One debate in the HIV literature is the extent to which HIV disease is associated with accelerated aging as opposed to other comorbid conditions or other lifestyle factors associated with HIV. However, it is difficult to differentiate the effect of HIV itself versus the downstream effects of HIV or lifestyle factors associated with risk of contracting HIV . For example, many studies have documented higher risk of vascular risk factors including hyperlipidemia, type II diabetes, hypertension, and abdominal obesity in PWH likely due to the cardiometabolic side effects of ART, chronic immune activation, comorbid conditions that are more common in PWH , and increased risk of chronic stressors . Cysique & Brew propose that vascular cognitive impairment is implicated in the pathogenesis of neurocognitive impairment in PWH, particularly older PWH, given that cardiovascular and cerebrovascular conditions can cause alterations in the blood-brain barrier, altered vascular reactivity, and brain changes, particularly in white matter. A recent meta analysis by McIntosh et al., found that cardiovascular disease, particularly type II diabetes, hyperlipidemia, and current smoking, are associated with an increased risk of cognitive impairment in PWH. CVD has been associated with brain changes in PWH, but the majority find an association with abnormal white matter , which was not examined in the current study. Several vascular risk factors were examined as covariates and were not found to be significantly associated with cognitive outcomes; although it is important to note that this group is limited in that participants with more significant vascular comorbidities such as stroke or myocardial infarction were excluded for these analyses.
Nevertheless,commercial racks further exploration of vascular risk factors and how they are associated with cognition and brain aging in this cohort and PWH more broadly is of course warranted to further understand the effects of HIV versus the effects of comorbid conditions associated with HIV. Comparing the results of the current study to the middle-aging literature is difficult. First, while brain changes due to AD pathology can begin in mid-life, it is still several years from midlife to when one would develop late-onset aMCI/AD; thus decades-long studies are needed to better understand brain changes in mid-life and how they relate to late-life AD. Therefore, the literature is sparse and generally relies on AD risk to examine memory and neuroimaging in mid-life. Second, many studies with an aging focus examine a memory composite and thus it is difficult to discern the association between delayed recall versus recognition and brain integrity from these studies. Even older-adult studies often do not specifically examine recognition memory as again they either examine aMCI diagnosis, which in the older adult literature does not necessarily imply recognition impairment, or a memory domain. Third, given the AD focus of middle-aging studies, many middle-aging studies focus on the medial temporal lobe and do not explore other regions such as the basal ganglia or the prefrontal cortex. From the sparse middle-aging research that examines both memory and neuroimaging, there is some indication that memory is associated with several neuroimaging correlates, most notably the medial temporal lobe. For example, the Wisconsin Registry for Alzheimer’s Prevention study, which focuses on adults aged 40-65 and is enriched with a family history of AD, has reported memory and neuroimaging associations. For example, in a study of 261 WRAP participants, those with subjective memory complaints had significant cortical thinning in the entorhinal, fusiform, posterior cingulate, and inferior parietal cortices and reduced amygdala volume compared to participants without subjective memory complaints.
In 109 participants in the WRAP study, participants that were Aβ+, determined via PET imaging, exhibited significantly thinner entorhinal cortex, accelerated age-associated thinning of the parahippocampal gyrus, and performed worse across cognitive measures, although not significantly worse, compared with the Aβ− group . Approximately 65% of WRAP participants were female and approximately 95% of participants were non-Hispanic white. In a study of 210 adults aged 40-59 by Ritchie et al. , worse spatial recall and visual recognition as well as greater dementia risk were associated with lower brain and hippocampal volume. Overall, the middle-aging literature is quite limited, so it is difficult to discern if episodic memory, regardless of the type of memory , reliably associates with the medial temporal lobe in middle age. While it is significant that these studies do find associations between memory, AD risk, and the medial temporal lobe as well as other brain structures, these studies do not report prefrontal involvement like that observed in the current study. Of note, the study participants in these two studies markedly differ from the CHARTER cohort; the CHARTER cohort was not enriched for family history of AD, is predominantly male , and this sub-sample is 50.5% African American/Black and 38.4% non-Hispanic White. However, Jak et al., , which examined men in their 50s , also found that MCI diagnosis was associated with smaller hippo campal volume, although only the hippocampus was examined in this study. One curious finding was that the post hoc analyses examining a sub-sample of participants showed that better delayed recall was associated with a thinner entorhinal cortex. The aim of these analyses were to examine and confirm that prior findings are applicable to participants that were ideally treated for HIV disease and did not have any current substance use that could confound results. Although it should be noted that full sample is already a group that somewhat differs from the general population of PWH in that this group excludes PWH with severe comorbid conditions, they have little to no current substance use, and are relatively well treated for HIV as compared to the general population . Nevertheless, this finding is opposite of what was hypothesized based on the literature.
