Reduced expression of N-methyl-D-aspartate receptor and calcium signaling genes in gray matter is associated with cancer-related cognitive impairment.

PURPOSE: Cognitive decline is common after cancer, but little is known regarding the etiology of this adverse effect, especially in terms of molecular mechanisms.

METHODS

This prospective study obtained brain imaging and cognitive testing from 50 newly diagnosed women with primary breast cancer prior to any cancer treatment and 53 female controls. Participants completed up to seven assessments for a total time span of 9.7 ± 0.92 years. Imaging transcriptomics was used to measure the expression of genes in the brain involved in N-methyl-D-aspartate (NMDA) and calcium-mediated neurotransmission.

RESULTS

GRIN2A, GRIN2B, and CACNA1C were significantly expressed in gray matter in both groups (R2 ≥ 0.092, p ≤ 0.015). GRIN2A (t = -2.72, p = 0.018) was significantly lower in the cancer group compared to controls across timepoints. GRIN2A declined over time in patients, and this was significantly different compared to controls (χ2 = 9.73, p = 0.005). Cognitive scores were significantly lower in patients compared to controls (p ≤ 0.004). In patients, GRIN2A was significantly associated with cognitive performance over time (p ≤ 0.009).

CONCLUSION

These findings suggest that gene expression involved in neurotransmission is disrupted in the brain among patients with breast cancer and may contribute to cognitive changes. Our results provide novel molecular insights regarding the roles of non-CNS cancer pathology and treatments in the brain related to NMDA signaling and pro-survival/plasticity-related pathways. Our findings also point to potential treatments for cognitive effects of cancer.