NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE
Biomarkers of cognitive dysfunction in traumatic brain injury
Zhao-Liang Sun • Dong-Fu Feng
Received: 18 January 2013 / Accepted: 30 July 2013 / Published online: 14 August 2013
� Springer-Verlag Wien 2013
Abstract Acetylcholine, glutamate, dopamine, serotonin
(5-HT), gamma-aminobutyric acid, substance P (SP),
amyloid-b (Ab) and neurotrophic protein S100B are
arguably the most important cognition-related biomarkers
in the brain. Among this list are five neurotransmitters that
signal through postsynaptic receptors. Our knowledge of
cognition-related biomarkers has been advanced through
translational experiments and clinical case-study data.
Although these biomarkers are widespread in the brain and
pronounced individual variations exist, these biomarkers
can be used to identify both acute and chronic abnormali-
ties following traumatic brain injury. Changes in these
biomarkers likely indicate damage to brain networks or to
key brain cell types that support cognitive functions.
Identification of such biomarker abnormalities could result
in earlier diagnoses, improved prognoses and therapies that
enable neurotransmitters to return to normal levels.
Keywords Cognitive dysfunction � Traumatic brain
injury � Biomarker
Introduction
An increase in the rate of traumatic brain injury (TBI) has
coincided with the rapid increase in industrial develop-
ment. This increase in TBI represents a global healthcare
crisis. An estimated 1.5–2 million people incur a TBI in the
USA each year (NIH Consensus Development Panel on
Rehabilitation of Persons with Traumatic Brain Injury
1999). Approximately 10–15 % of individuals with mild
TBI will have persistent cognitive symptoms, and a higher
percentage of patients with moderate or severe TBI will be
left with significant, long-term cognitive dysfunction
(Niogi et al. 2008). Following TBI, deficits are commonly
observed in frontal executive functioning (e.g., problem
solving, set shifting, impulse control and self-monitoring),
attention, short-term memory, learning, information pro-
cessing speed, speech and language (McAllister 2011).
Poor cognitive outcomes present significant challenges to
independent living, social re-adaptation, family life and
work. The severity of cognitive deficits resulting from
mechanical trauma has been found to depend on both the
primary mechanical damage and complex pathophysio-
logical events, particularly changes in several biomarkers
(Karakucuk et al. 1997). It would be beneficial for the
diagnosis, treatment and long-term prognostication of
cognitive dysfunction following TBI to explore the mech-
anisms underlying changes in related biomarkers. In this
article, we review cognition-related biomarkers in TBIs,
including acetylcholine, glutamate, substance P (SP),
dopamine, serotonin (5-HT), gamma-aminobutyric acid
(GABA), amyloid-b (Ab), neurotrophic protein S100B and
apolipoprotein E (ApoE) (Table 1). We purpose that this
review would be beneficial for the diagnosis, treatment and
long-term prognostication of cognitive dysfunction fol-
lowing TBI.
Z.-L. Sun � D.-F. Feng
Department of Neurosurgery, No. 3 People’s Hospital Shanghai
Jiaotong University School of Medicine, Shanghai, China
e-mail: [email protected]
D.-F. Feng (&)
Institute of Traumatic Medicine, Shanghai Jiaotong University
School of Medicine, 280 Mo-He Road, Shanghai 201900, China
e-mail: [email protected]
123
J Neural Transm (2014) 121:79–90
DOI 10.1007/s00702-013-1078-x
Table 1 Biomarkers associated with cognitive dysfunction after TBI
Biomarkers Distribution Regulation Cognitive function-
related receptors
Agonists Antagonists Cognitive functions
Acetylcholine
(ACh)
Cerebral cortex,
hippocampus,
retina, striatum
and other parts
Downregulated
(Scremin et al.
2006, Dixon
et al. 1996)
mAChR M1, M2,
M3,
M4,
M5
Arecoline,
cevimeline,
milameline,
milameline,
RS-86,
sabcomeline,
talsaclidine,
WAY-132983,
xanomeline
Scopolamine,
imidafenacin,
tropicamide,
VU0255035,
AFDX-116
Working memory,
attention,
processing speed
and short-term
memory
(Fernandes et al.
2006)
nAChR a7
nAChR
Ach, choline,
cytosine, PNU-
282987
a-BGT, MLA
a4b2
nAChR
Cytisine, nicotine,
DMPP,
carbamylcholine
Curare,
mecamylamine
Glutamate Extracellular fluid
of the brain and
cerebrospinal
fluid
Upregulated
(Zhou et al.
2003)
iGluRs NMDA MK-801, CGS
19755
Learning, episodic
memory and
short-term
memory (Zlotnik
et al. 2012;
Meldrum 2000)
a-amino-3-
hydroxy-5-
methyl-4-
isoxazole
propionate
(AMPA)
GYKI 52466,
Cerestat,
CNS1102
Kainic acid (KA) LY294486
mGluRs L-AP4 Eliprodil,D-
CPPene,CP
100581
Substance P
(SP)
Striatonigral
neurons,
midbrain,
preoptic area,
hypothalamus,
septum,
amygdala and in
the region of the
nucleus basalis
magnocellularis
Upregulated first,
then
downregulated
(Karakucuk
et al. 1997;
Donkin et al.
2009)
NK1 Rolapitant (SCH
619734)
NAT Depression,
memory, learning,
and excitotoxicity
(Parker et al.
1998; Huston and
Hasenohrl 1995)
Dopamine Prefrontal cortex
and striatum
Upregulated first,
then
downregulated
(Massucci et al.
2004; Wagner
et al. 2005;
Wagner et al.
2009)
D1 receptor SKF 81297 SCH 23390 Attention, memory,
and emotion
(Daubner et al.
2011; Bales et al.
2009)
D2 receptor Quinpirole Eticlopride
haloperidol
Serotonin
(5-HT)
Hippocampus and
frontal cortex
Downregulated
first, then
upregulated
(Visser et al.
2011;
Arciniegas
2011)
5-HT1–7 5-CT,5-MeOT,
8-OH-DPAT
WAY 100635,
M100907,
SB269970,
LY215840,RO
4368554,
SB656104
Object recognition
and social
discrimination
(Cifariello et al.
2008)
80 Z.-L. Sun, D.-F. Feng
123
Acetylcholine
The cholinergic system plays an important role in sleep,
emotion, learning, memory and other higher nervous sys-
tem activities. Damage to the acetylcholine (ACh) system
results in alterations in cerebral acetylcholine levels (either
an excess or a deficiency) and cognitive impairments,
including dementia (Arciniegas 2011). ACh is synthesized
by a reversible reaction catalyzed by choline acetyl trans-
ferase (ChAT) from acetylcoenzyme A (AcetylCoA) and
choline. Choline can be derived in an energy-independent
manner from phospholipid or ACh degradation or from the
uptake of blood (Scremin et al. 2006). Energy depletion
occurs in TBI tissue due to ischemia and glucose utilization
dysfunction (Nortje and Menon 2004). This energy deple-
tion limits the availability of substrates for ACh synthesis
by enhancing choline and decreasing AcetylCoA avail-
ability (Dixon et al. 1995a).
In animal models of TBI, there is an initial period of
acute cholinergic excess, followed by a decrease of ace-
tylcholine levels over the course of the first 2 weeks fol-
lowing injury (Dixon et al. 1995b), as evidenced from
measurements of basal extracellular acetylcholine levels in
animal models. During this time period, cognitive func-
tioning becomes less disordered as evidenced by normali-
zation of Morris Water Maze which is a device to
investigate spatial learning and memory in laboratory rats.
