified in approximately millimolar concentrations (referred to here as ‘institutional units’ (i.u.), since relaxation time corrections were not performed) relative to the unsuppressed water signal. Ratios relative to creatine (Cr) were also calculated. We did not do any volumetric morphometry as we reported metabolite ratios besides metabolite concentrations. The LCModel basis set contained 20 different metabolites, and also the standard LCModel macromolecule peaks. Concentration and ratio values were only included for statistical analysis if their Cramér-Rao lower bounds (CRLB) were less than or equal to 20%⁴⁴. A representative PC spectrum is shown from one subject in Figure 1.

Statistical Analysis

The objective of the current study was to compare metabolite concentration and ratio values between older HIV+ patients who were either asymptomatic or symptomatic for neurocognitive impairment. Using the Shapiro-Wilk test, the data were not normally distributed; therefore, we present the data as median and interquartile range (IQR, 25^th and 75^th percentile). Between groups comparisons were made using the non-parametric median test. Pearson correlation coefficients were calculated between metabolite values and concentrations and neurocognitive tests.

Results

45 subjects (mean age 58.9 ± 5.3 years; 33 (73%) male) were enrolled. All patients were receiving cART. 24 subjects were classified as asymptomatic and 21 as symptomatic. Patient demographics are given in Table 1. There were no significant group differences in age, education, gender, race, CD4 count or plasma HIV RNA between groups. The estimated IQ which was significantly lower in the symptomatic group (103.7 vs. 112.9 respectively, P=0.02). Apart from some small white matter hyperintensities in 2 individuals, which were avoided during MRS voxel placement, there were no significant T₂W or FLAIR lesions or other abnormalities in any of the subjects in this study.

Table 1.

Subject demographics in the two HIV+ groups: Asymptomatic neurocognitive impairment (ANI), and symptomatic HIV associated neurocognitive disorder (HAND). N = number of patients in each group. Values given are means ± standard deviation.

	ANI	HAND	P-value
N	24	21	–
Age, years	59.6 ± 5.7	58.2 ± 5.0	0.378
Male, n (%)	17 (71%)	16 (76%)	0.764
Education, years	14.9 ± 3.0	14.0 ± 2.7	0.263
Race (% African American)	12 (50%)	13 (62%)	0.655
Duration of Infection (years)	19.9±9.0	19.2±9.4	0.790
CES-D	7.7 ± 6.8	11.0 ± 11.7	0.253
HART Est IQ*	112.9 ± 12.8	103.7 ± 12.9	0.022
CD4 cell count (cells/mm3)	674 ± 281	676 ± 375	0.988
Plasma HIV RNA (Log10 copies/ml)	1.6 ± 0.1	2.3 ± 1.4	0.569

CES-D =Center for Epidemiological Studies Depression Score; HART Est IQ= Hopkins Adult Reading Test Estimated IQ; Plasma HIV RNA only among those with detectable viral load (n=2 ANI and n=3 HAND).

^*Significant P<0.05

In the frontal white matter, the median NAA/Cr ratio was lower in the symptomatic group compared to asymptomatic (1.21 vs. 1.30 respectively, P=0.005), and tNAA/Cr (1.46 vs. 1.56 respectively, p=.005) and the median myo-inositol/Cr (mI/Cr) (0.97 vs. 1.03 respectively, P=0.02) (Figure 2). There was also a trend towards lower FWM tNAA concentration in the symptomatic group compared to asymptomatic (7.46 vs. 7.81 mM respectively, P=0.06) (Figure 3). In the posterior cingulate cortex, median NAA/Cr was also significantly lower in the symptomatic group (1.16 vs. 1.21 respectively, P=0.01), as was median tNAA/Cr (1.32 vs. 1.40 respectively, P=0.02), and median mI/Cr (0.78 vs. 0.87 respectively, P=0.002) (Figure 2). In the precuneus, the median NAA/Cr was also significantly lower in the symptomatic group (1.14 vs. 1.23 respectively, P=0.02), as was median glutamate/Cr (Glu/Cr) (1.12 vs. 1.24 respectively, P=0.01) (Figure 2). There were no significant differences between groups in basal ganglia and hippocampus metabolite concentrations or ratios.

Figure 2.

Metabolite ratios for the frontal white matter, posterior cingulate, precuneus, basal ganglia and hippocampal voxels. *= significant.

Figure 3.

