Alteration of brain network topology in HIV-associated neurocognitive disorder: A novel functional connectivity perspective

Abstract

HIV is capable of invading the brain soon after seroconversion. This ultimately can lead to deficits in multiple cognitive domains commonly referred to as HIV-associated neurocognitive disorders (HAND). Clinical diagnosis of such deficits requires detailed neuropsychological assessment but clinical signs may be difficult to detect during asymptomatic injury of the central nervous system (CNS). Therefore neuroimaging biomarkers are of particular interest in HAND. In this study, we constructed brain connectivity profiles of 40subjects (20 HIV positive subjects and 20 age-matched seronegative controls) using two different methods: a non-linear mutual connectivity analysis approach and a conventional method based on Pearson's correlation. These profiles were then summarized using graph-theoretic methods characterizing their topological network properties. Standard clinical and laboratory assessments were performed and a battery of neuropsychological (NP) tests was administered for all participating subjects. Based on NP testing, 14 of the seropositive subjects exhibited mild neurologic impairment. Subsequently, we analyzed associations between the network derived measures and neuropsychological assessment scores as well as common clinical laboratory plasma markers (CD4 cell count, HIV RNA) after adjusting for age and gender. Mutual connectivity analysis derived graph-theoretic measures, Modularity and Small Worldness, were significantly (p<0.05, FDR adjusted) associated with the Executive as well as Overall z-score of NP performance. In contrast, network measures derived from conventional correlation-based connectivity did not yield any significant results. Thus, changes in connectivity can be captured using advanced time-series analysis techniques. The demonstrated associations between imaging-derived graph-theoretic properties of brain networks with neuropsychological performance, provides opportunities to further investigate the evolution of HAND in larger, longitudinal studies. Our analysis approach, involving non-linear time-series analysis in conjunction with graph theory, is promising and it may prove to be useful not only in HAND but also in other neurodegenerative disorders. Keywords: HIV, HIV associated neurocognitive disorder, Functional magnetic resonance imaging, Functional connectivity, Mutual connectivity analysi