Lower cognitive reserve in the aging human immunodeficiency virus-infected brain

Abstract

More HIV-infected individuals are living longer; however, how their brain function is affected by aging is not well understood. One hundred twenty-two men (56 seronegative control [SN] subjects, 37 HIV subjects with normal cognition [HIV+NC], 29 with HIV-associated neurocognitive disorder [HAND]) performed neuropsychological tests and had acceptable functional magnetic resonance imaging scans at 3 Tesla during tasks with increasing attentional load. With older age, SN and HIV+NC subjects showed increased activation in the left posterior (reserve, “bottom-up”) attention network for low attentional-load tasks, and further increased activation in the left posterior and anterior (“top-down”) attention network on intermediate (HIV+NC only) and high attentional-load tasks. HAND subjects had only age-dependent decreases in activation. Age-dependent changes in brain activation differed between the 3 groups, primarily in the left frontal regions (despite similar brain atrophy). HIV and aging act synergistically or interactively to exacerbate brain activation abnormalities in different brain regions, suggestive of a neuroadaptive mechanism in the attention network to compensate for declined neural efficiency. While the SN and HIV+NC subjects compensated for their declining attention with age by using reserve and “top-down” attentional networks, older HAND subjects were unable to compensate which resulted in cognitive decline.

Introduction

HIV-infected individuals are living longer because of effective combination antiretroviral therapy (cART); hence, half of the HIV-infected population in the United States will be older than 50 years by 2015 (Kirk and Goetz, 2009). Chronic HIV infection is associated with neuroinflammation, glial activation, and neuronal apoptosis (Gray et al., 2001; Kaul et al., 2001), which might lead to HIV-associated neurocognitive disorders (HAND) (Antinori et al., 2007). Despite viral suppression with cART, HIV patients continue to show ongoing neuroinflammation, with increased diffusivity on diffusion tensor imaging over time (Chang et al., 2008b).

With cART, HIV-associated dementia decreased from 7% to 1%, but the milder forms of HAND, including asymptomatic neurocognitive impairment and mild neurocognitive disorder, remain common—up to 50% (Heaton et al., 2011; McArthur et al., 2010). HAND subjects show deficits in attention, executive function, fluency, learning, memory, and slower psychomotor or motor speed (Heaton et al., 2011). Similarly, normal brain aging is associated with glial activation (Terry et al., 1987) and decline in the same cognitive domains (Goh et al., 2012; Mazaux et al., 1995). These cognitive changes might be related partly to decline in dopaminergic function that occurs with HIV-infection (Berger et al., 1994, 2000; Chang et al., 2008a) and aging (Volkow et al., 1996, 1998; Wang et al., 2004). In addition, structural brain changes occur with normal aging throughout the brain, but HIV-infected individuals showed either premature or accelerated age-related brain atrophy particularly in the subcortical brain regions, although the brain regions affected by aging and HIV-infection might be distinct (Holt et al., 2012). These structural brain changes might contribute to cognitive deficits in HIV subjects. Therefore, aging might lead to additional or exacerbated cognitive deficits in HIV-infected subjects.

HIV patients with normal cognition (HIV+NC) or mild dementia showed hypoactivation of the normal attention network but increased usage of reserve brain regions (adjacent or contralateral to the normal network) during attention-requiring tasks, such as those that require working memory (Chang et al., 2001; Ernst et al., 2002; Melrose et al., 2008), tracking moving targets (Chang et al., 2004b; Ernst et al., 2009), mental rotation (Schweinsburg et al., 2012), and even for memory encoding (Castelo et al., 2006). However, despite stable cART, HIV+NC subjects showed further increased brain activation during visual attention over 1 year, suggesting increased usage of brain reserve (Ernst et al., 2009). HIV patients also showed lower than normal resting cerebral blood flow across the age span (Ances et al., 2010), slower than normal return to baseline hemodynamic response function (HRF) (Juengst et al., 2007), and lesser functional connectivity between the striatal and frontal regions (Melrose et al., 2008).

Changes in brain activation also occur with normal aging. For example, older age is associated with increased hippocampal activation (Adler et al., 2001; Laurienti et al., 2002) and decreased parietal and prefrontal activation (Grossman et al., 2002; Rypma and D'Esposito 2000) during working memory tasks. However, older subjects who performed better on a category learning task had greater parietal activation (Fera et al., 2005). In addition, greater hippocampal atrophy was associated with greater activation of the right prefrontal cortex (Persson et al., 2006). Furthermore, age-related decline in cognitive abilities might result in dedifferentiation, difficulty in recruiting specialized cognitive networks leading to activation of nonspecific neuronal resources (Li and Lindenberger 1999; Voss et al., 2008), or compensation and recruitment of additional cognitive reserves to counteract cognitive decline (Cabeza et al., 2002). This is further demonstrated by the findings that only older adults with higher performance show evidence of compensation, and those with lower performance show no evidence of compensation and inefficient use of recruited networks (Cabeza et al., 2002). Therefore, these variable brain activation changes associated with normal aging might also be seen in the aging HIV-infected individuals.

Whether age and HIV interact on brain activation during attention-requiring tasks is unknown, and was evaluated in this study. To assess how the normal aging brain or the HIV-infected aging brain might differ in terms of their cognitive reserve capacity, we employed a well validated visual attention tasks with increasing task difficulty or attentional load (tracking 2 balls, 3 balls, and 4 balls). These tasks require both bottom-up visual attention (primarily in the inferior parietal regions, to detect the balls which are salient stimuli), as well as top-down control attention (in the dorsal parietal and prefrontal regions, to track the moving balls) (Jovicich et al., 2001). Previous studies showed that HIV-infected subjects showed greater load-dependent activation of the top-down attention network than seronegative (SN) healthy control subjects (Chang et al., 2004b). Based on the aforementioned studies, we hypothesized that, compared with SN subjects, HIV+NC subjects would show greater than normal age-dependent increases in activation of the reserve bottom-up network (parietal regions) on the simpler task, and additional increased activation of the top-down network (dorsal parietal and prefrontal regions) with increasing attentional load, whereas subjects with HAND would be unable to compensate, especially with higher attentional load, and show steeper age-dependent decreases in activation in both attention networks (prefrontal and parietal regions).