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: sun870119@126.com

D.-F. Feng (&)

Institute of Traumatic Medicine, Shanghai Jiaotong University

School of Medicine, 280 Mo-He Road, Shanghai 201900, China

e-mail: feng_df@yahoo.com

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.

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