As the number of older HIV+ individuals continues to rise, a growing need exists to understand the potential interactions between HIV and aging within the brain. Our results suggest that HIV infection and aging independently affect brain functional demands measured by fMRI.
While surprising, the lack of a synergistic interaction between age and HIV infection is comparable to larger a neuropsychological study that showed that age and HIV serostatus were independent risk factors for the development of HIV associated neurocognitive disorders [8
]. While our sample size is significantly smaller than the previous descriptive study, our cohort included women which may better reflect the gender diversity of the disease.
Conflicting results concerning the relationship between HIV and aging have been noted with structural neuroimaging [9
]. An interaction occurred in HAART naïve HIV+ subjects using magnetic resonance spectroscopy with a fivefold increase present in frontal white matter inflammatory and glial metabolites [10
]. In contrast, diffusion tensor imaging of tissue water molecules did not observe age dependent changes within HIV+ subjects on stable HAART [9
]. Discrepancies in results could reflect differences in neuroimaging techniques or the effect of HAART.
While most neuroimaging studies of HIV have investigated the role of subcortical or frontal areas in HIV associated neurocognitive disorders, primary cortical areas have been shown to be affected [11
]. Our analysis was not focused on studying the effects of HIV associated neurocognitive disorders on fMRI measures; but instead we investigated the impact of HIV itself on a cortical structure- the visual cortex. The effects of “normal” aging have been previously characterized in this region [12
]. Observed decreases in baseline cerebral blood flow in HIV− controls with increasing aging are similar to previous neuroimaging studies [12
]. In general, a decrease in baseline cerebral blood flow occurs with HIV infection [14
]. Derangements within primary cortical areas may cause disconnections among higher processing networks despite the absence of abnormalities on traditional structural imaging. The etiology of observed decreases in baseline cerebral blood flow remains unknown but could result from deleterious effects of HIV on platelet function, endothelial function, or dendritic arborization [14
In this cross sectional cohort observed parallel trends for HIV and aging in fMRI measures suggest pathophysiological similarities not only throughout the body but in the brain. Body frailty due to aging and HIV results from a complex interplay among viral factors, host responses, and immune dysfunction causing: 1) a shift in T-cell phenotypes from naïve to memory, 2) an increase in replicative senescence by reducing T-cell proliferation, and 3) an increase in the production and release of cytokines [1
]. Within the brain continued immunological challenges from “normal” aging could deplete available resources triggering increased functional metabolic demands. Although we did not directly correlate neuroimaging measures with markers of brain immune dysfunction, it is reasonable to hypothesize that persistent low levels of HIV and inflammation may deplete brain reserves augmenting functional metabolic requirements. Observed increases in metabolic demands could result from excessive neurotransmission from oxidative stress signaling pathways [15
]. Multiple neurodegenerative and neuroimmune mechanisms may converge in older HIV+ individuals. Future longitudinal analyses are needed as HIV and aging could proceed in parallel making it difficult to distinguish their individual effects.
A number of limitations exist with this study. Co-morbid substance abuse, such as alcoholism or stimulant dependence could influence fMRI outcomes. Many of our subjects had a previous history of drug abuse or used illegal drugs recreationally. However, approximately equal numbers within the HIV− controls (11/25) and HIV+ subjects (10/26) met these criteria. Future studies investigating the interaction between substance abuse, HIV infection, and age are needed. Second, although our cross sectional cohort was modest in size; a larger sample may have demonstrated even greater differences. Despite somewhat large variability within HIV+ patients, observed effect sizes for fMRI measures were quite robust (). Longitudinal studies of older HIV+ patients are required to confirm these initial findings. Third, the impact of HAART on aging could not be analyzed as most of the older HIV+ subjects were on medications. Prospective studies within older HIV+ subjects are needed to address the appropriateness of current HAART regimens, susceptibility to HAART side effects, and the potential for increased vulnerability to adverse drug reactions due to aging.
Despite these limitations our results highlight the potential role for fMRI in the evaluation of possible impact of HIV and aging on brain function. We found that both HIV-infection and advancing age challenge brain perfusion and functional metabolic pathways within the visual cortex. This may represent diminished capacity and functional frailty within this brain region of HIV+ and older adults. We are not advocating the routine use of fMRI for routine diagnostic evaluation of HIV+ subjects due to its relatively limited availability and expense. However, non-invasive fMRI in research settings could provide valuable information concerning basic pathophysiology of HIV in certain brain areas; the potential neurotoxic actions of HAART; and assist in the evaluation of neuroprotective therapeutic strategies for older HIV+ subjects.