New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

Johannes Boltze¹, Jaroslaw A Aronowski², Jerome Badaut³, Marion S Buckwalter⁴, Mateo Caleo^{5

6}, Michael Chopp^{7

8}, Kunjan R Dave⁹, Nadine Didwischus¹, Rick M Dijkhuizen¹⁰, Thorsten R Doeppner¹¹, Jens P Dreier^{12

13

14

15}, Karim Fouad¹⁶, Mathias Gelderblom¹⁷, Karen Gertz^{12

18}, Dominika Golubczyk¹⁹, Barbara A Gregson²⁰, Edith Hamel²¹, Daniel F Hanley²², Wolfgang Härtig²³, Friedhelm C Hummel^{24

25}, Maulana Ikhsan^{26

27

28}, Miroslaw Janowski²⁹, Jukka Jolkkonen³⁰, Saravanan S Karuppagounder^{31

32}, Richard F Keep³³, Inga K Koerte^{34

35}, Zaal Kokaia³⁶, Peiying Li³⁷, Fudong Liu³⁸, Ignacio Lizasoain³⁹, Peter Ludewig¹⁷, Gerlinde A S Metz⁴⁰, Axel Montagne⁴¹, Andre Obenaus⁴², Alex Palumbo^{26

27

28}, Monica Pearl⁴³, Miguel Perez-Pinzon⁹, Anna M Planas^{44

45}, Nikolaus Plesnila^{46

47

48}, Ami P Raval⁹, Maria A Rueger⁴⁹, Lauren H Sansing⁵⁰, Farida Sohrabji⁵¹, Charlotte J Stagg^{52

53}, R Anne Stetler⁵⁴, Ann M Stowe⁵⁵, Dandan Sun⁵⁶, Akihiko Taguchi⁵⁷, Mickael Tanter⁵⁸, Sabine U Vay⁴⁹, Raghu Vemuganti⁵⁹, Denis Vivien^{60

61}, Piotr Walczak²⁹, Jian Wang⁶², Ye Xiong⁶³, Marietta Zille^{26

27

28}

Affiliations

¹ School of Life Sciences, University of Warwick, Warwick, United Kingdom.
² Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
³ NRS UMR 5287, INCIA, Brain Molecular Imaging Team, University of Bordeaux, Bordeaux cedex, France.
⁴ Departments of Neurology and Neurological Sciences, and Neurosurgery, Wu Tsai Neurosciences Institute, Stanford School of Medicine, Stanford, CA, United States.
⁵ Neuroscience Institute, National Research Council, Pisa, Italy.
⁶ Department of Biomedical Sciences, University of Padua, Padua, Italy.
⁷ Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.
⁸ Department of Physics, Oakland University, Rochester, MI, United States.
⁹ Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
¹⁰ Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.
¹¹ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹² Department of Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹³ Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.
¹⁵ Einstein Center for Neurosciences Berlin, Berlin, Germany.
¹⁶ Faculty of Rehabilitation Medicine and Institute for Neuroscience and Mental Health, University of Alberta, Edmonton, AB, Canada.
¹⁷ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁸ Berlin Institute of Health, Berlin, Germany.
¹⁹ Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.
²⁰ Neurosurgical Trials Group, Institute of Neuroscience, The University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
²¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
²² Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD, United States.
²³ Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
²⁴ Clinical Neuroengineering, Center for Neuroprosthetics and Brain Mind Institute, Swiss Federal Institute of Technology Valais, Clinique Romande de Réadaptation, Sion, Switzerland.
²⁵ Clinical Neuroscience, University of Geneva Medical School, Geneva, Switzerland.
²⁶ Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
²⁷ Fraunhofer Research Institution for Marine Biotechnology and Cell Technology, Lübeck, Germany.
²⁸ Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany.
²⁹ Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States.
³⁰ Department of Neurology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
³¹ Burke Neurological Institute, White Plains, NY, United States.
³² Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.
³³ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States.
³⁴ Psychiatric Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
³⁵ Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Ludwig Maximilians University, Munich, Germany.
³⁶ Lund Stem Cell Center, Lund University, Lund, Sweden.
³⁷ Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³⁸ Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, United States.
³⁹ Unidad de Investigación Neurovascular, Departamento Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.
⁴⁰ Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.
⁴¹ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁴² Department of Pediatrics, University of California, Irvine, Irvine, CA, United States.
⁴³ The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
⁴⁴ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Àrea de Neurociències, Barcelona, Spain.
⁴⁵ Department d'Isquèmia Cerebral I Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
⁴⁶ Institute for Stroke and Dementia Research (ISD), Munich University Hospital, Munich, Germany.
⁴⁷ Graduate School of Systemic Neurosciences (GSN), Munich University Hospital, Munich, Germany.
⁴⁸ Munich Cluster of Systems Neurology (Synergy), Munich, Germany.
⁴⁹ Faculty of Medicine and University Hospital, Department of Neurology, University of Cologne, Cologne, Germany.
⁵⁰ Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.
⁵¹ Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX, United States.
⁵² Nuffield Department of Clinical Neurosciences, Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom.
⁵³ MRC Brain Network Dynamics Unit, University of Oxford, Oxford, United Kingdom.
⁵⁴ Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, United States.
⁵⁵ Department of Neurology and Neurotherapeutics, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, United States.
⁵⁶ Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, PA, United States.
⁵⁷ Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan.
⁵⁸ Institute of Physics for Medicine Paris, INSERM U1273, ESPCI Paris, CNRS FRE 2031, PSL University, Paris, France.
⁵⁹ Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States.
⁶⁰ UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging for Neurological Disorders (PhIND), Normandy University, Caen, France.
⁶¹ CHU Caen, Clinical Research Department, CHU de Caen Côte de Nacre, Caen, France.
⁶² Department of Human Anatomy, College of Medical Sciences, Zhengzhou University, Zhengzhou, China.
⁶³ Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, United States.

