Biomarkers for Acute Traumatic Brain Injury

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Biomarkers for Acute Traumatic Brain Injury

• Robert D. Welch, MD, MS
• Department of Emergency Medicine
• WSU School of Medicine

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Goals

• Discuss current and potential new biomarkers that
  can aid in the diagnosis and management of
  patients with TBI
• Diagnostic
• CT
• MRI
• Serum Biomarkers
• Potential application in monitoring therapy

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Disclosure

• ProTECT III (Progesterone for the Treatment of
  Traumatic Brain Injury (David Wright, MD PI)
• Funding Source NIH
• Role Site PI
• BIOMARKERS OF BRAIN INJURY MAGNITUDE AND OUTCOME
  OF MILD AND MODERATE TBI A FEASIBILITY STUDY
  (Ronald Hayes, PI)
• FUNDING SOURCE DOD VIA BANYAN BIOMARKERS
• ROLE SITE PI
• SAFETY FEASIBILITY OF MINOCYCLINE IN THE
  TREATMENT OF TBI (JAY METHAYLER, PI)
• FUNDING SOURCE MICHIGAN MODEL TBI SYSTEM GRANT
• ROLE SUB-INVESTIGATOR

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Disclosure (cont.)

• INTREPID-2566 Study (INvestigating TREatments for
  the Prevention of secondary Injury and Disability
  following TBI(A Randomized, Double-Blind,
  Placebo-Controlled, Dose-Escalation Study of
  NNZ-2566 in Patients with Traumatic Brain Injury
  (TBI)
• Funding Source DOD via Neuren Pharmaceuticals
• Role Site Investigator

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Requisite Review

• Scope of TBI
• 1.4 million suffer TBI each year
• 1.1 million treated and released from EDs
• gt 235,000 hospitalized
• gt 50,000 die
• Many more are permanently disabled (80,000 to
  90,000?)
• Progressive Mortality Reduction over 30 yrs.
• 50
• 35
• 25
• Even lower (guidelines?)

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Comparison of Annual Incidence
Spinal Cord Injuries
Breast Cancer
Multiple Sclerosis
Traumatic Brain Injury
HIV/AIDS
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From Brain Trauma Foundation Website

• Traumatic Brain Injury (TBI) is the leading cause
  of death and disability in children and adults
  from ages 1 to 44.
• Brain injuries are most often caused by motor
  vehicle crashes, sports injuries, or simple falls
  on the playground, at work or in the home.
• Every year, approximately 52,000 deaths occur
  from traumatic brain injury.
• An estimated 1.5 million head injuries occur
  every year in the United States emergency rooms.
  a
• An estimated 1.6 million to 3.8 million
  sports-related TBIs occur each year.
• At least 5.3 million Americans, 2 of the U.S.
  population, currently live with disabilities
  resulting from TBI.
• Moderate severe head injury (respectively) is
  associated with a 2.3 and 4.5 times increased
  risk of Alzheimers disease.
• Males are about twice as likely as females to
  experience a TBI.
• The leading causes of TBI are falls, motor
  vehicle crashes, struck by or against events, and
  assaults, respectively.
• TBI hospitalization rates have increased from 79
  per 100,000 in 2002 to 87.9 per 100,000 in 2003.
• Exposures to blasts are a leading cause of TBI
  among active duty military personnel in war
  zones.
• Veterans advocates believe that between 10 and
  20 of Iraq veterans, or 150,000 and 300,000
  service members have some level of TBI.
• 30 of soldiers admitted to Walter Reed Army
  Medical Center have been diagnosed as having had
  a TBI.

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Variability of Outcomes

• 58 y.o. male middle-school teacher
• Harley-Davidson Motorcycle accident
• GSC 8 on arrival
• Subdural, Contusion, and Traumatic SAH
• Fractured right humerus and pelvis
• Pulmonary contusions
• 1 month ICU and step-down unit care
• Inpatient/outpatient rehab
• Back teaching 9 in months

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Variability of Outcomes

• 28 y.o. male restaurant worker
• MCV unrestrained driver
• GCS 9 on arrival
• Small hemorrhages
• DAI
• No other significant injuries
• Neurological ICU for 5 days
• Prolonged inpatient rehab
• Persistent neurological and cognitive deficits

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Imaging
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Imaging - CT

• CT is the imaging needed in the hyper-acute phase
  of moderate/severe TBI!
• No decision rules are needed for this group
• Utility of CT
• Identify intracranial or extra-axial hematoma
• Basal Cistern compression - impending herniation
• Midline shift - sub-falx herniation or cerebral
  edema
• Traumatic SAH
• Skull fractures - potential delayed problems
• CT does have some predictive abilities for
  long-term prognosis (IMPACT) but not so good to
  assess efficacy of TBI therapy

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Some Advanced MRI Techniques

