Talia M Nir1, Jean-Paul Fouche2, Jintanat Ananworanich3,4,5, Beau M Ances6, Jasmina Boban7, Bruce J Brew8,9,10, Joga R Chaganti11, Linda Chang12,13,14,15, Christopher R K Ching1, Lucette A Cysique16, Thomas Ernst12,14,15, Joshua Faskowitz1, Vikash Gupta1, Jaroslaw Harezlak17, Jodi M Heaps-Woodruff18, Charles H Hinkin19, Jacqueline Hoare2, John A Joska20, Kalpana J Kallianpur21,22, Taylor Kuhn19, Hei Y Lam1, Meng Law23, Christine Lebrun-Frénay24, Andrew J Levine25, Lydiane Mondot26, Beau K Nakamoto14, Bradford A Navia27, Xavier Pennec28,29, Eric C Porges30, Lauren E Salminen1, Cecilia M Shikuma21, Wesley Surento1, April D Thames31, Victor Valcour32,33, Matteo Vassallo34, Adam J Woods30, Paul M Thompson1, Ronald A Cohen30, Robert Paul35, Dan J Stein36, Neda Jahanshad1. 1. Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey. 2. Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa. 3. The Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland. 4. South East Asian Research Collaboration in HIV, Thai Red Cross AIDS Research Centre, Bangkok, Thailand. 5. AIGHD, University of Amsterdam, Amsterdam, the Netherlands. 6. Department of Neurology, Washington University School of Medicine, St Louis, Missouri. 7. Faculty of Medicine, Department of Radiology, University of Novi Sad, Novi Sad, Serbia. 8. Department of Neurology, St Vincent's Hospital, St Vincent's Health Australia and University of New South Wales, Sydney, New South Wales, Australia. 9. Department of Immunology, St Vincent's Hospital, St Vincent's Health Australia and University of New South Wales, Sydney, New South Wales, Australia. 10. Peter Duncan Neurosciences Unit, St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia. 11. Department of Medical Imaging, St Vincent's Hospital, University of New South Wales, Sydney, New South Wales, Australia. 12. Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore. 13. Department of Neurology, University of Maryland School of Medicine, Baltimore. 14. Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu. 15. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland. 16. School of Psychology, University of New South Wales, Sydney, New South Wales, Australia. 17. Department of Epidemiology and Biostatistics, Indiana University School of Public Health, Bloomington. 18. Missouri Institute of Mental Health, University of Missouri, St Louis. 19. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles. 20. HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa. 21. Hawaii Center for AIDS, University of Hawaii, Honolulu. 22. Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii, Honolulu. 23. Department of Radiology, Alfred Health, Monash University, Melbourne, Victoria, Australia. 24. Neurology, UR2CA, Centre Hospitalier Universitaire Pasteur 2, Université Nice Côte d'Azur, Nice, France. 25. Department of Neurology, University of California, Los Angeles. 26. Department of Radiology, UR2CA, Centre Hospitalier Universitaire Pasteur 2, Université Nice Côte d'Azur, Nice, France. 27. Infection Unit, School of Public Health, Tufts University Medical School, Boston, Massachusetts. 28. Cote d'Azur University, Sophia Antipolis, France. 29. Epione Team, Inria, Sophia Antipolis Mediterrannee, Sophia Antipolis, France. 30. Center for Cognitive Aging and Memory, Department of Clinical and Health Psychology, McKnight Brain Institute, University of Florida, Gainesville. 31. Department of Psychology, University of Southern California, Los Angeles. 32. Memory and Aging Center, Department of Neurology, University of California, San Francisco. 33. Global Brain Health Institute, San Francisco, California. 34. Internal Medicine/Infectious Diseases, Centre Hospitalier de Cannes, Cannes, France. 35. Psychological Sciences, Missouri Institute of Mental Health, University of Missouri, St Louis. 36. SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Abstract
Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date. Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide. Design, Setting, and Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019. Main Outcomes and Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status. Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004). Conclusions and Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
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