PMID: 33584250
PMCID: PMC7876251
DOI: 10.3389/fnagi.2021.623751

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

Johannes Boltze et al. Front Aging Neurosci. 2021.

. 2021 Jan 28:13:623751.

doi: 10.3389/fnagi.2021.623751. eCollection 2021.

Authors

Affiliations

¹ School of Life Sciences, University of Warwick, Warwick, United Kingdom.
² Institute for Stroke and Cerebrovascular Diseases, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States.
³ NRS UMR 5287, INCIA, Brain Molecular Imaging Team, University of Bordeaux, Bordeaux cedex, France.
⁴ Departments of Neurology and Neurological Sciences, and Neurosurgery, Wu Tsai Neurosciences Institute, Stanford School of Medicine, Stanford, CA, United States.
⁵ Neuroscience Institute, National Research Council, Pisa, Italy.
⁶ Department of Biomedical Sciences, University of Padua, Padua, Italy.
⁷ Department of Neurology, Henry Ford Hospital, Detroit, MI, United States.
⁸ Department of Physics, Oakland University, Rochester, MI, United States.
⁹ Peritz Scheinberg Cerebral Vascular Disease Research Laboratory, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
¹⁰ Biomedical MR Imaging and Spectroscopy Group, Center for Image Sciences, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands.
¹¹ Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
¹² Department of Neurology, Center for Stroke Research Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹³ Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
¹⁴ Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany.
¹⁵ Einstein Center for Neurosciences Berlin, Berlin, Germany.
¹⁶ Faculty of Rehabilitation Medicine and Institute for Neuroscience and Mental Health, University of Alberta, Edmonton, AB, Canada.
¹⁷ Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁸ Berlin Institute of Health, Berlin, Germany.
¹⁹ Department of Neurosurgery, School of Medicine, University of Warmia and Mazury, Olsztyn, Poland.
²⁰ Neurosurgical Trials Group, Institute of Neuroscience, The University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom.
²¹ Laboratory of Cerebrovascular Research, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
²² Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD, United States.
²³ Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
²⁴ Clinical Neuroengineering, Center for Neuroprosthetics and Brain Mind Institute, Swiss Federal Institute of Technology Valais, Clinique Romande de Réadaptation, Sion, Switzerland.
²⁵ Clinical Neuroscience, University of Geneva Medical School, Geneva, Switzerland.
²⁶ Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
²⁷ Fraunhofer Research Institution for Marine Biotechnology and Cell Technology, Lübeck, Germany.
²⁸ Institute for Medical and Marine Biotechnology, University of Lübeck, Lübeck, Germany.
²⁹ Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States.
³⁰ Department of Neurology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
³¹ Burke Neurological Institute, White Plains, NY, United States.
³² Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.
³³ Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States.
³⁴ Psychiatric Neuroimaging Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
³⁵ Department of Child and Adolescent Psychiatry, Psychosomatic, and Psychotherapy, Ludwig Maximilians University, Munich, Germany.
³⁶ Lund Stem Cell Center, Lund University, Lund, Sweden.
³⁷ Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³⁸ Department of Neurology, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, United States.
³⁹ Unidad de Investigación Neurovascular, Departamento Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.
⁴⁰ Department of Neuroscience, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, AB, Canada.
⁴¹ Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
⁴² Department of Pediatrics, University of California, Irvine, Irvine, CA, United States.
⁴³ The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
⁴⁴ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Àrea de Neurociències, Barcelona, Spain.
⁴⁵ Department d'Isquèmia Cerebral I Neurodegeneració, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
⁴⁶ Institute for Stroke and Dementia Research (ISD), Munich University Hospital, Munich, Germany.
⁴⁷ Graduate School of Systemic Neurosciences (GSN), Munich University Hospital, Munich, Germany.
⁴⁸ Munich Cluster of Systems Neurology (Synergy), Munich, Germany.
⁴⁹ Faculty of Medicine and University Hospital, Department of Neurology, University of Cologne, Cologne, Germany.
⁵⁰ Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.
⁵¹ Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M College of Medicine, Bryan, TX, United States.
⁵² Nuffield Department of Clinical Neurosciences, Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom.
⁵³ MRC Brain Network Dynamics Unit, University of Oxford, Oxford, United Kingdom.
⁵⁴ Department of Neurology, Pittsburgh Institute of Brain Disorders and Recovery, University of Pittsburgh, Pittsburgh, PA, United States.
⁵⁵ Department of Neurology and Neurotherapeutics, Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, United States.
⁵⁶ Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, PA, United States.
⁵⁷ Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan.
⁵⁸ Institute of Physics for Medicine Paris, INSERM U1273, ESPCI Paris, CNRS FRE 2031, PSL University, Paris, France.
⁵⁹ Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States.
⁶⁰ UNICAEN, INSERM, INSERM UMR-S U1237, Physiopathology and Imaging for Neurological Disorders (PhIND), Normandy University, Caen, France.
⁶¹ CHU Caen, Clinical Research Department, CHU de Caen Côte de Nacre, Caen, France.
⁶² Department of Human Anatomy, College of Medical Sciences, Zhengzhou University, Zhengzhou, China.
⁶³ Department of Neurosurgery, Henry Ford Hospital, Detroit, MI, United States.

