Publications by authors named "Shelli R Kesler"

77 Publications

Measuring Self-Reported Cancer-Related Cognitive Impairment: Recommendations from the Cancer Neuroscience Initiative Working Group.

J Natl Cancer Inst 2021 Feb 26. Epub 2021 Feb 26.

School of Nursing, Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin, TX.

Cancer and its treatments are associated with increased risk for cancer-related cognitive impairment (CRCI). Methods and measures used to study and assess self-reported CRCI (sr-CRCI), however, remain diverse, resulting in heterogeneity across studies. The Patient-Reported Outcomes Working Group has been formed to promote homogeneity in the methods used to study sr-CRCI. In this report, using a psychometric taxonomy, we inventory and appraise instruments used in research to measure sr-CRCI, and we consider advances in patient-reported outcome methodology. Given its psychometric properties, we recommend the Patient-Reported Outcome Measurement Information System Cognitive Function Short Form 8a for measurement of sr-CRCI in cancer patients and survivors, at a minimum, in order to increase scientific rigor and progress in addressing CRCI.
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http://dx.doi.org/10.1093/jnci/djab027DOI Listing
February 2021

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

JAMA Netw Open 2020 11 2;3(11):e2025839. Epub 2020 Nov 2.

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL).

Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network.

Design, Setting, And Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020.

Exposure: ALL treatment using chemotherapy-only protocols.

Main Outcomes And Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count).

Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction.

Conclusions And Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.25839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679952PMC
November 2020

Functional connectome biotypes of chemotherapy-related cognitive impairment.

J Cancer Surviv 2020 08 10;14(4):483-493. Epub 2020 Mar 10.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.

Purpose: Cancer-related cognitive impairment (CRCI) is a common neurotoxicity among patients with breast and other cancers. Neuroimaging studies have demonstrated measurable biomarkers of CRCI but have largely neglected the potential heterogeneity of the syndrome.

Methods: We used retrospective functional MRI data from 80 chemotherapy-treated breast cancer survivors to examine neurophysiologic subtypes or "biotypes" of CRCI. The breast cancer group consisted of training (N = 57) and validation (N = 23) samples.

Results: An unsupervised clustering approach using connectomes from the training sample identified three distinct biotypes. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.001, corrected) differed significantly between the biotypes and also from 103 healthy female controls. We then built a random forest classifier using connectome features to distinguish between the biotypes (accuracy = 91%) and applied this to the validation sample to predict biotype assignment. Cognitive performance (p < 0.05, corrected) and regional connectome organization (p < 0.005, corrected) differed significantly between the predicted biotypes and healthy controls. Biotypes were also characterized by divergent clinical and demographic factors as well as patient reported outcomes.

Conclusions: Neurophysiologic biotypes may help characterize the heterogeneity associated with CRCI in a data-driven manner based on neuroimaging biomarkers.

Implications For Cancer Survivors: Our novel findings provide a foundation for detecting potential risk and resilience factors that warrant further study. With further investigation, biotypes might be used to personalize assessments of and interventions for CRCI.
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http://dx.doi.org/10.1007/s11764-020-00863-1DOI Listing
August 2020

Online Couple-Based Meditation Intervention for Patients With Primary or Metastatic Brain Tumors and Their Partners: Results of a Pilot Randomized Controlled Trial.

J Pain Symptom Manage 2020 06 13;59(6):1260-1267. Epub 2020 Feb 13.

Department of Palliative, Rehabilitation & Integrative Medicine, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.

Objectives: Although patients with primary and metastatic brain tumors and their partners are at risk of experiencing high symptom burden, they are often excluded from psychosocial intervention studies. Thus, we sought to examine the feasibility and preliminary efficacy of a couple-based meditation (CBM) program targeting symptom and well-being outcomes.

Methods: Couples completed baseline measures assessing symptom and well-being outcomes and were randomized to the CBM or a usual care control group. Couples in the CBM groups attended four weekly (60 minutes each) therapist-led sessions that were delivered via FaceTime (Apple Inc, Cupertino, CA). The CBM program focused on cultivating mindfulness, compassion, gratitude and purpose, and integrated emotional disclosure exercises. Both groups were reassessed six and 12 weeks after baseline.

Results: We approached 60 eligible dyads, of which 37 (62%) consented, 35 (95%) were randomized, and 22 (63%) completed all assessments. Couples in the CBM group attended a mean of 3.33 sessions (SD 1.09). For patients, significant group differences in favor of the CBM group were found for cognitive (d = 1.05) and general disease symptoms (d = 0.93), and relationship well-being (d = 0.68) and compassion (d = 0.96). No significant group differences were revealed for partners.

