BIOMARKERS FOR ACUTE TRAUMATIC BRAIN INJURY

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

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

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

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

Requisite Review

      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?)      Progressive Mortality Reduction over 30 yrs.

50% 35% 25% Even lower (guidelines?)

Comparison of Annual Incidence

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

            

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 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.

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

What ’ s the difference???

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

Imaging

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

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)

TBI Pathology and MR Approaches

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

Case: SWI and DTI can be Complimentary

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

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

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

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

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

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

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.

Study Subjects

 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%

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 0.14 µg/L – 2 patients

Sensitivity Specificity Negative predictive value Positive predictive value LR+ LR– No. of false-negative results 0.1

99.1 (95.0–100)* 12.2 (10.6–14.0) 99.4 (96.9–100) 8 (6.6–9.5) 1.13 (1.10–1.16) 0.07 (0.01–0.50) 1 0.12

99.1 (95.0–100) 19.7 (17.7–21.9) 99.7 (98.1–100) 8.6 (7.1–10.3) 0.14

97.3 (92.3–99.4) 26.8 (24.5–29.1) 99.2 (97.8–99.8) 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

Glial Fibrillary Acidic Protein

    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.

   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)

Neuron-Specific Enolase (NSE)

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

Myelin Basic Protein

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

Others

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

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

Clinical Evaluation

  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)

Oucomes

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

Alpha II-spectrin breakdown products

  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)

Future Utility?

    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

Thanks