Scientific Poster Session I - Original Research

Original Research
  Saturday, October 12, 2024
  11:30 AM–01:00 PM

Abstract

Introduction:

Cognitive impairment is a common feature of psychosis-spectrum disorders significantly affecting treatment outcomes and daily functioning. Impairment severity varies across patients and is worsened by anticholinergic activity from many commonly used medications. Genetic predispositions to adverse cognitive impacts of anticholinergic medications and related pathophysiological mechanisms have not been extensively investigated.

Research Question or Hypothesis:

How do genetic predispositions to cognitive ability or psychiatric conditions interact with anticholinergic burden (AChB) to impact cognition and brain structure in individuals with psychotic disorders?

Study Design:

Cross-sectional

Methods:

Individuals with psychosis-spectrum disorders (n=1,704) from the Bipolar-Schizophrenia Network for Intermediate Phenotypes,18-65 years of age, representing diverse ancestries, underwent neurocognitive assessments, structural neuroimaging, genotyping, and comprehensive medication review. The primary cognitive outcome was the Brief Assessment of Cognition in Schizophrenia (BACS) composite score, and the primary brain structural phenotype was total gray matter (GM) volume. AChB scores for scheduled medications were quantified using the CRIDECO Anticholinergic Load Scale. Polygenic scores (PGS) for cognition, schizophrenia, bipolar disorder, and depression were quantified using the PRS-CS algorithm, followed by generating a composite psychiatric PGS through principal component analyses. Linear regressions, adjusting for clinical covariates and correcting for multiple testing with false-discovery rate (FDR), examined AChB-PGS interactions and cognitive/brain structure outcomes. Hypothesis-driven moderated-mediation models explored potential causal pathways, with significance assessed via bootstrapping.

Results:

Higher AChB was associated with lower BACS performance (ß=-0.094, p=9.74x10^-13) and reduced GM (ß=-1253.06, p=0.002). Individuals with higher cognitive PGS exhibited greater impact of AChB on BACS (ß=-0.048, p_FDR=0.012), whereas those with lower psychiatric PGS demonstrated more pronounced GM volume reduction from AChB (ß=1421.48, p_FDR=0.018). AChB associations with cognitive impairment were partially mediated by GM atrophy which were moderated by psychiatric PGS (ß=0.008, bootstrapped 95%CI [0.003, 0.014]).

Conclusion:

Anticholinergic-polygenic interactions significantly impact cognition and brain structure in psychotic disorders, highlighting a novel gene-by-environment interaction that improves our mechanistic understanding of cognitive impairments in psychotic disorders.

Presenting Author

Lusi Zhang PharmD, MHI
University of Minnesota

Authors

Jeffrey R. Bishop PharmD, MS, BCPP, FCCP
University of Minnesota

Brett A. Clementz PhD
University of Georgia

Elliot S Gershon MD
University of Chicago

Scot K. Hill PhD
Rosalind Franklin University of Medicine and Science

Elena I. Ivleva MD
University of Texas Southwestern Medical Center

Sarah K. Keedy PhD
University of Chicago

Richard S.E. Keefe PhD
Duke University Medical Center

Matcheri S. Keshavan MD
Harvard Medical School

Paulo Lizano MD, PhD
Harvard Medical School

Jennifer E McDowell PhD
University of Georgia

David A Parker PhD
University of Georgia

Godfrey D. Pearlson MD
Yale University School of Medicine

John A. Sweeney PhD
University of Cincinnati

Carol A. Tamminga MD
University of Texas Southwestern Medical Center