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1. Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction

Author

Parker, Ellen, Aboghazleh, Refat, Mumby, Griffin, Veksler, Ronel, Ofer, Jonathan, Newton, Jillian, Smith, Rylan, Kamintsky, Lyna, Jones, Casey MA, O’Keeffe, Eoin, Kelly, Eoin, Doelle, Klara, Roach, Isabelle, Yang, Lynn T, Moradi, Pooyan, Lin, Jessica M, Gleason, Allison J, Atkinson, Christina, Bowen, Chris, Brewer, Kimberly D, Doherty, Colin P, Campbell, Matthew, Clarke, David B, van Hameren, Gerben, Kaufer, Daniela, and Friedman, Alon

Subjects
Brain Disorders, Traumatic Head and Spine Injury, Neurosciences, Physical Injury - Accidents and Adverse Effects, Traumatic Brain Injury (TBI), Aetiology, 2.1 Biological and endogenous factors, Neurological, Animals, Blood-Brain Barrier, Brain, Brain Concussion, Humans, Neuroimaging, Rats, Transforming Growth Factor beta, concussion, repetitive mild traumatic brain injury, blood-brain barrier, dynamic contrast-enhanced MRI, biomarker, blood–brain barrier, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

The mechanisms underlying the complications of mild traumatic brain injury, including post-concussion syndrome, post-impact catastrophic death, and delayed neurodegeneration remain poorly understood. This limited pathophysiological understanding has hindered the development of diagnostic and prognostic biomarkers and has prevented the advancement of treatments for the sequelae of mild traumatic brain injury. We aimed to characterize the early electrophysiological and neurovascular alterations following repetitive mild traumatic brain injury and sought to identify new targets for the diagnosis and treatment of individuals at risk of severe post-impact complications. We combined behavioural, electrophysiological, molecular, and neuroimaging techniques in a rodent model of repetitive mild traumatic brain injury. In humans, we used dynamic contrast-enhanced MRI to quantify blood-brain barrier dysfunction after exposure to sport-related concussive mild traumatic brain injury. Rats could clearly be classified based on their susceptibility to neurological complications, including life-threatening outcomes, following repetitive injury. Susceptible animals showed greater neurological complications and had higher levels of blood-brain barrier dysfunction, transforming growth factor β (TGFβ) signalling, and neuroinflammation compared to resilient animals. Cortical spreading depolarizations were the most common electrophysiological events immediately following mild traumatic brain injury and were associated with longer recovery from impact. Triggering cortical spreading depolarizations in mild traumatic brain injured rats (but not in controls) induced blood-brain barrier dysfunction. Treatment with a selective TGFβ receptor inhibitor prevented blood-brain barrier opening and reduced injury complications. Consistent with the rodent model, blood-brain barrier dysfunction was found in a subset of human athletes following concussive mild traumatic brain injury. We provide evidence that cortical spreading depolarization, blood-brain barrier dysfunction, and pro-inflammatory TGFβ signalling are associated with severe, potentially life-threatening outcomes following repetitive mild traumatic brain injury. Diagnostic-coupled targeting of TGFβ signalling may be a novel strategy in treating mild traumatic brain injury.

Published
2022

2. Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players

Author

Veksler, Ronel, Vazana, Udi, Serlin, Yonatan, Prager, Ofer, Ofer, Jonathan, Shemen, Nofar, Fisher, Andrew M, Minaeva, Olga, Hua, Ning, Saar-Ashkenazy, Rotem, Benou, Itay, Riklin-Raviv, Tammy, Parker, Ellen, Mumby, Griffin, Kamintsky, Lyna, Beyea, Steven, Bowen, Chris V, Shelef, Ilan, O’Keeffe, Eoin, Campbell, Matthew, Kaufer, Daniela, Goldstein, Lee E, and Friedman, Alon

