Cognitive Dysfunction in Patients Treated with Androgen Deprivation Therapy: A Multimodality Functional Imaging Study to Evaluate Neuroinflammation

Azeem Saleem, Syed Imran Ali Shah, Stephen A Mangar, Christopher Coello, Matthew B Wall, Gaia Rizzo, Terry Jones, Patricia M Price, Azeem Saleem, Syed Imran Ali Shah, Stephen A Mangar, Christopher Coello, Matthew B Wall, Gaia Rizzo, Terry Jones, Patricia M Price

Abstract

Background: Androgen deprivation therapy (ADT) for prostate cancer is implicated as a possible cause of cognitive impairment (CI). CI in dementia and Alzheimer's disease is associated with neuroinflammation. In this study, we investigated a potential role of neuroinflammation in ADT-related CI.

Methods: Patients with prostate cancer on ADT for ≥3 months were categorized as having ADT-emergent CI or normal cognition (NC) based on self-report at interview. Neuroinflammation was evaluated using positron emission tomography (PET) with the translocator protein (TSPO) radioligand [11C]-PBR28. [11C]-PBR28 uptake in various brain regions was quantified as standardized uptake value (SUVR, normalized to cerebellum) and related to blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) choice-reaction time task (CRT) activation maps.

Results: Eleven patients underwent PET: four with reported CI (rCI), six with reported NC (rNC), and one status unrecorded. PET did not reveal any between-group differences in SUVR regionally or globally. There was no difference between groups on brain activation to the CRT. Regardless of the reported cognitive status, there was strong correlation between PET-TSPO signal and CRT activation in the hippocampus, amygdala, and medial cortex.

Conclusions: We found no difference in neuroinflammation measured by PET-TSPO between patients with rCI and rNC. However, we speculate that the strong correlation between TSPO uptake and BOLD-fMRI activation in brain regions involved in memory and known to have high androgen-receptor expression mediating plasticity (hippocampus and amygdala) might reflect inflammatory effects of ADT with compensatory upregulated/increased synaptic functions. Further studies of this imaging readout are warranted to investigate ADT-related CI.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Copyright © 2023 Azeem Saleem et al.

Figures

Figure 1
Figure 1
Orthogonal cross sections of coregistered PET and MR images from two representative patients (003 and 101). PET images are shown as SUV summed from 0–90 minutes. Images show regional heterogeneity consistent with the expected distribution of TSPO.
Figure 2
Figure 2
Time–activity curves expressed as SUV for a set of cortical (frontal, occipital, temporal, parietal lobe and cerebellum) and subcortical regions (striatum, thalamus, hippocampus and amygdala), averaged across the rCI and rNC groups. Top and bottom rows report cortical and subcortical regions, respectively. (a) and (b) report rCI and rNC groups, respectively.
Figure 3
Figure 3
SUVR values in a subset of regions of interest, comparing rCI and rNC in temporal lobe, hippocampus, and striatum. In the bottom right panel rCI, rNC and unknown cognitive status patients SUVR values are compared in a large cortical region, to accommodate for the different spatial preprocessing of the PET images of the patient with unknown cognitive status.
Figure 4
Figure 4
Analysis of SUVR values vs BOLD signal change in a CRT task in the regions showing significant correlation (p < 0.05). Red circles indicate rCI patients, white circles indicate rNC patients.

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