Cancer Control Research7R01CA101318-05
Saykin, Andrew J.
NEURAL MECHANISMS OF CHEMOTHERAPY-INDUCED COGNITIVE DISORDER
DESCRIPTION (provided by applicant): Systemic cancer chemotherapy has been associated with cognitive and memory deficits that may be long-lasting (Ahles, Saykin et al, 2002). There are very few prospective studies of cognitive changes and the underlying pathophysiological mechanisms have not been systematically examined. Brain imaging could help to identify these mechanisms, yet there are no prospective, well-controlled studies. We will address this knowledge gap by employing an ensemble of magnetic resonance imaging (MRI) and analysis techniques to identify specific changes in brain structure and function associated with chemotherapy. The imaging study will build on our team's experience with NCI-sponsored cognitive studies of chemotherapy (CA87845). Our specific aims are to: (i) Determine the frequency, quantity and characteristics of short and long term changes in brain structure and tissue composition in patients undergoing chemotherapy, (ii) Detect and characterize alterations in brain activation during memory processing using fMRI to assess task-relevant circuits and (iii). Systematically examine key treatment, disease and individual difference factors (e.g., chemotherapy regimen, genetic risk, age, education, baseline functioning) as predictors of cognitive deficits and recovery, to facilitate future model building. Participants will include breast cancer patients undergoing chemotherapy (n=50) or local therapy only (n=50), and 30 healthy controls. Measures will be obtained before and 1 and 12 months after chemotherapy (or equivalent intervals). An integrated MRI exam will detect and measure: focal inflammation/demyelination (FLAIR) and distributed gray and white matter changes (voxel-based morphometry), the integrity of memory critical structures (hippocampal 3D volume and shape analysis) and white matter integrity and connectivity (diffusion tensor imaging, DTI), and brain activation patterns during working and episodic memory processing (functional MRI, fMRI). Expected outcomes: The study will determine which imaging measures are most sensitive, informative and specific to chemotherapy. Identification of the mechanisms of cognitive changes and introduction of new measures will help to drive advances in assessment of neurological side effects and risk/benefit analyses, and it will provide a foundation for design and evaluation of neuroprotective agents, neuropharmacologic treatment and rehabilitative approaches.