In the weeks that follow, there is a continued alteration in
evoked acetylcholine responses and the cholinergic
reserves of animals continue to decline (Dixon et al. 1996).
This persistent decrease in acetylcholine may account for
the long-term deficits in cognition experienced by TBI
survivors.
Persistent reductions in cortical cholinergic functions
may stem from the reduced synthesis of acetylcholine
(Dixon et al. 1994a), the altered release of acetylcholine
due to changes in autoreceptor binding and signal trans-
duction (Leonard et al. 1994), an injury to cholinergic
projections or to some combination of these factors. Sco-
polamine, a cholinergic receptor (AChR) blocker, has been
found in rats to induce spatial memory impairment (Dixon
et al. 1995a) in a dose-dependent fashion (Dixon et al.
1994b).
There are two types of AChRs: muscarinic cholinergic
receptors (mAChR) and nicotinic acetylcholine receptors
(nAChR). A relationship between mAChRs and cognitive
functioning has been well documented, but there is less
known about the role of nAChRs in cognition. Fernandes
et al. (2006) demonstrated that deleting the a7 nAChR
gene leads to impairments in working memory and epi-
sodic memory in mice. Working memory includes tem-
porary processing and storage of information, and episodic
memory is defined as the rapid formation of memory of
unique events or episodes in time that can be distinguished
from other related events. Pocivavsek et al. (2006) found
that a4b2 nAChR antagonists injected into the ventral
hippocampus of mice led to memory dysfunction. These
studies suggest that nAChR are critically important in
learning, memory and long-term potentiation.
Clinical evidence suggests that cognitive outcomes can
be improved following TBI through the enhancement of
cholinergic functioning with AChE inhibitors. This finding
Table 1 continued
Biomarkers Distribution Regulation Cognitive function-
related receptors
Agonists Antagonists Cognitive functions
Gamma-
aminobutyric
acid (GABA)
Midbrain and
substantia nigra
Upregulated
(Scremin et al.
2006)
GABAAR Muscimol Methyl beta-
carboline-3-
carboxylate,
bicuculline
Object perception,
selective attention,
working memory,
spatial memory
and cognitive
dysexecutive
(Johansson et al.
2002; Turkmen
et al. 2006)
Amyloid-b(Ab)
Extracellularly Upregulated
(Magnoni and
Brody 2010)
— — — Disruption of
cognition and
information
transmissionNeurotrophic
Protein
S100B
Extracellularly Upregulated
(Kleindienst
and Ross
Bullock 2006)
— — —
Apolipoprotein
E (ApoE)
Extracellularly Upregulated
(Horsburgh
et al. 1997)
— — —
Biomarkers of cognitive dysfunction in TBI 81
123
indicates that ACh is a key biomarker for cognition
(Tenovuo 2005). AChE inhibitors were first used in the
treatment of cognitive impairment following TBI in the
mid-1970s (Bogdanovitch et al. 1975). As reviewed in
subsequent case reports, large open-label randomized
controlled studies have demonstrated the potential benefits
of AChE inhibitor treatments in cognitive dysfunction
following TBI (Arciniegas and Silver 2006; Chew and
Zafonte 2009). But Beglinger demonstrated that AChE
inhibitor-induced improvements in cognitive function were
variable. In their clinical trials, the patients in the donepezil
(an ACE inhibitor) group performed slightly but signifi-
cantly worse on some tests of cognition functions com-
pared to the placebo and no-treatment group. The results
are counter to expectations and other experiments (Beg-
linger et al. 2004). Although such effects are variable,
based on the general clinical effects of pharmacotherapy,
they still proposed that the changes in cerebral cholinergic
levels might be due to a ‘‘reverse engineering’’ of post-
traumatic cognitive impairments. That means the treatment
of AChE inhibitor is beneficial for patients with cognition
dysfunction after TBI.
The ventral forebrain and the upper brainstem cholin-
ergic nuclei are particularly vulnerable to damage by
trauma due to their positions in the brain. Cognitive
impairments are easily produced because cholinergic
functioning is readily disturbed through either the excess or
deficiency of cerebral acetylcholine levels.
Glutamate
Glutamate is an important excitatory neurotransmitter in
the human brain and is involved in many central nervous
system activities, including learning and memory (Mel-
drum 2000). In the brain, glutamate dehydrogenase (GDH)
normally catalyzes the oxidative deamination of glutamate
to a-ketoglutarate (aKG) and ammonia, using nicotinamide
adenine dinucleotide (NAD?) or nicotinamide adenine
dinucleotide phosphate (NADP?) as a co-enzyme. How-
ever, in glutamatergic neurons with high levels of ammonia
in discrete microenvironments of the mitochondria, the
process of reductive amination can form glutamate from
aKG and ammonia (Rowley et al. 2012). Abnormally
increased glutamate concentrations in the extracellular
fluid of the brain and the cerebrospinal fluid are observed in
TBI and lead to significantly decreased neuronal survival in
diverse hippocampal regions known to be involved in
learning and memory in humans and in animals (Zlotnik
et al. 2012). Zhou et al. (2003) demonstrated significantly
increased expression of mGluR4 mRNA 1 h after initial
injury in animal models of TBI. The peak of mGluR4
overexpression occurred 6 h following injury and then
decreased to a near baseline level (Zhou et al. 2003).
Zlotnik demonstrated that the blood glutamate scavengers
provide neuroprotection in the following 90 min after TBI
in rats, expressed both by increased neuronal survival in the
hippocampus and improved neurologic outcomes (Zlotnik
et al. 2012). This makes it possible that reduced volume of
glutamate could contribute to functional outcome in the
early TBI stage.
There are three families of ionotropic glutamate recep-
tors (iGluRs) that incorporate ion channels and three
families of metabotropic glutamate receptors (mGluRs)
that consist of eight G protein-coupled glutamate receptors
in the central nervous system (CNS). The iGluRs and the
mGluRs play distinct roles in neuronal activity. The iGluRs
have been proved to play an important role in spatial
working memory, and the mGluRs have been implicated in
different forms of synaptic plasticity such as long-term
potentiation, long-term depression and in memory forma-
tion. Postsynaptic iGluRs mediate fast, direct information
transfer, whereas mGluRs tune postsynaptic neuronal
excitability and control presynaptic neurotransmitter
release. Various glutamate receptors regulate intracellular
signaling pathways, which can aggravate or attenuate
posttraumatic cellular injury (Luo et al. 2011). Both iGluRs
and mGluRs are critical for cognitive functioning.
Increased extracellular glutamate activates N-methyl-D-
aspartate (NMDA) glutamate receptors, leading to an
enhanced calcium influx and the disruption of normal
information transmission. As previously noted, in animal
experiment, extracellular glutamate levels are elevated
after TBI (Wakade et al. 2010), which increases the acti-
vation of both iGluRs and mGluRs (Faden et al. 1989). It is
found that increased expression of mGluR4, a group III
mGluR receptor subtype, was an important marker of
cognitive dysfunction in TBI. L-AP4, a specific mGluR4
agonist, also provided a remarkable neuroprotective effect
on cognitive performance following TBI in rats (Donkin
et al. 2011; Zhou et al. 2003).
The alterations in messaging pathways, including the
dysfunction, reduction or increase in the expression or
synaptic action of neurotransmitters, can affect cognitive
functioning. The postsynaptic receptor density coordinates
different signaling molecules with glutamate receptors,
thereby allowing the activation of postsynaptic signaling
pathways. After TBI, there are distinct changes in synaptic
glutamate levels and in various glutamate receptors that
regulate intracellular signaling pathways that can aggravate
or attenuate posttraumatic cellular injury (Kornau et al.
