The Journal of Neurotrauma - 8

EXPERT PANEL DISCUSSION
Dr. McCrea, do you think that these new diagnostic techniques or blood tests must be proven to
be at least as effective as the SCAT or the MACE 2
in prospective clinical trials before they are deployed or adopted widely?
Dr. McCrea: I do not necessarily know that the
validation of these biomarkers we are talking about,
for instance, would be validated against the SCAT or
against the MACE per se. I think from the discussion
we had before, the added value of a biomarker above
and beyond a clinician's assessment of a patient in the
emergency department, in the austere environment,
or on the sport sideline should be demonstrated by
whatever paradigm is appropriate for the setting.
I will add to what Dr. Manley described so nicely
earlier, that this stacking progression where in
TRACK-TBI, we have this cohort of patients who are
CT-negative but MR-positive, and then a cohort of
patients who are both CT-negative and MR-negative,
but they are still seen at a level 1 trauma center, as you
talked about. They were sufficiently injured to be either transported to and have their critical care at a
major trauma center.
But from our biomarker research in the sporting
environment, where we see really strong performance of GFAP and UCHL1, even in a cohort of all
MR-negative patients, athletes, Military Service
Academy Cadets, or those injured in combative
training and so forth.
When you think about the broad scope and potential
utility of biomarkers, certainly in a critical care or
neurotrauma setting, prediction of blood on CT is
absolutely critical and time sensitive. But what we are
seeing is the promising candidate biomarkers that we
have talked about here, and several inflammatory
markers, are actually showing strong performance in
the mildest of the mild TBI cases, including athletes,
civilians, and Service Members with concussion.
These are individuals who would never go to a hospital. Athletes, for instance, are evaluated by an athletic trainer and may never be seen by a physician, and
yet we are seeing really strong performance in these
biomarkers of acute concussion.
That is what leads Dr. Puccio and a lot of us to think
that this is really the future. We have been employing
cognitive tests and other clinical measures for a long
time that have their role in concussion assessment, but
we have come a long way in a matter of ten years with
emerging and promising biomarkers.
Dr. Marion: Dr. Bazarian, what are your thoughts?
Dr. Bazarian: I agree 100% with what Dr. McCrea
has said as the crux of the issue. What we are talking
about today is how to use biomarkers for diagnosis
8

and what that has to do with how we establish the
diagnosis of concussion. Right now, the reference
standard, if you will, is the self report. Many people would argue that is not really great. We talked
about how the symptoms are non-specific. So the
real issue is, what kind of reference standard are we
going to use to decide whether our markers are good
or bad? Symptoms will always predict symptoms.
Having symptoms after an injury will always correlate to progression or lack of progression of
symptoms later on.
What we really want to know is how these markers
reflect some objective standard for brain injury. We
cannot do a biopsy. It would be nice to take a brain
biopsy and vet blood levels, but we cannot do that. So
what is it we are going to use to decide whether the
MACE, the SAC, or a blood test is better at figuring out
whether someone has got a brain injury? My personal
bias is that DTI probably comes the closest to that, to a
quasi-objective reference standard for tissue injury.
As a field, we still need to figure out how we are
going to develop this reference standard so that we can
say, ''Yes, our marker does or does not reflect injury in
the brain.''
Dr. Marion: The thing that I struggle with is that
these blood biomarkers are FDA approved for
showing whether or not the CT scan is abnormal.
They are not FDA approved for the objective diagnosis of concussion. But, in addition to the presence of a surgical intracranial mass lesion, what we
really want to know is whether or not the patient
had a concussion so that they will not be sent back
into the game or the fight and have another concussion too soon after the first one.
In the Military I can certainly see the advantage
of having a point-of-care diagnostic device that you
could use to quickly tell whether or not you had a
serious head injury.
Do you have any final comments about this issue?
Dr. Puccio: I think just to follow up, Dr. Marion, with
what you were saying with making sure that we are
able to have an aid in a diagnosis of concussion and not
just whether or not you have a positive CT scan is
going to come down to a little bit more sensitivity of
the biomarkers as we get larger cohorts and different
sampling. The cutoff, I think, will be able to be made a
little bit more distinct for concussion versus the
different severities of head injury as we further develop these biomarkers with higher sensitivity. So
right now, we are able to focus on the biomarkers in
correlation to a positive CT scan or positive MRI.
But I think as we have larger sample cohorts being
performed, we will be able to determine specific
cutoff values as well.
ª 2020 by MARY ANN LIEBERT, INC.

The Journal of Neurotrauma

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