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

Vaibhav Singh^{1

2}, Shiv Verma^{1

2}, Eswar Shankar^{1

2

3}, Diya Swain^{1

4}, Belinda B Willard⁵, Herta H Chao^{6

7}, Chiang-Shan R Li⁸, Zhenghong Lee⁹, Gregory T MacLennan¹⁰, Lee E Ponsky^{1

2}, Sanjay Gupta^{11

12

13

14

15

16}

Affiliations

¹ Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
² The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106 , USA.
³ Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43,210, USA.
⁴ College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, 44,016, USA.
⁵ Proteomics and Metabolomics Core, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
⁶ Department of Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁷ Cancer Center, Veterans Administration Connecticut Healthcare Systems, West Haven, CT, 06516, USA.
⁸ Department of Psychiatry and of Neuroscience, Yale University School of Medicine, New Haven, CT, 06519, USA.
⁹ Department of Radiology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
¹⁰ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
¹¹ Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹² The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106 , USA. sanjay.gupta@case.edu.
¹³ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁴ Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁵ Department of Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁶ Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.

PMID: 41315084
DOI: 10.1007/s12035-025-05548-3

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

Vaibhav Singh et al. Mol Neurobiol. 2025.

. 2025 Nov 28;63(1):201.

doi: 10.1007/s12035-025-05548-3.

Authors

Affiliations

¹ Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
² The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106 , USA.
³ Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43,210, USA.
⁴ College of Arts and Sciences, Case Western Reserve University, Cleveland, OH, 44,016, USA.
⁵ Proteomics and Metabolomics Core, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, USA.
⁶ Department of Medicine, Yale University School of Medicine, New Haven, CT, 06510, USA.
⁷ Cancer Center, Veterans Administration Connecticut Healthcare Systems, West Haven, CT, 06516, USA.
⁸ Department of Psychiatry and of Neuroscience, Yale University School of Medicine, New Haven, CT, 06519, USA.
⁹ Department of Radiology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
¹⁰ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.
¹¹ Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹² The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106 , USA. sanjay.gupta@case.edu.
¹³ Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁴ Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁵ Department of Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.
¹⁶ Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, 44106, USA. sanjay.gupta@case.edu.

PMID: 41315084
DOI: 10.1007/s12035-025-05548-3

Abstract

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.

Keywords: Androgen deprivation therapy; Androgen receptor; Cognitive dysfunction; Enzalutamide; Proteomics.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no competing interests.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

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Grants and funding

LinkOut - more resources

Full Text Sources