title: Relationship of systemic cytokine concentrations to cognitive function over two years in women with early stage breast cancer.
abstract: Cancer and its treatment are frequently associated with cancer-related cognitive impairment (CRCI). While CRCI has been associated with linked to chemotherapy, there is increasing evidence that the condition may start prior to treatment and for some, remain unresolved after active treatment and into survivorship. Although the pathophysiology of the condition is complex, alterations in systemic cytokines, signaling molecules activated in response to infection or injury that trigger inflammation, are a possible mechanism linked to cognitive dysfunction in breast cancer and other conditions. Given the conflicting results in the literature, the lack of focus on domain specific cognitive testing, and the need for a longer time period given the multiple modalities of standard treatments for early-stage breast cancer, this longitudinal study was conducted to address these gaps.
  
  
  
  We assessed 75 women with early-stage breast cancer at five points over two years, starting prior to the initial chemotherapy through 24months after chemotherapy initiation. Measures included a validated computerized evaluation of domain-specific cognitive functioning and a 17-plex panel of plasma cytokines. Linear mixed-effects models were applied to test the relationships of clinical variables and cytokine concentrations to each cognitive domain.
  
  
  
  Levels and patterns of cytokine concentrations varied over time: six of the 17 cytokines (IL-6, IL-12, IL-17, G-CSF, MIPS-1β, and MCP-1) had the most variability. Some cytokine levels (e.g., IL-6) increased during chemotherapy but then decreased subsequently, while others (e.g., IL-17) consistently declined from baseline over time. There were multiple relationships among cytokines and cognition, which varied over time. At baseline, elevated concentrations of G-CSF and reduced concentrations of IL-17 were associated with faster psychomotor speed. At the second time-point (prior to the mid-chemotherapy), multiple cytokines had significant associations with psychomotor speed, complex attention, executive function, verbal memory, cognitive flexibility, composite memory and visual memory. Six months after chemotherapy initiation and at the one-year point, there were multiple, significant relationships among cytokines and multiple cognitive. At two years, fewer significant relationships were noted; however, lower concentrations of IL-7, a hematopoietic cytokine, were associated with better psychomotor speed, complex attention, and memory (composite, verbal and visual). MCP-1 was inversely associated with psychomotor speed and complex attention and higher levels of MIP-1β were related to better complex attention.
  
  
  
  Levels and patterns of cytokines changed over time and demonstrated associations with domain-specific cognitive functioning that varied over time. The observed associations between cytokines and cognitive performance provides evidence that not only prototypical cytokines (i.e., IL-6, TNF-α, and IL1-β) but also cytokines from multiple classes may contribute to the inflammatory environment that is associated with cognitive dysfunction. Future studies to better delineate the cytokine changes, both individually and in networks, are needed to precisely assess a mechanistic link between cytokines and cognitive function in women receiving treatments for breast cancer.
authors.affiliation: University of Florida, College of Nursing, United States. Electronic address: delyon@ufl.edu.
authors.forename: Debra E
authors.initials: DE
authors.lastname: Lyon
authors.affiliation: Center for Cognitive Aging and Memory, University of Florida, Institute on Aging, United States. Electronic address: roncohen@ufl.edu.
authors.forename: Ronald
authors.initials: R
authors.lastname: Cohen
authors.affiliation: College of Public Health & Health Professions, College of Medicine, University of Florida, United States. Electronic address: huaihouchen@ufl.edu.
authors.forename: Huaihou
authors.initials: H
authors.lastname: Chen
authors.affiliation: University of Florida, College of Nursing, United States. Electronic address: dlynchkelly@ufl.edu.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Kelly
authors.affiliation: Adult Health and Nursing Systems, Virginia Commonwealth University, United States. Electronic address: nlmccain@vcu.edu.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: McCain
authors.affiliation: Center for Advancement in Managing Pain, University of Connecticut, School of Nursing, United States. Electronic address: angela.starkweather@uconn.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: Starkweather
authors.affiliation: University of Texas Health Science Center at Houston, United States.
authors.forename: Hyochol
authors.initials: H
authors.lastname: Ahn
authors.affiliation: Biobehavioral Laboratory Services, Department of Family and Community Health Nursing, Virginia Commonwealth University, United States. Electronic address: sturgilljl@vcu.edu.
authors.forename: Jamie
authors.initials: J
authors.lastname: Sturgill
authors.affiliation: Cytogenetic Diagnostics Laboratory, Virginia Commonwealth University, United States. Electronic address: Colleen.Jackson-Cook@vcuhealth.org.
authors.forename: Colleen K
authors.initials: CK
authors.lastname: Jackson-Cook
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism*; D016207:Cytokines / Q000097:blood*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009483:Neuropsychological Tests; D013997:Time Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines
keywords: Breast cancer; Chemotherapy; Cognition; Cytokine; Hormonal therapy