Effects of pediatric HIV/antiretroviral therapy on basal ganglia metabolite-volume relationships
Frances C Robertson1, Martha J Holmes1, Emmanuel C Nwosu1, Francesca Little2, Mark F Cotton3, Els Dobbels3, Andre JW van der Kouwe4,5, Barbara Laughton3, and Ernesta M Meintjes1

1Department of Human Biology, University of Cape Town, Cape Town, South Africa, 2Department of Statistical Sciences, University of Cape Town, Cape Town, South Africa, 3Department of Paediatrics & Child Health, Stellenbosch University, Stellenbosch, South Africa, 4A.A. Martinos Centre for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States, 5Department of Radiology, Harvard Medical School, Boston, MA, United States

Synopsis

HIV is associated with structural deficits in the basal ganglia (BG). Volumes from structural MRI may relate to metabolic changes measurable with magnetic resonance spectroscopy. We investigated the relationship between BG NAA and Glutamate/Glutamine and caudate, putamen, nucleus accumbens and subcortical gray matter (GM) volumes in 7-year old HIV-infected children on antiretroviral therapy and uninfected controls. Higher NAA was associated with smaller accumbens and left putamen in all children. Higher Glutamate/Glutamine was associated with greater subcortical GM in controls, but not HIV-infected children. Relationships between brain metabolites and volumes add to the description of effects of HIV/ART on the BG.

Purpose

HIV infection is associated with structural deficits of the basal ganglia (BG). Volume deficits may be related to changes in cerebral metabolites measured with MRS. Altered relationships between metabolite levels and BG volumes may provide a clearer picture of the effects of HIV on the brain than one measure alone. However, relationships between these measures in healthy children are not known. Previous studies in HIV-infected adults have found lower BG N-acetyl-aspartate (NAA) to be associated with reduced temporal lobe(1), putamen, and thalamus volumes(2). Lower Glutamate/Glutamine (GluGln) has been associated with reduced cortical gray matter (GM), caudate and thalamus volumes(1), but also with increased putamen and thalamus volumes(2). Our aims were to investigate the relationship between NAA/GluGln and BG volumes in healthy children and to determine whether these relationships are altered in HIV-infected children on antiretroviral therapy (ART).

Methods

Participants were 104 isiXhosa children from a neuroimaging follow-on study of the Children with HIV Early Antiretroviral Therapy (CHER) trial. All HIV-infected children had started ART before 18 months of age and were stable on ART by the time of scanning at age 7.

Scanning was performed on a 3T Allegra (Siemens, Erlangen, Germany). The protocol included a high-resolution T1-weighted 3D EPI-navigated(3) multiecho magnetisation prepared rapid gradient echo (MEMPRAGE)(4) (FOV 224 x 224 mm2, TR 2530 ms, TI 1160 ms, TE’s = 1.53/3.19/4.86/6.53 ms, bandwidth 650Hz/px, 144 sagittal slices, 1.3 x 1.0 x 1.0 mm3). Single voxel ¹H spectroscopy (SVS) in the BG was obtained using an EPI volumetric navigated point-resolved spectroscopy (PRESS) sequence with real-time first-order shim and motion correction(5) (TR = 2000 ms, TE = 30 ms, 64 measurements, vector size 512, spectral bandwidth 1000 Hz). Water unsuppressed ¹H MRS measurements were acquired for water scaling and eddy current correction. Scans were performed according to protocols approved by the Human Research Ethics Committees of the Universities of Cape Town and Stellenbosch.

FreeSurfer version 5.1.0 was used to perform automated segmentation of subcortical structures to generate regional volume measures. LCModel(6) was used to calculate metabolite concentrations from frequency and phase-corrected water-suppressed spectra using water scaling. The SVS voxel was segmented using SPM12 to determine tissue type composition. SVS data were not acquired for 9 children, and spectra from a further 32 were excluded due to SNRs <7, leaving 63 children with both volume and SVS data (38 HIV-infected, 25 controls, age 7.2 ± 0.16 years, 26 boys).

Statistical analysis was performed using R. Subcortical GM, right and left caudate, putamen and nucleus accumbens volumes were regressed against NAA and GluGln concentrations, testing for an interaction of metabolite level with HIV infection status and accounting for age, gender and intracranial volume. Group differences in metabolites and volumes between HIV-infected children and controls were tested using ANCOVA controlling for the confounders.