1995). The interactions of glutamate with its receptor play
an important role in learning and memory. Therefore, for
the different clinical manifestations, restoration of their
balance may be expected to become a new target for the
treatment of learning and memory disorders. These data
indicated that cerebral glutamate deficits could lead to
82 Z.-L. Sun, D.-F. Feng
123
cognition dysfunction. All the findings may bring about
new therapeutic possibilities in a variety of clinical set-
tings. Unfortunately, the clinical effects cannot be accu-
rately evaluated with the lack of clinical data.
Substance P (SP)
SP belongs to a distinct family of neuropeptides called
tachykinins, which are defined by their common carboxy
(C)-terminal amino acid sequence. SP is a cognition-related
neuropeptide concentrated in the striatonigral pathway,
with high concentrations in the midbrain, preoptic area,
hypothalamus, septum, amygdala and regions of the
nucleus basalis magnocellularis. SP has been previously
implicated in depression, memory, learning (Huston and
Hasenohrl 1995), and excitoxicity (Parker et al. 1998).
SP levels in the human brain are significantly altered
following TBI (Karakucuk et al. 1997). In Donkin et al’s.
(2009) animal study, it was reported that depletion of SP
after injury caused cognitive deficits. Recent findings,
however, have instead suggested that SP is upregulated
following TBI, leading to cognitive dysfunction. SP plays
an important role in the development of CNS edema after
TBI. Uncontrolled brain edema commonly results in a
decrease in brain tissue perfusion, localized hypoxia and
ischemia, all of which combine to worsen preexisting
cognition dysfunction (Faden et al. 1989). The relationship
between SP and cognitive dysfunction, however, requires
further investigation.
SP is a putative ligand of tachykinin receptors. The
neurokinin-1 (NK1) receptor may specifically link SP and
TBI (Huston and Hasenohrl 1995), and SP receptor
antagonists are receiving increased attention as putative
neuroprotective agents. Donkin found that SP release was
linked to increased vascular permeability and edema.
Treatment with the NK1 receptor antagonist N-acetyl-L-
tryptophan (NAT) 30 min after TBI reduced edema and
improved neurological outcomes in rats (Donkin et al.
2009). In addition, Dakin et al. (2011) found that NAT also
reduced axonal injury 5 and 24 h after TBI.
NK1 receptors are densely concentrated in the hippo-
campus and striatum (Huston and Hasenohrl 1995), and
NK1 receptor immunoreactivity showed a specific increase
in damaged brain regions following TBI (Lin 1995). Inhi-
bition of NK1 receptors improved functional outcomes in
TBI (Vink et al. 2004) and in intestinal ischemia and
reperfusion injury (Souza et al. 2002). It is hypothesized
that these improvements in cognitive outcomes following
administration of an NK1 antagonist result from the
reduction in posttraumatic edema (Vink and Nimmo 2002).
Until now, there is lack of human research, but the animal
study supports the possible clinical positive affect of NK1
antagonist for TBI patients.
SP often coexists in neurons with other neurokinins and
classical neurotransmitters, such as dopamine, acetylcho-
line, opiates, serotonin and GABA (Huston and Hasenohrl
1995). In addition, SP can regulate the actions of other
neurotransmitters, including dopamine release (Gauchy
et al. 1996), acetylcholine release (Anderson et al. 2011)
and the opening of calcium channels (Shen and North
1992). It may modulate the presynaptic release and the
postsynaptic actions of a number of other neurotransmit-
ters. Finally, SP induces nitric oxide production in endo-
thelial cells (Phillips et al. 2003), which has been
implicated as a secondary injury factor in TBI and could
underlie the cognition dysfunction after TBI.
To date, substance P antagonists have been shown to
have an ability to reduce neurogenic inflammation, edema,
and lesion volume and improve functional outcome after
TBI. Such multi-effects make it an ideal candidate for
further investigation.
Dopamine
Tyrosine hydroxylase (TyrH) is the rate-limiting enzyme in
catecholamine synthesis. It catalyzes the hydroxylation of
tyrosine to L-DOPA. The catecholamines, including dopa-
mine, are the products of this pathway and are important as
hormones and neurotransmitters in both the central and the
peripheral nervous systems. Dopamine plays an important
role in many brain functions, such as attention, memory,
cognition, and emotion (Daubner et al. 2011).
The effects of dopamine are particularly notable during
the delay period in working memory tasks. In the delayed
attention task, depletion of dopamine in the dorsolateral
prefrontal cortex causes impairment equivalent to that
observed following surgical ablation of this region. The
effects of TBI on the dopamine system, including cognition
dysfunction, have been demonstrated in multiple studies
(Bales et al. 2009). Following TBI, dopamine levels were
shown to acutely increase (Massucci et al. 2004) and
subsequently decrease in the striatum (Wagner et al. 2005,
2009). Cognitive functioning improved following cate-
cholamine agonist therapy in both humans and animals
(Phillips et al. 2003). Methylphenidate (Kline et al. 2000)
and D-amphetamine (Hornstein et al. 1996), both of which
increase synaptic dopamine levels, have been shown to
improve functional outcomes following TBI. L-DOPA
(Kraus and Maki 1997) increases dopamine synthesis,
while amantadine (Sawyer et al. 2008) increases extracel-
lular dopamine concentrations and improve cognition in
patients; therefore, the human studies show that increases
in dopamine level might facilitate functional cognitive
recovery after TBI.
Dopamine receptors are abundantly expressed in brain
areas known to be damaged following TBI, such as the
Biomarkers of cognitive dysfunction in TBI 83
123
frontal cortex and striatum, which are also important for
cognitive functioning. The hippocampus, another region
critical for cognitive functioning, does not have a high
level of dopamine receptor expression. However, the hip-
pocampus can modulate functions that are dependent on
the dopamine activity. Increasing evidence suggests that
the cognitive effects of dopamine depend on the subtype of
dopamine receptor activated (Frank and Fossella 2011;
Frank and O’Reilly 2006; Seamans and Yang 2004). In
particular, recent animal work (Floresco and Jentsch 2011;
Van Holstein et al. 2011; Leonard et al. 1994) has impli-
cated the D2 dopamine receptor family in set-switching.
Blockage of D2 receptors in the prefrontal cortex led to a
decline in working memory task performance in animal
studies (Floresco et al. 2006). Despite the shortage of
clinical trials, the animal tests raise a therapy option for
cognition dysfunction after TBI. But the clinical effect of
dopamine receptors inhibitors still needs to be verified.
Overall, the data suggest an interdependency between
dopamine and cognition. Clinical and translational studies
have clearly demonstrated that dopamine-targeted thera-
pies represent an important clinical option in the treatment
of persistent cognitive dysfunction following TBI (Bales
et al. 2009). Recent studies have also linked dopamine to
differences in brain activity in normal individuals. Younger
adults showed greater functional connectivity of the frontal
caudate than did older adults and this activity was posi-
tively correlated with working memory performance. This
phenomenon suggests that the dopamine system may be
functioning suboptimally in normal aging.
Both human and animal studies in our searched litera-
tures indicate that dopamine-targeted therapies represent an
important clinical option in the treatment for the patients
with cognitive dysfunction following TBI.
Serotonin 5-HT
Many classical studies of the monoaminergic neurotrans-
mitter serotonin (5-HT) and its effects on cognitive func-
tion were completed more than 50 years ago (Cifariello
et al. 2008). Serotonin has been shown to have a multitude
of different physiological roles, in keeping with its wide
localization throughout the central neurons system (Barnes
and Sharp 1999; Hoyer et al. 2002). Serotonin (5-HT) cell
bodies contained in the raphe nuclei have both ascending
and descending axonal projections that form synapses
throughout the brain. Serotonin in the brain is synthesized
from the essential amino acid tryptophan (TRP). The rate-
limiting step is the hydroxylation of TRP to 5-hydroxy-
tryptophan by the enzyme tryptophan 5-monooxygenase.
