Treatments = 0 10/19/2018. Concussion is not a diagnosis!!! Multiple Clinical Trials for Traumatic Brain Injury (TBI) Treatment

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Steven Morton
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Penn Center for Brain Injury and Repair Blood Biomarkers for Concussion Promises and Pitfalls Douglas H.

of Neurosurgery University of Pennsylvania Multiple Clinical Trials for Traumatic Brain Injury (TBI) Treatment

clinical trials for severe TBI: Too heterogeneous to power?

Saatman et al., J Neurotrauma 2008 concussion A more Homogeneous population e.g., Concussion/ mtbi?

1 Penn Center for Brain Injury and Repair Blood Biomarkers for Concussion Promises and Pitfalls Douglas H. Smith Center for Brain Injury and Repair, Dept. of Neurosurgery University of Pennsylvania Multiple Clinical Trials for Traumatic Brain Injury (TBI) Treatment Treatments = 0 you are here Learning Curve Considerations for TBI Clinical Studies We are great at failing in clinical trials for severe TBI: Too heterogeneous to power? Homogeneous neuropathology Objective subject enrollment Detailed Gold Standard outcome measures biomarkers? Saatman et al., J Neurotrauma 2008 concussion A more Homogeneous population e.g., Concussion/ mtbi? Opportunity for Streamlined clinical trials Concussion is not a diagnosis!!! The term is akin to consumption as it was used long ago How long has that been there? Diagnosis: a statement or conclusion that describes the reason for a disease, illness, or problem. Merriam-Webster Dictionary 1

Towards a True Diagnosis for Concussion 50 45 40 35 30 25 20

biomarkers 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

2 Towards a True Diagnosis for Concussion Number of Publications per Year for concussion biomarkers There has been substantial confusion about the role of blood-based biomarkers in TBI. Obviousness Goals for biomarker evaluation in mtbi 1) Diagnose concussion. Return to play or combat decisions 2) Detect bleeds. Direct to CT or consult 3) Predict rapid vs. delayed recovery. 4) Monitor recovery/ treatment efficacy 2

3 Concussion = Diffuse Axonal Injury because of what you can t see Inertial Loading Contact Loading Primary anatomic substrate of concussion: Diffuse Axonal Injury (DAI) Diffuse Axonal Injury DAI is thought to be the primary anatomic substrate of mtbi/ Concussion Too small/ subtle to see non-invasively? Tang-Schomer et al., FASEB J 2010 Pre-injury Post-injury Reversible changes vs. brain pathologies 3% strain Could BBB opening alone be diagnostic of concussion? 5% strain 20% strain Strain-dependent threshold for ion influx with TAI Wolf et al., J. Neurosci. 21 (6) Iwata et al.,j Neurosci. 24(19) , Yuen et al., J Neurosci Res 87(16): ,

Blood Brain Barrier Opening after Concussion: Concussion: Inertial Brain Injury in the Pig

proteins into the blood Deceleration Parameters scaled to human concussion Johnson et al.

biomarker of outcome, but a marker of potential brain bleeds, Directing clinical evaluation.

Traumatic Brain Injury Compared to CT and MRI. McMahon et al., J Neurotrauma.

4 Blood Brain Barrier Opening after Concussion: Concussion: Inertial Brain Injury in the Pig Pre-Acceleration Acceleration Leakage of blood products into the brain, release of brain proteins into the blood Deceleration Parameters scaled to human concussion Johnson et al., Acta Neuropathologica 2018 Concussion diagnosis: micro- and macrobleeds GFAP not a blood biomarker of outcome, but a marker of potential brain bleeds, Directing clinical evaluation. FDA approval just granted Measurement of the GFAP-BDP Biomarker for the Detection of Traumatic Brain Injury Compared to CT and MRI. McMahon et al., J Neurotrauma Protein Biomarkers for mtbi Zetterberg, Smith, Blennow. Nature Rev Neurol, 2013 DAI diagnosis: e.g., SNTF, Tau, NFL SNTF Spectrin N-terminal fragment SNTF, Tau, NFL Cleaved by Calcium-activated Calpain Cleavage Protein Biomarkers for mtbi Zetterberg, Smith, Blennow. Nature Rev Neurol,

Tau protein in DAI Serum biomarker detection of Degenerative DAI SNTF Spectrin N-terminal fragment from

fragment (SNTF) Increased blood marker found in 20-30% of concussions shortly after injury predicts

02) Professional Ice Hockey Players Sustained increase in serum SNTF and tau after concussion, but not

And corresponded with advanced neuroimaging studies DIAGNOSIS: Degenerative DAI? Siman et al, Front.

