Curr Infect Dis Rep (2013) 15:451–452 DOI 10.1007/s11908-013-0386-5
INVITED COMMENTARY
The Metamorphosis of HIV-Associated Neurocognitive Disorders Jennifer Lyons
Published online: 19 October 2013 # Springer Science+Business Media New York 2013
Before the era of attainable control of HIV-1, up to 20 % of HIV-infected individuals at advanced stages of immune suppression developed a subcortical dementing illness. In the era of combination antiretroviral therapy (cART), this overt dementia has become much less common. However, more subtle forms of HIV-associated neurocognitive disorders (HAND) remain prevalent [1], insinuating that despite control of viral replication in the plasma, something continues to perturb the cerebrum in these individuals. Whether this is due to viral effects on chronic immune activation, direct toxicities from shed viral proteins in the parenchyma, medication toxicity, or some combination of the above remains to be sorted out, but it is incontrovertible that neurocognitive disease continues to be an important issue in HIV infection. The life expectancy of HIV-infected individuals who achieve viral suppression approaches that of the HIVuninfected [2], which has changed the face of neurological disease in the HIV-infected population. Aging is associated with metabolic and structural brain changes [3] and with increased importance of risk factors for cardiac disease and stroke. HIV has been hypothesized to accelerate age-related changes. These facts, combined with the increased prevalence of asymptomatic neurocognitive impairment (ANI) in the general HIV-infected population, could potentially have clinical implications, from ability to adequately perform activities of daily living when ostensibly asymptomatic to predilection for future overt cognitive decline. Indeed, when assessed objectively, those with formal diagnoses of ANI (a diagnosis that is distinguished from symptomatic forms of
J. Lyons (*) Department of Neurology, Division of Neurological Infections, Brigham and Women’s Hospital and Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA e-mail: [email protected]
HAND largely by subjective report) frequently do demonstrate functional impairment [4]. These discoveries have launched a quest to better understand the relationship between HIV and the brain, both longitudinally and in individuals of advancing age. Many imaging studies utilizing advanced techniques have been designed to inform the literature on the effects of HIV and aging on the brain and on the interactions between the two. In a brain volumetric analysis by structural magnetic resonance imaging (MRI) of a young cohort of HIV-infected individuals and uninfected controls, Ances et al. recently reported HIV-associated reduction in brain volume in several subcortical areas, including the amygdala, caudate, and corpus callosum; this finding obtained regardless of cART utilization. Advancing age volumetrically affects many of the same areas, and volumes for HIV-infected individuals in the caudate corresponded to those in HIVuninfected individuals who were 17 years older. However, there was no interaction between HIV and aging in this study that would suggest synergy [5]. A tractography study of older individuals by diffusion tensor imaging similarly demonstrated overlap between HIV-mediated and age-associated loss of white matter integrity, mainly in the corpus callosum, but also failed to find an interaction between the two [6]. Resting state functional connectivity MRI has also demonstrated abnormalities in networks for both HIV infection and aging, with some overlap between the two in a cohort of relatively young individuals, but again no interaction between HIV and aging was seen [7]. In a magnetic resonance spectroscopy study, Cysique et al. found neuronal dysfunction in frontal white matter that was demonstrative of an interaction between HIV infection, aging, and cardiovascular risk factors [8]. These are but a few examples of studies in this burgeoning field.
452
Individuals infected with HIV are at risk for structural and functional brain abnormalities regardless of viral control in the periphery. Added to this is the advancing age of the HIV population in general, which introduces risk for cognitive decline associated with aging. APOE4 seems to impart additional increased risk [9, 10]. At this point, it is unclear how or whether aging and HIV interact to affect this risk. Regardless, as the HIV-infected population ages, the threat is that cognitive impairment may become increasingly prevalent. Additionally, study cohorts are usually selected to—insofar as is possible—eliminate potential confounders such as substance use, head trauma, history of CNS infections, and concomitant psychiatric disease, which are comorbidities that are incredibly common in the HIV population at large. As such, for practical purposes, the findings in these studies may even underestimate the burden of disease in aging contemporary clinical cohorts. Compliance with Ethics Guidelines Conflict of Interest Jennifer Lyons declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Infect Dis Rep (2013) 15:451–452
References 1. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67:699–714. 2. Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis. 2013;26:17–25. 3. Holt JL, Kraft-Terry SD, Chang L. Neuroimaging studies of the aging HIV-1-infected brain. J Neurovirol. 2012;18:291–302. 4. Valcour VG. HIV, aging, and cognition: emerging issues. Top Antivir Med. 2013;21:119–23. 5. Ances BM, Ortega M, Vaida F, et al. Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr. 2012;59:469–77. 6. Nir TM, Jahanshad N, Busovaca E, et al. Mapping white matter integrity in elderly people with HIV. Hum Brain Mapp 2013. 7. Thomas JB, Brier MR, Snyder AZ, et al. Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity. Neurology. 2013;80:1186–93. 8. Cysique LA, Moffat K, Moore DM, et al. HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: a (1)H MRS study. PLoS One. 2013;8:e61738. 9. Chang L, Andres M, Sadino J, et al. Impact of apolipoprotein E epsilon4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. Neuroimage. 2011;58:1017– 27. 10. Jahanshad N, Valcour VG, Nir TM, et al. Disrupted brain networks in the aging HIV+ population. Brain Connect. 2012;2:335–44.
