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1
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Kalsariya RA, Kavila D, Shorter S, Negi D, Goodall ICA, Boussios S, Ovsepian SV. Molecular biomarkers of glial activation and injury in epilepsy. Drug Discov Today 2025; 30:104289. [PMID: 39799990 DOI: 10.1016/j.drudis.2025.104289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/24/2024] [Accepted: 01/06/2025] [Indexed: 01/15/2025]
Abstract
Increasing evidence from fluid biopsies suggests activation and injury of glial cells in epilepsy. The prevalence of clinical and subclinical seizures in neurodegenerative conditions such as Alzheimer's disease, frontotemporal dementia, and others merits review and comparison of the effects of seizures on glial markers in epilepsy and neurodegenerative diseases with concomitant seizures. Herein, we revisit preclinical and clinical reports of alterations in glial proteins in cerebrospinal fluid and blood associated with various types of epilepsy. We consider shared and distinct characteristics of changes in different age groups and sexes, in humans and animal models of epilepsy, and compare them with those reported in biofluids in neurodegenerative diseases. Our analysis indicates a significant overlap of glial response in these prevalent neurological conditions.
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Affiliation(s)
- Reema A Kalsariya
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK
| | - Dave Kavila
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK
| | - Susan Shorter
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK
| | - Deepika Negi
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK
| | - Iain C A Goodall
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK
| | - Stergios Boussios
- Department of Medical Oncology, Medway NHS Foundation Trust, Gillingham, ME7 5NY, UK; Faculty of Medicine, Health, and Social Care, Canterbury Christ Church University, Canterbury CT2 7PB, UK; Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King's College London, Strand, London WC2R 2LS, UK; Kent Medway Medical School, University of Kent, Canterbury CT2 7LX, UK; AELIA Organization, 9th Km Thessaloniki-Thermi, 57001 Thessaloniki, Greece
| | - Saak V Ovsepian
- Faculty of Engineering and Science, University of Greenwich London, Chatham Maritime ME4 4TB, UK; Faculty of Medicine, Tbilisi State University, Tbilisi 0179, Georgia.
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2
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Sakhr HM, Hassan MH, Salah AE, Bakri AH. Clinical and biochemical assessments of circulating High Mobility Group Box Protein1 in children with epilepsy: relation to cognitive function and drug responsiveness. Neurol Sci 2025; 46:887-897. [PMID: 39466324 PMCID: PMC11772407 DOI: 10.1007/s10072-024-07795-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 10/03/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Childhood epilepsy is a major health concern posing a significant burden and having disastrous consequences for cognitive function. High Mobility Group Box1 (HMGB1) is an activator of neuroinflammation, and it is possibly involved in the initiation and progression of epilepsy. We aimed to investigate circulating HMGB1 in children with epilepsy and its connection to cognitive function and drug responsiveness. METHODS Case-control research included 100 epileptic youngsters and 100 healthy matched controls. Serum HMGB1 was measured using a commercially available ELISA assay. Cognitive functions were evaluated by the Stanford-Binet test 5th edition. RESULTS Drug-resistant epilepsy (DRE) was found in 37% of the investigated patients. Epileptic children have lower cognitive function parameter levels versus the control group and lower cognitive function in the DRE group compared to the drug-responsive group (P-value < 0.0001). HMGB1 levels were significantly higher in the patients' group (6.279 µg/L) compared to the control group (2.093 µg/L) and in the drug-resistant group (14.26 µg/L) versus the drug-responsive group (4.88 µg/L). A significant negative correlation was detected between HMGB1 with Full-scale IQ (r = - 0.547, P = 0.000), Visual-spatial reasoning (r = - 0.501, P = 0.000), fluid reasoning (r = - 0.510, P = 0.000), and working memory (r = - 0.555, P = 0.000). Serum HMGB1 cut-off levels > 6.85 µg/L differentiate drug-responsive from resistant patients. CONCLUSION Elevated HMGB1 levels, especially in patients with drug-resistant epilepsy, correlate negatively with cognitive performance, emphasizing its importance as a potential marker for early prediction of drug resistance and impairment of cognitive function.
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Affiliation(s)
- Hala M Sakhr
- Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt.
| | - Mohammed H Hassan
- Department of Medical Biochemistry, Faculty of Medicine, South Valley University, Qena, Egypt.
| | - Asmaa E Salah
- Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Ali Helmi Bakri
- Department of Pediatrics, Faculty of Medicine, South Valley University, Qena, Egypt
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3
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Hall AM, Kamei N, Shao M, Mun HS, Chen K, Chen Y, Baram TZ. Inhibition of Neuron-Restrictive Silencing Factor (REST/NRSF) Chromatin Binding Attenuates Epileptogenesis. eNeuro 2024; 11:ENEURO.0006-24.2024. [PMID: 38641413 PMCID: PMC11103648 DOI: 10.1523/eneuro.0006-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/08/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024] Open
Abstract
The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections, and long seizures (status epilepticus, SE) increase the nuclear expression and chromatin binding of the neuron-restrictive silencing factor/RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12 d duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly or, alternatively, slowed epilepsy onset. Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (1) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation, or (2) prevented the onset of spontaneous seizures, measured with chronic digital video-electroencephalogram. Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE-ODN compared with scrambled-ODN cohorts. Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.
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Affiliation(s)
- Alicia M Hall
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Noriko Kamei
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
| | - Manlin Shao
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Hyun-Seung Mun
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
| | - Kevin Chen
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Yuncai Chen
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
| | - Tallie Z Baram
- Department of Pediatrics, University of California-Irvine, Irvine, California 92697
- Department of Anatomy and Neurobiology, University of California-Irvine, Irvine, California 92697
- Department of Neurology, University of California-Irvine, Irvine, California 92697
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4
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Szydlowska K, Bot A, Nizinska K, Olszewski M, Lukasiuk K. Circulating microRNAs from plasma as preclinical biomarkers of epileptogenesis and epilepsy. Sci Rep 2024; 14:708. [PMID: 38184716 PMCID: PMC10771472 DOI: 10.1038/s41598-024-51357-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/03/2024] [Indexed: 01/08/2024] Open
Abstract
Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.
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Affiliation(s)
- Kinga Szydlowska
- Laboratory of Epileptogenesis, Nencki Institute of Experimental Biology, Warsaw, Poland.
| | - Anna Bot
- Laboratory of Epileptogenesis, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Karolina Nizinska
- Laboratory of Epileptogenesis, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Maciej Olszewski
- Laboratory of Epileptogenesis, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Katarzyna Lukasiuk
- Laboratory of Epileptogenesis, Nencki Institute of Experimental Biology, Warsaw, Poland
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Tikhonova MA, Shvaikovskaya AA, Zhanaeva SY, Moysak GI, Akopyan AA, Rzaev JA, Danilenko KV, Aftanas LI. Concordance between the In Vivo Content of Neurospecific Proteins (BDNF, NSE, VILIP-1, S100B) in the Hippocampus and Blood in Patients with Epilepsy. Int J Mol Sci 2023; 25:502. [PMID: 38203674 PMCID: PMC10779095 DOI: 10.3390/ijms25010502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/25/2023] [Accepted: 12/27/2023] [Indexed: 01/12/2024] Open
Abstract
The identification of reliable brain-specific biomarkers in periphery contributes to better understanding of normal neurophysiology and neuropsychiatric diseases. The neurospecific proteins BDNF, NSE, VILIP-1, and S100B play an important role in the pathogenesis of neuropsychiatric disorders, including epilepsy. This study aimed to assess the correspondence of the expression of BDNF, NSE, VILIP-1, and S100B in the blood (serum and peripheral blood mononuclear cells (PBMCs)) to the in vivo hippocampal levels of subjects with drug-resistant epilepsy who underwent neurosurgery (N = 44) using multiplex solid-phase analysis, ELISA, and immunohistochemical methods, as well as to analyze the correlations and associations of the blood and hippocampal levels of these proteins with clinical parameters. We first studied the concordance between in vivo brain and blood levels of BDNF, NSE, VILIP-1, and S100B in epileptic patients. A positive correlation for NSE between hippocampal and PBMC levels was revealed. NSE levels in PBMCs were also significantly correlated with average seizure duration. BDNF levels in PBMCs were associated with seizure frequency and hippocampal sclerosis. Thus, NSE and BDNF levels in PBMCs may have potential as clinically significant biomarkers. Significant correlations between the levels of the neurospecific proteins studied herein suggest interactions between BDNF, NSE, VILIP-1, and S100B in the pathophysiology of epilepsy.
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Affiliation(s)
- Maria A. Tikhonova
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
| | - Anna A. Shvaikovskaya
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
| | - Svetlana Y. Zhanaeva
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
| | - Galina I. Moysak
- FSBI “Federal Center for Neurosurgery”, 630087 Novosibirsk, Russia (J.A.R.)
| | - Anna A. Akopyan
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
| | - Jamil A. Rzaev
- FSBI “Federal Center for Neurosurgery”, 630087 Novosibirsk, Russia (J.A.R.)
| | - Konstantin V. Danilenko
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
| | - Lyubomir I. Aftanas
- Scientific Research Institute of Neurosciences and Medicine (SRINM), 630117 Novosibirsk, Russia (S.Y.Z.); (L.I.A.)
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6
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Dallmer-Zerbe I, Jiruska P, Hlinka J. Personalized dynamic network models of the human brain as a future tool for planning and optimizing epilepsy therapy. Epilepsia 2023; 64:2221-2238. [PMID: 37340565 DOI: 10.1111/epi.17690] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/17/2023] [Accepted: 06/19/2023] [Indexed: 06/22/2023]
Abstract
Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long-term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy.
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Affiliation(s)
- Isa Dallmer-Zerbe
- Department of Complex Systems, Institute of Computer Science, Czech Academy of Sciences, Prague, Czech Republic
- Department of Physiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Premysl Jiruska
- Department of Physiology, Second Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Jaroslav Hlinka
- Department of Complex Systems, Institute of Computer Science, Czech Academy of Sciences, Prague, Czech Republic
- National Institute of Mental Health, Klecany, Czech Republic
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7
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Chong D, Jones NC, Schittenhelm RB, Anderson A, Casillas-Espinosa PM. Multi-omics Integration and Epilepsy: Towards a Better Understanding of Biological Mechanisms. Prog Neurobiol 2023:102480. [PMID: 37286031 DOI: 10.1016/j.pneurobio.2023.102480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 05/09/2023] [Accepted: 06/03/2023] [Indexed: 06/09/2023]
Abstract
The epilepsies are a group of complex neurological disorders characterised by recurrent seizures. Approximately 30% of patients fail to respond to anti-seizure medications, despite the recent introduction of many new drugs. The molecular processes underlying epilepsy development are not well understood and this knowledge gap impedes efforts to identify effective targets and develop novel therapies against epilepsy. Omics studies allow a comprehensive characterisation of a class of molecules. Omics-based biomarkers have led to clinically validated diagnostic and prognostic tests for personalised oncology, and more recently for non-cancer diseases. We believe that, in epilepsy, the full potential of multi-omics research is yet to be realised and we envisage that this review will serve as a guide to researchers planning to undertake omics-based mechanistic studies.
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Affiliation(s)
- Debbie Chong
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia
| | - Nigel C Jones
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia; Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, 3000, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, 3004, Victoria, Australia
| | - Ralf B Schittenhelm
- Monash Proteomics & Metabolomics Facility and Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
| | - Alison Anderson
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia; Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, 3000, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, 3004, Victoria, Australia
| | - Pablo M Casillas-Espinosa
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, 3004, Victoria, Australia; Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, 3000, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, 3004, Victoria, Australia
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8
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Cudna A, Bronisz E, Jopowicz A, Kurkowska-Jastrzębska I. Changes in serum blood-brain barrier markers after bilateral tonic-clonic seizures. Seizure 2023; 106:129-137. [PMID: 36841062 DOI: 10.1016/j.seizure.2023.02.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/10/2023] [Accepted: 02/12/2023] [Indexed: 02/17/2023] Open
Abstract
OBJECTIVE Seizures have been shown to increase blood-brain barrier (BBB) permeability, yet the role of this phenomenon is not fully understood. Additionally, dysfunction of the BBB leads to initiation and propagation of seizures in animal models. To demonstrate the increased permeability of the BBB in time, we investigated changes of the serum levels of BBB markers in patients with epilepsy after bilateral tonic-clonic seizures. We chose markers that might reflect endothelial activation (ICAM-1, selectins), BBB leakage (MMP-9, S100B) and mechanisms of BBB restoration (TIMP-1, thrombomodulin -TM). METHODS We enrolled 50 consecutive patients hospitalised after bilateral tonic-clonic seizures who agreed to take part in the study and 50 participants with no history of epilepsy. Serum levels of selected markers were measured by ELISA at 1-3, 24, and 72 hours after seizures and one time in the control group. RESULTS We found increased levels of S100B, ICAM-1, MMP-9 and P-selectin at 1-3 and 24 hours after seizures and TIMP-1 and TM at 24 and 72 hours after seizures as compared to the control group. The level of E-selectin was decreased at 72 hours after seizures. CONCLUSIONS Our findings suggest early activation of endothelium and increased BBB permeability after seizures. While we are aware of the limitations due to the non-specificity of the tested proteins, our results might indicate the presence of prolonged BBB impairment due to seizure activity.
