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Brain aging and cardiovascular factors in HIV:
a longitudinal volume and shape MRI study - cd4 nadir
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May 1 2022
David Jakabeka,b,c, Caroline D. Raec,e, Bruce J. Brewa,b,d and Lucette A. Cysiqueb,c,e
Abstract
Objective:
We aimed to examine the relative contributions of HIV infection, age, and cardiovascular risk factors to subcortical brain atrophy in people with HIV (PWH).
Design:
Longitudinal observational study.
Methods:
Virally suppressed PWH with low neuropsychological confounds (n = 75) and demographically matched HIV-negative controls (n = 31) completed baseline and 18-month follow-up MRI scans, neuropsychological evaluation, cardiovascular assessments, and HIV laboratory tests. PWH were evaluated for HIV-associated neurocognitive disorder (HAND). Subcortical volumes were extracted with Freesurfer after removal of white matter hyperintensities. Volumetric and shape analyses were conducted using linear mixed-effect models incorporating interactions between age, time, and each of HIV status, HAND status, HIV disease factors, and cardiovascular markers.
Results:
Across baseline and follow-up PWH had smaller volumes of most subcortical structures compared with HIV-negative participants. In addition, over time older PWH had a more rapid decline in caudate volumes (P = 0.041), predominantly in the more severe HAND subgroups (P = 0.042). Higher CD4+ cell counts had a protective effect over time on subcortical structures for older participants with HIV. Increased cardiovascular risk factors were associated with smaller volumes across baseline and follow-up for most structures, although a more rapid decline over time was observed for striatal volumes. There were no significant shape analyses findings.
Conclusion:
The study demonstrates a three-hit model of general (as opposed to localized) subcortical injury in PWH: HIV infection associated with smaller volumes of most subcortical structures, HIV infection and aging synergy in the striatum, and cardiovascular-related injury linked to early and more rapid striatal atrophy.
The study demonstrates a three-hit model of general (as opposed to localized) subcortical injury in PWH: HIV infection associated with smaller volumes of most subcortical structures, HIV infection and aging synergy in the striatum, and cardiovascular-related injury linked to early and more rapid striatal atrophy.
"In conclusion, we have demonstrated subcortical volume atrophy in PWH that is not shape specific. Pathological accelerated aging was observed in the caudate for PWH, potentially driven by symptomatic HAND subgroups. HIV duration and cardiovascular disease are risk factors to basal ganglia atrophy. Conversely, immune function, measured by CD4+ cell counts, has a protective effect in most structures. Further exploration of mediating and moderating effects of HIV disease and its treatment will be important in more diverse samples. More importantly, clinical implications of strict control of immunological and cardiovascular risk factors in healthy brain aging are suggested and will require further studies to evaluate effectiveness in protecting brain volumes.
In this longitudinal study of a virally suppressed PWH cohort with low neuropsychological confounds, we found evidence of a three-hit model of subcortical atrophy: first, HIV-driven atrophy in the hippocampus, thalamus, and pallidum; second, accelerated aging of the caudate in symptomatic HAND and accelerated aging in the striatum in PWH with longer HIV duration and lower CD4+ cell counts; and third, accelerated aging of the striatum in PWH with higher cardiovascular risk scores…..Subcortical volumetric atrophy associated with HIV infection at baseline and follow-up was observed for the pallidum, hippocampus, and thalamus. Accelerated aging was demonstrated in the caudate in conjunction with greater cognitive impairment, suggesting in aging PWH there are parallel axes of pathological insults. Our findings support results from a smaller study [34] and extend it to a larger set of virally controlled PWH with low neuropsychological confounds. In addition, a recent meta-analysis has posited that caudate atrophy may be a biomarker of neurocognitive impairment in HIV [35]. Together, these findings confirm the vulnerability of the caudate to HIV [36,37], show that this effect extends to the modern cART era, and provide a novel finding that aging effects may precipitate damage in this nucleus. Accelerated aging was also demonstrated in subcortical structures associated with longer HIV duration and lower baseline CD4+ cell counts. Furthermore, cardiovascular disease is a known complication of HIV infection [4,43]. Literature on brain atrophy due to cardiovascular risk in non-HIV samples has found smaller striatal, hippocampal and thalamic volumes associated with type 2 diabetes [44], and hypertension [45]. Our results also demonstrate atrophy in these volumes in PWH with increased cardiovascular risk factors using the Framingham score, and larger degrees of atrophy using the HIV-specific DAD score.
HIV status was associated with smaller mean volumes of the pallidum, hippocampus, and thalamus across the study period. In addition, for the mean caudate volume, there was significant HIV status by time by age interaction (Fig. 1), whereby older PWH had a greater decrease in caudate volume between baseline and follow-up than either younger PWH or the HIV-negative group.
There was no significant correlation between HIV duration and age (r = 0.15, P = 0.17). Thus, age and HIV duration were included separately as analysis terms. There was a significant three-way interaction between age, time, and HIV duration for mean caudate (Beta = - 0.4, SE = 0.2, P = 0.044) and putamen (Beta = -0.7, SE = 0.3, P = 0.017) volumes. This indicates that there was a more rapid decline in mean caudate and putamen volumes for older PWH with a longer duration of HIV compared with younger PWH with shorter HIV duration.
There were significant positive three-way interactions between baseline CD4+ cell counts, age, and time for the caudate, putamen, and thalamus volumes (P < 0.045; Supplemental Table S2, https://links.lww.com/QAD/C439) and approached significance for hippocampal volume (P = 0.066). This suggests that older PWH with lower baseline CD4+ cell counts had faster atrophy in these structures between baseline and follow-up.
There were multiple main effects observed for both the Framingham score and DAD score on subcortical structural volumes in PWH (see Supplemental Table S3 for all values, https://links.lww.com/QAD/C439). Higher Framingham scores were associated with significantly smaller mean volumes of all structures, although there were no statistically significant interactions over time. Similarly, for PWH with higher DAD scores, smaller caudate, putamen, hippocampal, and thalamic volumes were observed (Fig. 2). More importantly, there was a significant interaction with time with higher DAD scores for the caudate (Beta = -88, SE = 35, P = 0.016) and putamen (Beta = -105, SE = 49, P = 0.036)."
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