Effects of androgen deprivation on brain function in prostate cancer patients – a prospective observational cohort analysis

BackgroundDespite a lack of consensus regarding effectiveness, androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer. To examine a particular clinical concern regarding the possible impact of ADT on cognition, the current study combined neuropsychological testing with functional magnetic resonance imaging (fMRI) to assess both brain activation during cognitive performance as well as the integrity of brain connectivity.MethodsIn a prospective observational cohort analysis of men with non-metastatic prostate cancer at a Veterans Affairs medical center, patients receiving ADT were compared with patients not receiving ADT at baseline and at 6 months. Assessments included fMRI, the N-back task (for working memory), the stop-signal task (for cognitive control), and a quality of life questionnaire.ResultsAmong 36 patients enrolled (18 in each group), 30 completed study evaluations (15 in each group); 5 withdrew participation and 1 died. Results for the N-back task, stop-signal task, and quality of life were similar at 6 months vs. baseline in each group. In contrast, statistically significant associations were found between ADT use (vs. non use) and decreased medial prefrontal cortical activation during cognitive control, as well as decreased connectivity between the medial prefrontal cortex and other regions involved with cognitive control.ConclusionsAlthough ADT for 6 months did not affect selected tests of cognitive function, brain activations during cognitive control and functional brain connectivity were impaired on fMRI. The long-term clinical implications of these changes are not known and warrant future study.

[1]  R. Martins,et al.  One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men , 2004, Psychoneuroendocrinology.

[2]  S. Resnick,et al.  Free testosterone and risk for Alzheimer disease in older men , 2004, Neurology.

[3]  C. Nelson,et al.  Cognitive effects of hormone therapy in men with prostate cancer , 2008, Cancer.

[4]  E. R. Peskind,et al.  Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men , 2007, Psychoneuroendocrinology.

[5]  Erno J. Hermans,et al.  Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women , 2010, NeuroImage.

[6]  A. Saykin,et al.  Brain structure and function differences in monozygotic twins: possible effects of breast cancer chemotherapy. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Leila Mohammadi,et al.  BMC Cancer , 2001 .

[8]  A. Leemans,et al.  Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  A. Baddeley Working memory: looking back and looking forward , 2003, Nature Reviews Neuroscience.

[10]  M. Fox,et al.  Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging , 2007, Nature Reviews Neuroscience.

[11]  Jacob Cohen Statistical Power Analysis for the Behavioral Sciences , 1969, The SAGE Encyclopedia of Research Design.

[12]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[13]  Chiang-shan R. Li,et al.  Biological markers of the effects of intravenous methylphenidate on improving inhibitory control in cocaine-dependent patients , 2010, Proceedings of the National Academy of Sciences.

[14]  R. Schlösser,et al.  Fronto-striatal hypoactivation during correct information retrieval in patients with schizophrenia: An fMRI study , 2008, Neuroscience.

[15]  A. Shelton,et al.  Changes in neuronal activation patterns in response to androgen deprivation therapy: a pilot study , 2010, BMC Cancer.

[16]  W. E. Barnes,et al.  Testosterone treatment enhances regional brain perfusion in hypogonadal men. , 2003, The Journal of clinical endocrinology and metabolism.

[17]  D. Lubeck,et al.  Contemporary patterns of androgen deprivation therapy use for newly diagnosed prostate cancer. , 2002, Urology.

[18]  Susan M. Resnick,et al.  Long-term measures of free testosterone predict regional cerebral blood flow patterns in elderly men , 2007, Neurobiology of Aging.

[19]  G. Birbeck,et al.  A Systematic Review of Neuroimaging for Cerebral Palsy , 2007, Journal of child neurology.

[20]  P. Ganz,et al.  Breast Cancer Treatment and Cognitive Functioning: Current Status and Future Challenges in Assessment , 2005, Breast Cancer Research and Treatment.

[21]  S. Asthana,et al.  Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment , 2005, Neurology.

[22]  S. Gogov,et al.  Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. , 2006, Critical reviews in oncology/hematology.

