Mapping white matter integrity in elderly people with HIV

Abstract

People with HIV are living longer as combination antiretroviral therapy (cART) becomes more widely available. However, even when plasma viral load is reduced to untraceable levels, chronic HIV infection is associated with neurological deficits and brain atrophy beyond that of normal aging. HIV is often marked by cortical and subcortical atrophy, but the integrity of the brain's white matter (WM) pathways also progressively declines. Few studies focus on older cohorts where normal aging may be compounded with HIV infection to influence deficit patterns. In this relatively large diffusion tensor imaging (DTI) study, we investigated abnormalities in WM fiber integrity in 56 HIV+ adults with access to cART (mean age: 63.9 ± 3.7 years), compared to 31 matched healthy controls (65.4 ± 2.2 years). Statistical 3D maps revealed the independent effects of HIV diagnosis and age on fractional anisotropy (FA) and diffusivity, but we did not find any evidence for an age by diagnosis interaction in our current sample. Compared to healthy controls, HIV patients showed pervasive FA decreases and diffusivity increases throughout WM. We also assessed neuropsychological (NP) summary z-score associations. In both patients and controls, fiber integrity measures were associated with NP summary scores. The greatest differences were detected in the corpus callosum and in the projection fibers of the corona radiata. These deficits are consistent with published NP deficits and cortical atrophy patterns in elderly people with HIV.

Keywords: HIV; brain integrity; cART; cognition; diffusion tensor imaging; white matter.

Figure 1

FA, MD, RD, and AD analyses in HIV+ patients and controls. Here we show cumulative distribution function (CDF) plots of the distribution of the P‐values obtained from voxel‐wise linear regressions, which are subjected to multiple comparisons correction using standard FDR (Benjamini and Hochberg, 1995). (a) When comparing HIV+ patients to controls, the RD effects were much greater as denoted by the higher critical P‐values controlling the FDR (i.e., the highest non‐zero x‐coordinate where the CDF crosses the y = 20x line). When examining NPZ (b) and sNPZ (c) correlations, effects on FA were the greatest, followed by RD. These distributions were obtained from highly anisotropic white matter in voxels within the boundaries of the MDT mask thresholded at FA > 0.2 where the power is greater to detect differences. All anisotropy and diffusivity maps show FDR significant results. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 2

Statistical maps show where HIV+ patients differ from controls in their fractional anisotropy (a), and mean, radial and axial diffusivity (b–d). Rather than show P‐values for the group differences, which are higher where FA is higher, these maps show beta‐values (non‐normalized slope of the regression, representing the mean group difference in each imaging measure) within regions with significant differences between HIV+ patients and healthy controls (corrected P < 0.05; Langers et al., 2007). Both larger negative FA beta‐values — shown in (a) in red — and larger positive MD, RD, and AD beta‐values — shown in (b–c) in blue — suggest a decrease in fiber integrity in HIV+ relative to controls. Prominent differences were found in the corpus callosum, and in projection fibers extending throughout the corona radiata. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

These maps show that cognitive performance is related to detectable differences in fractional anisotropy (a), and mean, radial, and axial diffusivity (b–d) in the entire cohort, including both HIV+ patients and controls. These maps show beta‐values (non‐normalized slope of the regression in units of imaging measure per unit difference in cognitive z‐scores) within regions that significantly correlate with the short global NP summary z‐scores (sNPZ) in HIV+ and controls (corrected P < 0.05; Langers et al., 2007). The most notable differences were found in the corpus callosum and projection fibers extending throughout the corona radiata. Radial diffusivity shows widespread and robust associations, but all maps are significant after multiple comparisons correction via the searchlight FDR method. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

These maps show beta‐values of significant associations between diffusion measures and the global NP summary z‐scores (NPZ) in HIV+ patients (searchlight corrected P < 0.05; Langers et al., 2007). They are similar to those in Figure 2, but with a more general measure of cognitive performance. Strong associations are found in the corpus callosum, and commissural fibers extending throughout the corona radiata. (a) Areas of significance in FA; (b–d) Areas of significance in MD, RD, and AD, respectively. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 5

Venn diagram of ROIs from the HIV diagnosis regressions that were significantly associated with the age component, HIV diagnosis component, or both across any of the DTI measures (FA, MD, RD, AD). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]