After synthesis, 5-HT is transported by the vesicular
monoamine transporter and stored in vesicles at the pre-
synaptic terminal. When neurons fire, these vesicles fuse
with the synaptic membrane and release 5-HT into the
synaptic cleft. Released 5-HT can bind to many different
receptors both postsynaptically and presynaptically and can
be taken up by the serotonergic reuptake transporter sys-
tem. This transportation and reuptake system is altered
following TBI (Visser et al. 2011).
The precise changes in 5-HT release and reuptake that
occur after TBI remain to be fully elucidated. In experi-
mental models of head trauma, 5-HT is reported to accu-
mulate within the injured brain tissue. Within 2 h of
experimentally induced TBI in Wistar rats, brain tissue
showed an increase in biogenic amines. This increase was
stable over the course of 48 h. The metabolite 5-HT1A was
also shown to be increased in the damaged tissue. The
authors suggested that 5-HT accumulates in tissues fol-
lowing trauma and that its metabolism is increased. Other
researchers have suggested instead that there is a signifi-
cant decrease in 5-HT in TBI patients relative to controls
(Arciniegas 2011). This decrease may reflect either
increased turnover or increased accumulation of this neu-
rotransmitter in tissues following trauma.
Increased serotoninergic neurotransmission has also
been reported to enhance brain damage by disturbing local
blood circulation. In animal study, Pappius (1989) pro-
posed that serotoninergic activity was increased in TBI and
that this resulted in altered cognition through the alteration
of local cerebral glucose utilization. It has also been
reported that disturbed brain functioning following trauma
can be reversed by the inhibition of serotonin synthesis in
rats. Taken together, a high level of serotonin damages the
cognition function, so the treatment of inhibiting serotonin
synthesis could be beneficial for TBI patients left with
cognitive impairment.
Serotonin is important in pathways between the hippo-
campus and the frontal cortex, which are involved in
learning and memory (Cifariello et al. 2008). Serotonin
influences brain functioning through the activation of
numerous 5-HT receptor subtypes. There are at least 15
different 5-HT receptors, which are divided into 7 distinct
families (5-HT1–7). Postsynaptic receptor binding can be
either inhibitory or excitatory depending on which subtype
is stimulated. The presynaptic receptors 5-HT1A and
5-HT1B, localized somatodendritically and within synaptic
terminals, respectively, are autoreceptors that inhibit
serotonergic neurotransmission. Heteroreceptors influence
the release of neurotransmitters other than 5-HT (Visser
et al. 2011). A paucity of TBI data exists, although non-
TBI research has demonstrated that the 5-HT system, in
particular the 5-HT1A subtype, is an integral component of
cognitive processing (Olsen et al. 2012). The administra-
tion of 5-HT2A/2C (Harvey 1996), 5-HT4, 5-HT1A,
5-HT6, 5-HT3 or 5-HT1B receptor antagonists improves
memory and facilitates learning in situations involving
84 Z.-L. Sun, D.-F. Feng
123
high cognitive demand in animal research (Cifariello et al.
2008).
Serotonin is known to interact with other neurotrans-
mitter systems affecting cognition, particularly the cho-
linergic (Cifariello et al. 2008) and dopaminergic systems
(Mahesh et al. 2010). Serotonin can influence other neu-
rotransmitters in both an excitatory and an inhibitory
manner. One key aspect of serotonergic neurotransmission
is the availability of the 5-HT precursor, TRP. The above-
mentioned aspects of the serotonergic system may act in
concert to enable organisms to function properly.
In our literatures that we screened, 5-HT only in animal
study has been proved important for cognition dysfunction.
Despite a few human studies, we cannot ignore the role of
5-HT in the cognition function.
Gamma-aminobutyric acid (GABA)
GABA is the major inhibitory neurotransmitter in the CNS,
and the critical balance between inhibition and excitation is
disturbed following TBI (Scremin et al. 2006). Normal
neuronal function relies on the constant integration of
excitatory and inhibitory potentials. GABA regulates syn-
chronous neuronal oscillations that are critical for cognitive
functioning (Gibson et al. 2010). Thus, disruptions in
GABAergic signaling after TBI are very likely to impact
cognitive capacity.
An increase in inhibitory functioning through the stim-
ulation of GABAA receptors (GABAARs) may attenuate
excitotoxic effects and improve cognitive outcomes fol-
lowing TBI (Scremin et al. 2006). GABAARs mediate the
majority of inhibitory neurotransmission in the central
nervous system (Mohler et al. 1996). Positive allosteric
modulators of GABAARs impair memory processing (Jo-
hansson et al. 2002; Turkmen et al. 2006), whereas
GABAAR blockers or inverse agonists often potentiate
cognitive performance (Mtchedlishvili et al. 2010).
GABAAR-mediated inhibition in the hippocampal dentate
granule cells following TBI could result in cognitive dis-
turbances (Harvey 1996). Celikyurt found that GBP, a
GABA analog, improved the spatial performance of naive
mice (Celikyurt et al. 2011). Diazepam, a positive modu-
lator of GABAARs, improved posttraumatic cognitive
outcomes in TBI rats. These results provide strong support
for the potential beneficial effects of acute treatment with
GABAergic compounds following TBI (Scremin et al.
2006).
Furthermore, levels of Ca2? alter the functional status of
GABAARs (Gibson et al. 2010), indicating that these
receptors are likely to be affected by the glutamate-induced
excitotoxic effects of TBI (Stelzer and Shi 1994). While
potentiation of GABAergic neurotransmission was found
to be beneficial in an ischemic model, enhanced inhibition
has been found to be detrimental in some animal models of
injury. For example, diazepam blocks the normal recovery
of function after anteromedial cortex lesions in rats
(Schallert et al. 1986). Thus, GABAergic drugs may not be
beneficial for all types of cognitive dysfunction resulting
from brain injury. Despite no reports in human studies,
GABA is receiving increased attention as neuroprotective
agents that need clinical data to support.
Amyloid-b (Ab)
In its normal state, monomeric Ab is a peptide of 40–42
amino acids that is water soluble and secreted extracellu-
larly at an undetectable level. However, following TBI,
impaired axonal transport has been shown to cause multi-
ple forms of Ab to accumulate within the axonal membrane
compartment though enzymolysis of the b-amyloid pre-
cursor protein (b-APP) (Frank and Fossella 2011).
Several epidemiological studies have found that even
single-incident TBI is a significant risk factor for devel-
oping AD, of which the main hallmark is cognitive dys-
function (Frank and Fossella 2011). The Ab peptide may
mediate the relationship between TBI and cognition dys-
function. Progression of Ab accumulation could be found
in post-TBI survivals which were strikingly similar to those
observed in the early stages of AD (Chen et al. 2009). The
predominant type of Ab peptide in the plaques is Ab42, the
AD-associated form of Ab that is prone to aggregation
(DeKosky et al. 2007). Although TBI is associated with
AD, the role of TBI in the mechanism of AD development
and progression is still unclear (Sivanandam and Thakur
2012). It is possible that Ab levels are initially higher
following TBI and then increase further in concert with
clinical recovery (Magnoni and Brody 2010). The neuro-
toxic effects of Ab involve changes in neuronal membrane
composition and structure, which affect membrane physi-
cochemical properties (Zainaghi et al. 2007). Plaques
consisting of Ab can be found within days of TBI in
humans (Graham et al. 1995; Roberts et al. 1991). Indeed,
TBI accelerates the neurodegenerative processes caused by
Ab (Magnoni and Brody 2010). This abnormal change can
result in disordered information transmission and, thus,
cognitive dysfunction. Notably, patients with rapid cogni-
tive improvement typically have high Ab levels, which
may represent Ab clearance from the brain (Zainaghi et al.