Neurotrauma, 2015 Professional Ice Hockey Players Additional endpoint: Use validated mtbibms to

5 Tau protein in DAI Serum biomarker detection of Degenerative DAI SNTF Spectrin N-terminal fragment from calpain cleavage Blood test for axonal injury in human concussion CT negative: Spectrin N-terminal fragment (SNTF) Increased blood marker found in 20-30% of concussions shortly after injury predicts persisting cognitive dysfunction at 3 months (*p<0.02) Professional Ice Hockey Players Sustained increase in serum SNTF and tau after concussion, but not after training DIAGNOSIS: Degenerative DAI? And corresponded with advanced neuroimaging studies DIAGNOSIS: Degenerative DAI? Siman et al, Front. Neurology 2014 Siman et al., J. Neurotrauma, 2015 Professional Ice Hockey Players Additional endpoint: Use validated mtbibms to evaluate the relative accuracy of other BMs Professional Ice Hockey Players Serum levels of SNTF after concussion are related to serum tau but not S100β. Siman et al., J. Neurotrauma, in press Diagnostic accuracy of serum SNTF and tau under the curve (AUC) analyses Siman et al., J. Neurotrauma,

6 mdai: SNTF reveals injured axons mtbi in swine SNTF staining (spectrin-n-terminal fragment) Progressing calpain activation and proteolysis of axonal proteins (6 hours) UNDULATIONS (6 hours) (6 hours) VARICOSITIES DEGENERATIVE BEADING Johnson et al., Acta Neuropath Brown et al. J. Neurotrauma 2011 (72 hours) (72 hours) Johnson et al., Acta Neuropathologica 2016 Pathological analysis only reveals axon pathology, SNTF+ Diagnostic for Degenerative DAI? UNDULATIONS TERMINAL AXONAL BULBS 59M 4 days Survival. Fall. 17M 14 days Survival. MVC VARICOSITIES VASCULAR PATTERN 18M 10 hours Survival. Assault 18M 10 hours Survival. Assault Johnson et al., Acta Neuropathologica 2016 Neurofilament light and tau as blood biomarkers for sports-related concussion Pashtun Shahim, Yelverton Tegner, Niklas Marklund, Kaj Blennow, Henrik Zetterberg Neurology May 15, 2018; 90 (20) Current clinical promise of serum biomarkers: GFAP+ to direct need for CT in mtbi NFl+, SNTF+ and tau+ predict poor outcome. NFl 3d post-concussion in swine Johnson et al., Acta Neuropathologica 2016 Diagnosis: Degenerative DAI? 6

Goals for biomarker evaluation in mtbi 1) Diagnose concussion.

bleeds. Direct to CT or consult FDA approved 3) Predict rapid vs.

MAYBE 4) Monitor recovery/ treatment efficacy NOT YET Towards

Biomarkers for a Win in the Near Future? 1) Test the Paradigm

, Evaluate mtbi rehab strategies to develop evidence based practice

7 Goals for biomarker evaluation in mtbi 1) Diagnose concussion. Return to play or combat decisions NOT YET Concussion 2) Detect bleeds. Direct to CT or consult FDA approved 3) Predict rapid vs. delayed recovery. MAYBE 4) Monitor recovery/ treatment efficacy NOT YET Towards Evidence Based Practice and Medicine Focused Goals of TBI Biomarkers for a Win in the Near Future? 1) Test the Paradigm: e.g., Evaluate mtbi rehab strategies to develop evidence based practice mtbi subject selection for targeted studies 2) Targeted Drug therapy, e.g., for DAI Multiple targets identified via NINDS workshop 3) Emulate ADNI-type BM evaluations for long-term screening Can TBI switch the brain from a normal aging track onto an accelerated neurodegenerative track? CTE? Smith, Hicks, Povlishock, J. Neurotrauma

8 Long-term screening BM identification of progressive neuropathological processes Atrophy Will it be a long slog until there is general use of concussion biomarkers? Inflammation Tau and amyloid pathologies/ CTE Scientists would rather share a toothbrush than use each other s paradigms or markers Biomarker data to be shared for BIG DATA CDEs for concussion biomarkers to enable big data studies NINDS Common Data Element (CDE) Project Protocol & Form research Management System (ProFoRMS) Tool to customize data entry sheets Everybody Wins!! Data can be directly ported to One step entry! Investment in the TBI research community. 8

This work was supported by: NIH Grants: P01 NS056202 Acknowledgements and R01 NS038104, and DOD grant PT110785 Willie Stewart David Meaney Harvey Levin Lisa Wilde

Dolle Bai-Nan Xu Andrew Jaye Tracy Yuen John Dutton Kacy Cullen Laura Scholsser John Wolf Mindy Ezra Bryan Pfister Zarina Ali Amy Kim Amanda Rabinowitz Niranjan

9 This work was supported by: NIH Grants: P01 NS Acknowledgements and R01 NS038104, and DOD grant PT Willie Stewart David Meaney Harvey Levin Lisa Wilde Bob Siman John Trojanowski Virginia Lee Victoria Johnson Vivek Shenoy Lab Members Past: Current: John Wolf Maura Weber John Cognetti Xiao-Han Chen Jean Pierre Dolle Bai-Nan Xu Andrew Jaye Tracy Yuen John Dutton Kacy Cullen Laura Scholsser John Wolf Mindy Ezra Bryan Pfister Zarina Ali Amy Kim Amanda Rabinowitz Niranjan kameswaran Andrew Voyadjis Min Tang-Schomer Theresa Williamson Andrew Eng Ariana Barckley Kristin Hamman Dev Patel Timur Litvinov Isaac Chen Kevin Brown Mind your brain! 9

The Calpain / Calpastatin System in TBI and Chronic Neurodegeneration

The Calpain / Calpastatin System in TBI and Chronic Neurodegeneration Kathryn E. Saatman, Ph.D. Departments of Physiology and Neurosurgery Spinal Cord and Brain Injury Research Center Saatman lab: Dr.