Mechanisms Underlying HIV-Associated Neurocognitive Disorders Based On FMRI And DTI

Magnetic resonance imaging(MRI)is one of the several diagnostic techniques that have transformed our understanding of disease neuropathology.However,for decades,little is known about the fundamental mechanisms attributing to HIV-associated neurocognitive disorders(HAND),which appear prevalent among HIV patients despite the advancement of antiretroviral therapy.Understanding neuromechanics of HAND would aid to new therapeutic discoveries.This study,first,provides a comprehensive insights into possible pathways of HIV entry to the brain and how blocking these HIV pathways would be clinically advantageous to halting the progression of HAND.Here we have elucidated cellular innate-immune system-mediated activities that weaken the strength of the brain-blood barrier and CSF-blood barriers,leading to the permeability of the HIV-mediated microphage and several neurotic elements.In the second part of this study,we established scientific evidence describing the functional dynamics that may underlie cognitive impairments observed in 30-70%of HIV patients.Here,we applied fMRI data,sliding windows,K-means clustering algorithms,and general linear models to construct and assess the properties of dynamic resting-state functional connectivity(dynamic RSFC)and transient states.Sixteen HIV patients with asymptomatic neurocognitive impairment and 16-age-gender-matched healthy controls were recruited.Results showed that HIV patients exhibited greater variability in the dynamic RSFC of the left pallidum and regions of the right precentral and postcentral gyri.The dynamic RSFC variability of the regions of the right supramarginal gyrus and regions of the right putamen and left pallidum was also increased.Increased variability was further found in the frontal RSFC of the regions of the left inferior frontal gyrus(pars orbitalis)and the right superior frontal gyrus(medial part).These dynamic changes in the striato-sensorimotor RSFC were associated with deficits in learning and memory(recall),suggesting their contribution to impairment for these cognitive functions.Deficits in attention and working memory were also associated with dynamic changes in the frontal RSFC,indicative of the impact of frontal dynamics on the function of this cognitive domain.Dynamic changes expressed by striato-parietal RSFC and reduced state transitioning in the weakly connected occipital networks were related to immunological functions(CD4+/CD8+and CD4+T-cell counts).In the third part of this study,we evaluated in-depth how the waste product clearance system of the brain,called the glymphatic system,in cART treatment,may provide new therapeutic mechanisms for restoration of the deteriorating cognitive function in HIV patients,following the disruption of the micro-environmental fluid homeostasis due to inflammatory components,HVI-neurotoxins,abnormal metabolites,elevated CSF quinolinic acid,immune-mediated toxins,and abnormal microglial or astroglial activation.Here,diffusion tensor imaging(DTI)-guided and unguided approaches,and the novel technique called "the analysis of along the perivascular space"(ALPS)were applied to examine the glymphatic flow and clearance along the perivascular space(PVS)in the middle-aged HIV-patients(n=27)successfully virosuppressed with no signs of cognitive impairment in the neuropsychological battery tests,and healthy controls(n=27).Innovatively,the analysis was performed using DTI-unguided atlas-based,manually DTI-guided delineated,and 5mm-diameter DTI-guided regions of interest(ROIs)placed on the areas of projection and association fibers.The results demonstrated that the DTI-ALPS index,an indicator of glymphatic status,of middle-aged HIV-patients who have been receiving cART over one-to-six years increased significantly in both the left and right PVSs.The ALPS index of the right PVS which was increasing with increasing performance of attention and working memory demonstrated higher discriminating power than that of the left PVS,while generally,the ALPS index of the DTI-guided approaches shows discrimination superiority over that of the DTI-unguided approach.We also found that the longer duration on cART was positively correlated with the improvement of abstract and executive function,and learning and recall.Fourthly,this research investigates cerebrovascular reactivity(CVR)of individuals living with HIV using the BOLD-fMRI signal.The evidence that signaling between various elements of neurovascular units becomes dysfunctional,leading to uncoupling and dysregulation of cerebral blood flow(CBF)in response to neural and metabolic demands in cognitively impaired individuals,has motivated probing the impact of HIV in CVR and investigating whether early HAND is to some degree attributed to dysfunctional CVR in HIV patients.This is clinically important as dysfunctional CVR impairs blood delivery to brain regions,which may precede and contributes to neuropathology over time.Eighteen HIV patients and 20 health controls were recruited.Neuroimaging and clinical data were collected and analyzed.HIV patients demonstrated increased CVR index in the sensorimotor regions,cerebellum and regions of basal ganglia,especially the caudate nucleus.These changes in cerebrovascular reactivity were associated with cognitive performances of Learning and recall and attention and working memory.Collectively,our findings provide novel insights that(1)functional dynamics are vulnerable to HIV infections and their alterations have a significant impact on cognitive dysfunctions;(2)HIV also disrupts the cognitively relevant micro-environmental fluid homeostasis and glymphatic flow and clearance that might play a key role in these cognitive dysfunctions seen among the HIV patients;(3)cerebrovascular dysfunction may to some degree contribute to HAND.These findings also suggest that therapeutic initiatives to halt or restore HAND should target enhancing glymphatic flow and clearance,pathways of cerebral blood flow,and dynamics of the synaptic communications.