Abstract
9
Role of insulin signaling in the brain metabolism
1Lund University, Lund, Sweden
2Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
3Queen’s University, Kingston, Canada
4Sapienza University of Rome, Rome, Italy
5University of Washington, Seattle, USA
Abstract
Brain insulin signaling acts as a key regulator for gene expression and cellular metabolism, both events sustaining neuronal activity and synaptic plasticity mechanisms. The actions of insulin in the brains of healthy individuals include central modulation of body metabolism and enhancement or regulation of memory and learning functions. Moreover, brain insulin controls oxidative metabolism via mitochondrial dynamics, thus protecting neurons against oxidative damage. Alterations of brain insulin signaling are associated with a higher risk to develop age-related cognitive decline and neurodegenerative diseases. The aim of this symposium is to discuss recent evidence about the crosstalk between insulin signaling and energy homeostasis and how their fluctuations impact on neurodegenerative processes. We will first provide an overview of the impact of insulin resistance on brain function and metabolism in neurons and astrocytes (
Presenter #1: João MN Duarte
Title of the talk: Impact of insulin resistance on brain metabolism and function
Presenter #2: Fernanda G De Felice
Title of the talk: Metabolic disorders and their link to Alzheimer’s disease and neurodegeneration
Presenter #3: Eugenio Barone
Title of the talk: Role of early alterations of brain insulin signaling in neurodegenerative processes
Presenter #4: Elizabeth Rhea
Title of the talk: Transport of insulin across the blood-brain barrier
10
The brain endothelial glycocalyx in health and disease
1University of Washington, Seattle, USA
2Gifu University, Gifu, Japan
3University of Colorado, Aurora, USA
4University of Copenhagen, Copenhagen, Denmark
Abstract
Presenter #1: Aric, Logsdon
Title of the talk: Introduction to the brain endothelial glycocalyx
Presenter #2: Hideshi
Title of the talk: Ultrastructure of the brain capillary endothelial glycocalyx
Presenter #3: Joseph Hippensteel
Title of the talk: Pathologic effects of systemic endothelial glycocalyx degradation on the brain
Presenter #4: Martin Lauritzen
Title of the talk: Intravital imaging of the brain endothelial glycocalyx compartment
11
Brain hemorrhage: Beyond the neuron
1University of Vienna, Vienna, Austria
2University of Texas John P and Katherine G McGovern Medical School, Department of Neurology, Houston, USA
3Munich University Medical Center, Department of Neurosurgery, Germany
4University of Florida, Center for Translational Research in Neurodegenerative Disease, Gainesville, USA
Abstract
Hemorrhagic stroke remains a major cause of mortality and permanent disability. Targeting primary injury by removing the hematoma has been of limited success and a complete evacuation of the hematoma is unlikely to be achieved in every patient. It is clear that clot-derived factors such as hemoglobin and heme are major contributors to secondary tissue damage. Recently, the mechanisms underlying neuronal cell death exposed to blood breakdown products have been described in detail. However, it is unlikely that targeting neurons alone will suffice to successfully treat hemorrhagic stroke patients. Hence, elucidating the pathophysiological mechanisms in other brain cells and their potential to contribute to reducing brain damage will be crucial for the development of novel combinatorial therapeutic approaches.
In this symposium, we aim to present novel insights on the role of non-neuronal cells in brain hemorrhage. This will include evidence for a differential vulnerability of different brain cells to blood breakdown products and how non-neuronal cells contribute to the pathophysiology of brain hemorrhage. We will discuss among others mitochondrial transfer between astrocytes and microglia, as well as the role of brain endothelial cells and the cerebral microcirculation. Furthermore, we will address how our knowledge on the regulation of hemoglobin and heme translates to the clinic.
