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Heart Disease, HCV, Poverty, Early-Life
Stress Tied to Brain Aging With HIV
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International Workshop on HIV and Aging, October 13-14, 2022
By Mark Mascolini for NATAP and Virology Education
A set of non-HIV factors could contribute to brain aging in people with HIV infection, according a sophisticated analysis using MRI brain imaging, Framingham cardiovascular risk score, census tract-derived area deprivation index (a socioeconomic measure), and brain age gap (BAG), the difference between chronological age and brain-predicted age [1]. (Greater BAG means more pathology.) The four predictors of faster brain aging with HIV that emerged from this analysis were Framingham risk score, hepatitis C virus (HCV) coinfection, area deprivation index, and early life stressors.
Much research links HIV infection to structural changes in brain. About one third of people with HIV have some cognitive impairment, which can adversely affect quality of life even if classified as mild. In addition, HIV-positive people have higher rates of comorbidities than HIV-negative people. The long list of factors that can affect brain aging with HIV includes comorbidities like cardiovascular disease and coinfections, substance use, social determinants of health, environmental exposures, and viral pathology and inflammation caused by HIV itself.
Researchers from Washington University in St. Louis conducted this study to address three questions on brain aging in people with or without HIV infection:
1. Can variability in the brain age gap (BAG) be attributed to non-HIV factors?
2. Do predictors of brain aging differ between people with versus without HIV?
3. What spatial patterns are linked to brain aging?
The Washington University group defined brain aging as premature or accelerated appearance of age-like changes in brain structure and function associated with a disease state. In recent years they have devoted time to finding out how social determinants of health might affect brain aging. These determinants include the area deprivation index-an aggregate socioeconomic index that reflects neighborhood factors such as income, employment, and housing quality. The researchers also asked participants to complete the Early Life Stress Questionnaire (ELSQ), which tallies the number of major stressors in childhood or adolescence.
The investigators used machine learning to distill complex neuroimaging data into a single outcome measure. Previous work by their group and others determined that BAG is elevated in people with HIV infection. The Washington University team also recently showed that people with HIV, as a group, have accelerated structural brain aging compared with HIV-negative people (P < 0.001) [2].
The new comparison involved 379 people with HIV and 259 without HIV. The HIV group was significantly older (average 44.8 vs 38.3 years, P < 0.001), included a significantly higher proportion of men (78.1% vs 49.8%, P < 0.001), and had a significantly higher proportion of blacks (68.6% vs 56.4%, P = 0.002).
Generalized linear models probing for HIV-specific risk factors for greater BAG found three: detectable HIV viral load (P = 0.006), HCV infection (P = 0.006), and a trend for an association with lower recent CD4 count and lower nadir CD4 count (P = 0.038). Non-HIV risk factors for elevated BAG were higher Framingham cardiovascular risk score (P = 0.002) and a trend for a protective effect with educational attainment measured by the Wide-Range Achievement Test, but only in HIV-negative people.
Next the researchers used a "best subsets" approach to isolate predictors of accelerated brain aging (greater BAG) separately for people with and without HIV. This method, explained Washington University's Kalen Petersen, "fits all possible variable combinations and selects the model that best explains the outcome variance, while penalizing overly complex models with many predictor terms." For the HIV group this process yielded four predictors: worse Framingham cardiovascular risk score, HCV coinfection, area deprivation index (the socioeconomic metric), and early-life stressors.
Finally, the researchers wanted to know what brain regions might be driving these effects. To get a better grasp of the neural mechanisms leading to brain aging, they aimed to identify volumetric features salient to the machine-learning model. This analysis determined that reductions in both grey-matter structures like hippocampus and amygdala and white-matter structures like corpus callosum correlated with greater brain aging, as did ventricular enlargement and white matter lesion volume.
These observations led the researchers to devise a model "in which growing older with HIV while experiencing comorbid disease burden and adverse socioeconomic circumstances worsens chronic stress and possible inflammation." This in turn leads to increased brain aging-seen as faster changes in brain structure-which could promote cognitive impairment and worse quality of life.
References
1. Petersen K, Wisch J, Cooley S, Ances B. Social and co-morbid determinants of brain aging in persons with and without HIV. International Workshop on HIV and Aging, October 13-14, 2022. Abstract 6.
2. Petersen KJ, Metcalf N, Cooley S, et al. Accelerated brain aging and cerebral blood flow reduction in persons with human immunodeficiency virus. Clin Infect Dis. 2021;73:1813-1821. doi: 10.1093/cid/ciab169. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599198/
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