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Affiliation(s)
- Agnieszka Cudna
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Elżbieta Bronisz
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
| | - Anna Jopowicz
- 2nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland
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9
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Riikonen R. Biochemical mechanisms in pathogenesis of infantile epileptic spasm syndrome. Seizure 2023; 105:1-9. [PMID: 36634586 DOI: 10.1016/j.seizure.2023.01.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 01/01/2023] [Accepted: 01/05/2023] [Indexed: 01/09/2023] Open
Abstract
The molecular mechanisms leading to infantile epileptic spasm syndrome (IESS) remain obscure. The only common factor seems to be that the spasms are restricted to a limited period of infancy, during a certain maturational state. Here the current literature regarding the biochemical mechanisms of brain maturation in IESS is reviewed, and various hypotheses of the pathophysiology are put together. They include: (1) imbalance of inhibitory (NGF, IGF-1, ACTH, GABA) and excitatory factors (glutamate, nitrites) which distinguishes the different etiological subgroups, (2) abnormality of the hypothalamic pituitary adrenal (HPA) axis linking insults and early life stress, (3) inflammation (4) yet poorly known genetic and epigenetic factors, and (5) glucocorticoid and vigabatrin action on brain development, pinpointing at molecular targets of the pathophysiology from another angle. An altered maturational process may explain why so many, seemingly independent etiological factors lead to the same clinical syndrome and frequently to developmental delay. Understanding these factors can provide ideas for novel therapies.
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Affiliation(s)
- Raili Riikonen
- Children's Hospital, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
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10
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Peplow P, Martinez B. MicroRNAs as potential biomarkers in temporal lobe epilepsy and mesial temporal lobe epilepsy. Neural Regen Res 2023; 18:716-726. [DOI: 10.4103/1673-5374.354510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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11
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Li XL, Wang S, Tang CY, Ma HW, Cheng ZZ, Zhao M, Sun WJ, Wang XF, Wang MY, Li TF, Qi XL, Zhou J, Luan GM, Guan YG. Translocation of High Mobility Group Box 1 From the Nucleus to the Cytoplasm in Depressed Patients With Epilepsy. ASN Neuro 2022; 14:17590914221136662. [PMID: 36383501 PMCID: PMC9677174 DOI: 10.1177/17590914221136662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 10/15/2022] [Accepted: 10/17/2022] [Indexed: 08/05/2023] Open
Abstract
Depression is a common psychiatric comorbidity in patients with epilepsy, especially those with temporal lobe epilepsy (TLE). The aim of this study was to assess changes in high mobility group box protein 1 (HMGB1) expression in epileptic patients with and without comorbid depression. Sixty patients with drug-resistant TLE who underwent anterior temporal lobectomy were enrolled. Anterior hippocampal samples were collected after surgery and analyzed by immunofluorescence (n = 7/group). We also evaluated the expression of HMGB1 in TLE patients with hippocampal sclerosis and measured the level of plasma HMGB1 by enzyme-linked immunosorbent assay. The results showed that 28.3% of the patients (17/60) had comorbid depression. HMGB1 was ubiquitously expressed in all subregions of the anterior hippocampus. The ratio of HMGB1-immunoreactive neurons and astrocytes was significantly increased in both TLE patients with hippocampal sclerosis and TLE patients with comorbid depression compared to patients with TLE only. The ratio of cytoplasmic to nuclear HMGB1-positive neurons in the hippocampus was higher in depressed patients with TLE than in nondepressed patients, which suggested that more HMGB1 translocated from the nucleus to the cytoplasm in the depressed group. There was no significant difference in the plasma level of HMGB1 among patients with TLE alone, TLE with hippocampal sclerosis, and TLE with comorbid depression. The results of the study revealed that the translocation of HMGB1 from the nucleus to the cytoplasm in hippocampal neurons may play a previously unrecognized role in the initiation and amplification of epilepsy and comorbid depression. The direct targeting of neural HMGB1 is a promising approach for anti-inflammatory therapy.
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Affiliation(s)
- Xiao-Li Li
- Department of Neurology, Affiliated ZhongDa Hospital, Southeast University, Nanjing, China
| | - Shu Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Chong-Yang Tang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Hao-Wei Ma
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Zi-Zhang Cheng
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Meng Zhao
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Wei-Jin Sun
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Xiong-Fei Wang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Meng-Yang Wang
- Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Tian-Fu Li
- Department of Neurology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Epilepsy, Beijing, China
- Center of Epilepsy, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| | - Xue-Ling Qi
- Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Jian Zhou
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Guo-Ming Luan
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Epilepsy, Beijing, China
- Center of Epilepsy, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
| | - Yu-Guang Guan
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Epilepsy, Beijing, China
- Center of Epilepsy, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
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12
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Zhao J, Wang C, Sun W, Li C. Tailoring Materials for Epilepsy Imaging: From Biomarkers to Imaging Probes. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2203667. [PMID: 35735191 DOI: 10.1002/adma.202203667] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/11/2022] [Indexed: 06/15/2023]
Abstract
Excising epileptic foci (EF) is the most efficient approach for treating drug-resistant epilepsy (DRE). However, owing to the vast heterogeneity of epilepsies, EF in one-third of patients cannot be accurately located, even after exhausting all current diagnostic strategies. Therefore, identifying biomarkers that truly represent the status of epilepsy and fabricating probes with high targeting specificity are prerequisites for identifying the "concealed" EF. However, no systematic summary of this topic has been published. Herein, the potential biomarkers of EF are first summarized and classified into three categories: functional, molecular, and structural aberrances during epileptogenesis, a procedure of nonepileptic brain biasing toward epileptic tissue. The materials used to fabricate these imaging probes and their performance in defining the EF in preclinical and clinical studies are highlighted. Finally, perspectives for developing the next generation of probes and their challenges in clinical translation are discussed. In general, this review can be helpful in guiding the development of imaging probes defining EF with improved accuracy and holds promise for increasing the number of DRE patients who are eligible for surgical intervention.
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Affiliation(s)
- Jing Zhao
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Zhangheng Road 826, Shanghai, 201203, China
| | - Cong Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Zhangheng Road 826, Shanghai, 201203, China
- Academy for Engineering and Technology, Fudan University, 20 Handan Road, Yangpu District, Shanghai, 200433, China
- Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, 200031, China
| | - Wanbing Sun
- Department of Neurology and Research Center of Neurology in Second Affiliated Hospital and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Cong Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Zhangheng Road 826, Shanghai, 201203, China
- State Key Laboratory of Medical Neurobiology, School of Pharmacy, Fudan University, Shanghai, 201203, China
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13
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Bindila L, Eid T, Mills JD, Hildebrand MS, Brennan GP, Masino SA, Whittemore V, Perucca P, Reid CA, Patel M, Wang KK, van Vliet EA. A companion to the preclinical common data elements for proteomics, lipidomics, and metabolomics data in rodent epilepsy models. A report of the TASK3-WG4 omics working group of the ILAE/AES joint translational TASK force. Epilepsia Open 2022. [PMID: 36259125 DOI: 10.1002/epi4.12662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 05/19/2022] [Indexed: 11/07/2022] Open
Abstract
The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. This is the second in a two-part series of omics papers, with the other including genomics, transcriptomics, and epigenomics. The aim of the CDEs was to improve the standardization of experimental designs across a range of epilepsy research-related methods. We have generated CDE tables with key parameters and case report forms (CRFs) containing the essential contents of the study protocols for proteomics, lipidomics, and metabolomics of samples from rodent models and people with epilepsy. We discuss the important elements that need to be considered for the proteomics, lipidomics, and metabolomics methodologies, providing a rationale for the parameters that should be documented.
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Affiliation(s)
- Laura Bindila
- Clinical Lipidomics Unit, Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Tore Eid
- Department of Laboratory Medicine, Yale School of Medicine, New Haven, Connecticut, USA
| | - James D Mills
- Amsterdam UMC location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
| | - Michael S Hildebrand
- Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
- Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria, Australia
| | - Gary P Brennan
- UCD School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Ireland
- FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Susan A Masino
- Neuroscience Program and Psychology Department, Life Sciences Center, Trinity College, Hartford, Connecticut, USA
| | - Vicky Whittemore
- Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Piero Perucca
- Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
- Bladin-Berkovic Comprehensive Epilepsy Program, Austin Health, Heidelberg, Victoria, Australia
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Department of Neurology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Christopher A Reid
- Epilepsy Research Centre, Department of Medicine (Austin Health), The University of Melbourne, Heidelberg, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Manisha Patel
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kevin K Wang
- Program for Neurotrauma, Neuroproteomics & Biomarker Research (NNBR), Department of Emergency Medicine, Psychiatry and Neuroscience, University of Florida, Gainesville, Florida, USA
- Brain Rehabilitation Research Center, Malcom Randall VA Medical Center, North Florida/South Georgia Veterans Health System, Gainesville, Florida, USA
| | - Erwin A van Vliet
- Amsterdam UMC location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, the Netherlands
- Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands
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14
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Geng Y, Jin L, Tang G, Zhao Z, Gu Y, Yang D. LiqBioer: a manually curated database of cancer biomarkers in body fluid. Database (Oxford) 2022; 2022:6687198. [PMID: 36053554 PMCID: PMC9438745 DOI: 10.1093/database/baac077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/15/2022] [Accepted: 08/27/2022] [Indexed: 11/14/2022]
Abstract
Cancer biomarkers are measurable indicators that play vital roles in clinical applications. Biomarkers in body fluids have gained considerable attention since the development of liquid biopsy, and their data volume is rapidly increasing. Nevertheless, current research lacks the compilation of published cancer body fluid biomarkers into a centralized and sustainable repository for researchers and clinicians, despite a handful of small-scale and specific data resources. To fulfill this purpose, we developed liquid biomarker (LiqBioer) containing 6231 manually curated records from 3447 studies, covering 3056 biomarkers and 74 types of cancer in 22 tissues. LiqBioer allows users to browse and download comprehensive information on body liquid biomarkers, including cancer types, source studies and clinical usage. As a comprehensive resource for body fluid biomarkers of cancer, LiqBioer is a powerful tool for researchers and clinicians to query and retrieve biomarkers in liquid biopsy.
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Affiliation(s)
- Yiding Geng
- Department of Biochemistry and Molecular Biology, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150081, China
| | - Lu Jin
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150081, China
| | - Guangjue Tang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150081, China
| | - Zhangxiang Zhao
- The Sino-Russian Medical Research Centre, The Institute of Chronic Disease, The First Affiliated Hospital, Jinan University , Guangzhou, Guangdong 510630, China
| | - Yunyan Gu
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150081, China
| | - Dan Yang
- Department of Biochemistry and Molecular Biology, Harbin Medical University , 157 Baojian Road, Nangang District, Harbin 150081, China
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15
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Sun Y, Ren G, Ren J, Wang Q. High-frequency oscillations detected by electroencephalography as biomarkers to evaluate treatment outcome, mirror pathological severity and predict susceptibility to epilepsy. ACTA EPILEPTOLOGICA 2021. [DOI: 10.1186/s42494-021-00063-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AbstractHigh-frequency oscillations (HFOs) in the electroencephalography (EEG) have been extensively investigated as a potential biomarker of epileptogenic zones. The understanding of the role of HFOs in epilepsy has been advanced considerably over the past decade, and the use of scalp EEG facilitates recordings of HFOs. HFOs were initially applied in large scale in epilepsy surgery and are now being utilized in other applications. In this review, we summarize applications of HFOs in 3 subtopics: (1) HFOs as biomarkers to evaluate epilepsy treatment outcome; (2) HFOs as biomarkers to measure seizure propensity; (3) HFOs as biomarkers to reflect the pathological severity of epilepsy. Nevertheless, knowledge regarding the above clinical applications of HFOs remains limited at present. Further validation through prospective studies is required for its reliable application in the clinical management of individual epileptic patients.
