Accelerated and Premature Aging Characterizing Regional Cortical Volume Loss in Human Immunodeficiency Virus Infection: Contributions From Alcohol, Substance Use, and Hepatitis C Coinfection.

BACKGROUND Life expectancy of successfully treated human immunodeficiency virus (HIV)-infected individuals is approaching normal longevity. The growing HIV population ≥50 years of age is now at risk of developing HIV-associated neurocognitive disorder, acquiring coinfection with the hepatitis C virus (HCV), and engaging in hazardous drinking or drug consumption that can adversely affect trajectories of the healthy aging of brain structures. METHODS This cross-sectional/longitudinal study quantified regional brain volumes from 1101 magnetic resonance imaging scans collected over 14 years in 549 participants (25 to 75 years of age): 68 HIV-infected individuals without alcohol dependence, 60 HIV-infected individuals with alcohol dependence, 222 alcohol-dependent individuals, and 199 control subjects. We tested 1) whether localized brain regions in HIV-infected individuals exhibited accelerated aging, or alternatively, nonaccelerated premature aging deficits; and 2) the extent to which alcohol or substance dependence or HCV coinfection altered brain aging trajectories. RESULTS The HIV-infected cohort exhibited steeper declining volume trajectories than control subjects, consistently in the frontal cortex. Nonaccelerated volume deficits occurred in the temporal, parietal, insular, and cingulate regions of all three diagnostic groups. Alcohol and drug dependence comorbidities and HCV coinfection exacerbated HIV-related volume deficits. Accelerated age interactions in frontal and posterior parietal volumes endured in HIV-infected individuals free of alcohol or substance dependence and HCV infection comorbidities. Functionally, poorer HIV-associated neurocognitive disorder scores and Veterans Aging Cohort Study indices correlated with smaller regional brain volumes in the HIV-infected individuals without alcohol dependence and alcohol-dependent groups. CONCLUSIONS HIV infection itself may confer a heightened risk of accelerated brain aging, potentially exacerbated by HCV coinfection and substance dependency. Confirmation would require a prospective study with a preinfection baseline.

[1]  Terry L. Jernigan,et al.  Clinical factors related to brain structure in HIV: the CHARTER study , 2011, Journal of NeuroVirology.

[2]  F. Higa,et al.  Are MMSE and HDS-R neuropsychological tests adequate for screening HIV-associated neurocognitive disorders? , 2014, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[3]  S. Kapiga,et al.  Alcohol Consumption among HIV-Infected Persons in a Large Urban HIV Clinic in Kampala Uganda: A Constellation of Harmful Behaviors , 2015, PloS one.

[4]  W. Fawzi,et al.  Prevalence and factors associated with alcohol drinking among HIV and tuberculosis co-infected patients in Dar es Salaam, Tanzania , 2018, AIDS care.

[5]  M W Weiner,et al.  Brain atrophy in HIV infection is more strongly associated with CDC clinical stage than with cognitive impairment , 1997, Journal of the International Neuropsychological Society.

[6]  L. Cysique,et al.  The Chronicity of HIV Infection Should Drive the Research Strategy of NeuroHIV Treatment Studies: A Critical Review , 2016, CNS Drugs.

[7]  Torsten Rohlfing,et al.  Thalamic volume deficit contributes to procedural and explicit memory impairment in HIV infection with primary alcoholism comorbidity , 2014, Brain Imaging and Behavior.

[8]  Torsten Rohlfing,et al.  Variation in longitudinal trajectories of regional brain volumes of healthy men and women (ages 10 to 85years) measured with atlas-based parcellation of MRI , 2013, NeuroImage.

[9]  K. Marder,et al.  Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment , 2003, Neurology.

[10]  J. Becker,et al.  Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study. , 2017, The lancet. HIV.

[11]  Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models , 2016, Journal of Neuroimmune Pharmacology.

[12]  Cortical brain atrophy and intra-individual variability in neuropsychological test performance in HIV disease , 2016, Brain Imaging and Behavior.

[13]  A. Bechara,et al.  Delayed nonmatch-to-sample performance in HIV-seropositive and HIV-seronegative polydrug abusers. , 2003, Neuropsychology.

[14]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[15]  D. Sharp,et al.  No Evidence for Accelerated Aging-Related Brain Pathology in Treated Human Immunodeficiency Virus: Longitudinal Neuroimaging Results From the Comorbidity in Relation to AIDS (COBRA) Project , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  M. Jorge Cardoso,et al.  Patterns of progressive atrophy vary with age in Alzheimer's disease patients , 2018, Neurobiology of Aging.

[17]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[18]  Gregory R. Kirk,et al.  Peripheral blood HIV DNA is associated with atrophy of cerebellar and subcortical gray matter , 2013, Neurology.

[19]  A. Saykin,et al.  Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia , 2013, Seminars in Neurology.

[20]  J. Berman,et al.  Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis. , 2016, Current HIV research.

[21]  C. Marra,et al.  A multinational study of neurological performance in antiretroviral therapy-naïve HIV-1-infected persons in diverse resource-constrained settings , 2011, Journal of NeuroVirology.

[22]  Olga Meulenbroek,et al.  Cognitive functioning, wellbeing and brain correlates in HIV-1 infected patients on long-term combination antiretroviral therapy , 2015, AIDS (London).

