Hovda, David

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  • of the body’s energy
  •  
  • In a FDG-PET study to look at CMRglc after TBI: 32 patients with a GCS less than or = 12 - Normal ~7.30 mg/100g/minute
  •  
  • Hovda, David

    1. 1. David A. Hovda, Ph.D. Director, UCLA Brain Injury Research Center Professor of Neurosurgery Molecular and Medical Pharmacology David Geffen School of Medicine at UCLA WWW.BIRC.UCLA.EDU 2011 National Neurotrauma Conference Hollywood Beach, FL July 13, 2011 Mechanisms of Concussion Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. NOTHING TO DISCLOSE
    2. 2. WHAT IS TRAMATIC BRAIN INJURY? <ul><li>It is an injury to the brain caused by biomechanical forces. </li></ul><ul><li>It is not ischemia or stroke! </li></ul><ul><li>It results in regional and temporal </li></ul><ul><li>cellular dysfunction including cell death. </li></ul><ul><li>In areas that survive it produces a state </li></ul><ul><li> of energy crisis and subsequent metabolic diaschisis </li></ul>4. Surviving brain cells alter their use of fuels 5. There are implications to rehabilitation in terms of energy demands
    3. 3. EVERY TBI STARTS OUT AS A CONCUSSION What is so mild about mild traumatic brain injury? Walker, A.E et al, 1944; The physiological basis of concussion. J. Neurosurgery, 1: 103-166
    4. 4. Constantin van Monakow 1853-1930 Swiss Neurologist of Russian Extraction Diaschisis To distinguish between the transient central nervous disorders due to suppression of brain activity and the deficits resulting from brain lesions that never disappear.
    5. 5. Adenosine Triphosphate (ATP) 116 Watts/Hour
    6. 6. SAGITTAL HEAD AND BRAIN MOTION Dr. Gennarelli Dr. Gurdjian
    7. 7. Neurometabolic Cascade: Potassium & Glutamate Flux Katayama , et.al., J Neurosurg 1990 K+ K+ K+ K+ K+ Glutamate Glutamate
    8. 8. Neurometabolic Cascade: Hyperglycolysis and Energy Crisis K+ Pump Energy Crisis!!! ADP ATP Glucose ATP ADP Glutamate Glutamate
    9. 9. Neurometabolic Cascade: Calcium, mitochondrial dysfunction and death ATP Glucose Energy Crisis!!! Mito Cell Damage/ Death!!! ATP For review, see Giza and Hovda, J Athl Training, 2001 Ca2+ Protease activation Glutamate Glutamate
    10. 10. Neurometabolic Cascade: Axonal Injury Axonal swelling Myelin Damage Axonal blebs and swelling Microtubule and neurofilament injury Impaired axonal transport Axonal degeneration Ca2+ Inflammation Glutamate
    11. 11. Neurometabolic Cascade: Now we can see it Energy Crisis Mito PET, MRS Protein Biomarkers? Cell Damage/ Death Protease activation MRI Axonal injury DTI Altered neurotrans-mission Glutamate fMRI
    12. 12. McAllister, et al. Neurology, 1999 Human mTBI: Impaired Activation (fMRI) Mildly injured individuals demonstrate abnormal activation patterns during a more difficult working memory task. Mild TBI patients (GCS 13-15), n=12; controls n=11 Average time of testing was 22.1 ± 10.5 days after TBI. Loss of consciousness: 1 to 30 min. Post-traumatic amnesia: 15 min to 24 hrs. % correct mTBI control 0-back 95.1 96.2 1-back 95.8 95.5 2-back 81.0 89.4 No significant differences Mild TBIs Controls
    13. 13. Human mTBI: Abnormal axons (DTI) Wilde E, et.al. Neurology, 2008 In adolescents with mTBI, DTI of the CC performed within 6 days showed increased FA and decreased diffusivity. These abnormalities in DTI correlated well with post-concussion symptoms.
    14. 15. CMRglc CBF CMRO 2 OEF
    15. 16. TBI as a Metabolic Disorder: Clinical Studies Acute Hyperglycolysis Bergsneider et al., 1997 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Months Post-injury 0 1 2 3 4 5 6 7 8 9 10 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Days Post-injury Cortical CMRglc Chronic Metabolic Depression 1st PET 2nd PET
    16. 17. Human mTBI: Altered metabolism (MRS) Vagnozzi, et.al. Neurosurgery, 2008 Single concussion Double concussion There were significant reductions of NAA/Cr for 30 days after 1 concussion and 45 days after 2 concussions. Vagnozzi, et.al. Brain, 2010
    17. 18. GLUCOSE GLUCOSE LACTATE LACTATE C P C M C E G-6-P BBB brain capillary endothelial cytoplasm PYRUVATE PYRUVATE ACETYL-CoA TCA CO 2 H 2 O k 1 k 3 k 2 Pentose Shunt GLYCOGEN GLYCOGEN – ~97% ~13% Amino Acids ~5% GLUCOSE G-6-P G-1-P PYRUVATE LACTATE hexokinase ASTROCYTE NEURON 2 ATPs 36 ATPs Oxygen/ Glucose Ratio 1 Glucose:5.6 parts Oxygen 5.6 Oxygen G1 G1 G3 G1 G1 G1 G1 MCT MCT MCT MCT MCT hexokinase glucose-6- phosphatase
    18. 19. Molar Oxygen-to-Glucose Ratio (OGR): Normal ~ 5.6 CMRO2 CMRglc CMRO 2 OGR Image Processing Low OGR High OGR
    19. 20. Lactate Uptake Occurs Frequently During the Post-Acute Phase Uptake Release Trauma Normal Post-Injury Day % Positive CMRlac 0 65.2% 1 58.1% 2 39.0% 3 40.5% 4 43.9% 5 20.0%
    20. 21. Glucose Lactate Glucose Lactate Probe 1 Probe 2
    21. 22. Metabolic Priorities After Traumatic Brain Injury The role for Glucose and Lactate had Changed! Astrocytes may need help! Bartnik et al. J Neurotrauma 2005, 2007a,b Dusick et al. J Cereb Blood Flow Metab 2007
    22. 23. Significance <ul><li>Metabolic intervention …. BRUINADE? </li></ul><ul><ul><ul><li>Lactate (Chen et al. 2000; Rice et al. 2002; Holloway et al. 2007) </li></ul></ul></ul><ul><ul><ul><ul><li>Improves functional outcome and spares glucose </li></ul></ul></ul></ul><ul><ul><ul><li>Pyruvate (Fukushima et al. 2005; Moro et al. 2007) </li></ul></ul></ul><ul><ul><ul><ul><li>Uptake and reduced lesion size </li></ul></ul></ul></ul><ul><ul><ul><li>b-hydroxybutyrate (Prins et al. 2004, 2005) </li></ul></ul></ul><ul><ul><ul><ul><li>Uptake, oxidation and increased ATP synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Age dependent neuroprotection and reduced lesion size </li></ul></ul></ul></ul>
    23. 24. TBI– Induced Hyperglycemia Vespa et al. Crit Care Med 2006 Start of insulin infusion
    24. 25. Intensive Insulin Treatment is Associated with Increased Microdialysis Markers of Injury Vespa et al Crit Care Med 2006
    25. 26. Tight Glycemic Control may be Associated with Increased Oxygen Extraction
    26. 27. WHAT IS TRAMATIC BRAIN INJURY? <ul><li>It is an injury to the brain caused by biomechanical forces. </li></ul><ul><li>It is not ischemia or stroke! </li></ul><ul><li>It results in regional and temporal </li></ul><ul><li>cellular dysfunction including cell death. </li></ul><ul><li>In areas that survive it produces a state </li></ul><ul><li> of energy crisis and subsequent metabolic diaschisis. </li></ul>4. Surviving brain cells alter their use of fuels 5. There are implications to rehabilitation in terms of energy demands
    27. 28. The UCLA Brain Injury Research Center Basic Scientists Chris Giza, M.D. Fernando Gomez-Pinilla, Ph.D. Grace Griesbach, Ph.D. Neil Harris, Ph.D. Mayumi Prins, Ph.D. Richard Sutton, Ph.D. Graduate Students Gretchen Miller. Maxine Reger Naomi Santa Maria Derek Verley Lab Assistants Yan Cai, M.S. Sima Ghavim Nurses Maria Etchepare Sue Yudovin Clinical Investigators Thomas Glenn, Ph.D. Neil Martin, M.D. Paul Vespa, M.D. Marvin Bergsneider, M.D Robert Asarnow, M.D. Andy Madikians, M.D. David McArthur, Ph.D M.P.H. Michelle van Hirtum-Das, M.D. Talin Babikian, Ph.D. Funded by: NS02197, NS27544, NS052406 UC Neurotrauma Initiative, UCLA Faculty Grant Program and the Lind Lawrence Foundation. www.birc.ucla.edu Post Doctoral Fellows Sarah Copeland, M.D. Ph.D. Nobouhiro Moro, M.D., Ph.D Katsunori Shijo, M.D., Ph.D.
    28. 29. Thank You!

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