2007). Indeed, Sandra found that the Ab levels in the brain
interstitial fluid increased in neurologically improving
patients, remained stable in clinically stable patients and
declined in neurologically worsening patients (Zainaghi
et al. 2007). In support of this hypothesis, Marklund
described a patient with rapid clinical improvement and
Biomarkers of cognitive dysfunction in TBI 85
123
good recovery who had relatively high Ab levels, whereas
another patient with persistent coma and a relatively poorer
outcome had nearly undetectable levels of Ab (Marklund
et al. 2009). In in vitro experiments, neurons were unable
to maintain K? and H? homeostasis following Ab treat-
ment, leading to a prolonged extrusion of potassium and an
influx of protons into the neurons (Ray et al. 2011). After
four consecutive days, the presence of Ab can cause axonal
swelling in cultured neurons (Ray et al. 2011). When
neurons are chronically exposed to high levels of both
intracellular and extracellular Ab, the resulting pathology
is similar to AD (Ray et al. 2011).
These findings suggest that extracellular Ab is a bio-
marker for cognitive dysfunction following TBI. Changes
in Ab co-occur with changes in cognitive function.
Accelerating the discharge of Ab from cells might reduce
its toxic effects, which could be a way to improve cognitive
outcomes following TBI.
Neurotrophic Protein S100B
Neurotrophic protein S100B is a calcium-binding protein
primarily produced by glial cells (Heizmann et al. 2002).
Serum S100B levels are negatively correlated with cogni-
tive outcomes (Kleindienst and Ross Bullock 2006). In
normal, uninjured neuronal-plus-glial cultures, the level of
S100B in the growth medium is measurable (Kleindienst
and Ross Bullock 2006). Numerous reports indicate that
S100B is released following TBI (Kleindienst and Ross
Bullock 2006). In cell culture models, S100B release
continues to increase up to 48 h following injury. S100B
serum levels in patients are normally highest directly fol-
lowing injury and normalize within 24 h, even in those
patients who later show poor outcomes (Kleindienst and
Ross Bullock 2006). Another study in TBI patients dem-
onstrated a delayed increase of S100B serum levels on the
6 day after injury, which correlated with cognitive out-
comes (Raabe and Seifert 2000).
New data support the currently held view that serum
measurement of S100B is a valid biomarker of brain
damage in TBI and that S100B may decrease neuronal
injury and/or contribute to repair following TBI. Hence,
S100B, far from being a negative predictor, has potential
therapeutic value for TBI patients (Kleindienst and Ross
Bullock 2006).
Furthermore, a specific role for S100B has been pro-
posed in developmental plasticity and in cell processes
thought to be involved in learning and memory. This
hypothesis has been supported by the injection of S100B
antiserum into the cerebral hemispheres of chicks, resulting
in amnesia for a passive avoidance task (O’Dowd et al.
1997). In addition, S100B infused into the rat hippocam-
pus, which is particularly susceptible to TBI and is the
most critical region for cognitive performance, has been
shown to facilitate long-term memory for an inhibitory
avoidance task (Mello e Souza et al. 2000). Finally, S100B
may impact cognition via lesion-induced collateral
sprouting and reactive synaptogenesis. This phenomenon
may occur through interaction with growth factors (Kle-
indienst and Ross Bullock 2006).
In addition to the growth factors that have been found to
upregulate neurogenesis, the neurotrophic protein S100B is
also a potential contributor to hippocampal network repair
after TBI, as shown by its promotion of memory consoli-
dation in the normal rat during development (Zainaghi
et al. 2007).
However, transgenic mice with an inserted human
S100B gene overexpress S100B throughout the brain and
show behavioral abnormalities (Winocur et al. 2001).
Studies in these S100B transgenic mice at different ages
suggested that S100B may accelerate hippocampal devel-
opment, as demonstrated by an increased density of hip-
pocampal dendrites during the early stages, followed by
increased aging and loss of dendrites. These findings are
supported by data showing an accumulation of S100B
during developmental synaptogenesis in normal rodents
and in humans (Kleindienst and Ross Bullock 2006).
S100B promotes the functional integration of injury-
induced hippocampal neurogenesis and enhances cognitive
recovery. These findings offer a possible new treatment
approach: utilizing the experimentally demonstrated ben-
eficial effects of S100B clinically to enhance the restora-
tion of cognitive function following TBI.
Taken together, we propose that S100B, far from being a
negative factor of cognition outcome, as suggested previ-
ously in the human and animal TBI literatures, may
improve cognition function recovery following TBI and
may be a new potentially therapy option, which might
improve the cognition outcome of TBI patients.
Apolipoprotein E (ApoE)
ApoE, synthesized primarily by astrocytes and microglia,
plays a vital role in the maintenance of neuronal mem-
branes, neuronal tissue repair, remodeling, and synapto-
genesis (Dardiotis et al. 2010). After TBI, ApoE is
locally upregulated and is released by astrocytes into the
extracellular space. It is subsequently absorbed by neu-
rons (Horsburgh et al. 1997). It has also been demon-
strated that intraventricular infusion of ApoE reduces
neuronal damage (Dardiotis et al. 2010). However, a
recent preliminary study reported reduced levels of ApoE
in the cerebrospinal fluid (CSF) within 3 days of TBI. It
has been proposed that this reduction reflects the
increased utilization of ApoE–lipid complexes for repair
86 Z.-L. Sun, D.-F. Feng
123
processes, or alternatively their adsorption onto amyloid
plaques (Kay et al. 2003a).
In humans, there are three major isoforms of ApoE (e2,
e3, and e4), which differ in their amino acid sequences at
positions 112 and 158 (Dardiotis et al. 2010). Several
association studies have investigated the role of ApoE gene
polymorphism in patients sustaining TBI. Possession of the
ApoE e4 allele confers an increased risk for poor outcome
following TBI, whereas the more frequent ApoE e3 and the
rare ApoE e2 alleles both reduce risk (Kay et al. 2003b). In
14 cohort studies and a meta-analysis with a total of 2,427
pooled participants, it was found that the ApoE e4 allele
increases the risk of poor clinical outcomes 6 months after
injury (Zhou et al. 2008). Moreover, the APOE e4 allele is
associated with an earlier age of onset of AD (Gomez-Isla
et al. 1996; Roses 1996). In addition, Corder et al. (1993)
demonstrated that the person with two e4 alleles had a
higher risk and earlier age of onset than individuals who
had only one e4 allele. But the relationship between ApoE
levels and AD is not well studied (Kandimalla et al. 2013).
To date, ApoE have been shown to have association
with neurotoxicity and neurodegeneration, mitochondrial
dysfunction, increased intracellular calcium, disruption of
cholinergic transmission, dysregulation of the neuronal
signaling pathways, and apoptosis. Further research should
focus on a possible way to stop or decrease these patho-
logical changes that could shed more light on the effect of
ApoE on TBI cognition outcome.
Conclusion
The experimental injury literature, human CSF sampling
studies, and postmortem human literature offer consistent
support for the presence of multiple biomarkers in the early
and long-term post-injury periods following TBI. Without
question, other factors, such as age and initial injury
severity, and medical, psychological and environmental
factors also contribute to the development and maintenance
of cognitive impairments after TBI. Nevertheless, there is a
substantial body of evidence demonstrating a relationship
between posttraumatic biomarker dysfunction and cogni-
tive impairment. This suggests that there is a reasonable
scientific foundation to propose treating posttraumatic
cognitive impairments via the rebalancing of these bio-
marker levels. Additional studies are needed to find
effective methods of altering biomarker levels and to assess
the efficacy of such treatments for posttraumatic cognitive
impairment.