PMID: 33584250
PMCID: PMC7876251
DOI: 10.3389/fnagi.2021.623751

Abstract

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.

Keywords: cell therapies; dementia; experimental therapy; hemorrhage; neuroprotection; neurorehabilitation; stroke; translational research.

Copyright © 2021 Boltze, Aronowski, Badaut, Buckwalter, Caleo, Chopp, Dave, Didwischus, Dijkhuizen, Doeppner, Dreier, Fouad, Gelderblom, Gertz, Golubczyk, Gregson, Hamel, Hanley, Härtig, Hummel, Ikhsan, Janowski, Jolkkonen, Karuppagounder, Keep, Koerte, Kokaia, Li, Liu, Lizasoain, Ludewig, Metz, Montagne, Obenaus, Palumbo, Pearl, Perez-Pinzon, Planas, Plesnila, Raval, Rueger, Sansing, Sohrabji, Stagg, Stetler, Stowe, Sun, Taguchi, Tanter, Vay, Vemuganti, Vivien, Walczak, Wang, Xiong and Zille.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AL declared a shared affiliation, though no other collaboration, with several of the authors (IK, NP) to the handling Editor.

Figures

**Figure 1**
Proposed model for a combinatorial therapy in intracerebral hemorrhage (ICH). **(A)** Minimally invasive surgery for the evacuation of the hematoma (primaryintervention). **(B)** Minimally invasive surgery offers the particular opportunity to deliver potential therapeutics (cell transplantation, biomaterials/scaffolds, neuroprotective, and/or immunomodulatorydrugs) as secondary intervention directly into the lesion site, reducing drug delivery issues and potential systemic side effects of the drugs.

**Figure 2**
Intraarterial magnetic resonance imaging (MRI)-guided injection of mesenchymal stem cells into the canine brain. **(A)** Raw T2*w MRI after intraarterial injection of superparamagnetic iron oxide particle-labeled mesenchymal stem cells showing cell accumulation throughout the ipsilateral middle cerebral artery territory. **(B)** Segmentation of hypo-intense pixels and 3D visualization of stem cell biodistribution. Please see the Supplementary Video 1 for a dynamic visualization of stem cell injection.

See this image and copyright information in PMC

References

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New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

Affiliations

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous