March 2022 • DALLAS MEDICAL JOURNAL | 21
in the context of this evolving neurotrauma
pathology. Further, because of the complex
heterogeneity of TBI, it is likely that the optimal
tool for assessing TBI will involve multimodal
components; specifically, a panel of
blood-based and physiological biomarkers
coupled with advanced neuroimaging that
are appropriately obtained at multiple time
points. It is also important to understand
how a biomarker can be used to advance
treatment for chronic somatosensory, neuropsychiatric,
and cognitive deficits post-TBI.
As part of the Brain Trauma Blueprint, TBI
State of the Science, this article provides a
review of the current state of TBI biomarker
evaluation and development and provides
a framework of recommendations needed
to fill current research gaps in biomarker
development.
The following section outlines a framework
of the steps required to develop multi-modal
TBI biomarkers into useful tools for clinical
application:
• Establish validity and reliability of the
biomarker (i.e., can it be accurately and
reproducibly measured)
• Determine the biomarker’s window of
use (i.e., when is it best measured in relation
to the injury event or disease onset)
• Demonstrate that the assay/marker is
clinically and pre-clinically applicable
(to improve therapy translation)
• Show qualification (i.e., is the biomarker
associated with the target end-point)
• Select utilization (i.e., what is the context
of use)
• Understand the biological rationale
for using the biomarker (i.e., the causal
pathway in which the biomarker is
positioned)
• Establish that interventions show relevant
effects on the biomarker prediction
in patient outcome
• Demonstrate reproducibility (i.e., consistency
between a test data set and a
confirmatory data set)
• Achieve qualification for regulatory
acceptance (i.e., going through the FDA
qualification process)
Biomarkers and
Treatment Development
Individuals with TBI present a diverse range
of symptoms (from persistent symptoms to
full recovery) because of the multiple clinical
endophenotypes and biological underpinnings
of their injuries. Many efforts have
focused on identifying common, specific,
and well-defined injury characteristics associated
with TBI, with an overriding goal of
identifying biomarkers that closely align with
injury characteristics.
Biomarkers have multiple uses: diagnostic
biomarkers identify the presence of TBI,
prognostic biomarkers inform about expected
outcomes in injured individuals, and
predictive biomarkers predict response to a
specific therapy and can be used to monitor
response to therapy. Biomarkers may support
clinical risk analysis and decision making, and
can be used to stratify patients into pathobiologically
defined (endophenotype-guided)
subpopulations in clinical trials. Biomarkers
can serve to screen and identify patients
who may expect an altered, delayed, or
complicated recovery or who might later develop
progressive neurobehavioral symptoms
and deficits (e.g., cognitive decline) as they
age. Using biomarkers to provide inclusion/
exclusion criteria for stratifying patients
for specific outcomes could help reduce
confounders in randomized controlled trials
(RCTs) and will facilitate the development of
targeted interventions in TBI.
Biomarkers can assess treatment effectiveness
by narrowly determining target
engagement or broadly tracking progressive
atrophy and neurodegeneration caused by
brain cell injury or death. Biomarkers that
can accurately quantify decreased functioning
and reversible injury are essential to
monitor patient status and severity in the
acute and subacute periods, especially after
mild TBI (mTBI). However, to date, objective
TBI indicators are still not commonly used in
clinical practice (particularly in the absence
of focal lesions) and biomarker use for mTBI
remains unrealized despite being an active
area of research. Finally, predictive and
pharmacodynamic biomarkers may serve as
early end-points in clinical trials evaluating
new therapies, making biomarkers relevant
as surrogate end-points. Thus, successful
clinical biomarkers will channel heterogeneity
in the presentation of patients with
TBI and optimize diagnosis and treatment.
Importantly, each biomarker needs to show
robustness, validity, and reliability within its
specific context of use.
