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Frontostriatal white matter microstructure alterations in HIV and aging
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Aging Workshop Oct 14-15 2022
Shiva Hassanzadeh-Behbahani,1 Kyle F. Shattuck,1 Fan Zhang,2 R. Craig Gallagher Jr.,1 Princy Kumar,1 Lauren J. O’Donnell,2 Ashley S. VanMeter,1 David J. Moore,3 Ronald J. Ellis,3 Xiong Jiang1
1 Georgetown University Medical Center; 2 Brigham and Women’s Hospital, Harvard Medical School; 3 University of California, San Diego
Abstract
Background: Despite the advent of combination antiretroviral therapy, the prevalence of HIV-associated neurocognitive disorders (HAND) remains high. While the neural mechanisms of HAND are unknown, prior studies point to dysfunction within the frontostriatal pathway in people with HIV
(PWH). In this study, we tested the effects of aging and HIV disease on frontostriatal white matter microstructure as measured by diffusion tensor imaging.
Methods: Participants 41-70 years of age were recruited for this study from the greater Washington, D.C. metropolitan area between 2018 and 2021. Diffusion MRI (dMRI) data were acquired with 70 gradient directions using a 3T Siemens Prisma Fit scanner at Georgetown University. Whole-brain tractography was computed for each participant using the two-tensor unscented Kalman filter (UKF) method, as implemented in the open-source ukftractography package
(https://github.com/pnlbwh/ukftractography). We performed tractography analysis and visualization in 3D Slicer
(http://www.slicer.org) via the SlicerDMRI project (https://github.com/SlicerDMRI). Using the O’Donnell Research Group Atlas, the left and right frontostriatal tracts were identified in each participant. Three measures of white matter microstructure were calculated from the frontostriatal tracts: fractional anisotropy, mean diffusivity, and number of streamlines (i.e., the number of reconstructed fibers). We then entered these three dMRI measures as dependent variables in 6 ANCOVA models examining the main effects of HIV serostatus and age on left or right frontostriatal tract microstructure. Education, sex and race were additional covariates. The alpha level was set to 0.05 and p-values were corrected for multiple comparisons using the false discovery rate. Executive and motor function T-scores were compared between PWH and controls and correlated with frontostriatal dMRI measures.
Results: Participants were 66 PWH (mean (SD) age 57.3 (7.2) years, 27% female, 56% Black, education 14.4 (3) years, duration of HIV infection 25.2 (9.8) years, median
(interquartile range) nadir and current CD4+ T-lymphocytes/uL 180 (302) and 617 (413), on ART 98.5%, 90% with undetectable plasma HIV RNA) and 20 demographically comparable controls (age 58 (4.9) years, 25% female, 60% Black, education 14.6 (2.7)). PWH had significantly worse motor performance compared to controls, F(5,80)=5.8, p=0.02, but there was no difference in executive function. Increased age was associated with higher left, F(5,80)=12.3, p=0.003, and right, F(5,80)=11.7, p=0.003, frontostriatal mean diffusivity and fewer left, F(5,80)=5.1, p=0.04, and right,
F(5,80)=9.4, p=0.006, frontostriatal streamlines. Compared to controls, PWH had higher mean diffusivity in the left frontostriatal tract, F(5,80)=6.8, p=0.046, and fewer streamlines in the right frontostriatal tract,
F(5,80)=6.1, p=0.046. There were no significant correlations between behavioral performance and frontostriatal dMRI measures.
Conclusions: Our results support the hypothesis that frontostriatal white matter microstructure is compromised in middle-to-advanced aged PWH compared to controls. Analysis of the main effects of age and HIV serostatus indicates that deterioration in the frontostriatal connections in PWH could be independently impacted by older age. Early identification of brain changes is often associated with neurocognitive impairment and could inform the development of diagnostic methods for HAND.
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