Individual variability and the severity of the posttrau-
matic biomarker deficits will confound any research or
clinical endeavors that fail to take them into account. As
discussed previously, cholinesterase inhibitors appear to be
the most effective for the treatment of persistent declar-
ative memory impairments after TBI. However, memory
is not a unitary function, and memory impairments are not
sufficiently reliable predictors of posttraumatic choliner-
gic deficits or of cholinesterase inhibitor treatments to use
as guides for clinical practice. Practical and effective
methods for identifying functionally relevant posttrau-
matic cholinergic deficits are needed to guide treatment
selection and to evaluate treatment response. Ideally,
these methods would use a combination of symptom-
based, neuropsychological and cholinergic-specific neu-
roimaging metrics to identify individuals whose post-
traumatic cognitive impairments are enhanced by cerebral
cholinergic deficits. With findings from such assessments,
clinicians could select from related therapies for use in
patients who are most likely to benefit.
In conclusion, we have described several biomarkers
associated with cognitive dysfunction after TBI and
determined that these markers could elucidate progressive
pathogenesis, provide candidate targets for therapeutic
strategies, and predict cognitive outcomes. Biomarkers
could be used as a screening tool for cognitive dysfunction;
in so doing, clinicians might be possible to prescribe
pharmacologic interventions earlier to rescue cognitive
functions or to interrupt the development of pathology in
the future. In the same time, the research community must
also realize that it is impossible to resolve cognition dys-
function following TBI via biomarkers alone. Accordingly,
a set of biomarkers, a clinical history and a record of
clinical symptoms are all essential to improve our current
ability to make an early diagnosis and to predict the cog-
nitive outcomes of TBI patients.
Acknowledgments This study was supported by grants from the
Shanghai Committee of Science and Technology (No. 114119a8300),
Shanghai Health Bureau (No. 2010167) and BaoShan Scientific and
Technological Development Fund (11-E-1).
Conflict of interest The authors declare no conflict of interest.
References
Anderson JJ, Chase TN, Engber TM (2011) Substance P increases
release of acetylcholine in the dorsal striatum of freely moving
rats. Brain Res 623:189–194
Arciniegas DB (2011) Cholinergic dysfunction and cognitive impair-
ment after traumatic brain injury. Part 2: evidence from basic
and clinical investigations. J Head Trauma Rehabil 26:319–323
Arciniegas DB, Silver JM (2006) Pharmacotherapy of posttraumatic
cognitive impairments. Behav Neurol 17:25–42
Bales JW, Wagner AK, Kline AE, Dixon CE (2009) Persistent
cognitive dysfunction after traumatic brain injury: a dopamine
hypothesis. Neurosci Biobehav Rev 33:981–1003
Barnes NM, Sharp T (1999) A review of central 5-HT receptors and
their function. Neuropharmacology 38:1083–1152
Biomarkers of cognitive dysfunction in TBI 87
123
Beglinger LJ, Gaydos BL, Kareken DA, Tangphao-Daniels O,
Siemers ER, Mohs RC (2004) Neuropsychological test perfor-
mance in healthy volunteers before and after donepezil admin-
istration. J Psychopharmacol 18:102–108
Bogdanovitch UJ, Bazarevitch GJ, Kirillov AL (1975) The use of
cholinesterase in severe head injury. Resuscitation 4:139–141
Celikyurt IK, Mutlu O, Ulak G, Akar FY, Erden FG (2011)
Gabapentin: a GABA analogue, enhances cognitive performance
in mice. Neurosci Lett 492:124–128
Chen XH, Johnson VE, Uryu K, Trojanowski JQ, Smith DH (2009) A
lack of amyloid beta plaques despite persistent accumulation of
amyloid beta in axons of long-term survivors of traumatic brain
injury. Brain Pathol 19:214–223
Chew E, Zafonte RD (2009) Pharmacological management of
neurobehavioral disorders following traumatic brain injury—a
state-of-the-art review. J Rehabil Res Dev 46:851–879
Cifariello A, Pompili A, Gasbarri A (2008) 5-HT receptors in the
modulation of cognitive processes. Behav Brain Res
195:171–179
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell
PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA
(1993) Gene dose of apolipoprotein E type 4 allele and the risk
of Alzheimer’s disease in late onset families. Science
261:921–923
Dardiotis E, Fountas KN, Dardioti M, Xiromerisiou G, Kapsalaki E,
Tasiou A, Hadjigeorgiou GM (2010) Genetic association studies
in patients with traumatic brain injury. Neurosurg Focus 28:E9
Daubner SC, Le T, Wang S (2011) Tyrosine hydroxylase and
regulation of dopamine synthesis. Arch Biochem Biophys
508:1–12
DeKosky ST, Abrahamson EE, Ciallella JR, Paljug WR, Wisniewski
SR, Clark RS, Ikonomovic MD (2007) Association of increased
cortical soluble abeta42 levels with diffuse plaques after severe
brain injury in humans. Arch Neurol 64:541–544
Dixon CE, Bao J, Bergmann JS, Johnson KM (1994a) Traumatic
brain injury reduces hippocampal high-affinity [3H] choline
uptake but not extracellular choline levels in rats. Neurosci Lett
180:127–130
Dixon CE, Hamm RJ, Taft WC, Hayes RL (1994b) Increased
anticholinergic sensitivity following closed skull impact and
controlled cortical impact traumatic brain injury in the rat.
J Neurotrauma 11:275–287
Dixon CE, Bao J, Johnson KM, Yang K, Whitson J, Clifton GL,
Hayes RL (1995a) Basal and scopolamine-evoked release of
hippocampal acetylcholine following traumatic brain injury in
rats. Neurosci Lett 198:111–114
Dixon CE, Liu SJ, Jenkins LW, Bhattachargee M, Whitson JS, Yang
K, Hayes RL (1995b) Time course of increased vulnerability of
cholinergic neurotransmission following traumatic brain injury
in the rat. Behav Brain Res 70:125–131
Dixon CE, Bao J, Long DA, Hayes RL (1996) Reduced evoked
release of acetylcholine in the rodent hippocampus follow-
ing traumatic brain injury. Pharmacol Biochem Behav
53:679–686
Donkin JJ, Nimmo AJ, Cernak I, Blumbergs PC, Vink R (2009)
Substance P is associated with the development of brain edema
and functional deficits after traumatic brain injury. J Cereb Blood
Flow Metab 29:1388–1398
Donkin JJ, Cernak I, Blumbergs PC, Vink R (2011) A substance P
antagonist reduces axonal injury and improves neurologic
outcome when administered up to 12 hours after traumatic brain
injury. J Neurotrauma 28:217–224
Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of
excitatory amino acids and NMDA receptors in traumatic brain
injury. Science 244:798–800
Fernandes C, Hoyle E, Dempster E, Schalkwyk LC, Collier DA
(2006) Performance deficit of alpha7 nicotinic receptor knockout
mice in a delayed matching-to-place task suggests a mild
impairment of working/episodic-like memory. Genes Brain
Behav 5:433–440
Floresco SB, Jentsch JD (2011) Pharmacological enhancement of
memory and executive functioning in laboratory animals.