Presenter #1: Marietta Zille
Title of the talk: Differential vulnerability of neurons, axons and endothelial cells to blood breakdown products
Presenter #2: Jaroslaw (Jarek)
Title of the talk: How astrocytic mitochondria could contribute to reducing ICH-mediated damage
Presenter #3: Nicole A. Terpolilli,
Title of the talk: Posthemorrhagic changes in the cerebral microcirculation after subarachnoid hemorrhage
Presenter #4: Sylvain Doré
Title of the talk: Role of haptoglobin from preclinical research to the clinic
19
Cerebral blood flow imaging in the era of PET/MRI and machine learning
1Department of Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark
2University of Stanford, Stanford, USA
3Department of Radiology, Washington University in St. Louis, St. Louis, USA
4Department of Medical Imaging, Taipei Medical University, Taipei, Taiwan
5Department of Biomedical Engineering, University of California Riverside, Riverside, USA
Abstract
Despite the recognized value of cerebral blood flow (CBF) imaging to identify brain ischemia in cerebrovascular patients, perfusion quantification remains challenging in clinical settings. Non-invasive approaches such as arterial spin labeling MRI lack validation with a reference standard such as PET, especially in patients with abnormal, long arterial transit times that create image artifacts.
Simultaneous PET/MRI enables an ideal validation of CBF measures from the two modalities by observing the same brain perfusion state, particularly when a vascular “stress test” is applied to evaluate cerebrovascular reactivity. The first half of the symposium describes direct regional CBF comparisons between PET and arterial spin labeling MRI, and how this validation informs optimal CBF acquisition in patients. Hybrid perfusion biomarkers from PET/MRI and image-derived input functions can minimize the invasiveness of PET scans, and also facilitate quantification of brain oxygen metabolism in neurovascular patients.
Beyond validation, PET/MRI offers rich physiological and anatomical datasets that are well-suited for machine learning enhancement of CBF. Cutting-edge deep learning models have leveraged the simultaneous PET and MRI training pairs to learn to synthesize PET-like, “gold standard” CBF maps from non-invasive, MRI-only inputs. Multi-modal information from baseline scans can also be integrated by deep learning networks to predict cerebrovascular reactivity without administration of drugs or gases. Once trained, these networks have broad applications for accurate CBF imaging even in sites with only MRI.
The combination of PET/MRI perfusion scans and advanced machine learning thus provide powerful tools to improve CBF imaging for researchers and clinicians.
Presenter #1: Otto Henriksen, M.D. Ph.D.
Title of the talk: Multi-modal imaging overview and validation of cerebral blood flow
Presenter #2: Hongyu An, Ph.D.
Title of the talk: PET/MRI for non-invasive perfusion mapping and beyond
Presenter #3: Jia Guo, Ph.D.
Title of the talk: Reduction of radiation dose for PET perfusion imaging
Presenter #4: David Chen, M.D.
Title of the talk: Predicting cerebrovascular reactivity without a stress test using deep learning
27
Modelling co-morbidities in preclinical stroke models
1University of Manchester, Manchester, UK
2Autónoma University of Madrid, Madrid, Spain
3University of Pittsburgh School of Medicine, Pittsburgh, USA
4Medical University of South Carolina, Charleston, USA
Abstract
While not exclusively a disease of the elderly, the risk of stroke increases significantly with age. Many people who have a stroke also have one or more comorbidities that can independently increase stroke risk. In addition to this increased risk of stroke, advanced age and comorbidities such as hypertension and diabetes can affect stroke progression, leading to worse outcome and/or modify the response to treatment. Despite this, the majority of preclinical studies to date continue to be performed in young and therefore ‘healthy’ non-comorbid animals. Failure of preclinical studies to consider fully the advanced age and comorbidities present in most stroke patients has been proposed to contribute to the poor translation of many drugs to the clinic. Even though more than 10 years since the 2009 STAIR criteria recommended inclusion of animals with comorbid conditions, there is limited evidence this is being adhered to. This symposium will address this issue and consider how pre-existing comorbidities (infection, hypertension, diabetes, aging) affect stroke, and highlight the importance of including these clinically-relevant comorbidities in future preclinical research. The symposium brings together established and early career researchers and should have broad appeal to the stroke research community.
Presenter #1: Kieron South
Title of the talk: Subclinical S. pneumoniae infection and risk of stroke in healthy young adults
Presenter #2: Maria Gutierrez-Fernández
Title of the talk: Cell therapy in preclinical models of stroke in hypertensive rats
Presenter #3: Jun Chen
Title of the talk: The effect of aging on recovery after stroke
Presenter #4: Adviye Ergul
Title of the talk: Of Rats to WoMen: Impact of Diabetes on Acute Ischemic Stroke Injury and Recovery
30
Pericytes in disease
1School of Psychology, University of Sussex, Brighton, UK
2Seattle Children’s Research Institute, Seattle, Sweden
3Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
4IGP, Uppsala University, Uppsala, Sweden
Abstract
In this symposium, we will explore the spectrum of ways in which pericyte function contributes to neuropathological disease processes, from setting the physiological environment upon which disease acts, to mediating the effects of normal ageing, before considering pericytes’ roles in neurological and infectious disease.
