Ligand-gated ion channels as potential biomarkers for ADT-mediated cognitive decline in prostate cancer patients.

Men with prostate cancer are at increased risk of developing cognitive decline by the use of second-generation androgen signaling inhibitors. To date, reliable and sensitive biomarkers that could distinguish men at high risk of cognitive dysfunction under androgen deprivation therapy (ADT) have not been characterized. We used high-throughput transcriptional profiling utilizing human prostate cancer cell culture models mimicking ADT, biomarker selection using minimal common oncology data elements-cytoscape, and bioinformatic analyses employing Advaita® iPathwayGuide and DisGeNET for identification of disease-related gene associations. Validation analysis of genes was performed on brain neuronal and glial cells by quantitative real-time polymerase chain reaction assay. Our systematic analysis of androgen deprivation-associated genes involved multiple biological processes, including neuroactive ligand-receptor interaction, axon guidance, cytokine-cytokine receptor interaction, and metabolic and cancer signaling pathways. Genes associated with neuroreceptor ligand interaction, including gamma-aminobutyric acid (GABA) A and B receptors and nuclear core proteins, were identified as top upstream regulators. Functional enrichment and protein-protein interaction network analysis highlighted the role of ligand-gated ion channels (LGICs) and their receptors in cognitive dysfunction. Gene-disease association assigned forgetfulness, intellectual disability, visuospatial deficit, bipolar disorder, and other neurocognitive impairment with upregulation of type-1 angiotensin II receptor, brain-derived neurotrophic factor, GABA type B receptor subunit 2 (GABBR2), GABRA3, GABRA5, GABRB1, glycine receptor beta, glutamate ionotropic receptor N-methyl-D-aspartate receptor (NMDA) type subunit 1, glutamate ionotropic receptor NMDA type subunit 2D, 5-hydroxytryptamine receptor 1D, interferon beta 1, and nuclear receptor subfamily 3 group C member 1 as top differentially expressed genes. Validation studies of brain glial cells, neurons, and patients on ADT demonstrated the association of these genes with cognitive decline. Our findings highlight LGICs as potential biomarkers for ADT-mediated cognitive decline. Further validation of these biomarkers may lead to future practical clinical use.

Sex differences in the effects of trait anxiety and age on resting-state functional connectivities of the amygdala.

Background: Numerous studies characterized how resting-state functional connectivities (rsFCs) of the amygdala were disrupted in emotional disorders and varied with emotional traits, including anxiety. With trait anxiety known to diminish with age, a critical issue concerns disambiguating the effects of age and anxiety on amygdala rsFCs in studying the neural bases of individual differences in anxiety. Methods: Two-hundred adults (83 women) 19-85 years of age underwent fMRI and assessment for trait anxiety. Amygdala rsFC correlates were identified using multiple regression with age and anxiety in the same model for all and separately in men and women. The rsFC correlates were examined for age-anxiety interaction. Results: Anxiety was negatively correlated with amygdala-temporooccipital gyri rsFC in all and in men alone. In women, amgydala rsFC with the thalamus/pallidum, angular/supramarginal gyri, inferior temporal gyrus, and posterior insula correlated positively and rsFC with calcarine cortex and caudate correlated negatively with anxiety. We also observed sex differences in age correlation of amgydala-posterior cingulate cortex/precuneus and -insula/temporoparietal rsFCs, with stronger associations in women. In women alone, anxiety and age interacted to determine amygdala rsFC with the thalamus/pallidum, calcarine cortex, and caudate, with older age associated with stronger correlation between anxiety and the rsFCs. Limitations: The findings need to be validated in an independent sample and further explored using task-based data. Conclusion: Highlighting anxiety- and age- specific as well as interacting correlates of amygdala rsFCs and sex differences in the correlates, the findings may shed light on the neural markers of anxiety.

Age-related reduction in trait anxiety: Behavioral and neural evidence of automaticity in negative facial emotion processing.