[23]  Florin Vaida,et al.  Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures , 2012, Journal of acquired immune deficiency syndromes.

[24]  David J. Sharp,et al.  Increased brain-predicted aging in treated HIV disease , 2017, Neurology.

[25]  M. Ticchioni,et al.  Virologically suppressed patients with asymptomatic and symptomatic HIV‐associated neurocognitive disorders do not display the same pattern of immune activation , 2015, HIV medicine.

[26]  M. Maschke,et al.  Structural gray and white matter changes in patients with HIV , 2011, Journal of Neurology.

[27]  Paul M. Thompson,et al.  Disrupted cerebral metabolite levels and lower nadir CD4 + counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatment☆ , 2013, NeuroImage: Clinical.

[28]  C. Gamaldo,et al.  The Psychiatric Impact of HIV. , 2017, ACS chemical neuroscience.

[29]  I. Grant,et al.  Variable patterns of neuropsychological performance in HIV-1 infection , 2008, Journal of clinical and experimental neuropsychology.

[30]  Andrew Levine,et al.  Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study , 2016, Neurology.

[31]  A. Winston,et al.  HIV, dementia and antiretroviral drugs: 30 years of an epidemic , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[32]  Natalie M. Zahr,et al.  The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity , 2018, Front. Aging Neurosci..

[33]  A. Copas,et al.  Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort. , 2017, The Lancet. Public health.

[34]  Janet B W Williams,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[35]  W. Thompson,et al.  The Role of Aging, Drug Dependence, and Hepatitis C Comorbidity in Alcoholism Cortical Compromise , 2018, JAMA psychiatry.

[36]  Torsten Rohlfing,et al.  Regional Brain Structural Dysmorphology in Human Immunodeficiency Virus Infection: Effects of Acquired Immune Deficiency Syndrome, Alcoholism, and Age , 2012, Biological Psychiatry.

[37]  N. Zahr.  Peripheral TNFα elevations in abstinent alcoholics are associated with hepatitis C infection , 2018, PloS one.

[38]  Anil Kumar,et al.  Role of Autophagy in HIV Pathogenesis and Drug Abuse , 2017, Molecular Neurobiology.

[39]  A. Winston,et al.  Associations between cognitive impairment and patient‐reported measures of physical/mental functioning in older people living with HIV , 2017, HIV medicine.

[40]  M. Albert,et al.  Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years , 2018, Brain : a journal of neurology.

[41]  P. Szewczyk,et al.  Value of Perfusion-Weighted MR Imaging in the Assessment of Early Cerebral Alterations in Neurologically Asymptomatic HIV-1-Positive and HCV-Positive Patients , 2014, PloS one.

[42]  T. Jernigan,et al.  Progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. HIV Neurobehavioral Research Center Group. , 1998, Archives of neurology.

[43]  R. Fonseca,et al.  Longitudinal evaluation of resting-state connectivity, white matter integrity and cortical thickness in stable HIV infection: Preliminary results , 2017, The neuroradiology journal.

[44]  S. Aguilar-Navarro,et al.  Cognitive impairment among older adults living with HIV/AIDS and frailty , 2019, Gaceta de M�xico.

[45]  Tony W Wilson,et al.  Multimodal neuroimaging evidence of alterations in cortical structure and function in HIV‐infected older adults , 2015, Human brain mapping.

[46]  Shinichi Nakagawa,et al.  A general and simple method for obtaining R2 from generalized linear mixed‐effects models , 2013 .

[47]  C. Studholme,et al.  Evidence for ongoing brain injury in human immunodeficiency virus-positive patients treated with antiretroviral therapy , 2009, Journal of NeuroVirology.

[48]  Richard D Moore,et al.  CD4 count at presentation for HIV care in the United States and Canada: Are those over 50 years more likely to have a delayed presentation? , 2010, AIDS research and therapy.

[49]  Torsten Rohlfing,et al.  Adolescent Development of Cortical and White Matter Structure in the NCANDA Sample: Role of Sex, Ethnicity, Puberty, and Alcohol Drinking. , 2016, Cerebral cortex.

[50]  Torsten Rohlfing,et al.  Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study , 2014, Neurobiology of Aging.

[51]  C. Jack,et al.  A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer's disease severity , 2016, NeuroImage: Clinical.

[52]  James J. Goedert,et al.  Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada , 2013, PloS one.

[53]  D. Louis Collins,et al.  Association of Brain Structure Changes and Cognitive Function With Combination Antiretroviral Therapy in HIV-Positive Individuals , 2018, JAMA neurology.

[54]  M. Gill,et al.  Neurologic disease burden in treated HIV/AIDS predicts survival , 2010, Neurology.

[55]  O. Monchi,et al.  Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico-Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features , 2018, Cerebral cortex.

[56]  J. Kramer,et al.  Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years , 2017, Journal of acquired immune deficiency syndromes.

[57]  No association between Apoε4 alleles, HIV infection, age, neuropsychological outcome, or death , 2015, Journal of NeuroVirology.

[58]  P. Coupé,et al.  Structural imaging biomarkers of Alzheimer's disease: predicting disease progression , 2015, Neurobiology of Aging.

[59]  Anil Kumar,et al.  HIV-1, HCV and alcohol in the CNS: potential interactions and effects on neuroinflammation. , 2014, Current HIV research.