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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.

Older cancer survivors are at risk for cognitive decline. Physical activity can improve cognition, and better cognitive function may facilitate greater physical activity.We examined the potential bidirectional relationship between cognitive function and physical activity in older breast cancer survivors and controls.The sample included women with newly diagnosed, nonmetastatic breast cancer (n = 395) and women without cancer (n = 374) ages 60-98. Participants were recruited as part of a larger multisite study, assessed prior to systemic therapy, and followed yearly for 36 months. Attention, processing speed, and executive function was measured using six neuropsychological tests, self-reported cognitive function using the Perceived Cognitive Impairments subscale of the Functional Assessment of Cancer Therapy-Cognitive Function , and physical activity using the International Physical Activity Questionnaire-Short Form. Separate random intercepts cross-lagged panel models were used to examine the between- and within-person effects for survivors and controls, controlling for age, education, and study site.Survivors reported significantly less physical activity than controls at baseline (1,284.92 vs. 2,085.98 MET min/week, p.05). When survivors reported higher activity, they simultaneously had better objective cognition at 12 months (β = 0.24, p = .04) and reported better perceived cognition at 12 and 24 months (β = 0.25, p = .03), but this relationship was not seen in controls. Cognition did not predict subsequent physical activity or vice versa in either group.Cognition and physical activity are cross-sectionally associated in survivors, but the expected prospective relationships were not found.Physical activity may improve cognitive function for older cancer survivors; however, cognitive function may also affect the ability to organize oneself to be physically active. We examined this potential bidirectional relationship in a sample of 395 women with newly diagnosed, nonmetastatic breast cancer, and 374 noncancer controls. These women completed cognitive tests and surveys yearly for 36 months. Surveys included their subjective cognitive function and physical activity. We examined the relationships between cognitive function (both objective and subjective) and physical activity over time (baseline, 12, 24, and 36 months). We found that when cancer survivors reported higher physical activity, they had better objective cognitive function at 12 months, and they reported better subjective cognitive function at 12 and 24 months. However, physical activity did not predict cognitive function at later time points, and cognitive function did not predict physical activity at later time points. In controls, better subjective cognitive function was related to higher physical activity overall, but there were not relationships over time or at specific time points. This was an observational study; therefore, future research should consider the potential impact of cognitive function when older cancer survivors are attempting to increase their physical activity.

Purpose: Tumor features associated with aggressive cancers may affect cognition prior to systemic therapy. We evaluated associations of pre-treatment cognition 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 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 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.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

Background: Early detection of dementia has become important for interventions that are developed to slow disease progression. Due to technological advancements, healthcare is trending toward using more telehealth screenings due to the convenience it provides patients. In our research, we evaluate the accuracy of a phone-based memory screen at diagnosing mild cognitive impairment. Methods: 181 participants from the Indiana Alzheimer’s Disease Research Center (IADRC)were screened using the Memory and Aging Telephone Screen (MATS) and diagnosed as cognitively normal (CN), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). 177 underwent Rey Auditory Verbal Learning Testing (RAVLT); 103 received Aβ PET scans([18F]florbetapir or [18F]florbetaben); 91 had plasma tau levels measured; and 140 received MRI scans (Freesurfer v6). ANCOVAs were used to evaluate differences between diagnostic groups covarying for age, sex, and education. ROC analysis and logistic regressions were used to predict MCI and Aβ positivity. Partial correlations covarying for sex and age (and education for RAVLT) were conducted to evaluate relationships between MATS scores with RAVLT, brain atrophy, pTau level, and amyloid deposition. Results: MCI patients showed significantly lower MATS scores for immediate (p

PURPOSE: Older cancer patients are susceptible to long-term effects of chemotherapy, including cancer-related cognitive decline and impairments to quality of life. Taxane-based chemotherapies are associated with physical declines among older women and may negatively impact cognitive performance. We sought to examine whether changes in objective and subjective measures of cognitive performance and well-being differ among older breast cancer survivors as a function of taxane-based chemotherapy treatment regimens. METHODS: Individual-level data was pooled and harmonized from two large prospective studies of older (greater than 60 years) breast cancer survivors. Assessments were conducted prior to systemic therapy and up to 36-months after. Cognitive performance was assessed with objective (working memory, processing speed and executive functions) and subjective tests and physical, emotional and functional well-being was also assessed. RESULTS: One hundred and sixty-seven (M age = 67.3 years) women, with 116 receiving chemotherapy with taxanes and 51 without taxanes contributed data. Declines in subjective cognition for both groups were significant between pre-treatment and 12-month follow-up. Significant improvements were seen on a measure of objective cognition (working memory) from 12 to 36-months. Measures of well-being improved from prior to systemic therapy to 12-months. Longitudinal changes across all measures did not vary as a function of receipt of taxane-based treatment. CONCLUSION: Older women who received treatment with taxanes did not have greater declines in cognitive performance or well-being than women receiving other chemotherapy regimens. Despite older cancer survivors being at greater risk for negative outcomes, treatment with taxane-based chemotherapies does not appear to exacerbate these health consequences.

