Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity

Abstract

Objective: Resting-state functional connectivity MRI (rs-fcMRI) may provide insight into the neurophysiology of HIV and aging.

Methods: In this cross-sectional study, we used rs-fcMRI to investigate intra- and internetwork connectivity among 5 functional brain networks in 58 HIV-infected (HIV+) participants (44% receiving highly active antiretroviral therapy) and 53 HIV-uninfected (HIV-) controls. An analysis of covariance assessed the relationship among age, HIV laboratory markers, or degree of cognitive impairment and brain networks.

Results: Individuals who were HIV+ had decreased rs-fcMRI intranetwork correlations in the default mode (DMN, p = 0.01), control (CON, p = 0.02), and salience (SAL, p = 0.02) networks, but showed no changes in the sensorimotor (SMN) or dorsal attention (DAN) network. Compared with HIV- controls, participants who were HIV+ had a significant loss of internetwork correlations between the DMN-DAN (p = 0.02), trending loss in DMN-SAL (p = 0.1) and CON-SMN (p = 0.1), and trending increase in CON-SAL (p = 0.1). Neither HIV markers (plasma HIV viral load or CD4(+) cell count) nor degree of cognitive impairment correlated with rs-fcMRI measures. Aging correlated with a decrease in the magnitude of intranetwork functional connectivity within the DMN (p = 0.04) and SAL (p = 0.006) and with decreased magnitude of internetwork functional connectivity between DMN and SAL (p = 0.009) for both HIV+ and HIV- participants. No interaction was observed between HIV and aging.

Conclusions: HIV and aging may cause independent decreases in rs-fcMRI. HIV may lead to a baseline decrease in brain function similar to deterioration that occurs with aging.

Figure 1. DMN rs-fcMRI connectivity (HIV−) − (HIV+)

Whole-brain blood oxygen level–dependent resting-state functional connectivity (rs-fc) correlation maps using the right lateral parietal cortex as a seed region: (A) HIV uninfected (HIV−), (B) HIV infected (HIV+), and (C) difference between HIV− and HIV+ subjects. Using a threshold of p < 0.01 and a voxel cluster size of 5, a reduction in functional correlations was seen within default mode network (DMN) regions including the medial prefrontal cortex (green oval) and posterior cingulate cortex (purple oval; DMN). A loss of anticorrelations was seen in anterior portions of the right lateral parietal cortex belonging to the salience network (red circles).

Figure 2. Intra- and internetwork rs-fcMRI connectivity (HIV−) − (HIV+)

Intranetwork composite correlation values for each of the 5 major networks (DMN, DAN, CON, SAL, SMN) were computed for each HIV-infected (HIV+) (red) and HIV-uninfected (HIV−) (blue) subject by averaging all within-network correlation pairs for each network. Internetwork composite scores were computed by averaging between-network correlation pairs. ** Significant effects (p < 0.05). * Trend-level (p < 0.1) effects. Among the intranetwork composites, DMN (p = 0.006), CON (p = 0.005), and SAL (p = 0.03) showed significant decreases between the 2 groups. Among the internetwork composites, DMN-DAN (p = 0.02), and trending loss in DMN-SAL (p = 0.1), SAL-CON (p = 0.1), and CON-SMN (p = 0.1). A trending increase in positive internetwork correlations was observed in CON-SAL (p = 0.1). CON = control network; DAN = dorsal attention network; DMN = default mode network; rs-fcMRI = resting-state functional connectivity MRI; SAL = salience; SMN = sensorimotor network.

Figure 3. Independent effects of HIV and aging on rs-fcMRI correlations

Parallel best-fit lines with differing intercepts model the effects of HIV and aging on intranetwork composite correlation value in both (A) the default mode network (DMN) and (B) the salience (SAL) network showing that the effects of HIV and aging are independent for each network. (C) Similar lines model the independent effects of HIV and aging on internetwork DMN-SAL anticorrelation. For all composite values, the magnitude of functional correlations diminishes toward zero (dashed line) due to HIV and aging. However, no interaction was seen between HIV and aging.