Subjects
Brain Disorders, Traumatic Brain Injury (TBI), Physical Injury - Accidents and Adverse Effects, Neurodegenerative, Acquired Cognitive Impairment, Biomedical Imaging, Traumatic Head and Spine Injury, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Animals, Athletes, Blood-Brain Barrier, Brain, Brain Concussion, Brain Ischemia, Chronic Traumatic Encephalopathy, Diffusion Tensor Imaging, Football, Humans, Magnetic Resonance Imaging, Male, Microvessels, Rats, Rats, Sprague-Dawley, Stroke, Tauopathies, United States, White Matter, tau Proteins, blood-brain barrier, repetitive mild traumatic brain injury, dynamic contrast-enhanced magnetic resonance imaging, American football, transcellular transport, blood–brain barrier, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Repetitive mild traumatic brain injury in American football players has garnered increasing public attention following reports of chronic traumatic encephalopathy, a progressive tauopathy. While the mechanisms underlying repetitive mild traumatic brain injury-induced neurodegeneration are unknown and antemortem diagnostic tests are not available, neuropathology studies suggest a pathogenic role for microvascular injury, specifically blood-brain barrier dysfunction. Thus, our main objective was to demonstrate the effectiveness of a modified dynamic contrast-enhanced MRI approach we have developed to detect impairments in brain microvascular function. To this end, we scanned 42 adult male amateur American football players and a control group comprising 27 athletes practicing a non-contact sport and 26 non-athletes. MRI scans were also performed in 51 patients with brain pathologies involving the blood-brain barrier, namely malignant brain tumours, ischaemic stroke and haemorrhagic traumatic contusion. Based on data from prolonged scans, we generated maps that visualized the permeability value for each brain voxel. Our permeability maps revealed an increase in slow blood-to-brain transport in a subset of amateur American football players, but not in sex- and age-matched controls. The increase in permeability was region specific (white matter, midbrain peduncles, red nucleus, temporal cortex) and correlated with changes in white matter, which were confirmed by diffusion tensor imaging. Additionally, increased permeability persisted for months, as seen in players who were scanned both on- and off-season. Examination of patients with brain pathologies revealed that slow tracer accumulation characterizes areas surrounding the core of injury, which frequently shows fast blood-to-brain transport. Next, we verified our method in two rodent models: rats and mice subjected to repeated mild closed-head impact injury, and rats with vascular injury inflicted by photothrombosis. In both models, slow blood-to-brain transport was observed, which correlated with neuropathological changes. Lastly, computational simulations and direct imaging of the transport of Evans blue-albumin complex in brains of rats subjected to recurrent seizures or focal cerebrovascular injury suggest that increased cellular transport underlies the observed slow blood-to-brain transport. Taken together, our findings suggest dynamic contrast-enhanced-MRI can be used to diagnose specific microvascular pathology after traumatic brain injury and other brain pathologies.

Published
2020

3. Fiber-Flux Diffusion Density for White Matter Tracts Analysis: Application to Mild Anomalies Localization in Contact Sports Players

Author

Benou, Itay, Veksler, Ronel, Friedman, Alon, and Raviv, Tammy Riklin

Subjects
Computer Science - Computer Vision and Pattern Recognition, Quantitative Biology - Quantitative Methods
Abstract

We present the concept of fiber-flux density for locally quantifying white matter (WM) fiber bundles. By combining scalar diffusivity measures (e.g., fractional anisotropy) with fiber-flux measurements, we define new local descriptors called Fiber-Flux Diffusion Density (FFDD) vectors. Applying each descriptor throughout fiber bundles allows along-tract coupling of a specific diffusion measure with geometrical properties, such as fiber orientation and coherence. A key step in the proposed framework is the construction of an FFDD dissimilarity measure for sub-voxel alignment of fiber bundles, based on the fast marching method (FMM). The obtained aligned WM tract-profiles enable meaningful inter-subject comparisons and group-wise statistical analysis. We demonstrate our method using two different datasets of contact sports players. Along-tract pairwise comparison as well as group-wise analysis, with respect to non-player healthy controls, reveal significant and spatially-consistent FFDD anomalies. Comparing our method with along-tract FA analysis shows improved sensitivity to subtle structural anomalies in football players over standard FA measurements.

Published
2017

5. Peripapillary and fovea avascular zone optical coherence tomography angiography parameters in exfoliation glaucoma versus primary open-angle glaucoma versus healthy eyes

Author

Zloto, Ofira, Veksler, Ronel, Moroz, Iris, Goldberg, Hila, and Levkovitch-Verbin, Hani

Subjects
Coherence (Optics) -- Evaluation, Glaucoma -- Diagnosis -- Care and treatment, Angiography -- Evaluation, Health
Abstract

Byline: Ofira. Zloto, Ronel. Veksler, Iris. Moroz, Hila. Goldberg, Hani. Levkovitch-Verbin Purpose: To examine the differences in the peripapillary vascular parameters and foveal-avascular-zone (FAZ) vascularity parameters between primary open-angle-glaucoma (POAG) [...]

Published
2022

7. White‐matter correlates of anxiety: The contribution of the corpus‐callosum to the study of anxiety and stress‐related disorders.

Author

Saar‐Ashkenazy, Rotem, Guez, Jonathan, Jacob, Yael, Veksler, Ronel, Cohen, Jonathan E., Shelef, Ilan, Friedman, Alon, and Benifla, Mony

Subjects
ACUTE stress disorder, POST-traumatic stress disorder, KIRKENDALL effect, STATE-Trait Anxiety Inventory, ANXIETY, MIND-wandering, ANXIETY disorders
Abstract

Objectives: Traumatic stress has been associated with increased risk for brain alterations and development of anxiety disorders. Studies conducted in posttraumatic patients have shown white‐mater volume and diffusion alterations in the corpus‐callosum. Decreased cognitive performance has been demonstrated in acute stress disorder and posttraumatic patients. However, whether cognitive alterations result from stress related neuropathology or reflect a predisposition is not known. In the current study, we examined in healthy controls, whether individual differences in anxiety are associated with those cognitive and brain alterations reported in stress related pathologies. Methods: Twenty healthy volunteers were evaluated for anxiety using the state‐trait inventory (STAI), and were tested for memory performance. Brain imaging was employed to extract volumetric and diffusion characteristics of the corpus‐callosum. Results: Significant correlations were found between trait anxiety and all three diffusion parameters (fractional‐anisotropy, mean and radial‐diffusivity). Associative‐memory performance and corpus‐callosum volume were also significantly correlated. Conclusion: We suggest that cognitive and brain alterations, as tested in the current work and reported in stress related pathologies, are present early and possibly persist throughout life. Our findings support the hypothesis that individual differences in trait anxiety predispose individuals towards negative cognitive outcomes and brain alterations, and potentially to stress related disorders. [ABSTRACT FROM AUTHOR]

