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. 2025 Feb;132(2):275-286.
doi: 10.1007/s00702-024-02824-9. Epub 2024 Sep 26.

Self-reported cancer-related cognitive impairment is associated with perturbed neurotransmission pathways

Kate R Oppegaard  1 , Yvette P Conley  2 , Steven Paul  3 , Bruce Cooper  3 , Carolyn S Harris  2 , Joosun Shin  4 , Lisa Morse  3 , Jon D Levine  5 , Frances Cartwright  6 , Ritu Roy  5 , Michelle Melisko  5 , Kord M Kober  3 , Marilyn J Hammer  4 , Christine Miaskowski  7
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Self-reported cancer-related cognitive impairment is associated with perturbed neurotransmission pathways

Kate R Oppegaard et al. J Neural Transm (Vienna). 2025 Feb.

Abstract

Background: Cancer-related cognitive impairment (CRCI) is reported by 45% of patients with cancer. Significant gaps in knowledge remain regarding the mechanisms that underlie CRCI.

Objectives: Using a data-driven approach, the study purpose was to evaluate for perturbed pathways associated with membership in the High versus the Low CRCI profiles.

Methods: Patients completed the Attentional Function Index six times over two cycles of chemotherapy. Using findings from a previous latent profile analysis, subgroups of patients with high versus low levels of CRCI were evaluated (i.e., High versus Low CRCI profiles). Gene expression was quantified using either ribonucleic (RNA)-sequencing or microarray analyses and pathway impact analyses were performed. Signaling pathways were defined using the Kyoto Encyclopedia of Genes and Genomes database.

Results: A total of 508 patients had data available for analysis. Of the 261 patients in the RNA-sequencing sample, 48.7% were in the High class and 51.3% were in the Low class. Of the 247 patients the microarray sample, 46.6% were in the High class and 53.4% were in the Low class. Pathway impact analyses identified seven perturbed pathways related to neurotransmission (i.e., glutamatergic synapse, GABAergic synapse, dopaminergic synapse, serotonergic synapse, long-term depression, cholinergic synapse, retrograde endocannabinoid signaling).

Conclusions: This study is the first to describe associations between self-reported CRCI in patients receiving chemotherapy for breast, gastrointestinal, gynecological, or lung cancer and seven neurotransmission pathways. These findings provide new insights into potential targets for mechanistically based interventions.

Keywords: Cancer; Chemotherapy-related cognitive impairment; Cognition; Gene expression; Neurotransmission; Pathway analysis; Patient-reported outcomes.

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Conflict of interest statement

Declarations. Competing interests: The authors declare that they have no conflicts of interest. Ethical approval: This study adhered to the principles of the Declaration of Helsinki. The study was approved by the Institutional Review Board at the University of California, San Francisco and at each of the study sites. Consent: All of the patients signed written informed consent.

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