Neuropsychopharmacology 36:227–250
Floresco SB, Magyar O, Ghods-Sharifi S, Vexelman C, Tse MT
(2006) Multiple dopamine receptor subtypes in the medial
prefrontal cortex of the rat regulate set-shifting. Neuropsycho-
pharmacology 31:297–309
Frank MJ, Fossella JA (2011) Neurogenetics and pharmacology of
learning, motivation, and cognition. Neuropsychopharmacology
36:133–152
Frank MJ, O’Reilly RC (2006) A mechanistic account of striatal
dopamine function in human cognition: psychopharmacological
studies with cabergoline and haloperidol. Behav Neurosci
120:497–517
Gauchy C, Desban M, Glowinski J, Kemel ML (1996) Distinct
regulations by septide and the neurokinin-1 tachykinin receptor
agonist [pro9] substance P of the N-methyl-D-aspartate-evoked
release of dopamine in striosome- and matrix-enriched areas of
the rat striatum. Neuroscience 73:929–939
Gibson CJ, Meyer RC, Hamm RJ (2010) Traumatic brain injury and
the effects of diazepam, diltiazem, and MK-801 on GABA-A
receptor subunit expression in rat hippocampus. J Biomed Sci
17:38
Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH,
Locascio JJ, Perls TT, Lipsitz LA, Hyman BT (1996) Clinical
and pathological correlates of apolipoprotein E epsilon 4 in
Alzheimer’s disease. Ann Neurol 39:62–70
Graham DI, Gentleman SM, Lynch A, Roberts GW (1995) Distri-
bution of beta-amyloid protein in the brain following severe head
injury. Neuropathol Appl Neurobiol 21:27–34
Harvey JA (1996) Serotonergic regulation of associative learning.
Behav Brain Res 73:47–50
Heizmann CW, Fritz G, Schafer BW (2002) S100 proteins:structure,
functions and pathology. Front Biosci 7:d1356–d1368
Hornstein A, Lennihan L, Seliger G, Lichtman S, Schroeder K (1996)
Amphetamine in recovery from brain injury. Brain Inj
10:145–148
Horsburgh K, Fitzpatrick M, Nilsen M, Nicoll JA (1997) Marked
alterations in the cellular localisation and levels of apolipopro-
tein E following acute subdural haematoma in rat. Brain Res
763:103–110
Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological
and functional diversity of 5-HT receptors. Pharmacol Biochem
Behav 71:533–554
Huston JP, Hasenohrl RU (1995) The role of neuropeptides in
learning: focus on the neurokinin substance P. Behav Brain Res
66:117–127
Johansson IM, Birzniece V, Lindblad C, Olsson T, Backstrom T
(2002) Allopregnanolone inhibits learning in the Morris water
maze. Brain Res 934:125–131
Kandimalla RJ, Wani WY, Anand R, Kaushal A, Prabhakar S, Grover
VK, Bharadwaj N, Jain K, Gill KD (2013) Apolipoprotein e
levels in the cerebrospinal fluid of north Indian patients with
Alzheimer’s disease. Am J Alzheimers Dis Other Demen
28:258–262
Karakucuk EI, Pasaoglu H, Pasaoglu A, Oktem S (1997) Endogenous
neuropeptides in patients with acute traumatic head injury II:
changes in the levels of cerebrospinal fluid substance P,
serotonin and lipid peroxidation products in patients with head
trauma. Neuropeptides 31:259–263
88 Z.-L. Sun, D.-F. Feng
123
Kay AD, Petzold A, Kerr M, Keir G, Thompson E, Nicoll JA (2003a)
Alterations in cerebrospinal fluid apolipoprotein E and amyloid
beta-protein after traumatic brain injury. J Neurotrauma
20:943–952
Kay AD, Petzold A, Kerr M, Keir G, Thompson EJ, Nicoll JA
(2003b) Cerebrospinal fluid apolipoprotein E concentration
decreases after traumatic brain injury. J Neurotrauma
20:243–250
Kleindienst A, Ross Bullock M (2006) A critical analysis of the role
of the neurotrophic protein S100B in acute brain injury.
J Neurotrauma 23:1185–1200
Kline AE, Yan HQ, Bao J, Marion DW, Dixon CE (2000) Chronic
methylphenidate treatment enhances water maze performance
following traumatic brain injury in rats. Neurosci Lett
280:163–166
Kornau HC, Schenker LT, Kennedy MB, Seeburg PH (1995) Domain
interaction between NMDA receptor subunits and the postsyn-
aptic density protein PSD-95. Science 269:1737–1740
Kraus MF, Maki P (1997) The combined use of amantadine and
l-dopa/carbidopa in the treatment of chronic brain injury. Brain
Inj 11:455–460
Leonard JR, Maris DO, Grady MS (1994) Fluid percussion injury
causes loss of forebrain choline acetyltransferase and nerve
growth factor receptor immunoreactive cells in the rat. J Neuro-
trauma 11:379–392
Lin RC (1995) Reactive astrocytes express substance-P immunore-
activity in the adult forebrain after injury. NeuroReport
7:310–312
Luo P, Fei F, Zhang L, Qu Y, Fei Z (2011) The role of glutamate
receptors in traumatic brain injury: implications for postsynaptic
density in pathophysiology. Brain Res Bull 85:313–320
Magnoni S, Brody DL (2010) New perspectives on amyloid-beta
dynamics after acute brain injury: moving between experimental
approaches and studies in the human brain. Arch Neurol
67:1068–1073
Mahesh R, Pandey DK, Katiyar S, Kukade G, Viyogi S, Rudra A
(2010) Effect of anti-depressants on neuro-behavioural conse-
quences following impact accelerated traumatic brain injury in
rats. Indian J Exp Biol 48:466–473
Marklund N, Blennow K, Zetterberg H, Ronne-Engstrom E, Enblad P,
Hillered L (2009) Monitoring of brain interstitial total tau and
beta amyloid proteins by microdialysis in patients with traumatic
brain injury. J Neurosurg 110:1227–1237
Massucci JL, Kline AE, Ma X, Zafonte RD, Dixon CE (2004) Time
dependent alterations in dopamine tissue levels and metabolism
after experimental traumatic brain injury in rats. Neurosci Lett
372:127–131
McAllister TW (2011) Neurobiological consequences of traumatic
brain injury. Dialogues Clin Neurosci 13:287–300
Meldrum BS (2000) Glutamate as a neurotransmitter in the
brain: review of physiology and pathology. J Nutr 130:
1007S–1015S
Mello e Souza T, Rohden A, Meinhardt M, Goncalves CA, Quillfeldt
JA (2000) S100B infusion into the rat hippocampus facilitates
memory for the inhibitory avoidance task but not for the open-
field habituation. Physiol Behav 71:29–33
Mohler H, Fritschy JM, Luscher B, Rudolph U, Benson J, Benke D
(1996) The GABAA receptors. From subunits to diverse
functions. Ion Channels 4:89–113
Mtchedlishvili Z, Lepsveridze E, Xu H, Kharlamov EA, Lu B, Kelly
KM (2010) Increase of GABAA receptor-mediated tonic inhi-
bition in dentate granule cells after traumatic brain injury.
