Progressive brain atrophy in chronically infected and treated HIV+ individuals

Talia M Nir¹, Neda Jahanshad¹, Christopher R K Ching^{1

2}, Ronald A Cohen³, Jaroslaw Harezlak⁴, Giovanni Schifitto⁵, Hei Y Lam¹, Xue Hua¹, Jianhui Zhong⁶, Tong Zhu⁷, Michael J Taylor⁸, Thomas B Campbell⁹, Eric S Daar¹⁰, Elyse J Singer¹¹, Jeffry R Alger¹¹, Paul M Thompson¹², Bradford A Navia¹³; HIV Neuroimaging Consortium

Affiliations

¹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralty Way Suite 200, Marina del Rey, Los Angeles, CA, 90292, USA.
² Graduate Interdepartmental Program in Neuroscience, UCLA School of Medicine, Los Angeles, CA, USA.
³ Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
⁴ Indiana University School of Public Health, Bloomington, IN, USA.
⁵ Department of Neurology, University of Rochester, Rochester, NY, USA.
⁶ Department of Imaging Sciences, University of Rochester, Rochester, NY, USA.
⁷ Department Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA.
⁸ Department of Psychiatry, University of California, San Diego, CA, USA.
⁹ Medicine/Infectious Diseases, University of Colorado Denver, Aurora, CO, USA.
¹⁰ Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, University of California, Los Angeles, CA, USA.
¹¹ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralty Way Suite 200, Marina del Rey, Los Angeles, CA, 90292, USA. pthomp@usc.edu.
¹³ Department of Public Health, Infection Unit, Tufts University School of Medicine, Boston, MA, USA.

PMID: 30767174
PMCID: PMC6635004
DOI: 10.1007/s13365-019-00723-4

Progressive brain atrophy in chronically infected and treated HIV+ individuals

Talia M Nir et al. J Neurovirol. 2019 Jun.

. 2019 Jun;25(3):342-353.

doi: 10.1007/s13365-019-00723-4. Epub 2019 Feb 14.

Authors

Affiliations

¹ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralty Way Suite 200, Marina del Rey, Los Angeles, CA, 90292, USA.
² Graduate Interdepartmental Program in Neuroscience, UCLA School of Medicine, Los Angeles, CA, USA.
³ Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
⁴ Indiana University School of Public Health, Bloomington, IN, USA.
⁵ Department of Neurology, University of Rochester, Rochester, NY, USA.
⁶ Department of Imaging Sciences, University of Rochester, Rochester, NY, USA.
⁷ Department Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA.
⁸ Department of Psychiatry, University of California, San Diego, CA, USA.
⁹ Medicine/Infectious Diseases, University of Colorado Denver, Aurora, CO, USA.
¹⁰ Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, University of California, Los Angeles, CA, USA.
¹¹ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹² Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, 4676 Admiralty Way Suite 200, Marina del Rey, Los Angeles, CA, 90292, USA. pthomp@usc.edu.
¹³ Department of Public Health, Infection Unit, Tufts University School of Medicine, Boston, MA, USA.

PMID: 30767174
PMCID: PMC6635004
DOI: 10.1007/s13365-019-00723-4

Abstract

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

Keywords: ADC; Brain volume; HIV; MRI; TBM; cART.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Jeffry R Alger owns NeuroSpectroScopics LLC. Thomas B Campbell is a consultant for Gilead Sciences and Theratechnologies Inc. Xue Hua now works for M3 Biotechnology; the work included in the manuscript was conducted during her appointment at USC, and she reports no disclosures. The remaining authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Atrophy rates in HIV+ individuals. Annual volumetric change (%) maps averaged across **(a)** the full HIVNC cohort (mean age: 48.01 ± 8.88 yrs; N=155) revealed significant ventricular expansion (*red*) and tissue atrophy (*blue*) throughout the brain (regions with no change are colored *gray/white*; one-sample T-test; P_corrected ≤ 0.05). Maps of the **(b)** subset of neuro-asymptomatic individuals (NA; ADC Stage=0; N=92) and **(c)** those who are NA with undetectable viral load (NA-uVL; plasma HIV RNA < 400 copies/mL; N=76) showed a similar distribution and magnitude of change as the full cohort. **(d-f)** In the full cohort and the NA subsets, older age at baseline was significantly associated with greater annual ventricular and sulcal expansion and tissue atrophy (P_corrected ≤ 0.05). However, the association between brain atrophy and age was relatively localized and did not account for the pervasive brain atrophy detected across participants over time

**Fig. 2**
Brain tissue loss rates are associated with measures of HIV infection severity. **(a-c)** In the full cohort and **(d-f)** the subset of neuro-asymptomatic (NA) participants (ADC=0), lower nadir CD4+ cell count, suppressed immune status at baseline (current CD4+ ≤350 cells/mm³), and detectable viral load (plasma HIV RNA ≥ 400 cp/mL) at baseline were significantly associated (P_corrected ≤ 0.05) with a greater annual ventricular and sulcal expansion (*red*) and tissue atrophy (*blue*). Only **(g)** current CD4+ was associated with volume loss in NA participants with undetectable viral load (NA-uVL)

**Fig. 3**
Brain tissue loss rates are associated with change in ADC stage. **(a)** Total number of participants (out of 134) for each type of change in ADC stage between baseline and follow-up assessments. Relative to participants with **(b)** stable or improved neurocognitive status (no change or decreased ADC stage; N=115) or **(c)** just improved neurocognitive status (decreased ADC stage; N=10) over time, a decline in neurocognitive status (an increase in ADC stage; N=19) was significantly associated (P_corrected ≤ 0.05) with greater rates of tissue atrophy (*blue*) and ventricular expansion (*green-red*)

**Fig. 4**
Atrophy rates in HIV+ individuals compared to healthy controls. Compared to a subset of age matched controls (N=48; mean age: 55.6 ± 9.5 yrs), HIV+ individuals (N=65; mean age: 54.2 ± 7.9 yrs) showed significantly (P_corrected ≤ 0.05) greater rates of GM atrophy bilaterally in the temporal lobes and the left precuneus.

See this image and copyright information in PMC

References

1. Ances BM and Ellis RJ (2007). Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol, 27(1): 86–92. - PubMed
1. Ances BM, Ortega M, Vaida F, Heaps J and Paul R (2012). Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr, 59(5): 469–477. - PMC - PubMed
1. Anderson AM, Harezlak J, Bharti A, Mi D, Taylor MJ, Daar ES, Schifitto G, Zhong J, Alger JR, Brown MS, Singer EJ, Campbell TB, McMahon DD, Buchthal S, Cohen R, Yiannoutsos C, Letendre SL, Navia BA and Consortium HIVN (2015). Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy. J Acquir Immune Defic Syndr, 69(1): 29–35. - PMC - PubMed
1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V and Wojna VE (2007). Updated research nosology for HIV-associated neurocognitive disorders. Neurology, 69(18): 1789–1799. - PMC - PubMed
1. Becker JT, Maruca V, Kingsley LA, Sanders JM, Alger JR, Barker PB, Goodkin K, Martin E, Miller EN, Ragin A, Sacktor N, Selnes O and Multicenter ACS (2012). Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology, 54(2): 113–121. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Progressive brain atrophy in chronically infected and treated HIV+ individuals

Affiliations

Progressive brain atrophy in chronically infected and treated HIV+ individuals

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials