Greater neuroimmune system deficit in women than men with alcohol use disorder

Yasmin Zakiniaeiz; Ansel T Hillmer; Hannah Shi; Brian Pittman; Nabeel Nabulsi; Yiyun Huang; Robin Bonomi; David Matuskey; Gustavo A Angarita; Sherry A McKee; Kelly P Cosgrove

doi:10.1016/j.biopsych.2025.05.012

Greater neuroimmune system deficit in women than men with alcohol use disorder

Biol Psychiatry. 2025 May 22:S0006-3223(25)01196-5. doi: 10.1016/j.biopsych.2025.05.012. Online ahead of print.

Authors

Affiliations

¹ Department of Psychiatry, Yale University, New Haven, CT. Electronic address: yasmin.zakiniaeiz@yale.edu.
² Department of Psychiatry, Yale University, New Haven, CT; Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT.
³ Yale College, Yale University, New Haven, CT.
⁴ Department of Psychiatry, Yale University, New Haven, CT.
⁵ Yale Positron Emission Tomography (PET) Center, Yale University, New Haven, CT; Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT.

PMID: 40412787
DOI: 10.1016/j.biopsych.2025.05.012

Abstract

Background: Women who drink are more vulnerable than men to many of the consequences of alcohol use, including alcohol-related cancers, cardiovascular disease, liver cirrhosis, and immune system dysfunction. Acute alcohol triggers neuroimmune cells including microglia, the brain's resident immune cells. Excessive activation can contribute to neuronal dysfunction and alcohol-induced neurodegeneration. Women have a greater vulnerability to alcohol-induced neurodegeneration, thus, there is a critical need to examine sex differences in neuroimmune mechanisms underlying AUD to inform novel treatment strategies for women.

Methods: Forty-one individuals with mild-to-moderate AUD (20 women) and 37 sex-matched controls completed one positron emission tomography brain imaging scan with the radiotracer [¹¹C]PBR28, which binds to 18-kDa translocator protein (TSPO), a microglial marker. Volume of distribution was estimated regionally in the cerebellum, hippocampus, striatum, and frontal cortex as a measure of TSPO availability. Neurocognitive function was also assessed.

Results: People with versus without AUD had significant lower TSPO availability in all brain regions. Women (but not men) with AUD had significantly lower TSPO availability (average of 21%) in all four regions (p=0.022) compared to sex-matched controls. Women with vs. without AUD performed worse on executive function (p=0.020). Lower hippocampal (p=0.059) and cerebellar (p=0.097) TSPO availability were trendingly related to more errors on the executive function task in women with AUD.

Conclusions: This study showed lower TSPO levels in people with mild-to-moderate AUD versus controls, and demonstrated that the deficit is significantly greater in women than men with AUD. This suggests that women with AUD may particularly benefit from novel neuroimmune-modulating treatments for AUD.

Keywords: PET imaging; alcohol use disorder; cognition; microglia; neuroimmune system; sex differences.