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Androgen deprivation therapy and cognitive decline—associations with brain connectomes, endocrine status, and risk genotypes

Subjects

Abstract

Background

Evidence suggests that prostate cancer (PC) patients undergoing androgen deprivation therapy (ADT) are at risk for cognitive decline (CD), but the underlying mechanisms are less clear. In the present study, changes in cognitive performance and structural brain connectomes in PC patients undergoing ADT were assessed, and associations of cognitive changes with endocrine status and risk genotypes were explored.

Methods

Thirty-seven PC patients underwent cognitive assessment, structural MRI, and provided blood samples prior to ADT and after 6 months of treatment. Twenty-seven age- and education-matched healthy controls (HCs) underwent the same assessments. CD was determined using a standardized regression-based approach and defined as z-scores ≤ −1.64. Changes in brain connectomes were evaluated using graph theory. Associations of CD with testosterone levels and genotypes (APOE, COMT, BDNF) were explored.

Results

Compared with HCs, PC patients demonstrated reduced testosterone levels (p < 0.01) and higher rates of decline for 13 out of 15 cognitive outcomes, with three outcomes related to two cognitive domains, i.e., verbal memory and visuospatial learning and memory, reaching statistical significance (p ≤ 0.01–0.04). Testosterone level changes did not predict CD. COMT Met homozygote PC patients evidenced larger reductions in visuospatial memory compared with Val carriers (p = 0.02). No between-group differences were observed in brain connectomes across time, and no effects were found of APOE and BDNF.

Conclusions

Our results indicate that PC patients undergoing ADT may evidence CD, and that COMT Met homozygotes may be at increased risk of CD. The results did not reveal changes in brain connectomes or testosterone levels as underlying mechanisms. More research evaluating the role of ADT-related disruption of the dynamics of the hypothalamic–pituitary–gonadal axis is needed.

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Fig. 1: Study flow diagram.

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

CHG is a member of the European Reference Network on Rare Endocrine Conditions (ENDO-ERN), Project ID number 739543.

Funding

This work was supported by grants from Aase & Ejnar Danielsens Fond; Fabrikant Einar Willumsens Mindelegat; Fonden for Laegevidenskabens fremme; and C.C. Klestrup & hustru Henriette Klestrups Mindelegat.

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Correspondence to Cecilie R. Buskbjerg.

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The authors declare no competing interests.

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The present study was conducted in accordance with the Declaration of Helsinki and approved by The Regional Scientific Ethical Committee for Central Denmark Region (No. 1-10-72-406-17). The data were collected and stored in accordance with the Danish Data Protection Agency guidelines, and written informed consent was obtained from all participants upon enrollment.

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Buskbjerg, C.R., Amidi, A., Buus, S. et al. Androgen deprivation therapy and cognitive decline—associations with brain connectomes, endocrine status, and risk genotypes. Prostate Cancer Prostatic Dis (2021). https://doi.org/10.1038/s41391-021-00398-1

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