Electrophysiological Biomarkers of Chemotherapy-related Cognitive Impairment and Recovery
Condition: Myelodysplastic Syndrome; Effects of Chemotherapy; Mild Cognitive Impairment; Multiple Myeloma; Non-hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Acute Lymphoid Leukemia; Chronic Myeloid Leukemia; Acute Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Multiple Myeloma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Chemotherapy-Related Cognitive Impairment; Cognitive Dysfunction
Study type: Observational

Summary: 
      Broadly speaking, the goal of this study is to better understand the influence of
      chemotherapy treatment on the cognitive and neural mechanisms underlying human behavior.
      Extant literature lacks diversity in studied cancer populations and treatment protocols, and
      provides limited understanding of the cognitive abilities that are impaired by chemotherapy.
      To overcome these limitations, this study will employ a sophisticated battery of tests on an
      understudied cancer population. Eligible participants will either be patients diagnosed with
      hematological malignancy (HM) or demographically matched healthy control patients.

      After HM diagnosis and treatment protocols have been established, patients will be inducted
      into the longitudinal study comprised of three visits: 1) after diagnosis but prior to
      chemotherapy treatment (baseline), 2) after one treatment cycle (one month post-baseline),
      and 3) after three treatment cycles (three months post-baseline). Patients will undergo a
      test battery designed to measure specific behavioral and neural mechanisms of attention;
      tests will either be computer-based cognitive tasks or simulated driving tests that immerse
      patients into virtual driving scenarios. During each test, EEG will be concurrently measured
      through non-invasive scalp electrophysiology recordings; EEG recordings will reveal
      underlying neural mechanisms affected by chemotherapy. Additionally, neuropsychological tests
      of vision, attention, and memory will be administered, as well as questionnaires to evaluate
      health, mobility, and life space. Finally, blood samples will be collected to examine levels
      of circulating inflammation-specific proteins typically present in cancer patients. This
      study will allow us to better understand the mechanisms through which chemotherapy influences
      cognitive performance. Results from this study will influence the administration of
      chemotherapy treatments so that patients can continue to receive the highest medical care
      while maintaining optimal cognitive abilities and quality of life.
    

Detailed description: 
      The broad goal of this research project is to develop a core set of biomarkers for
      chemotherapy-related cognitive impairment (or chemobrain). Clinical studies have documented
      mild cognitive impairment in chemotherapy patients most frequently within the domains of
      attention and memory, though impairments have been observed across a broad range of cognitive
      abilities. In addition, neuroimaging studies have demonstrated chemotherapy-related
      structural and functional changes in distributed cortical areas, including regions of the
      fronto-parietal attention network. While these studies suggest chemotherapy treatment
      negatively impacts patient health and cognitive function, it remains unclear how chemotherapy
      affects neural mechanisms of cognitive abilities. Current literature is limited in four major
      ways: (1) most research has focused on breast cancer populations, providing little insight
      into impact of tumor type, (2) few studies have examined the parametric effects of
      chemotherapy toxicity, (3) neuropsychological exams provide weak resolution of specific
      cognitive functions, and (4) neural factors associated with cognitive impairment are
      difficult to dissociate from non-neural (e.g. psychosocial) factors. To overcome these
      central limitations, the investigators propose a one-year longitudinal study that aims to
      systematically examine the influence of cancer stage and treatment toxicity on mild cognitive
      impairment observed in hematological malignancy (HM) patients by implementing a core battery
      of behavioral and neural measures of attention.

      Our specific aims (SA) are to:

      SA1: Quantify chemotherapy-related impairments of attention-specific processes in HM
      patients.

      H1a: No difference in behavioral measures of attention will be observed across HM groups
      prior to treatment, and HM groups will perform worse than healthy controls.

      H1b: Exposure to chemotherapy will predict behavioral impairments of attention, and the
      magnitude of impairment will be linked with treatment toxicity.

      SA2: Quantify electrophysiological measures of attention-specific processes and determine the
      link between chemotherapy-related impairments in neural activity and cognitive ability.

      H2a: No difference in electrophysiological measures of attention will be observed across HM
      and healthy control groups prior to treatment.

      H2b: Exposure to chemotherapy will predict functional impairments in electrophysiological
      measures of attention, and the magnitude of impairment will be linked with treatment
      toxicity.

      H2c: Chemotherapy-related impairment in neural measures of attention will be predicted by
      concurrent impairments in behavioral measures of attention (as in H1b).

      SA3: Implement controlled simulations of on-road driving scenarios that probe specific
      attention processes to determine the impact of chemotherapy on complex real-world behavior.

      H3a: No difference in driving performance will be observed across HM groups prior to
      treatment, and driving performance will be better in healthy controls compared to HM
      patients.

      H3b: Exposure to chemotherapy will predict greater impairment in simulated driving
      performance, and the magnitude of impairment will be linked with treatment toxicity.

      H3c: Impairments in behavioral (as in H1a) and neural measures (as in H2a) of attention will
      predict greater impairment in simulated on-road driving performance.

      Our empirical approach will allow us to more rigorously study the neural mechanisms of
      chemotherapy-related cognitive impairment. The current proposal aims to extend previous
      research by longitudinally investigating an understudied cancer population whose constituents
      are assigned to a treatment group at diagnosis, thus providing sufficient experimental
      control for examining parametric effects of cancer burden and treatment toxicity on specific
      mechanisms of attention. Results obtained from this study will be critical to understanding
      risk factors associated with chemotherapy, which will allow clinicians to make informed
      treatment recommendations in order to reduce the likelihood of cognitive impairment and
      maintain the highest quality of life possible for the ever-increasing cancer survivor
      population.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The 2008 World Health Organization (WHO) classification is used to diagnose MDS. Patients
        diagnosed with MDS are stratified into one of five risk categories, based on a prognostic
        score calculated according to the revised International Prognostics Scoring System
        (IPSS-R): very-low risk, low risk, intermediate risk, high risk, and very-high risk. IPSS-R
        scores are estimated from percent of bone marrow blasts, number and depth of cytopenias,
        and presence of specific cytogenetic abnormalities, collectively reflecting the total
        number of risk factors.
      
Biospecimen description: 
      Blood serum