Published
2023
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9. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model

Author

Tagge, Chad A, Fisher, Andrew M, Minaeva, Olga V, Gaudreau-Balderrama, Amanda, Moncaster, Juliet A, Zhang, Xiao-Lei, Wojnarowicz, Mark W, Casey, Noel, Lu, Haiyan, Kokiko-Cochran, Olga N, Saman, Sudad, Ericsson, Maria, Onos, Kristen D, Veksler, Ronel, Senatorov, Vladimir V, Jr, Kondo, Asami, Zhou, Xiao Z, Miry, Omid, Vose, Linnea R, Gopaul, Katisha R, Upreti, Chirag, Nowinski, Christopher J, Cantu, Robert C, Alvarez, Victor E, Hildebrandt, Audrey M, Franz, Erich S, Konrad, Janusz, Hamilton, James A, Hua, Ning, Tripodis, Yorghos, Anderson, Andrew T, Howell, Gareth R, Kaufer, Daniela, Hall, Garth F, Lu, Kun P, Ransohoff, Richard M, Cleveland, Robin O, Kowall, Neil W, Stein, Thor D, Lamb, Bruce T, Huber, Bertrand R, Moss, William C, Friedman, Alon, Stanton, Patric K, McKee, Ann C, and Goldstein, Lee E

Published
2018
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10. Abstract 3401: Whole genome cell-free tumor DNA mutational signatures for noninvasive monitoring of pediatric brain cancers

Author

Tran, Ivy, primary, Galbraith, Kristyn, additional, Zhao, Guisheng, additional, Borsuk, Robyn, additional, Varkey, Joyce, additional, Gardner, Sharon, additional, Allen, Jeffrey, additional, Harter, David, additional, Wisoff, Jeffrey, additional, Hidalgo, Eveline T., additional, Deochand, Sunil, additional, Maloney, Dillon, additional, Afterman, Danielle, additional, Lauterman, Tomer, additional, Friedman, Noah, additional, Bourzgui, Imane, additional, Ramaraj, Nidhi, additional, Donenhirsh, Zohar, additional, Veksler, Ronel, additional, Rosenfeld, Jonathan, additional, Kandasamy, Ravi, additional, Tavassoly, Iman, additional, Oklander, Boris, additional, Raju, G. Praveen, additional, Nicolaides, Theodore, additional, Zviran, Asaf, additional, and Snuderl, Matija, additional

Published
2022
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11. Abstract 1959: Sensitive detection of circulating tumor DNA by whole genome sequencing: Validation of MRDetect using serial blood samples from stage III colorectal cancer patients

Author

Frydendahl, Amanda, primary, Reinert, Thomas, additional, Nors, Jesper, additional, Deochand, Sunil, additional, Maloney, Dillon, additional, Friedman, Noah, additional, Lauterman, Tomer, additional, Afterman, Danielle, additional, Bourzgui, Imane, additional, Ramaraj, Nidhi, additional, Donenhirsh, Zohar, additional, Veksler, Ronel, additional, Kandasamy, Ravi, additional, Tavassoly, Iman, additional, Rosenfeld, Jonathan, additional, Andersen, Anders Husted, additional, Løve, Uffe S., additional, Andersen, Per V., additional, Thorlacius-Ussing, Ole, additional, Iversen, Lene Hjerrild, additional, Gotschalck, Kåre Andersson, additional, Oklander, Boris, additional, Zviran, Asaf, additional, and Andersen, Claus Lindbjerg, additional

Published
2022
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12. Abstract 5114: Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC)

Author

Tan, Aaron C., primary, Saw, Stephanie P., additional, Lai, Gillianne G., additional, Chua, Kevin L., additional, Takano, Angela, additional, Ong, Boon-Hean, additional, Koh, Tina P., additional, Jain, Amit, additional, Tan, Wan Ling, additional, Ng, Quan Sing, additional, Kanesvaran, Ravindran, additional, Rajasekaran, Tanujaa, additional, Deochand, Sunil, additional, Maloney, Dillon, additional, Afterman, Danielle, additional, Lauterman, Tomer, additional, Friedman, Noah, additional, Bourzgui, Imane, additional, Ramaraj, Nidhi, additional, Donenhirsh, Zohar, additional, Veksler, Ronel, additional, Rosenfeld, Jonathan, additional, Kandasamy, Ravi, additional, Tavassoly, Iman, additional, Oklander, Boris, additional, Zviran, Asaf, additional, Lim, Wan-Teck, additional, Tan, Eng-Huat, additional, Skanderup, Anders J., additional, Ang, Mei-Kim, additional, and Tan, Daniel S., additional

Published
2022
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13. Abstract 540: Genome-wide circulating tumor DNA for monitoring treatment response and metastatic relapse in bladder cancer

Author

Nordentoft, Iver, primary, Birkenkamp-Demtröder, Karin, additional, Christensen, Emil, additional, Deochand, Sunil, additional, Maloney, Dillon, additional, Afterman, Danielle, additional, Lauterman, Tomer, additional, Friedman, Noah, additional, Bourzgui, Imane, additional, Ramaraj, Nidhi, additional, Donenhirsh, Zohar, additional, Veksler, Ronel, additional, Viborg, Sia, additional, Agerbæk, Mads, additional, Jensen, Jørgen Bjerggaard, additional, Rosenfeld, Jonathan, additional, Kandasamy, Ravi, additional, Tavassoly, Iman, additional, Oklander, Boris, additional, Zviran, Asaf, additional, and Dyrskjøt, Lars, additional

Published
2022
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14. Concussion susceptibility is mediated by spreading depolarization-induced neurovascular dysfunction

Author

Parker, Ellen, primary, Aboghazleh, Refat, additional, Mumby, Griffin, additional, Veksler, Ronel, additional, Ofer, Jonathan, additional, Newton, Jillian, additional, Smith, Rylan, additional, Kamintsky, Lyna, additional, Jones, Casey M A, additional, O’Keeffe, Eoin, additional, Kelly, Eoin, additional, Doelle, Klara, additional, Roach, Isabelle, additional, Yang, Lynn T, additional, Moradi, Pooyan, additional, Lin, Jessica M, additional, Gleason, Allison J, additional, Atkinson, Christina, additional, Bowen, Chris, additional, Brewer, Kimberly D, additional, Doherty, Colin P, additional, Campbell, Matthew, additional, Clarke, David B, additional, van Hameren, Gerben, additional, Kaufer, Daniela, additional, and Friedman, Alon, additional

Published
2021
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15. “Anterior Chamber Depth After Phacovitrectomy” – Response to Letter to the Editor [Response to Letter]

Author

Katz,Gabriel, Zahalka,Fidaa, Veksler,Ronel, Ayalon,Anfisa, and Moisseiev,Elad

Subjects
Clinical Ophthalmology
Abstract

Gabriel Katz,1,2 Fidaa el Zhalka,3 Ronel Veksler,1 Anfisa Ayalon,3 Elad Moisseiev2,3 1Department of Ophthalmology, Sheba Medical Center, Ramat Gan, Israel; 2Sackler School of Medicine, TelAviv University, TelAviv, Israel; 3Department of Ophthalmology, Meir Medical Center, Kfar Saba, IsraelCorrespondence: Elad MoisseievDepartment of Ophthalmology, Meir Medical Center, 59 Tshernichovsky St, Kfar Saba 4428164, IsraelEmail elad_moi@netvision.net.il View the original paper by Dr Katz and colleagues This is in response to the Letter to the Editor

Published
2021

16. The Role of Anterior Chamber Depth on Post-operative Refractive Error After Phacovitrectomy

Author

Katz,Gabriel, el Zhalka,Fidaa, Veksler,Ronel, Ayalon,Anfisa, Moisseiev,Elad, Katz,Gabriel, el Zhalka,Fidaa, Veksler,Ronel, Ayalon,Anfisa, and Moisseiev,Elad

Abstract

Gabriel Katz, 1, 2,* Fidaa el Zhalka, 3,* Ronel Veksler, 1 Anfisa Ayalon, 3 Elad Moisseiev 2, 3 1Department of Ophthalmology, Sheba Medical Center, Ramat Gan, Israel; 2Sackler School of Medicine, TelAviv University, TelAviv, Israel; 3Department of Ophthalmology, Meir Medical Center, Kfar Saba, Israel*These authors contributed equally to this workCorrespondence: Elad MoisseievDepartment of Ophthalmology, Meir Medical Center, 59 Tshernichovsky St., Kfar Saba, 4428164, IsraelTel +97297471527Fax +97297472427Email elad_moi@netvision.net.ilPurpose: To investigate the effect of phacovitrectomy on the post-operative anterior chamber depth (ACD) and refractive outcomes, and to analyze the potential differences between vitreous filling with BSS, air and gas.Methods: Patients who underwent phacovitrectomy were included in this study and invited for repeated post-operative examination including refraction and biometry at least 3 months after the surgery. Data retrieved included demographic information, indication for phacovitrectomy, surgical details, type of vitreous filling (BSS, air or gas), pre-operative and post-operative biometric data including K-readings, axial length (AL), and ACD, as well as spherical equivalent (SE) values of the target and final refraction.Results: Forty-three eyes of 43 patients were included in this study, including 10 eyes filled with BSS, 18 with air and 15 with gas. The mean difference between the final measured spherical equivalent (SE) and the SE of the intended target refraction was 0.61± 0.68 D (p = 0.019). Only 58.1% of eyes had a final SE within ± 0.5D of the target refraction. Following surgery, AL remained unchanged, while mean pre-operative ACD increased significantly from 3.11± 0.34 mm to 4.77± 0.47 mm (p < 0.001). There was no difference in refractive error between the vitreous fillings and no correlation with AL or ACD.Conclusions: Phacovitrectomy is associated with lower accuracy o

Published
2021

18. Dynamic Blood–Brain Barrier Regulation in Mild Traumatic Brain Injury

Author

O'Keeffe, Eoin, primary, Kelly, Eoin, additional, Liu, Yuzhe, additional, Giordano, Chiara, additional, Wallace, Eugene, additional, Hynes, Mark, additional, Tiernan, Stephen, additional, Meagher, Aidan, additional, Greene, Chris, additional, Hughes, Stephanie, additional, Burke, Tom, additional, Kealy, John, additional, Doyle, Niamh, additional, Hay, Alison, additional, Farrell, Michael, additional, Grant, Gerald A., additional, Friedman, Alon, additional, Veksler, Ronel, additional, Molloy, Michael G., additional, Meaney, James F., additional, Pender, Niall, additional, Camarillo, David, additional, Doherty, Colin P., additional, and Campbell, Matthew, additional

Published
2020
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19. Quantitative imaging assessment of blood-brain barrier permeability in humans

Author

Chassidim Yoash, Veksler Ronel, Lublinsky Svetlana, Pell Gaby S, Friedman Alon, and Shelef Ilan

Subjects
Blood–brain barrier, Magnetic resonance imaging, Permeability, Brain insult, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The blood–brain barrier (BBB) is a functional and structural barrier separating the intravascular and neuropil compartments of the brain. It characterizes the vascular bed and is essential for normal brain functions. Dysfunction in the BBB properties have been described in most common neurological disorders, such as stroke, traumatic injuries, intracerebral hemorrhage, tumors, epilepsy and neurodegenerative disorders. It is now obvious that the BBB plays an important role in normal brain activity, stressing the need for applicable imaging and assessment methods. Recent advancements in imaging techniques now make it possible to establish sensitive and quantitative methods for the assessment of BBB permeability. However, most of the existing techniques require complicated and demanding dynamic scanning protocols that are impractical and cannot be fulfilled in some cases. We review existing methods for the evaluation of BBB permeability, focusing on quantitative magnetic resonance-based approaches and discuss their drawbacks and limitations. In light of those limitations we propose two new approaches for BBB assessment with less demanding imaging sequences: the “post-pre” and the “linear dynamic” methods, both allow semi-quantitative permeability assessment and localization of dysfunctional BBB with simple/partial dynamic imaging protocols and easy-to-apply analysis algorithms. We present preliminary results and show an example which compares these new methods with the existing standard assessment method. We strongly believe that the establishment of such “easy to use” and reliable imaging methods is essential before BBB assessment can become a routine clinical tool. Large clinical trials are awaited to fully understand the significance of BBB permeability as a biomarker and target for treatment in neurological disorders.

Published
2013
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21. Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

