Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study

Abstract

Advances in treatment have transformed human immunodeficiency virus (HIV) infection from an inexorable march to severe morbidity and premature death to a manageable chronic condition, often marked by good health. Thus, infected individuals are living long enough that there is a potential for interaction with normal senescence effects on various organ systems, including the brain. To examine this interaction, the brains of 51 individuals with HIV infection and 65 uninfected controls were studied using 351 magnetic resonance imaging and a battery of neuropsychological tests collected 2 or more times over follow-up periods ranging from 6 months to 8 years. Brain tissue regions of interest showed expected age-related decrease in volume; cerebrospinal fluid-filled spaces showed increase in volume for both groups. Although HIV-infected individuals were in good general health, and free of clinically-detectable dementia, several brain regions supporting higher-order cognition and integration of functions showed acceleration of the normal aging trajectory, including neocortex, which extended from the frontal and temporal poles to the parietal lobe, and the thalamus. Beyond an anticipated increase in lateral ventricle and Sylvian fissure volumes and decrease in tissue volumes (specifically, the frontal and sensorimotor neocortices, thalamus, and hippocampus) with longer duration of illness, most regions also showed accelerated disease progression. This accelerated loss of cortical tissue may represent a risk factor for premature cognitive and motor compromise if not dementia. On a more promising note, HIV-infected patients with increasing CD4 counts exhibited slower expansion of Sylvian fissure volume and slower declines of frontal and temporoparietal cortices, insula, and hippocampus tissue volumes. Thus, attenuated shrinkage of these brain regions, likely with adequate pharmacologic treatment and control of further infection, has the potential of abating decline in associated higher-order functions, notably, explicit memory, executive functions, self-regulation, and visuospatial abilities.

Introduction

Advances in antiretroviral treatment have transformed infection with the human immunodeficiency virus (HIV) and its sequelae, acquired immune deficiency syndrome (AIDS), from an inexorable march to severe morbidity and premature death to a manageable chronic condition, often marked by good health (Aberg et al., 2009, Holt et al., 2012, Justice, 2010). Young adults infected early in the epidemic age, however, face the cognitive and health challenges of normal aging burdened by the somatic, neurologic, and neuropsychological consequences of HIV and/or AIDS. One projection indicates that by 2015, more than half of HIV-infected individuals will be at least 50 years old (Luther and Wilkin, 2007). In addition, this cohort of long-infected, more than 50 years old HIV or AIDS patients is now being supplemented by a wave of newly infected elders (for sources, see Karpiak, 2011), with the incidence of first infections after the age of 50 years now accounting for 17% of new HIV or AIDS diagnoses (The AIDS Institute National HIV or AIDS and Aging Awareness Day Fact Sheet). Older individuals newly acquiring HIV infection are typically less likely than younger ones to seek treatment early, and thus initially present with lower CD4 counts and higher incidence of AIDS-defining events than those under the age of 50 years (Althoff et al., 2010). Although antiretroviral treatment (ART) regimens have allowed many HIV-infected individuals to maintain normal lives, increasing evidence indicates that the early viral assault, reflected in depleted CD4 counts (nadir CD4), leaves a persistent stigma on the brain (Jernigan et al., 2011, Pfefferbaum et al., 2012) and residual cognitive deficits (Valcour et al., 2006) even when current viral load remains suppressed and CD4 counts rise to healthy levels (Heaton et al., 2011).

More than 2 decades of cross-sectional magnetic resonance imaging (MRI) studies of HIV-infected groups have revealed structural volume deficits in various brain regions and tissue types relative to controls. Initial reports identified striatal volume deficits (Aylward et al., 1993). Early in the ART era, white matter volume deficits and ventricular and sulcal enlargement were observed (Stout et al., 1998), although greater gray than white matter volume deficits accompanied advanced Centers for Disease Control (CDC) symptom stage (Di Sclafani et al., 1997). Local cortical thinning, particularly frontal and temporal, was related to low CD4 cell count (Thompson et al., 2005) and high peripheral mononuclear cell load (Kallianpur et al., 2011). Although cognition has been shown to benefit from antiretroviral therapies (Heaton et al., 2011), there is evidence for potential neurotoxicity of long-term use of these potent pharmacotherapies (Ances et al., 2012, Becker et al., 2011b, Letendre et al., 2008). Brain structure-function relations are also reported, where poorer performance on cognitive or motor tests correlated with smaller regional brain volumes (Becker et al., 2011a, Castelo et al., 2007, Kuper et al., 2011, Paul et al., 2008, Pfefferbaum et al., 2006, Sullivan et al., 2011b, Thompson et al., 2005). HIV-infected adults who had experienced an AIDS-defining event had thinner primary sensory, motor, and premotor cortices (Thompson et al., 2005), smaller cortical volumes, larger total ventricular size (Cohen et al., 2010), and smaller corpora callosa (Pfefferbaum et al., 2006, Thompson et al., 2006). Further, HIV disease-related factors associated with greater volume abnormalities included: CD4 cell-count nadir, clinical staging, history of AIDS-defining events, infection age, and current age (Pfefferbaum et al., 2012).