PurposeOlder cancer survivors required medical care during the COVID-19 pandemic despite infection risks, but there are limited data on medical care in this age group. Methods. We evaluated care disruptions in a longitudinal cohort of non-metastatic breast cancer survivors ages 60-98 from five US regions (n=321). Survivors completed a web-based or telephone survey from May 27, 2020 to September 11, 2020. Care disruptions included self-reported interruptions in ability to see doctors, receive treatment or supportive therapies, or fill prescriptions. Logistic regression models evaluated bivariate and multivariate associations between care disruptions and education, medical, psychosocial and COVID-19-related factors. Multivariate models included age, county COVID-19 rates, comorbidity and post-diagnosis time. Results. There was a high response rate (n=262, 81.6%). Survivors were 32.2 months post-diagnosis (SD 17.5, range 4-73). Nearly half (48%) reported a medical disruption. The unadjusted odds of care disruptions were significantly higher with more education (OR 1.23 per one-year increase, 95% CI 1.09-1.39, p =0.001) and greater depression (OR 1.04 per one-point increase in CES-D score, CI 1.003-1.08, p=0.033); tangible support decreased the odds of disruptions (OR 0.99, 95% CI 0.97-0.99 per one-point increase, p=0.012). There was a trend for associations between disruptions and comorbidity (unadjusted OR 1.13 per 1 added comorbidity, 95% CI 0.99-1.29, p=0.07). Adjusting for covariates, only higher education (p=0.001) and tangible social support (p=0.006) remained significantly associated with having care disruptions. Conclusions. Older breast cancer survivors reported high rates of medical care disruptions during the COVID-19 pandemic and psychosocial factors were associated with care disruptions.

Alzheimer’s disease (AD) is the leading cause of dementia in individuals over 65 in the U.S. Prevalence is projected to double by 2050, but current treatments cannot stop the progression of AD. Treatments administered before severe cognitive decline may be effective; identification of biomarkers for preclinical and prodromal stages of AD is therefore imperative. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. Characterization should include the relationships between CBF and AD risk factors and pathologies. We assessed the relationships between CBF quantified by arterial spin labeled MRI, hypertension,APOEε4, and tau and amyloid PET in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension orAPOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.

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., Older breast cancer survivors and matched noncancer controls experienced similar increases in loneliness from before to during the COVID‐19 pandemic. Women who reported increased loneliness also experienced worsening depression and anxiety symptoms and higher stress during the pandemic.

Prior research has found that individuals with a pre-injury psychiatric history report greater difficulty with executive functioning after mild traumatic brain injury (mTBI). The present study examined self-rated executive functioning after the acute phase of recovery in individuals with mTBI having no prior psychiatric history. Participants included 59 individuals with mTBI and 27 healthy comparison subjects (HC). They completed the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and Beck Depression Inventory-II. Participants had no prior history of psychiatric diagnosis based on semi-structured interview. In those with a valid BRIEF-A, the mTBI group (n = 54; days since injury: M = 465.04, SD = 146.92, range = 315–1144) endorsed poorer executive functioning than the HC group (n = 24) on several BRIEF-A scales. Only the Working Memory and Inhibit scales remained significant after adjusting for group differences in education and depression score, but they did not survive adjustment for multiple comparisons. The mean standardized scores for the mTBI group were well within normal limits across scales. Furthermore, there were no group differences on any BRIEF-A scales for percentage of participants with clinically elevated scores. Individuals with mTBI and no prior psychiatric history did not endorse significant executive dysfunction. Our findings support previous literature indicating that self-rated executive dysfunction in those with mTBI after the acute phase of recovery is likely due to factors other than brain injury, such as subclinical symptoms of depression.

