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An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study.

ABSTRACT: Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy were assessed at baseline, the midpoint, and the end of chemotherapy. DNA was extracted from whole blood, and genotyping was performed using Sanger sequencing. Patients' self-perceived cognitive function and cognitive performance were assessed at three different time points using FACT-Cog (v.3) and a neuropsychological battery, respectively. The association between DNMT1 rs2162560 and cognitive function was evaluated using logistic regression analyses. Overall, 33.3% of the patients reported impairment relative to baseline in one or more cognitive domains. Cognitive impairment was observed in various objective cognitive domains, with incidences ranging from 7.2% to 36.9%. The DNMT1 rs2162560 A allele was observed in 21.8% of patients and this was associated with lower odds of self-reported cognitive decline in the concentration (OR?=?0.45, 95% CI: 0.25-0.82, P?=?0.01) and functional interference (OR?=?0.48, 95% CI: 0.24-0.95, P?=?0.03) domains. No significant association was observed between DNMT1 rs2162560 and objective cognitive impairment. This is the first study to show a significant association between the DNMT1 rs2162560 polymorphism and CACI. Our data suggest that epigenetic processes could contribute to CACI, and further studies are needed to validate these findings.

SUBMITTER: Chan A

PROVIDER: S-EPMC6787348 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study.

Chan Alexandre A Yeo Angie A Shwe Maung M Tan Chia Jie CJ Foo Koon Mian KM Chu Pat P Khor Chiea Chuen CC Ho Han Kiat HK

Scientific reports 20191010 1

Strong evidence suggests that genetic variations in DNA methyltransferases (DNMTs) may alter the downstream expression and DNA methylation patterns of neuronal genes and influence cognition. This study investigates the association between a DNMT1 polymorphism, rs2162560, and chemotherapy-associated cognitive impairment (CACI) in a cohort of breast cancer patients. This is a prospective, longitudinal cohort study. From 2011 to 2017, 351 early-stage breast cancer patients receiving chemotherapy we ...[more]

PMID: 31601979

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Project description: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.

Project description:BackgroundCognitive impairment is commonly reported in patients receiving chemotherapy, but the acuity of onset is not known. This study utilized the psychomotor vigilance test (PVT) and trail-making test B (TMT-B) to assess cognitive impairment immediately post-chemotherapy.MethodsPatients aged 18-80 years receiving first-line intravenous chemotherapy for any stage of breast or colorectal cancer were eligible. Patient symptoms, peripheral neuropathy and Stanford Sleepiness Scale were assessed. A five-minute PVT and TMT-B were completed on a tablet computer pre-chemotherapy and immediately post-chemotherapy. Using a mixed linear regression model, changes in reciprocal transformed PVT reaction time (mean 1/RT) were assessed. A priori, an increase in median PVT reaction times by > 20 ms (approximating PVT changes with blood alcohol concentrations of 0.04-0.05 g%) was considered clinically relevant.ResultsOne hundred forty-two cancer patients (73 breast, 69 colorectal, median age 55.5 years) were tested. Post-chemotherapy, mean 1/RT values were significantly slowed compared to pre-chemotherapy baseline (p = 0.01). This corresponded to a median PVT reaction time slowed by an average of 12.4 ms. Changes in PVT reaction times were not correlated with age, sex, cancer type, treatment setting, or use of supportive medications. Median post-chemotherapy PVT reaction time slowed by an average of 22.5 ms in breast cancer patients and by 1.6 ms in colorectal cancer patients. Post-chemotherapy median PVT times slowed by > 20 ms in 57 patients (40.1%). Exploratory analyses found no statistically significant association between the primary outcome and self-reported anxiety, fatigue or depression. TMT-B completion speed improved significantly post-chemotherapy (p = 0.03), likely due to test-retest phenomenon.ConclusionsPVT reaction time slowed significantly immediately post-chemotherapy compared to a pre-chemotherapy baseline, and levels of impairment similar to effects of alcohol consumption in other studies was seen in 40% of patients. Further studies assessing functional impact of cognitive impairment on patients immediately after chemotherapy are warranted.

