Proteome-Based Plasma Biomarkers for Cognitive Dysfunction in an Androgen Deprivation Model

Cognitive dysfunction frequently arises from androgen deprivation therapy (ADT), a primary treatment for men with prostate cancer. ADT affects key cognitive functions like memory, learning, reasoning, and decision-making. Extant studies lack a systematic evaluation of biomarkers related to ADT's cognitive impact. To address this, we used nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS) to identify biomarkers in specific brain regions of a mouse model. Sixteen-week-old BALB/c mice received enzalutamide, a nonsteroidal antiandrogen, at 50 mg/kg/day via oral gavage 5 days a week for 8 weeks to simulate the ADT protocol. Control mice received a comparable volume of the vehicle. Enzalutamide treatment resulted in modest weight gain along with behavioral changes, including attention deficits and reduced social activity. ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) showed altered glucose metabolism in the brain and peripheral tissues of treated mice. Histological analysis of brain sections revealed preserved neuron structure in control mice, whereas enzalutamide-treated mice showed decreased neuron density, signs of neuron damage, and astrocyte swelling. Proteomic analysis of the cortex, cerebellum, and hippocampus after euthanasia identified 29 proteins with altered expression linked to cognitive dysfunction in ADT-treated mice. Further validation showed significantly increased levels of Pum2, Mcur1, Slc39a14, Fbxo7, Myo10, Arl6ip1, Slc8a3, Mt1, and Mt3 in the blood plasma of treated mice compared to controls. These results suggest that blood could be a valuable source of biomarkers for ADT-induced cognitive dysfunction. Further studies are needed to assess their clinical applicability in monitoring cognitive decline in prostate cancer patients on ADT and in neurotypical aging.