ABSTRACT
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 Statement
The authors have declared no competing interest.
Footnotes
Grant Support: This work was supported by The National Institutes of Health (NIH; R01 MH099921, R01 AG054328, and R01 MH118020).
Abbreviations
- cART
- Combined antiretroviral therapy
- CNS
- central nervous system
- BBB
- blood brain barrier
- WM
- white matter
- HAND
- HIV associated neurocognitive disorder
- FW
- free water
- DTI
- diffusion tensor imaging
- FA
- fractional anisotropy
- AD
- axial diffusivity
- RD
- radial diffusivity
- MD
- mean diffusivity
- TBSS
- Tract-based spatial statistics
- CSF
- cerebrospinal fluid
- FAT
- free water corrected
- FA; MDT
- free water corrected MD
- FBA
- fixel based analysis
- FD
- fiber density
- FC
- fiber bundle cross section
- FDC
- fiber density cross section
- AFD
- apparent fiber density
- FOD
- fiber orientation distribution
- MT-CSD
- multi tissue constrained spherical deconvolution
- GM
- grey matter
- NfL
- neurofilament light chain
- VVL
- viral load
- GLM
- general linear model
- CFE
- connectivity based fixel enhancement
- FDR
- false discovery rate
- ROI
- region of interest
- TFCE
- threshold-free cluster enhancement
- WNL
- within normal limits
- ANI
- asymptomatic neurological impairment
- MND
- minor neurocognitive impairment
- CI
- cognitively impaired
- kPCA
- kernel principal component analysis
- LDA
- linear discriminant analysis
- PPV
- positive predictive value
- ROC
- receiver operating characteristic
- AUC
- area under the curve
- fwcDTI
- free water corrected DTI
- DWI
- diffusion weighted imaging
- PLIC
- posterior limb of the internal capsule
- MCP
- middle cerebellar peduncles
- SCR
- superior corona radiata
- CP
- cerebellar peduncle
- SLF
- superior longitudinal fasciculus
- AdaBoost
- adaptive boosting
- PRC
- precision recall curve
- DMN
- default mode network
- CST
- corticospinal tract