Additional considerations for TBI Biomarkers: Towards Evidence Based Practice and Medicine?

Transcription

1 TBI Treatment Development Meeting February 19, 2015 Washington, DC Additional considerations for TBI Biomarkers: Towards Evidence Based Practice and Medicine? Douglas H. Smith Center for Brain Injury and Repair, Dept. of Neurosurgery University of Pennsylvania

2 We are great at failing in clinical trials for severe TBI: Too heterogeneous to power?

3 Considerations for TBI Clinical Studies Homogeneous neuropathology Objective subject enrollment Subjects compliant with detailed outcome measures

4 concussion A more Homogeneous population e.g., Concussion/ mtbi? Opportunity for Streamlined clinical trials How long has that been there?

5 Mild TBI is an oxymoron Just recently recognized as a major health issue, yet Over 1.3 million cases of mtbi in the US each year! Approx % of mtbi patients have persisting cognitive dysfunction!

6 Goals for biomarker evaluation in mtbi Assessment: Sideline and Battlefield testing remove from play/ duty Direct evaluation with CT/ MRI (e.g., GFAP+) Return to play/ duty Therapeutic efficacy studies *Identify individuals at risk of poor outcome *Specific Diagnosis *Subject enrollment selection *Evaluation of targeted Tx.

7 mtbi = Diffuse Axonal Injury because of what you can t see

8 Contact Loading Inertial Loading Primary anatomic substrate of mtbi: Diffuse Axonal Injury (DAI)

9 Diffuse Axonal Injury DAI is thought to be the primary anatomic substrate of mtbi

10 Homogeneous Neuropath? mtbi Corpus Callosum Anterior & Posterior Internal Capsules Frontal & Temporal Lobes Combined ROIs for OI (left) DAI is the predominant structural change found with advanced neuroimaging in mtbi

11 DAI diagnosis: e.g., SNTF and Tau SNTF, Tau Protein Biomarkers for mtbi Zetterberg et al. Nature Rev Neurol, 2013

12 Blood test for axonal injury in 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) And corresponded with DIAGNOSIS: DAI? advanced neuroimaging studies Siman et al, Front. Neurology 2014

13 Professional Ice Hockey Players Sustained increase in serum SNTF after concussion, but not after Training DIAGNOSIS: DAI? Siman et al., J. Neurotrauma, 2015

14 Additional endpoint: Use validated mtbi BMs to evaluate the relative accuracy of other BMs Professional Ice Hockey Players Diagnostic accuracy of serum SNTF and tau under the curve (AUC) analyses Siman et al., J. Neurotrauma, 2015

15 UNDULATIONS Since SNTF IHC only reveals axon pathology, is SNTF+ serum - Diagnostic for DAI? TERMINAL AXONAL BULBS 59M 4 days Survival. Fall. VARICOSITIES 17M 14 days Survival. MVC VASCULAR PATTERN 18M 10 hours Survival. Assault 18M 10 hours Survival. Assault

16 You buy the premise, you buy the bit.

17 Towards Evidence Based Practice and Medicine mtbi subject selection for targeted studies

18 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

19 2) Targeted Drug therapy, e.g., DAI Multiple targets identified via NINDS workshop Smith, Hicks, Povlishock, J. Neurotrauma 2013

20 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?

21 Long-term screening BM identification of progressive neuropathological processes Atrophy Inflammation Tau and amyloid pathologies

22 Endpoints for mtbi BMs (toolbox) Assessment: ED, Sideline and Battlefield testing remove from play/ duty Direct management such as CT/ MRI (e.g., GFAP+) Evaluate therapeutic efficacy of randomly selected subjects Additionally, Diagnosis of neuropath/ anatomic substrates (e.g. DAI) Identify mtbi pts. at risk of persisting neruocognitive dysfunction Return to play/ service pt. management Serve as gold standard for testing additional non-invasive methods Select relatively homogeneous subjects for study enrollment Evaluate efficacy of targeted rehab strategies and drug treatments Evaluate long-term outcome, e.g., chronic neurodegeneration or inflammation Collectively to: Shorten time to approval of new treatments, allowing effective treatments to reach target patient populations sooner

23 Everybody Wins!!