Browsing by Author "Ahles, Tim A."

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    Applying a Life Course Biological Age Framework to Improving the Care of Individuals with Adult Cancers: Review and Research Recommendations
    (American Medical Association, 2021) Mandelblatt, Jeanne S.; Ahles, Tim A.; Lippman, Marc E.; Isaacs, Claudine; Adams-Campbell, Lucile; Saykin, Andrew J.; Cohen, Harvey J.; Carroll, Judith; Radiology and Imaging Sciences, School of Medicine
    Importance: The practice of oncology will increasingly involve the care of a growing population of individuals with midlife and late-life cancers. Managing cancer in these individuals is complex, based on differences in biological age at diagnosis. Biological age is a measure of accumulated life course damage to biological systems, loss of reserve, and vulnerability to functional deterioration and death. Biological age is important because it affects the ability to manage the rigors of cancer therapy, survivors' function, and cancer progression. However, biological age is not always clinically apparent. This review presents a conceptual framework of life course biological aging, summarizes candidate measures, and describes a research agenda to facilitate clinical translation to oncology practice. Observations: Midlife and late-life cancers are chronic diseases that may arise from cumulative patterns of biological aging occurring over the life course. Before diagnosis, each new patient was on a distinct course of biological aging related to past exposures, life experiences, genetics, and noncancer chronic disease. Cancer and its treatments may also be associated with biological aging. Several measures of biological age, including p16INK4a, epigenetic age, telomere length, and inflammatory and body composition markers, have been used in oncology research. One or more of these measures may be useful in cancer care, either alone or in combination with clinical history and geriatric assessments. However, further research will be needed before biological age assessment can be recommended in routine practice, including determination of situations in which knowledge about biological age would change treatment, ascertaining whether treatment effects on biological aging are short-lived or persistent, and testing interventions to modify biological age, decrease treatment toxic effects, and maintain functional abilities. Conclusions and relevance: Understanding differences in biological aging could ultimately allow clinicians to better personalize treatment and supportive care, develop tailored survivorship care plans, and prescribe preventive or ameliorative therapies and behaviors informed by aging mechanisms.
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    Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: a brain magnetic resonance imaging pilot study
    (BMC, 2018-05-02) Chen, Bihong T.; Sethi, Sean K.; Jin, Taihao; Patel, Sunita K.; Ye, Ningrong; Sun, Can-Lan; Rockne, Russell C.; Haacke, E. Mark; Root, James C.; Saykin, Andrew J.; Ahles, Tim A.; Holodny, Andrei I.; Prakash, Neal; Mortimer, Joanne; Waisman, James; Yuan, Yuan; Somlo, George; Li, Daneng; Yang, Richard; Tan, Heidi; Katheria, Vani; Morrison, Rachel; Hurria, Arti; Medicine, School of Medicine
    BACKGROUND: Cognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy. METHODS: Women aged ≥ 60 years with stage I-III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using Neuroreader™ software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models. RESULTS: A total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy (p > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = - 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = - 6.94) compared to the non-TC group (change = - 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02). CONCLUSIONS: There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings.
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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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    Chemotherapy-induced amenorrhea: a prospective study of brain activation changes and neurocognitive correlates
    (Springer US, 2013-12) Conroy, Susan K.; McDonald, Brenna C.; Ahles, Tim A.; West, John D.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, School of Medicine
    Chemotherapy-induced amenorrhea (CIA) often occurs in pre- and peri-menopausal BC patients, and while cancer/chemotherapy and abrupt estrogen loss have separately been shown to affect cognition and brain function, studies of the cognitive effects of CIA are equivocal, and its effects on brain function are unknown. Functional MRI (fMRI) during a working memory task was used to prospectively assess the pattern of brain activation and deactivation prior to and one month after chemotherapy in BC patients who experienced CIA (n=9), post-menopausal BC patients undergoing chemotherapy (n=9), and pre- and post-menopausal healthy controls (n=6 each). Neurocognitive testing was also performed at both time points. Repeated measures general linear models were used to assess statistical significance, and age was a covariate in all analyses. We observed a group-by-time interaction in the combined magnitudes of brain activation and deactivation (p = 0.006): the CIA group increased in magnitude from baseline to post-treatment while other groups maintained similar levels over time. Further, the change in brain activity magnitude in CIA was strongly correlated with change in processing speed neurocognitive testing score (r=0.837 p=0.005), suggesting this increase in brain activity reflects effective cognitive compensation. Our results demonstrate prospectively that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Cognitive correlates add to the potential clinical significance of these findings. These findings have implications for risk appraisal and development of prevention or treatment strategies for cognitive changes in CIA.