Conclusion: It seems to be feasible, acceptable, and possibly efficacious to deliver a dyadic intervention via FaceTime to brain tumor couples. Although both patients and partners in the CBM group rated the intervention as beneficial, significant group differences with medium-to-large effect sizes were only found for patients.
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http://dx.doi.org/10.1016/j.jpainsymman.2020.02.004DOI Listing
June 2020

Cortical Brain Age from Pre-treatment to Post-chemotherapy in Patients with Breast Cancer.

Neurotox Res 2020 Apr 4;37(4):788-799. Epub 2020 Jan 4.

University of Texas at Austin School of Nursing, 1710 Red River St, Austin, TX, 78701, USA.

Chemotherapy-related cognitive impairment and associated brain changes may reflect accelerated brain aging; however, empirical evidence for this theory is limited. The purpose of this study was to measure brain aging in newly diagnosed patients with breast cancer treated with chemotherapy (n = 43) and compare its longitudinal change to that of controls (n = 50). Brain age indices, derived from cortical measures, were compared between women with breast cancer and matched healthy controls across 3 timepoints (time 1: pre-surgery, time 2: 1 month following chemotherapy completion, and time 3: 1-year post-chemotherapy). The breast cancer group showed a significant decrease in cortical thickness across the 3 timepoints (p < .001) and a trend towards significant increase in predicted brain age especially from pre-treatment (time 1) to post-chemotherapy (time 2) compared to controls (p = 0.08). Greater increase in predicted brain age was related to several clinical factors (HER-2 status, surgery type, and history of neoadjuvant chemotherapy) and greater decrease in cortical thickness was associated with greater decrease in performance on a verbal learning task from time 1 to time 3 (r = - 0.48, p < .01). This study demonstrated evidence of increased cortical brain aging in middle-aged patients with breast cancer following chemotherapy treatment that was associated with decreased verbal memory performance.
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http://dx.doi.org/10.1007/s12640-019-00158-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089817PMC
April 2020

Predicting Patient Reported Outcomes of Cognitive Function Using Connectome-Based Predictive Modeling in Breast Cancer.

Brain Topogr 2020 01 19;33(1):135-142. Epub 2019 Nov 19.

School of Nursing, University of Texas at Austin, 1710 Red River St., Austin, TX, 78712, USA.

Being able to predict who will likely experience cancer related cognitive impairment (CRCI) could enhance patient care and potentially reduce economic and human costs associated with this adverse event. We aimed to determine if post-treatment patient reported CRCI could also be predicted from baseline resting state fMRI in patients with breast cancer. 76 newly diagnosed patients (n = 42 planned for chemotherapy; n = 34 not planned for chemotherapy) and 50 healthy female controls were assessed at 3 times points [T1 (prior to treatment); T2 (1 month post chemotherapy); T3 (1 year after T2)], and at yoked intervals for controls. Data collection included self-reported executive dysfunction, memory function, and psychological distress and resting state fMRI data converted to connectome matrices for each participant. Statistical analyses included linear mixed modeling, independent t tests, and connectome-based predictive modeling (CPM). Executive dysfunction increased over time in the chemotherapy group and was stable in the other two groups (p < 0.001). Memory function decreased over time in both patient groups compared to controls (p < 0.001). CPM models successfully predicted executive dysfunction and memory function scores (r > 0.31, p < 0.002). Support vector regression with a radial basis function (SVR RBF) showed the highest performance for executive dysfunction and memory function (r = 0.68; r = 0.44, p's < 0.001). Baseline neuroimaging may be useful for predicting patient reported cognitive outcomes which could assist in identifying patients in need of surveillance and/or early intervention for treatment-related cognitive effects.
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http://dx.doi.org/10.1007/s10548-019-00746-4DOI Listing
January 2020

Pre-surgical connectome features predict IDH status in diffuse gliomas.

Oncotarget 2019 Nov 5;10(60):6484-6493. Epub 2019 Nov 5.

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Gliomas are the most common type of malignant brain tumor. Clinical outcomes depend on many factors including tumor molecular characteristics. Mutation of the isocitrate dehydrogenase (IDH) gene confers significant benefits in terms of survival and quality of life. Preoperative determination of IDH genotype can facilitate surgical planning, allow for novel clinical trial designs, and assist clinical counseling surrounding the individual patient's disease.

Methods: In this study, we aimed to evaluate a novel approach for non-invasively predicting IDH status from conventional MRI via connectomics, a whole-brain network-based technique. We retrospectively extracted 93 connectome features from the preoperative, T1-weighted MRI data of 234 adult patients (148 IDH mutated) and evaluated the performance of four common machine learning models to predict IDH genotype.

Results: Area under the curve (AUC) of the receiver operator characteristic were 0.76 to 0.94 with random forest (RF) showing significantly higher performance ( < 0.01) than other algorithms. Feature selection schemes and the addition of age and tumor location did not change RF performance.