Trait anxiety diminishes with age, which may result from age-related decline in registering salient emotional stimuli and/or enhancement in emotion regulation. We tested the hypotheses in 88 adults 21 to 85 years of age and studied with fMRI of the Hariri task. Age-related decline in stimulus registration would manifest in delayed reaction time (RT) and diminished saliency circuit activity in response to emotional vs. neutral stimuli. Enhanced control of negative emotions would manifest in diminished limbic/emotional circuit and higher prefrontal cortical (PFC) responses to negative emotion. The results showed that anxiety was negatively correlated with age. Age was associated with faster RT and diminished activation of the medial PFC, in the area of the dorsal and rostral anterior cingulate cortex (dACC/rACC) - a hub of the saliency circuit - during matching of negative but not positive vs. neutral emotional faces. A slope test confirmed the differences in the regressions. Further, age was not associated with activation of the PFC in whole-brain regression or in region-of-interest analysis of the dorsolateral PFC, an area identified from meta-analyses of the emotion regulation literature. Together, the findings fail to support either hypothesis; rather, the findings suggest age-related automaticity in processing negative emotions as a potential mechanism of diminished anxiety. Automaticity results in faster RT and diminished anterior cingulate activity in response to negative but not positive emotional stimuli. In support, analyses of psychophysiological interaction demonstrated higher dACC/rACC connectivity with the default mode network, which has been implicated in automaticity in information processing. As age increased, individuals demonstrated faster RT with higher connectivity during matching of negative vs. neutral images. Automaticity in negative emotion processing needs to be investigated as a mechanism of age-related reduction in anxiety.

Does ADT Influence the Risk of Suicidal Ideation among US Veteran Prostate Cancer Patients Pre-Exposed to PTSD?

Post-traumatic stress disorder (PTSD) is defined as a mental health disease that has a high probability of developing among individuals who have experienced traumatic events [...].

The effects of age on the severity of problem drinking: Mediating effects of positive alcohol expectancy and neural correlates.

Aging is associated with reduction in the severity of alcohol misuse. However, the psychological and neural mechanisms underlying the age-related changes remain unclear. Here, we tested the hypothesis that age-related diminution of positive alcohol expectancy (AE) mediated the effects of age on problem drinking and investigated the neural correlates of the mediating effects. Ninety-six drinkers 21-85 years of age, including social drinkers and those with mild/moderate alcohol use disorder (AUD), were assessed for global positive (GP) AE and problem drinking, each with the Alcohol Expectancy Questionnaire and Alcohol Use Disorders Identification Test (AUDIT), and with brain imaging during alcohol cue exposure. We processed imaging data with published routines; identified the correlates shared between whole-brain regression against age, GP and AUDIT scores; and performed mediation and path analyses to explore the interrelationships between the clinical and neural variables. The results showed that age was negatively correlated with both GP and AUDIT scores, with GP score completely mediating the correlation between age and AUDIT score. Lower age and higher GP correlated with shared cue responses in bilateral parahippocampal gyrus and left middle occipital cortex (PHG/OC). Further, higher GP and AUDIT scores were associated with shared cue responses in bilateral rostral anterior cingulate cortex and caudate head (ACC/caudate). Path analyses demonstrated models with significant statistical fit and PHG/OC and ACC/caudate each interrelating age to GP and GP to AUDIT scores. These findings confirmed change in positive AE as a psychological mechanism mitigating alcohol misuse as individuals age and highlighted the neural processes of cue-reactivity interrelating age and alcohol use severity.

Quality-of-life outcomes and risk prediction for patients randomized to nivolumab plus ipilimumab vs nivolumab on LungMAP-S1400I.

BACKGROUND: An important issue for patients with cancer treated with novel therapeutics is how they weigh the effects of treatment on survival and quality of life (QOL). We compared QOL in patients enrolled to SWOG S1400I, a substudy of the LungMAP biomarker-driven master protocol. METHODS: SWOG S1400I was a randomized phase III trial comparing nivolumab plus ipilimumab vs nivolumab for treatment of immunotherapy-naïve disease in advanced squamous cell lung cancer. The primary endpoint was the MD Anderson Symptom Inventory-Lung Cancer severity score at week 7 and week 13 with a target difference of 1.0 points, assessed using multivariable linear regression. A composite risk model for progression-free and overall survival was derived using best-subset selection. RESULTS: Among 158 evaluable patients, median age was 67.6 years and most were male (66.5%). The adjusted MD Anderson Symptom Inventory-Lung Cancer severity score was 0.04 points (95% confidence interval [CI] = -0.44 to 0.51 points; P = .89) at week 7 and 0.12 points (95% CI = -0.41 to 0.65; P = .66) at week 13. A composite risk model showed that patients with high levels of appetite loss and shortness of breath had a threefold increased risk of progression or death (hazard ratio [HR] = 3.06, 95% CI = 1.88 to 4.98; P < .001) and that those with high levels of both appetite loss and work limitations had a fivefold increased risk of death (HR = 5.60, 95% CI = 3.27 to 9.57; P < .001)-compared with those with neither risk category. CONCLUSIONS: We found no evidence of a benefit of ipilimumab added to nivolumab compared with nivolumab alone for QOL in S1400I. A risk model identified patients at high risk of poor survival, demonstrating the prognostic relevance of baseline patient-reported outcomes even in those with previously treated advanced cancer.

