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

Abstract

Background: Despite 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.

Methods: In 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.

Results: Among 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.

Conclusions: Although 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.

Figure 1

Regional brainactivations duringcognitive controlwhile performingthe stopsignal task. ADT = patients who received 6 months of androgen deprivation therapy; Controls = patients who did not receive any hormonal therapy; B = baseline; F = at 6- month follow-up. The significance of activation, as reflected by a map of T values (color bar), is shown here on a structural brain image in axial sections, from z = -10 to z = +60, with adjacent sections 10 mm apart. Neurological orientation: Right (R) = right. Note that ADT patients showed diminished activations in a number of brain regions at 6 month follow-up, including the medial prefrontal cortex (MPFC), an area critical for cognitive control.

Figure 2

The effectsize ofmedial prefrontalcortical (MPFC)activations. Control patients are shown on the left panel; ADT patients are shown on the right panel; B = baseline; F = at 6-month follow-up. In each panel, each symbol and line represents the data of an individual patient. The gray bars indicate the mean value of the effect sizes of MPFC activations. Individuals varied in the change of MPFC activations from baseline to follow-up, but, on average, the ADT group showed significant decrease in MPFC activations after 6 months of ADT, as compared to the control group.

Figure 3

Changes inresting statefunctional connectivitywith themedial prefrontalcortex asresult ofADT. After 6 months of ADT, patients showed decreased connectivity with the dorsolateral prefrontal cortex (DLPFC), rostral anterior cingulate cortex, and the insula, all on the right side, as compared to control patients. (a) ADT_B > ADT_F; (b) Control_B > Control_F; (c) (Control_F > Control_B) – (ADT_F > ADT_B). B: baseline; F: follow-up. The significance of difference, as reflected by a map of T values (color bar), is shown here on a structural brain image in axial sections, from z = -10 to z = +60, with adjacent sections 10 mm apart. Neurological orientation: Right (R) = right.