Document Type

Dissertation

Date of Degree

2013

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmacy

First Advisor

Daryl J. Murry

Abstract

Cognitive decline is increasingly recognized as a side effect of chemotherapy. However, cognitive decline doesn't occur in all patients receiving chemotherapy, and there is variability in the cognitive domains affected (Ahles; JCO,Oct 20, 2012:3675-3686). Safety pharmacogenomics, i.e. using genetic variations to predict response/toxicity, offers an exciting approach to identify the subset of patients most likely to suffer from cognitive decline post chemotherapy. Consequently specific therapeutic interventions can be developed to target this group of patients, and/or alternate chemotherapeutic regimens can be used to limit toxicity, thereby offering a way to individualize therapy while minimizing toxicity.

In our research we studied the effect of 16 SNPs in 6 genes on cognition in a sample of healthy older adults. We found that SNPs that affect serotonin, dopamine and glutamate levels in the brain influence cognition in a healthy sample of older adults, possibly in a domain specific manner. This allowed us to identify a group of healthy adults who inherently have lower cognitive functioning in some domains but that is still within the normal range. In addition individuals with SNPs that previously were associated with lower levels of myeloperoxidase performed better on the executive functions, verbal memory, verbal IQ and IQ. SNPs associated with lower levels were also associated with improvement in self reported verbal and visual memory post chemotherapy. APOE E2 allele was associated with higher cognitive performance compared to other alleles. However we didn't see an effect of APOE post chemotherapy.

In chapter five, the effects of 31 SNPs in 15 genes on cognition post chemotherapy were evaluated in community dwelling lymphoma patients. Changes in the domains of verbal memory, visual perceptual memory, and attention of the Multiple Ability Self Report Questionnaire were observed following chemotherapy, but only when groups were stratified by genotype. Contrary to what we might expect, patients showed improvements in function after chemotherapy. However, using patient stratification based on genotype, specific groups of patients had a measurable decline in cognitive function post chemotherapy. Interestingly a SNP in the DNA replication enzyme and the target of doxorubicin topoisomerase II was associated with varying degree of self reported attention; specifically the AA genotype of rs471692 was associated with statistically significant decline in attention post chemotherapy. This indicates that cognitive changes following chemotherapy can be subtle, and stratification by genotype helps us in identifying susceptible individuals and provides some insights on the inconsistencies that are frequently reported in the literature.

These results allow for identifying genetic risk factors associated with chemotherapy-induced cognitive changes, which will ultimately help in developing therapeutic approaches for the management of those deficits. Strategies to avoid chemotherapy-induced cognitive changes will be prospectively evaluated in future studies and include alternative chemotherapy and less toxic regimens, intervention strategies to improve cognitive abilities, and drug therapy to improve cognition in patients who develop chemotherapy-induced cognitive changes. The overarching goals of our studies are to help improve cancer patients' quality of life while maintaining or improving cancer cure rates.

Keywords

Cognition, Doxorubicin, Elderly, Lymphoma, Pharmacogenomics

Pages

xi, 145 pages

Bibliography

Includes bibliographical references (pages 131-145).

Copyright

Copyright 2013 Rowan AlEjielat

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