Developmental Cerebral Blood Flow and Metabolism Symposium

Developmental Cerebral Blood Flow and Metabolism Symposium
June 8 - 11, 2000
The Hershey Hotel, Hershey, Pennsylvania, USA

• Agenda
  • June 8
  • June 9
  • June 10
  • June 11
• Conclusions
• Participants

THURSDAY, JUNE 8, 2000

5:30 PM Registration Garden Terrace Lounge

7:00 PM Evening Reception Starlight Terrace

FRIDAY, JUNE 9, 2000 - Morning Session - DEVELOPMENT ASPECTS/MECHANISMS

7:00 AM Registration Mezzanine

• Continental Breakfast Castilian Room

8:00 AM Welcome & Announcements Castilian

• Robert C. Vannucci, MD, Professor of Pediatrics/Neurology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center

8:15 AM Pathophysiology of Perinatal Brain Damage and Neuro-Protection

• Philippe Evrard, MD, University of Paris, Paris, France

9:00 AM Discussion

9:15 AM Nutrient Transport in the Developing Brain

• Susan J. Vannucci, MD Associate Professor of Pediatrics/Neuroscience and Anatomy Pennsylvania State University College of Medicine The Milton S. Hershey Medical Center

9:45 AM Discussion

10:00 AM Development of Creatine Kinase Catalyzed Reaction in Rabbit Cerebral Gray and White Matter

• David Holzman, Tea Kekelidze, Harvard Medical School, Boston, MA

10:20 AM Discussion

10:30 AM Coffee Break

10:50 AM Neurotransmitters as Growth-Regulatory Signals: The Serotonergic Example

• Jean M. Lauder, University of North Carolina School of Medicine, Chapel Hill, NC

11:20 AM Discussion

11:30 AM Maturation Modulates cGMP-Mediated Decreases in Ca2+ Concentration and

• Sensitivity in Ovine Cranial Arteries, S. M. Nauli, W. J. Pearce, Loma Linda University, Loma Linda, CA

11:45 AM Discussion

11:55 AM Developmental Changes in Pial Arteriolar Vasodilation to the KATP Channel Activator, Pinacidil, in Fetal Sheep

• Y. Watanabe, R. J. Traystman, R. C. Koehler, Johns Hopkins University, Baltimore, MD

12:10 PM Discussion

12:30 PM Lunch Formal Gardens West

1:30 PM Oxidant Mechanisms in Neonatal Hypoxia-Ischemia

• Donna M. Ferriero, University of California at San Francisco

2:00 PM Discussion

2:10 PM Mitochondrial Dysfunction and Caspase Activation in the Immature CNS After Hypoxia-Ischemia

• Henrik Hagberg, GÖteborg University, GÖteborg, Sweden

2:40 PM Discussion

2:50 PM Iminobiotin, Allopurinol, and Deferoxamine Reduce Changes in Cerebral Energy Status and Prevent Vasogenic Edema in Newborn Piglets After Hypoxia- Ischemia

• C. Petters, I. Borst, T. Ioroi, K. Braun, W. Veldhuis, K. Nicolay, F. van Bel, F. Groenendaal, UMC, Utrecht, The Netherlands

3:05 PM Discussion

3:15 PM Apoptosis Detection in Neuronal Cells and Tissues

• Katherine Wood, Trevigen, Inc., Gaithersburg, MD

3:45 PM Discussion

3:55 PM Delayed Neurodegeneration After Hypoxia-Ischemia in the Immature Brain is Apoptosis

• Frances J. Northington, D. M. Ferriero, E. M. Graham, L. J. Martin, Johns Hopkins University School of Medicine, Baltimore, MD, and University of California at San Francisco

4:25 PM Discussion

4:35 PM Poster Session & Reception Mezzanine

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SATURDAY, JUNE 10, 2000 - Morning Session - PET, MR, SEIZURES

7:00 AM Continental Breakfast Castilian

8:00 AM Ontogeny of Human Brain GABA Receptor Binding Studies with PET

• Harry Chugani, Wayne State University, Detroit, MI

8:30 AM Discussion

8:40 AM Correlation of Development of Oxidative Glucose Metabolism with Functional Development of the Neocortex