Beginning with Catherine Hall (University of Sussex), we will consider how regional differences in pericytes across the normally-functioning brain may set the sensitivity of a given brain region to subsequent damage. Andy Shih (Seattle Children’s Research Institute) will then discuss how pericyte plasticity is affected by normal ageing, driving changes in capillary blood flow. Next, Nils Korte, (ECI from David Attwell’s lab at UCL), will demonstrate the mechanisms by which pericytes are constricted during cerebral ischaemia and Alzheimer’s disease, leading to neurological impairment. Finally, Maarja Mäe, (ECI from Christer Betsholtz’s lab at Uppsala University), will show how pericyte damage alters cerebrovascular function via the release of procoagulants from endothelial cells, and how pericytes might be the prime target for infection by SARS CoV-2.
Together, this series of talks present complementary mechanisms covering the effects of increasingly pathological conditions on different aspects of pericyte function: morphology, plasticity, regulation of vascular tone and modulation of endothelial cell function. We hope this symposium will generate rich discussions concerning the different ways in which these functions of pericytes can be affected by disease and themselves modulate how disease progresses and neuronal function.
CHAIR: Dr Clare Howarth
Presenter #1: Catherine Hall
Title of the talk: Introduction AND Do regional differences in brain pericytes shape sensitivity to disease?
Presenter #2: Andy Shih
Title of the talk: Structural plasticity of pericytes and its effect on capillary flow in the aged brain.
Presenter #3: Nils Korte
Title of the talk: Pericyte-mediated capillary constriction driven by TMEM16A chloride and L-type calcium channels impairs cerebral blood flow in stroke and Alzheimer’s disease
Presenter #4: Maarja Mäe
Title of the talk: Pericytes – orchestrators of endothelial proinflammatory and procoagulant responses and putative targets of SARS-CoV-2 infection
31
Gut-brain axis in aging and neurodegeneration
1University of Kentucky, Lexington, USA
2Buck Institute for Research on Aging, Novato, USA
3Wake Forest School of Medicine, Winston-Salem, USA
4Klinikum der Universität München, Munich, Germany
Abstract
Multiple emerging evidence indicating that the central nervous system (brain) and the enteric nervous system (gut) communicate bi-directionally in a complex manner to shape brain vasculature, metabolism and cognitive function. Developing data further provide evidence that nutrition can affect intestinal microbiome and brain structure and function. This can happen by multiple mechanisms such as metabolite and/or immune connections between gut and brain. In this symposium, we will discuss how this bi-directional communication might be altered and/or disrupted in aging, stroke and Alzheimer’s disease, and how interventions such as ketogenic diet may reverse the course. We will present the findings from pre-clinical and clinical research using cutting-edge neuroimaging, metagenomic sequencing, inflammatory profiling, metabolomics and machine learning methods. We believe the topic will be of great interest to a broad audience of the Brain & Brain PET 2021 conference.
Presenter #1: Ai-Ling Lin
Title of the talk: Neuroimaging and gut microbiome in aging, dementia and stroke (including introduction/overview of the symposium)
Presenter #2: John Newman
Title of the talk: Ketone bodies and gut-brain axis in brain aging
Presenter #3: Hariom Yadav
Title of the talk: Ketogenic diet, gut microbiome and and Alzheimer’s disease: a mini clinical trial
Presenter #4: Corinne Benakis
Title of the talk: Elucidating the gut-brain axis in post-stroke recovery
33
Neuronal–immune system cross-talk after brain injury
1Weill Cornell Medicine, White Plains, USA
2McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA
3Shanghai Jiao Tong University, Shanghai, China
4Adelaide Medical School, the University of Adelaide, Adelaide, Australia
Abstract
Functional interactions between the neuronal and immune systems have been reported in health and disease. Neurons can trigger molecular cascades that lead to the activation of innate and adaptive immune cells, influencing immunity to infection, chronic inflammation, and restoration of tissue homeostasis. Currently, many groups are working on identifying pathways that operate in the other direction, whereby immune cells modulate neuronal activity or neurovascular function.
