Browsing by Author "Nakamura, Zev M."

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    Associating persistent self-reported cognitive decline with neurocognitive decline in older breast cancer survivors using machine learning: The Thinking and Living with Cancer study
    (Elsevier, 2022-11) Van Dyk, Kathleen; Ahn, Jaeil; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma A.; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Mandelblatt, Jeanne S.; Root, James C.; Radiology and Imaging Sciences, School of Medicine
    Introduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors. Materials and Methods: We enrolled breast cancer survivors with non-metastatic disease (n=435) and age- and education-matched non-cancer controls (n=441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline. Results: The sample of survivors and controls ranged in age from were ages 60–89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n=60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC=0.736) and survivors without decline (n=147; AUC=0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures. Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention.
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    Associating Persistent Self-Reported Cognitive Decline with Neurocognitive Decline in Older Breast Cancer Survivors Using Machine Learning: The Thinking and Living with Cancer Study
    (Elsevier, 2022) Van Dyk, Kathleen; Ahn, Jaeil; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma A.; Graham, Deena; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Mandelblatt, Jeanne S.; Root, James C.; Radiology and Imaging Sciences, School of Medicine
    Introduction: Many cancer survivors report cognitive problems following diagnosis and treatment. However, the clinical significance of patient-reported cognitive symptoms early in survivorship can be unclear. We used a machine learning approach to determine the association of persistent self-reported cognitive symptoms two years after diagnosis and neurocognitive test performance in a prospective cohort of older breast cancer survivors. Materials and methods: We enrolled breast cancer survivors with non-metastatic disease (n = 435) and age- and education-matched non-cancer controls (n = 441) between August 2010 and December 2017 and followed until January 2020; we excluded women with neurological disease and all women passed a cognitive screen at enrollment. Women completed the FACT-Cog Perceived Cognitive Impairment (PCI) scale and neurocognitive tests of attention, processing speed, executive function, learning, memory and visuospatial ability, and timed activities of daily living assessments at enrollment (pre-systemic treatment) and annually to 24 months, for a total of 59 individual neurocognitive measures. We defined persistent self-reported cognitive decline as clinically meaningful decline (3.7+ points) on the PCI scale from enrollment to twelve months with persistence to 24 months. Analysis used four machine learning models based on data for change scores (baseline to twelve months) on the 59 neurocognitive measures and measures of depression, anxiety, and fatigue to determine a set of variables that distinguished the 24-month persistent cognitive decline group from non-cancer controls or from survivors without decline. Results: The sample of survivors and controls ranged in age from were ages 60-89. Thirty-three percent of survivors had self-reported cognitive decline at twelve months and two-thirds continued to have persistent decline to 24 months (n = 60). Least Absolute Shrinkage and Selection Operator (LASSO) models distinguished survivors with persistent self-reported declines from controls (AUC = 0.736) and survivors without decline (n = 147; AUC = 0.744). The variables that separated groups were predominantly neurocognitive test performance change scores, including declines in list learning, verbal fluency, and attention measures. Discussion: Machine learning may be useful to further our understanding of cancer-related cognitive decline. Our results suggest that persistent self-reported cognitive problems among older women with breast cancer are associated with a constellation of mild neurocognitive changes warranting clinical attention.
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    Association of markers of tumor aggressivity and cognition in women with breast cancer before adjuvant treatment: The Thinking and Living with Cancer Study
    (Springer, 2022) Root, James C.; Zhou, Xingtao; Ahn, Jaeil; Small, Brent J.; Zhai, Wanting; Bethea, Traci; Carroll, Judith E.; Cohen, Harvey Jay; Dilawari, Asma; Extermann, Martine; Graham, Deena; Isaacs, Claudine; Jacobsen, Paul B.; Jim, Heather; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly; Saykin, Andrew J.; Van Dyk, Kathleen; Mandelblatt, Jeanne S.; Ahles, Tim A.; Radiology and Imaging Sciences, School of Medicine
    Purpose: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of cognition prior to adjuvant therapy and tumor aggressivity in older breast cancer patients. Methods: Women diagnosed with non-metastatic breast cancer (n = 705) ages 60-98 were enrolled from August 2010-March 2020. Cognition was measured post-surgery, pre-systemic therapy using self-reported (FACT-Cog Perceived Cognitive Impairment [PCI]) and objective tests of attention, processing speed, and executive function (APE domain) and learning and memory [LM domain]. Linear regression tested associations of pre-treatment tumor features and cognition, adjusting for age, race, and study site. HER2 positivity and higher stage (II/III vs. 0/I) were a priori predictors of cognition; in secondary analyses we explored associations of other tumor features and cognitive impairment (i.e., PCI score < 54 or having 2 tests < 1.5 SD or 1 test < 2 SD from the mean APE or LM domain score). Results: HER2 positivity and the hormone receptor negative/HER2 + molecular subtype were associated with lower adjusted mean self-reported cognition scores and higher impairment rates (p values < .05). Higher stage of disease was associated with lower objective performance in APE. Other tumor features were associated with cognition in unadjusted and adjusted models, including larger tumor size and lower PCI scores (p = 0.02). Tumor features were not related to LM. Conclusions: Pre-adjuvant therapy cognition was associated with HER2 positivity and higher stage of disease and other features of aggressive tumors. Additional research is needed to confirm these results and assess potential mechanisms and clinical management strategies.
