The Journal of Neurotrauma - 4

EXPERT PANEL DISCUSSION
seeing NfL in a chronic state in veterans who have had
multiple brain injuries and remain symptomatic.
We are really extending these biomarkers that we
thought were more acute in the subacute and more
chronic phases. The more that we are seeing that these
individuals who have these injuries and then become
symptomatic maintain these elevations indicate that
they are related to symptomatology or some type of
pathophysiology that relates to development, as well
as the maintenance of these symptoms over time.
So we are extending them, and we really did not
even think - I think Mike will say, too, we did not even
measure these at six months when we had an opportunity one or two years ago because we just did not
think that they were there, and now we are actually
seeing them there six months after injury, both being
diagnostic of having the injury, as well as prognostic
value in having lasting neurological symptoms and
deficits.
It is promising to see consistent findings across
different groups and the same biomarkers really
lending evidence to say that what we are seeing means
something, and that we now need to really understand
the mechanisms to provide preventive interventions
for individuals who are most at risk.
Dr. Marion: So, Dr. Gill, you believe that the protein biomarkers are important for characterizing
the nature of the injury as well as for diagnosis?
Dr. Gill: Yes. In some of our studies we have at NIH
that we are submitting for publication soon, we are
actually finding that they are not indicative of just
having CT findings or MRI findings, but subtypes
within an MRI. Specifically, we are looking a lot at
meningeal injury to understand how that impacts the
proteins that we are then detecting in the blood, but also
how that type of blood-brain barrier can have an impact.
A lot of these studies are focused on some of the
Military findings we have had, especially with blastrelated injuries, in which we are seeing reductions in
the same proteins that we actually see elevations in in
these more blunt-force minor injuries.
A couple of months ago we published that GFAP
was actually reduced after a moderate blast exposure.3
We have also seen that tau as well as NfL are reduced,
and so those findings lend us to say we know that there
is some type of damage because of the magnitude of
the exposure. But, where are these proteins, and how
can we see them, and what is the time impact? When
are we actually being able to detect them in the blood?
And so that has really been the focus of our lab over
the last year, to understand how the nature of the injury
as well as the timing of when that blood is collected
really has an impact on what we are seeing for the
personalization of the individuals exposed.
4

Dr. Marion: Dr. Manley, a lot of individuals who
have a concussion never end up in the TRACK-TBI
cohort. They never end up in the emergency department even though they are usually not allowed
to return to play. They may see their doctor on
Monday morning or something like that if they
have persistent symptoms.
In the Military there also is probably more injury
than we think with low-level blasts, a blast from
shoulder-mounted recoilless rifles, or artillery that
never causes a classic concussion but does cause
micro-imaging abnormalities down the road.
So the question is this: Is that subgroup of individuals also at risk for secondary insults or secondary injury from going back and getting another
hit to their head too soon, or is it just those people
who are severe enough that somebody decides they
have to go to a level 1 trauma center, and they have
to get a CT scan of their head, that is at risk?
Dr. Manley: Well, I think we do not yet know, because thus far we have only seen and enrolled patients
in level 1 trauma centers for our study; we have only
seen the people we can. In our Lancet Neurology
article,4 we looked at a group of people who were
brought to level 1 trauma centers with a history of
traumatic brain injury within 24 hours and who met
the widely accepted American Congress of Rehabilitation Medicine (ACRM) criteria5 with some
sort of alteration of consciousness or loss of consciousness - so certainly weighted toward more significant, but certainly within the definitions such as
the ACRM criteria that we would all agree had sustained a traumatic brain injury and even in those
patients who had a negative head CT, there was a
subset of those who had pathology that could be seen
on an MRI scan, which is, as we all know, more
sensitive at finding abnormalities than a head CT.
Even in those patients with a negative head CT, we
saw associations with elevated levels of GFAP, suggesting that the GFAP biomarker is more sensitive
than a CT scan for identifying pathology that can be
confirmed on an MRI scan.
The other thing that was in that article that we did
not really highlight, but I would speak to here, is that
even when you look at the GFAP levels in the patients
with a negative MRI - and I am talking about structural clinical MRI, not some of the more advanced
sequences that many of us are running today, but just
looking at a structural MRI, even people who were
negative on a structural MRI had higher levels of
GFAP than the orthopedic trauma controls.
What that says to me is that there is a level of injury
that is not detectable with a standard 3T MRI or CT
scan, which still exists. And again, if we are talking
about diagnosis, I would say that it's likely that if we
ª 2020 by MARY ANN LIEBERT, INC.

The Journal of Neurotrauma

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