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16
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Wang N, Liu H, Ma B, Zhao T, Chen Y, Yang Y, Zhao P, Han X. CSF high-mobility group box 1 is associated with drug-resistance and symptomatic etiology in adult patients with epilepsy. Epilepsy Res 2021; 177:106767. [PMID: 34543830 DOI: 10.1016/j.eplepsyres.2021.106767] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 09/01/2021] [Accepted: 09/10/2021] [Indexed: 01/08/2023]
Abstract
PURPOSE Extracellular high-mobility group box 1 (HMGB1) is considered a proinflammatory mediator and is involved in various neurological disorders. This study aims to determine the expression profiles of HMGB1 in cerebrospinal fluid (CSF) and paired serum, and to explore whether there is a relationship between CSF HMGB1 concentrations with seizure parameters in adult patients with epilepsy. METHODS CSF and paired serum HMGB1 concentrations were measured in patients with drug-refractory epilepsy (DRE, n = 27), newly diagnosed epilepsy (NDE, n = 56), and other non-inflammatory neurological disorders (ONNDs, n = 22). The correlations in HMGB1 levels between CSF and blood were performed. The associations between HMGB1 levels and seizure parameters were analyzed. RESULTS Mean (± SD) CSF HMGB1 concentrations were 5.08 ± 3.06, 3.03 ± 2.25, 0.83 ± 0.77 ng/mL in patients with DRE, NDE, and ONNDs, respectively. Corresponding mean (± SD) serum concentrations were 4.53 ± 2.81, 2.32 ± 1.54, 1.56 ± 0.84 ng/mL. The CSF HMGB1 concentrations were significantly higher in the DRE and NDE groups compared with the ONNDs group (p < 0.001). There were no correlations in HMGB1 levels between CSF and serum in the DRE, NDE, and ONNDs groups. Furthermore, patients with symptomatic etiology showed significantly high levels of CSF HMGB1. Patients without remission expressed elevated levels of CSF HMGB1 at one-year follow-up. Additionally, the CSF HMGB1 levels were positively associated with seizure frequency. CONCLUSION Our study shows that HMGB1 may be a critical player in seizure mechanisms and CSF HMGB1 might be predictive in determining epilepsy etiology and prognosis.
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Affiliation(s)
- Na Wang
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Haipeng Liu
- Department of Neurological Rehabilitation, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Bingqian Ma
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China; Department of Rehabilitation Medicine, Xinxiang Central Hospital, Xinxiang, Henan, 453000, China
| | - Ting Zhao
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Yanan Chen
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Yongguang Yang
- Ministry of Scientific Research and Discipline Construction, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Pan Zhao
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China
| | - Xiong Han
- Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, 450003, China.
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do Prado-Lima PAS, Costa-Ferro ZSM, Souza BSDF, da Cruz IBM, Lab B. Is there a place for cellular therapy in depression? World J Psychiatry 2021; 11:553-567. [PMID: 34631460 PMCID: PMC8474995 DOI: 10.5498/wjp.v11.i9.553] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/05/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023] Open
Abstract
Although efforts have been made to improve the pharmacological treatment of depression, approximately one-third of patients with depression do not respond to conventional therapy using antidepressants. Other potential non-pharmacological therapies have been studied in the last years, including the use of mesenchymal stem cell therapies to treat depression. These therapies are reviewed here since it is clinically relevant to develop innovative therapeutics to treat psychiatric patients. Experimental data corroborate that mesenchymal stem cell therapy could be considered a potential treatment for depression based on its anti-inflammatory and neurotrophic properties. However, some clinical trials involving treatment of depression with stem cells are in progress, but with no published results. These studies and other future clinical investigations will be crucial to define how much mesenchymal stem cells can effectively be used in psychiatric clinics as a strategy for supporting depression treatment.
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Affiliation(s)
- Pedro Antônio Schmidt do Prado-Lima
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Rio Grande do Sul, Brazil
| | - Zaquer Suzana Munhoz Costa-Ferro
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul, Porto Alegre 90610-000, Rio Grande do Sul, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Bahia, Brazil
- D’Or Institute for Research and Education (IDOR), Salvador 41253-190, Bahia, Brazil
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Bahia, Brazil
- D’Or Institute for Research and Education (IDOR), Salvador 41253-190, Bahia, Brazil
- Laboratory of Tissue Engineering and Immunopharmacology, Gonçalo Moniz Institute, Fiocruz, Salvador 40296-710, Bahia, Brazil
| | | | - Biogenomics Lab
- Health Sciences Center, Federal University of Santa Maria, Santa Maria 97105900, RS, Brazil
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18
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Pototskiy E, Vinokuroff K, Ojeda A, Major CK, Sharma D, Anderson T, Howard K, Borenstein R, Musto AE. Downregulation of CD40L-CD40 attenuates seizure susceptibility and severity of seizures. Sci Rep 2021; 11:17262. [PMID: 34446808 PMCID: PMC8390750 DOI: 10.1038/s41598-021-96760-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 08/11/2021] [Indexed: 12/04/2022] Open
Abstract
Unregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40-CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40-CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40-CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L-CD40 interaction can serve as a target for an immuno-therapy for TLE.
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Affiliation(s)
- Esther Pototskiy
- Department of Pathology and Anatomy, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA
| | | | - Andrew Ojeda
- Department of Pathology and Anatomy, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA
| | | | | | | | | | - Ronen Borenstein
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, 23507, USA
| | - Alberto E Musto
- Department of Pathology and Anatomy, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA.
- Department of Neurology, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA.
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Petrillo S, Pietrafusa N, Trivisano M, Calabrese C, Saura F, Gallo MG, Bertini ES, Vigevano F, Specchio N, Piemonte F. Imbalance of Systemic Redox Biomarkers in Children with Epilepsy: Role of Ferroptosis. Antioxidants (Basel) 2021; 10:antiox10081267. [PMID: 34439515 PMCID: PMC8389337 DOI: 10.3390/antiox10081267] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022] Open
Abstract
To assess if ferroptosis, a new type of programmed cell death accompanied by iron accumulation, lipid peroxidation, and glutathione depletion, occurs in children with epilepsy, and in order to identify a panel of biomarkers useful for patient stratification and innovative-targeted therapies, we measured ferroptosis biomarkers in blood from 83 unrelated children with a clinical diagnosis of epilepsy and 44 age-matched controls. We found a marked dysregulation of three ferroptosis key markers: a consistent increase of 4-hydroxy-2-nonenal (4-HNE), the main by-product of lipid peroxidation, a significant decrease of glutathione (GSH) levels, and a partial inactivation of the enzyme glutathione peroxidase 4 (GPX4), the mediator of lipid peroxides detoxification. Furthermore, we found a significant increase of NAPDH oxidase 2 (NOX2) in the blood of children, supporting this enzyme as a primary source of reactive oxygen species (ROS) in epilepsy. Additionally, since the nuclear factor erythroid 2-related factor 2 (NRF2) induction protects the brain from epileptic seizure damage, we also evaluated the NRF2 expression in the blood of children. The antioxidant and anti-inflammatory transcription factor was activated in patients, although not enough to re-establish a correct redox homeostasis for counteracting ferroptosis. Ferroptosis-mediated oxidative damage has been proposed as an emergent mechanism underlying the pathogenesis of epilepsy. Overall, our study confirms a crucial role for ferroptosis in epilepsy, leading to the identification of a panel of biomarkers useful to find new therapeutic targets. Developing innovative drugs, which act by inhibiting the ferroptosis signaling axis, may represent a promising strategy for new anti-seizure medications.
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Affiliation(s)
- Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy; (S.P.); (M.G.G.); (E.S.B.)
| | - Nicola Pietrafusa
- Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy; (N.P.); (M.T.); (C.C.)
| | - Marina Trivisano
- Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy; (N.P.); (M.T.); (C.C.)
| | - Costanza Calabrese
- Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165 Rome, Italy; (N.P.); (M.T.); (C.C.)
| | - Francesca Saura
- Department of Laboratory Medicine, Children’s Hospital Bambino Gesù, Piazza S. Onofrio 4, 00165 Rome, Italy;
| | - Maria Giovanna Gallo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy; (S.P.); (M.G.G.); (E.S.B.)
| | - Enrico Silvio Bertini
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy; (S.P.); (M.G.G.); (E.S.B.)
| | - Federico Vigevano
- Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Piazza S. Onforio 4, 00165 Rome, Italy; (F.V.); (N.S.)
| | - Nicola Specchio
- Department of Neuroscience, Bambino Gesu Children’s Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies EpiCARE, Piazza S. Onforio 4, 00165 Rome, Italy; (F.V.); (N.S.)
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Viale San Paolo 15, 00146 Rome, Italy; (S.P.); (M.G.G.); (E.S.B.)
- Correspondence: ; Tel.: +39-06-6859-2102
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20
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Sunwoo JS, Jo H, Kang KW, Kim KT, Kim D, Kim DW, Kim MJ, Kim S, Kim W, Moon HJ, Park HR, Byun JI, Seo JG, Lim SC, Chu MK, Han SH, Hwang KJ, Seo DW. Survey on Antiepileptic Drug Therapy in Patients with Drug Resistant Epilepsy. J Epilepsy Res 2021; 11:72-82. [PMID: 34395226 PMCID: PMC8357558 DOI: 10.14581/jer.21010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 06/15/2021] [Accepted: 06/18/2021] [Indexed: 12/03/2022] Open
Abstract
Background and Purpose Individualized anti-epileptic drug (AED) selection in patient with epilepsy is crucial. However, there is no unified opinion in treating patients with drug resistant epilepsy (DRE). This survey aimed to make a consolidate consensus with epileptologists’ perspectives of the treatment for Korean DRE patients by survey responses. Methods The survey was conducted with Korean epilepsy experts who have experience prescribing AEDs via e-mail. Survey questionnaires consisted of six items regarding prescription patterns and practical questions in treating patients with DRE in Korea. The research period was from February 2021 to March 2021. Results The survey response rate was 83.3% (90/108). Most (77.8%) of the responders are neurologists. The proportion of patients whose seizures were not controlled by the second AED was 26.9%. The proportion of patients who had taken five or more AEDs is 13.9%, and those who are currently taking five or more AEDs are 7.3%, of which 54.5% and 37.9% reported positive effects on additional AED, respectively. The majority (91.1%) of respondents answered that the mechanism of action was the top priority factor when adding AED. Regarding data priority, responders considered that expert opinion should have the top priority, followed by clinical experiences, reimbursement guidelines and clinical evidence. Responders gave 64.9 points (range from 0 to 100) about overall satisfaction on reimbursement system of Health Insurance Review and Assessment Service for AED. Conclusions This study on AED therapy for DRE patients is the first nationwide trial in Korean epilepsy experts. In five drug failure, the top priorities on AED selection are mechanism of action and expert opinion. These findings might help to achieve consensus and recognize the insight on optimal therapy of AED in DRE.