INVITED COMMENTARY
The Metamorphosis of HIV-Associated Neurocognitive Disorders Jennifer Lyons
Published online: 19 October 2013 # Springer Science+Business Media New York 2013
Before the era of attainable control of HIV-1, up to 20 % of HIV-infected individuals at advanced stages of immune suppression developed a subcortical dementing illness. In the era of combination antiretroviral therapy (cART), this overt dementia has become much less common. However, more subtle forms of HIV-associated neurocognitive disorders (HAND) remain prevalent [1], insinuating that despite control of viral replication in the plasma, something continues to perturb the cerebrum in these individuals. Whether this is due to viral effects on chronic immune activation, direct toxicities from shed viral proteins in the parenchyma, medication toxicity, or some combination of the above remains to be sorted out, but it is incontrovertible that neurocognitive disease continues to be an important issue in HIV infection. The life expectancy of HIV-infected individuals who achieve viral suppression approaches that of the HIVuninfected [2], which has changed the face of neurological disease in the HIV-infected population. Aging is associated with metabolic and structural brain changes [3] and with increased importance of risk factors for cardiac disease and stroke. HIV has been hypothesized to accelerate age-related changes. These facts, combined with the increased prevalence of asymptomatic neurocognitive impairment (ANI) in the general HIV-infected population, could potentially have clinical implications, from ability to adequately perform activities of daily living when ostensibly asymptomatic to predilection for future overt cognitive decline. Indeed, when assessed objectively, those with formal diagnoses of ANI (a diagnosis that is distinguished from symptomatic forms of
J. Lyons (*) Department of Neurology, Division of Neurological Infections, Brigham and Women’s Hospital and Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA e-mail: [email protected]
HAND largely by subjective report) frequently do demonstrate functional impairment [4]. These discoveries have launched a quest to better understand the relationship between HIV and the brain, both longitudinally and in individuals of advancing age. Many imaging studies utilizing advanced techniques have been designed to inform the literature on the effects of HIV and aging on the brain and on the interactions between the two. In a brain volumetric analysis by structural magnetic resonance imaging (MRI) of a young cohort of HIV-infected individuals and uninfected controls, Ances et al. recently reported HIV-associated reduction in brain volume in several subcortical areas, including the amygdala, caudate, and corpus callosum; this finding obtained regardless of cART utilization. Advancing age volumetrically affects many of the same areas, and volumes for HIV-infected individuals in the caudate corresponded to those in HIVuninfected individuals who were 17 years older. However, there was no interaction between HIV and aging in this study that would suggest synergy [5]. A tractography study of older individuals by diffusion tensor imaging similarly demonstrated overlap between HIV-mediated and age-associated loss of white matter integrity, mainly in the corpus callosum, but also failed to find an interaction between the two [6]. Resting state functional connectivity MRI has also demonstrated abnormalities in networks for both HIV infection and aging, with some overlap between the two in a cohort of relatively young individuals, but again no interaction between HIV and aging was seen [7]. In a magnetic resonance spectroscopy study, Cysique et al. found neuronal dysfunction in frontal white matter that was demonstrative of an interaction between HIV infection, aging, and cardiovascular risk factors [8]. These are but a few examples of studies in this burgeoning field.
452
Individuals infected with HIV are at risk for structural and functional brain abnormalities regardless of viral control in the periphery. Added to this is the advancing age of the HIV population in general, which introduces risk for cognitive decline associated with aging. APOE4 seems to impart additional increased risk [9, 10]. At this point, it is unclear how or whether aging and HIV interact to affect this risk. Regardless, as the HIV-infected population ages, the threat is that cognitive impairment may become increasingly prevalent. Additionally, study cohorts are usually selected to—insofar as is possible—eliminate potential confounders such as substance use, head trauma, history of CNS infections, and concomitant psychiatric disease, which are comorbidities that are incredibly common in the HIV population at large. As such, for practical purposes, the findings in these studies may even underestimate the burden of disease in aging contemporary clinical cohorts. Compliance with Ethics Guidelines Conflict of Interest Jennifer Lyons declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Curr Infect Dis Rep (2013) 15:451–452
References 1. McArthur JC, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol. 2010;67:699–714. 2. Nakagawa F, May M, Phillips A. Life expectancy living with HIV: recent estimates and future implications. Curr Opin Infect Dis. 2013;26:17–25. 3. Holt JL, Kraft-Terry SD, Chang L. Neuroimaging studies of the aging HIV-1-infected brain. J Neurovirol. 2012;18:291–302. 4. Valcour VG. HIV, aging, and cognition: emerging issues. Top Antivir Med. 2013;21:119–23. 5. Ances BM, Ortega M, Vaida F, et al. Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr. 2012;59:469–77. 6. Nir TM, Jahanshad N, Busovaca E, et al. Mapping white matter integrity in elderly people with HIV. Hum Brain Mapp 2013. 7. Thomas JB, Brier MR, Snyder AZ, et al. Pathways to neurodegeneration: effects of HIV and aging on resting-state functional connectivity. Neurology. 2013;80:1186–93. 8. Cysique LA, Moffat K, Moore DM, et al. HIV, vascular and aging injuries in the brain of clinically stable HIV-infected adults: a (1)H MRS study. PLoS One. 2013;8:e61738. 9. Chang L, Andres M, Sadino J, et al. Impact of apolipoprotein E epsilon4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging. Neuroimage. 2011;58:1017– 27. 10. Jahanshad N, Valcour VG, Nir TM, et al. Disrupted brain networks in the aging HIV+ population. Brain Connect. 2012;2:335–44.