Metabolite concentrations for the frontal white matter, posterior cingulate, precuneus, basal ganglia and hippocampal voxels. *= significant.

In regards to correlations between MRS results and NP tests (Table 2, Figures 4, 5, 6), lower FWM tNAA/Cr was associated with worse performance on measures of executive function, fine motor, and psychomotor speed (Trail Making Test, part B, Grooved Pegboard Test, non-dominant hand, and Digit Symbol (P= 0.005, 0.01 and 0.001, respectively). Furthermore, lower FWM Glu/Cr was associated with lower performance on delayed recall on the Hopkins Verbal Learning Test (P = 0.02) (Figure 4). Lower tNAA/Cr in the posterior cingulate was associated with worse performance on tests of psychomotor speed (Digit Symbol and Stroop Test, P = 0.02 and 0.04 respectively) (Figure 5). Lower precuneus NAA/Cr was associated with worse performance on the Stroop Test, a test of processing speed (P=0.04); while precuneus Glu/Cr decreases were associated with worse performance in the Trail Making Test Part B, a measure of executive functioning (P=0.04) (Figure 6).

Table 2.

Pearson correlation of brain metabolites with neurocognitive test scores. Correlation coefficients (r) and significance (P values) for frontal white matter (FWM), posterior cingulate cortex (PCC) and precuneus (PC). Values in bold are significant (P<0.05)

	Trail-making test B			Grooved pegboard non-dominant hand			Digit symbol			Hopkins Verbal Learning Test Delayed recall			Stroop
	FWM	PCC	PC	FWM	PCC	PC	FWM	PCC	PC	FWM	PCC	PC	FWM	PCC	PC
NAA	0.38 (0.01)	NS	NS	0.35 (0.01)	NS		NS	0.46 (0.006)	0.44 (0.008)	0.46 (0.001)	NS	NS	NS	NS	0.38 (0.02)
NAA/Cr	0.36 (0.01)	NS	NS	NS	NS	NS	0.33 (0.02)	0.35 (0.04)	0.33 (0.04)	0.31 (0.04)	NS	NS	NS	0.37 (0.03)	0.33 (0.04)
tNAA	0.43 (0.003)	NS	NS	0.45 (0.002)	NS	NS	NS	0.48 (0.004)	NS	0.35 (0.01)	NS	NS	NS	NS	NS
tNAA/Cr	0.41 (0.005)	NS	NS	0.35 (0.01)	NS	NS	0.46 (0.001)	0.39 (0.02)	NS	NS	NS	NS	NS	0.35 (0.04)	NS
Glu	0.3 (0.04)	NS	NS	0.36 (0.01)	NS	NS	NS	0.48 (0.003)	NS	0.46 (0.001)	NS	NS	NS	0.4 (0.01)	0.46 (0.005)
Glu/Cr	NS	NS	0.34 (0.04)	NS	NS	NS	NS	NS	NS	0.32 (0.02)	NS	NS	0.32 (0.03)	0.38 (0.02)	NS
Glx	0.29 (0.05)	NS	NS	0.35 (0.01)	NS	NS	NS	0.42 (0.01)	NS	0.32 (0.03)	NS	NS	NS	NS	0.36 (0.03)
Glx/Cr	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS
Cho	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	− 0.34 (0.04)	NS	NS	0.4 (0.01)
Cho/Cr	NS	NS	NS	NS	NS	NS	0.31 (0.04)	NS	NS	−0.37 (0.02)	NS	NS	NS	NS	NS
mI	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS
mI/Cr	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	NS	0.35 (0.04)	NS

Figure 4.

Scatter plots showing significant positive correlations of FWM Glu/Cr with HVLT delayed recall, and FWM tNAA/Cr with Grooved Pegboard non dominant, Digit Symbol and Trail-Making Test B z scores.

Figure 5.

Scatter plots showing significant positive correlation of posterior cingulate tNAA/Cr with Digital Symbol and Stroop Trail z scores.

Figure 6.

Scatter plots showing significant positive correlation of precuneus NAA/Cr and Glu/Cr with Stroop Trail and Trail Making part B z scores respectively.

Discussion

The main finding of this study is that 7T MRS was able to find significant differences in metabolite levels between symptomatic and asymptomatic HIV+ subjects, with the primary result being lower levels of (t)NAA (or the ratio (t)NAA/Cr) in frontal white matter, posterior cingulate, and precuneus. Glu/Cr was also lower in the precuneus in the symptomatic group. In addition, significant correlations were found between FWM measures of (t) NAA (and (t)NAA/Cr) and Glu (and Glu/Cr, Glx and Glx/Cr) and multiple neuropsychological test scores. Posterior cingulate cortex and precuneus measures of NAA and Glu also correlated with performance on the Digit Symbol and Stroop tests. Overall, these results suggest that MRS measurements of NAA and glutamate in these brain regions reflect neuroaxonal loss or dysfunction, which correlates with worse performance on neuropsychological tests.

Findings of decreased NAA and Glx (Glu+Gln) in HIV infection are well established from MRS studies at lower field strengths; for instance, in one study long TE performed at 1.5T found decreased levels of NAA/Cr in parietal-occipital white matter in asymptomatic HIV+ men compared to normal controls⁴⁵. 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}. 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− controls¹⁹. Although some 3T studies have used the technique of TE-averaged PRESS¹⁹ to selectively detect Glu, generally it can be difficult to reliably separate Glu and from Gln using conventional MRS. Prior studies comparing 7T to lower field strengths have shown improved ability at 7T to quantify Glu and Gln⁴³; the current study at 7T confirms that only significant HIV-associated correlations are found for Glu, with no significant associations found for Gln. NAA and Glu are known to be primarily located in neurons, and have been shown in previous studies of various pathologies to decrease when neuronal damage occurs. The mechanisms by which neuronal damage occur in HIV infection are complicated, but it is believed that infiltration of infected macrophages and lymphocytes result in inflammation, astrocytosis, oxidative stress and synaptodendritic injury⁴⁷.

Several studies performed at 1.5 and 3.0 T have reported reduced increased myo-inositol (mI) in HIV infection, and symptomatic HIV+ subjects compared to asymptomatic^{6, 19}. The current study is consistent with these findings. Previous studies at lower field strengths, and usually in younger cohorts of subjects, have generally reported increased levels of mI in HIV+ subjects compared to HIV− controls, with higher mI in symptomatic HIV+ subjects compared to asymptomatic^{18, 48}. The current study did not find strong differences in mI (or mI/Cr) between asymptomatic and symptomatic groups in most brain regions, with the exception of slightly lower mI/Cr in FWM in the symptomatic group (i.e. in the opposite direction to prior findings)^{18, 49}. There were also few significant positive correlations between high mI and worse performance on neuropsychological tests. These findings may be due to the older nature of the HIV+ cohort studied here, with a longer disease duration, generally well-controlled viral load and less neuroinflammation than in previous studies.

Regarding correlations between brain metabolites and neuropsychological test scores, frontal white matter test NAA and Glu measures correlated positively with measures of executive function, motor speed, verbal and working memory, whereas posterior cingulate cortex and precuneus measures of NAA and Glu predominantly correlated with the Digit Symbol and Stroop tests, measures of working memory and information processing speed respectively. The precuneus and posterior cingulate cortex are both visual processing areas, and neuronal dysfunction as measured by the metabolite changes in these areas could contribute to impaired performance in neuropsychological tests which include visuo-spatial processing, such as the Digit-Symbol and Stroop tests. Specifically, decreased FWM Glu/Cr and Glx were correlated with verbal recall; while post cingulate and precuneus Glu Glu/Cr and Glx were associated with attention and working memory and information speed processing tests. These findings are generally consistent with prior studies performed at 1.5 or 3.0T; for instance, in patients receiving cART, significant correlations were found between 3T measures of Glu, Glx and NAA with performance on motor and psychomotor speed, attention and working memory⁶. A study performed at 1.5T²⁵ in HIV+ subjects (the majority being on cART) assessed motor skills (fine and gross), psychomotor function, information processing speed, and verbal memory and expressed the results as a composite score (NPZ-8). Consistent with the concept of HIV+ as a predominantly subcortical dementia, NPZ-8 scores correlated positively with NAA/Cr (and NAA/Cho and NAA/mI) in the FWM, similar to the current study. Negative correlations in that study were also found between basal ganglia mI/Cr and NPZ-8²⁵. Another study at 1.5T in 45 antiretroviral naïve HIV+ subjects also found elevated frontal white matter mI and Cho compared to HIV− controls, which were correlated with slow performance in fine motor (Grooved Pegboard), psychomotor (Trail Making Test), and executive functions (Stroop tasks) tests⁵⁰. The relative lack of correlations in the current study between neuropsychological test performance and measures of Cho (only PC Cho negatively correlated with Hopkins Verbal Learning Test (HVLT) Delayed recall task) or mI (PCC mI/Cr did correlate with performance on the Stroop task) most likely reflect differences in patient populations between the current and previous studies (older HIV+ subjects, all on cART).