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Affiliation(s)
- Jun-Sang Sunwoo
- Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea
| | - Hyunjin Jo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Wook Kang
- Department of Neurology, Chonnam National University Hospital, Chonnam National University School of Medicine, Gwangju, Korea
| | - Keun Tae Kim
- , KoreaDepartment of Neurology, Keimyung University School of Medicine, Daegu
| | - Daeyoung Kim
- Department of Neurology, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea
| | - Dong Wook Kim
- Department of Neurology, Konkuk University School of Medicine, Seoul, Korea
| | - Min-Jee Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Saeyoon Kim
- Department of Pediatrics, College of Medicine, Yeungnam University, Daegu, Korea
| | - Woojun Kim
- Department of Neurology, The Catholic University of Korea Seoul St. Mary's Hospital, Seoul, Korea
| | - Hye-Jin Moon
- Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Ha Ree Park
- Department of Neurology, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Jung-Ick Byun
- Department of Neurology, Kyung Hee University Hospital at Gangdong, Seoul, Korea
| | - Jong-Geun Seo
- Department of Neurology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Sung Chul Lim
- Department of Neurology, The Catholic University of Korea St. Vincent's Hospital, Suwon, Korea
| | - Min Kyung Chu
- Department of Neurology, Severance Hospital, Seoul, Korea
| | - Su-Hyun Han
- Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea
| | - Kyoung Jin Hwang
- Department of Neurology, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Dae-Won Seo
- Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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21
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Impact of Stress on Epilepsy: Focus on Neuroinflammation-A Mini Review. Int J Mol Sci 2021; 22:ijms22084061. [PMID: 33920037 PMCID: PMC8071059 DOI: 10.3390/ijms22084061] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 02/08/2023] Open
Abstract
Epilepsy, one of the most common neurological disorders worldwide, is characterized by recurrent seizures and subsequent brain damage. Despite strong evidence supporting a deleterious impact on seizure occurrence and outcome severity, stress is an overlooked component in people with epilepsy. With regard to stressor duration and timing, acute stress can be protective in epileptogenesis, while chronic stress often promotes seizure occurrence in epilepsy patients. Preclinical research suggests that chronic stress promotes neuroinflammation and leads to a depressive state. Depression is the most common psychiatric comorbidity in people with epilepsy, resulting in a poor quality of life. Here, we summarize studies investigating acute and chronic stress as a seizure trigger and an important factor that worsens epilepsy outcomes and psychiatric comorbidities. Mechanistic insight into the impact of stress on epilepsy may create a window of opportunity for future interventions targeting neuroinflammation-related disorders.
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22
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Hossain SF, Huang M, Ono N, Morita A, Kanaya S, Altaf-Ul-Amin M. Development of a biomarker database toward performing disease classification and finding disease interrelations. Database (Oxford) 2021; 2021:baab011. [PMID: 33705530 PMCID: PMC7951048 DOI: 10.1093/database/baab011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/19/2021] [Accepted: 02/25/2021] [Indexed: 12/11/2022]
Abstract
A biomarker is a measurable indicator of a disease or abnormal state of a body that plays an important role in disease diagnosis, prognosis and treatment. The biomarker has become a significant topic due to its versatile usage in the medical field and in rapid detection of the presence or severity of some diseases. The volume of biomarker data is rapidly increasing and the identified data are scattered. To provide comprehensive information, the explosively growing data need to be recorded in a single platform. There is no open-source freely available comprehensive online biomarker database. To fulfill this purpose, we have developed a human biomarker database as part of the KNApSAcK family databases which contain a vast quantity of information on the relationships between biomarkers and diseases. We have classified the diseases into 18 disease classes, mostly according to the National Center for Biotechnology Information definitions. Apart from this database development, we also have performed disease classification by separately using protein and metabolite biomarkers based on the network clustering algorithm DPClusO and hierarchical clustering. Finally, we reached a conclusion about the relationships among the disease classes. The human biomarker database can be accessed online and the inter-disease relationships may be helpful in understanding the molecular mechanisms of diseases. To our knowledge, this is one of the first approaches to classify diseases based on biomarkers. Database URL: http://www.knapsackfamily.com/Biomarker/top.php.
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Affiliation(s)
- Shaikh Farhad Hossain
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
| | - Ming Huang
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
| | - Naoaki Ono
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
| | - Aki Morita
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
| | - Shigehiko Kanaya
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
| | - Md Altaf-Ul-Amin
- Computational Systems Biology Lab, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5, Takayama, Ikoma, Nara 630-0192, Japan
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23
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Mühlebner A, van Scheppingen J, de Neef A, Bongaarts A, Zimmer TS, Mills JD, Jansen FE, Spliet WGM, Krsek P, Zamecnik J, Coras R, Blumcke I, Feucht M, Scholl T, Gruber VE, Hainfellner JA, Söylemezoğlu F, Kotulska K, Lagae L, Jansen AC, Kwiatkowski DJ, Jozwiak S, Curatolo P, Aronica E. Myelin Pathology Beyond White Matter in Tuberous Sclerosis Complex (TSC) Cortical Tubers. J Neuropathol Exp Neurol 2021; 79:1054-1064. [PMID: 32954437 PMCID: PMC7559237 DOI: 10.1093/jnen/nlaa090] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patients are candidates for epilepsy surgery. White matter abnormalities, such as loss of myelin and oligodendroglia, have been described in a small subset of resected tubers but mechanisms underlying this phenomenon are unclear. Herein, we analyzed a variety of neuropathologic and immunohistochemical features in gray and white matter areas of resected cortical tubers from 46 TSC patients using semi-automated quantitative image analysis. We observed divergent amounts of myelin basic protein as well as numbers of oligodendroglia in both gray and white matter when compared with matched controls. Analyses of clinical data indicated that reduced numbers of oligodendroglia were associated with lower numbers on the intelligence quotient scale and that lower amounts of myelin-associated oligodendrocyte basic protein were associated with the presence of autism-spectrum disorder. In conclusion, myelin pathology in cortical tubers extends beyond the white matter and may be linked to cognitive dysfunction in TSC patients.
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Affiliation(s)
- Angelika Mühlebner
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jackelien van Scheppingen
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Andrew de Neef
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Anika Bongaarts
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Till S Zimmer
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - James D Mills
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Floor E Jansen
- Department of Pediatric Neurology, Brain Center University Medical Center
| | - Wim G M Spliet
- Department of Pathology, University Medical Center Utrecht (WGMS) Utrecht, The Netherlands
| | | | | | - Roland Coras
- Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic; Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
| | - Ingmar Blumcke
- Second Faculty of Medicine, Charles University, Motol University Hospital, Prague, Czech Republic; Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany
| | | | | | | | | | - Figen Söylemezoğlu
- Medical University of Vienna, Vienna, Austria; Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Katarzyna Kotulska
- Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Lieven Lagae
- Department of Development and Regeneration-Section Pediatric Neurology, University Hospitals KU Leuven, Leuven
| | - Anna C Jansen
- Pediatric Neurology Unit-UZ Brussel, Brussels Belgium
| | | | - Sergiusz Jozwiak
- Department of Neurology and Epileptology, The Children's Memorial Health Institute.,Department of Child Neurology, Medical University of Warsaw Warsaw, Poland
| | - Paolo Curatolo
- Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy
| | - Eleonora Aronica
- Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, The Netherlands
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24
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Garcia-Rosa S, de Freitas Brenha B, Felipe da Rocha V, Goulart E, Araujo BHS. Personalized Medicine Using Cutting Edge Technologies for Genetic Epilepsies. Curr Neuropharmacol 2021; 19:813-831. [PMID: 32933463 PMCID: PMC8686309 DOI: 10.2174/1570159x18666200915151909] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/08/2020] [Accepted: 08/28/2020] [Indexed: 11/22/2022] Open
Abstract
Epilepsy is the most common chronic neurologic disorder in the world, affecting 1-2% of the population. Besides, 30% of epilepsy patients are drug-resistant. Genomic mutations seem to play a key role in its etiology and knowledge of strong effect mutations in protein structures might improve prediction and the development of efficacious drugs to treat epilepsy. Several genetic association studies have been undertaken to examine the effect of a range of candidate genes for resistance. Although, few studies have explored the effect of the mutations into protein structure and biophysics in the epilepsy field. Much work remains to be done, but the plans made for exciting developments will hold therapeutic potential for patients with drug-resistance. In summary, we provide a critical review of the perspectives for the development of individualized medicine for epilepsy based on genetic polymorphisms/mutations in light of core elements such as transcriptomics, structural biology, disease model, pharmacogenomics and pharmacokinetics in a manner to improve the success of trial designs of antiepileptic drugs.
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Affiliation(s)
- Sheila Garcia-Rosa
- Brazilian Biosciences National Laboratory (LNBio), Center for Research in Energy and Material (CNPEM), Campinas, SP, Brazil
| | - Bianca de Freitas Brenha
- Laboratory of Embryonic Genetic Regulation, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil
| | - Vinicius Felipe da Rocha
- Brazilian Biosciences National Laboratory (LNBio), Center for Research in Energy and Material (CNPEM), Campinas, SP, Brazil
| | - Ernesto Goulart
- Human Genome and Stem-Cell Research Center (HUG-CEL), Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, SP, Brazil
| | - Bruno Henrique Silva Araujo
- Brazilian Biosciences National Laboratory (LNBio), Center for Research in Energy and Material (CNPEM), Campinas, SP, Brazil
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25
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Juvale IIA, Che Has AT. Possible interplay between the theories of pharmacoresistant epilepsy. Eur J Neurosci 2020; 53:1998-2026. [PMID: 33306252 DOI: 10.1111/ejn.15079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/22/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023]
Abstract
Epilepsy is one of the oldest known neurological disorders and is characterized by recurrent seizure activity. It has a high incidence rate, affecting a broad demographic in both developed and developing countries. Comorbid conditions are frequent in patients with epilepsy and have detrimental effects on their quality of life. Current management options for epilepsy include the use of anti-epileptic drugs, surgery, or a ketogenic diet. However, more than 30% of patients diagnosed with epilepsy exhibit drug resistance to anti-epileptic drugs. Further, surgery and ketogenic diets do little to alleviate the symptoms of patients with pharmacoresistant epilepsy. Thus, there is an urgent need to understand the underlying mechanisms of pharmacoresistant epilepsy to design newer and more effective anti-epileptic drugs. Several theories of pharmacoresistant epilepsy have been suggested over the years, the most common being the gene variant hypothesis, network hypothesis, multidrug transporter hypothesis, and target hypothesis. In our review, we discuss the main theories of pharmacoresistant epilepsy and highlight a possible interconnection between their mechanisms that could lead to the development of novel therapies for pharmacoresistant epilepsy.
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Affiliation(s)
- Iman Imtiyaz Ahmed Juvale
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
| | - Ahmad Tarmizi Che Has
- Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia
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26
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Wang C, Zhang J, Song S, Li Z, Yin S, Duan W, Wei Z, Qi M, Sun W, Zhang L, Chen L, Gao X, Mao Y, Wang H, Chen L, Li C. Imaging epileptic foci in mouse models via a low-density lipoprotein receptor-related protein-1 targeting strategy. EBioMedicine 2020; 63:103156. [PMID: 33348091 PMCID: PMC7753923 DOI: 10.1016/j.ebiom.2020.103156] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 10/24/2020] [Accepted: 11/18/2020] [Indexed: 11/27/2022] Open
Abstract
Background In the setting of drug-resistant epilepsy (DRE), the success of surgery depends on the ability to accurately locate the epileptic foci to be resected or disconnected. However, the epileptic foci in a considerable percentage of the DRE patients cannot be adequately localised. This warrants the need for a reliable imaging strategy to identify the “concealed” epileptic regions. Methods Brain specimens from DRE patients and kainate-induced epileptic mouse models were immuno-stained to evaluate the integrity of the blood-brain barrier (BBB). The expression of low-density lipoprotein receptor-related protein-1 (LRP1) in the epileptic region of DRE patients and kainate models was studied by immunofluorescence. A micellar-based LRP1-targeted paramagnetic probe (Gd3+-LP) was developed and its ability to define the epileptic foci was investigated by magnetic resonance imaging (MRI). Findings The integrity of the BBB in the epileptic region of DRE patients and kainate mouse models were demonstrated. LRP1 expression levels in the epileptic foci of DRE patients and kainate models were 1.70–2.38 and 2.32–3.97 folds higher than in the control brain tissues, respectively. In vivo MRI demonstrated that Gd3+-LP offered 1.68 times higher (P < 0.05) T1-weighted intensity enhancement in the ipsilateral hippocampus of chronic kainite models than the control probe without LRP1 specificity. Interpretation The expression of LRP1 is up-regulated in vascular endothelium, activated glia in both DRE patients and kainate models. LRP1-targeted imaging strategy may provide an alternative strategy to define the “concealed” epileptic foci by overcoming the intact BBB. Funding This work was supported by the National Natural Science Foundation, Shanghai Science and Technology Committee, Shanghai Municipal Science and Technology, Shanghai Municipal Health and Family Planning Commission and the National Postdoctoral Program for Innovative Talents.
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Affiliation(s)
- Cong Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, China
| | - Jianping Zhang
- Institute of Modern Physics, Fudan University, Shanghai, China; Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, China; Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Shaoli Song
- Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Zhi Li
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Shujie Yin
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Wenjia Duan
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Zixuan Wei
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Ming Qi
- Department of Nuclear Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Wanbing Sun
- Department of Neurology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Lu Zhang
- Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Luo Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China
| | - Xihui Gao
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ying Mao
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai, China.
| | - Liang Chen
- Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Cong Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.