Results

In controls, NAA in BG was negatively associated with volumes of the right (slope=-180, p=0.008, figure 1) and left (slope=-143, p=0.03, figure 2) nucleus accumbens and left putamen (slope= -727, p=0.04). There was no significant interaction of HIV status. GluGln related positively to subcortical GM volume in controls only (slope=380, p=0.02), with a significant interaction effect of HIV status (p=0.04, figure 3). ANCOVAs controlling for age, gender and ICV indicated smaller right (p=0.01) and left (p=0.0008) nucleus accumbens, lef t putamen (p=0.009) and subcortical GM (p=0.01) in HIV-infected children. Higher mean NAA and GluGln in the HIV-infected children than controls was not significant (p=0.9, p=0.4 respectively).

Discussion

Increased NAA – a marker of neuronal health – is associated with smaller volumes of nucleus accumbens and putamen in both HIV-infected children and controls. This suggests that smaller volumes reflect denser neuronal organization in both groups, consistent with previous studies indicating that NAA gradually increases during childhood(7), while absolute volumes of subcortical structures including nucleus accumbens decrease during the same period(8). However, it does not explain why in our sample the controls have larger nucleus accumbens and putamen volumes than HIV-infected children, unless this is due to accelerated maturation in the HIV-infected group that is only evident in the narrow age range of this sample.

The positive relationship of GluGln with subcortical GM volume seen in controls is not seen in HIV-infected children on ART, suggesting a possible effect of HIV/ART.

Conclusion

Measurement of metabolites as well as volumes may provide a more complete – and more complex – description of the effects of HIV/ART on the brain. Normal relationships between metabolites and BG volumes should be established to determine when the breakdown of these relationships may be an indicator of disease.

Acknowledgements

Support for this study was provided by NRF/DST South African Research Chairs Initiative; US National Institute of Allergy and Infectious Diseases (NIAID) through the CIPRA network, Grant U19 AI53217; NIH grants R01HD071664, R21MH096559 and R21MH10834601; NRF grant CPR20110614000019421, and the Medical Research Council (MRC). We thank the CUBIC radiographers (Marie-Louise de Villiers and Nailah Maroof), our research staff (Thandiwe Hamana and Rosy Khethelo), and Shabir A. Madhi for access to control participants on the CIPRA-SA04 trial.

References

(1) Cohen RA, et al. Cerebral metabolite abnormalities in human immunodeficiency virus are associated with cortical and subcortical volumes. J Neurovirol. 2010;16(6):435-44.

(2) Hua X, et al. Disrupted cerebral metabolite levels and lower nadir CD4 + counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatment. Neuroimage Clin. 2013; 3(3):132-42.

(3) Tisdall MD, Hess AT, et al. Volumetric navigators for prospective motion correction and selective reacquisition in neuroanatomical MRI. Magn Reson Med. 2012;68(2):389-99.

(4) van der Kouwe AJ, Benner T, Salat DH, Fischl B. Brain morphometry with multiecho MPRAGE. Neuroimage. 2008 Apr 1;40(2):559-69.

(5) Hess AT, Tisdall MD, Andronesi OC, Meintjes EM, van der Kouwe AJ. Real-time motion and B0 corrected single voxel spectroscopy using volumetric navigators. Magn Reson Med. 2011;66(2):314-23

(6) Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn. Reson. Med. 1993; 30, 672–679.

(7) Blüml S, Wisnowski JL, et al. Metabolic Maturation of the Human Brain From Birth Through Adolescence: Insights From In Vivo Magnetic Resonance Spectroscopy. Cerebral Cortex. 2013;23:2944–2955

(8) Wierenga L, Langen M et al. Typical development of basal ganglia, hippocampus, amygdala and cerebellum from age 7 to 24. Neuroimage. 2014 Aug 1;96:67-72.

Figures

Figure 1: Negative association of NAA with right accumbens volumes in HIV-infected children and controls, with no significant between-group difference in slope (p=0.1)

Figure 2: Negative association of NAA with left accumbens volumes in HIV-infected children and controls, with no significant between-group difference in slope (p=0.5)

Figure 3: Association of GluGln with total subcortical gray matter volumes in HIV-infected children and controls, with a significant between-group difference in slope (p=0.04)



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
4435