HIV and Low Omega-3 Levels May Heighten Hippocampal Volume Differences Between Men and Women With Substance Use

Hong Lai; Jiachen Zhuo; Glenn Treisman; Gary Gerstenblith; David D Celentano; Yihong Yang; Betty Jo Salmeron; Hong Gu; Thorsten M Leucker; Xiao Liang; Raul N Mandler; Jag Khalsa; Óscar Peña-Nogales; Shaoguang Chen; Shenghan Lai; Elana Rosenthal; Karl Goodkin; Vincent A Magnotta

doi:10.1016/j.bbih.2025.100988

HIV and Low Omega-3 Levels May Heighten Hippocampal Volume Differences Between Men and Women With Substance Use

Brain Behav Immun Health. 2025 Apr 5:45:100988. doi: 10.1016/j.bbih.2025.100988. eCollection 2025 May.

Authors

Hong Lai¹, Jiachen Zhuo², Glenn Treisman³, Gary Gerstenblith⁴, David D Celentano⁵, Yihong Yang⁶, Betty Jo Salmeron⁶, Hong Gu⁶, Thorsten M Leucker⁴, Xiao Liang², Raul N Mandler⁷, Jag Khalsa¹, Óscar Peña-Nogales⁸, Shaoguang Chen¹, Shenghan Lai^{1

4

5}, Elana Rosenthal¹, Karl Goodkin⁹, Vincent A Magnotta¹⁰

Affiliations

¹ Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.
² Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
³ Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁴ Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
⁷ National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.
⁸ QMENTA, US Headquarters, Boston, MA, USA.
⁹ Department of Psychiatry, University of Texas Rio Grande Valley School of Medicine, Edinburg, TX, USA.
¹⁰ Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Abstract

Background: Sex differences in hippocampal volumes are well-documented, but their interaction with HIV status and omega-3 fatty acids-particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-remains unclear, especially in underserved populations. This study examines how HIV and omega-3 fatty acids influence sex differences in hippocampal volume and explores whether cognitive performance related to episodic memory modifies the association of omega-3 levels with hippocampal volume, considering both HIV status and sex.

Methods: We enrolled 166 participants aged over 45 years from a Baltimore, Maryland cohort. Brain MRIs were performed using a 3.0-T Siemens scanner, and volumetric segmentation was conducted with FreeSurfer (version 6.0), adjusting for intracranial volume (ICV).

Results: Our study found that: (1) Among HIV-negative participants, females had significantly lower hippocampal volumes than males in 1 of 26 regions, whereas HIV-positive females had lower volumes in 13 of 26 regions (p < 0.006 for HIV-negative vs. HIV-positive females), (2) In HIV-positive individuals with EPA levels ≤0.40 %, females exhibited lower volumes in 11 of 26 regions, compared to no differences in those with EPA levels >0.40 % (p = 0.0003 for ≤0.40 % vs. >0.40 %), (3) Across all participants, lower EPA and DHA levels were associated with greater sex differences in hippocampal volumes, which diminished or disappeared at higher EPA and DHA levels (p < 0.00001 for EPA ≤0.40 % vs. >0.40 %; p = 0.004 for DHA ≤2.0 % vs. >2.0 %), and (4) Among Adults with lower episodic memory, higher log-scaled EPA levels were independently associated with greater hippocampal volume.

Conclusions: HIV may amplify sex differences in hippocampal volumes, disproportionately affecting females. Higher EPA and DHA levels may mitigate these effects, suggesting a protective role against hippocampal atrophy. Further studies are warranted to confirm these findings and explore whether the benefits extend to males with HIV or individuals without HIV.

Keywords: Brain MRI; Docosahexaenoic acid (DHA); Eicosapentaenoic acid (EPA); Hippocampal volume; Sex differences; Substance use.

Abstract

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