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27
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Simani L, Sadeghi M, Ryan F, Dehghani M, Niknazar S. Elevated Blood-Based Brain Biomarker Levels in Patients with Epileptic Seizures: A Systematic Review and Meta-analysis. ACS Chem Neurosci 2020; 11:4048-4059. [PMID: 33147022 DOI: 10.1021/acschemneuro.0c00492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Recently, growing attention has been paid to the changes of brain biomarkers following the epilepsy. However, establishing specific epilepsy-related biomarkers has been impeded due to contradictory findings. This study systematically reviewed the evidence on brain biomarkers in epilepsy and determined reliable biomarkers in epileptic patients. A comprehensive systematic search of online databases was performed to find eligible studies up to August 2019. The quality of studies methodologically was assessed using the Newcastle-Ottawa Scale score. Among the several biomarkers, S100 calcium binding protein B (S100B) and neuron specific enolase (NSE) have been qualified for meta-analysis of the association between epilepsy and the brain biomarkers. Inverse-variance weights method was used to calculate pooled standardized mean difference (SMD) estimate with 95% CI, and random effects meta-analysis was conducted taking into account conceptual heterogeneity. Sensitivity analysis and publication bias assessment was performed using Stata. Of 29 studies that were qualified for further analysis, only 22 studies were eligible to quantify by meta-analysis. Significant increase of serum S100B levels (SMD = 0.80; 95% CI 0.18 to 1.42) but not NSE (SMD = 0.45; 95% CI -0.09 to 1.00) has been found in epileptic patients compared with healthy controls. Subgroup meta-analysis by age demonstrated that S100B could be found in pediatric (SMD = 1.15; 95% CI 0.03 to 2.27) not adult patients (SMD = 0.43; 95% CI -0.12 to 0.98). Findings of this meta-analysis indicate that serum level of S100B is significantly increased in epileptic patients, suggesting the elevation and release of the brain biomarkers from brain to blood following epileptic seizures.
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Affiliation(s)
- Leila Simani
- Skull base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Masoumeh Sadeghi
- Department of Epidemiology, Faculty of Health, Mashhad University of Medical Sciences, Mashhad 13131-99137, Iran
| | - Fari Ryan
- Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, 1650 Cedar Ave., Montreal, Quebec H3A 1A1, Canada
| | - Mohsen Dehghani
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran 14496-14535, Iran
| | - Somayeh Niknazar
- Hearing Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
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28
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Salih KS, Hamdan FB, Al-Mayah QS. Diagnostic value of matrix metalloproteinase-2 and high mobility group box 1 in patients with refractory epilepsy. THE EGYPTIAN JOURNAL OF NEUROLOGY, PSYCHIATRY AND NEUROSURGERY 2020. [DOI: 10.1186/s41983-020-00235-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Introduction
There are large numbers of inflammatory molecules and humoral mediators that can be involved in the epileptogenesis such as cytokines, matrix metalloproteinases (MMP), and high mobility group box-1 (HMGB1). We aimed to evaluate serum levels and the diagnostic value of MMP-2 and HMGB1 in Iraqi patients with epilepsy.
Methods
One hundred epileptic patients comprised 60 controlled epileptics and 40 refractory patients to treatment with multi antiepileptic drugs (AEDs). Other 50 family-unrelated age- and sex-matched healthy subjects were selected to represent the control group. Serum levels of MMP-2 and HMGB1 were estimated using ELISA. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of these markers when required.
Results
MMP-2 level was significantly higher in controls than epileptic patients in general (controlled and refractory patients). ROC curve, showed poor diagnostic value of MMP-2 in discriminating epileptics into responsive or refractory to treatment from controls (AUC = 0.679 (95% CI = 0.536-0.823), and AUC = 0.77 (95% CI = 0.637-902), respectively). Serum HMGB1 level in epileptic patients and controls was in close approximation to each other.
Conclusions
MMP-2 is significantly decreased in patients particularly those with refractory epilepsy (RE); however, it has poor diagnostic value. No difference in the serum HMGB1 level between epileptic patients and controls.
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29
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Parvareshi Hamrah M, Rezaei Tavirani M, Movahedi M, Ahmadi Karvigh S. Identification of Serum Biomarkers for Differentiating Epileptic Seizures from Psychogenic Attacks Using a Proteomic Approach; a Comparative study. ARCHIVES OF ACADEMIC EMERGENCY MEDICINE 2020; 8:e87. [PMID: 33244522 PMCID: PMC7682629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Differentiating actual epileptic seizures (ESs) from psychogenic non-epileptic seizures (PNES) is of great interest. This study compares the serum proteomics of patients diagnosed with ESs and PNES. METHODS Eight patients with seizure (4 with PNES and 4 with TLE (temporal lope epilepsy)) were enrolled in this comparative study. Venous blood samples were drawn during the first hour following the seizure. Standard protein purification technique was employed and proteins were subsequently separated via 2-D electrophoresis. After comparison of the serum proteomes from the two groups, protein expression was analyzed. The differentially expressed bands were determined using both matrix-assisted laser ionization time-of-flight (MALDI/TOF) and electrospray ionization quadruple mass spectrometry (MS). RESULTS This study identified 361 proteins, the expression of 110 proteins increased, and 87 proteins decreased in the PNES group compared with TLE group. Four separate proteins were finally identified with MALDI/TOF MS analysis. Compared with PNES group, alpha 1-acid glycoprotein, ceruloplasmin, and S100-β were down-regulated and malate dehydrogenase 2 was up-regulated in the serum of TLE patients. CONCLUSION Our results indicated that changes in serum levels of S100-β, ceruloplasmin, alpha 1-acid glycoprotein 1, and malate dehydrogenase 2 after seizure could be introduced as potential markers to differentiate ES from PNES; however, more advanced studies are required to reach a better understanding of the underlying mechanisms.
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Affiliation(s)
- Mohsen Parvareshi Hamrah
- Department of Biochemistry, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Mostafa Rezaei Tavirani
- Proteomics Research Center, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Corresponding author: Mostafa Rezaei Tavirani; Proteomics Research Center, School of Allied Medical Sciences, Darband Street, Tehran, Iran. , Tel: 00989122650447
| | - Monireh Movahedi
- Department of Biochemistry, Faculty of Biological Science, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Sanaz Ahmadi Karvigh
- Department of Neurology, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
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30
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Alekseeva LA, Zheleznikova GF, Gorelik EY, Sckripchenko NV, Zhirkov AA. Cytokines and neuro-specific proteins in viral encephalitis and convulsive syndrome in children. II. Convulsive syndrome. RUSSIAN JOURNAL OF INFECTION AND IMMUNITY 2020; 11:433-446. [DOI: 10.15789/2220-7619-can-1449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
In this Section we provide new data on the pathogenetic factors in pediatric convulsive syndrome, including a prominent role of viral infection in developing seizures and epilepsy (EPL) in children, as evidenced by clinical and experimental studies. Various forms of convulsive syndrome associated with viral infection include febrile convulsions and febrile epileptic status, encephalitis-related acute symptomatic seizures, and postencephalitic epilepsy. The human herpesvirus-6 isolated in temporal lobe epilepsy is a frequent causative agent of febrile seizures and febrile epileptic status. Febrile seizures and, especially, febrile epileptic status are associated with further developing epilepsy. Of special note is the febrile infection-related epileptic syndrome (FIRES) more often affecting school-aged children and characterized by extremely severe course and unfavorable outcome. Convulsive syndrome is associated with systemic inflammation and overproduced pro-inflammatory cytokines that increase permeability of the blood-brain barrier and functional activity of brain-resident cells, which are involved in eliciting seizures and maintaining epileptogenesis. Taking into consideration the key role of inflammation underlying convulsive syndrome, in recent decades cytokines and chemokines have been widely studied as possible prognostic criteria for epileptogenesis. Neuron-specific proteins are examined as markers of brain cell damage in various inflammatory diseases of the central nervous system. The first Section of the review presented current understanding on systemic and local cytokine/chemokine response in viral encephalitis. Here we present clinical trials published within the last 5—7 years assessing cytokines/chemokines and neuron-specific proteins in children with various forms of convulsive syndrome, including epilepsy. Association between biomarker level and disease clinical parameters as well as potential for their use to diagnose and predict its further course are discussed.
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31
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Brennan GP, Bauer S, Engel T, Jimenez-Mateos EM, Del Gallo F, Hill TDM, Connolly NMC, Costard LS, Neubert V, Salvetti B, Sanz-Rodriguez A, Heiland M, Mamad O, Brindley E, Norwood B, Batool A, Raoof R, El-Naggar H, Reschke CR, Delanty N, Prehn JHM, Fabene P, Mooney C, Rosenow F, Henshall DC. Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy. Neurobiol Dis 2020; 144:105048. [PMID: 32800995 DOI: 10.1016/j.nbd.2020.105048] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/04/2020] [Accepted: 08/08/2020] [Indexed: 12/11/2022] Open
Abstract
Epilepsy diagnosis is complex, requires a team of specialists and relies on in-depth patient and family history, MRI-imaging and EEG monitoring. There is therefore an unmet clinical need for a non-invasive, molecular-based, biomarker to either predict the development of epilepsy or diagnose a patient with epilepsy who may not have had a witnessed seizure. Recent studies have demonstrated a role for microRNAs in the pathogenesis of epilepsy. MicroRNAs are short non-coding RNA molecules which negatively regulate gene expression, exerting profound influence on target pathways and cellular processes. The presence of microRNAs in biofluids, ease of detection, resistance to degradation and functional role in epilepsy render them excellent candidate biomarkers. Here we performed the first multi-model, genome-wide profiling of plasma microRNAs during epileptogenesis and in chronic temporal lobe epilepsy animals. From video-EEG monitored rats and mice we serially sampled blood samples and identified a set of dysregulated microRNAs comprising increased miR-93-5p, miR-142-5p, miR-182-5p, miR-199a-3p and decreased miR-574-3p during one or both phases. Validation studies found miR-93-5p, miR-199a-3p and miR-574-3p were also dysregulated in plasma from patients with intractable temporal lobe epilepsy. Treatment of mice with common anti-epileptic drugs did not alter the expression levels of any of the five miRNAs identified, however administration of an anti-epileptogenic microRNA treatment prevented dysregulation of several of these miRNAs. The miRNAs were detected within the Argonuate2-RISC complex from both neurons and microglia indicating these miRNA biomarker candidates can likely be traced back to specific brain cell types. The current studies identify additional circulating microRNA biomarkers of experimental and human epilepsy which may support diagnosis of temporal lobe epilepsy via a quick, cost-effective rapid molecular-based test.
