Structural and functional brain imaging in acute HIV

Abstract

Background: HIV RNA is identified in cerebrospinal fluid (CSF) within eight days of estimated viral exposure. Neurological findings and impaired neuropsychological testing performance are documented in a subset of individuals with acute HIV infection (AHI). The purpose of this study was to determine whether microstructural white matter and resting-state functional connectivity (rsFC) are disrupted in AHI.

Methods: We examined 49 AHI (100% male; mean age = 30 ± SD 9.9) and 23 HIV-uninfected Thai participants (78% male; age = 30 ± 5.5) with diffusion tensor imaging (DTI) and rsFC acquired at 3 Tesla, and four neuropsychological tests (summarized as NPZ-4). MRI for the AHI group was performed prior to combination antiretroviral treatment (ART) in 26 participants and on average two days (range:1-5) after ART in 23 participants. Fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivity (RD) were quantified for DTI. Seed-based voxelwise rsFC analyses were completed for the default mode (DMN), fronto-parietal, and salience and 6 subcortical networks. rsFC and DTI analyses were corrected for family-wise error, with voxelwise comparisons completed using t-tests. Group-specific voxelwise regressions were conducted to examine relationships between imaging indices, HIV disease variables, and treatment status.

Results: The AHI group had a mean (SD) CD4 count of 421(234) cells/mm³ plasma HIV RNA of 6.07(1.1) log₁₀ copies/mL and estimated duration of infection of 20(5.5) days. Differences between AHI and CO groups did not meet statistical significance for DTI metrics. Within the AHI group, voxelwise analyses revealed associations between brief exposure to ART and higher FA and lower RD and MD bilaterally in the corpus callosum, corona radiata, and superior longitudinal fasciculus (p < 0.05). Diffusion indices were unrelated to clinical variables or NPZ-4. The AHI group had reduced rsFC between left parahippocampal cortex (PHC) of the DMN and left middle frontal gyrus compared to CO (p < 0.002). Within AHI, ART status was unrelated to rsFC. However, higher CD4 cell count associated with increased rsFC for the right lateral parietal and PHC seeds in the DMN. Direct associations were noted between NPZ-4 correspond to higher rsFC of the bilateral caudate seed (p < 0.002).

Conclusions: Study findings reveal minimal disruption to structural and functional brain integrity in the earliest stages of HIV. Longitudinal studies are needed to determine if treatment with ART initiated in AHI is sufficient to prevent the evolution of brain dysfunction identified in chronically infected individuals.

Fig. 1

No statistically different DTI indices between AHI and HIV uninfected controls: AHI exhibited no statistically significant differences in DTI metrics (FA, MD, RD, AD) compared to uninfected controls. Statistical map shown overlaid on tract based skeleton mask where comparisons were made in cyan (no voxels indicated p < 0.05, corrected for family wise error).

Fig. 2

Reduced rsFC in AHI versus uninfected controls. AHI exhibited reduced rsFC between left parahippocampal cortex (L PHC) of the default mode network and left middle frontal gyrus. Images from left to right: L PHC rsFC for the AHI group; L PHC rsFC for the uninfected control group; Group difference map showing significantly reduced connectivity in AHI as compared with uninfected controls (AHI-Controls) (p < 0.001 uncorrected, pFWE < 0.002, *significant after Bonferroni-correction). Results are displayed on the group average structural MRI in MNI template space. Color bar indicates uncorrected t values.

Fig. 3

Blood biomarkers and neuropsychological performance associate with rsFC in AHI. A. Top, Greater rsFC between right lateral parietal seed and left precuneus associated with greater CD4 counts; Bottom, scatterplot shows the relationship between right lateral parietal-left precuneus connectivity values and CD4 count. B. Top, Greater rsFC between right parahippocampal seed and right inferior occipital gyrus associated with greater CD4 count; Bottom, scatterplot shows the relationship between right parahippocampal-right inferior occipital connectivity values and CD4 count. C. Top, Greater rsFC between the bilateral dorsal caudate seed and right inferior parietal lobe associated with greater NPZ-4 global scores; Bottom, scatterplot shows the relationship between bilateral dorsal caudate-right inferior parietal connectivity values and NPZ-4 global scores. p < 0.001 uncorrected, p_FWE < 0.002, *significant after Bonferroni-correction. Results are displayed on the group average structural MRI in MNI template space.