Cancer- and treatment-related cognitive dysfunction (CRCD) is a common challenge faced by patients diagnosed with non-central nervous system (CNS) cancer. It has become increasingly recognized that multiple factors likely play a role in these symptoms, including the cancer disease process, systemic treatments (e.g., chemotherapy and endocrine therapies), and risk factors that may predispose an individual to both cancer and cognitive dysfunction. As the field has evolved, advanced neuroimaging techniques have been applied to better understand the neural correlates of CRCD. This review focuses on structural neuroimaging findings related to CRCD in adult non-CNS cancer populations, including examination of gray matter volume/density and white matter integrity differences between cancer patients and comparison groups, as well as emerging findings regarding structural network abnormalities. Overall, this literature has demonstrated consistent findings of reduced gray matter volume/density and white matter integrity in cancer patients relative to comparison groups. These are most prominent in individuals treated with chemotherapy, though alterations have also been noted in those treated with anti-estrogen and androgen-deprivation therapies. Alterations in gray and white matter structural network connectivity have also been identified. These structural abnormalities have been observed most prominently in frontal and temporal brain regions, and have been shown to correlate with subjective and objective cognitive function, as well as with physiological and clinical variables, helping to inform understanding of CRCD mechanisms. To date, however, structural neuroimaging techniques have not been utilized in systematic studies of potential CRCD treatments, suggesting a potentially fruitful avenue for future research. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01096-5.

Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10−8), and rs78786199 (chromosome 2, p = 1.925 × 10−8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.

Background We evaluated deficit accumulation and how deficits affected cognition and physical activity among breast cancer survivors and non-cancer controls. Methods Newly diagnosed nonmetastatic survivors (n = 353) and matched non-cancer controls (n = 355) ages 60-98 years without neurological impairments were assessed presystemic therapy (or at enrollment for controls) from August 2010 to December 2016 and followed for 36 months. Scores on a 42-item index were analyzed in growth-mixture models to determine deficit accumulation trajectories separately and combined for survivors and controls. Multilevel models tested associations between trajectory and cognition (FACT-Cog and neuropsychological tests) and physical activity (IPAQ-SF) for survivors and controls. Results Deficit accumulation scores were in the robust range, but survivors had higher scores (95% confidence intervals [CI]) than controls at 36 months (0.18, 95% CI = 0.16 to 0.19, vs 0.16, 95% CI = 0.14 to 0.17; P = .001), and averages included diverse deficit trajectories. Survivors who were robust but became frailer (8.8%) had similar baseline characteristics to those remaining robust (76.2%) but experienced a 9.6-point decline self-reported cognition (decline of 9.6 vs 3.2 points; P = .04) and a 769 MET minutes per week decline in physical activity (P < .001). Survivors who started and remained prefrail (15.0%) had self-reported and objective cognitive problems. At baseline, frail controls (9.5%) differed from robust controls (83.7%) on deficits and self-reported cognition (P < .001). Within combined trajectories, frail survivors had more sleep disturbances than frail controls (48.6% [SD = 17.4%] vs 25.0% [SD = 8.2%]; P = .05). Conclusions Most survivors and controls remained robust, and there were similar proportions on a frail trajectory. However, there were differences in deficit patterns between survivors and controls. Survivor deficit accumulation trajectory was associated with patient-reported outcomes. Additional research is needed to understand how breast cancer and its treatments affect deficit accumulation.

BACKGROUND: Self and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function. OBJECTIVE: We examined the relationship between CCI and ECog self and informant-based evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments. METHODS: 950 participants (57.1% female, mean age = 71.2 years) from ADNI and the Indiana ADRC with self-based evaluations and 279 participants (60.9% female, mean age = 71.8 years) with informant-based evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Spearman correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, age, years of education, race/ethnicity, APOE ε4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates. RESULTS: CCI and ECog total scores were highly correlated for the self (r = 0.795, p < 0.001) and informant-based (r = 0.840, p < 0.001) versions, as expected. Frequency distributions of self and informant total scores were generated and plotted separately. Quadratic regressions for self (r(2) = 0.626) and informant (r(2) = 0.741) scores were used to create a translation table between the CCI and ECog total scores. CONCLUSION: Self and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome.