Platelet decline across biannual examination in seropositive patients aged 50 years and older was predictive of extent of gray matter volume deficits (but not measures of white matter or cerebrospinal fluid [CSF] volumes) observed at a single MRI; curiously, greater CSF volumes correlated with higher CD4 counts (Ragin et al., 2011). Another cross-sectional MRI study of 251 HIV-infected individuals reported that lower nadir CD4 cell counts, higher current CD4 cell counts, detectable viral load, hepatitis C virus (HCV) infection, and longer ART exposure all predicted white matter and CSF volume abnormalities (Jernigan et al., 2011). Our finding that age at HIV infection was a significant unique predictor of smaller anterior cingulate volumes suggests a greater vulnerability of an older brain to the deleterious effects of the disease (Pfefferbaum et al., 2012).

Cross-sectional studies have been instrumental in identifying brain regions and systems that are affected in HIV infection and factors that might contribute to enhanced effects but remain limited to speculation about the potential interaction of these effects with aging and variables that change with disease progression or mitigation (e.g., Ances et al., 2012). A magnetic resonance spectroscopy (MRS) study reported local differences in brain-disease variable relations, where abnormally low metabolite levels of N-acetylaspartate, a marker of neuronal integrity, showed accelerated decline with age in the frontal white matter but not in other sampled areas of the brain. By contrast, lower N-acetylaspartate occurred in the caudate nucleus with longer disease duration, suggesting local differences in vulnerability to disease variables in an aging context (also see Chang et al., 2013, Cysique et al., 2013). Although older HIV-infected men and women can exhibit greater brain structural volume deficits or functional abnormalities, identified with resting state functional MRI, than their younger counterparts, absence of an age-HIV infection interaction failed to support exacerbation of the consequences of infection with age for either volumetric measures (Ances et al., 2012) or connectivity measures (Thomas et al., 2013). In contrast, with these resting state functional MRI and volumetric findings but in concert with the MRS results, a task-activated functional MRI study observed an age-HIV infection interaction locally in the attention network in cognitively intact HIV-infected individuals but compromised in an HIV-infected group with cognitive impairment. Absence of an age-HIV infection interaction was also noted in a study using magnetic resonance diffusion tensor imaging to measure the integrity of local white matter microstructure (Nir et al., 2013), although another diffusion tensor imaging study identified age and presence of the E4 allele genotype as risk factors for greater abnormalities in local white matter integrity (Jahanshad et al., 2012). The inconsistency of these findings may be, at least in part, attributable to the cross-sectional examination of a dynamic disease. Indeed, any conclusion determining whether aging interacts and exacerbates the untoward effects of HIV infection, or alternatively, whether disease progression is a greater contributor than age to decline requires longitudinal study of the relevant variables in HIV-infected groups (Holt et al., 2012, Spudich and Ances, 2012).

The few published longitudinal volumetric MRI studies have been conducted over relatively brief intervals, typically 1 to 2 years. The initial study found faster rate of cortical volume decline in mild (CDC stage A) and severe (CDC stage C) stages of HIV infection relative to changes observed in infection-free controls and faster rates of white matter volume decline in the HIV-infected subgroup with stage C than stage A severity level. Further, decline in caudate nucleus volume and increase in ventricular volume were greater in the HIV-infected group that progressed from a less severe to a more severe CDC stage across MRI sessions, and these changes in brain volumes correlated with decline in CD4 cell count (Stout et al., 1998). A 2-year longitudinal study indicated widespread white matter volume loss or posterior gray matter loss (parietal, occipital, and cerebellar) in virally-suppressed HIV individuals, depending on analysis approach; those without complete viral suppression exhibited accelerated volume loss in gray and white matter compared with declines measured in controls (Cardenas et al., 2009). Examination of HIV-infected individuals before and about 6 months after starting highly active antiretroviral treatment (HAART) revealed improvement in neuropsychological test performance but no appreciable change in regional brain volumes (Ances et al., 2012). Furthermore, in this study, older age at MRI and age at HIV infection were each independently related to smaller brain volumes.

Given that the aging brain is increasingly vulnerable to endogenous and exogenous insult, we expected that HIV infection would interact with normal aging to produce accelerated cortical volume decline and CSF volume increase relative to changes known from longitudinal study to occur in normal aging (e.g., Driscoll et al., 2009, Pfefferbaum et al., 2013, Raz et al., 2010, Resnick et al., 2003, Taki et al., 2011). The potential of accelerated cortical volume loss would put HIV-infected individuals at heightened risk for cognitive compromise and dementia. Thus, the principal aim of this longitudinal neuroimaging study was to identify interactions between brain insults such as HIV-related regional tissue volume decline or ventricular or sulcal expansion and aging that increase susceptibility to premature functional decline. Further aims were to identify HIV-related factors, including age at onset of infection, duration of infection, and central nervous system (CNS) penetration burden of HIV medications, that are significant correlates of regional brain structural volume changes, and to examine whether and when over the course of HIV infection brain volume changes contribute to deterioration in clinical, cognitive, and motor abilities over and above that expected with normal aging.