Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Feb 26, 2017; 8(1): 21-31
Published online Feb 26, 2017. doi: 10.4331/wjbc.v8.i1.21
Biochemical changes in the injured brain
Seelora Sahu, Deb Sanjay Nag, Amlan Swain, Devi Prasad Samaddar
Seelora Sahu, Deb Sanjay Nag, Amlan Swain, Devi Prasad Samaddar, Department of Anaesthesia and Critical Care, Tata Main Hospital, Jamshedpur 831001, India
Author contributions: All the authors contributed to the manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Deb Sanjay Nag, Department of Anaesthesia and Critical Care, Tata Main Hospital, C Road West, Northern Town, Bistupur, Jamshedpur 831011, India. debsanjay@gmail.com
Telephone: +91-943-1166582 Fax: +91-657-2224559
Received: August 30, 2016
Peer-review started: September 1, 2016
First decision: September 29, 2016
Revised: October 23, 2016
Accepted: December 13, 2016
Article in press: December 14, 2016
Published online: February 26, 2017


Brain metabolism is an energy intensive phenomenon involving a wide spectrum of chemical intermediaries. Various injury states have a detrimental effect on the biochemical processes involved in the homeostatic and electrophysiological properties of the brain. The biochemical markers of brain injury are a recent addition in the armamentarium of neuro-clinicians and are being increasingly used in the routine management of neuro-pathological entities such as traumatic brain injury, stroke, subarachnoid haemorrhage and intracranial space occupying lesions. These markers are increasingly being used in assessing severity as well as in predicting the prognostic course of neuro-pathological lesions. S-100 protein, neuron specific enolase, creatinine phosphokinase isoenzyme BB and myelin basic protein are some of the biochemical markers which have been proven to have prognostic and clinical value in the brain injury. While S-100, glial fibrillary acidic protein and ubiquitin C terminal hydrolase are early biomarkers of neuronal injury and have the potential to aid in clinical decision-making in the initial management of patients presenting with an acute neuronal crisis, the other biomarkers are of value in predicting long-term complications and prognosis in such patients. In recent times cerebral microdialysis has established itself as a novel way of monitoring brain tissue biochemical metabolites such as glucose, lactate, pyruvate, glutamate and glycerol while small non-coding RNAs have presented themselves as potential markers of brain injury for future.

Key Words: Biomarkers, Brain injuries, Brain ischemia, Epilepsy, Subarachnoid hemorrhage

Core tip: The biochemical markers of brain injury are being increasingly used to assess the severity and prognosis in the injured brain. While S-100, glial fibrillary acidic protein and ubiquitin C terminal hydrolase have been used as early biomarkers to aid in clinical decision-making and initial management, other biomarkers help in long-term prognosis. Cerebral microdialysis is a novel way of monitoring brain tissue biochemical metabolites and each component gives an idea about the severity and type of pathologic process in the brain. In addition, small non-coding RNAs have presented themselves as potential markers of brain injury for future research.

Citation: Sahu S, Nag DS, Swain A, Samaddar DP. Biochemical changes in the injured brain. World J Biol Chem 2017; 8(1): 21-31

The brain is one of the most energy intensive organs of the body, utilizing around 60% of the available energy for the fulfillment of electrophysiological function, and the remaining 40% is expended in the homeostasis of the internal milieu of the brain cells[1]. Brain metabolism is an energy intensive phenomenon involving a wide spectrum of chemical intermediaries and their consequent usage in brain energy production.

The evolution of techniques to monitor brain metabolism started in the late 19th century[2]. However, major strides in the understanding of the cerebral metabolic processes have happened only in the last 50 years and have greatly contributed to our understanding of the processes governing the myriad and complex activities of the central nervous system in general and the brain in particular.

In this editorial we focus on the basics as well as perturbations of brain metabolism in the different clinical scenarios of neurological injury such as traumatic brain injury (TBI), stroke and subarachnoid hemorrhage (SAH). The aim of this review is also to discuss the means at our disposal to monitor such deviations and the practical clinical applications of such techniques[2].


As mentioned earlier, brain metabolism is peculiar for being a highly energy intensive process. Although it contributes approximately (only) 2%-2.5% of the total body weight, it receives approximately 20% of the total blood supply and 25% of the total oxygen supply[3].

The biochemical processes in the brain exhibit various peculiarities with ramifications in brain injury. First is the presence of a blood brain barrier formed by endothelial cell layers of the brain vessels[4-6], which plays an important role in the maintenance of homeostasis in relation to the electrolytes and energy substrates such as glucose, glutamate and ketone bodies[7-9]. Nerve impulse propagation is the key function within the brain and is basically an amalgamation of electrical and chemical processes. The electrical processes are responsible largely for impulse propagation within a neuron whereas chemical reactions influence signal transmission from one neuron to another as well as at the effector cells and axon ends in the synapse[10]. The synapses perform the critical function of transferring electrical impulses across the synaptic cleft or for further impulse propagation on to another neuron or muscle for a particular desired action. Impulse transmission through a synaptic cleft is a complex biochemical process involving neurotransmitters like glutamate and γ-aminobutyric acid as well as the activation of various ion channels. Sodium and potassium are the major ions involved in the generation of action potentials, especially in the process of hyperpolarization and depolarization of neurons[11-14]. The enormity of the biochemical processes involved in the signal transduction of neural impulse can be gauged from the fact that while a single neuron has 1000 to 20000 synapses, there are around 90 billion neurons in an adult human brain[15]. Brain injured states such as stroke and head injury have a detrimental effect on the biochemical processes involved in the aforesaid homeostatic and electrophysiological properties of the brain.