Conclusions: Our findings suggest that connectomics is a feasible approach for preoperatively predicting IDH genotype in patients with gliomas. Our results support prior evidence that RF is an ideal machine learning method for this area of research. Additionally, connectomics provides unique insights regarding potential mechanisms of tumor genotype on large-scale brain network organization.
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http://dx.doi.org/10.18632/oncotarget.27301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849657PMC
November 2019

A comprehensive preclinical assessment of late-term imaging markers of radiation-induced brain injury.

Neurooncol Adv 2019 May-Dec;1(1):vdz012. Epub 2019 Jul 2.

Department of Pediatrics, Hematology-Oncology Section, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

Background: Cranial radiotherapy (CRT) is an important part of brain tumor treatment, and although highly effective, survivors suffer from long-term cognitive side effects. In this study we aim to establish late-term imaging markers of CRT-induced brain injury and identify functional markers indicative of cognitive performance. Specifically, we aim to identify changes in executive function, brain metabolism, and neuronal organization.

Methods: Male Sprague Dawley rats were fractionally irradiated at 28 days of age to a total dose of 30 Gy to establish a radiation-induced brain injury model. Animals were trained at 3 months after CRT using the 5-choice serial reaction time task. At 12 months after CRT, animals were evaluated for cognitive and imaging changes, which included positron emission tomography (PET) and magnetic resonance imaging (MRI).

Results: Cognitive deficit with signs of neuroinflammation were found at 12 months after CRT in irradiated animals. CRT resulted in significant volumetric changes in 38% of brain regions as well as overall decrease in brain volume and reduced gray matter volume. PET imaging showed higher brain glucose uptake in CRT animals. Using MRI, irradiated brains had an overall decrease in fractional anisotropy, lower global efficiency, increased transitivity, and altered regional connectivity. Cognitive measurements were found to be significantly correlated with six image features that included myelin integrity and local organization of the neural network.

Conclusions: These results demonstrate that CRT leads to late-term morphological changes, reorganization of neural connections, and metabolic dysfunction. The correlation between imaging markers and cognitive deficits can be used to assess late-term side effects of brain tumor treatment and evaluate efficacy of new interventions.
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http://dx.doi.org/10.1093/noajnl/vdz012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777502PMC
July 2019

Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice.

Oncotarget 2018 Oct 30;9(85):35581-35597. Epub 2018 Oct 30.

Neuroimmunology Laboratory, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called 'chemobrain'. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.
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http://dx.doi.org/10.18632/oncotarget.26272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238972PMC
October 2018

Neurocognitive dysfunction in adult cerebellar medulloblastoma.

Psychooncology 2019 01 5;28(1):131-138. Epub 2018 Nov 5.

Section of Neuropsychology, Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Objective: Impaired neurocognitive function (NCF) is a well-established consequence of pediatric medulloblastoma (MB) and its treatments. However, the frequency and features of neurocognitive dysfunction in adult-onset MB patients are largely unknown.

Methods: Adult patients (≥ 18 years) with MB who had received formal neurocognitive evaluation (N = 27) were identified. Demographic, medical, and treatment histories were extracted from the medical record. Lesion properties on MRI were analyzed and used to evaluate lesion-symptom mapping further. Demographically adjusted z-scores were calculated for each neurocognitive test and used to assess impairment frequency. Regression analyses were conducted to identify clinical and paraclinical factors associated with impaired NCF.

Results: Mean age of the patient sample was 33 years (SD = 11) at the time of MB diagnosis. Prior therapy included surgical resection (89%), radiation (70%), and chemotherapy (26%). A significant proportion of patients were impaired on tests of verbal learning and memory (32%), executive function (29%), and naming (18%). Age, education, lesion size, time from surgery, and number of chemotherapy cycles had the greatest contribution to test performance in random-forest regression models.

Conclusion: This study identifies frequent impairment of NCF in adult patients with MB, particularly in the domains of learning and memory and executive function. Neurocognitive impairment is influenced by patients' demographic, disease, and treatment history. Further study is warranted to characterize the clinical impact of adult MB more fully.
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http://dx.doi.org/10.1002/pon.4920DOI Listing
January 2019

Functional and structural connectome properties in the 5XFAD transgenic mouse model of Alzheimer's disease.

Netw Neurosci 2018 1;2(2):241-258. Epub 2018 Jun 1.

Neurodegeneration Consortium, Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Neurodegeneration in Alzheimer's disease (AD) is associated with amyloid-beta peptide accumulation into insoluble amyloid plaques. The five-familial AD (5XFAD) transgenic mouse model exhibits accelerated amyloid-beta deposition, neuronal dysfunction, and cognitive impairment. We aimed to determine whether connectome properties of these mice parallel those observed in patients with AD. We obtained diffusion tensor imaging and resting-state functional magnetic resonance imaging data for four transgenic and four nontransgenic male mice. We constructed both structural and functional connectomes and measured their topological properties by applying graph theoretical analysis. We compared connectome properties between groups using both binarized and weighted networks. Transgenic mice showed higher characteristic path length in weighted structural connectomes and functional connectomes at minimum density. Normalized clustering and modularity were lower in transgenic mice across the upper densities of the structural connectome. Transgenic mice also showed lower small-worldness index in higher structural connectome densities and in weighted structural networks. Hyper-correlation of structural and functional connectivity was observed in transgenic mice compared with nontransgenic controls. These preliminary findings suggest that 5XFAD mouse connectomes may provide useful models for investigating the molecular mechanisms of AD pathogenesis and testing the effectiveness of potential treatments.
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http://dx.doi.org/10.1162/netn_a_00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130552PMC
June 2018

Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.

