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Genetic variants and cognitive functions in patients with brain tumors.

ABSTRACT: BACKGROUND:Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this population. METHODS:One hundred and fifty brain tumor patients treated with RT ± CT or CT alone completed a neurocognitive assessment and provided a blood sample for genotyping. We genotyped genes/SNPs in these pathways: (i) LOAD risk/inflammation/cholesterol transport, (ii) dopamine regulation, (iii) myelin regulation, (iv) DNA repair, (v) blood-brain barrier disruption, (vi) cell cycle regulation, and (vii) response to oxidative stress. White matter (WM) abnormalities were rated on brain MRIs. RESULTS:Multivariable linear regression analysis with Bayesian shrinkage estimation of SNP effects, adjusting for relevant demographic, disease, and treatment variables, indicated strong associations (posterior association summary [PAS] ? 0.95) among tests of attention, executive functions, and memory and 33 SNPs in genes involved in: LOAD/inflammation/cholesterol transport (eg, PDE7A, IL-6), dopamine regulation (eg, DRD1, COMT), myelin repair (eg, TCF4), DNA repair (eg, RAD51), cell cycle regulation (eg, SESN1), and response to oxidative stress (eg, GSTP1). The SNPs were not significantly associated with WM abnormalities. CONCLUSION:This novel study suggests that polymorphisms in genes involved in aging and inflammation, dopamine, myelin and cell cycle regulation, and DNA repair and response to oxidative stress may be associated with cognitive outcome in patients with brain tumors.

SUBMITTER: Correa DD

PROVIDER: S-EPMC6784270 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genetic variants and cognitive functions in patients with brain tumors.

Correa Denise D DD Satagopan Jaya J Martin Axel A Braun Erica E Kryza-Lacombe Maria M Cheung Kenneth K Sharma Ajay A Dimitriadoy Sofia S O'Connell Kelli K Leong Siok S Karimi Sasan S Lyo John J DeAngelis Lisa M LM Orlow Irene I

Neuro-oncology 20191001 10

<h4>Background</h4>Patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT) often experience cognitive dysfunction. We reported that single nucleotide polymorphisms (SNPs) in the APOE, COMT, and BDNF genes may influence cognition in brain tumor patients. In this study, we assessed whether genes associated with late-onset Alzheimer's disease (LOAD), inflammation, cholesterol transport, dopamine and myelin regulation, and DNA repair may influence cognitive outcome in this po ...[more]

PMID: 31123752

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Project description:BACKGROUND: Cognitive dysfunction is prevalen among brain tumor patients treated with radiotherapy (RT) and chemotherapy (CT). However, little is known about genetic risk factors that may moderate their vulnerability for developing cognitive impairment. In this study, we examined the association of single nucleotide polymorphisms (SNPs) in three genes, Catechol-O-Methyl-Transferase (COMT), Brain-Derived-Neurotrophic-Factor (BDNF), and dystrobrevin binding protein 1 (DTNBP1), and cognitive functions in brain tumor survivors. METHODS: One hundred and fifty brain tumor patients participated in the study: ninety had been treated with RT ± CT, fifty-seven had CT alone, and three had no therapy. All Patients completed a battery of neuropsychological tests of attention, executive functions and memory, and provided a blood sample. Genotyping of SNPs in the BDNF (n = 9), COMT (n = 17) and DTNBP1 (n = 7) genes was performed. RESULTS: Linear regressions with stepwise backward elimination of SNPs based on change in AIC criterion, adjusting for age, education, and treatment type indicated a significant (p< 0.05) association between the COMT SNP rs4680 (Val158Met) and cognitive function, with lower working memory scores in homozygotes (G/G) and higher executive function and delayed recall scores in heterozygotes (A/G). Five additional SNPs in the COMT gene were significantly associated with lower scores in attention and executive functions. There were significant associations among five SNPs in the BDNF gene and lower performance in executive function, learning and delayed recall. Four SNPs in the DTNBP1 gene were associated with attention and memory scores. CONCLUSION: The findings suggest that in brain tumor patients, cognitive outcome may be differentially affected by polymorphisms in genes previously associated with executive and memory functions in healthy individuals and other clinical populations. Further work is underway to quantify the variation in cognitive outcomes explained by these polymorphisms.