Effects of androgen deprivation on white matter integrity and processing speed in prostate cancer patients.

Studies have associated chemotherapy-elicited changes in cognitive function with impaired white matter integrity in cancer patients. Androgen deprivation therapy (ADT) may lead to cognitive deficits in prostate cancer patients; however, whether ADT influences white matter integrity has never been investigated. In a prospective study, 15 men with non-metastatic prostate cancer receiving ADT and 15 not receiving ADT (controls or CON), comparable in age and years of education, participated in N-back task, flankers' task, and quality-of-life (QoL) assessments. All participants underwent diffusion tensor imaging of the brain at baseline and at 6 months. Imaging data were processed with published routines. The results of a paired t-test of 6-month follow-up vs. baseline were evaluated at a corrected threshold for the whole brain each in ADT and CON. ADT patients showed significantly worse 1-back accuracy during follow-up, but the two groups did not differ in 2-back accuracy, 1- or 2-back reaction time (RT), flankers' task RT or QoL across time points. In ADT, significantly reduced fractional anisotropy (FA) was noted in the corpus callosum, forceps minor/anterior thalamic radiation, superior and posterior corona radiata. The differences in FA correlated significantly with changes in 2-back and flankers' task RT. No significant FA changes were noted during follow-up in CON. Six-month ADT affects white matter integrity, and the deficits were associated with slower processing speed. These findings add to the literature supporting the deleterious effects of androgen deprivation on the brain and cognition in prostate cancer patients.

Hypothalamic Functional Connectivity and Apathy in People with Alzheimer's Disease and Cognitively Normal Healthy Controls.

BACKGROUND: Earlier studies have described the neural markers of apathy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. OBJECTIVE: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. METHODS: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-ß-verified AD. RESULTS: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. CONCLUSION: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction.

Brief Report: Implementation of a Universal Prescreening Protocol to Increase Recruitment to Lung Cancer Studies at a Veterans Affairs Cancer Center.

Introduction: The oncology clinical trial recruitment process is time, labor, and resource intensive, and poor accrual rates are common. We describe the VA Connecticut Cancer Center experience of implementing a standardized, universal prescreening protocol and its impact on thoracic oncology research recruitment. Methods: Research coordinators prescreened potentially eligible patients with confirmed or suspected cancer from multiple clinical sources and entered relevant patient and research study information into a centralized electronic database. The database provided real-time lists of potential studies for each patient. This enabled the research team to alert the patient's oncologist in advance of clinic visits and to prepare documents needed for enrollment. Clinicians could ensure sufficient time and attention in clinic to the informed consent process, therefore maximizing enrollment opportunities. Patients were also monitored on waitlists for future studies. Results: From March 2017 to December 2020, a total of 1518 patients with lung nodules and suspected or confirmed lung cancers were prescreened. Of these, 379 patients were enrolled to a study, 103 patients declined participation, and 639 were monitored for future studies. Our prescreening protocol identified all new patients with lung cancer who were ultimately added to the cancer registry. We found a substantial increase in study enrollment after prescreening implementation. Conclusions: Universal prescreening was associated with improved patient enrollment to thoracic oncology studies. The protocol was integral in our VA becoming the top accruing VA site for National Cancer Institute's National Clinical Trials Network studies for 2019 to 2021.

Hypothalamic connectivities predict individual differences in ADT-elicited changes in working memory and quality of life in prostate cancer patients.