To evaluate the acceptability, satisfaction, and preliminary efficacy of cognitive training for improving cognitive function and health outcomes in breast cancer survivors (BCS).BCS enrolled in this 2-group randomized, double-masked controlled trial of cognitive training. Primary outcomes included the acceptability and satisfaction of the interventions. Secondary outcomes included examining the effect size and reliable improvement of perceived cognitive function and health outcomes, including work ability, health perception (status and change), and quality of life. Exploratory outcomes were performance on neuropsychological tests and plasma levels of brain-derived neurotropic factor (BDNF). Data were collected at baseline and immediately post-intervention. Using ANCOVA models, the intervention was compared to attention control while adjusting for covariates and baseline values. The effect sizes for differences in means and the reliable improvement percentage were reported.Thirty-six BCS completed the study and were on average 57.6 (SD = 8.0) years old, 59.4% Caucasian, and had some college education (74.5%). Both programs were reported to be satisfactory and acceptable. Non-significant small effect sizes were noted for the intervention on cognitive abilities (d = 0.26) and cognitive concerns (d = - 0.32), with reliable improvement noted in 32% and 28% of BCS, respectively. Small to medium effect sizes were noted in improvement in work ability (d = 0.37) and health perception status (d = 0.30) and change (d = 0.60, p 0.05).Cognitive training was acceptable to BCS and resulted in improvement in perceived cognitive function and perceptions of "real-world" health benefits. A larger randomized controlled trial is warranted to determine its effectiveness for objective cognitive performance.

Mechanisms underpinning age-related variations in cortical thickness in the human brain remain poorly understood. We investigated whether inter-regional age-related variations in cortical thinning (in a multicohort neuroimaging dataset from the ENIGMA Lifespan Working Group totalling 14,248 individuals, aged 4-89 years) depended on cell-specific marker gene expression levels. We found differences amidst early-life (60 years) in the patterns of association between inter-regional profiles of cortical thickness and expression profiles of marker genes for CA1 and S1 pyramidal cells, astrocytes, and microglia. Gene ontology and enrichment analyses indicated that each of the three life-stages was associated with different biological processes and cellular components: synaptic modeling in early life, neurotransmission in mid-life, and neurodegeneration in late-life. These findings provide mechanistic insights into age-related cortical thinning during typical development and aging.

INTRODUCTION: Concern surrounding short- and long-term consequences of participation in contact sports has become a significant public health topic. Previous literature utilizing diffusion tensor imaging in sports-related concussion has exhibited notable variety of analysis methods and analyzed regions of interest, and largely focuses on acute effects of concussion. The current study aimed to compare diffusivity metrics across a single season within athlete cohorts with no history of concussion. METHODS: A prospective cohort of 75 contact and 79 non-contact division I athletes were compared across diffusion tensor imaging metrics (i.e., TRACULA); examinations were also performed assessing the relationship between neuroimaging metrics, head impact exposure metrics (in-helmet accelerometer), and neurocognitive variables. Assessment occurred at pre-and post-season time points. RESULTS: Seasonal changes in fractional anisotropy and mean diffusivity values did not differ between athlete cohorts, nor did they differ within cohort groups, across pre- and post-season scans. Specific to contact athletes, positive associations were found between uncinate fasciculus mean diffusivity values and season linear acceleration (p = .018), season rotational acceleration (p = .017), and season hit severity (p = .021). CONCLUSIONS: Results suggest an influence of impact frequency, type, and severity on white matter integrity in select brain regions in contact athletes. Current findings expand our knowledge of anatomical changes over the course of a single season, and underscore the importance of considering methodology when interpreting findings in this population, as differing image analysis techniques may lead to different conclusions regarding significant effects.

PurposeCancer patients are concerned about treatment-related cognitive problems. We examined effects of antiestrogen hormonal therapy on brain imaging metrics in older women with breast cancer.MethodsWomen aged 60+ treated with hormonal therapy only and matched non-cancer controls (n=29/group) completed MRI and objective and self-reported cognitive assessment at pre-treatment/enrollment and 12 months later. Gray matter was examined using voxel-based morphometry (VBM), FreeSurfer, and brain age calculations. Functional MRI (fMRI) assessed working memory-related activation. Analyses examined cross-sectional and longitudinal differences and tested associations between brain metrics, cognition, and days on hormonal therapy.ResultsThe cancer group showed regional reductions over 12 months in frontal, temporal, and parietal gray matter on VBM, reduced FreeSurfer cortical thickness in prefrontal, parietal, and insular regions, and increased working memory-related fMRI activation in frontal, cingulate, and visual association cortex. Controls showed only reductions in fusiform gyrus on VBM and FreeSurfer temporal and parietal cortex thickness. Women with breast cancer showed higher estimated brain age and lower regional gray matter volume than controls at both timepoints. The cancer group showed a trend toward decreased performance in attention, processing speed, and executive function over time. There were no significant associations between brain imaging metrics and cognition or days on hormonal therapy.ConclusionOlder women with breast cancer showed brain changes in the first year of hormonal therapy. Increased brain activation during working memory processing may be a sign of functional compensation for treatment-related structural changes. This hypothesis should be tested in larger samples over longer time periods.