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    Cognitive function in long-term testicular cancer survivors: impact of modifiable factors
    (Oxford University Press, 2024) Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; Sesso, Howard D.; Feldman, Darren R.; Vaughn, David J.; Hamilton, Robert J.; Huddart, Robert; Martin, Neil E.; Kollmannsberger, Christian; Althouse, Sandra; Einhorn, Lawrence H.; Frisin, Robert; Root, James C.; Ahles, Tim A.; Travis, Lois B.; Medicine, School of Medicine
    No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) affecting cognitive function in long-term testicular cancer survivors (TC survivors). TC survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those that assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC survivors (median age = 46; interquartile range [IQR] = 38-54); median time since chemotherapy = 10.9 years, IQR = 7.9-15.9), 13.7% reported cognitive dysfunction. Hearing loss (odds ratio [OR] = 2.02; P = .040), neuropathic pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P < .001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive decline. Factors associated with impaired cognition identify TC survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC survivors.
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    Cognitive function prior to systemic therapy and subsequent well-being in older breast cancer survivors: longitudinal findings from the Thinking and Living with Cancer Study
    (Wiley, 2020-06) Kobayashi, Lindsay C.; Cohen, Harvey Jay; Zhai, Wanting; Zhou, Xingtao; Small, Brent J.; Luta, George; Hurria, Arti; Carroll, Judith; Tometich, Danielle; McDonald, Brenna C.; Graham, Deena; Jim, Heather S.L.; Jacobsen, Paul; Root, James C.; Saykin, Andrew J.; Ahles, Tim A.; Mandelblatt, Jeanne; Radiology and Imaging Sciences, School of Medicine
    Objective: To investigate the relationships between self-reported and objectively measured cognitive function prior to systemic therapy and subsequent well-being outcomes over 24 months in older breast cancer survivors. Methods: Data were from 397 women aged 60 to 98 diagnosed with non-metastatic breast cancer in the Thinking and Living with Cancer Study recruited from 2010-2016. Cognitive function was measured at baseline (following surgery, prior to systemic therapy) using neuropsychological assessments of attention, processing speed, and executive function (APE), learning and memory (LM), and the self-reported FACT-Cog scale. Well-being was measured using the FACT-G functional, physical, social, and emotional well-being domain scales at baseline and 12 and 24 months later, scaled from 0 (low) to 100 (high). Linear mixed-effects models assessed the relationships between each of baseline APE, LM, and FACT-Cog quartiles with well-being scores over 24 months, adjusted for confounding variables. Results: At baseline, older survivors in the lowest APE, LM, and FACT-Cog score quartiles experienced poorer global well-being than those in the highest quartiles. At 24 months, older survivors tended to improve in well-being, and there were no differences according to baseline APE or LM scores. At 24 months, mean global well-being was 80.3 (95% CI: 76.2-84.3) among those in the lowest vs 86.6 (95% CI: 83.1-90.1) in the highest FACT-cog quartile, a clinically meaningful difference of 6.3 points (95% CI: 1.5-11.1). Conclusions: Among older breast cancer survivors, self-reported, but not objective cognitive impairments, were associated with lower global well-being over the first 2 years of survivorship.
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    Effect of chemotherapy on default mode network connectivity in older women with breast cancer
    (Springer, 2022) Chen, Bihong T.; Chen, Zikuan; Patel, Sunita K.; Rockne, Russell C.; Wong, Chi Wah; Root, James C.; Saykin, Andrew J.; Ahles, Tim A.; Holodny, Andrei I.; Sun, Can-Lan; Sedrak, Mina S.; Kim, Heeyoung; Celis, Ashley; Katheria, Vani; Dale, William; Radiology and Imaging Sciences, School of Medicine
    Chemotherapy may impair cognition and contribute to accelerated aging. The purpose of this study was to assess the effects of chemotherapy on the connectivity of the default mode network (DMN) in older women with breast cancer. This prospective longitudinal study enrolled women aged ≥60 years with stage I–III breast cancer (CTx group) and matched healthy controls (HC group). Study assessments, consisting of resting-state functional MRI (rs-fMRI) and the Picture Sequence Memory (psm) test for episodic memory from the NIH Toolbox for Cognition, were obtained at baseline and within one month after the completion of chemotherapy for the CTx group and at matched intervals for the HC group. Two-sample t-test and FDR multiple comparison were used for statistical inference. Our analysis of the CTx group (N=19; 60–82 years of age, mean=66.6, SD=5.24) compared to the HC group (N=14; 60–78 years of age, mean=68.1, SD=5.69) revealed weaker DMN subnetwork connectivity in the anterior brain but stronger connectivity in the posterior brain at baseline. After chemotherapy, this pattern was reversed, with stronger anterior connectivity and weaker posterior connectivity. In addition, the meta-level functional network connectivity (FNC) among DMN subnetworks after chemotherapy was consistently weaker than the baseline FNC as seen in the couplings between anterior cingulate cortex (ACC) and retrosplenial (rSplenia) region, with ΔFNC(‘ACC’,’rSplenia’)=−0.14, t value=−2.44, 95%CI=[−0.27, −0.10], pFDR<0.05). The baseline FNC matrices of DMN subnetworks were correlated with psm scores (corr=0.58, p<0.05). Our results support DMN alterations as a potential neuroimaging biomarker for cancer-related cognitive impairment and accelerated aging.