White matter microstructure among perinatally HIV-infected youth: A diffusion tensor imaging study
Manoj Kumar Sarma1, Margaret Keller2, Rajakumar Nagarajan1, David E Michalik3, Judy Hayes2, Karin Nielsen-Saines4, Jaime Deville4, Joseph A Church5, Irwin Walot6, and M. Albert Thomas1

1Radiological Sciences, UCLA School of Medicine, Los angeles, Los Angeles, CA, United States, 2Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, United States, 3Infectious disease-Pediatrics, Miller’s Children’s Hospital of Long Beach, Long Beach, CA, United States, 4Pediatrics, UCLA School of Medicine, Los angeles, Los Angeles, CA, United States, 5Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, United States, 6Radiology, Harbor-UCLA Medical Center, Torrance, CA, United States

Synopsis

DTI was used to derive in vivo tissue status measurements of subcortical brain regions that are vulnerable to injury in perinatally HIV-infected youths. Quantitative measurements, including the mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were determined in of the whole brain in 12 well-characterized HIV youths and in 12 healthy control subjects. We observed widespread brain regions with increased AD values in perinatally HIV-infected youths compared to healthy controls, indicating axonal changes. We also observed increased FA, MD and RD. To confirm these findings a correlation study with neurodevelopement and neurocognitive changes as well as ART effect is needed. Understanding the impact of HIV disease severity on white matter integrity provides potentially useful clinical tools for evaluating ART efficacy during a dynamic period of brain development.

Purpose/Introduction:

As perinatally infected youth survive to adolescence and adulthood due to successful antiretroviral therapy (ART)1, noninvasive imaging techniques are needed to provide early detection of deterioration in brain health. Since these patients acquired HIV at a time of relative immune compromise (in utero and at birth), signs of neurocognitive compromise are common2. Although HIV infection has been associated with abnormal white matter (WM) microstructure in adults3,4,5, more information is needed about the impact of chronic HIV and HIV treatment in perinatally HIV-Infected youths. In this study, we investigated the WM microstructure integrity in perinatally HIV-infected youth with four diffusion tensor imaging (DTI) derived parameters, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) using voxel-based morphometry (VBM)6. We hypothized that there will be alteration in FA, MD, AD, and RD values in different brain regions of perinatally HIV-infected youth compared to healthy controls.

Materials and Methods:

We investigated twelve parinatally HIV infected patients (age 17.7± 2.7 years, range 13.6-22.4) and twelve healthy controls (HC) (age 19.2y± 2.3, range 13.4-23.6) who underwent MRI/MRS using 16 channel head phased array ‘receive’ coil. All subjects gave informed consent according to an institutionally approved research protocol. A Siemens 3T MRI scanner was used and DTI was performed using a single-shot multi-section spin-echo echo-planar pulse sequence [TR=10,000ms; TE=90ms; average=4] in the axial plane, with matrix size= a 130x130, FOV=256x256mm2, slice thickness=2.0mm, 75 slices. For each slice, diffusion gradients were applied along 64 directions (b=0, 700 sec/mm2).

The statistical parametric mapping package SPM127, DTI-Studio8, MRIcroN9, and custom MATLAB-based software were used for evaluation of images, data processing, and analyses. The diffusion tensor was calculated at each voxel, from which whole-brain maps of FA, MD, AD and RD were derived. DTI maps and b0 images from each series were realigned to remove any possible misalignment. The normalization parameters derived from b0 images were used to normalize DTI maps followed by smoothing with an 8 mm Gaussian filter. VBM6 was then used to define regional differences in FA, MD, AD and RD values between patients and controls using an ANCOVA model with age and gender as co-variates. We onset our results at a height threshold of p < 0.001 uncorrected and an extent threshold of 10 voxels.

Results:

Figure 1 shows regions with significantly increased MD values in patients compared with HC. Significant changes were observed in right cerebral white matter, and middle singulate gyrus. Figure 2 shows regions of increased FA values in patients. The areas that showed increased FA values are bilateral cerebral white matter, left: precentral, superior frontal, supramarginal gyrus, and right: precuneus, precentral gyrus, occipital fusiform gyrus. Figure 3 and 4 shows regions of increased AD and RD values in HIV patients relative to control subjects. Multiple brain sites in HIV patients showed widespread increased AD values, including left: cerebral white matter, supplementary motor cortex, middle cingulate gyrus, superior frontal gyrus, precentral gyrus, middle frontal gyrus, anterior cingulate gyrus, and superior frontal gyrus medial segment. After using false discovery rate correction of 0.05 the significance remained. Increased RD was observed in the right cerebral white matter, right middle cingulate gyrus, left opercular part of the inferior frontal gyrus, left middle frontal gyrus. No regions showed decreased FA, MD, AD and RD values in patients compared to control subjects.

Discussion:

AD is thought to reflect water diffusivity parallel to axonal fibers and increased AD10,11 to be linked to axonal damage. The findings with MD, RD parallel those with adults12. Both lower and higher FA has been reported in HIV-infected adults13-15. Our finding of increased FA may reflect increases in myelination in those regions. However, if myelinated nerve sheaths are affected in a patient population, it is possible that neurobiological compensation could lead to myelin hyperplasia, and higher fractional anisotropy could be related to poorer cognition16. Also, it may be the effect of ART as these HIV youths have been on medication for long. Radial diffusivity may be a proxy for myelination, with higher radial diffusivity reflecting less myelination of tracts12. Higher mean diffusivity, observed in HIV youth may represent neurodegeneration of white matter17.

Conclusion:

Our results showed widespread brain regions with increased AD values in perinatally HIV-infected youths compared to healthy controls, indicating axonal changes. To confirm these findings a correlation study with neurodevelopement and neurocognitive changes as well as ART effect is needed. Understanding the impact of HIV disease severity on white matter integrity provides potentially useful clinical tools for evaluating ART efficacy.

Acknowledgements

This research was supported by National Institute of Health (NIH) grant 1R21NS08064901A1.

References

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17. Uban KA, Herting MM, Williams PL,et al. White matter microstructure among youth with perinatally acquired HIV is associated with disease severity. AIDS. 2015;29(9):1035-44.

Figures

Figure 1: Brain regions with significantly increased MD values in HIV patients vs. healthy control subjects (uncorrected threshold, P = 0.001) are shown in the 2D axial, sagittal, and coronal views. All brain images are in neurological convention (L = left, R = right), and the color scale shows t-statistic values.

Figure 2: Brain sites with significantly increased FA values in HIV patients vs. control subjects. Figure conventions are the same as for Figure 1.

Figure 3: Brain sites with significantly increased AD values in HIV patients vs. control subjects. Figure conventions are the same as for Figure 1.

Figure 4: Brain regions with significantly increased RD values in HIV patients vs. control subjects are shown in glass brain format with projections across the 3D onto the 2D axial, sagittal, and coronal views



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