In this symposium, we will have four speakers to present their work in neuronal-immune interaction in the context of brain injury. Dr. Sunghee Cho from the Burke Neurological Institute at Weill Cornell Medicine will present her work on temporal changes of immune genes and trafficking of peripheral immune cells at acute and recovery phases of stroke. Dr. Anjali Chauhan from University of Texas will present her work on the role of T cells and pro-inflammatory factors on histologic and functional outcomes in an aged mouse model. Dr. Yongting Wang from Shanghai Jiao Tong University will present her team’s recent work probing the role of C3-C3aR pathway after cerebral ischemia. Last but not least, Dr. Renée Turner from University of Adelaide will discuss the role of neurogenic inflammation in blood-brain barrier disruption and development of cerebral oedema following acute CNS injury. We believe that this symposium will provide the attendees an opportunity to discuss the crucial hypothesis to examine in order to further our understanding of neuronal–immune cell interactions after brain injury.
Presenter #1: Dr. Sunghee Cho
Title of the talk: Sustained neuro-immune interactions across multiple phases of cerebral ischemia
Presenter #2: Dr. Anjali Chauhan
Title of the talk: B and T lymphocytes in aging and stroke
Presenter #3: Dr. Yongting
Title of the talk: The role of C3-C3aR pathway after cerebral ischemia
Presenter #4: Dr. Renée Turner
Title of the talk:Targeting neurogenic inflammation in acute CNS injury
36
The extracellular fluids of the brain
1University of Copenhagen, Copenhagen, Denmark
2University College London, London, UK
3University of Edinburgh, Edinburgh, UK
4Amsterdam University Medical Center, Amsterdam, the Netherlands
Abstract
The extracellular fluids of the brain include interstitial fluid and cerebrospinal fluid (CSF). Both fluids are important in maintaining cellular homeostasis as carriers for nutrients, signaling molecules, ions, and waste removal. In this symposium, we would like to address the formation, exchange, and pathological changes associated with the extracellular fluids in disease. Herein, perivascular spaces may play an important role. Flow along perivascular spaces, and its mechanisms of propulsion, remain a controversial topic. In the first talk, we will discuss the origin of brain extracellular fluids, and how this differs with the rest of the body. Second, we would like to present novel data regarding the non-invasive quantitation of CSF formation, which is mainly attributed to the choroid plexus. Third, we would like to discuss the role of perivascular spaces, as these facilitate interaction of CSF with interstitial fluid. Lastly, we would like to illustrate the impact of hypertension on cerebral fluid management, which is associated with disruption of interstitial fluid balance, enlargement of the CSF compartment, and impaired perivascular flow.
Presenter #1: Nanna MacAulay
Title of the talk: Water transport in the brain – not quite like other tissues?
Presenter #2: Jack Wells
Title of the talk: Non-invasive MRI of Blood-Cerebrospinal Fluid Barrier Function
Presenter #3: Angela Jochems
Title of the talk: Perivascular spaces: Insights from human MRI
Presenter #4: Erik N.T.P. Bakker
Title of the talk: Impact of hypertension on cerebral fluid management
38
The unique and varied roles of glycogen in brain
1University of California San Francisco, San Francisco, USA
2San Francisco Veterans Affairs Health Care System, San Francisco, USA
3Hacettepe University, Ankara, Turkey
4University of Lausanne, Lausanne, Switzerland
5King Abdullah University of Science and Technology, Thuwal, Saudi Arabia
6IQS Barcelona – Ramon Llull University, Barcelona, Spain
7IBEC Barcelona, Barcelona, Spain
Abstract
Glycogen in the liver serves as a systemic store of glucose, but brain glycogen does not have this function. Moreover, brain glycogen is localized primarily to astrocytes, despite the high energy demand of neurons. What then, is the function of brain glycogen? The answers to this question continue to unfold and identify interactions between different cell types in brain, along with novel links between brain energy metabolism and function. Pierre Magistretti, a leader in this field since its inception, will introduce the topic and salient aspects of its history. He will then present new findings pertaining to astrocyte glycogen dynamics in cognitive function, synaptic plasticity, and sleep. Muge Yemisci will describe a newly identified interaction between astrocytes and pericytes by which astrocyte glycogen metabolism influences microvascular patency in normal and ischemic brain. In addition to astrocytes, neurons also contain some glycogen along with the full complement of glycogen metabolizing enzymes. Jordi Duran will present the specific roles of glial vs. neuronal glycogen metabolism as identified in mice with cell-type specific disruption of glycogen synthase. A question central to each of these speakers’ topics is why glycogen is utilized at all in brain, given that glucose is normally present in excess. To address this question, Raymond Swanson will present a thermodynamic mechanism by which metabolism of glycogen serves to ensure a maximal energy yield from ATP at sites of rapid ATP consumption. This function of glycogen may be particularly important in very small confines such as distal astrocyte and neuronal processes.