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Affiliation(s)
- Gary P Brennan
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland; Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland.
| | - Sebastian Bauer
- Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany; Department of Neurology, Phillips University, Marburg, Germany
| | - Tobias Engel
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Eva M Jimenez-Mateos
- Discipline of Physiology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Federico Del Gallo
- Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy
| | - Thomas D M Hill
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Niamh M C Connolly
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Lara S Costard
- Department of Neurology, Phillips University, Marburg, Germany; Department of Regenerative Medicine, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Valentin Neubert
- Department of Neurology, Phillips University, Marburg, Germany; Oscar-Langendorff Institute of Physiology, Rostock University Medical Center, Germany
| | - Beatrice Salvetti
- Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy
| | - Amaya Sanz-Rodriguez
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Mona Heiland
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Omar Mamad
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Elizabeth Brindley
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Braxton Norwood
- Expesicor Inc, Kalispell, MT, USA; FYR Diagnostics, Missoula, MT, USA
| | - Aasia Batool
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Rana Raoof
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Hany El-Naggar
- School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland
| | - Cristina R Reschke
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Norman Delanty
- FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; Department of Neurology, Beaumont Hospital, Dublin, Ireland; Department of Molecular and Cellular Therapeutics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
| | - Paolo Fabene
- Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy
| | - Catherine Mooney
- FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; School of Computer Science, University College Dublin, Ireland
| | - Felix Rosenow
- Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt and Center for Personalized Translational Epilepsy Research (CePTER), Goethe University, Frankfurt, Germany; Department of Neurology, Phillips University, Marburg, Germany
| | - David C Henshall
- Department of Physiology and Medical Physics, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland; FutureNeuro SFI Research Center, Royal College of Surgeons Ireland, Dublin D02 YN77, Ireland
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Interictal scalp fast ripple occurrence and high frequency oscillation slow wave coupling in epileptic spasms. Clin Neurophysiol 2020; 131:1433-1443. [PMID: 32387963 DOI: 10.1016/j.clinph.2020.03.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/27/2020] [Accepted: 03/12/2020] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Intracranial high frequency oscillation (HFO) occurrence rate (OR) and slow wave activity (SWA) coupling are potential markers of epileptogenicity in epileptic spasms (ES). Scalp ripple (R) detection and SWA coupling have been described in ES; however, the feasibility of scalp fast ripple (FR) detection and measurement of scalp FR coupling to SWA is not known. We evaluated interictal scalp R and FR OR and SWA coupling in pre-treatment EEG in children with short-term treatment-refractory ES compared to short-term treatment non-refractory ES. METHODS We retrospectively identified children with ES and identified HFOs using a semi-automated HFO detector on pre-treatment scalp EEG during sleep. We evaluated HFO OR and event-triggered modulation index (MI) to quantify R (100-250 Hz) and FR (250-600 Hz) coupling strength with different SWA passbands (0.5-1, 1-2, 2-3, 3-4, and 4-8 Hz). We used HFO phasor transform and circular statistics to evaluate phase coupling angle distributions. RESULTS We identified 15 children with ES with pre-treatment EEG recorded at 2000 Hz. Thirteen out of 15 patients had HFOs and were included for analysis. There were six treatment responders and seven nonresponders three months after treatment initiation. Responders and nonresponders were similar in age (6.1 vs 7.2 mo), ES diagnosis duration (0.7 vs 2.6 mo), and HFO OR (R: 1.07 vs 2.30/min, FR: 0.43 vs 1.96/min). No differences between responders and nonresponders were seen in HFO MI at different SWA. Coupling of R and FR to 2-3 Hz SWA demonstrated increased incidence rate ratio in nonresponders relative to responders at distinct phase coupling angle distributions. CONCLUSIONS This study demonstrates the feasibility of interictal scalp R and FR detection and quantification of scalp R and FR coupling to SWA in ES. SIGNIFICANCE HFO phase coupling with SWA may be useful as a marker of potential treatment refractoriness in patients with ES.
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Mu RZ, Liu S, Liang KG, Jiang D, Huang YJ. A Meta-Analysis of Neuron-Specific Enolase Levels in Cerebrospinal Fluid and Serum in Children With Epilepsy. Front Mol Neurosci 2020; 13:24. [PMID: 32210762 PMCID: PMC7076182 DOI: 10.3389/fnmol.2020.00024] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/03/2020] [Indexed: 01/29/2023] Open
Abstract
Background: Studies suggest that neuron-specific enolase (NSE) levels in the cerebrospinal fluid (CSF) and serum play an important role in childhood epilepsy. However, these investigations remain controversial due to inconsistent clinical results. The present study aimed to quantitatively summarize and assess whether CSF and serum NSE levels are associated with epilepsy in children. Methods : A systematic search of the Harvard Hollis+, Clinicaltrials, Open Gray, China National Knowledge Infrastructure, and Wanfang databases was performed. Studies investigating NSE and epilepsy were identified and retrieved. Original studies with data overlapping those from other investigations and those lacking the necessary data were excluded. The included studies were extracted and synthesized, and data were analyzed using a random-effects model in R Studio and Comprehensive Meta-Analysis version 3 (Biostat, Englewood, NJ, USA). Results: Random-effects meta-analysis of 26 studies, including 1,360 patients, and 1,256 healthy control, revealed that childhood epilepsy exhibited meaningfully increased CSF and serum levels of NSE compared with controls [Hedges' g = 1.962 (95% confidence interval, 1.413-2.512); P < 0.001]. No single study meaningfully influenced the overall association between CSF and serum levels of NSE and epilepsy after sensitivity analysis. Subgroup analyses according to sample source and assay type revealed a significant association between NSE levels and epilepsy. Stratified analysis confirmed that NSE levels were significantly correlated with the severity of neurological compromise. Metaregression analyses revealed that sample size, mean age, and sex may contribute to effect-size reductions; however, sample source, assay type, and country did not moderate effect size. Funnel plots constructed using the trim-and-fill method confirmed that the outcome of the meta-analysis could not be due to publication bias. Conclusion: The results demonstrated that childhood epilepsy exhibits significantly elevated levels of NSE in the CSF and serum, thus strengthening the association between increased NSE levels and epilepsy.
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Affiliation(s)
- Rong-Zheng Mu
- Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China.,College of Equipment Management and UAV Engineering, Air Force Engineering University, Xi'an, China
| | - Shuang Liu
- Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China
| | - Kai-Ge Liang
- Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China
| | - Dan Jiang
- College of Food Science and Engineering, Dalian Ocean University, Dalian, China
| | - Yao-Jiang Huang
- Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China.,Harvard T.H. Chan School of Public Health, Boston, MA, United States
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Correlation of blood biomarkers with early-onset seizures after an acute stroke event. Epilepsy Behav 2020; 104:106549. [PMID: 31677998 DOI: 10.1016/j.yebeh.2019.106549] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Blood biomarkers have not been widely studied in stroke-related seizures. In this study, we aimed to describe clinical factors and biomarkers present during acute stroke and to analyze their association with early-onset seizures. METHODS We retrospectively evaluated a panel of 14 blood biomarkers in 1115 patients with ischemic and hemorrhagic stroke. Biomarkers were normalized and standardized using Z scores. We also recorded stroke and epilepsy-related variables, including stroke severity (National Institute of Health Stroke Scale [NIHSS] scores), type, and causes, time from onset of stroke to occurrence of early seizures, and type of seizure. Adjusted logistic regression models were built to identify clinical variables and biomarkers independently associated with early seizures. RESULTS Mean ± standard deviation (SD) age was 72.3 ± 13.2 years, and 56.8% of the patients were men. Thirty-eight patients (3.9%) developed early seizures with a median time to onset of 1 day (interquartile range (IQR), 0-4). A higher NIHSS score (odds ratio [OR] = 1.046; 95% confidence interval (CI): 1.001-1.094; p = 0.044) and hemorrhagic stroke (OR = 2.133; 95% CI: 1.010-4.504; p = 0.047) were independently associated with a greater risk of early seizures. Independent blood biomarkers predictive of early seizures were lower levels of tumor necrosis factor receptor 1 (TNF-R1) (<0.013) (p = 0.006; OR = 3.334; 95% CI: 1.414-7.864) and higher levels of neural cell adhesion molecule (NCAM) (>0.326) (p = 0.009; OR = 2.625; 95% CI: 1.271-5.420). The predictive power of the regression model was greater when clinical variables were combined with blood biomarkers (73.5%; 95% CI: 65.1%-81.9%) than when used alone (64%; 95% CI: 55%-72.9%). CONCLUSION Higher NCAM and lower TNF-R1 levels may help predict the occurrence of early seizures. The combined use of these biomarkers and clinical variables could be useful for identifying patients at risk of seizures. This article is part of the Special Issue "Seizures & Stroke".
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Gunawan PI, Saharso D, Sari DP. Correlation of serum S100B levels with brain magnetic resonance imaging abnormalities in children with status epilepticus. KOREAN JOURNAL OF PEDIATRICS 2019; 62:281-285. [PMID: 31096740 PMCID: PMC6642919 DOI: 10.3345/kjp.2018.07017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 05/04/2019] [Accepted: 05/08/2019] [Indexed: 11/27/2022]
Abstract
PURPOSE To evaluate the association between elevated S100B levels with brain tissue damage seen in abnormalities of head magnetic resonance imaging (MRI; diffusion tensor imaging [DTI] sequence) in patients with status epilepticus (SE). METHODS An analytical observational study was conducted in children hospitalized at Dr Soetomo Hospital, Surabaya, from July to December 2016. The patients were divided into 2 groups: SE included all children with a history of SE; control included all children with febrile seizure. Blood samples of patients were drawn within 24 hours after admission. SE patients also underwent cranial MRI with additional DTI sequencing. The Mann-Whitney test and Spearman test were used for statistical analysis. RESULTS Fifty-three patients were enrolled the study. In the 24 children with SE who met the inclusion criteria, serum S100B and cranial MRI findings were assessed. Twenty-two children admitted with febrile seizures became the control group. Most patients were male (66.7%); the mean age was 35.8 months (standard deviation, 31.09). Mean S100B values of the SE group (3.430±0.141 μg/L) and the control group (2.998±0.572 μg/L) were significantly different (P<0.05). A significant difference was noted among each level of encephalopathy based on the cranial MRI results with serum S100B levels and the correlation was strongly positive with a coefficient value of 0.758 (P<0.001). CONCLUSION In SE patients, there is an increase of serum S100B levels within 24 hours after seizure, which has a strong positive correlation with brain damage seen in head MRI and DTI.
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Affiliation(s)
- Prastiya Indra Gunawan
- Division of Neurology, Department Of Child Health, Airlangga University, Soetomo Hospital, Surabaya, Indonesia
| | - Darto Saharso
- Division of Neurology, Department Of Child Health, Airlangga University, Soetomo Hospital, Surabaya, Indonesia
| | - Dian Purnama Sari
- Division of Neurology, Department Of Child Health, Airlangga University, Soetomo Hospital, Surabaya, Indonesia
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Liang KG, Mu RZ, Liu Y, Jiang D, Jia TT, Huang YJ. Increased Serum S100B Levels in Patients With Epilepsy: A Systematic Review and Meta-Analysis Study. Front Neurosci 2019; 13:456. [PMID: 31156363 PMCID: PMC6532535 DOI: 10.3389/fnins.2019.00456] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 04/23/2019] [Indexed: 12/27/2022] Open
Abstract
Importance: Accumulating evidence suggests that serum levels of S100B may play a role in epilepsy. Objective: We performed a meta-analysis to quantitatively summarize the serum S100B data available for patients with epilepsy. Data source: Two independent researchers conducted a systematic investigation of the Harvard Hollis+, Open Gray, Clinicaltrials, Wanfangdata, and CNKI databases through Dec 6, 2018, for all studies published in English and Chinese. The search terms included S100B and calcium-binding protein B in combination with epilepsy. Study selection: Original studies and reported data from these search terms are included. Studies where data overlapped with other studies were excluded. Data extraction and synthesis: investigators extracted, pooled and analyzed data from the included studies using a fixed-effects model in the Comprehensive Meta-Analysis3.3 and R software. Main outcomes and measures: Peripheral blood levels of S100B in patients with epilepsy compared with controls. Aberrations in peripheral blood levels of S100B were hypothesized to be related to epilepsy. Results: a fixed-effects meta-analysis of all 18 studies, including 1,057 unique participants, indicated that patients with epilepsy had significantly increased peripheral blood levels of S100B compared to controls (Hedges g = 1.568, 95% CI =1.431-1.706, P < 0.001). Sensitivity analysis showed that no single study significantly influenced the overall association of peripheral blood levels of S100B and epilepsy. Most of the subgroup analyses, including those of country, assay type and publication language, demonstrated a statistically significant association between peripheral blood levels of S100B and epilepsy. Meta-regression analyses indicated that gender (regression coefficient [SE], -0.2524 [0.0641]; 95%CI, -0.3781 to -0.1267; P = 0.0001) and mean age (regression coefficient [SE], -0.1224 [0.0426]; 95% CI, -0.2058 to -0.0390; P = 0.0040) might present serum S100B reductions, but sample size, years, assay type, publication language and country did not show moderating effects on the effect sizes. Furthermore, the trim-and-fill method used to adjust for funnel plot asymmetry in our meta-analysis confirmed that a positive outcome is unlikely to be due to publication bias. Conclusion and relevance: the results of this meta-analysis provide evidence for a significant increase in serum S100B levels in patients with epilepsy. Serum S100B is the most worthwhile biomarker of epilepsy, which is helpful for the clinical diagnosis and prognosis of epilepsy.