Brain Connect 2018 08;8(6):333-342

4 Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital , Memphis, Tennessee.

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.
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http://dx.doi.org/10.1089/brain.2017.0574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103246PMC
August 2018

Neurocognitive Outcomes and Interventions in Long-Term Survivors of Childhood Cancer.

J Clin Oncol 2018 07 6;36(21):2181-2189. Epub 2018 Jun 6.

Kevin R. Krull, St Jude Children's Research Hospital, Memphis, TN; Kristina K. Hardy, Children's National Medical Center, Washington, DC; Lisa S. Kahalley, Baylor College of Medicine; Shelli R. Kesler, University of Texas MD Anderson Cancer Center, Houston, TX; and Ilse Schuitema, Leiden University, Leiden, the Netherlands.

Recent research has demonstrated that survivors of childhood cancer are at risk for a myriad of late effects that affect physical and mental quality of life. We discuss the patterns and prevalence of neurocognitive problems commonly experienced by survivors of CNS tumors and acute lymphoblastic leukemia, the two most commonly researched cancer diagnoses. Research documenting the direct effects of tumor location and treatment type and intensity is presented, and patient characteristics that moderate outcomes (eg, age at diagnosis and sex) are discussed. Potential biologic mechanisms of neurotoxic treatment exposures, such as cranial irradiation and intrathecal and high-dose antimetabolite chemotherapy, are reviewed. Genetic, brain imaging, and neurochemical biomarkers of neurocognitive impairment are discussed. Long-term survivors of childhood cancer are also at risk for physical morbidity (eg, cardiac, pulmonary, endocrine) and problems with health behaviors (eg, sleep); research is reviewed that demonstrates these health problems contribute to neurocognitive impairment in survivors with or without exposure to neurotoxic therapies. We conclude this review with a discussion of literature supporting specific interventions that may be beneficial in the treatment of survivors who already experience neurocognitive impairment, as well as in the prevention of impairment manifestation.
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http://dx.doi.org/10.1200/JCO.2017.76.4696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553837PMC
July 2018

Identifying cytokine predictors of cognitive functioning in breast cancer survivors up to 10 years post chemotherapy using machine learning.

J Neuroimmunol 2018 07 19;320:38-47. Epub 2018 Apr 19.

University of Texas MD Anderson Cancer Center, Neuro-Oncology, USA.

Introduction: The purpose of this study is to explore 13 cytokine predictors of chemotherapy-related cognitive impairment (CRCI) in breast cancer survivors (BCS) 6 months to 10 years after chemotherapy completion using a multivariate, non-parametric approach.

Methods: Cross sectional data collection included completion of a survey, cognitive testing, and non-fasting blood from 66 participants. Data were analyzed using random forest regression to identify the most significant predictors for each of the cognitive test scores.

Results: A different cytokine profile predicted each cognitive test. Adjusted R for each model ranged from 0.71-0.77 (p's < 9.50). The relationships between all the cytokine predictors and cognitive test scores were non-linear.

Conclusions: Our findings are unique to the field of CRCI and suggest non-linear cytokine specificity to neural networks underlying cognitive functions assessed in this study.
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http://dx.doi.org/10.1016/j.jneuroim.2018.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030687PMC
July 2018

Changes in Brain Structural Networks and Cognitive Functions in Testicular Cancer Patients Receiving Cisplatin-Based Chemotherapy.

J Natl Cancer Inst 2017 12;109(12)

Unit for Psychooncology and Health Psychology, Department of Oncology and Department of Psychology and Behavioural Sciences, Aarhus University Hospital and Aarhus University, Aarhus, Denmark.

Background: Cisplatin-based chemotherapy may have neurotoxic effects within the central nervous system. The aims of this study were 1) to longitudinally investigate the impact of cisplatin-based chemotherapy on whole-brain networks in testicular cancer patients undergoing treatment and 2) to explore whether possible changes are related to decline in cognitive functioning.

Methods: Sixty-four newly orchiectomized TC patients underwent structural magnetic resonance imaging (T1-weighted and diffusion-weighted imaging) and cognitive testing at baseline prior to further treatment and again at a six-month follow-up. At follow-up, 22 participants had received cisplatin-based chemotherapy (CT) while 42 were in active surveillance (S). Brain structural networks were constructed for each participant, and network properties were investigated using graph theory and longitudinally compared across groups. Cognitive functioning was evaluated using standardized neuropsychological tests. All statistical tests were two-sided.