Neurobiol Dis 38:464–475
NIH Consensus Development Panel on Rehabilitation of Persons with
Traumatic Brain Injury (1999) Rehabilitation of persons with
traumatic brain injury. JAMA 282:974–983
Niogi SN, Mukherjee P, Ghajar J, Johnson C, Kolster RA, Sarkar R,
Lee H, Meeker M, Zimmerman RD, Manley GT, McCandliss
BD (2008) Extent of microstructural white matter injury in
postconcussive syndrome correlates with impaired cognitive
reaction time: a 3T diffusion tensor imaging study of mild
traumatic brain injury. AJNR Am J Neuroradiol 29:967–973
Nortje J, Menon DK (2004) Traumatic brain injury: physiology,
mechanisms, and outcome. Curr Opin Neurol 17:711–718
O’Dowd BS, Zhao WQ, Ng KT, Robinson SR (1997) Chicks injected
with antisera to either S-100 alpha or S-100 beta protein develop
amnesia for a passive avoidance task. Neurobiol Learn Mem
67:197–206
Olsen AS, Sozda CN, Cheng JP, Hoffman AN, Kline AE (2012)
Traumatic brain injury-induced cognitive and histological def-
icits are attenuated by delayed and chronic treatment with the
5-HT-receptor agonist buspirone. J Neurotrauma 29:1898–1907
Pappius HM (1989) Involvement of indoleamines in functional
disturbances after brain injury. Prog Neuropsychopharmacol
Biol Psychiatry 13:353–361
Parker D, Zhang W, Grillner S (1998) Substance P modulates NMDA
responses and causes long-term protein synthesis-dependent
modulation of the lamprey locomotor network. J Neurosci
18:4800–4813
Phillips JP, Devier DJ, Feeney DM (2003) Rehabilitation pharma-
cology: bridging laboratory work to clinical application. J Head
Trauma Rehabil 18:342–356
Pocivavsek A, Icenogle L, Levin ED (2006) Ventral hippocampal
alpha7 and alpha4beta2 nicotinic receptor blockade and cloza-
pine effects on memory in female rats. Psychopharmacology
188:597–604
Raabe A, Seifert V (2000) Protein S-100B as a serum marker of brain
damage in severe head injury: preliminary results. Neurosurg
Rev 23:136–138
Ray S, Howells C, Eaton ED, Butler CW, Shabala L, Adlard PA,
West AK, Bennett WR, Guillemin GJ, Chung RS (2011) Tg2576
cortical neurons that express human Ab are susceptible to
extracellular Ab-induced, K? efflux dependent neurodegenera-
tion. PLoS One 6:e19026
Roberts GW, Gentleman SM, Lynch A, Graham DI (1991) beta A4
amyloid protein deposition in brain after head trauma. Lancet
338:1422–1423
Roses AD (1996) Apolipoprotein E alleles as risk factors in
Alzheimer’s disease. Annu Rev Med 47:387–400
Rowley NM, Madsen KK, Schousboe A, Steve WH (2012) Glutamate
and GABA synthesis, release, transport and metabolism as
targets for seizure control. Neurochem Int 61:546–558
Sawyer E, Mauro LS, Ohlinger MJ (2008) Amantadine enhancement
of arousal and cognition after traumatic brain injury. Ann
Pharmacother 42:247–252
Schallert T, Hernandez TD, Barth TM (1986) Recovery of function
after brain damage: severe and chronic disruption by diazepam.
Brain Res 379:104–111
Scremin OU, Li MG, Roch M, Booth R, Jenden DJ (2006)
Acetylcholine and choline dynamics provide early and late
markers of traumatic brain injury. Brain Res 1124:155–166
Seamans JK, Yang CR (2004) The principal features and mechanisms
of dopamine modulation in the prefrontal cortex. Prog Neurobiol
74:1–58
Shen KZ, North RA (1992) Substance P opens cation channels and
closes potassium channels in rat locus coeruleus neurons.
Neuroscience 50:345–353
Sivanandam TM, Thakur MK (2012) Traumatic brain injury: a risk
factor for Alzheimer’s disease. Neurosci Biobehav Rev
36:1376–1381
Souza DG, Mendonca VA, de A Castro MS, Poole S, Teixeira MM
(2002) Role of tachykinin NK receptors on the local and remote
Biomarkers of cognitive dysfunction in TBI 89
123
injuries following ischaemia and reperfusion of the superior
mesenteric artery in the rat. Br J Pharmacol 11:303–312
Stelzer A, Shi H (1994) Impairment of GABAA receptor function by
N-methyl-D-aspartate-mediated calcium influx in isolated CA1
pyramidal cells. Neuroscience 62:813–828
Tenovuo O (2005) Central acetylcholinesterase inhibitors in the
treatment of chronic traumatic brain injury-clinical experience in
111 patients. Prog Neuropsychopharmacol Biol Psychiatry
29:61–67
Turkmen S, Lofgren M, Birzniece V, Backstrom T, Johansson IM
(2006) Tolerance development to Morris water maze test
impairments induced by acute allopregnanolone. Neuroscience
139:651–659
van Holstein M, Aarts E, van der Schaaf ME, Geurts DE, Verkes RJ,
Franke B, van Schouwenburg MR, Cools R (2011) Human
cognitive flexibility depends on dopamine D2 receptor signaling.
Psychopharmacology 218:567–578
Vink R, Nimmo AJ (2002) Novel therapies in development for the
treatment of traumatic brain injury. Expert Opin Investig Drugs
11:1375–1386
Vink R, Donkin JJ, Cruz MI, Nimmo AJ, Cernak I (2004) A substance
P antagonist increases brain intracellular free magnesium
concentration after diffuse traumatic brain injury in rats. J Am
Coll Nutr 23:538S–540S
Visser AK, van Waarde A, Willemsen AT, Bosker FJ, Luiten PG, den
Boer JA, Kema IP, Dierckx RA (2011) Measuring serotonin
synthesis: from conventional methods to PET tracers and their
clinical implications. Eur J Nucl Med Mol Imaging 38:576–591
Wagner AK, Sokoloski JE, Ren D, Chen X, Khan AS, Zafonte RD,
Michael AC, Dixon CE (2005) Controlled cortical impact injury
affects dopaminergic transmission in the rat striatum. J Neuro-
chem 95:457–465
Wagner AK, Sokoloski JE, Chen X, Harun R, Clossin DP, Khan AS,
Andes-Koback M, Michael AC, Dixon CE (2009) Controlled
cortical impact injury influences methylphenidate-induced changes
in striatal dopamine neurotransmission. J Neurochem 110:801–810
Wakade C, Sukumari-Ramesh S, Laird MD, Dhandapani KM, Vender
JR (2010) Delayed reduction in hippocampal postsynaptic
density protein-95 expression temporally correlates with cogni-
tive dysfunction following controlled cortical impact in mice.
J Neurosurg 113:1195–1201
Winocur G, Roder J, Lobaugh N (2001) Learning and memory in
S100-beta transgenic mice: an analysis of impaired and
preserved function. Neurobiol Learn Mem 75:230–243
Zainaghi IA, Forlenza OV, Gattaz WF (2007) Abnormal APP
processing in platelets of patients with Alzheimer’s disease:
correlations with membrane fluidity and cognitive decline.
Psychopharmacology 192:547–553
Zhou F, Hongmin B, Xiang Z, Enyu L (2003) Changes of mGluR4
and the effects of its specific agonist L-AP4 in a rodent model of
diffuse brain injury. J Clin Neurosci 10:684–688
Zhou W, Xu D, Peng X, Zhang Q, Jia J, Crutcher KA (2008) Meta-
analysis of APOE4 allele and outcome after traumatic brain
injury. J Neurotrauma 25:279–290
Zlotnik A, Sinelnikov I, Gruenbaum BF, Gruenbaum SE, Dubilet M,
Dubilet E, Leibowitz A, Ohayon S, Regev A, Boyko M, Shapira
Y, Teichberg VI (2012) Effect of glutamate and blood glutamate
scavengers oxaloacetate and pyruvate on neurological outcome
and pathohistology of the hippocampus after traumatic brain
injury in rats. Anesthesiology 116:73–83
90 Z.-L. Sun, D.-F. Feng
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