Presenter #1: Pierre J. Magistretti
Title of the talk: Astrocyte glycogen dynamics in learning and synaptic plasticity
Presenter #2: Muge Yemisci
Title of the talk: Roles of perivascular glial glycogen in brain microcirculation
Presenter #3: Jordi Duran
Title of the talk: Cell-type specific roles of glycogen in astrocytes and neurons
Presenter #4: Raymond Swanson
Title of the talk: The thermodynamic function of glycogen in brain
39
How to image the brain better: Reflections on progress in brain PET tracers, targets and validation
1King’s College London, London, UK
2University of Oxford, Oxford, UK
3Karolinska Institutet, Stockholm, Sweden
Abstract
PET imaging has already benefited the field of neuroscience significantly, and continues to advance through development of many “second generation” tracers – probes targeting inflammation, synapses, protein synthesis and aggregation, myelination, neurotransmitter activity, oxygenation, metabolism etc. However, while some of these approaches have been undoubtfully successful in revealing pathologies or generating new hypotheses, some have failed to deliver the expected results, or the results were met with controversies. During this symposium we aim to evaluate the current state of play, reflect on previous experience and examine in more detail the processes needed to identify suitable targets as well as to match tracers to biomarkers of interest. With this in mind we will explore several areas of clinical importance where brain PET imaging is already firmly established: neuroinflammation, neurotransmitters, enzymatic fluxes and pathological protein aggregations.
After a short overview, we will examine how despite the proliferation of tracers, we are still seeking more specific and precise methods to measure neuroinflammation in vivo. We will explore the need to better understand nuances and complexities of neurotransmitters glutamate and GABA in order to replicate the accomplishment of PET imaging of dopamine. Given the success of PET in measuring brain metabolism via glycolysis & 18FDG, we will argue for the importance of employing a similar strategy to other enzymatic systems as novel biomarkers. Finally, we will summarize recent efforts toward developing and improving methods to detect aggregates of proteins such as tau and α-synuclein, as critically important targets in the battle against neurodegeneration.
Presenter #1: Diana Cash
Title of the talk: Tracing neuroinflammation and synapses
Presenter #2: Nisha Singh
Title of the talk: Tracing neurotransmitters
Presenter #3: Federico Turkheimer
Title of the talk: Tracing enzymatic fluxes
Presenter #4: Agneta Nordberg
Title of the talk: Tracing protein aggregates
54
Relationships between synaptic dysfunction, neuronal injury and tau PET in the course of Alzheimer’s disease
1University of Gothenburg, Gothenburg, Sweden
2Yale School of Medicine, New Haven, USA
3Massachusetts General Hospital, Martinos Center for Biomedical Imaging, Boston, USA
4Karolinska Institutet, Stockholm, Sweden
Abstract
Presenter #1: Joana B. Pereira
Title of the talk: Introduction to the Symposium, and “Untangling the roles of amyloid and tau in synaptic and axonal loss in the course of Alzheimer’s disease”
Presenter #2: Adam P. Mecca
Title of the talk: "Relationships between synaptic density, tau deposition, and cognition in Alzheimer’s disease"
Presenter #3: Elena Rodriguez-Vieitez
Title of the talk: "The relationship between cortical microstructural changes and in vivo amyloid, tau and cognitive decline in aging and preclinical Alzheimer’s disease"
Presenter #4: Nicholas Ashton
Title of the talk: "Plasma phospho-tau in Alzheimer disease: what is the relationship with amyloid PET, tau PET and post-mortem neuropathology”
55
Progress in tau PET imaging
1Mcgill University, Montreal, Canada
2University of Fukui, Fukui, Japan
3Harvard University, Boston, USA
4Pittsburg University, Pittsburg, USA
5Lawrence Berkeley National Lab, Berkeley, USA
6Melbourne University, Melbourne, Australia
Abstract
Provide a biological interpretation of the PET outcome measures of tau imaging agents Identify the stages of Alzheimer’s disease revealed by tau PET Understand how to quantify the effects of protein aggregation as drivers of disease progression using PET Identify differences and similarities between tau imaging agents
Presenter #1: Price, Julie
Title of the talk: The State of the art and challenges in the quantification of tau imaging
Presenter #2:Pascoal, Tharick
Title of the talk: Staging Symptomatic and asymptomatic Alzheimer’s disease with tau imaging.
Presenter #3: Baker, Suzanne
Title of the talk: Quantifying disease progression using tau PET
Presenter #4: Villemagne, Victor
Title of the talk: How to harmonize PET outcome measures across tau imaging agents?
56
Cognitive declines in perioperative patients – Multidisciplinary advances and perspectives
1Clinical Research Center, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
2Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine
3PET Center, Department of Nuclear Medicine Huashan Hospital Shanghai Medical College, Fudan University, Shanghai, China
4Department of Anesthesiology and Perioperative Medicine Xijing Hospital, Fourth Military Medical University Xian, Xian, China
Abstract
Recent findings highlight the significance of perioperative cognitive dysfunction. Considering the devastating long-term consequence of cognitive dysfunction, in-depth mechanism study and translational strategies are turning out as hot research topics in this field. In this symposium, Dr. Peiying Li from Shanghai Jiaotong University will start with the instruction of this symposium, an introduction of the unmet need of perioperative brain protection. Dr. Ruquan Han from Beijing will present the multi-center CANVAS study, which highlights the significance of perioperative covert stroke on the long-term cognitive declines in the perioperative patients. Since surgery usually elicits profound inflammation which can jeopardize the neurological functions. We will have Yueman Zhang (ECI, female) to discuss the impact of phagocytes and inflammation on the neurological functions of stroke. The evolving brain imaging techniques, such as PET imaging, are developing in an unprecedented speed and may provide novel perspectives for the early detection of high-risk patients that may develop perioperative cognitive dysfunction. We will have Dr. Zhemin Huang (ECI, male) from Huashan Hospital to introduce the recent advances in the PET imaging techniques in detecting the neurodegenerative diseases in the elderly. Finally, as for the translational consideration, we will have Dr. Li Tian (ECI, female) from Xian to introduce her exploration of therapeutic strategies for protecting the perioperative neurological functions for an anesthesiologist’s view. Collectively, this will be a multi-disciplinary symposium focusing on the perioperative cognitive declines with the hope to stimulate novel insights and future research directions.
Organizer: Peiying Li, MD, PhD. Shanghai, China
Presenter #1: Peiying Li, MD, PhD.
Title of the talk: Multi-center cohort study of perioperative covert stroke and cognitive declines in the elderly.
Presenter #2: Yueman Zhang, MD, PhD.
Title of the talk: Phagocytes and inflammation after stroke
Presenter #3: Zhemin Huang, MD, PhD.
Title of the talk: Novel imaging techniques in detecting the neurodegenerative diseases in the elderly
Presenter #4: Li Tian, MD, PhD
Title of the talk: Exploration of therapeutic strategies for protecting the perioperative neurological functions.
59
Brain vasculature: Architecture, collaterals and capillaries
1University of Newcastle, Australia
2University Hospital of Zurich
3Paris Brain Institute, Paris, France
4University of Vermont, USA
5University of California Los Angeles, USA
6University of Zurich, Zurich, Germany
7Seattle Children’s Hospital, Seattle, USA
Abstract
Structural integrity of the brain vasculature is a major determinant of the local metabolic supply. Brain vasculature is anatomically and functionally compartmentalized into arteries, capillaries, and veins. The cortex receives its blood supply via pial arteries, which diverge into arterioles and eventually end in the capillary network. The pial arterial network is heavily influenced by the extensive interconnections between terminal branches providing small anastomosis of so-called the collaterals. These collaterals play a pivotal role in the pathophysiology of cerebrovascular disease such as stroke.