Results: Compared with the S group, the CT group demonstrated altered global and local brain network properties from baseline to follow-up as evidenced by decreases in important brain network properties such as small-worldness (P = .04), network clustering (P = .04), and local efficiency (P = .02). In the CT group, poorer overall cognitive performance was associated with decreased small-worldness (r = -0.46, P = .04) and local efficiency (r = -0.51, P = .02), and verbal fluency was associated with decreased local efficiency (r = -0.55, P = .008).

Conclusions: Brain structural networks may be disrupted following treatment with cisplatin-based chemotherapy. Impaired brain networks may underlie poorer performance over time on both specific and nonspecific cognitive functions in patients undergoing chemotherapy. To the best of our knowledge, this is the first study to longitudinally investigate changes in structural brain networks in a cancer population, providing novel insights regarding the neurobiological mechanisms of cancer-related cognitive impairment.
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http://dx.doi.org/10.1093/jnci/djx085DOI Listing
December 2017

International Cognition and Cancer Task Force Recommendations for Neuroimaging Methods in the Study of Cognitive Impairment in Non-CNS Cancer Patients.

J Natl Cancer Inst 2018 03;110(3):223-231

Center for Neuroimaging, Department of Radiology and Imaging Sciences and Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN.

Cancer- and treatment-related cognitive changes have been a focus of increasing research since the early 1980s, with meta-analyses demonstrating poorer performance in cancer patients in cognitive domains including executive functions, processing speed, and memory. To facilitate collaborative efforts, in 2011 the International Cognition and Cancer Task Force (ICCTF) published consensus recommendations for core neuropsychological tests for studies of cancer populations. Over the past decade, studies have used neuroimaging techniques, including structural and functional magnetic resonance imaging (fMRI) and positron emission tomography, to examine the underlying brain basis for cancer- and treatment-related cognitive declines. As yet, however, there have been no consensus recommendations to guide researchers new to this field or to promote the ability to combine data sets. We first discuss important methodological issues with regard to neuroimaging study design, scanner considerations, and sequence selection, focusing on concerns relevant to cancer populations. We propose a minimum recommended set of sequences, including a high-resolution T1-weighted volume and a resting state fMRI scan. Additional advanced imaging sequences are discussed for consideration when feasible, including task-based fMRI and diffusion tensor imaging. Important image data processing and analytic considerations are also reviewed. These recommendations are offered to facilitate increased use of neuroimaging in studies of cancer- and treatment-related cognitive dysfunction. They are not intended to discourage investigator-initiated efforts to develop cutting-edge techniques, which will be helpful in advancing the state of the knowledge. Use of common imaging protocols will facilitate multicenter and data-pooling initiatives, which are needed to address critical mechanistic research questions.
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http://dx.doi.org/10.1093/jnci/djx285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658857PMC
March 2018

Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial.

Support Care Cancer 2018 Apr 14;26(4):1019-1028. Epub 2017 Dec 14.

James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Purpose: Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms.

Methods: Cancer patients (N = 355, 56 ± 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP©®). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness.

Results: Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076).

Conclusions: Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients.

Trial Registration: Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov .
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http://dx.doi.org/10.1007/s00520-017-4013-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823751PMC
April 2018

Probability of Alzheimer's disease in breast cancer survivors based on gray-matter structural network efficiency.

Alzheimers Dement (Amst) 2017 1;9:67-75. Epub 2017 Nov 1.

Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Introduction: Breast cancer chemotherapy is associated with accelerated aging and potentially increased risk for Alzheimer's disease (AD).

Methods: We calculated the probability of AD diagnosis from brain network and demographic and genetic data obtained from 47 female AD converters and 47 matched healthy controls. We then applied this algorithm to data from 78 breast cancer survivors.

Results: The classifier discriminated between AD and healthy controls with 86% accuracy ( < .0001). Chemotherapy-treated breast cancer survivors demonstrated significantly higher probability of AD compared to healthy controls ( < .0001) and chemotherapy-naïve survivors ( = .007), even after stratifying for apolipoprotein e4 genotype. Chemotherapy-naïve survivors also showed higher AD probability compared to healthy controls ( = .014).

Discussion: Chemotherapy-treated breast cancer survivors who have a particular profile of brain structure may have a higher risk for AD, especially those who are older and have lower cognitive reserve.
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http://dx.doi.org/10.1016/j.dadm.2017.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700833PMC
November 2017

Predicting Long-Term Cognitive Outcome Following Breast Cancer with Pre-Treatment Resting State fMRI and Random Forest Machine Learning.

Front Hum Neurosci 2017 15;11:555. Epub 2017 Nov 15.