OBJECTIVE: Older women are at increased risk of developing Alzheimer’s disease compared to men. One proposed reason is that following menopause there is a decline in estrogens. Estrogens are important for cholinergic functioning and attenuate the impact of cholinergic antagonists on cognitive performance in postmenopausal women. Self-reported or subjective cognitive complaints in middle or older age may represent a harbinger of cognitive decline and those who endorse cognitive complaints appear more likely to develop future cognitive impairment. However, the response of individuals with cognitive complaints after menopause to estrogen and the relationship to cholinergic functioning has not been investigated. This study investigated the effect of estrogen treatment using 17β-estradiol on cognitive performance following anticholinergic blockade in postmenopausal women and the relationship of this interaction with the level of self-reported (subjective) postmenopausal cognitive complaints. METHODS: Forty postmenopausal women (aged 50–60 years) completed a 3-month treatment regimen of either 1 mg oral estradiol or placebo. Participants then completed four challenge days in which they completed cognitive and behavioral tasks after one of four cholinergic antagonist drug conditions (oral mecamylamine (MECA), intravenous scopolamine, combined MECA and scopolamine, or PLC). RESULTS: Compared to PLC, the estradiol treated group performed worse on attention tasks under cholinergic challenge including the choice reaction time task and the critical flicker fusion task. In addition, participants who endorsed greater cognitive complaints showed reduced performance on the N-back working memory task, regardless of whether they received estradiol treatment. CONCLUSIONS: The findings of this study indicate that estradiol treatment was unable to mitigate anticholinergic blockade in postmenopausal women with subjective cognitive complaints, and worsened performance on attention tasks. Moreover, the present study suggests that greater levels of cognitive complaints following menopause may be associated with an underlying decline in cholinergic function that may manifest as an inability to compensate during working memory tasks.

Purpose: Cancer-related cognitive problems may result from peripheral inflammation effects on the brain. We tested whether differences in cognitive performance between breast cancer survivors and non-cancer controls was explained by elevated inflammatory cytokines. Methods: We enrolled women >60 years, newly diagnosed with primary breast cancer (stage 0-III) (n=400) and frequency-matched non-cancer controls (n=329) from six national centers from 2010- 2020, with blood collection beginning in 2016. Baseline assessments occurred pre-systemic therapy (or enrollment for controls) with annual follow-up to 60-months. The primary outcome was the score on neurocognitive tests of the attention, processing speed and executive function (APE) domain. Plasma levels of IL-6, IL-10, and TNF-alpha were determined using multiplex testing and mixed linear models compared results for each marker across all timepoints by survivor/control group, adjusting for age, race, WRAT scores, recruitment site, comorbidities, and BMI. Multi-level mediation analyses tested the simultaneous direct effects of survivor/control group on cognition and indirect effects of group on each immune marker and the effect of the marker on cognition, controlling for covariates. Results: Participants had an average age of 67.7 years (range: 60-90). Most survivors had stage I (60.9%) estrogen-receptor positive (87.6%) tumors. Survivors had significantly higher adjusted IL-6 levels than controls at baseline, 12-, 24- and 60-months (p=< 0.001 to 0.014), but there were no differences for other markers. Survivors had lower adjusted APE scores than controls, and this effect was due to the indirect effects of being a survivor vs. control on IL-6 (p=0.047). Conclusion: Cancer and its treatments were related to poorer attention, processing speed, and executive function compared to non-cancer frequency matched controls, and this difference was partially explained by elevated IL-6. Citation Format: Jeanne S. Mandelblatt, Brent J. Small, Xingtao Zhou, Zev M. Nakamura, Harvey J. Cohen, Tim A. Ahles, Jaeil Ahn, Traci N. Bethea, Martine Extermann, Heather S.L. Jim, Brenna C. McDonald, Sunita K. Patel, Kelly Rentscher, James Root, Andrew J. Saykin, Kathleen Van Dyk, Wanting Zhai, Elizabeth C. Breen, Judith E. Carroll. Differences in attention, processing speed, and executive function in older breast cancer survivors compared to controls is partially explained by plasma IL-6: The Thinking and Living with Cancer (TLC) Study [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A012.