• Diffusion Weighted Imaging (DWI)
• Detection of non-hemorrhagic shearing lesions
  (Diffuse Axonal Injury -DAI)
• Diffusion Tensor Imaging (DTI)
• Used to evaluated white-matter track integrity
• May be good for DAI
• Fractional Anisotropy (FA) has been correlated
  with injury severity and outcome
• Susceptibility-Weighted Imaging (SWI)
• Small hemorrhagic shearing lesions
• Fluid-Attenuated Inversion Recovery (FLAIR) MRI
• Multiple different lesions (edema, extra-axial
  blood, other)

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TBI Pathology and MR Approaches
Compliments of E. Mark Haacke, Ph.D. and Zhifeng
Kou, Ph.D. WSU MR Research Facility
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MR Research Center HUH
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Case SWI and DTI can be Complimentary
SWI - Hemorrhage
FA Z-map (DTI) White Matter Shearing
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MRI Difficulty Interpreting Utility

• Small sample sizes
• Lack of consistent methodology
• Most not performed during the hyper-acute phase
• No clear definition of normal/abnormal
• Pre-existing brain abnormalities

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Serum Biomarkers

• No biomarkers are yet of proven clinical utility
  for the diagnosis and management of TBI
• All seem to lack specificity
• Added value concept
• Use in mild vs. moderate/severe

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S100B

• S100-B, a 21-kDa calcium-binding glial-specific
  protein mainly expressed by astrocytes
• Most extensively studied
• Detected soon after injury
• May not cross intact blood-brain barrier
• Found in other body injuries or ischemia
• Melanoma biomarker?
• Studies cannot demonstrate utility

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S100-B Protein as a Screening Tool for the Early
Assessment of Minor Head Injury

• Zongo D, et al. Ann Emerg Med. March
  201259209-218

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Goal

• Assess the potential role of measuring blood
  S100-B protein levels as a screening tool for
  patients with minor head injury.
• The main outcome was the diagnostic performance
  of the S100-B test compared with CT scan findings.

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Study Subjects

• 1560 patients
• Age median 57 (IQR 3282)
• 55.8 males
• GCS
• 15 (76)
• 14 (21.5)
• 13 (2.5)
• Mechanism
• Falls 38
• Other/Unknown 32.6

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Results

• 111 - positive CT scans
• Evaluated at three s110b levels
• 0.10, 0.12, and 0.14 µg/L
• At levels below 0.10 µg/L only 1 patient had a
  positive CT
• Between 0.12 and 0.14µg/L 2 patients

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Glial Fibrillary Acidic Protein

• Appears to be brain-specific
• Expressed by astrocytes
• Appears to be predictive
• Needs evaluation in mild/moderate head injury

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Elevated Levels of Serum Glial Fibrillary Acidic
Protein Breakdown Products in Mild and Moderate
Traumatic Brain Injury Are Associated With
Intracranial Lesions and Neurosurgical
Intervention
Papa, L, et al. Ann Emerg Med. 2012xxxxx.
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• 307 patients enrolled
• 108 TBI patients
• 97 with GCS score 13 to 15
• 11 with GCS score 9 to 12
• 199 controls
• Area under the ROC of 0.90 (95 CI 0.86 to 0.94)

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Neuron-Specific Enolase (NSE)

• Glycolytic enzyme
• Detected within 6 hours of injury
• Slow elimination
• Marker of other pathologies (lung cancer, stroke,
  etc.) and hemolysis

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Myelin Basic Protein

• Major component of myelin
• Released after white-matter injury
• Not noted in ischemia or absence of white matter
  pathology

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Others

• Fatty acid binding proteins
• Inflammatory markers
• Chemokines
• Lipid metabolites
• Etc.

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Ubiquitin C-terminal hydrolase (UCH-L1)

• Also called neuronal-specific protein gene
  product (PGP 9.3)
• High abundance and specific expression in neurons
• High specificity and abundance in central nervous
  system
• Candidate biomarker for TBI

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Clinical Evaluation

• Prospective case control study (TBI vs
  Hydrocephalus)
• GCS score lt 8 and requiring a ventricular ICP
  monitoring
• CSF Levels measured

(Papa, et al Crit Care Med 2010 38138 144)
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Oucomes

• Short-term
• GCS score
• Initial CT findings using the Marshall
  classification
• Complicated post-injury course
• Long-term
• Mortality
• Glasgow outcome score

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Alpha II-spectrin breakdown products

• aII-spectrin found primarily in neurons (axonal
  skeleton)
• SBDPs
• SPDP150 and SBDP145 by calpain (necrosis products
  formed early)
• SBDP120 by caspase-3 (apoptosis formed later)

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Future Utility?

• Panel of biomarkers
• For diagnosis of mild TBI rather than mod/severe
• Evaluate patients course and effects of
  treatment for all patients
• Study new potential therapies

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Thanks