Author

Małecki, Andrzej, primary, Skipor-Lahuta, Janina, additional, Toborek, Michal, additional, Abbott, N. Joan, additional, Antonetti, David A., additional, Su, Enming Joe, additional, Lawrence, Daniel A., additional, Atış, Müge, additional, Akcan, Uğur, additional, Yılmaz, Canan Uğur, additional, Orhan, Nurcan, additional, Düzgün, Poyraz, additional, Ceylan, Umut Deniz, additional, Arıcan, Nadir, additional, Karahüseyinoğlu, Serçin, additional, Şahin, Gizem Nur, additional, Ahıshalı, Bülent, additional, Kaya, Mehmet, additional, Aydin, Sidar, additional, Klopstein, Armelle, additional, Engelhardt, Britta, additional, Baumann, Julia, additional, Tsao, Chih-Chieh, additional, Huang, Sheng-Fu, additional, Ogunshola, Omolara, additional, Boytsova, Elizaveta B., additional, Morgun, Andrey V., additional, Khilazheva, Elena D., additional, Pozhilenkova, Elena A., additional, Gorina, Yana V., additional, Martynova, Galina P., additional, Salmina, Alla B., additional, Bueno, David, additional, Garcia-Fernàndez, Jordi, additional, Castro, Victor, additional, Skowronska, Marta, additional, Chupel, Matheus Uba, additional, Minuzzi, Luciele Guerra, additional, Filaire, Edith, additional, Teixeira, Ana Maria, additional, Corsi, Mariangela, additional, Versele, Romain, additional, Fuso, Andrea, additional, Sevin, Emmanuel, additional, Di Lorenzo, Cherubino, additional, Businaro, Rita, additional, Fenart, Laurence, additional, Gosselet, Fabien, additional, Candela, Pietra, additional, Deli, Mária A., additional, Delaney, Conor, additional, O’Keefe, Eoin, additional, Farrell, Michael, additional, Doyle, Sarah, additional, Campbell, Matthew, additional, Drewes, Lester R., additional, Appelt-Menzel, A., additional, Cubukova, A., additional, Metzger, M., additional, Fischer, R., additional, Francisco, David M. F., additional, Bruggmann, Rémy, additional, Fries, Alexa, additional, Blecharz, Kinga G., additional, Wagner, Josephin, additional, Winkler, Lars, additional, Schneider, Ulf, additional, Vajkoczy, Peter, additional, Furuse, Mikio, additional, Gabbert, Lydia, additional, Dilling, Christina, additional, Sisario, Dmitri, additional, Soukhoroukov, Vladimir, additional, Burek, Malgorzata, additional, Guérit, S., additional, Fidan, E., additional, Devraj, K., additional, Czupalla, C. J., additional, Macas, J., additional, Thom, S., additional, Plate, K. H., additional, Gerhardt, H., additional, Liebner, S., additional, Harazin, András, additional, Bocsik, Alexandra, additional, Váradi, Judit, additional, Fenyvesi, Ferenc, additional, Tubak, Vilmos, additional, Vecsernyés, Miklós, additional, Helms, Hans Christian, additional, Waagepetersen, Helle Sønderby, additional, Nielsen, Carsten Uhd, additional, Brodin, Birger, additional, Hoyk, Zsófia, additional, Tóth, Melinda E., additional, Lénárt, Nikolett, additional, Dukay, Brigitta, additional, Kittel, Ágnes, additional, Vígh, Judit, additional, Veszelka, Szilvia, additional, Walter, Fruzsina, additional, Zvara, Ágnes, additional, Puskás, László, additional, Sántha, Miklós, additional, Engelhardt, Sabrina, additional, Ogunshola, Omolara O., additional, Huber, Anna, additional, Reitner, Alexander, additional, Osmen, Samar, additional, Hahn, Kathrin, additional, Bounzina, Neli, additional, Gerhartl, Anna, additional, Schönegger, Anna, additional, Steinkellner, Hannes, additional, Laccone, Franco, additional, Neuhaus, Winfried, additional, Hudson, Natalie, additional, Celkova, Lucia, additional, Iltzsche, Anne, additional, Drndarski, Svetlana, additional, Begley, David J, additional, Janiurek, Mette Mathiesen, additional, Kucharz, Krzysztof, additional, Christoffersen, Christina, additional, Nielsen, Lars Bo, additional, Lauritzen, Martin, additional, Johnson, Rebecca H, additional, Kho, Dan T, additional, O’Carroll, Simon J, additional, Angel, Catherine E, additional, Graham, E. Scott, additional, Pereira, Jennifer, additional, Karali, Christina Simoglou, additional, Cheng, Vinton, additional, Zarghami, Niloufar, additional, Soto, Manuel Sarmiento, additional, Couch, Yvonne, additional, Anthony, Daniel C., additional, Sibson, Nicola R., additional, Kealy, John, additional, Keep, Richard F., additional, Routhe, Lisa J., additional, Xiang, Jianming, additional, Ye, Hong, additional, Hua, Ya, additional, Moos, Torben, additional, Xi, Guohua, additional, Kristensen, M., additional, Bach, A., additional, Strømgaard, K., additional, Kutuzov, Nikolay, additional, Lopes-Pinheiro, Melissa A., additional, Lim, Jamie, additional, Kamermans, Alwin, additional, van Horssen, Jack, additional, Unger, Wendy W.J., additional, Fontijn, Ruud, additional, de Vries, Helga E., additional, Majerova, Petra, additional, Garruto, Ralph M., additional, Marchetti, Luca, additional, Francisco, David, additional, Gruber, Isabelle, additional, Lyck, Ruth, additional, Mészáros, Mária, additional, Porkoláb, Gergő, additional, Kiss, Lóránd, additional, Pilbat, Ana-Maria, additional, Török, Zsolt, additional, Bozsó, Zsolt, additional, Fülöp, Lívia, additional, Michalicova, Alena, additional, Galba, Jaroslav, additional, Mihaljevic, Sandra, additional, Novak, Michal, additional, Kovac, Andrej, additional, Morofuji, Yoichi, additional, Fujimoto, Takashi, additional, Watanabe, Daisuke, additional, Nakagawa, Shinsuke, additional, Ujifuku, Kenta, additional, Horie, Nobutaka, additional, Izumo, Tsuyoshi, additional, Anda, Takeo, additional, Matsuo, Takayuki, additional, Niu, Fang, additional, Buch, Shilpa, additional, Nyúl-Tóth, Ádám, additional, Kozma, Mihály, additional, Nagyőszi, Péter, additional, Nagy, Krisztina, additional, Fazakas, Csilla, additional, Haskó, János, additional, Molnár, Kinga, additional, Farkas, Attila E., additional, Galajda, Péter, additional, Wilhelm, Imola, additional, Krizbai, István A., additional, Kelly, Eoin, additional, Wallace, Eugene, additional, Greene, Chris, additional, Hughes, Stephanie, additional, Doyle, Niamh, additional, Humphries, Marian M., additional, Grant, Gerald A., additional, Friedman, Alon, additional, Veksler, Ronel, additional, Molloy, Michael G., additional, Meaney, James F., additional, Pender, Niall, additional, Doherty, Colin P., additional, Park, Minseon, additional, Liskiewicz, Arkadiusz, additional, Przybyla, Marta, additional, Kasprowska-Liśkiewicz, Daniela, additional, Nowacka-Chmielewska, Marta, additional, Malecki, Andrzej, additional, Pombero, Ana, additional, Garcia-Lopez, Raquel, additional, Martinez-Morga, Marta, additional, Martinez, Salvador, additional, Prager, Ofer, additional, Solomon-Kamintsky, Lyna, additional, Schoknecht, Karl, additional, Bar-Klein, Guy, additional, Milikovsky, Dan, additional, Vazana, Udi, additional, Rosenbach, Dror, additional, Kovács, Richard, additional, Radak, Zsolt, additional, Rodríguez-Lorenzo, Sabela, additional, Bruggmann, Remy, additional, Kooij, Gijs, additional, de Vries, Helga E, additional, Oxana, Semyachkina-Glushkovskaya, additional, Denis, Bragin, additional, Elena, Vodovozova, additional, Anna, Alekseeva, additional, Alla, Salmina, additional, Vladimir, Salmin, additional, Andrey, Morgun, additional, Nataliya, Malinovskaya, additional, Elena, Khilazheva, additional, Elizaveta, Boytsova, additional, Alexander, Shirokov, additional, Nikita, Navolokin, additional, Alla, Bucharskaya, additional, Yirong, Yang, additional, Arkady, Abdurashitov, additional, Artem, Gekalyuk, additional, Mariya, Ulanova, additional, Anastasia, Shushunova, additional, Madina, Bodrova, additional, Artem, Sagatova, additional, Alexander, Khorovodov, additional, Esmat, Shareef Ali, additional, Valery, Pavlov, additional, Artem, Tuchin, additional, Jürgen, Kurths, additional, de Abreu, Marcelle Silva, additional, Calpena, Ana C., additional, Espina, Marta, additional, García, Maria Luisa, additional, Romero, Ignacio A., additional, Male, David, additional, Storck, Steffen, additional, Hartz, Anika, additional, Pahnke, Jens, additional, Surma, Claus U., additional, Surma, M., additional, Giżejewski, Z., additional, Zieliński, H., additional, Szczepkowska, Aleksandra, additional, Kowalewska, Marta, additional, Krawczynska, Agata, additional, Herman, Andrzej P., additional, Skipor, Janina, additional, Kachappilly, Nicole, additional, Veenstra, Mike, additional, Rivera, Rosiris Leon, additional, Williams, Dionna W., additional, Morgello, Susan, additional, Berman, Joan W., additional, Wyneken, Ursula, additional, Batiz, Luis Federico, additional, Temizyürek, Arzu, additional, Khodadust, Rouhollah, additional, Küçük, Mutlu, additional, Gürses, Candan, additional, Emik, Serkan, additional, Zielińska, Magdalena, additional, Obara-Michlewska, Marta, additional, Milewski, Krzysztof, additional, Skonieczna, Edyta, additional, Fręśko, Inez, additional, Neuwelt, Edward A., additional, Maria, Ana Raquel Santa, additional, Bras, Ana Rita, additional, Lipka, Dóra, additional, Valkai, Sándor, additional, Kincses, András, additional, Dér, András, additional, and Deli, Maria A., additional