Cancer and its treatments are thought to increase risk for accelerated aging in survivors, and biological aging may be a key mechanism; however, no research to date has examined epigenetic markers of aging in long-term breast cancer survivors. We used data from the Thinking and Living with Cancer (TLC) study to examine whether older breast cancer survivors have accelerated epigenetic aging compared to non-cancer controls several years after treatment completion and whether epigenetic aging related to cognitive and physical function. Non-metastatic breast cancer survivors ages 62–84 years (n=89) and frequency-matched controls (n=101) provided two blood samples between 24- and 60-months post-diagnosis. DNA methylation profiling (Illumina Infinium EPIC array) derived epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging Methylation. Participants completed neuropsychological testing and questionnaires to assess cognitive and physical function at each visit. Mixed-effects models adjusted for chronological age and comorbidities and applied false discovery rate correction for multiple testing. Survivors were 1.04–2.22 years older biologically than controls at the first blood sample based on Horvath, Hannum, and GrimAge measures (corrected ps=.025, .025, and .058, respectively), with marginal differences for Dunedin Pace of Aging (corrected p=.096); however, survivors and controls showed similar changes in epigenetic aging over time. Exposure to prior chemotherapy (with or without hormonal therapy; n=29) was associated with an epigenetic age 1.97–2.71 years older than controls (corrected ps=.005 to .065). Among survivors who received chemotherapy, an older Hannum epigenetic age was associated with poorer self-reported cognition relative to controls (coeff=-0.64, uncorrected p=.047; n.s. after correction). Older breast cancer survivors, particularly those receiving chemotherapy, showed an accelerated epigenetic aging profile compared to their peers without cancer at 24 months or more post-diagnosis, following the completion of active therapy. This study also provides preliminary evidence that survivors who received chemotherapy may be at increased risk for poorer age-related survivorship outcomes. Citation Format: Kelly E. Rentscher, Wanting Zhai, Brent J. Small, Jaeil Ahn, Tim A. Ahles, Traci N. Bethea, Elizabeth C. Breen, Harvey J. Cohen, Martine Extermann, Deena M.A. Graham, Paul B. Jacobsen, Heather S.L. Jim, Brenna C. McDonald, Zev M. Nakamura, Sunita K. Patel, James C. Root, Andrew J. Saykin, Danielle B. Tometich, Kathleen M. Van Dyk, Xingtao Zhou, Jeanne S. Mandelblatt, Judith E. Carroll. Long-term epigenetic aging in older breast cancer survivors and non-cancer controls: Preliminary findings from the Thinking and Living with Cancer (TLC) Stud [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B018.

Introduction: While some cancer survivors experience minimal lasting effects of diagnosis and treatment, others report persistent decrements in physical and cognitive function. These changes may represent aging beyond that expected for the chronological age (i.e., “accelerated aging”). Racial minority groups often have an accelerated aging phenotype even before cancer diagnosis, partly due to chronic stress and other multi-level factors that affect aging and the ability to repair physiologic damage, leaving them more vulnerable to poor survivorship outcomes. However, we know little about physical and cognitive aging in this group and few studies have collected objective measures of physical and cognitive aging in minority cancer survivors. Methods: We examined changes in physical and cognitive function across 60 months of follow-up among Black and White survivors in the Thinking and Living with Cancer Study (TLC). TLC is an ongoing prospective multi-site cohort study recruiting non-metastatic breast cancer survivors aged ≥60 years. Participants completed questionnaires and objective assessments prior to systemic therapy with annual follow-up for up to 60 months. Physical function was measured using the timed up and go test (TUG); cognitive function was measured with Z scores on 11 neuropsychological tests for two domains: learning and memory (LM) and attention, processing, and executive function (APE). Mixed linear regression models predicting TUG, APE, or LM adjusted for age, study site, time, and cognitive reserve using the Wide Range Achievement Test (WRAT). Results: Black and White survivors in TLC were similar in age, education, comorbidities, and year of enrollment (p>0.14), but differed by study site (p Citation Format: Traci N. Bethea, Wanting Zhai, Xingtao Zhou, Tim A. Ahles, Jaeil Ahn, Harvey J. Cohen, Asma A. Dilawari, Deena Graham, Heather Jim, Brenna C. McDonald, Zev M. Nakamura, Sunita K. Patel, Kelly E. Rentscher, James C. Root, Andrew J. Saykin, Brent J. Small, Kathleen Van Dyk, Jeanne S. Mandelblatt, Judith E. Carroll. Black-White differences in physical and cognitive aging among older breast cancer survivors in the Thinking and Living with Cancer Study [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B111.

