To explore COMT genotypes and their potential role in cognitive resilience in patients with primary brain tumors.

Catechol-O-methyltransferase (COMT) is an enzyme that plays a crucial role in regulating neurotransmitters and is believed to influence cognitive function. Prior studies have correlated specific COMT single-nucleotide polymorphism (SNP), rs4680, with key cognitive domains, including executive functioning, working memory, and cognitive flexibility. Studies suggest the Met/Met genotype is associated with lower COMT activity, resulting in higher dopamine levels and improved cognitive performance, but poor emotional adaptability. The converse is true for the Val/Val genotype (higher COMT activity, lower dopamine), resulting in lower cognitive performance, but improved emotional adaptability.  

In a prospective single-center trial, patients with primary brain tumors scheduled for radiation therapy (RT) were evaluated with cognitive testing, including Trails Making Test A/B (TMTA/B). Testing intervals were before RT, after RT, and 2-6 months later. Cognitive performance was measured using Z-scores and ranked as deficient, average, or above average. Above-average performance on both A/B portions reflects cognitive resilience. COMT genotypes were evaluated and correlated with cognitive performance after RT. 

Thirty-four patients (29 GBM and 5 IDH-mutant high-grade glioma) were enrolled. Testing was completed for 26 patients.  For SNP rs4680 of interest, genotypes included Val/Val (38.2%), Met/Val (38.2%), and Val/Val (23.5%). TMT A/B scores: 4 deficient, 8 average, 6 above-average in one domain, 8 above-average in both. For patients with above-average Z-scores in both TMT A/B, there was enrichment of Val/Val genotype at 62.5% compared to Met/Met (12.5%) and Met/Val (25%). For those who were deficient, 75% had Met/Met genotype and 25% had Met/Val.

Primary brain tumor patients with Val/Val genotype exhibited cognitive resilience after RT. Initial observations suggest COMT genotypes potentially improve understanding of cognitive outcomes in glioma patients. We are further exploring the relationship between emotional adaptability and cognition in this population.