TY - JOUR T1 - Fixel-Based Analysis and Free Water Corrected DTI Evaluation of HIV Associated Neurocognitive Disorders JF - bioRxiv DO - 10.1101/2021.05.06.443022 SP - 2021.05.06.443022 AU - Alan Finkelstein AU - Abrar Faiyaz AU - Miriam T. Weber AU - Xing Qiu AU - Md Nasir Uddin AU - Jianhui Zhong AU - Giovanni Schifitto Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/07/2021.05.06.443022.abstract N2 - Background White matter (WM) damage is a consistent finding in HIV infected (HIV+) individuals. Previous studies have evaluated WM fiber tract specific brain regions in HIV-associated neurocognitive disorders (HAND) using conventional diffusion tensor imaging (DTI). However, DTI might lack an accurate biological interpretation, and the technique suffers from several limitations. Fixel-based analysis (FBA) and free water corrected DTI (fwcDTI) have recently emerged as useful techniques to quantify abnormalities in WM. Here, we sought to evaluate FBA and fwcDTI metrics between HIV+ and HIV-individuals. Using machine learning classifiers, we compared the specificity of both FBA and fwcDTI metrics in their ability to distinguish between individuals with and without cognitive impairment.Methods Forty-two HIV+ and 52 HIV-participants underwent MRI exam, clinical and neuropsychological assessments. FBA metrics included fiber density (FD), fiber bundle cross-section (FC), and fiber density and cross-section (FDC). We also obtained fwcDTI metrics such as fractional anisotropy (FAT) and mean diffusivity (MDT). Tract-based spatial statistics (TBSS) was performed on FAT and MDT. We evaluated the correlations between MRI metrics with cognitive performance and blood markers, such as neurofilament light chain NfL, and Tau protein. Statistical significance was evaluated at α = 0.05. Four different binary classifiers were used to show the specificity of the MRI metrics for classifying cognitive impairment in HIV+ individuals.Results Whole brain FBA showed significant reductions (up to 15%) in various fiber bundles, specifically, the cerebral peduncle, posterior limb of internal capsule, middle cerebellar peduncle and superior corona radiata. TBSS of fwcDTI metrics revealed decreased FAT (by 1-2%) in HIV+ individuals compared to HIV-individuals in areas consistent with those observed in FBA, but these were not significant. An adaptive boosting binary classifier reliably distinguished between cognitively normal patients and those with cognitive impairment with 80% precision and 78% recall. The mean area under the curve (AUC) was 0.805 ± 0.093 for the receiver operatic characteristic (ROC) curve, and 0.859 ± 0.133 for the precision-recall curve, using five-fold cross validation.Conclusion Our findings lend support that FBA may serve as a potential in vivo biomarker for evaluating and monitoring patients with HIV at risk for neurocognitive impairment, and emphasizes the importance of utilizing more complex diffusion models in evaluating HIV infection.Competing Interest StatementThe authors have declared no competing interest.cARTCombined antiretroviral therapyCNScentral nervous systemBBBblood brain barrierWMwhite matterHANDHIV associated neurocognitive disorderFWfree waterDTIdiffusion tensor imagingFAfractional anisotropyADaxial diffusivityRDradial diffusivityMDmean diffusivityTBSSTract-based spatial statisticsCSFcerebrospinal fluidFATfree water correctedFA; MDTfree water corrected MDFBAfixel based analysisFDfiber densityFCfiber bundle cross sectionFDCfiber density cross sectionAFDapparent fiber densityFODfiber orientation distributionMT-CSDmulti tissue constrained spherical deconvolutionGMgrey matterNfLneurofilament light chainVVLviral loadGLMgeneral linear modelCFEconnectivity based fixel enhancementFDRfalse discovery rateROIregion of interestTFCEthreshold-free cluster enhancementWNLwithin normal limitsANIasymptomatic neurological impairmentMNDminor neurocognitive impairmentCIcognitively impairedkPCAkernel principal component analysisLDAlinear discriminant analysisPPVpositive predictive valueROCreceiver operating characteristicAUCarea under the curvefwcDTIfree water corrected DTIDWIdiffusion weighted imagingPLICposterior limb of the internal capsuleMCPmiddle cerebellar pedunclesSCRsuperior corona radiataCPcerebellar peduncleSLFsuperior longitudinal fasciculusAdaBoostadaptive boostingPRCprecision recall curveDMNdefault mode networkCSTcorticospinal tract ER -