BACKGROUND Little is known about longitudinal symptom burden, its consequences for well-being, and whether lifestyle moderates the burden in older survivors. METHODS The authors report on 36-month data from survivors aged ≥60 years with newly diagnosed, nonmetastatic breast cancer and noncancer controls recruited from August 2010 through June 2016. Symptom burden was measured as the sum of self-reported symptoms/diseases as follows: pain (yes or no), fatigue (on the Functional Assessment of Cancer Therapy [FACT]-Fatigue scale), cognitive (on the FACT-Cognitive scale), sleep problems (yes or no), depression (on the Center for Epidemiologic Studies Depression scale), anxiety (on the State-Trait Anxiety Inventory), and cardiac problems and neuropathy (yes or no). Well-being was measured using the FACT-General scale, with scores from 0 to 100. Lifestyle included smoking, alcohol use, body mass index, physical activity, and leisure activities. Mixed models assessed relations between treatment group (chemotherapy with or without hormone therapy, hormone therapy only, and controls) and symptom burden, lifestyle, and covariates. Separate models tested the effects of fluctuations in symptom burden and lifestyle on function. RESULTS All groups reported high baseline symptoms, and levels remained high over time; differences between survivors and controls were most notable for cognitive and sleep problems, anxiety, and neuropathy. The adjusted burden score was highest among chemotherapy-exposed survivors, followed by hormone therapy-exposed survivors versus controls (P

BackgroundSelf and informant (proxy or study partner) reports of everyday cognitive functioning have been shown to be associated with incipient neurodegenerative disease. The 20-item Cognitive Change Index (CCI) and the 39-item Measurement of Everyday Cognition (ECog) were each developed to characterize early subjective changes in cognitive function.ObjectiveWe examined the relationship between CCI and ECog self and informant evaluations to determine content overlap and provide a co-calibration for converting between these widely used instruments.Methods950 participants (57.1% female, mean age=71.2yrs) from ADNI and the Indiana ADRC with self evaluations and 279 participants (60.9% female, mean age=71.8yrs) with informant evaluations (Indiana ADRC) were included. Analyzed variables for the CCI and ECog included domain mean scores, memory domain total scores, and total scores for all items. Pearson correlations, regression analyses, and frequency distributions were used to assess the relationship between CCI and ECog. Sex, years of education, race, APOE ε4 carrier status, and baseline diagnosis were also analyzed as potentially relevant covariates.ResultsCCI and ECog total scores were highly correlated for the self (r=0.790, p2=0.682) and informant (r2=0.863) scores were used to create a translation table between the CCI and ECog total scores.ConclusionSelf and informant total scores can be harmonized and translated between the CCI and ECog to facilitate cross-study and longitudinal assessment of perceived cognitive change, an important patient-reported outcome.

BACKGROUND Sleep disturbance and genetic profile are risks for cognitive decline in noncancer populations, yet their role in cancer-related cognitive problems remains understudied. This study examined whether sleep disturbance was associated with worse neurocognitive outcomes in breast cancer survivors and whether sleep effects on cognition varied by genotype. METHODS Newly diagnosed female patients (n = 319) who were 60 years old or older and had stage 0 to III breast cancer were recruited from August 2010 to December 2015. Assessments were performed before systemic therapy and 12 and 24 months later. Neuropsychological testing measured attention, processing speed, executive function, learning, and memory; self-perceived cognitive functioning was also assessed. Sleep disturbance was defined by self-report of routine poor or restless sleep. Genotyping included APOE, BDNF, and COMT polymorphisms. Random effects fluctuation models tested associations of between-person and within-person differences in sleep, genotype, and sleep-genotype interactions and cognition and controlled for age, reading level, race, site, and treatment. RESULTS One-third of the patients reported sleep disturbances at each time point. There was a sleep-APOE e4 interaction (P = .001) in which patients with the APOE e4 allele and sleep disturbances had significantly lower learning and memory scores than those who were APOE e4-negative and without sleep disturbances. There was also a sleep disturbance-COMT genotype interaction (P = .02) in which COMT Val carriers with sleep disturbances had lower perceived cognition than noncarriers. CONCLUSIONS Sleep disturbance was common and was associated with worse cognitive performance in older breast cancer survivors, especially those with a genetic risk for cognitive decline. Survivorship care should include sleep assessments and interventions to address sleep problems.