Department of Psychiatry and Behavioral Sciences, School of Medicine, Stanford University, Palo Alto, CA, United States.

We aimed to determine if resting state functional magnetic resonance imaging (fMRI) acquired at pre-treatment baseline could accurately predict breast cancer-related cognitive impairment at long-term follow-up. We evaluated 31 patients with breast cancer (age 34-65) prior to any treatment, post-chemotherapy and 1 year later. Cognitive testing scores were normalized based on data obtained from 43 healthy female controls and then used to categorize patients as impaired or not based on longitudinal changes. We measured clustering coefficient, a measure of local connectivity, by applying graph theory to baseline resting state fMRI and entered these metrics along with relevant patient-related and medical variables into random forest classification. Incidence of cognitive impairment at 1 year follow-up was 55% and was predicted by classification algorithms with up to 100% accuracy ( < 0.0001). The neuroimaging-based model was significantly more accurate than a model involving patient-related and medical variables ( = 0.005). Hub regions belonging to several distinct functional networks were the most important predictors of cognitive outcome. Characteristics of these hubs indicated potential spread of brain injury from default mode to other networks over time. These findings suggest that resting state fMRI is a promising tool for predicting future cognitive impairment associated with breast cancer. This information could inform treatment decision making by identifying patients at highest risk for long-term cognitive impairment.
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http://dx.doi.org/10.3389/fnhum.2017.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694825PMC
November 2017

Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy.

Mol Cell Neurosci 2018 01 24;86:65-71. Epub 2017 Nov 24.

Department of Neurobiology and Anatomy, The University of Texas, Houston Medical School, Houston, TX, United States; The University of Texas Graduate School of Biomedical Sciences, Houston, TX, United States. Electronic address:

Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general.
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http://dx.doi.org/10.1016/j.mcn.2017.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996272PMC
January 2018

Exercise ameliorates neurocognitive impairments in a translational model of pediatric radiotherapy.

Neuro Oncol 2018 04;20(5):695-704

Department of Pediatrics, Texas Children's Cancer Center, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.

Background: While cranial radiation therapy (CRT) is an effective treatment, healthy areas surrounding irradiation sites are negatively affected. Frontal lobe functions involving attention, processing speed, and inhibition control are impaired. These deficits appear months to years after CRT and impair quality of life. Exercise has been shown to rejuvenate the brain and aid in recovery post-injury through its effects on neurogenesis and cognition.

Methods: We developed a juvenile rodent CRT model that reproduces neurocognitive deficits. Next, we utilized the model to test whether exercise ameliorates these deficits. Fischer rats (31 days old) were irradiated with a fractionated dose of 4 Gy × 5 days, trained and tested at 6, 9, and 12 months post-CRT using 5-choice serial reaction time task. After testing, fixed rat brains were imaged using diffusion tensor imaging and immunohistochemistry.

Results: CRT caused early and lasting impairments in task acquisition, accuracy, and latency to correct response, as well as causing stunting of growth and changes in brain volume and diffusion. Exercising after irradiation improved acquisition, behavioral control, and processing speed, mitigated the stunting of brain size, and increased brain fiber numbers compared with sedentary CRT values. Further, exercise partially restored global connectome organization, including assortativity and characteristic path length, and while it did not improve the specific regional connections that were lowered by CRT, it appeared to remodel these connections by increasing connectivity between alternate regional pairs.

Conclusions: Our data strongly suggest that exercise may be useful in combination with interventions aimed at improving cognitive outcome following pediatric CRT.
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http://dx.doi.org/10.1093/neuonc/nox197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892168PMC
April 2018

Silent Sentence Completion Shows Superiority Localizing Wernicke's Area and Activation Patterns of Distinct Language Paradigms Correlate with Genomics: Prospective Study.

Sci Rep 2017 09 21;7(1):12054. Epub 2017 Sep 21.

Section of Neuroradiology, Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

Preoperative mapping of language areas using fMRI greatly depends on the paradigms used, as different tasks harness distinct capabilities to activate speech processing areas. In this study, we compared the ability of 3 covert speech paradigms: Silent Sentence Completion (SSC), category naming (CAT) and verbal fluency (FAS), in localizing the Wernicke's area and studied the association between genomic markers and functional activation. Fifteen right-handed healthy volunteers and 35 mixed-handed patients were included. We focused on the anatomical areas of posterosuperior, middle temporal and angular gyri corresponding to Wernicke's area. Activity was deemed significant in a region of interest if P < 0.05. Association between fMRI activation and genomic mutation status was obtained. Results demonstrated SSC's superiority at localizing Wernicke's area. SSC demonstrated functional activity in 100% of cancer patients and healthy volunteers; which was significantly higher than those for FAS and CAT. Patients with 1p/19q non-co-deleted had higher extent of activation on SSC (P < 0.02). Those with IDH-1 wild-type were more likely to show no activity on CAT (P < 0.05). SSC is a robust paradigm for localizing Wernicke's area, making it an important clinical tool for function-preserving surgeries. We also found a correlation between tumor genomics and functional activation, which deserves more comprehensive study.
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http://dx.doi.org/10.1038/s41598-017-11192-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608896PMC
September 2017

Disrupted brain network functional dynamics and hyper-correlation of structural and functional connectome topology in patients with breast cancer prior to treatment.