Beside pial vessels, capillaries mediate the on-demand delivery of oxygen and nutrients required to support the function of active cells throughout the brain. But how blood flow is directed to cells in active brain regions and how capillaries communicate their needs with upstream pial arteries is poorly understood.
In the proposed symposia, we will share novel description of the organization and remodeling of the vasculature in mouse models of stroke. Furthermore, we will discuss the role of collaterals in stroke. We will also address the effect of collaterals on the hemodynamic response in neurovascular coupling. We will present new discoveries about brain capillaries and endothelial cells functions in healthy and stroke brains. We will address the question of how endothelial cells sense the neural activity and produce a rapidly propagating retrograde hyperpolarization wave that causes upstream arteriolar dilation to increase blood flow into the capillary bed.
Presenter #1: Nicolas Renier
Title of the talk: Mapping the Fine-Scale Organization of the Brain Vasculature
Presenter #2: Zhaojin Li, Burlington
Title of the talk: Introducing collateral vessel function and the effect of co-morbidities
Presenter #3: Mark T. Nelson
Title of the talk: Translating thought into blood flow in the brain: Capillaries as sensors of neural activity
Presenter #4: Britta Engelhardt
Title of the talk: BBB tight junctions: the secret door for immune cell entry into the CNS
Presenter #5: David Liebeskind
Title of the talk: Translating collateral therapeutics to the real-world
60
Translational strategies for application of stem cells and their extracellular vesicles as modulators of post-stroke neuroregeneration
1Okayama University, Japan
2Germany University of Göttingen Medical School, Department of Neurology, Germany
3Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, USA
4Department of Neurosurgical Engineering and Translational Neuroscience, Japan
5University of Cambridge, Department of Clinical Neuroscience, UK
6University Hospital Essen, Department of Neurology, Germany
Abstract
Stem cells yield both neuroprotection and neuroregeneration, and feasible algorithms for successful stem cell transplantation under stroke and related settings are still a matter of debate. Emerging evidence proposes mesenchymal stem cells (MSCs), multilineage-differentiating stress enduring (Muse) cells, to be a promising cell resource for ischemic stroke treatment. Indeed, intraarterial administration of bone marrow-derived NCS-01 improves neurological function by reducing infarct volume in a stroke animal model. In line with this, intravenously administered allogenic-Muse cells have been already applied to clinical trials for acute myocardial infarction, stroke, spinal cord injury and neonatal cerebral palsy, all without HLA matching or long-term immunosuppressant treatment.
Although stem cells are attractive candidates for future stroke treatment, the majority of stem cell-induced actions is due to secretion of extracellular vesicles (EVs), small vesicles ranging from 30 nm to 1000 nm in diameter that contain proteins, DNA and non-coding RNAs. First evidence suggests that EVs modulate both peripheral and central post-stroke immune responses by affecting a plethora of signaling molecules that will be introduced herein. Changes of post-stroke immune responses affect, in turn, both acute neural cell survival as well as endogenous neuroregenerative capacities. The former affects the post-stroke blood-brain barrier integrity as well as cellular survival signaling cascades directly. Of note, EVs do not only yield short-term effects but also stimulate post-stroke long-term neuroregeneration due to a modulation of the extracellular pro-inflammatory milieu of the brain parenchyma. The latter thus provides a proper cellular milieu helping boost endogenous repair mechanisms in the ischemic hemisphere. Some of these mechanisms are about to be understood and will be introduced in the present symposium, suggesting EVs to be an interesting tool of future adjuvant stroke treatment.
In this symposium, we focus on cell replacement therapies with regulation of secretome profiles, and discuss the present/future applications for post-stroke patients.
Presenter #1: Cesar V, Borlongan
Title of the talk: Bone Marrow-Derived NCS-01 Cells for Stroke Therapy
Presenter #2: Kuniyasu, Niizuma
Title of the talk: Application of Muse Cell Therapy to Stroke
Presenter #3: Thorsten R., Döppner
Title of the talk: Effects of extracellular vesicles in brain parenchyma and at blood-brain interface
Presenter #4: Stefano, Pluchino
Title of the talk: Extracellular vesicles in regenerative neuroimmunology
Presenter #5: Dirk M., Hermann
Title of the talk: Immune mechanisms of extracellular vesicle-induced neuroprotection