• Edward Novotny, Yale University College of Medicine, New Haven, CT

9:10 AM Discussion

9:20 AM Predicting Brain Damage with Multi-Slice T1, T2, and Diffusion-Weighted MRI

• Michael B. Smith, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center

9:50 AM Discussion

10:00 AM Coffee Break

10:20 AM Age-Dependent Consequences of Seizures and the Development of Temporal Lobe Epilepsy

• Astrid Nehlig, Celine Dube, Faculty of Medicine, Strasbourg, France

10:50 AM Discussion

11:00 AM Controlled Normothermia Protects the Brain from Seizure Exacerbation of Damage Following Hypoxia-Ischemia

• J. Y. Yager, E. Armstrong, E. C. Wirrell, University of Saskatchewan, Saskatoon, Canada

11:15 AM Discussion

11:25 AM The Mechanisms of Neuroprotective Effects of Hypothermia on Brain Damage in Neonatal Seizure Models

• Y. Takei, S. Takashima, M. Itoh, Y. Gotoh, T. Takami, Tokyo Medical University and National Center of Neurology and Psychiatry, Tokyo, Japan

11:40 AM Discussion

11:50 AM A New Technique for Monitoring EcoG and Seizures with Telemetry Following a Hypoxic-Ischemic Injury in the Developing Brain

• R. Abi Raad, M. I. Gunning, P. D. Gluckman, C. E. Williams, University of Auckland, New Zealand

12:05 PM Discussion

12:15 PM Lunch Mosiac

1:30 PM The Premature Fetus: Not as Defenseless as We Thought, But Still Paradoxically Vulnerable?

• A. J. Gunn, J. Quaedackers, J. Guan, S. George, M. I. Gunning, L. Bennet, University of Auckland, New Zealand

2:00 PM Discussion

2:10 PM White Matter Injury in the Preterm Human Brain: Role of Perfusion

• Gorm Greisen, Rigshospitalet, Copenhagen, Denmark

2:40 PM Discussion

2:50 PM Birth Asphyxia Causes Transient Effects on Kynurenine Pathway Metabolism in the Rat Brain

• G. Ceresoli-Borroni, J. O'Brien, M. C. McKenna, R. Schwarcz, University of Maryland School of Medicine, Baltimore, MD

3:05 PM Discussion

3:15 PM The Effect of Recurrent Hypoxia on Respiratory Control and Brainstem Apoptosis in the Developing Rat

• M. J. Miller, A. R. Hartman, M. A. Haxhiu, Rainbow Babies and Children's Hospital, Cleveland, OH

3:30 PM Discussion

3:40 PM Coffee Break

4:00 PM Embryonic Stem (ES) Cells as a Tool and Strategy to Repair the Damaged Nervous System

• John W. McDonald, Washington University School of Medicine, St. Louis, MO

4:30 PM Discussion

4:40 PM Embryonic Stem (ES) Cells Survive and Differentiate Following Transplantation in the Developing Rat S-1 Somatosensory Cortex

• D. C. Kadunce, M. F. Jackquin, J. W. McDonald, Washington University School of Medicine, St. Louis, MO

4:55 PM Discussion

5:05 PM Insulin-Like Growth Factor-1 Protects Against the White Matter Damage Following Ischemic Brain Injury in Fetal Sheep

• J. Guan, L. Bennet, S. George, D. Wu, P. D. Gluckman, H. Keunen, A. J. Gunn, University of Auckland, New Zealand

5:20 PM Discussion

5:30 PM Adjourn

6:00 PM Reception Castilian

7:00 PM Dinner Castilian

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SUNDAY, JUNE 11, 2000 - Morning Session - HYPOXIA-ISCHEMIA, INFLAMMATION, EXCITOTOXCITY

7:00 AM Continental Breakfast Castilian

8:00 AM Cerebral Oxidative Metabolism Following Severe Hypoxia-Ischemia in the Neonatal Piglet

• John S. Wyatt, University College London, London, UK

8:30 AM Discussion

8:40 AM Glial Development in Normal and Pathological Environments

• Wendy B. Macklin, Cleveland Clinic Foundation, Cleveland, OH

9:10 AM Discussion

9:20 AM Cerebral Glucose Metabolism (CMRglc) and Early EEG/aEEG in Term Newborn Infants with Hypoxic-Ischemic Encephalopathy

• K. Thorngren-Jerneck, L. HellstrÖm-Westas, T. Ohlsson, A. Sandell, K. Erlandsson, S.-E. Strand, E. Ryding, I. Rosen, University Hospital, Lund, Sweden

9:35 AM Discussion

9:45 AM The Relationship Between Electrocortical Brain Activity and Cerebral Oxygenation and Hemodynamics During Hypoxia in Piglets

• K. D. Liem, J. H. G. M. Klaessens, J. C. W. Hopman, S. H. G. van Os, J. M. Thijssen, M. van de Bor, University Medical Center, St. Radvoud, Nijmegen, The Netherlands

10:00 AM Discussion

10:10 AM Break

10:30 AM Bacterial Endotoxins Sensitizes the Immature Brain to Injury

• C. Mallard, S. Eklind, E. Gilland, K. Blomgren, H. Hagberg, Goteborg University, Goteborg, Sweden

10:45 AM Discussion

10:55 AM Correlation of Neonatal Cytokines and Coagulation Factors with Neurologic Injury and Outcome in Perinatal Hypoxia-Ischemia

• A. Foster-Barber, B. Dickens, T. M. Phillips, A. J. Barkovich, D. M. Ferriero, University of California at San Francisco and George Washington University, Medical Center, Washington, DC

11:10 AM Discussion

11:20 AM In Vivo Effects of Glutamine Perfusion on Extracellular Levels of Glutamate in Rat Hippocampus. Are g-Glutamyltransferase and/or Glutaminase Involved?

• F. V. Mena, H. R. Zielke, University of Maryland, Baltimore, MD

11:35 AM Discussion

12:00 Noon Adjourn

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Conclusions

The Second Hershey Conference on Developmental Cerebral Blood Flow and Metabolism was held at the Hotel Hershey, Hershey, PA, June 8-11, 2000. Drs. Susan and Robert Vannucci, Department of Pediatrics, Pennsylvania State University College of Medicine, organized this conference following the very successful initial conference in Hershey in June, 1997. This was a relatively small (approximately 70 participants), highly interactive, international meeting whose sole focus was on the immature brain. Participants came from 10 countries, including the USA. This conference was funded largely by the National Institute of Neurological Disorders and Stroke (1R13 NS 39832) with an additional contribution from the Department of Pediatrics at Hershey.

Scientific sessions began Friday morning, June 9, 2000 with the keynote address by Dr. Philippe Evrard, Professor and Chief, Service of Pediatric Neurology and Metabolic Disorders, INSERM E9935, Paris, France. Dr. Evrard discussed the pathophysiology of perinatal brain damage and neuroprotection, and set the stage for the rest of the meeting by discussing basic mechanisms of normal and abnormal development in human infants as well as experimental animal models. Other aspects of normal cerebral development, which are also prime targets for the development of brain injury included nutrient transport and transporters (Susan J. Vannucci, Ph.D., Hershey, PA) and the role of neurotransmitters as growth factors ( Jean M. Lauder, Ph.D., Chapel Hill, NC). The afternoon session was more focused on mechanisms of hypoxic-ischemic brain damage in the immature animal and human infant. The neonatal rat model of unilateral hypoxia-ischemia developed in the Vannucci laboratory in 1981 is currently being used around the world. Several of the studies presented were based on this model which provided a common basis for interpretation. Donna Ferriero, MD, UCSF, San Francisco, CA provided a comprehensive analysis of oxidant mechanisms in neonatal hypoxia-ischemia with special emphasis on the way in which the immature brain is different from the adult brain, and the effects of oxidative stress on processes leading to necrotic vs apoptotic cell death. The theme of the differences between the immature and adult brain in response to injury was continued by Henrik Hagberg, MD, Ph.D., Goteborg, Sweeden, in his presentation on mitochondrial impairment and caspase activation following hypoxia-ischemia in the immature rat brain.

An invited presentation by Dr. Katherine Wood, Trevigen, Inc, Gaithersburg, MD on apoptosis detection in neuronal cells and tissues ended the first day's sessions with an extremely informative analysis of the capabilities and limitations of available methods of detecting forms of cell death.

The morning session of the second day focussed on PET and MR studies, and seizures. Diane Chugani, Ph.D., Detroit, MI, discussed developmental changes in cerebral glucose metabolism in human infants and children, as studied with PET and compared that with the ontogeny of GAGAA receptor binding and serotonin synthesis. Edward Novotny, MD, New Haven, CT, used MR techniques in both immature rats and brain slices to correlate development of oxidative glucose metabolism with the functional development of the neocortex. The remainder of the morning dealt with issues of neonatal seizures, age-related effects in susceptibility to damage from seizures, and the important issue of temperature in induction of damage. The afternoon session on Saturday dealt with issues of prematurity, hypoxia-ischemia, and repair. Alistair Gunn, MD, Auckland, New Zealand provided an in depth overview of the cardiovascular and cerebrovascular responses on fetal sheep to asphyxia. Gorm Greisen, MD, Copenhagen, Denmark then contrasted several non-invasive techniques to assess cerebral blood flow in very small preterm infants, and the potential consequences of neonatal ischemia on white matter injury. The presentations then turned to current studies on embryonic stem cells and potential mechanisms for repair of the damaged nervous system. John McDonald, MD, Ph.D., St. Louis, MO presented their latest results on transplantation of ES cells into normal and injured immature rat.

The final session Sunday morning dealt with issues of hypoxia-ischemia, inflammation, and excitotoxicity and the studies presented provided information relevant to the interaction of these processes in the pathogenesis of damage in the immature brain. John Wyatt, MD, London, UK, described MR studies in the neonatal piglet examining cerebral oxygen and glucose consumption and cerebral lactate production during the development of secondary energy failure following hypoxia-ischemia. Wendy Macklin, Ph.D., Cleveland, OH, addressed the issue of the impact of such pathological environments on glial, and especially oligodendrocyte, development. The session ended with several presentations on the impact of inflammatory mediators and cytokines on injury and neurologic outcome in both animal models and human infants.

At the end of this second Hershey conference there was complete agreement that this had been an extremely exciting and enlightening meeting. All of the sessions were characterized by a great deal of interaction and truly constructive discussion. Ample time had been allowed for discussion of each presentation, and the time was used to the fullest. Common themes that developed were 1) that the immature brain is quite distinct in its response to hypoxic-ischemic injury from the adult such that there is a great deal to be learned from perinatal studies, and 2) that each experimental perinatal animal model employed in the study of hypoxic-ischemic injury has its own unique features relative to developmental stage, type and severity of insult, and neurologic outcome. By appreciating the difference, and the similarities to human infants, the ongoing compilation of research in this area will have a very significant impact on developing appropriate methods of neuroprotection for asphyxiated infants. Because of the extreme importance of the participation of all of these research groups from around the world coming together in an intimate setting for a sharing of results and ideas, it was unanimously decided to schedule the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism in two years time, June 2002.

Some comments from the participants:

"Thank you for a great meeting in Hershey....Many of the researchers in the field of perinatal brain injury were present and participated actively in the discussions and there was enough time to allow discussions - very stimulating!"

"Thank you so much for the chance to feel a member of a diverse group with common goals. A highlight....seizures are common in newborns with hypoxic-ischemic brain injury but the benefit of intervention is debatable, and of great clinical importance. The study ( Jerry Yager, MD, Saskatoon, Canada) highlighted the complexity of the interactions between primary brain injury, complicating seizures, and secondary aggravating/ameliorating factors, such as temperature."