Brain Behav 2017 03 6;7(3):e00643. Epub 2017 Feb 6.

Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford CA USA.

Introduction: Several previous studies have demonstrated that cancer chemotherapy is associated with brain injury and cognitive dysfunction. However, evidence suggests that cancer pathogenesis alone may play a role, even in non-CNS cancers.

Methods: Using a multimodal neuroimaging approach, we measured structural and functional connectome topology as well as functional network dynamics in newly diagnosed patients with breast cancer. Our study involved a novel, pretreatment assessment that occurred prior to the initiation of any cancer therapies, including surgery with anesthesia. We enrolled 74 patients with breast cancer age 29-65 and 50 frequency-matched healthy female controls who underwent anatomic and resting-state functional MRI as well as cognitive testing.

Results: Compared to controls, patients with breast cancer demonstrated significantly lower functional network dynamics ( = .046) and cognitive functioning ( < .02, corrected). The breast cancer group also showed subtle alterations in structural local clustering and functional local clustering ( < .05, uncorrected) as well as significantly increased correlation between structural global clustering and functional global clustering compared to controls ( = .03). This hyper-correlation between structural and functional topologies was significantly associated with cognitive dysfunction ( = .005).

Conclusions: Our findings could not be accounted for by psychological distress and suggest that non-CNS cancer may directly and/or indirectly affect the brain via mechanisms such as tumor-induced neurogenesis, inflammation, and/or vascular changes, for example. Our results also have broader implications concerning the importance of the balance between structural and functional connectome properties as a potential biomarker of general neurologic deficit.
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http://dx.doi.org/10.1002/brb3.643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346525PMC
March 2017

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin.

Aging (Albany NY) 2016 12;8(12):3507-3519

Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA.

Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin.
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http://dx.doi.org/10.18632/aging.101144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270683PMC
December 2016

The effect of IDH1 mutation on the structural connectome in malignant astrocytoma.

J Neurooncol 2017 02 15;131(3):565-574. Epub 2016 Nov 15.

Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 431, Houston, TX, 77030, USA.

Mutation of the IDH1 gene is associated with differences in malignant astrocytoma growth characteristics that impact phenotypic severity, including cognitive impairment. We previously demonstrated greater cognitive impairment in patients with IDH1 wild type tumor compared to those with IDH1 mutant, and therefore we hypothesized that brain network organization would be lower in patients with wild type tumors. Volumetric, T1-weighted MRI scans were obtained retrospectively from 35 patients with IDH1 mutant and 32 patients with wild type malignant astrocytoma (mean age = 45 ± 14 years) and used to extract individual level, gray matter connectomes. Graph theoretical analysis was then applied to measure efficiency and other connectome properties for each patient. Cognitive performance was categorized as impaired or not and random forest classification was used to explore factors associated with cognitive impairment. Patients with wild type tumor demonstrated significantly lower network efficiency in several medial frontal, posterior parietal and subcortical regions (p < 0.05, corrected for multiple comparisons). Patients with wild type tumor also demonstrated significantly higher incidence of cognitive impairment (p = 0.03). Random forest analysis indicated that network efficiency was inversely, though nonlinearly associated with cognitive impairment in both groups (p < 0.0001). Cognitive reserve appeared to mediate this relationship in patients with mutant tumor suggesting greater neuroplasticity and/or benefit from neuroprotective factors. Tumor volume was the greatest contributor to cognitive impairment in patients with wild type tumor, supporting our hypothesis that greater lesion momentum between grades may cause more disconnection of core neurocircuitry and consequently lower efficiency of information processing.
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http://dx.doi.org/10.1007/s11060-016-2328-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377918PMC
February 2017

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons.

Sci Rep 2016 05 11;6:25705. Epub 2016 May 11.

Department of Neurobiology and Anatomy, University of Texas, Houston Medical School, Houston, TX, USA.

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors.
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http://dx.doi.org/10.1038/srep25705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863375PMC
May 2016

Task-based neurofeedback training: A novel approach toward training executive functions.

Neuroimage 2016 07 22;134:153-159. Epub 2016 Mar 22.

Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Cognitive training is an emergent approach to improve cognitive functions in various neurodevelopmental and neurodegenerative diseases. However, current training programs can be relatively lengthy, making adherence potentially difficult for patients with cognitive difficulties. Previous studies suggest that providing individuals with real-time feedback about the level of brain activity (neurofeedback) can potentially help them learn to control the activation of specific brain regions. In the present study, we developed a novel task-based neurofeedback training paradigm that benefits from the effects of neurofeedback in parallel with computerized training. We focused on executive function training given its core involvement in various developmental and neurodegenerative diseases. Near-infrared spectroscopy (NIRS) was employed for providing neurofeedback by measuring changes in oxygenated hemoglobin in the prefrontal cortex. Of the twenty healthy adult participants, ten received real neurofeedback (NFB) on prefrontal activity during cognitive training, and ten were presented with sham feedback (SHAM). Compared with SHAM, the NFB group showed significantly improved executive function performance including measures of working memory after four sessions of training (100min total). The NFB group also showed significantly reduced training-related brain activity in the executive function network including right middle frontal and inferior frontal regions compared with SHAM. Our data suggest that providing neurofeedback along with cognitive training can enhance executive function after a relatively short period of training. Similar designs could potentially be used for patient populations with known neuropathology, potentially helping them to boost/recover the activity in the affected brain regions.
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http://dx.doi.org/10.1016/j.neuroimage.2016.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912915PMC
July 2016

Predictors of Optimal Cognitive Aging in 80+ Women: The Women's Health Initiative Memory Study.

J Gerontol A Biol Sci Med Sci 2016 Mar;71 Suppl 1:S62-71

Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Background: Independent predictors of preserved cognitive functioning and factors associated with maintaining high preserved cognitive function in women ≥ 80 years remain elusive.

Methods: Two thousand two hundred twenty-eight women with a mean age of 85 years who participated in the Women's Health Initiative Memory Study were classified as cognitively normal (n = 1,905, 85.5%), mild cognitive impairment (n = 88, 3.9%), dementia (n = 121, 5.4%) or other cognitive impairment (n = 114, n = 5.1%) by central adjudication. Global cognitive functioning was assessed using telephone interview for cognitive status-modified in those women who did not meet cognitive impairment criteria. Differences between women grouped by cognitive status with respect to each potential risk factor were assessed using chi-squared tests and t-tests. Backward stepwise logistic regression was used to select factors that were independently associated with cognitive status.

Results: Factors associated with preserved cognitive functioning were younger age, higher education, and family incomes, being non-Hispanic white, better emotional wellbeing, fewer depressive symptoms, more insomnia complaints, being free of diabetes, and not carrying the apolipoprotein E-epsilon 4 allele. Cognitively normal women who demonstrated sustained high preserved cognition were younger, more educated, and endorsed better self-reported general health, emotional wellbeing, and higher physical functioning.

Conclusions: Addressing sociodemographic disparities such as income inequality, and targeting interventions to improve depressive symptoms and vascular risk factors, including diabetes, may play an important role in preserving cognition among women who survive to 80 years of age. Person-centered approaches that combine interventions to improve physical, cognitive, and psychosocial functioning may promote maintenance of high preserved cognitive health in the oldest-old.
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http://dx.doi.org/10.1093/gerona/glv055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759985PMC
March 2016

Atypical Structural Connectome Organization and Cognitive Impairment in Young Survivors of Acute Lymphoblastic Leukemia.

Brain Connect 2016 05 29;6(4):273-82. Epub 2016 Mar 29.

3 Department of Neurology, Dyslexia Center and Memory and Aging Center, University of California at San Francisco , San Francisco, California.

Survivors of pediatric acute lymphoblastic leukemia (ALL) are at increased risk for cognitive impairments that disrupt everyday functioning and decrease quality of life. The specific biological mechanisms underlying cognitive impairment following ALL remain largely unclear, but previous studies consistently demonstrate significant white matter pathology. We aimed to extend this literature by examining the organization of the white matter connectome in young patients with a history of ALL treated with chemotherapy only. We applied graph theoretical analysis to diffusion tensor imaging obtained from 31 survivors of ALL age 5-19 years and 39 matched healthy controls. Results indicated significantly lower small-worldness (p = 0.007) and network clustering coefficient (p = 0.019), as well as greater cognitive impairment (p = 0.027) in the ALL group. Regional analysis indicated that clustered connectivity in parietal, frontal, hippocampal, amygdalar, thalamic, and occipital regions was altered in the ALL group. Random forest analysis revealed a model of connectome and demographic variables that could automatically classify survivors of ALL as having cognitive impairment or not (accuracy = 0.89, p < 0.0001). These findings provide further evidence of brain injury in young survivors of ALL, even those without a history of central nervous system (CNS) disease or cranial radiation. Efficiency of local information processing, reorganization of hub connectivity, and cognitive reserve may contribute to cognitive outcome in these children. Certain connectome properties showed U-shaped relationships with cognitive impairment suggesting an optimal range of regional connectivity.
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http://dx.doi.org/10.1089/brain.2015.0409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876554PMC
May 2016