Shelli R. Kesler, Ph.D. - US grants

Abstract Some studies indicate that breast cancer (BC) survivors are at significant risk for long- term cognitive deficits. Increasing BC survival rates may thus result in a large and rapidly growing cohort of women with extended disease-related disability. Adjuvant chemotherapy may be a significant contributing factor to cognitive impairments in BC. However, the role of chemotherapy in BC cognitive outcome is controversial. The specific cognitive deficits in BC, their incidence and underlying mechanisms are largely unknown due to a paucity of research in this area. There currently are no treatments for cognitive deficits related to BC. The goals of the proposed research are to 1) define the specific cognitive deficits associated with BC and chemotherapy using comprehensive, ecologically valid neuropsychological assessment, 2) elucidate the neurobiologic states underlying cognitive impairments in women with BC using advanced neuroimaging techniques, 3) identify demographic, medical and genetic factors associated with cognitive outcome in BC and 4) test the efficacy of two innovative treatment methods - one for improving existing cognitive impairments and the other for preventing cognitive impairments. The proposed research will implement highly innovative methods including measurement of hippocampal neural stem cells, using neurofeedback as a preventative treatment method and evaluating a combination of genetic variants believed to influence cognitive outcome. Results of this project will provide prognostic information regarding and treatment options for cognitive effects of BC, will address the lack of treatment methods for cognitive impairments in general by providing a new model of cognitive rehabilitation, and will increase our understanding of neural injury, recovery and repair. Additionally, cancer in general affects millions of individuals - males and females of all age groups, socioeconomic strata and ethnicities. Therefore, results from this project may have broad applications by providing direction for studies of cognitive effects in other cancers and conditions treated with chemotherapy.

DESCRIPTION (provided by applicant): With the rising number of children who survive invasive brain tumors such as medulloblastoma (MB) which is the second most common tumor type, cognitive sequelae of these neoplasms and their treatments have begun to receive increased attention. This attention is particularly focused on the extensive, long-term disabilities that these cognitive impairments pose for patients and their families. Studies indicate that anti- cancer treatments (chemotherapy and cranial radiation) increase the risk for long-term cognitive deficits in children and that these impairments are often progressive. The prospect of intervening to change this trajectory thus has tremendous significance from a lifespan perspective - potentially affecting school services, family dynamics, vocational readiness and social services support. However, factors mediating the risk for cognitive impairments in children with MB or other types of cancer have not been adequately explored. The overarching aim of this project is to use advanced, multi-modal magnetic resonance imaging (MRI) techniques, focused genetic analyses and cognitive-behavioral assessment to elucidate the effects of MB and its treatments on functional neuroanatomy and cognitive-behavioral outcome. The specific aims are 1) to examine the neuroanatomical and neurofunctional substrates of cognitive impairment and decline in children with MB, 2) elucidate neurobiologic factors subserving gender differences in cognitive outcome among children with MB, and 3) determine the interaction of genetic, demographic and medical variables in predicting the cognitive trajectory of children with MB. Forty children with MB and 30 age and gender matched healthy controls age 3-14 years will undergo comprehensive neuropsychological and neuroimaging assessments at baseline and 12 months. Additionally, DNA will be extracted from saliva samples from all subjects and genotyped for catechol-O-methyltransferase (COMT) which is believed to influence cognitive outcome in individuals with brain injury. The ultimate goal of this research is to inspire the development of more specific and precise interventions, as well as to better understand when intervention is most needed and most effective. The research proposed here also will contribute more broadly to a better understanding. RELEVANCE : The ultimate goal of this research is to inspire the development of more specific and precise interventions for children with cancer, as well as to better understand when intervention is most needed and most effective. The research proposed here also will contribute more broadly to a better understanding of how early cancer- related brain injury affects brain development and neural organization in humans.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Introduction: Turner syndrome (TS) provides a model for elucidating critical linkages among X chromosome gene function, brain development, and cognition. Specific Aims: To determine the neurobiologic and genetic correlates of visual-spatial skills, emotion processing and executive function impairments in girls with TS compared to controls. Methods: Cognitive-behavioral and neuroimaging assessments (including volumetric MRI, functional MRI, DTI and 1H MRS) are administered to 100 subjects with TS and 50 age matched female controls. Subjects are re-assessed at 12-18 months. Local subjects additionally participate in cognitive intervention programs designed to improve visual-spatial planning or math skills. Subjects enrolled in the intervention programs are assessed before and after the intervention.

DESCRIPTION (provided by applicant): Women with breast cancer, particularly those who are older and who receive adjuvant chemotherapy, are at significantly increased risk for mild cognitive impairment (MCI). Our previous research shows persistent and progressive MCI long after cancer treatment has ended. This cognitive impairment tends to involve difficulties with memory and executive function (i.e. multi-tasking, problem solving) that interfere with daily livin skills and reduce quality of life. The default mode network (DMN) is a brain circuit important for normal cognitive function. The connections between the DMN brain regions tend to naturally decrease in strength as we age. DMN functional connectivity has been demonstrated to be a highly promising neuroimaging biomarker of MCI in non-cancer populations. Disruption of DMN functional connectivity is strongly associated with conversion to dementia and has even been show to precede other biomarkers of neurodegeneration. Previous studies, including our own, show atrophy of DMN regions and damage to the white matter pathways that connect these regions following breast cancer chemotherapy. We believe that chemotherapy treatment accelerates DMN decline resulting in increased frequency of MCI following breast cancer. However, no studies to date have directly assessed the DMN or its relationship to MCI in breast cancer. The specific aims of the proposed study are therefore to 1) determine the frequency of MCI in older breast cancer subjects who receive chemotherapy, 2) identify DMN neuroimaging biomarkers in older breast cancer subjects treated with chemotherapy, and 3) develop models that predict vulnerability to MCI in this population. We will accomplish these aims by integrating longitudinal multidimensional neuropsychological assessments of cognitive function, mood and behavior with advanced, non-invasive multimodal magnetic resonance imaging techniques and APOE genotyping. We will evaluate 55 women with primary breast cancer prior to chemotherapy, one month following chemotherapy and six months following chemotherapy. We will compare the chemotherapy-treated group to 55 women with breast cancer who do not receive chemotherapy and 55 healthy females, all matched on important demographic and clinical factors. All groups will be assessed at the same time intervals. We will emphasize the assessment of memory and executive function as well as DMN functional connectivity. We will incorporate clinical, demographic, psychiatric (e.g. depression, fatigue) and genetic (e.g. APOE) factors with DMN connectivity into our predictive models of MCI. Identifying neuroimaging biomarkers underlying chemotherapy-related MCI will improve identification of individuals at highest risk for neurodegeneration and aid the development of treatments for these impairments. This is of critical importance given an aging society and the increased incidence of and vulnerability to both breast cancer and MCI.

DESCRIPTION (provided by applicant): Our laboratory, as well as others, has demonstrated abnormalities in brain structure and function associated with breast cancer chemotherapy, most consistently in the prefrontal cortex. The prefrontal cortex is critical for skills such as multi-tasking, attention, processing speed and memory; skills that are often impaired in patients who have undergone breast cancer chemotherapy. Because prefrontal cortex changes have also been observed in patients prior to chemotherapy treatment as well as in those treated with radiation and/or hormonal blockade, the specific effects of chemotherapy on prefrontal cortex remain unclear. It is also currently unknown why some patients treated with chemotherapy show improvement in cognitive function over time while others do not. The proposed research will examine prefrontal cortex structure and function as well as cognitive status in 50 patients with primary breast cancer scheduled for chemotherapy. These patients will be evaluated across the treatment course, from pre-surgery to 12 months post-chemotherapy. We will compare the chemotherapy-treated group to 50 patients who do not receive chemotherapy and to 50 healthy females who are all assessed at the same time intervals as the chemotherapy-treated group. We will utilize non-invasive neuroimaging (MRI) methods to measure prefrontal cortex volume and functional activation in combination with neuropsychological measures of executive function, memory, processing speed and attention. We will also explore possible predictors of individual outcome such as demographic, disease, psychiatric and treatment factors. Increasing our understanding regarding the neurobiologic mechanisms underlying chemotherapy-related cognitive impairments may improve identification of patients at highest risk for cognitive deficit and aid the development of treatments for these impairments.