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Affiliation(s)
- Kai-Ge Liang
- College of Life and Environmental Sciences, Minzu University of China, Beijing, China.,Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China
| | - Rong-Zheng Mu
- College of Equipment Management and UAV Engineering, Air Force Engineering University, Xian, China
| | - Yu Liu
- Jarud Banner Agriculture and Animal Husbandry Bureau, Tongliao, China
| | - Dan Jiang
- Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China
| | - Tian-Tian Jia
- College of Life and Environmental Sciences, Minzu University of China, Beijing, China
| | - Yao-Jiang Huang
- College of Life and Environmental Sciences, Minzu University of China, Beijing, China.,Beijing Engineering Research Center of Food Environment and Public Health, Minzu University of China, Beijing, China.,Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, United States
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Vitaliti G, Pavone P, Marino S, Saporito MAN, Corsello G, Falsaperla R. Molecular Mechanism Involved in the Pathogenesis of Early-Onset Epileptic Encephalopathy. Front Mol Neurosci 2019; 12:118. [PMID: 31156384 PMCID: PMC6529508 DOI: 10.3389/fnmol.2019.00118] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Accepted: 04/25/2019] [Indexed: 11/24/2022] Open
Abstract
Recent studies have shown that neurologic inflammation may both precipitate and sustain seizures, suggesting that inflammation may be involved not only in epileptogenesis but also in determining the drug-resistant profile. Extensive literature data during these last years have identified a number of inflammatory markers involved in these processes of “neuroimmunoinflammation” in epilepsy, with key roles for pro-inflammatory cytokines such as: IL-6, IL-17 and IL-17 Receptor (IL-17R) axis, Tumor-Necrosis-Factor Alpha (TNF-α) and Transforming-Growth-Factor Beta (TGF-β), all responsible for the induction of processes of blood-brain barrier (BBB) disruption and inflammation of the Central Nervous System (CNS) itself. Nevertheless, many of these inflammatory biomarkers have also been implicated in the pathophysiologic process of other neurological diseases. Future studies will be needed to identify the disease-specific biomarkers in order to distinguish epilepsies from other neurological diseases, as well as recognize different epileptic semiology. In this context, biological markers of BBB disruption, as well as those reflecting its integrity, can be useful tools to determine the pathological process of a variety of neurological diseases. However; how these molecules may help in the diagnosis and prognostication of epileptic disorders remains yet to be determined. Herein, authors present an extensive literature review on the involvement of both, systemic and neuronal immune systems, in the early onset of epileptic encephalopathy.
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Affiliation(s)
- Giovanna Vitaliti
- Unit of Pediatrics and Pediatric Emergency, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy
| | - Piero Pavone
- Unit of Pediatrics and Pediatric Emergency, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy
| | - Silvia Marino
- Unit of Pediatrics and Pediatric Emergency, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy
| | - Marco Andrea Nicola Saporito
- Neonatal Intensive Care Unit, Santo Bambino Hospital of Catania, Policlinico-Vittorio Emanuele University Hospital, University of Catania, Catania, Italy
| | - Giovanni Corsello
- Department of Maternal and Child Health, University of Palermo, Palermo, Italy
| | - Raffaele Falsaperla
- Unit of Pediatrics and Pediatric Emergency, University Hospital "Policlinico-Vittorio Emanuele", Catania, Italy
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Biosensors for Epilepsy Management: State-of-Art and Future Aspects. SENSORS 2019; 19:s19071525. [PMID: 30925837 PMCID: PMC6480455 DOI: 10.3390/s19071525] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 03/24/2019] [Accepted: 03/25/2019] [Indexed: 12/16/2022]
Abstract
Epilepsy is a serious neurological disorder which affects every aspect of patients’ life, including added socio-economic burden. Unfortunately, only a few suppressive medicines are available, and a complete cure for the disease has not been found yet. Excluding the effectiveness of available therapies, the timely detection and monitoring of epilepsy are of utmost priority for early remediation and prevention. Inability to detect underlying epileptic signatures at early stage causes serious damage to the central nervous system (CNS) and irreversible detrimental variations in the organ system. Therefore, development of a multi-task solving novel smart biosensing systems is urgently required. The present review highlights advancements in state-of-art biosensing technology investigated for epilepsy diseases diagnostics and progression monitoring or both together. State of art epilepsy biosensors are composed of nano-enabled smart sensing platform integrated with micro/electronics and display. These diagnostics systems provide bio-information needed to understand disease progression and therapy optimization timely. The associated challenges related to the development of an efficient epilepsy biosensor and vision considering future prospects are also discussed in this report. This review will serve as a guide platform to scholars for understanding and planning of future research aiming to develop a smart bio-sensing system to detect and monitor epilepsy for point-of-care (PoC) applications.
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Paudel YN, Semple BD, Jones NC, Othman I, Shaikh MF. High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches. J Neurochem 2019; 151:542-557. [DOI: 10.1111/jnc.14663] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Yam Nath Paudel
- Neuropharmacology Research Laboratory Jeffrey Cheah School of Medicine and Health Sciences Monash University Malaysia Bandar Sunway Selangor Malaysia
| | - Bridgette D. Semple
- Department of Neuroscience Central Clinical School Monash University The Alfred Hospital Melbourne Australia
- Department of Medicine (Royal Melbourne Hospital) The University of Melbourne Royal Parade Parkville Victoria Australia
| | - Nigel C. Jones
- Department of Neuroscience Central Clinical School Monash University The Alfred Hospital Melbourne Australia
- Department of Medicine (Royal Melbourne Hospital) The University of Melbourne Royal Parade Parkville Victoria Australia
| | - Iekhsan Othman
- Neuropharmacology Research Laboratory Jeffrey Cheah School of Medicine and Health Sciences Monash University Malaysia Bandar Sunway Selangor Malaysia
| | - Mohd. Farooq Shaikh
- Neuropharmacology Research Laboratory Jeffrey Cheah School of Medicine and Health Sciences Monash University Malaysia Bandar Sunway Selangor Malaysia
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Thom M, Boldrini M, Bundock E, Sheppard MN, Devinsky O. Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking. Neuropathol Appl Neurobiol 2019; 44:32-55. [PMID: 29178443 PMCID: PMC5820128 DOI: 10.1111/nan.12453] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 11/14/2017] [Indexed: 12/14/2022]
Abstract
Awareness and research on epilepsy-related deaths (ERD), in particular Sudden Unexpected Death in Epilepsy (SUDEP), have exponentially increased over the last two decades. Most publications have focused on guidelines that inform clinicians dealing with these deaths, educating patients, potential risk factors and mechanisms. There is a relative paucity of information available for pathologists who conduct these autopsies regarding appropriate post mortem practice and investigations. As we move from recognizing SUDEP as the most common form of ERD toward in-depth investigations into its causes and prevention, health professionals involved with these autopsies and post mortem procedure must remain fully informed. Systematizing a more comprehensive and consistent practice of examining these cases will facilitate (i) more precise determination of cause of death, (ii) identification of SUDEP for improved epidemiological surveillance (the first step for an intervention study), and (iii) biobanking and cell-based research. This article reviews how pathologists and healthcare professionals have approached ERD, current practices, logistical problems and areas to improve and harmonize. The main neuropathology, cardiac and genetic findings in SUDEP are outlined, providing a framework for best practices, integration of clinical, pathological and molecular genetic investigations in SUDEP, and ultimately prevention.
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Affiliation(s)
- M Thom
- Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK
| | - M Boldrini
- Department of Psychiatry, Columbia University Medical Centre, Divisions of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, NY, USA
| | - E Bundock
- Office of the Chief Medical Examiner, Burlington, VT, USA
| | - M N Sheppard
- Department of Pathology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - O Devinsky
- Department of Neurology, NYU Epilepsy Center, New York, NY, USA
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Requena M, Fonseca E, Olivé M, Abraira L, Quintana M, Mazuela G, Toledo M, Salas‐Puig X, Santamarina E. The ADAN scale: a proposed scale for pre‐hospital use to identify status epilepticus. Eur J Neurol 2019; 26:760-e55. [DOI: 10.1111/ene.13885] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Accepted: 12/06/2018] [Indexed: 12/20/2022]
Affiliation(s)
- M. Requena
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - E. Fonseca
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - M. Olivé
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - L. Abraira
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - M. Quintana
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - G. Mazuela
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - M. Toledo
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - X. Salas‐Puig
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
| | - E. Santamarina
- Epilepsy Unit Hospital Universitario Vall d'Hebron Barcelona Spain
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Raoof R, Bauer S, El Naggar H, Connolly NMC, Brennan GP, Brindley E, Hill T, McArdle H, Spain E, Forster RJ, Prehn JHM, Hamer H, Delanty N, Rosenow F, Mooney C, Henshall DC. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine 2018; 38:127-141. [PMID: 30396857 PMCID: PMC6306312 DOI: 10.1016/j.ebiom.2018.10.068] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 10/17/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022] Open
Abstract
Background There are no blood-based molecular biomarkers of temporal lobe epilepsy (TLE) to support clinical diagnosis. MicroRNAs are short noncoding RNAs with strong biomarker potential due to their cell-specific expression, mechanistic links to brain excitability, and stable detection in biofluids. Altered levels of circulating microRNAs have been reported in human epilepsy, but most studies collected samples from one clinical site, used a single profiling platform or conducted minimal validation. Method Using a case-control design, we collected plasma samples from video-electroencephalogram-monitored adult TLE patients at epilepsy specialist centers in two countries, performed genome-wide PCR-based and RNA sequencing during the discovery phase and validated findings in a large (>250) cohort of samples that included patients with psychogenic non-epileptic seizures (PNES). Findings After profiling and validation, we identified miR-27a-3p, miR-328-3p and miR-654-3p with biomarker potential. Plasma levels of these microRNAs were also changed in a mouse model of TLE but were not different to healthy controls in PNES patients. We determined copy number of the three microRNAs in plasma and demonstrate their rapid detection using an electrochemical RNA microfluidic disk as a prototype point-of-care device. Analysis of the microRNAs within the exosome-enriched fraction provided high diagnostic accuracy while Argonaute-bound miR-328-3p selectively increased in patient samples after seizures. In situ hybridization localized miR-27a-3p and miR-328-3p within neurons in human brain and bioinformatics predicted targets linked to growth factor signaling and apoptosis. Interpretation This study demonstrates the biomarker potential of circulating microRNAs for epilepsy diagnosis and mechanistic links to underlying pathomechanisms.
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Affiliation(s)
- Rana Raoof
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland; Department of Anatomy, Mosul Medical College, University of Mosul, Mosul, Iraq
| | - Sebastian Bauer
- Epilepsy Center Hessen, Department of Neurology, Philipps University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhine-Main, Neurocenter, Goethe-University Frankfurt, Frankfurt a.m., Germany; Center for Personalized Translational Epilepsy Research (CePTER), Frankfurt/Main, Germany
| | - Hany El Naggar
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland; Beaumont Hospital, Beaumont Road, Dublin, Ireland
| | | | - Gary P Brennan
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland
| | | | - Thomas Hill
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland
| | - Hazel McArdle
- School of Chemical Sciences, National Centre for Sensor Research, Dublin City University, Dublin, Ireland
| | - Elaine Spain
- School of Chemical Sciences, National Centre for Sensor Research, Dublin City University, Dublin, Ireland
| | - Robert J Forster
- School of Chemical Sciences, National Centre for Sensor Research, Dublin City University, Dublin, Ireland; FutureNeuro Research Centre, RCSI, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland; FutureNeuro Research Centre, RCSI, Dublin, Ireland
| | - Hajo Hamer
- Epilepsy Centre, Department of Neurology, University of Erlangen, Erlangen, Germany
| | - Norman Delanty
- Beaumont Hospital, Beaumont Road, Dublin, Ireland; FutureNeuro Research Centre, RCSI, Dublin, Ireland; Department of Molecular & Cellular Therapeutics, RCSI, Dublin, Ireland
| | - Felix Rosenow
- Epilepsy Center Hessen, Department of Neurology, Philipps University Marburg, Marburg, Germany; Epilepsy Center Frankfurt Rhine-Main, Neurocenter, Goethe-University Frankfurt, Frankfurt a.m., Germany; Center for Personalized Translational Epilepsy Research (CePTER), Frankfurt/Main, Germany
| | - Catherine Mooney
- FutureNeuro Research Centre, RCSI, Dublin, Ireland; School of Computer Science, UCD, Dublin, Ireland
| | - David C Henshall
- Department of Physiology & Medical Physics, RCSI, Dublin, Ireland; FutureNeuro Research Centre, RCSI, Dublin, Ireland.