[23]  G. Logan,et al.  On the ability to inhibit simple and choice reaction time responses: a model and a method. , 1984, Journal of experimental psychology. Human perception and performance.

[24]  Michael E. Phelps,et al.  Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy , 2007, Breast Cancer Research and Treatment.

[25]  Z. Shahrivar,et al.  Structured Clinical Interview for DSM-IV (SCID): Persian Translation and Cultural Adaptation , 2007 .

[26]  J. Goodwin,et al.  Increasing use of gonadotropin‐releasing hormone agonists for the treatment of localized prostate carcinoma , 2005, Cancer.

[27]  C. Li,et al.  Activation of the pre-supplementary motor area but not inferior prefrontal cortex in association with short stop signal reaction time – an intra-subject analysis , 2009, BMC Neuroscience.

[28]  M. Phillips,et al.  Healthy adolescents' neural response to reward: associations with puberty, positive affect, and depressive symptoms. , 2010, Journal of the American Academy of Child and Adolescent Psychiatry.

[29]  P. Goldman-Rakic,et al.  Impairment of Working Memory Maintenance and Response in Schizophrenia: Functional Magnetic Resonance Imaging Evidence , 2008, Biological Psychiatry.

[30]  W. Kirchner Age differences in short-term retention of rapidly changing information. , 1958, Journal of experimental psychology.

[31]  Chiang-shan Ray Li,et al.  Neural correlates of speeded as compared with delayed responses in a stop signal task: an indirect analog of risk taking and association with an anxiety trait. , 2009, Cerebral cortex.

[32]  M. Rushworth Intention, Choice, and the Medial Frontal Cortex , 2008, Annals of the New York Academy of Sciences.

[33]  Ruth O'Hara,et al.  Prefrontal cortex and executive function impairments in primary breast cancer. , 2011, Archives of neurology.

[34]  L. Parvinen,et al.  Androgen deprivation and cognition in prostate cancer , 2003, British Journal of Cancer.

[35]  Abraham Z. Snyder,et al.  A method for using blocked and event-related fMRI data to study “resting state” functional connectivity , 2007, NeuroImage.

[36]  K. R. Ridderinkhof,et al.  Neurocognitive mechanisms of cognitive control: The role of prefrontal cortex in action selection, response inhibition, performance monitoring, and reward-based learning , 2004, Brain and Cognition.

[37]  R. Gardiner,et al.  Altered cognitive function in men treated for prostate cancer with luteinizing hormone‐releasing hormone analogues and cyproterone acetate: a randomized controlled trial , 2002, BJU international.

[38]  K. Pienta,et al.  Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. , 1997, Urology.

[39]  A. Kenny,et al.  Effects of testosterone on behavior, depression, and cognitive function in older men with mild cognitive loss. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[40]  Jean-Luc Anton,et al.  Region of interest analysis using an SPM toolbox , 2010 .

[41]  J. Buitelaar,et al.  Testosterone Increases Amygdala Reactivity in Middle-Aged Women to a Young Adulthood Level , 2008, Neuropsychopharmacology.

[42]  C. Cotman,et al.  Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. , 2006, Archives of neurology.

[43]  T. Edginton,et al.  Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study , 2005, BJU international.

[44]  A. Meyer-Lindenberg,et al.  Dysfunctional prefrontal regional specialization and compensation in schizophrenia. , 2006, The American journal of psychiatry.

[45]  I. Tannock,et al.  Impact of androgen deprivation therapy on physical and cognitive function, as well as quality of life of patients with nonmetastatic prostate cancer. , 2006, The Journal of urology.

[46]  William J Jagust,et al.  Estrogen- and tamoxifen-associated effects on brain structure and function , 2004, NeuroImage.

[47]  Steven P. Miller,et al.  Neurology of congenital heart disease: insight from brain imaging , 2007, Archives of Disease in Childhood Fetal and Neonatal Edition.

[48]  Robert C. Wolpert,et al.  A Review of the , 1985 .

[49]  I. Tannock,et al.  Impact of androgen-deprivation therapy on cognitive function in men with nonmetastatic prostate cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.