Project description:Abstract BACKGROUND Cognitive dysfunction is common in patients with brain tumors treated with radiotherapy (RT) and chemotherapy (CT). We reported previously that single nucleotide polymorphisms (SNPs) in the APOE, COMT and BDNF genes may influence cognitive outcome in this clinical population. In this study, we assessed whether additional genes with known associations with aging, Alzheimer’s disease and inflammation may contribute to cognitive dysfunction in brain tumor survivors. METHODS One hundred and fifty patients with brain tumors participated in the study: ninety had been treated with RT ± CT, fifty-seven had CT alone, and three had no therapy. All patients completed neuropsychological tests of attention, executive functions and memory, and provided a blood sample for genotyping. We used a Bayesian penalized multivariate regression approach to estimate the associations between the SNPs and cognitive outcome, adjusting for age, education, tumor location, treatment with RT ± CT, time since treatment completion, and APOE epsilon є-4 allele. We quantified the strength of association between a SNP and a cognitive test score using a novel measure referred to as the posterior association summary (PAS) that takes value between 0 (= no association) and 1 (= very strong association). RESULTS Several SNPs previously reported in association with age-related cognitive decline and Alzheimer’s disease (PDE7A rs10808746, CD2AP rs9349407, ABCC1 rs8187858, APOE rs405697) and inflammation (IL-1A rs1800587, IL-1 rs1143634, IL-6 rs1474348) were strongly associated with tests of attention, executive functions and memory (PAS ≥ 0.95). Several additional SNPs that mapped to the ABCA7, CD33, COMT, IL-6, MS4A4E, PDE7A, PICALM, SERPINA3 and SORC1 genes were also associated with tests of attention and executive functions with PAS ≥ 0.90. CONCLUSION The findings provide new evidence that polymorphisms in genes associated with aging, Alzheimer’s disease and inflammation may be functionally relevant and influence cognitive outcome in patients with brain tumors.

Project description:A fundamental set of cognitive abilities enable humans to efficiently process goal-relevant information, suppress irrelevant distractions, maintain information in working memory, and act flexibly in different behavioral contexts. Yet, studies of human cognition and their underlying neural mechanisms usually evaluate these cognitive constructs in silos, instead of comprehensively in-tandem within the same individual. Here, we developed a scalable, mobile platform, "BrainE" (short for Brain Engagement), to rapidly assay several essential aspects of cognition simultaneous with wireless electroencephalography (EEG) recordings. Using BrainE, we rapidly assessed five aspects of cognition including (1) selective attention, (2) response inhibition, (3) working memory, (4) flanker interference and (5) emotion interference processing, in 102 healthy young adults. We evaluated stimulus encoding in all tasks using the EEG neural recordings, and isolated the cortical sources of the spectrotemporal EEG dynamics. Additionally, we used BrainE in a two-visit study in 24 young adults to investigate the reliability of the neuro-cognitive data as well as its plasticity to transcranial magnetic stimulation (TMS). We found that stimulus encoding on multiple cognitive tasks could be rapidly assessed, identifying common as well as distinct task processes in both sensory and cognitive control brain regions. Event related synchronization (ERS) in the theta (3-7 Hz) and alpha (8-12 Hz) frequencies as well as event related desynchronization (ERD) in the beta frequencies (13-30 Hz) were distinctly observed in each task. The observed ERS/ERD effects were overall anticorrelated. The two-visit study confirmed high test-retest reliability for both cognitive and neural data, and neural responses showed specific TMS protocol driven modulation. We also show that the global cognitive neural responses are sensitive to mental health symptom self-reports. This first study with the BrainE platform showcases its utility in studying neuro-cognitive dynamics in a rapid and scalable fashion.

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Genetic variants and cognitive functions in patients with brain tumors.

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Genetic variants and cognitive functions in patients with brain tumors.

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