Clinical Science Session

Biomarkers and
Surrogate Markers

Mentari Ginting, S.Ked

G1A218068

Acute injuries to the brain,
resulting from trauma, stroke, or
cardiac arrest are the number one
cause of death in people under
the age of 40.
Computed tomography (CT) or
magnetic resonance imaging
(MRI) is used to determine
whether the TBI is localized or
diffuse, without elucidating any
of the biochemical cascades
involved in brain injury
following trauma.
An accurate and reliable
prediction of outcome following
brain injury is important for head
injury patients, clinicians, and
society.
Most limitations of current
clinical assessment systems of
brain injury are due to the fact
that TBI is complex in pathology.
So far, the outcome
measurements most often used
are the Glasgow Coma Scale
(GCS) and the Glasgow
Outcome Score (GOS).
Development of other tools to
assess the severity of the initial
brain injury, to identify patients
at high risk for mortality and
morbidity, and to predict
outcome. The terms used for
these tools are biomarkers or
surrogate markers.
Surrogate markers: Surrogate or end point markers are intended to substitute for a clinical
end point. They are expected to predict clinical benefit or harm (or lack of benefit or harm)
based on epidemiological, therapeutic, pathophysiological, or other scientific evidence.

Biomarkers: A biomarker is a characteristic that is objectively measured and evaluated as an

indicator of normal biological processes, pathological processes, or responses to a therapeutic
intervention. It should appear in easily accessible material such as blood or cerebrospinal
fluid (CSF) and should be highly sensitive and specific.

Intention of using biomarkers or surrogate markers: The intention of using bio- or

surrogate markers is to get new insights into the pathophysiology of brain trauma, that is, the
effects of therapeutic interventions as well as the chance of a sufficient and efficient
evaluation of patient outcome after traumatic brain injury at early time points.
• Evidence for efflux of brain proteins in humans was provided by reports
showing that levels of certain neuronal and astroglial proteins are increased
measurably in CSF or serum after TBI.
• The most extensively studied markers are the astroglial protein S-100β,
myelin basic protein (MBP), neuron-specific enolase (NSE), and a
proteolytic fragment of the microtubule associated protein tau, called
cleaved-tau (C-tau).
• Unfortunately, high serum concentrations of those proteins have also been
found with chronic disease unrelated to acute brain injury or even in its
absence.
• Not all kinds of brain injury occur with a measurable elevation in S-100β,
MBP, NSE, or C-tau.
• None of those proteins has been established as a broadly accepted surrogate
marker for acute brain injury.
S-100β
TBI triggers a rapid increase in S-100β
serum concentrations, which normalize
4 to 6 hour after a mild TBI but remain
elevated 12 hours after severe TBI.

It is believed that there is a continuous

release of S-100β by injured glial
cells and that the serum levels remain
elevated due to a disrupted BBB.
Neuron-Specific
Enolase (NSE)
• NSE concentrations measured in CSF have served as markers of neuronal
damage due to a variety of neurological disorders such as status epilepticus
or Creutzfeldt-Jacob disease.
• Elevated NSE levels are also found in the CSF and serum after TBI and
were thus thought to be a possible surrogate marker for TBI.
Glial Fibrillary
Acidic Protein
(GFAP)
• Recent clinical studies revealed that GFAP is released to
serum after TBI and the levels are related to trauma severity.
• Pelinka’s studies clearly showed that GFAP serum levels were
related to the extent of brain damage, and that different
patterns of TBI seemed to beassociated with differences in
GFAP release. They finally found that GFAP is a strong
predictor in mortality and correlated well with severe disability
and vegetative state.
Cleaved
Tau
• After experimental TBI are missing so far. Instead, histological assessment of
lesion size and tissue loss is used to calculate trauma severity and the efficacy of
neuroprotective drugs in experimental TBI. On the other hand, surrogate markers
should also be potentially clinically applicable. Previous biomarkers NSE and S-
100- have failed to fulfill both requirements.
Spectrin Breakdown
Products (SBDPs)
• Despite the fact that focal and diffuse brain injuries can be evoked by
different mechanisms, several studies to date have shown that similar
biochemical cascades take part in the pathobiology of these different injury
types.
• SBDP immunoblots provide concurrent information about calpain76 and
caspase-388 activation, two of the most important regulators of cell death
after TBI, thus offering interesting insight into the pathobiochemical
mechanisms of trauma. Moreover, as the characteristic spectrin-derived
products appear in easy accessible material, this may lead to a better
monitoring of the progression of damage, response to medical intervention,
and even prediction of patient outcome, thus making SSDPs a potential
bio- and surrogate marker for TBI.
Apoptosis
Marker
• The initial tissue injury of the brain is proportional to the primary impact;
however, recent studies suggest that acute and chronic cell death after TBI
may also be due to PCD or apoptosis.
• There is an increasing amount of PCD markers but we focused on those
molecules that give the most useful insights in brain pathology after TBI
and that allow determination of biopathological pathways. Caspase-3 as
effector, the pro-apoptotic Fas, or bcl-2 as a potential antiapoptotic agent
seem to be the most valuable candidates in this group of biomarkers. The
parallel increase of these three molecules may indicate that PCD plays a
pivotal role in posttraumatic cell loss and edema and emphasize the
significance of apoptosis markers as potential bio/surrogate markers for
TBI.
 Conclusion
Despite several bio- or surrogate markers being available for several aspects of TBI,
none of them so far meet the demands of an independent, highly specific, and
sensitive marker for severity of TBI, which highlights the underlying
pathomechanisms and estimates the outcome of patients.

However, recent studies lead to the suggestion that it may be possible to develop a panel of
clinically useful bio- and surrogate markers. These combinations of markers could provide
better clinical information and help clinicians evaluate the prognosis of patients at early
time points and may even help to identify patients at risk for clinical deterioration after
mild TBI.

Promising candidates such as SBDPs, apoptosis markers, and maybe a combination of two
or more glial or neuronal markers (S-100-β, GFAP, NSE) need to be evaluated in future
studies using larger sample sizes to be able to reach this goal