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

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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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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

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

1,600,000
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
10,400
Multiple
Sclerosis
11,000
Spinal Cord
Injuries
43,681
HIV/AIDS
1,500,000
176,300
Breast
Cancer
Traumatic Brain
Injury

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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 Alzheimer ’ s 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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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

What ’ s the difference???

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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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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 longterm prognosis (IMPACT) but not so good to assess efficacy of TBI therapy

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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)

Hemorrhage*
Pathology
Ischemia
Shearing of WM*
Hypoperfusion
Altered Biochemistry
SWI
DWI / ADC
MR Method
Diffusion Tensor (FA)
Perfusion (BT, ASL)
MR Spectroscopy
Compliments of E. Mark Haacke, Ph.D. and Zhifeng Kou, Ph.D.
WSU MR Research Facility

T2
FA
MRSI
SWI
DTI
SVS
PWI fMRI
MRS I
MR Research Center HUH

CT
MRI-T2 MRI-FLAIR standard
T2*-GRE
SWI

SWI - Hemorrhage FA Z map (DTI) – White Matter
Shearing

 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

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

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 S100-B, a 21-kDa calcium-binding glialspecific 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

 Zongo D, et al. Ann Emerg Med. March
2012;59:209-218

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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.

 1560 patients
 Age median 57 (IQR = 32–82)
 55.8% males
 GCS
 15 (76%)
 14 (21.5%)
 13 (2.5%)
 Mechanism
 Falls – 38%
 Other/Unknown 32.6%

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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 0.14 µg/L – 2 patients

Sensitivity
0.1
99.1 (95.0–100)*
Specificity 12.2 (10.6–14.0)
Negative predictive value 99.4 (96.9–100)
Positive predictive value 8 (6.6–9.5)
LR+
LR–
No. of false-negative results
1.13 (1.10–1.16)
0.07 (0.01–0.50)
1
0.12
0.14
99.1 (95.0–100) 97.3 (92.3–99.4)
19.7 (17.7–21.9) 26.8 (24.5–29.1)
99.7 (98.1–100) 99.2 (97.8–99.8)
8.6 (7.1–10.3) 9.2 (7.6–11.0)
1.24 (1.20–1.28) 1.33 (1.27–1.39)
0.04 (0.006–0.32) 0.06 (0.03–0.31)
1 3

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

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. 2012;xx:xxx.

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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)

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

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

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Fatty acid binding proteins
Inflammatory markers
Chemokines
Lipid metabolites
Etc.

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

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Prospective case control study (TBI vs
Hydrocephalus)
GCS score < 8 and requiring a ventricular ICP monitoring
 CSF Levels measured
(Papa, et al: Crit Care Med 2010; 38:138 –144)

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

Early necrosis (calpain mediated)
Later apoptosis (caspase-3 mediated)

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