Regular articleLower cognitive reserve in the aging human immunodeficiency virus-infected brain
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).
Section snippets
Research participants
A group of 128 men fulfilling study criteria completed the protocol after signing a written consent form approved by our institution. Only men were studied because brain activation on attention tasks varies with sex (Speck et al., 2000). Sixty-nine HIV-infected individuals [39 HIV+NC, 30 HAND] and 59 SN control subjects with similar age ranges and education were evaluated with detailed clinical assessments, including neuropsychological tests. Three SN control subjects and 2 HIV+NC subjects who
Subject characteristics and cognitive function
Table 1 shows that SN and the 2 HIV groups were similar in age and age range, and had similar hematocrit (which might affect BOLD signals) (Levin et al., 2001). However, the HIV subjects had more depressive symptoms (on Center for Epidemiological Studies-depression scale) than SN control subjects. The 2 HIV groups had similar HIV disease severity, as assessed by CD4 count, nadir CD4 count, plasma viral load, and similar proportion of subjects with undetectable viral loads, duration of HIV
Discussion
This study found: (1) healthy SN control subjects showed age-dependent increases in activation primarily in the left temporal and parietal (bottom-up attention) regions with low attentional load but additionally required the left frontal (top-down attention) region for high attentional load. (2) HIV+NC subjects had age-dependent increases in activation primarily in the left attention network during the 2-ball task, but showed load-dependent decrease rather than the normal increased activation
Disclosure statement
The authors have no actual or potential conflicts of interest.
All study participants completed the protocol after signing a written consent form approved by our institution.
Acknowledgements
The authors thank the research participants who enrolled in this study, all of our clinical and technical research staff who helped with the data collection, and the community HIV care providers (especially Drs Drew Kovach, Cyril Goshima, and Jennifer Frank), who referred many of their patients to our study. We thank Dr Eric Miller for his valuable advice on the cognitive testing. This work was supported by the National Institute on Mental Health (2R01-MH061427), the National Institute on Drug
References (65)
- et al.
Aging gracefully: compensatory brain activity in high-performing older adults
Neuroimage
(2002) - et al.
Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load
Cortex
(2010) - et al.
Impact of apolipoprotein E epsilon4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging
Neuroimage
(2011) - et al.
A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age
Neuroimage
(2004) - et al.
Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse
Neuroimage
(2008) - et al.
Age-related changes in working memory during sentence comprehension: an fMRI study
Neuroimage
(2002) - et al.
Alterations in the hemodynamic response function in cognitively impaired HIV/AIDS subjects
J. Neurosci. Methods
(2007) - et al.
Influence of baseline hematocrit and hemodilution on BOLD fMRI activation
Magn. Reson. Imaging
(2001) - et al.
Compromised fronto-striatal functioning in HIV: an fMRI investigation of semantic event sequencing
Behav. Brain Res.
(2008) - et al.
Brain metabolism and cognitive impairment in HIV infection: a 3-T magnetic resonance spectroscopy study
Magn. Reson. Imaging
(2010)
Inflammation markers in relation to cognition in a healthy aging population
J. Neuroimmunol.
Different activation patterns for working memory load and visual attention load
Brain Res.
Practice-induced changes of brain function during visual attention: a parametric fMRI study at 4 Tesla
Neuroimage
Dedifferentiation in the visual cortex: an fMRI investigation of individual differences in older adults
Brain Res.
CSF neurofilament protein (NFL)–a marker of active HIV-related neurodegeneration
J. Neurol.
Age-related changes in regional activation during working memory in young adults: an fMRI study
Synapse
HIV infection and aging independently affect brain function as measured by functional magnetic resonance imaging
J. Infect. Dis.
Updated research nosology for HIV-associated neurocognitive disorders
Neurology
Cerebrovascular changes in the basal ganglia with HIV dementia
Neurology
Cerebrospinal fluid dopamine in HIV-1 infection
AIDS
Age-related differences in neural activity during memory encoding and retrieval: a positron emission tomography study
J. Neurosci.
Altered hippocampal-prefrontal activation in HIV patients during episodic memory encoding
Neurology
Cerebral metabolite abnormalities correlate with clinical severity of HIV-cognitive motor complex
Neurology
Neural correlates of attention and working memory deficits in HIV patients
Neurology
Adaptation of the attention network in human immunodeficiency virus brain injury
Ann. Neurol.
Greater than age-related changes in brain diffusion of HIV patients after 1 year
J. Neuroimmune Pharmacol.
Microglia in the aging brain
J. Neuropathol. Exp. Neurol.
Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients
Neurology
Lower brain glutamate is associated with cognitive deficits in HIV patients: a new mechanism for HIV-associated neurocognitive disorder
J. Magn. Reson. Imaging
Declined neural efficiency in cognitively stable human immunodeficiency virus patients
Ann. Neurol.
Neural mechanisms underlying probabilistic category learning in normal aging
J. Neurosci.
Top-down modulation and normal aging
Ann. N. Y. Acad. Sci.
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