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    Associations between longitudinal changes in sleep disturbance and depressive and anxiety symptoms during the COVID-19 virus pandemic among older women with and without breast cancer in the thinking and living with breast cancer study
    (Wiley, 2022) Bethea, Traci N.; Zhai, Wanting; Zhou, Xingtao; Ahles, Tim A.; Ahn, Jaeil; Cohen, Harvey J.; Dilawari, Asma A.; Graham, Deena M.A.; Jim, Heather S.L.; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Rentscher, Kelly E.; Root, James; Saykin, Andrew J.; Small, Brent J.; Van Dyk, Kathleen M.; Mandelblatt, Jeanne S.; Carroll, Judith E.; Radiology and Imaging Sciences, School of Medicine
    Purpose: Several studies have reported sleep disturbances during the COVID-19 virus pandemic. Little data exist about the impact of the pandemic on sleep and mental health among older women with breast cancer. We sought to examine whether women with and without breast cancer who experienced new sleep problems during the pandemic had worsening depression and anxiety. Methods: Breast cancer survivors aged ≥60 years with a history of nonmetastatic breast cancer (n = 242) and frequency-matched noncancer controls (n = 158) active in a longitudinal cohort study completed a COVID-19 virus pandemic survey from May to September 2020 (response rate 83%). Incident sleep disturbance was measured using the restless sleep item from the Center for Epidemiological Studies-Depression Scale (CES-D). CES-D score (minus the sleep item) captured depressive symptoms; the State-Anxiety subscale of the State Trait Anxiety Inventory measured anxiety symptoms. Multivariable linear regression models examined how the development of sleep disturbance affected changes in depressive or anxiety symptoms from the most recent prepandemic survey to the pandemic survey, controlling for covariates. Results: The prevalence of sleep disturbance during the pandemic was 22.3%, with incident sleep disturbance in 10% and 13.5% of survivors and controls, respectively. Depressive and anxiety symptoms significantly increased during the pandemic among women with incident sleep disturbance (vs. no disturbance) (β = 8.16, p < 0.01 and β = 6.14, p < 0.01, respectively), but there were no survivor-control differences in the effect. Conclusion: Development of sleep disturbances during the COVID-19 virus pandemic may negatively affect older women's mental health, but breast cancer survivors diagnosed with the nonmetastatic disease had similar experiences as women without cancer.
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    Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study
    (American Society of Clinical Oncology, 2023) Carroll, Judith E.; Nakamura, Zev M.; Small, Brent J.; Zhou, Xingtao; Cohen, Harvey J.; Ahles, Tim A.; Ahn, Jaeil; Bethea, Traci N.; Extermann, Martine; Graham, Deena; Isaacs, Claudine; Jim, Heather S. L.; Jacobsen, Paul B.; McDonald, Brenna C.; Patel, Sunita K.; Rentscher, Kelly; Root, James; Saykin, Andrew J.; Tometich, Danielle B.; Van Dyk, Kathleen; Zhai, Wanting; Breen, Elizabeth C.; Mandelblatt, Jeanne S.; Radiology and Imaging Sciences, School of Medicine
    Purpose: To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. Methods: English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. Results: There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls (P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance (v controls), with significant interactions with CRP only for the Trails B test. Conclusion: Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.
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    Epigenetic Aging in Older Breast Cancer Survivors and Non-Cancer Controls: Preliminary Findings from the Thinking and Living with Cancer (TLC) Study
    (Wiley, 2023) Rentscher, Kelly E.; Bethea, Traci N.; Zhai, Wanting; Small, Brent J.; Zhou, Xingtao; Ahles, Tim A.; Ahn, Jaeil; Breen, Elizabeth C.; Cohen, Harvey Jay; Extermann, Martine; Graham, Deena M. A.; Jim, Heather S. L.; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Root, James C.; Saykin, Andrew J.; Van Dyk, Kathleen; Mandelblatt, Jeanne S.; Carroll, Judith E.; Radiology and Imaging Sciences, School of Medicine
    Background: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. Methods: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. Results: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. Conclusion: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.
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    Loneliness and mental health during the COVID‐19 pandemic in older breast cancer survivors and noncancer controls
    (Wiley, 2021-10-01) Rentscher, Kelly E.; Zhou, Xingtao; Small, Brent J.; Cohen, Harvey J.; Dilawari, Asma A.; Patel, Sunita K.; Bethea, Traci N.; Van Dyk, Kathleen M.; Nakamura, Zev M.; Ahn, Jaeil; Zhai, Wanting; Ahles, Tim A.; Jim, Heather S.L.; McDonald, Brenna C.; Saykin, Andrew J.; Root, James C.; Graham, Deena M.A.; Carroll, Judith E.; Mandelblatt, Jeanne S.; Radiology and Imaging Sciences, School of Medicine
    Background: The coronavirus disease 2019 (COVID-19) pandemic has had wide-ranging health effects and increased isolation. Older with cancer patients might be especially vulnerable to loneliness and poor mental health during the pandemic. Methods: The authors included active participants enrolled in the longitudinal Thinking and Living With Cancer study of nonmetastatic breast cancer survivors aged 60 to 89 years (n = 262) and matched controls (n = 165) from 5 US regions. Participants completed questionnaires at parent study enrollment and then annually, including a web-based or telephone COVID-19 survey, between May 27 and September 11, 2020. Mixed-effects models were used to examine changes in loneliness (a single item on the Center for Epidemiologic Studies-Depression [CES-D] scale) from before to during the pandemic in survivors versus controls and to test survivor-control differences in the associations between changes in loneliness and changes in mental health, including depression (CES-D, excluding the loneliness item), anxiety (the State-Trait Anxiety Inventory), and perceived stress (the Perceived Stress Scale). Models were adjusted for age, race, county COVID-19 death rates, and time between assessments. Results: Loneliness increased from before to during the pandemic (0.211; P = .001), with no survivor-control differences. Increased loneliness was associated with worsening depression (3.958; P < .001) and anxiety (3.242; P < .001) symptoms and higher stress (1.172; P < .001) during the pandemic, also with no survivor-control differences. Conclusions: Cancer survivors reported changes in loneliness and mental health similar to those reported by women without cancer. However, both groups reported increased loneliness from before to during the pandemic that was related to worsening mental health, suggesting that screening for loneliness during medical care interactions will be important for identifying all older women at risk for adverse mental health effects of the pandemic.
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    Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study
    (Wiley, 2023) Mandelblatt, Jeanne S.; Small, Brent J.; Zhou, Xingtao; Nakamura, Zev M.; Cohen, Harvey J.; Ahles, Tim A.; Ahn, Jaeil; Bethea, Traci N.; Extermann, Martine; Graham, Deena; Isaacs, Claudine; Jim, Heather S. L.; Jacobsen, Paul B.; McDonald, Brenna C.; Patel, Sunita K.; Rentscher, Kelly E.; Root, James C.; Saykin, Andrew J.; Tometich, Danielle B.; Van Dyk, Kathleen; Zhai, Wanting; Breen, Elizabeth C.; Carroll, Judith E.; Radiology and Imaging Sciences, School of Medicine
    Background: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. Methods: Women >60 years old with primary breast cancer (stages 0-III) (n = 400) were assessed before systemic therapy with frequency-matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin-6 (IL-6), IL-8, IL-10, tumor necrosis factor α (TNF-α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate-adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. Results: Participants were aged 60-90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor-positive tumors (87.6%). Survivors had significantly higher IL-6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001-.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL-6, IL-10, and TNF-α were related to APE, with IL-6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. Conclusions: Older breast cancer survivors had worse long-term neurocognitive performance than controls, and this relationship was explained in part by elevated IL-6.
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    Prediction of cognitive decline in older breast cancer survivors: the Thinking and Living with Cancer study
    (Oxford University Press, 2024) McDeed, Arthur Patrick; Van Dyk, Kathleen; Zhou, Xingtao; Zhai, Wanting; Ahles, Tim A.; Bethea, Traci N.; Carroll, Judith E.; Cohen, Harvey Jay; Nakamura, Zev M.; Rentscher, Kelly E.; Saykin, Andrew J.; Small, Brent J.; Root, James C.; Jim, Heather; Patel, Sunita K.; Mcdonald, Brenna C.; Mandelblatt, Jeanne S.; Ahn, Jaeil; Radiology and Imaging Sciences, School of Medicine
    Purpose: Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment. Methods: We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function. Results: Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score. Conclusions: Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings.