Disrupted brain networks in the aging HIV+ population

Abstract

Antiretroviral therapies have become widely available, and as a result, individuals infected with the human immunodeficiency virus (HIV) are living longer, and becoming integrated into the geriatric population. Around half of the HIV+ population shows some degree of cognitive impairment, but it is unknown how their neural networks and brain connectivity compare to those of noninfected people. Here we combined magnetic resonance imaging-based cortical parcellations with high angular resolution diffusion tensor imaging tractography in 55 HIV-seropositive patients and 30 age-matched controls, to map white matter connections between cortical regions. We set out to determine selective virus-associated disruptions in the brain's structural network. All individuals in this study were aged 60-80, with full access to antiretroviral therapy. Frontal and motor connections were compromised in HIV+ individuals. HIV+ people who carried the apolipoprotein E4 allele (ApoE4) genotype-which puts them at even greater risk for neurodegeneration-showed additional network structure deficits in temporal and parietal connections. The ApoE4 genotype interacted with duration of illness. Carriers showed greater brain network inefficiencies the longer they were infected. Neural network deficiencies in HIV+ populations exceed those typical of normal aging, and are worse in those genetically predisposed to brain degeneration. This work isolates neuropathological alterations in HIV+ elders, even when treated with antiretroviral therapy. Network impairments may contribute to the neuropsychological abnormalities in elderly HIV patients, who will soon account for around half of all HIV+ adults.

FIG. 1.

The proportion of fibers connecting cortical regions is altered in the presence of human immunodeficiency virus (HIV). The average connectivity matrices for (A) 30 HIV− subjects and (B) for 55 HIV+ participants are shown; (C) controlling for effects of age and sex, HIV+ participants show lower fiber densities in the left and right superior frontal cortices, and in the connections between the right superior frontal cortex and the right precentral cortex, the right precentral cortex and right posterior cingulate, the right posterior cingulate and left superior frontal cortex, and the right inferior parietal and right isthmus of the cingulate. Tested connections (i.e., those present in >50% of individuals) are dark gray; (D) the significant intercortical connections are shown again (blue lines). Nonsignificant tested connections are in black. The connection strength (defined as the total fiber density of connections for each region) is significantly lower in the presence of the virus (green spheres) in the left paracentral, the left and right posterior cingulate, the left and right superior frontal, and the right caudal anterior cingulate. In the top view, the left hemisphere is shown on the left. Larger spheres indicate greater effect sizes (lower p-values).

FIG. 2.

HIV+ individuals who also carry a copy of the apolipoprotein E4 (ApoE4) Alzheimer's disease risk allele (N=9) have impaired cortical connections, compared to HIV+ people who do not carry the ApoE4 risk allele (N=46). The connection between the right inferior and medial temporal gyri, as well as the connection between the left and right precuneus, shows significantly reduced FA (shown as blue lines connecting those nodes). Also the local efficiency of the connections to and from the left precentral gyrus, left precuneus, and right superior parietal cortices are significantly reduced (green spheres are proportional in size to –log(p), the negative logarithm of the p-value of the association).

FIG. 3.

(A) ApoE4 status and its interaction with HIV duration together show associations with the integrity in connections (blue lines) between the left supramarginal and precentral cortex, the left supramarginal cortex and left insula, and the right isthmus of the cingulate with the posterior cingulate. The mean fiber integrity of the tracts of the right superior temporal cortex and supramarginal cortex also show ApoE4 effects. The nodal efficiency (green spheres) of the left precentral gyrus, the left precuneus, left superior temporal cortex, and the right superior parietal and right supramarginal cortices, additionally show a reduction when jointly evaluating ApoE4 and the interaction between ApoE4 and the self-reported duration of infection. (B) Individually, the interaction term (when controlling for the effect of ApoE4) showed reduced fiber integrity in the connection between the left supramarginal cortex and the precentral cortex. The FA and efficiency are also reduced in the right supramarginal cortex. Larger spheres are associated with greater effect sizes (lower p-values). The left hemisphere is colored blue-green, and the right hemisphere is colored red-yellow.