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.

Fig. 1

Illustration of quantification method. The left side panels show the modified Witelson protocol where the CC is divided into five functionally related areas. The right side of the figure shows the linear widths measurement method developed by our lab to quantify the width of the CC at 100 equidistant points along the length of the CC. First step for each method (see A) is to manually trace the midsagittal CC. In step B, the CC is divided into different area based on a standard division of the linear length. In step C, the CC is labeled and quantified. In step D, the manual tracing is subjected to a smoothing algorithm and the median curve of the CC is produced (black line). In step E, the median curve is divided into 100 equal points where the line is then bisected to produce a linear width at that point

Fig. 2

Comparison of the line widths between the groups. a The actual beta (black line; x-axis) and the 95% confidence interval (blue dashed line) when comparing the ADC patients and controls. b The actual beta (black line) and the 95% confidence interval (blue dashed line) when comparing the NA patients and controls. c The actual beta (black line) and the 95% confidence interval (blue dashed line) when comparing the ADC and NA patients. d The actual linear width differences along the whole length of the CC for each of the groups (controls = black line, NA = red dashed line, and ADC = green dashed line)

Fig. 3

Figure illustrating the beta values (black line; x-axis) and the 95% confidence interval (blue dashed lines) for each multivariable regression analysis

Fig. 4

Figure illustrating readily observable qualitative difference across controls and patients with similar demographic and clinical variables. ADC ADC staging, Nadir Nadir CD4 cell count, PVL plasma viral load (all patients were less than 75), CCD4 current CD4 cell count