The Journal of Neurotrauma - 3

EXPERT PANEL DISCUSSION
will present with orthopedic injuries or other injuries
that are going to confound their assessment, so you
have to tease that out. A lot of times the patient will not
have the mental capacity to answer those questions
correctly at that assessment time, so they may need a
little bit of time to absorb their injury status prior to
answering questionnaires.
But it would be great to have more of an objective
biomarker type blood test to triage those patients and
determine that these are the patients who need to be
evaluated further for a concussion diagnosis and obtain
the questionnaires for a more detailed evaluation.
Practitioners need to have the biomarkers made
available for the different orthopedic controls and need
to make sure they are distinguishing between different
age levels with other normal baseline values.
But all of that aids individualizing that patient at that
time point. Ideally having a complete package of the
biomarkers values and the evaluations with concussive
symptom questionnaires and a thorough concussive
history of a patient needs to be done.
Dr. Marion: Dr. McCrea, you are a neuropsychologist so I think you would consider the neuropsychological evaluation or cognitive evaluation
that is a part of the MACE and SCAT very important, right? I mean, in the case of the MACE you
created it after all.
Dr. McCrea: Well, I think a number of important
points have been raised here and speak to the evolutionary context of this discussion over the last 25
years. I agree with the point made by Dr. Manley that
the diagnosis of any medical condition based on selfreported or subjective signs and symptoms is less than
ideal. What our patients tell us is important, but ideally, we do not want to make a formal diagnosis based
solely on self-report.
I think the nomenclature might require some revision here, too, because I am thinking back 25 years
ago, when really the state of the art for concussion
assessment was solely symptom evaluation and based
on self-reported symptoms. At that time, cognitive
testing, balance testing, eye tracking, quantitative
EEG, and other clinical measures were being touted as
objective diagnostic tools for assessment of concussion beyond symptom reporting.
What we have graduated to at this point, and what we
are really talking about today is the development and
the optimization of physiological markers of injury and
recovery. While the various clinical measures and
cognitive tests we have at our disposal to evaluate
concussion may be additive to self-reported symptoms,
they are also known to be influenced by factors other
than concussion. So, in fact, they are more objective
than self-reported symptoms, but they themselves are
not perfectly objective markers of brain injury either.
ª 2020 by MARY ANN LIEBERT, INC.

I support the multi-dimensional, multi-pronged
approach to injury evaluation, which encompasses
listening to what patients tell us in conjunction with
more objective clinical outcome assessments. But
ideally, as cited in the example from Dr. Bazarian, the
combination of the patient coming in with chest pain,
what their EKG says, and what their troponin biomarker level tells us is really what Dr. Bazarian looks
at in the emergency department in evaluating heart
attack patients.
In my mind, as Dr. Manley pointed out, blood and
physiological biomarkers of injury would be additive
to observed signs, reported symptoms, and the results
of clinical testing, whether that is cognitive, balance,
eye tracking, visual ocular motor, or otherwise. I do
not think anyone is touting that we would be making
the diagnosis of brain injury solely based on a biomarker level, independent of what clinical information
we have.
These blood biomarkers go a lot further in our
assessment and characterization of brain injury.
Even when there is not a critical need because it is
clearly evident that this patient has a brain injury of
some level, deeper enrichment and characterization
of the injury by virtue of these biomarkers adds
enormous value over and above our current clinical
methods.
Dr. Marion: I want to move on to the next question
and will address this to Dr. Gill. In most cases, a
concussion is considered primarily a physiologic
injury without significant brain tissue damage. At
least, that is what I have always thought. So why do
we think that we can use these brain-derived
structural proteins as useful blood biomarkers
following a concussion?
Dr. Gill: I have been surprised over time to see the
same biomarkers coming up over and over - glial fibrillary acidic protein (GFAP), neurofilament light
chain (NfL), and tau as prognostic biomarkers. So,
really, extending not just to diagnostic biomarkers, but
also these biomarkers in the acute and subacute period.
Just thinking about how they are coming out in the
blood, a lot of the work that we are doing in our lab
now is looking at things that would change the clearance of those proteins to then be detectable in the
blood, including the glymphatic function and the
blood-brain barrier, which I think are two major
components. It is like creatinine when we think about
urine. We need to know about the flow and how it is
coming out of the glymphatics and the cerebral spinal
fluid, and we can detect it in the blood.
But consistently, we are seeing the same findings
across multiple studies of patients with mild TBIs, including GFAP being diagnostic, and that NfL and tau
are more prognostic biomarkers. Recently, we are even
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