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Mussulini BHM, Vizuete AFK, Braga M, Moro L, Baggio S, Santos E, Lazzarotto G, Zenki KC, Pettenuzzo L, Rocha JBTD, de Oliveira DL, Calcagnotto ME, Zuanazzi JAS, Burgos JS, Rico EP. Forebrain glutamate uptake and behavioral parameters are altered in adult zebrafish after the induction of Status Epilepticus by kainic acid. Neurotoxicology 2018; 67:305-312. [DOI: 10.1016/j.neuro.2018.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/18/2022]
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Blood-Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit. eNeuro 2018; 5:eN-NWR-0123-18. [PMID: 29854942 PMCID: PMC5975718 DOI: 10.1523/eneuro.0123-18.2018] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 04/01/2018] [Indexed: 01/26/2023] Open
Abstract
Increased permeability of the blood-brain barrier (BBB) following cerebral injury results in regional extravasation of plasma proteins and can critically contribute to the pathogenesis of epilepsy. Here, we comprehensively explore the spatiotemporal evolution of a main extravasation component, albumin, and illuminate associated responses of the neurovascular unit (NVU) contributing to early epileptogenic neuropathology. We applied translational in vivo MR imaging and complementary immunohistochemical analyses in the widely used rat pilocarpine post-status epilepticus (SE) model. The observed rapid BBB leakage affected major epileptogenesis-associated brain regions, peaked between 1 and 2 d post-SE, and rapidly declined thereafter, accompanied by cerebral edema generally following the same time course. At peak of BBB leakage, serum albumin colocalized with NVU constituents, such as vascular components, neurons, and brain immune cells. Surprisingly, astroglial markers did not colocalize with albumin, and aquaporin-4 (AQP4) was clearly reduced in areas of leaky BBB, indicating a severe disturbance of astrocyte-mediated endothelial-neuronal coupling. In addition, a distinct adaptive reorganization process of the NVU vasculature apparently takes place at sites of albumin presence, substantiated by reduced immunoreactivity of endothelial and changes in vascular basement membrane markers. Taken together, degenerative events at the level of the NVU, affecting vessels, astrocytes, and neurons, seem to outweigh reconstructive processes. Considering the rapidly occurring BBB leakage and subsequent impairment of the NVU, our data support the necessity of a prompt BBB-restoring treatment as one component of rational therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of SE.
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Rana A, Musto AE. The role of inflammation in the development of epilepsy. J Neuroinflammation 2018; 15:144. [PMID: 29764485 PMCID: PMC5952578 DOI: 10.1186/s12974-018-1192-7] [Citation(s) in RCA: 432] [Impact Index Per Article: 61.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/06/2018] [Indexed: 12/18/2022] Open
Abstract
Epilepsy, a neurological disease characterized by recurrent seizures, is often associated with a history of previous lesions in the nervous system. Impaired regulation of the activation and resolution of inflammatory cells and molecules in the injured neuronal tissue is a critical factor to the development of epilepsy. However, it is still unclear as to how that unbalanced regulation of inflammation contributes to epilepsy. Therefore, one of the goals in epilepsy research is to identify and elucidate the interconnected inflammatory pathways in systemic and neurological disorders that may further develop epilepsy progression. In this paper, inflammatory molecules, in neurological and systemic disorders (rheumatoid arthritis, Crohn’s, Type I Diabetes, etc.) that could contribute to epilepsy development, are reviewed. Understanding the neurobiology of inflammation in epileptogenesis will contribute to the development of new biomarkers for better screening of patients at risk for epilepsy and new therapeutic targets for both prophylaxis and treatment of epilepsy.
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Affiliation(s)
- Amna Rana
- Department of Pathology and Anatomy, Department of Neurology, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA
| | - Alberto E Musto
- Department of Pathology and Anatomy, Department of Neurology, Eastern Virginia Medical School, 700 W. Olney Road, Lewis Hall, Office 2174, Norfolk, VA, 23507, USA.
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Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. Neuropsychiatr Dis Treat 2018; 14:2989-3000. [PMID: 30510421 PMCID: PMC6231511 DOI: 10.2147/ndt.s125620] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Biomarkers can be broadly defined as qualitative or quantitative measurements that convey information on the physiopathological state of a subject at a certain time point or disease state. Biomarkers can indicate health, pathology, or response to treatment, including unwanted side effects. When used as outcomes in clinical trials, biomarkers act as surrogates or substitutes for clinically meaningful endpoints. Biomarkers of disease can be diagnostic (the identification of the nature and cause of a condition) or prognostic (predicting the likelihood of a person's survival or outcome of a disease). In addition, genetic biomarkers can be used to quantify the risk of developing a certain disease. In the specific case of traumatic brain injury, surrogate blood biomarkers of imaging can improve the standard of care and reduce the costs of diagnosis. In addition, a prognostic role for biomarkers has been suggested in the case of post-traumatic epilepsy. Given the extensive literature on clinical biomarkers, we will focus herein on biomarkers which are present in peripheral body fluids such as saliva and blood. In particular, blood biomarkers, such as glial fibrillary acidic protein and salivary/blood S100B, will be discussed together with the use of nucleic acids (eg, DNA) collected from peripheral cells.
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Affiliation(s)
| | | | | | - Damir Janigro
- FloTBI Inc., Cleveland, OH, USA, .,Department of Physiology, Case Western Reserve University, Cleveland, OH, USA,
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van Dijkman SC, Voskuyl RA, de Lange EC. Biomarkers in epilepsy-A modelling perspective. Eur J Pharm Sci 2017; 109S:S47-S52. [PMID: 28528284 DOI: 10.1016/j.ejps.2017.05.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Accepted: 05/15/2017] [Indexed: 10/19/2022]
Abstract
Biomarkers can be categorised from type 0 (genotype or phenotype), through 6 (clinical scales), each level representing a part of the processes involved in the biological system and drug treatment. This classification facilitates the identification and connection of information required to fully (mathematically) model a disease and its treatment using integrated information from biomarkers. Two recent reviews thoroughly discussed the current status and development of biomarkers for epilepsy, but a path towards the integration of such biomarkers for the personalisation of anti-epileptic drug treatment is lacking. Here we aim to 1) briefly categorise the available epilepsy biomarkers and identify gaps, and 2) provide a modelling perspective on approaches to fill such gaps. There is mainly a lack of biomarker types 2 (target occupancy) and 3 (target activation). Current literature typically focuses on qualitative biomarkers for diagnosis and prediction of treatment response or failure, leaving a need for biomarkers that help to quantitatively understand the overall system to explain and predict differences in disease and treatment outcome. Due to the complexity of epilepsy, filling the biomarker gaps will require collaboration and expertise from the fields of systems biology and systems pharmacology.
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Affiliation(s)
- Sven C van Dijkman
- Division of Pharmacology, Leiden Academic Centre for Drug Research, The Netherlands.
| | - Rob A Voskuyl
- Division of Pharmacology, Leiden Academic Centre for Drug Research, The Netherlands
| | - Elizabeth C de Lange
- Division of Pharmacology, Leiden Academic Centre for Drug Research, The Netherlands
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48
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Rossini L, Garbelli R, Gnatkovsky V, Didato G, Villani F, Spreafico R, Deleo F, Lo Russo G, Tringali G, Gozzo F, Tassi L, de Curtis M. Seizure activity per se does not induce tissue damage markers in human neocortical focal epilepsy. Ann Neurol 2017; 82:331-341. [PMID: 28749594 DOI: 10.1002/ana.25005] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 07/10/2017] [Accepted: 07/17/2017] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The contribution of recurring seizures to the progression of epileptogenesis is debated. Seizure-induced brain damage is not conclusively demonstrated either in humans or in animal models of epilepsy. We evaluated the expression of brain injury biomarkers on postsurgical brain tissue obtained from 20 patients with frequent seizures and a long history of drug-resistant focal epilepsy. METHODS The expression patterns of specific glial, neuronal, and inflammatory molecules were evaluated by immunohistochemistry in the core of type II focal cortical dysplasias (FCD-II), at the FCD boundary (perilesion), and in the adjacent normal-appearing area included in the epileptogenic region. We also analyzed surgical specimens from cryptogenic patients not presenting structural alterations at imaging. RESULTS Astroglial and microglial activation, reduced neuronal density, perivascular CD3-positive T-lymphocyte clustering, and fibrinogen extravasation were demonstrated in the core of FCD-II lesions. No pathological immunoreactivity was observed outside the FCD-II or in cryptogenetic specimens, where the occurrence of interictal and ictal epileptiform activity was confirmed by either stereo-electroencephalography or intraoperative electrocorticography. INTERPRETATION Recurrent seizures do not induce the expression of brain damage markers in nonlesional epileptogenic cortex studied in postsurgical tissue from cryptogenic and FCD patients. This evidence argues against the hypothesis that epileptiform activity per se contributes to focal brain injury, at least in the neocortical epilepsies considered here. Ann Neurol 2017;82:331-341.
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Affiliation(s)
- Laura Rossini
- Epilepsy Unit, C. Besta Neurological Institute Foundation
| | - Rita Garbelli
- Epilepsy Unit, C. Besta Neurological Institute Foundation
| | | | | | - Flavio Villani
- Epilepsy Unit, C. Besta Neurological Institute Foundation
| | | | | | | | - Giovanni Tringali
- Neurosurgery Unit, C. Besta Neurological Institute Foundation, Milan, Italy
| | | | - Laura Tassi
- C. Munari Epilepsy Surgery Center, Niguarda Hospital
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Bauer J, Becker AJ, Elyaman W, Peltola J, Rüegg S, Titulaer MJ, Varley JA, Beghi E. Innate and adaptive immunity in human epilepsies. Epilepsia 2017; 58 Suppl 3:57-68. [PMID: 28675562 PMCID: PMC5535008 DOI: 10.1111/epi.13784] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2017] [Indexed: 01/10/2023]
Abstract
Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medically refractory and, as such, could be used for diagnostic, prognostic, or therapeutic purposes. Establishing an autoimmune basis in patients with drug-resistant epilepsy allows for efficacious and targeted immunotherapy. Although current immunotherapies can give great benefit to the correctly identified patient, there are limitations to their efficacy and they may have considerable side effects. Thus the identification of new immunomodulatory compounds remains of utmost importance.
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Affiliation(s)
- Jan Bauer
- Department of Neuroimmunology, Center for Brain Research Medical University of Vienna, Vienna, Austria
| | - Albert J Becker
- Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn - Medical Center, Bonn, Germany
| | - Wassim Elyaman
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A.,The Broad Institute, Cambridge, Massachusetts, U.S.A
| | - Jukka Peltola
- Department Neurology, Tampere University Hospital, Tampere, Finland
| | - Stephan Rüegg
- Department Neurology, University Hospital Basel, Basel, Switzerland
| | - Maarten J Titulaer
- Department Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - James A Varley
- Nuffield Department Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom
| | - Ettore Beghi
- IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy
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50
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Popova I, Malkov A, Ivanov AI, Samokhina E, Buldakova S, Gubkina O, Osypov A, Muhammadiev RS, Zilberter T, Molchanov M, Paskevich S, Zilberter M, Zilberter Y. Metabolic correction by pyruvate halts acquired epilepsy in multiple rodent models. Neurobiol Dis 2017; 106:244-254. [PMID: 28709994 DOI: 10.1016/j.nbd.2017.07.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 01/22/2023] Open
Abstract
Metabolic intervention strategy of epilepsy treatment has been gaining broader attention due to accumulated evidence that hypometabolism, manifested in humans as reduced brain glucose consumption, is a principal factor in acquired epilepsy. Therefore, targeting deficient energy metabolism may be an effective approach for treating epilepsy. To confront this pathology we utilized pyruvate, which besides being an anaplerotic mitochondrial fuel possesses a unique set of neuroprotective properties as it: (i) is a potent reactive oxygen species scavenger; (ii) abates overactivation of Poly [ADP-ribose] polymerase 1 (PARP-1); (iii) facilitates glutamate efflux from the brain; (iv) augments brain glycogen stores; (v) is anti-inflammatory; (vi) prevents neuronal hyperexcitability; and (vii) normalizes the cytosolic redox state. In vivo, chronic oral pyruvate administration completely abolished established epileptic phenotypes in three accepted and fundamentally different rodent acquired epilepsy models. Our study reports metabolic correction by pyruvate as a potentially highly effective treatment of acquired epilepsies.
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Affiliation(s)
- I Popova
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - A Malkov
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France; Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - A I Ivanov
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France
| | - E Samokhina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - S Buldakova
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France
| | - O Gubkina
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France
| | - A Osypov
- Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia
| | - R S Muhammadiev
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | | | - M Molchanov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - S Paskevich
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - M Zilberter
- Neuronal Oscillations Lab, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Y Zilberter
- Aix Marseille Université, Inserm, INS UMR_S 1106, 13005 Marseille, France.
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