Androgen deprivation therapy (ADT) has been associated with adverse effects on cognition. However, we currently lack understanding of the neurobiology and prognostic markers of these effects. Given that ADT acts via the hypothalamus-pituitary-gonadal axis, we assessed whether baseline hypothalamic resting state functional connectivity (rsFC) could predict changes in working memory and quality of life in prostate cancer patients following androgen deprivation. In a prospective observational study, 28 men with non-metastatic prostate cancer receiving ADT and 38 patients not receiving ADT (controls), matched in age, years of education and Montreal Cognitive Assessment score, participated in brain imaging at baseline, and N-back task and quality-of-life (QoL) assessments at baseline and at 6 months follow-up. Imaging data were processed with published routines and evaluated at a corrected threshold. ADT and control groups did not differ in N-back performance or QoL across time points. In ADT, the changes in 0-back correct response rate (follow-up-baseline) were correlated with baseline hypothalamus-precentral gyrus rsFC; the changes in 1-back correct response rate and reaction time were each correlated with hypothalamus-middle frontal gyrus and superior parietal lobule rsFC. The changes in physical well-being subscore of QoL were correlated with baseline hypothalamus-anterior cingulate and cuneus rsFC. The hypothalamus rsFCs predicted N-back and QoL change with an area under the receiver operating characteristic curve of 0.93 and 0.73, respectively. Baseline hypothalamus-frontoparietal and salience network rsFC's predict inter-subject variations in the changes in working-memory and QoL following 6 months of ADT. Whether and how hypothalamic rsFCs may predict the cognitive and QoL effects with longer-term ADT remain to be investigated.

Aggressive End-of-Life Care in the Veterans Health Administration versus Fee-for-Service Medicare among Patients with Advanced Lung Cancer.

Background: Unlike fee-for-service Medicare, the Veterans Health Administration (VHA) allows for the provision of concurrent care, incorporating cancer treatment while in hospice. Methods: We compared trends of aggressive care at end of life between Medicare and VHA decedents with advanced nonsmall cell lung cancer from 2006 to 2012, and the relation between regional level end-of-life care between Medicare and VHA beneficiaries. Results: Among 18,371 Veterans and 25,283 Medicare beneficiaries, aggressive care at end of life decreased 15% in VHA and 4% in SEER (Surveillance, Epidemiology, and End Results)-Medicare (p < 0.001). Hospice use significantly increased within both cohorts (VHA 28%-41%; SM 60%-73%, p < 0.001). Veterans receiving care in regions with higher hospice admissions among Medicare beneficiaries were significantly less likely to receive aggressive care at end of life (adjusted odds ratio: 0.13, 95% confidence interval: 0.08-0.23, p < 0.001). Conclusions: Patients receiving lung cancer care in the VHA had a greater decline in aggressive care at end of life, perhaps due to increasing concurrent care availability.

Emotion Processing Dysfunction in Alzheimer's Disease: An Overview of Behavioral Findings, Systems Neural Correlates, and Underlying Neural Biology.

We described behavioral studies to highlight emotional processing deficits in Alzheimer's disease (AD). The findings suggest prominent deficit in recognizing negative emotions, pronounced effect of positive emotion on enhancing memory, and a critical role of cognitive deficits in manifesting emotional processing dysfunction in AD. We reviewed imaging studies to highlight morphometric and functional markers of hippocampal circuit dysfunction in emotional processing deficits. Despite amygdala reactivity to emotional stimuli, hippocampal dysfunction conduces to deficits in emotional memory. Finally, the reviewed studies implicating major neurotransmitter systems in anxiety and depression in AD supported altered cholinergic and noradrenergic signaling in AD emotional disorders. Overall, the studies showed altered emotions early in the course of illness and suggest the need of multimodal imaging for further investigations. Particularly, longitudinal studies with multiple behavioral paradigms translatable between preclinical and clinical models would provide data to elucidate the time course and underlying neurobiology of emotion processing dysfunction in AD.

The effects of androgen deprivation on working memory and quality of life in prostate cancer patients: The roles of hypothalamic connectivity.

