Dataset Information

Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy.

ABSTRACT: The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaute 2 (Ago2)-bound miRNAs in plasma samples collected from mice subject to status epilepticus induced by intraamygdala microinjection of kainic acid. This identified time-dependent changes in plasma levels of miRNAs with known neuronal and microglial-cell origins. To explore whether the circulating miRNAs had originated from the brain, we generated mice expressing FLAG-Ago2 in neurons or microglia using tamoxifen-inducible Thy1 or Cx3cr1 promoters, respectively. FLAG immunoprecipitates from the plasma of these mice after seizures contained miRNAs, including let-7i-5p and miR-19b-3p. Taken together, these studies confirm that a portion of the circulating pool of miRNAs in experimental epilepsy originates from the brain, increasing support for miRNAs as mechanistic biomarkers of epilepsy.

SUBMITTER: Brindley E

PROVIDER: S-EPMC10556253 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy.

Brindley Elizabeth E Heiland Mona M Mooney Catherine C Diviney Mairead M Mamad Omar O Hill Thomas D M TDM Yan Yan Y Venø Morten T MT Reschke Cristina R CR Batool Aasia A Langa Elena E Sanz-Rodriguez Amaya A Heller Janosch P JP Morris Gareth G Conboy Karen K Kjems Jørgen J Brennan Gary P GP Henshall David C DC

Frontiers in molecular neuroscience 20230922

The diagnosis of epilepsy is complex and challenging and would benefit from the availability of molecular biomarkers, ideally measurable in a biofluid such as blood. Experimental and human epilepsy are associated with altered brain and blood levels of various microRNAs (miRNAs). Evidence is lacking, however, as to whether any of the circulating pool of miRNAs originates from the brain. To explore the link between circulating miRNAs and the pathophysiology of epilepsy, we first sequenced argonaut ...[more]

PMID: 37808470

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Project description:We studied with functional magnetic resonance imaging (fMRI) differences in resting-state networks between patients with mesial temporal lobe epilepsy (MTLE) and healthy subjects. To avoid any a priori hypothesis, we use a data-driven analysis assessing differences between groups independently of structures involved. Shared and specific independent component analysis (SSICA) is an exploratory method based on independent component analysis, which performs between-group network comparison. It extracts and classifies components (networks) in those common between groups and those specific to one group. Resting fMRI data were collected from 10 healthy subjects and 10 MTLE patients. SSICA was applied multiple times with altered initializations and different numbers of specific components. This resulted in many components specific to patients and to controls. Spatial clustering identified the reliable resting-state networks among all specific components in each group. For each reliable specific network, power spectrum analysis was performed on reconstructed time-series to estimate connectivity in each group and differences between groups. Two reliable networks, corresponding to statistically significant clusters robustly detected with clustering were labeled as specific to MTLE and one as specific to the control group. The most reliable MTLE network included hippocampus and amygdala bilaterally. The other MTLE network included the postcentral gyri and temporal poles. The control-specific network included bilateral precuneus, anterior cingulate, thalamus, and parahippocampal gyrus. Results indicated that the two MTLE networks show increased connectivity in patients, whereas the control-specific network shows decreased connectivity in patients. Our findings complement results from seed-based connectivity analysis (1). The pattern of changes in connectivity between mesial temporal lobe structures and other areas may help us understand the cognitive impairments often reported in patients with MTLE.

Project description:A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of disease in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM for a supplementary and preliminary comparison: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We analyzed the group of patients and controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), β-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p < 0.05). In addition, we found some suggestive metabolites (without enough predictability) by multivariate analysis (VIP scores > 2), such as lipoproteins, lactate, glucose, unsaturated lipids, isoleucine, and proline, that might be relevant to the process of pharmacoresistance in the comparison between patients with refractory and responsive MTLE. The identified metabolites for the comparison between MTLE patients and controls were linked to different biological pathways related to cell-energy metabolism and pathways related to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In conclusion, in addition to insights into the mechanisms underlying MTLE, our results suggest that plasma metabolites may be used as disease biomarkers. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE.

Dataset Information

Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy.

Publications

Brain cell-specific origin of circulating microRNA biomarkers in experimental temporal lobe epilepsy.

Similar Datasets

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