Dataset Information

CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

ABSTRACT:

Aims

Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and frequently develops drug resistance. Studies have investigated the value of peripheral DNA methylation signature as molecular biomarker for diagnosis or prognosis. We aimed to explore methylation biomarkers for TLE diagnosis and pharmacoresistance prediction.

Methods

We initially conducted genome-wide DNA methylation profiling in TLE patients, and then selected candidate CpGs in training cohort and validated in another independent cohort by employing machine learning algorithms. Furthermore, nomogram comprising DNA methylation and clinicopathological data was generated to predict the drug response in the entire patient cohort. Lastly, bioinformatics analysis for CpG-associated genes was performed using Ingenuity Pathway Analysis.

Results

After screening and validation, eight CpGs were identified for diagnostic biomarker with an area under the curve (AUC) of 0.81 and six CpGs for drug-resistant prediction biomarker with an AUC of 0.79. The nomogram for drug-resistant prediction comprised methylation risk score, disease course, seizure frequency, and hippocampal sclerosis, with AUC as high as 0.96. Bioinformatics analysis indicated drug response-related CpGs corresponding genes closely related to DNA methylation.

Conclusions

This study demonstrates the ability to use peripheral DNA methylation signature as molecular biomarker for epilepsy diagnosis and drug-resistant prediction.

SUBMITTER: Xiao W

PROVIDER: S-EPMC7539843 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

Xiao Wenbiao W Liu Chaorong C Zhong Kuo K Ning Shangwei S Hou Rui R Deng Na N Xu Yuchen Y Luo Zhaohui Z Fu Yujiao Y Zeng Yi Y Xiao Bo B Long Hongyu H Long Lili L

CNS neuroscience & therapeutics 20200610 10

<h4>Aims</h4>Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and frequently develops drug resistance. Studies have investigated the value of peripheral DNA methylation signature as molecular biomarker for diagnosis or prognosis. We aimed to explore methylation biomarkers for TLE diagnosis and pharmacoresistance prediction.<h4>Methods</h4>We initially conducted genome-wide DNA methylation profiling in TLE patients, and then selected candidate CpGs in training coh ...[more]

PMID: 32519815

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Project description:ContextDespite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death.ObjectiveWe sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL).Design, setting, and participantsThe Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged ≥12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual.InterventionReceipt of continued AED treatment (n = 23) or a standardized AMTR plus AED treatment (n = 15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery.Main outcome measuresThe primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation.ResultsZero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio = ∞; 95% CI, 11.8 to ∞; P < .001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect = 8.5; 95% CI, -1.0 to 18.1; P = .08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect = 9.9; 95% CI, 2.2 to 17.7; P = .01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group.ConclusionsAmong patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution.Trial registrationclinicaltrials.gov Identifier: NCT00040326.

Project description:BackgroundCurrently, more than one-third of patients with drug-resistant temporal lobe epilepsy (TLE) continue to develop seizures after resection surgery. Dynamic functional network connectivity (DFNC) analyses, capturing temporal properties of functional connectivity during MRI acquisition, may help us identify unfavorable surgical outcomes. The purpose of this work was to explore the association of DFNC variations of preoperative resting-state MRI and surgical outcomes in patients with drug-resistant TLE.MethodsWe evaluated 61 patients with TLE matched for age and gender with 51 healthy controls (HC). Patients with TLE were classified as seizure-free (n = 39) and not seizure-free (n = 16) based on the Engel surgical outcome scale. Six patients were unable to confirm the postoperative status and were not included in the subgroup analysis. The DFNC was calculated using group spatial independent component analysis and the sliding window approach.ResultsDynamic functional network connectivity analyses suggested two distinct connectivity "States." The dynamic connectivity state of patients with TLE was different from HC. TLE subgroup analyses showed not seizure-free (NSF) patients spent significantly more time in State II compared to seizure-free (SF) patients and HC. Further, the number of transitions from State II to State I was significantly lower in NSF patients. SF patients had compensatory enhancement of DFNC strengths between default and dorsal attention network, as well as within the default network. While reduced DFNC strengths of within-network and inter-network were both observed in NSF patients, patients with abnormally temporal properties and more extension DFNC strength alterations were less likely to receive seizure freedom.ConclusionsOur study indicates that DFNC could offer a better understanding of dynamic neural impairment mechanisms of drug-resistant TLE functional network, epileptic brain network reorganization, and provide an additional preoperative evaluation support for surgical treatment of drug-resistant TLE.

Project description:Seminal animal studies demonstrated the role of sleep oscillations such as cortical slow waves, thalamocortical spindles, and hippocampal ripples in memory consolidation. In humans, whether ripples are involved in sleep-related memory processes is less clear. Here, we explored the interactions between sleep oscillations (measured as traits) and general episodic memory abilities in 26 adults with drug-resistant temporal lobe epilepsy who performed scalp-intracranial electroencephalographic recordings and neuropsychological testing, including two analogous hippocampal-dependent verbal and nonverbal memory tasks. We explored the relationships between hemispheric scalp (spindles, slow waves) and hippocampal physiological and pathological oscillations (spindles, slow waves, ripples, and epileptic spikes) and material-specific memory function. To differentiate physiological from pathological ripples, we used multiple unbiased data-driven clustering approaches. At the individual level, we found material-specific cerebral lateralization effects (left-verbal memory, right-nonverbal memory) for all scalp spindles (rs > 0.51, ps < 0.01) and fast spindles (rs > 0.61, ps < 0.002). Hippocampal epileptic spikes and short pathological ripples, but not physiological oscillations, were negatively (rs > -0.59, ps < 0.01) associated with verbal learning and retention scores, with left lateralizing and antero-posterior effects. However, data-driven clustering failed to separate the ripple events into defined clusters. Correlation analyses with the resulting clusters revealed no meaningful or significant associations with the memory scores. Our results corroborate the role of scalp spindles in memory processes in patients with drug-resistant temporal lobe epilepsy. Yet, physiological and pathological ripples were not separable when using data-driven clustering, and thus our findings do not provide support for a role of sleep ripples as trait-like characteristics of general memory abilities in epilepsy.

Dataset Information

CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

Aims

Methods

Results

Conclusions

Publications

CpG methylation signature defines human temporal lobe epilepsy and predicts drug-resistant.

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