For each of the mentioned biomarker usecategory,
biomarker examples include:
• Neuroimaging biomarkers, such as
computed tomography (CT), structural
magnetic resonance imaging (sMRI),
functional MRI (fMRI), perfusion weighted
imaging (PWI), magnetic resonance
spectroscopy (MRS), positron emissions
tomography (PET), magnetization transfer
imaging (MTI), arterial spin labeling
(ASL), near-infrared spectroscopy (NIRS),
and single photon emission computed
tomography (SPECT)
• Neurophysiological biomarkers, such
as electroencephalography (EEG),
magnetoencephalography (MEG), and
eye-tracking
• Biofluid biomarkers, such as those from
cerebrospinal fluid (CSF), saliva, sweat,
urine, blood, and blood fractions, and
include genetic, proteomic, and other
marker classes
• Digital biomarkers, such as devicebased
readouts and wearables
• The following sections provide examples
of individual biomarkers that demonstrate
how these tools may augment
clinical trials and advance injury-alleviating
treatments.
Current State of TBI Biomarker
Evaluation and Development
Biomarker development in the field of TBI is
less developed than those in fields of oncology,
cardiovascular disease, stroke, and some
neurodegenerative disorders such as Parkinson’s
disease or multiple sclerosis. Progress in
TBI biomarkers has been hampered by injury
heterogeneity and limited availability of
large, systematic observational studies that
longitudinally (hours to years) collect and
analyze multi-modal candidate biomarkers
throughout the course of injury. Consequently,
despite many peer-reviewed publications
of candidate TBI biomarkers, most studies
report small, cross-sectional cohorts and are
not yet independently validated in larger,
well-defined cohorts to determine clinical
use. Nearly all biomarkers reported do not
reach Level 1 Evidence (highest quality of
methodology), which requires data obtained
in a well-designed prospective RCT,
meta-analysis of RCTs, or rigorous testing
of previously developed diagnostic criteria.
Rather, evidence for the use of imaging as
a biomarker, for example, is generally Level
II-III (prospective or retrospective cohort
studies). To date, neuroimaging biomarkers
are best established clinically for acute
moderate to severe TBI (e.g., non-contrast
head CT has Level I recommendation as a
test for acute TBI and when there are signs
of neurological deterioration), but aside from
non-contrast head CT, most other imaging
modalities are considered Level II-III (e.g.,
diffusion imaging).2 Advanced neuroimaging
approaches, including MRI-based and
PET-based modalities, provide insight into
microstructural, functional, and physiological
changes following TBI. However, these may
require both large-scale normative data
and FDA-approved quantitative diagnostic
standards for clinical use. As such, many
advanced neuroimaging approaches remain
confined to the research setting. Likewise,
physiological biomarkers hold great promise
but are early in their development.
Diagnostic Biomarkers
Using diagnostic TBI biomarkers for inclusion
and exclusion of participants in RCTs will
be a critical enhancement for clinical trials.
Currently, many studies, particularly those
including mTBI, are limited by the subjective
nature of current diagnostic criteria that rely
on clinical symptoms. Until objective candidate
diagnostic biomarkers are validated,
often subjective or inadequate clinical symptoms
remain the status quo for diagnosis.
Besides distinguishing between those with
and without TBI, diagnostic biomarkers may
also allow clinicians to distinguish patients
based on their TBI endophenotype, and subsequently
identify patients who may benefit
most from specific interventions. Additionally,
biomarker measures obtained prior to, during,
and at the conclusion of an intervention
can be used to assess treatment efficacy
and classification accuracy. In the next section
we summarize the use of biomarkers for
diagnostic indications.
The Future of Precision Medicine:
Mult-Modal Biomarkers and
Biomarker Panels
TBI symptoms and pathophysiology vary
from patient to patient and over time;
therefore, a single biomarker is not sufficient
for diagnosis, prognosis, or monitoring
across the TBI spectrum. It is more likely that
biomarker panels are needed to best assess
the diverse clinical phenotypes and heterogeneous
pathophysiology of patients with