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Cerebral Metabolite Changes and Cognitive Clinical Correlates in Perinatally HIV-infected Young Adults

Manoj K Sarma¹, Margaret A Keller², Tamara Welikson³, Sathya Arumugam ¹, David E Michalik⁴, Irwin Walot⁵, Karin Nielsen-Saines⁶, Jaime Deville⁶, Andrea Kovacs⁷, Eva Operskalski⁷, Joseph Ventura⁸, and M. Albert Thomas¹

¹Radiological Sciences, UCLA School of Medicine, Los Angeles, CA, United States, ²Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States, ³Semel Institute for Neuroscience and Human Behavior, UCLA School of Medicine, Los Angeles, CA, United States, ⁴Infectious disease-Pediatrics, Miller Children's Hospital, Long Beach, CA, United States, ⁵Radiology, Harbor-UCLA Medical Center, Torrance, CA, United States, ⁶Pediatrics, UCLA School of Medicine, Los Angeles, CA, United States, ⁷Pediatrics, Keck School of Medicine of USC, Los Angeles, CA, United States, ⁸Psychiatry and Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA, United States

Synopsis

A recently implemented 5D echo-planar J-resolved spectroscopic sequence using 8x acceleration and compressed sensing reconstruction was evaluated in 7 perinatally infected and 8 healthy youths. Selected metabolite ratios with respect to Cr were detected bilaterally in the basal ganglia, anterior insular cortex, posterior insular cortex, frontal white and occipital/frontal gray regions of the two groups. Statistically significant differences were found between metabolite ratios (/Cr) of HIV-infected youing adults and healthy control subjects in the occipital gray N-acetylaspartate, right basal ganglia glutamine/glutamate, left anterior insular cortex choline, and left posterior insular cortex. Also, our pilot findings suggest a possible difference in energy metabolism between perinatally HIV-infected young adults and controls without HIV. The metabolite ratios correlated with neuropsychological test scores showing cognitive impairment as result of HIV-infection and/or long term ART.

Introduction

Perinatally HIV-infected young adults represent a highly unique population, having been infected at a time of immune compromise (in utero and at birth) and having experienced many years of antiretroviral therapy (ART)¹. Despite the success of ART², signs of neurocognitive compromise are common. Hence, non-invasive monitoring is needed to ensure early detection of neurocognitive disorders or other CNS abnormalities arising from HIV infection and its treatment. MRS can detect metabolic changes in cerebral metabolite resulting from HIV infections^3,4. One dimensional (1D) MRS has previously been used to investigate the differences between healthy children and pediatric patients with perinatal HIV^5-10. The purpose of this study was to evaluate changes between healthy and perinatally HIV-infected young adults using a semi-laser based accelerated five-dimensional (5D) echo-planar J-resolved spectroscopic imaging (EP-JRESI)¹¹ sequence. We also explored the relationship between brain metabolite ratios and cognitive performance as well as the clinical variables.

Materials and Methods:

We investigated seven perinatally HIV infected patients (age 21.1± 2.0years) and eight healthy controls (HC) (age 20.8± 1.8years). All data were collected on a Siemens 3T Prisma MRI scanner using a 16 channel head receive coil. The following parameters were used for water-suppressed 5D EP-JRESI: TR/TE=1.2s/40ms, voxel resolution=1.13x1.13x1.5cm³, 64 ∆t₁ increments, 512 bipolar echo pair, FOV=18x18x12cm³, 1 average, non-uniform sampling (NUS)= 12.5% with a scan time≈20min. A maximum echo sampling scheme was applied and after post-processing¹²bandwidth was ±250Hz along F₁ and 1190Hz along F₂. This was followed by a non water-suppressed scan with only the first t₁. The 5D EP-JRESI data were reconstructed as discussed previously¹¹. The undersampled data were reconstructed using a modified Split Bregman algorithm¹³ which solves the optimization problem, $$\min_{u} TV(u) \quad \text{s.t.} \|R\mathcal{F}u - f\|_2^2 < \sigma^2$$ where u is the reconstructed data, f is the undersampled data, $$$\sigma^2$$$ is an estimate of the noise variance, TV is the total variation norm, R is the NUS masking operator, and $$$\mathcal{F}$$$ is the Fourier transform operator. Acquired data were post-processed with a custom MATLAB-based program and metabolite ratios with respect to the 3.0 ppm creatine (Cr) peak were calculated using peak integration. The metabolite differences between the two groups were tested with a two-tailed t-test. To explore for any relationship between the metabolite ratios and clinical parameters along with the Neuropsychological (NP) Raw Test Scores data from a battery of tests including verbal fluency (FLUENCY), trail making test (TRAILS), stroop word score (STROOP WORDS), and WMS-III spatial span (WMS) a Pearson correlation was performed on the patient data from the regions where we found metabolite differences. All statistical analysis was done using the SPSS software.

Results:

Fig. 1(A) shows the PRESS-localized volume of interest (VOI) on a T₁-weighted axial brain MRI of a 20-year-old HIV-infected youth. Representative 2D J-resolved spectra extracted from the right occipital gray (ROG) regions of the same subject is shown in Figure 1(B). Fig. 2 and Fig. 3 show selected metabolite ratios with respect to Cr for the two groups. Statistically significant differences were found between HIV-infected young adults and HC subjects in the occipital gray (OG) N-acetylaspartate(NAA)/Cr (1.86[0.35] vs 2.23[0.28]), right basal ganglia (RBG) Glx/Cr (1.80[0.42] vs 2.53[0.59]), left anterior insular cortex (LAIC) choline(Cho)/Cr (0.34[0.07] vs 0.26[0.06]), and left posterior insular cortex (LPIC) Cho/Cr (0.34[0.05] vs 0.27[0.05]) ratios. Table 2 shows the results from the correlation analysis between the metabolite ratios versus the clinical and NP tests.

Discussion:

Our pilot data showed increased Glx/Cr, NAA/Cr and decreased Cho/Cr in agreement with some of the previous studies in perinatally HIV-infected children^14-16. Assuming the mechanisms for glutamate (Glu) transportation and uptake are unhindered, an increase in Glu can cause increases in glutamine (Gln) and increased asparate which indirectly may cause NAA to increase¹⁴. Both Glx and NAA have been reported to decrease in in different regions of the brain in adults and in children^15-18 when neurological disorders were present. Our findings suggest a possible difference in energy metabolism between perinatally HIV-infected young adults despite many years of therapy. Also, to be noted that 3 of the 7 HIV-infected youth had a diagnosis of HIV encephalopathy. The negative and positive correlations of CD4 count with NAA and Cho respectively in HIV youth are reflective of our finding in metabolite changes. The metabolite correlation with NP scores showed cognitive impairment as result of HIV-infection and/or long term ART.

Conclusion:

Our findings are indicative of an abnormal energy metabolism in the brain of the perinatally HIV-infected young adults despite long term A=RT. Future studies using a larger sample size are required to further authenticate the observations of the current study.

Acknowledgements

This research was supported by two NIH grants: 1R21-NS090956 (PI: Sarma) and 5R21NS080649-02 (PI: Thomas). Authors thank Z. Iqbal for his help.

References

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Figures

Fig. 1: (A) T1-weighted axial MRI of a 20-year-old HIV-infected youth with the white box indicating the PRESS localized VOI, (B) selected 2D J-resolved spectrum extracted from the right occipital gray (voxel in yellow).

Fig. 2: Bar graphs showing mean metabolite ratios (±SD) of NAA and Cho with respect to Cr in different brain regions for the two groups: healthy controls (HC) and perinatally HIV-infected youth. *Significant at the 0.05 level. RBG=right basal ganglia, LBG=left basal ganglia, OG=occipital gray, RAIC=right anterior insular cortex, RPIC=right posterior insular cortex, LAIC=left anterior insular cortex, LPIC=left posterior insular cortex, RFW= right frontal white, LFW=left frontal white.

Fig. 3: Bar graphs showing mean metabolite ratios (±SD) of mI and Glx (glutamate, Glu + glutamine, Gln) with respect to Cr in different brain regions of healthy controls (HC) and perinatally HIV-infected young adults. *Significant at the 0.05 level.

Table 1: Pearson Correlation between the metabolite ratios with clinical and NP parameters significant at 0.05* level.

Proc. Intl. Soc. Mag. Reson. Med. 25 (2017)

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