Published
2017
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22. Imaging blood–brain barrier dysfunction as a biomarker for epileptogenesis

Author

Bar-Klein, Guy, primary, Lublinsky, Svetlana, additional, Kamintsky, Lyn, additional, Noyman, Iris, additional, Veksler, Ronel, additional, Dalipaj, Hotjensa, additional, Senatorov, Vladimir V., additional, Swissa, Evyatar, additional, Rosenbach, Dror, additional, Elazary, Netta, additional, Milikovsky, Dan Z., additional, Milk, Nadav, additional, Kassirer, Michael, additional, Rosman, Yossi, additional, Serlin, Yonatan, additional, Eisenkraft, Arik, additional, Chassidim, Yoash, additional, Parmet, Yisrael, additional, Kaufer, Daniela, additional, and Friedman, Alon, additional

Published
2017
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23. Autosomal dominant epilepsy with auditory features : a new LGI1 family including a phenocopy with cortical dysplasia

Author

Klein, Karl Martin, Pendziwiat, Manuela, Cohen, Rony, Appenzeller, Silke, de Kovel, Carolien G.F., Rosenow, Felix, Koeleman, Bobby P.C., Kuhlenbäumer, Gregor, Sheintuch, Liron, Veksler, Ronel, Friedman, Alon, Afawi, Zaid, Helbig, Ingo, Klein, Karl Martin, Pendziwiat, Manuela, Cohen, Rony, Appenzeller, Silke, de Kovel, Carolien G.F., Rosenow, Felix, Koeleman, Bobby P.C., Kuhlenbäumer, Gregor, Sheintuch, Liron, Veksler, Ronel, Friedman, Alon, Afawi, Zaid, and Helbig, Ingo