While thicker cortex has been associated with cognitive dysfunction in some settings, suggesting that it is the deviation from normal cortical thickness that is meaningful , within the HIV and AD literature this has not been observed. In HAND and AD , atrophy is consistently related to worse cognitive functioning. Therefore, it is likely that this is a spurious finding. Given that this is a relatively small sub-sample and may not be generalizable, and thus this finding should not be over interpreted. To further validate the specificity of memory and medial temporal lobe relationships and show that memory is not just related to overall brain integrity, processing speed and psychomotor skills were also examined in aim 1c. It was hypothesized that these two domains would be more associated with fronto-striatal structures implicated in HAND. In the entire sample, processing speed and psychomotor skills were not significantly associated with the medial temporal lobe as hypothesized. However, they were not significantly associated with prefrontal or basal ganglia structures either. Overall, these findings were not in line with the hypotheses, and given that episodic memory was not associated with medial temporal lobes,greenhouse rolling benches these findings do not help to demonstrate that associations with the medial temporal lobe are specific to memory and not cognitive functioning in general. In post hoc analyses, a thinner pars orbitalis was significantly associated with worse psychomotor functioning, which was somewhat in line with the hypotheses; however, the literature would suggest that we may expect psychomotor function to be more related to basal ganglia structures, particularly the putamen . When examining covariates for this aim of the study, AIDS status and APOE e4 status were associated with worse delayed recall. Regarding AIDS status, nadir CD4 count has repeatedly been associated with riskof HAND both within the CHARTER cohort and in other cohorts around the world . While nadir CD4 count was examined as a potential covariate and was not found to be associated with delayed recall, AIDS status is of course associated with nadir CD4 given that an AIDS diagnosis is defined by either an opportunistic infection or if CD4 cell count drops below 200 cells per milliliter of blood at any point in one’s life . It is thought that greater immunosuppression is associated with CNS injury and those neurologic consequences may persist even after treatment with ART and immune recovery ; this highlights the importance of HIV identification and initiation of ART to avoid immunosuppression. Based on the estimated duration of HIV, most of these participants contracted HIV either before ART was available or in the era in which ART was not recommended to be initiated until after immunosuppression. This cohort on average is characterized by a history of immunosupression with immune recovery given that there is high rates of AIDS with evidence of immune recovery as evidenced by a median CD4 count of almost 500 and high rates of current ART use.
Given that ART policies have changed and it is now recommended that ART is initiated immediately after diagnosis , continued research on aging with HIV will be needed to understand different cohort effects . Nadir CD4 has been associated with thinner cortex and smaller brain volumes throughout the brain, particularly in the parietal, temporal, and frontal lobes, and the hippocampus . Therefore, it is important to reiterate that episodic memory and prefrontal regions were significantly associated with one another even when accounting for AIDS status. Interestingly, one study found that low nadir CD4 was associated with reduced functional connectivity in the memory networks in APOE e4 carriers not but non-carriers . Regarding APOE status, several studies have examined the association between memory and APOE status in middle age, finding that APOE e4 carriers have similar memory and cognitive performance to non-carriers until the mid-to-late 50s when differences start to appear . Interestingly, the association between APOE e4 status and worse memory, specifically delayed recall but not recognition, was found within this group of PWH whose mean age was in the early 50s. However, other early markers associated with preclinical AD, such as the association between memory and medial temporal lobe structures were not, although APOE by medial temporal lobe interactions were not explored. Previous HIV studies have shown mixed results when examining the association between APOE status and cognition within PWH. Within the larger CHARTER cohort, Morgan et al. found that APOE e4 status was not associated with a greater risk of HAND; however, this study was from an earlier time point in which participants were, on average, 44.1 years old. Moreover, in another CHARTER study by Cooley et al. in a sub-sample of CHARTER participants aged 50 and over, APOE e4 status was not associated with volumetric differences on MRI or MR spectroscopy metabolite analyses. However, these structural analyses may not have had the specificity to detect more minute differences in specific regions of the brain such as the medial temporal lobe. Nevertheless, the HIV literature is mixed as a review found that some HIV studies do find worse cognitive and brain integrity in PWH who are APOE e4 carriers whereas others do not . Several HIV studies, particularly in PWH over the age of 50, have found that APOE e4 status is associated with worse brain integrity in several regions including cerebral white matter, the thalamus, and temporal, parietal, and frontal regions. Additionally, one study comparing PWH to HIV-negative controls found APOE e4 carrier status to be beneficial in younger age, consistent with the well-documented antagonistic pleiotropy effect of APOE across the lifespan, but found that the negative effect of APOE e4 status in persons over the age of 50 was stronger in PWH compared to HIV-negative participants . Despite this one study, few studies have examined if there is a synergistic effect between APOE status and HIV status on cognition and brain integrity, although animal models do suggest possible mechanisms of a synergistic interaction between HIV and APOE status . Notably missing from the HIV literature is an examination of differential associations by sex or race/ethnicity and APOE’s association with cognition and brain integrity. In a meta analysis of aging research studies, APOE e4 women were found to be at greater risk of AD compared to APOE e4 men but only between the ages of 65 and 75 . Additionally, there are known differential effects of APOE status on AD risk by race. The effect of APOE status on AD risk is significantly attenuated in African Americans/Black people compared to non-Hispanic white people . Therefore, future examination of the relationship between sex, race/ethnicity, APOE status, and other genetic markers of AD risk within PWH is certainly warranted.