ENIGMA-HIV: White matter microstructural abnormalities in a global sample of people living with HIV
Presented During:
Wednesday, June 26, 2024: 11:30 AM - 12:45 PM
COEX
Room:
Grand Ballroom 103
Poster No:
158
Submission Type:
Abstract Submission
Authors:
Talia Nir1, Elizabeth Haddad1, Catherine Wedderburn2,3, Aliaa Ibnidris2, Jasmina Boban4, Linda Chang5,6, Lucette Cysique7, Thomas Ernst5, Jaroslaw Harezlak8, Jonathan Ipser2, John Joska2, Kalpana Kallianpur9,10, Joel Kramer11, Taylor Kuhn12, Hei Lam1, Andrew Levine12, Beau Nakamoto9, Bradford Navia13, Eric Porges14, Cecilia Shikuma9, April Thames12, Victor Valcour11, Sophia Thomopoulos1, Ronald Cohen14, Paul Thompson1, Robert Paul15, Dan Stein2, Neda Jahanshad1
Institutions:
1University of Southern California Keck School of Medicine, Marina del Rey, CA, 2University of Cape Town, Cape Town, South Africa, 3London School of Hygiene & Tropical Medicine, London, United Kingdom, 4University of Novi Sad, Novi Sad, Serbia, 5University of Maryland School of Medicine, Baltimore, MD, 6Johns Hopkins School of Medicine, Baltimore, MD, 7University of New South Wales, Sydney, New South Wales, 8Indiana University School of Public Health, Bloomington, IN, 9University of Hawaii, Honolulu, HI, 10Kamehameha Schools - Kapālama, Honolulu, HI, 11University of California San Francisco, San Francisco, CA, 12University of California Los Angeles, Los Angeles, CA, 13Tufts University Medical School, Boston, MA, 14University of Florida, Gainesville, FL, 15University of Missouri St. Louis, St. Louis, MO
First Author:
Co-Author(s):
Catherine Wedderburn
University of Cape Town|London School of Hygiene & Tropical Medicine
Cape Town, South Africa|London, United Kingdom
University of Cape Town|London School of Hygiene & Tropical Medicine
Cape Town, South Africa|London, United Kingdom
Linda Chang
University of Maryland School of Medicine|Johns Hopkins School of Medicine
Baltimore, MD|Baltimore, MD
University of Maryland School of Medicine|Johns Hopkins School of Medicine
Baltimore, MD|Baltimore, MD
Introduction:
HIV remains a global public health challenge with an estimated 39 million people living with HIV [1]. Despite widespread access to antiretroviral therapy (ART), neurocognitive impairment is a persistent issue in people living with chronic HIV infection [2]. Persistent HIV viral reservoir instigates an inflammatory cascade that leads to neural dysfunction, often accompanied by white matter (WM) damage. However, clinical and demographic heterogeneity in people with HIV (PwH) worldwide, and variations in MRI acquisition, processing, and analysis methods yielded inconsistencies in reported HIV-related WM differences detected across studies. Here, we pooled diffusion MRI (dMRI) data from ten independent worldwide neuroHIV studies as part of the ENIGMA-HIV consortium [3]; we aimed to identify generalizable WM microstructural associations with infection using standardized data analysis pipelines.
Methods:
The ENIGMA-HIV DTI working group is currently made up of ten neuroHIV studies from the United States, South Africa, Australia, and Serbia (Table 1). In total, dMRI data from 840 PwH (all studies; aged 20.5-80 yrs; 71.8% male; 78.1% on ART) and 280 HIV-negative controls were analyzed (6 studies; aged 17-29 yrs; 66.8% male). dMRI were preprocessed and DTI FA, MD, RD, and AD maps were computed, in addition to a more advanced dMRI model FA, TDF FA [4]. Using the standardized ENIGMA-DTI protocols [5], each subject's dMRI maps were warped to the ENIGMA-DTI template and dMRI indices projected onto the template skeleton with TBSS [6]. Mean skeletonized dMRI measures were extracted from 24 JHU WM atlas regions of interest (ROIs) and the full WM skeleton (FullWM). Random effects linear regressions were performed to evaluate associations between regional dMRI measures and 1) HIV-diagnosis when compared to controls (Dx; 6 studies); or 2) blood plasma markers in PwH (all studies): current CD4+ T-cell count (cells/mm3) and a detectable or undetectable viral load (VL). We also tested for Dx- or plasma marker-by-age interactions, as HIV may accelerate age-related effects on WM microstructure. Study was used as the random-effects grouping variable; fixed-effects covariates included age, sex, and their interaction. Statistical models testing for HIV plasma marker associations within PwH also included ART status at the time of scan (ART+ or ART-) as a covariate. The false discovery rate was used to correct for multiple comparisons (q=0.05).
Results:
Lower anisotropy and higher diffusivity measures were associated with (1) HIV-Dx when compared to controls (Fig 2a,b) and (2) lower CD4+ counts in PwH (Fig 2d); no associations with detectable VL were found. Widespread regional associations were detected across all dMRI measures except DTI FA. Significant FullWM CD4+ and Dx associations were also found suggesting global WM effects. The largest effect sizes in case-control analyses were found in regions of the CC, CR, UNC, and Fx; these effects remained significant when also covarying for FullWM dMRI values. The largest CD4+ dMRI associations were found in the TAP, CR, EC, FX, and FX/ST. Only AD FX and TAP effects were significant beyond the FullWM effect (Fig 2a).
Widespread Dx-by-age interactions revealed steeper negative anisotropy and positive diffusivity slopes with respect to age in PwH compared to controls (Fig 2c). No plasma marker-by-age interactions were found.
Widespread Dx-by-age interactions revealed steeper negative anisotropy and positive diffusivity slopes with respect to age in PwH compared to controls (Fig 2c). No plasma marker-by-age interactions were found.
Conclusions:
In a large-scale international population of PwH, widespread WM microstructural abnormalities were consistently associated with HIV infection. While effects were often global, the largest effects were detected in limbic and temporal lobe tracts often implicated in aging and neurodegenerative conditions such as Alzheimer's disease. Coupled with significant HIV diagnosis-by-age interactions, our results support evidence that common age and HIV-related pathological processes, such as inflammation and blood brain barrier impairment, may accelerate age-related neurodegenerative processes [7].
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis 2
Keywords:
Infections
White Matter
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
Other - HIV; ENIGMA
1|2Indicates the priority used for review
Provide references using author date format
[2] Keng LD, et al. (2023), 'The global burden of cognitive impairment in people with HIV', AIDS, 37(1):61-70.
[3] Nir TM, et al. (2021), 'Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV', JAMA Network Open, 4(1):e2031190.
[4] Nir TM, et al. (2017), 'Fractional anisotropy derived from the diffusion tensor distribution function boosts power to detect Alzheimer's disease deficits', Magn Reson Med, 78(6):2322-2333.
[5] Jahanshad N et al. (2013), 'Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: a pilot project of the ENIGMA-DTI working group', Neuroimage, 1(8)1:455-469.
[6] Smith SM et al. (2006), 'Tract-based spatial statistics: Voxelwise analysis of multi-subject diffusion data', NeuroImage, 31:1487-1505.
[7] Cysique LA, Brew BJ (2014), 'The effects of HIV and aging on brain functions: proposing a research framework and update on last 3 years' findings', Current opinion in HIV and AIDS, 9(4):355-364.