Project description:ImportanceWorsening vision and declining cognitive functioning are common conditions among elderly individuals. Understanding the association between them could be beneficial in mitigating age-related cognitive changes.ObjectiveTo evaluate the longitudinal associations between visual impairment and cognitive function over time in a population-based study of older US adults.Design, setting, and participantsProspective longitudinal population-based study of older adults in the greater Salisbury area in Maryland. Overall, 2520 community-residing adults aged 65 to 84 years were assessed at baseline between September 1993 and August 1995 (round 1) and 2 (round 2), 6 (round 3), and 8 (round 4) years later.Main outcomes and measuresVisual acuity (VA) was measured using Early Treatment Diabetic Retinopathy Study charts, and cognitive status was assessed using the Mini-Mental State Examination (MMSE).ResultsOf 2520 individuals, the mean (SD) age was 73.5 (5.1) years, 1458 (58%) were women, and 666 (26%) were black. There were 2240 (89%), 1504 (61%), and 1250 (50%) participants in the second, third, and fourth round of study, respectively, with more than half of the loss being due to death. Both VA and MMSE score worsened over time. The mean biannual decline of VA was 0.022 logMAR (approximately 1 line during 8 years; 95% CI, 0.018-0.026), and the mean biannual worsening of MMSE score was -0.59 (95% CI, -0.64 to -0.54; both P < .001). Worse baseline VA was associated with worse baseline MMSE score (r = -0.226; 95% CI, -0.291 to -0.16; P < .001). The rate of worsening VA was associated with the rate of declining MMSE score (r = -0.139; 95% CI, -0.261 to -0.017; P = .03). Cross-lagged models indicated VA in the previous round was associated with MMSE score in the subsequent round (β = -0.995, P < .001), and MMSE score in the previous round was associated with VA in the following round (β = -0.003, P < .001). However, the standardized effect size of VA on MMSE score (β = -0.074; SE, 0.015; P < .001) is larger relative to the reverse effect (β = -0.038; SE, 0.013; P < .001), demonstrating VA is likely the driving force in these dynamic associations.Conclusions and relevanceIn a population-based sample of older US adults, visual impairment measured at distance is associated with declining cognitive function both cross-sectionally and longitudinally over time with worsening vision having a stronger association with declining cognition than the reverse. Worsening vision in older adults may be adversely associated with future cognitive functioning. Maintaining good vision may be an important interventional strategy for mitigating age-related cognitive declines.

Project description:PurposeCancer-related cognitive impairment (CRCI) is a recognised adverse consequence of cancer and its treatment. This study assessed the feasibility of collecting longitudinal data on cognition in patients with newly diagnosed, aggressive lymphoma undergoing standard therapy with curative intent via self-report, neuropsychological assessment, peripheral markers of inflammation, and neuroimaging. An exploration and description of patterns of cancer-related cognitive impairment over the course of treatment and recovery was also undertaken and will be reported separately.MethodsEligible participants completed repeated measures of cognition including self-report and neuropsychological assessment, and correlates of cognition including blood cell-based inflammatory markers, and neuroimaging at three pre-specified timepoints, time 1 (T1) - pre-treatment (treatment naïve), time 2 (T2) - mid-treatment, and time 3 (T3) - 6 to 8 weeks post-completion of treatment.Results30/33 eligible patients (91%, 95% CI: 76%, 97%) were recruited over 10 months. The recruitment rate was 3 patients/month (95% CI: 2.0, 4.3 patients/month). Reasons for declining included feeling overwhelmed and rapid treatment commencement. Mean age was 57 years (SD = 17 years) and 16/30 (53%) were male. Most patients (20/30, 67%) had diffuse large B cell lymphoma or Hodgkin lymphoma (4/30, 13%). The neuroimaging sub-study was optional, 11/30 participants (37%) were eligible to take part, and all agreed. The remaining 19 participants were ineligible as their diagnostic PET/CT scan was completed prior. Retention and compliance with all assessments were 89 to 100% at all timepoints. Only one participant was withdrawn due to disease progression.ConclusionsFindings from this study including excellent recruitment, retention, and compliance rates demonstrate it is feasible to longitudinally assess cognition in people with newly diagnosed aggressive lymphoma during their initial treatment and recovery to inform the development of future research to improve patient experiences and cognitive outcomes.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12619001649101.

Dataset Information

An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study.

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An Evaluation of DNA Methyltransferase 1 (DNMT1) Single Nucleotide Polymorphisms and Chemotherapy-Associated Cognitive Impairment: A Prospective, Longitudinal Study.

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