Imaging Correlates of the Blood Brain Barrier Disruption in HIV Associated Neurocognitive Disorder and Therapeutic Implications

Abstract

Background and Purpose: Neurocognitive impairment in HIV infection, known as HIV associated neurocognitive disorder (HAND), in the context of suppressive combination antiretroviral therapy still occurs. We hypothesized that ongoing chronic systemic inflammation, a feature of HIV disease despite viral suppression, causes blood brain barrier (BBB) disruption thereby allowing entry of neurotoxic cytokines/chemokines or HIV itself. To test this hypothesis, we have used dynamic contrast enhancement derived metrics (K-trans) to measure the capillary permeability as a direct indicator for BBB disruption and correlated it with neuro inflammatory markers in the cerebrospinal fluid as well as with MR spectroscopy derived metabolites and clinical indices of neurocognition (neuropsychological scores). Materials and Methods: We used the Dynamic contrast enhanced perfusion MR metric, K-trans to measure the BBB disruption in a cohort of 20 patients with HAND who were virally suppressed in both CSF and blood compared with 16 healthy age and sex matched volunteers. Measurement of K-trans, a marker for capillary permeability and hence BBB integrity, was obtained from different regions of the brain and was compared to the age and sex matched controls. Results: The K-trans data showed significantly impaired BBB when compared to the normal controls in the region of basal ganglia and anterior frontal white matter above the ventricular level (both p<0.0001). The CSF -Blood albumin ratios as well as neopterin have correlated positively with K-trans. Conclusion: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region specific (areas known to be vulnerable to HIV) BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that 1. HIV and not systemic inflammation is driving the BBB disturbance and 2. That the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease. These findings generate novel testable hypotheses for HAND pathogenesis with potentially significant therapeutic implications.