"The Developmental Cerebral Blood Flow and Metabolism conference at Hershey was an exciting and enlightening symposium. Information was shared from studies involving human newborns ( functional imaging, MRI, MRS, NIRS), and a variety of animal models. It was very interesting to hear data from a variety of animal models ( sheep, rat, mouse, piglet, rabbit) using different paradigms and to be able to make cross comparisons. The information shared on potential neuroprotective strategies, including the potential for using stem cells, will enable all of the investigators to alter approaches for the best results. The symposium allowed a forum for this small community to come together to learn from one another, and to share unpublished data. This conference is unique in that aspect."

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Participants

Edward Armstrong University of Saskatcakwan
Elizabeth Bossart The Milton S. Hershey Medical Center
Christine Brazel Penn State College of Medicine
Diane Chugani, PhD Childrens Hospital of Michigan
James Connor The Milton S. Hershey Medical Center
Christopher Corpe, PhD The Milton S. Hershey Medical Center
Philippe Evrard, MD Faculte de Medecine Xavier-Bichat
Donna Ferriero U. of California - San Francisco
Audrey Foster-Barber, MD, PhD UCSF
Rastifa Geddes The Milton S. Hershey Medical Center
Gorm Greisen, MD Rigshospitalet Copenhagen Denmark
Jian Guan, MD, PhD University of Auckland
Alistair Gunn, MD The University of Auckland
Henrik Hagberg, PhD Sahlgrenska University Hospital
Lena Hellstrom-Westas, MD University Hospital - Lund, Sweden
Rebecca Ichord, MD Johns Hopkins Medical Institute
Raymond Koehler, PhD Johns Hopkins University
Jean Lauder, PhD University of N. C. School of Medicine
Steven Levison, PhD Penn State College of Medicine
K.D. Liem, MD, PhD University Med. Ctr. Nymegen
Wendy Macklin, PhD Cleveland Clinic Foundation
Carina Mallard, PhD University of Goteborg
John McDonald, MD, PhD Washington University
Mary McKenna, PhD University of Maryland
Martha Miller, MD, PhD Rainbow Baby's & Children's Hospital
Dawn Mueller-Agnew Johns Hopkins Bayview
Surya Nauli Loma Linda University
Astrid Nehlig, PhD INSERM U
Jennifer Ness The Milton S. Hershey Medical Center
Frances Northington, MD Johns Hopkins Hospital
Edward Novotny, MD Yale University School of Medicine
Charles Palmer, MD The Milton S. Hershey Medical Center
William Pearce, PhD Loma Linda University
Cacha Peeters, MD Wilhelmina Childrens Hospital
Ronnie Abi Raad University of Auckland
Sarah Robb The Milton S. Hershey Medical Center
Raymond Rothstein The Milton S. Hershey Medical Center
Linda Ruggierro Penn State College of Medicine
Elie Saliba, MD, PhD Inserm
Ian Simpson, MD The Milton S. Hershey Medical Center
Michael Smith, PhD Penn State College of Medicine
Giovanna Spinella, MD Nat'l. Inst. Of Neurological Disorders
Yukito Takei, MD Tokyo Medical University Hospital
Kristina Thorngren-Jerneck, MD Lund University Hospital
Frank van Bel, MD, PhD Wilhelmina Children's Hospital
Margot van de Bor, MD, PhD University of Nijmegen Medical Center
Robert Vannucci, MD The Milton S. Hershey Medical Center
Susan Vannucci, PhD Penn State College of Medicine
Zinaida Vexler, PhD University of California - San Francisco
Mohan Viswanathan, PhD Childrens Research Institute
Jianli Wang The Milton S. Hershey Medical Center
Katherine Wood Trevigen, Inc.
Teresa Wood The Milton S. Hershey Medical Center
John Stephen Wyatt University of London
Jerome Yager, MD Royal University Hospital
Feng Zhang, MD The Milton S. Hershey Medical Center
Liqun Zhang, MD The Milton S. Hershey Medical Center
Carol Zielke, PhD University of Maryland
Ronald Zielke, PhD Univeristy of Maryland Top