BACKGROUND: Androgen deprivation therapy (ADT) has been associated with adverse effects on the brain. ADT alters testosterone levels via its action on the hypothalamus-pituitary-gonadal axis and may influence hypothalamic functions. Given the wide regional connectivity of the hypothalamus and its role in regulating cognition and behavior, we assessed the effects of ADT on hypothalamic resting state functional connectivity (rsFC) and their cognitive and clinical correlates. METHODS: In a prospective observational study, 22 men with nonmetastatic prostate cancer receiving ADT and 28 patients not receiving ADT (controls), matched in age, years of education, and Montreal Cognitive Assessment score, participated in N-back task and quality of life (QoL) assessments and brain imaging at baseline and at 6 months. Imaging data were processed with published routines and the results of a group by time flexible factorial analysis were evaluated at a corrected threshold. RESULTS: ADT and control groups did not differ in N-back performance or QoL across time points. Relative to controls, patients receiving ADT showed significantly higher hypothalamus-right mid-cingulate cortex (MCC) and precentral gyrus (PCG) rsFC during follow-up versus baseline. Further, the changes in MCC and PCG rsFC were correlated positively with the change in QoL score and 0-back correct response rate, respectively, in patients with undergoing ADT. CONCLUSION: Six-month ADT affects hypothalamic functional connectivity with brain regions critical to cognitive motor and affective functions. Elevated hypothalamic MCC and PCG connectivity likely serve to functionally compensate for the effects of ADT and sustain attention and overall QoL. The longer-term effects of ADT remain to be investigated.

Cerebral Volumetric Correlates of Apathy in Alzheimer's Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort.

BACKGROUND: Affecting nearly half of the patients with Alzheimer's disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. OBJECTIVE: To identify neuroanatomical correlates of AD-associated apathy. METHODS: We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. RESULTS: Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. CONCLUSION: The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

Cognitive dysfunction and cerebral volumetric deficits in individuals with Alzheimer's disease, alcohol use disorder, and dual diagnosis.

Epidemiological surveys suggest that excessive drinking is associated with higher risk of Alzheimer's disease (AD). The present study utilized data from the National Alzheimer's Coordinating Center to examine cognition as well as gray/white matter and ventricular volumes among participants with AD and alcohol use disorder (AD/AUD, n = 52), AD only (n = 701), AUD only (n = 67), and controls (n = 1283). AUD diagnosis was associated with higher Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) in AD than in non-AD. AD performed worse on semantic fluency and Trail Making Test A + B (TMT A + B) and showed smaller total GMV, WMV, and larger ventricular volume than non-AD. AD had smaller regional GMV in the inferior/superior parietal cortex, hippocampal formation, occipital cortex, inferior frontal gyrus, posterior cingulate cortex, and isthmus cingulate cortex than non-AD. AUD had significantly smaller somatomotor cortical GMV and showed a trend towards smaller volume in the hippocampal formation, relative to non-AUD participants. Misuse of alcohol has an additive effect on dementia severity among AD participants. Smaller hippocampal volume is a common feature of both AD and AUD. Although AD is associated with more volumetric deficits overall, AD and AUD are associated with atrophy in largely distinct brain regions.

Catechol-O-Methyltransferase Gene Polymorphisms and the Risk of Chemotherapy-Induced Prospective Memory Impairment in Breast Cancer Patients with Varying Tumor Hormonal Receptor Expression.

BACKGROUND Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). MATERIAL AND METHODS A total of 232 patients with breast cancer (113 with ER-/PR- and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). RESULTS The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER-/PR- group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=-7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (ß=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. CONCLUSIONS The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.

Age-Related Changes in the Neural Processes of Reward-Directed Action and Inhibition of Action.

Aging is associated with structural and functional brain changes which may impact the regulation of motivated behaviors, including both action and inhibition of action. As behavioral regulation is often exercised in response to reward, it remains unclear how aging may influence reward-directed action and inhibition of action differently. Here we addressed this issue with the functional magnetic resonance imaging data of 72 participants (aged 21-74) performing a reward go/no-go (GNG) task with approximately 2/3 go and 1/3 no-go trials. The go and no-go success trials were rewarded with a dollar or a nickel, and the incorrect responses were penalized. An additional block of the GNG task without reward/punishment served as the control to account for age-related slowing in processing speed. The results showed a prolonged response time (RT) in rewarded (vs. control) go trials with increasing age. Whole-brain multiple regressions of rewarded (vs. control) go trials against age and RT both revealed an age-related reduced activity of the anterior insula, middle frontal gyrus, and rostral anterior cingulate cortex. Furthermore, activity from these regions mediated the relationship between age and go performance. During rewarded (vs. control) no-go trials, age was associated with increased accuracy rate but decreased activation in the medial superior frontal and postcentral gyri. As these regions also exhibited age-related activity reduction during rewarded go, the finding suggests aging effects on common brain substrates that regulate both action and action inhibition. Taken together, age shows a broad negative modulation on neural activations but differential effects on performance during rewarded action and inhibition of action.

Concurrent Hospice Care and Cancer-Directed Treatment for Advanced Lung Cancer and Receipt of Aggressive Care at the End of Life in the Veteran's Health Administration.

Background: Aggressive care at the end of life (EOL) is a persistent issue for patients with stage IV nonsmall cell lung cancer (NSCLC). We evaluated the use of concurrent care (CC) with hospice care and cancer-directed treatment simultaneously within the Veteran's Health Administration (VHA) and aggressive care at the EOL. Objective: To determine whether VHA facility-level CC is associated with changes in aggressive care at the EOL. Design/Setting: Veterans with stage IV NSCLC who died between 2006 and 2012 and received lung cancer care within the VHA. Measurements: The primary outcome was aggressive care at EOL (i.e., hospital admissions, chemotherapy, and intensive care unit) within the last month of life. To compare aggressive care across VHA facilities, we used a random intercept multilevel logistic regression model to examine the association between facility-level CC within each study year (<10%, 10% to 19%, and ≥20%) and aggressive care at the EOL among the decedents as a binary outcome. Results: In total, 18,371 veterans with NSCLC at 154 VHA facilities were identified. Facilities delivering CC for ≥20% of veterans (high CC) increased from 20.0% in 2006 to 43.2% in 2012 (p < 0.001). Overall, hospice care significantly increased and aggressive care at EOL decreased over the study period. However, facility-level CC adoption was not associated with any difference in aggressive care at EOL (adjusted odds ratio high CC vs. low CC: 0.91 [95% CI, 0.79 to 1.05], p = 0.21). Conclusions: Although the VHA adoption of CC increased hospice use among patients with NSCLC, additional measures may be needed to decrease aggressive care at the EOL.

Androgen Deprivation Therapy and Cognitive Function in Prostate Cancer.

PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is widely used in prostate cancer. Interest in assessing how ADT impacts cognition is growing. RECENT FINDINGS: Studies in animals and humans suggest that androgens may affect cognitive function. However, extant studies utilizing common neurocognitive tests have not consistently demonstrated ADT-induced cognitive impairment. Retrospective analyses investigating the association between ADT and risk of dementia in large electronic patient databases have also produced conflicting results. There is only limited data on ADT-induced changes in the brain as detected by functional imaging. It remains unclear whether cognitive deficits can occur in a patient undergoing ADT. Commonly used neurocognitive tests may not be optimal for detection of more subtle but clinically relevant cognitive impairment. While large electronic patient databases are attractive sources of information, their heterogeneity, complexity, and potential reporting biases can be a challenge. Better tools are needed to assess the cognitive impact of ADT prospectively.

The effects of age on reward magnitude processing in the monetary incentive delay task.

Previous studies have suggested age-related differences in reward-directed behavior and cerebral processes in support of the age effects. However, it remains unclear how age may influence the processing of reward magnitude. Here, with 54 volunteers (22-74 years of age) participating in the Monetary Incentive Delay Task (MIDT) with explicit cues ($1, ¢1, or nil) and timed response to win, we characterized brain activations during anticipation and feedback and the effects of age on these regional activations. Behaviorally, age was associated with less reaction time (RT) difference between dollar and cent trials, as a result of slower response to the dollar trials; i.e., age was positively correlated with RT dollar - RT cent, with RT nil as a covariate. Both age and the RT difference ($1 - ¢1) were correlated with diminished activation of the right caudate head, right anterior insula, supplementary motor area (SMA)/pre-SMA, visual cortex, parahippocampal gyrus, right superior/middle frontal gyri, and left primary motor cortex during anticipation of $1 vs. ¢1 reward. Further, these regional activities mediated the age effects on RT differences. In responses to outcomes, age was associated with decreases in regional activations to dollar vs. cent loss but only because of higher age-related responses to cent losses. Together, these findings suggest age-related differences in sensitivity to the magnitude of reward. With lower cerebral responses during anticipation to win large rewards and higher responses to outcomes of small loss, aging incurs a constricted sensitivity to the magnitude of reward.