7T MRS has been shown to offer increased signal-to-noise ratios (SNR) and spectral resolution compared to MRS at lower field strengths; however, it also presents some technical challenges, including increased chemical shift dispersion effects (CSDE), difficulty shimming, and increased radiofrequency power deposition (‘specific absorption rate’, SAR). Localized 2^nd order shimming was used in this study to minimize the effects of field inhomogeneity. In addition, the STEAM pulse sequence was used for spatial localization since the 90˚ slice selective pulses in STEAM have excellent slice profiles, low CSDE and SAR^{51, 52}. However, in the future, other sequences such as semi-LASER and/or magnetic resonance spectroscopic imaging sequences may be used which provide higher SNR, spatial resolution and coverage.

The study also has some limitations; although subjects with overt medical or neurological abnormalities were excluded, the older HIV+ subjects in this study may well have had varying degrees of risk factors commonly encountered in the general population which contribute to aging and cognitive decline, such as microvascular disease, diabetes or hypertension. All subjects were taking cART, which is known to affect brain metabolite concentrations⁵³. Although 3D T₁W images were recorded, no volumetric analysis has been performed to date in these subjects due to intensity and contrast variations due to transmit B₁ inhomogeneity. However, we do not expect morphometric differences to significantly affect results, since metabolite ratios (relative to Cr) are relatively insensitive to voxel composition (particularly CSF contamination). Finally, no significant changes were observed in the hippocampus in this study, despite the well-known importance of this structure for memory and other age-related cognitive dysfunction^{40, 54, 55}. Lack of significant findings may be in part due to the generally lower spectral quality obtained in this region due to magnetic susceptibility effects from bone/air/tissue interfaces proximal to the anterior temporal lobe, as well as partial volume with surrounding tissue due to the small size of the hippocampus. Spectral quality was also lower in the basal ganglia because of the high iron content of the globus pallidus and putamen which is known to increase line widths in MR spectra from this region^56–58; this may have also contributed to the lack of significant group differences or neurocognitive correlations detectable in this region.

Conclusion

7-Tesla MRS measurements of NAA and Glu may be useful indicators of neuroaxonal loss or dysfunction and correlate with neuropsychological performance in the older subject population with HIV infection. 7T MRS may therefore be a useful adjunct technique for monitoring disease progression or response to therapy in future treatment trials. Other future studies are needed to track longitudinal changes over time, as well as comparisons to HIV− negative control subjects to determine if cognitive decline and brain metabolite changes occur at a greater rate in HIV+ subjects, and if there are specific metabolic changes only associated with HIV infection in the older population.

Abbreviations

cART

Combined Anti-retroviral therapy

HIV

human immunodeficiency virus

Cr

Creatine

Glx

Glutamate and glutamine

mI

myo-inositol

Cho

Choline

Gln

Glutamine

Glu

Glutamate

NAA

N-acetylaspartate

NAAG

N-acetylaspartyl-gluamate

tNAA

NAA+NAAG

GABA

γ-Aminobutyric acid

MRS

Magnetic resonance spectroscopy

MRSI

Magnetic resonance spectroscopic imaging

MRI

Magnetic resonance imaging

Lip

Lipid

ANI

Asymptomatic neurocognitive impairment

HAND

HIV associated neurocognitive disorder

MND

mild neurocognitive disorder

HAD

HIV associated dementia

STEAM

Stimulated echo acquisition mode

IRB

Institutional Review Board

RNA

Ribonucleic acid

FWM

Frontal white matter

PCC

Posterior cingulate cortex

PC

Precuneus

BG

Basal Ganglia

Hippo

Hippocampus

HVLT

Hopkins Verbal Learning Test

NP

Neuropsychological

T

Tesla

AAN

American Academy of Neurology

CES-D

Center for epidemiological studies depression score

PCR

Polymerase chain reaction

IADL

Instrumental activities of daily living

QOL

Quality of life

VAPOR

Variable power and optimized relaxation

LCModel

Linear Combination of Model Spectra

CRLB

Cramér-Rao lower bounds

PRESS

Point Resolved SpectroScopy

i.u

Institutional units

IQR

Interquartile range