Brain aging and cardiovascular factors in HIV: a longitudinal volume and shape MRI study

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 ¼ 75) and demographically matched HIV-negative controls (n ¼ 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 ¼ 0.041), predominantly in the more severe HAND subgroups (P ¼ 0.042). Higher CD4 þ 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 followup 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.

Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy

“…In summary, we present evidence that peripheral markers of vascular injury are more closely associated with HAND and CNS injury in PWH on suppressive ART than markers of inflammation. Our findings are consistent with the three-hit model proposed by Jakabek et al [20] in which HIV infection, aging, and vascular disease contribute to brain aging in PWH, and suggest that vascular injury markers, particularly VCAM-1, may help to distinguish relative contributions of VCI to HAND. Further studies are warranted to better understand the utility of VCAM-1 and other peripheral markers of vascular injury for identification of HAND biotypes [11,13] and development of tailored interventions in virally suppressed PWH on ART.…”

“…Consistent with these findings, cardiovascular risk factors and diagnoses were more prevalent in HAND vs. no HAND and biomarker clustering identified HAND subgroups distinguished by high prevalence of vascular disease and progression to HAD. In the current ART era, HAND frequently has non-HIV-etiologies, with vascular disease being one of the most common [10,[19][20][21]46], and neurocognitive profiles can resemble VCI [10,17,[19][20][21]24,25,46]. Although plasma inflammation markers (e.g., IL-1b, IL-8, IP-10, MCP-1) were increased in PWH, only IL-6 was associated with HAND (particularly MND).…”

“…Due to earlier onset and progression of vascular disease, PWH are also at increased risk for vascular cognitive impairment (VCI) at younger ages compared with the general population [10,19]. Given evidence that VCI contributes to cognitive impairment in PWH on ART [17,20,21], vascular disease has emerged as a significant contributing factor to HAND in the current ART era [10,19,[22][23][24][25]. Accordingly, biomarkers that can distinguish VCI from other causes of cognitive impairment will be useful for diagnosis and clinical management.…”

A new perspective on HIV: effects of HIV on brain-heart axis

“…Blahak et al suggested that white matter injury can disrupt the prefrontal subcortical motor circuit, resulting in impaired balance and an increased risk of falls (123). In addition to white matter injury, advanced HAND patients may exhibit decreased subcortical volume, caudate nucleus volume, cerebral malacia foci, and brain atrophy (66,124,125). HIV can also contribute to other acute central nervous system diseases, such as stroke.…”

CSF Extracellular Vesicle Aβ42 and Tau/Aβ42 Ratio Are Associated with Cognitive Impairment in Older People with HIV

“…The mechanisms involved in HAND are heterogeneous, including ongoing viral replication in the CNS, neuroinflammation, oxidative stress, vascular disease, blood–brain barrier (BBB) dysfunction, ART-related neurotoxicity, and substance use [ 3 , 4 , 5 ]. Due to persistent inflammation, cerebrovascular disease, and small-vessel disease-related brain injury, PWH are also at increased risk of premature brain aging [ 1 , 6 , 7 , 8 , 9 , 10 ]. However, the relative risk of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) in PWH remains unclear [ 11 , 12 ].…”