? DESCRIPTION (provided by applicant): Difficulties with cognitive skills such as memory, thinking and attention are very common after breast cancer chemotherapy. These cognitive difficulties have been associated with chemotherapy-related injury to several brain regions, particularly those regions that also tend to be affected by brain aging. There is concern that chemotherapy may accelerate brain aging and increase patients' risk for Alzheimer's disease. Certain previous studies support this concern while others do not and therefore the effect of breast cancer chemotherapy on risk for Alzheimer's disease remains unclear. The proposed research will compare brain anatomy of breast cancer survivors to that of women who later developed Alzheimer's disease. Using machine learning, a form of artificial intelligence, we will determine a pattern of brain anatomy that indicates the probability of developing Alzheimer's disease. This pattern, or classifier, will be determined using magnetic resonance imaging (MRI) scans that were obtained for approximately 100 women with Alzheimer's disease compared to MRI scans from a group of approximately 100 healthy, unaffected women. We will then apply the classifier to MRI scans from 108 breast cancer survivors, 67 who received chemotherapy treatment and 41 who did not. Using the machine learning classifier, we will calculate a score for each breast cancer survivor that indicates her probability of developing Alzheimer's disease based on her brain anatomy. We believe that probability scores will be significantly higher in the chemotherapy group compared to the no-chemotherapy group. We will also explore possible predictors of probability score such as demographic, disease, genetic and treatment factors. This project has the potential to improve our ability to identify patients at risk for persistent and/or progressive chemotherapy-related brain injury using a simple, non-invasive five minute MRI scan. This information could potentially inform treatment decision-making and prioritize patients for early intervention.

ABSTRACT Chemotherapy-related cognitive impairment (CRCI) affects an estimated 60% of patients, negatively impacting quality of life. Currently, there is no established method for predicting which patients will develop CRCI. This information could be practice-changing by assisting clinicians with treatment decision-making for individual patients. We have shown that the brain network (?connectome?) is significantly altered in patients with CRCI. Therefore, we measured the connectome is patients prior to any treatment and demonstrated that these connectome properties could be used in combination with machine learning to predict 1 year post-chemotherapy cognitive impairment with 100% accuracy. The proposed project aims to test this preliminary prediction model in a new, larger sample with the overarching goal of validating its use for clinical practice. We will enroll 100 newly diagnosed patients with primary breast cancer scheduled for adjuvant chemotherapy who will be assessed prior to any treatment, including surgery with general anesthesia, 1 month after chemotherapy treatment and again 1 year later. We will also enroll matched healthy female controls who will be assessed at yoked intervals. We will combine these data with retrospective data we obtained during a prior study for a total sample of 150 in each group. Data from healthy controls will be used to determine impairment status in patients with breast cancer and to provide a template of typical connectome organization for comparison. We hypothesize that our machine learning model will accurately predict 1 year post- chemotherapy cognitive impairment and that it will be more accurate than a model that includes patient- related and medical variables alone. We will also examine longitudinal changes in connectome organization associated with impairment subtypes (i.e. persistent vs. late onset impairment) as well as changes in specific functional networks (e.g. default mode, salience, executive-attention and sensory- motor networks). This information will provide novel insights regarding the neural mechanisms of CRCI and may also help us refine our prediction models.

PROJECT SUMMARY/ABSTRACT Chemotherapy-related cognitive impairment (CRCI) is associated with reduced quality of life and survival making it a significant problem that remains understudied. Research by our group and others has demonstrated that CRCI is associated with altered brain structure and function from pretreatment to post treatment. There is significant overlap between chemotherapy actions and physiologic processes involved in aging. Neurocognitive have been found in patients up to 20+ years post- treatment and work by our group and others suggests an accelerated brain aging phenotype in breast cancer survivors treated with chemotherapy. We have also observed that patients may demonstrate unique trajectories of cognitive impairment that require further study. Existing prospective, longitudinal studies of cancer and cognition, including our own, have been limited to relatively short-term post- treatment follow-ups (e.g. 6-12 months). To begin addressing these limitations, we aim to extend our current prospective study (CA172145), which longitudinally examines cognitive function and brain structure/function pre-surgery, 1-month post chemotherapy, and 1-year post chemotherapy. We will continue to assess cohorts of women treated with chemotherapy, chemotherapy naïve patients, and healthy controls at yearly intervals for 5 additional years (up to 10 years). Using non-invasive neuroimaging methods, we will advance our original aims from the initial project to measure very long- term neurobiologic outcomes with an emphasis on the assessment of neural connectivity rather than specific regional changes (Aim 1). We will also examine very long-term cognitive outcomes as measured by standardized neuropsychological testing (Aim 2). Finally, we will explore different trajectories or subtypes of impairment and their neural phenotypes (Aim 3). The proposed project will significantly advance the understanding of chemotherapy-related cognitive impairments by extending our knowledge on very long-term neurobiological outcomes along with the different subtypes of cognitive impairments and associated neural profiles following breast cancer chemotherapy.