Published
2016

24. Autosomal dominant epilepsy with auditory features: a new LGI1 family including a phenocopy with cortical dysplasia

Author

Groep Rabouille, UMC Utrecht, Genetica Groep Koeleman, Child Health, Circulatory Health, Brain, Klein, Karl Martin, Pendziwiat, Manuela, Cohen, Rony, Appenzeller, Silke, de Kovel, Carolien G.F., Rosenow, Felix, Koeleman, Bobby P.C., Kuhlenbäumer, Gregor, Sheintuch, Liron, Veksler, Ronel, Friedman, Alon, Afawi, Zaid, Helbig, Ingo, Groep Rabouille, UMC Utrecht, Genetica Groep Koeleman, Child Health, Circulatory Health, Brain, Klein, Karl Martin, Pendziwiat, Manuela, Cohen, Rony, Appenzeller, Silke, de Kovel, Carolien G.F., Rosenow, Felix, Koeleman, Bobby P.C., Kuhlenbäumer, Gregor, Sheintuch, Liron, Veksler, Ronel, Friedman, Alon, Afawi, Zaid, and Helbig, Ingo

Published
2016

26. Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

Author

Vazana, Udi, Veksler, Ronel, Pell, Gaby S., Prager, Ofer, Fassler, Michael, Chassidim, Yoash, Roth, Yiftach, Shahar, Hamutal, Zangen, Abraham, Raccah, Ruggero, Onesti, Emanuela, Ceccanti, Marco, Colonnese, Claudio, Santoro, Antonio, Salvati, Maurizio, D'Elia, Alessandro, Nucciarelli, Valter, Inghilleri, Maurizio, and Friedman, Alon

Subjects
*BLOOD-brain barrier disorders, *DRUG delivery systems, *GLUTAMIC acid, *METHYL aspartate receptors, *MAGNETIC resonance imaging of the brain, *TRANSCRANIAL magnetic stimulation, *DISEASE risk factors
Abstract

The blood- brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo. Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood- brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood- brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. [ABSTRACT FROM AUTHOR]

Published
2016
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27. Neurite orientation dispersion and density imaging reveals abnormal white matter and glymphatic function in active young boxers.

Author

Huang, Wenjing, Ma, Laiyang, Yan, Jiahao, Hu, Wanjun, Liu, Guangyao, Wang, Rui, and Zhang, Jing

Subjects
BRAIN concussion diagnosis, BOXING, BOXING injuries, LYMPHATICS, T-test (Statistics), DATA analysis, RESEARCH funding, NEURONS, MAGNETIC resonance imaging, DESCRIPTIVE statistics, QUANTITATIVE research, WHITE matter (Nerve tissue), STATISTICS, COMPARATIVE studies, COGNITION, ADULTS
Abstract

The neurological effects and underlying pathophysiological mechanisms of sports‐related concussion (SRC) in active young boxers remain poorly understood. This study aims to investigate the impairment of white matter microstructure and assess changes in glymphatic function following SRC by utilizing neurite orientation dispersion and density imaging (NODDI) on young boxers who have sustained SRC. A total of 60 young participants were recruited, including 30 boxers diagnosed with SRC and 30 healthy individuals engaging in regular exercise. The assessment of whole‐brain white matter damage was conducted using diffusion metrics, while the evaluation of glymphatic function was performed through diffusion tensor imaging (DTI) analysis along the perivascular space (DTI‐ALPS) index. A two‐sample t‐test was utilized to examine group differences in DTI and NODDI metrics. Spearman correlation and generalized linear mixed models were employed to investigate the relationship between clinical assessments of SRC and NODDI measurements. Significant alterations were observed in DTI and NODDI metrics among young boxers with SRC. Additionally, the DTI‐ALPS index in the SRC group exhibited a significantly higher value than that of the control group (left side: 1.58 vs. 1.48, PFDR = 0.009; right side: 1.61 vs. 1.51, PFDR = 0.02). Moreover, it was observed that the DTI‐ALPS index correlated with poorer cognitive test results among boxers in this study population. Repetitive SRC in active young boxers is associated with diffuse white matter injury and glymphatic dysfunction, highlighting the detrimental impact on brain health. These findings highlight the importance of long‐term monitoring of the neurological health of boxers. Highlights: Boxing is a contact sport involving direct physical impact, leading to the occurrence of repeated concussions and sub‐concussions among boxers throughout their careers; however, the routine detection of brain tissue lesions through CT and MRI remains a challenging task.Advanced magnetic resonance diffusion imaging diffusion MRI is performed on young active boxers to assess the extent of white matter damage and glymphatic function.The brains of active young boxers have extensive white matter microstructure damage and glymphatic dysfunction, which is associated with poorer cognitive performance. [ABSTRACT FROM AUTHOR]

Published
2024
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28. Pharmacological inhibition of HDAC6 reverses cognitive impairment and tau pathology as a result of cisplatin treatment.

Author

Ma, Jiacheng, Huo, XiaoJiao, Jarpe, Matthew B., Kavelaars, Annemieke, and Heijnen, Cobi J.

Subjects
HISTONE deacetylase inhibitors, MILD cognitive impairment, CISPLATIN
Abstract

Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control. [ABSTRACT FROM AUTHOR]

Published
2018
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