TPS12143 Background: Cancer-related cognitive impairment (CRCI) can include persistent memory symptoms, and affects many cancer survivors. Memory and Attention Adaptation Training (MAAT) is an evidence-based cognitive behavioral therapy (CBT) that improves CRCI with demonstrated efficacy in telehealth delivery. MAAT consists of 8 weekly (45-minute) video visits. The aims of this study are to confirm MAAT telehealth efficacy in a phase III RCT (MAAT versus Supportive Therapy; ST) across large catchment areas of two comprehensive cancer centers. A secondary aim is to evaluate treatment-induced brain activation as assessed by functional MRI (fMRI) in a subset of participants. We present remote treatment and data capture methods of this open NCI-sponsored (R01CA244673) randomized clinical trial (NCT 04586530). These methods have high success in participant accrual despite COVID-19 pandemic conditions, and can be readily adopted to other clinical trials to enhance rural/underserved enrollment. Methods: We are enrolling 200 adult, stage I-III breast cancer survivors 1-5 years post-chemotherapy with cognitive complaints. Individuals with CNS disease, previous brain injury, dementia or psychiatric disorder are excluded. All study procedures are completed from the participant’s home (except fMRI). Eligibility screening is a semi-structured phone interview followed by detailed informed consent online (Research Electronic Data Capture: REDCap) with staff phone guidance. Consented participants complete baseline brief phone-based neurocognitive assessment and validated patient-reported outcome measures (PROs) of cognition and quality of life via REDCap. Participants are randomized to MAAT or ST and assigned treating clinicians at respective cancer centers. All 8 visits are completed through secure telehealth platforms, followed by repeat phone/online assessment post-treatment and again at 6 months. Enrollment began in 3/2021. As of 1/2022 (9 months), 56 participants are enrolled (28% of the planned sample), 47 randomized (MAAT 24; ST 23), with 24 completing post-treatment assessments. If all assessments and treatment visits were in person, travel burden per participant is 968 miles/20.5 hours driven, and $542 (US 2021 Federal rate). Thus, study travel savings to date are $30,352. Participant feedback indicates telehealth makes participation possible, similar to previous MAAT research. The current RCT demonstrates utility, efficiency and cost-savings of telehealth and remote data capture technology in the conduct of cancer control research. Elements of methods described can also be adopted for cancer therapeutic trials. Comprehensive cancer centers, where most clinical trials are based, can enhance participation of remote and/or underserved populations that have higher rates of cancer, more disease burden and less opportunity for trial participation. Clinical trial information: NCT04586530.

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

Dopamine D1 and D2 receptors differ with respect to patterns of regional brain distribution and behavioral effects. Pre-clinical work suggests that D1 agonists enhance working memory, but the absence of selective D1 agonists has constrained using this approach in humans. This study examines working memory performance in mild traumatic brain injury (mTBI) patients when given pergolide, a mixed D1/D2 agonist, compared with bromocriptine, a selective D2 agonist. Fifteen individuals were studied 1 month after mTBI and compared with 17 healthy controls. At separate visits, participants were administered 1.25 mg bromocriptine or 0.05 mg pergolide prior to functional magnetic resonance imaging (MRI) using a working memory task (visual-verbal n-back). Results indicated a significant group-by-drug interaction for mean performance across n-back task conditions, where the mTBI group showed better performance on pergolide relative to bromocriptine, whereas controls showed the opposite pattern. There was also a significant effect of diagnosis, where mTBI patients performed worse than controls, particularly while on bromocriptine, as shown in our prior work. Functional MRI activation during the most challenging task condition (3-back > 0-back contrast) showed a significant group-by-drug interaction, with the mTBI group showing increased activation relative to controls in working memory circuitry while on pergolide, including in the left inferior frontal gyrus. Across participants there was a positive correlation between change in activation in this region and change in performance between drug conditions. Results suggest that activation of the D1 receptor may improve working memory performance after mTBI. This has implications for the development of pharmacological strategies to treat cognitive deficits after mTBI.

Background Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated. Methods We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity. Results There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores. Conclusions APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.