Regional areas and widths of the midsagittal corpus callosum among HIV-infected patients on stable antiretroviral therapies

Abstract

Recent reports suggest that a growing number of human immunodeficiency virus (HIV)-infected persons show signs of persistent cognitive impairment even in the context of combination antiretroviral therapies (cART). The basis for this finding remains poorly understood as there are only a limited number of studies examining the relationship between CNS injury, measures of disease severity, and cognitive function in the setting of stable disease. This study examined the effects of HIV infection on cerebral white matter using quantitative morphometry of the midsagittal corpus callosum (CC) in 216 chronically infected participants from the multisite HIV Neuroimaging Consortium study currently receiving cART and 139 controls. All participants underwent MRI assessment, and HIV-infected subjects also underwent measures of cognitive function and disease severity. The midsagittal slice of the CC was quantified using two semi-automated procedures. Group comparisons were accomplished using ANOVA, and the relationship between CC morphometry and clinical covariates (current CD4, nadir CD4, plasma and CSF HIV RNA, duration of HIV infection, age, and ADC stage) was assessed using linear regression models. HIV-infected patients showed significant reductions in both the area and linear widths for several regions of the CC. Significant relationships were found with ADC stage and nadir CD4 cell count, but no other clinical variables. Despite effective treatment, significant and possibly irreversible structural loss of the white matter persists in the setting of chronic HIV disease. A history of advanced immune suppression is a strong predictor of this complication and suggests that antiretroviral intervention at earlier stages of infection may be warranted.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders

“…To date, diffusion tensor and magnetic resonance imaging studies and a single transcriptome study have been performed to examine white matter dysfunction in HIV and HAND patients (17, 19, 20), but changes in postmortem myelin protein levels have not been reported. The cohort contained age-matched HIV-negative, HIV-positive patients who were cART-naïve (HIV-positive), and HIV-positive cART-medicated >12 month individuals (HIV-positive/ART) (n = 20 for each group).…”

“…Despite effective viral suppression through antiretroviral therapy, HIV-Associated Neurocognitive Disorders (HAND) persists in infected individuals and is frequently accompanied by pathologic white matter abnormalities (6, 17, 19). Here, we investigated the effects of antiretrovirals in vitro on oligodendrocyte survival and maturation and in vivo on myelin maintenance in both adult mice and HIV-positive individuals.…”

“…An intriguing possibility is whether PIs disrupt the crucially important myelin-lipid balance, which may result in inappropriate organization of myelin components, as previously reported (87, 88, 92, 93). Because PIs have been shown to cause dyslipidemia in patients and in non-CNS cell types (71, 94, 95), this could contribute to the white matter loss seen in HAND patients (17, 19). …”

“…Notably, white matter abnormalities are prevalent and the degree of neurocognitive impairment has been correlated with the amount of damage (15, 16). Imaging studies have also revealed cortical myelin disruption, volume loss, and diminished structural integrity of the corpus callosum in HAND patients, which were even more pronounced in cART-treated individuals (17–19). Furthermore, transcriptome analysis in HAND patients on cART revealed dysregulation of genes critical to oligodendrocyte maturation and myelination, including myelin-associated oligodendrocyte basic protein, myelin transcription factor 1, and myelin basic protein (MBP) (20).…”

Neuroimaging of HIV-associated neurocognitive disorders (HAND)

“…This neuroimaging technique measures the diffusion of water molecules [45,51–53]**. In the isotropic state water motion is equal in all directions (e.g.…”