The biochemical basis of brain injury can be explained on the basis of either one or a combination of the following broad pathological mechanisms[16]: Ischemia; traumatic brain injury; epileptogenesis.

Ischemic brain injury

Ischemia and resultant hypoxia lead to the derangement of energy intensive processes critical to homeostasis in the brain. Dysfunctional ATP dependent ion pumps result in consequent disequilibrium in sodium, calcium and potassium ion homeostasis, culminating in the release of excitatory amino acids such as glutamate[17,18]. Glutamate plays a pivotal role in the ensuing excitotoxicity by activating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, N-methyl-D-aspartic acid (NMDA) and metabolic receptors. Calcium, free radicals and phospholipase activation also contribute significantly in the cellular damage of the brain.

An important aspect of ischemic injury in the brain is the nature of ischemia. Global ischemia of the brain follows events such as cardiac arrest, whereas focal ischemic changes are seen after events such as episode of stroke. In focal ischemia there exists a penumbra region which is responsive to brain resuscitation measures albeit within a critical time frame of a few minutes. In the scenario of ongoing global ischemia, the severity of brain damage is dependent on the time until re-establishment of brain circulation as well as the differential susceptibility of the various regions of the brain to hypoxia[19,20].

Traumatic brain injury

Primary injury following trauma to the brain consists of direct concussional neuronal damage, herniation of important structures as well as ischemic injury because of damage to blood vessels. Reversal of primary injury is impossible. However, amelioration of secondary effects is possible. The biochemical processes detailed previously play a pathologic role in traumatic brain injury and calcium is an important ion implicated in traumatic brain injury at the cellular level[21,22].

Epileptogenic injury

Epilepsy is defined as sudden and excessive electrical discharge from neurons and occurs from a plethora of causes such as electrolyte and metabolic perturbations, temperature disturbances, and structural insults such as tumors, trauma and infections. The mechanism of epileptiform damage resembles ischemia and involves the previously detailed sequences culminating in glutamate excitotoxicoty and NMDA and metabotropic nerve activation[23,24].

The ongoing process of cellular injury in the injured brain leaves in its wake a multitude of biochemical markers. An ideal marker for injury should be specific to the brain, pick up brain injury within a reasonable and defined time frame and exhibit low variation with age and sex[25,26]. However, the search for such a marker remains elusive till date.


The biochemical markers of brain injury are a recent addition in the armamentarium of neuro-clinicians and are being increasingly used in the routine management of neuro-pathological entities such as traumatic brain injury, stroke, SAH, and intracranial space occupying lesions. The use of such markers in the brain via-a-vis their use in the heart had been limited by various factors such as the heterogeneity of different cell types in the brain, the differential integrity of the blood brain barrier as well as the multimodal mechanisms contributing to neuronal death. However, they are recently being increasingly used in assessing severity as well as in predicting the prognostic course of neuropathological lesions. S-100 protein, neuron specific enolase (NSE), creatinine phosphokinase isoenzyme BB (CPK-BB) and myelin basic protein (MBP) are some of the biochemical markers which have been proven to have prognostic and clinical value in the brain injury and are dealt henceforth in a detailed perspective.


S-100 is a calcium binding protein with a molecular weight of 21 kDa and is present in two isoforms - “α” (25%) and “β” (75%). While S-100 “α” protein is found in melanocytes, S-100 β isoform is found predominantly in glial cells and Schwann cells of the peripheral nervous system and central nervous system. Although the β isoform is found in adipocytes and chondrocytes, the concentration of S-100 β in non-neural tissue (100-200 ng/mg of soluble brain protein) is minimal as compared with glial and Schwann cells (3500 ng/mg of brain protein)[26,27].

S-100 β protein is metabolized and excreted by the kidneys, has a t1/2 of 2 h and a mean serum level of 0.050 ± 0.081 g/L[28]. S-100 β protein levels have been found to increase especially following brain tissue injury in various experimental models[29].

S-100 β in head injury: Elevated levels of S-100 β have been found in patients after minor and major head injury[26,30-36]. In patients with mild head injury (GCS 13-15) where initial computed tomography (CT) scans of their brain do not exhibit any abnormality, S-100 β levels have been found to be high, especially in the golden hour following trauma[26]. Elevated levels of S-100 β in serum following head injury have also been associated with impaired cognition score[37].

In severe head injury an increased serum S 100 β level of > 2 g/L just after and during evolution of TBI has been found to be associated with a high mortality rate. Persistent elevations of S-100 β have shown an association with ongoing secondary brain damage following the primary insult. S-100 β has exhibited correlations with CT pathologies, with lower values being more common in diffuse type I and type II injuries. As a marker of clinical outcome following TBI, S-100 β has shown promising results[33-36,38-42].

Hence S-100 β in TBI can be concluded to be of clinical utility in assessing the extent of primary and secondary brain injury. It also has a role in predicting the time course of recovery and probability of an improved clinical outcome.

S-100 β protein in SAH: Plasma concentration of S-100 β in patients with SAH has shown a correlation with the severity of hemorrhagic affliction in the early phase of the disease as well as with the incidence of delayed cerebral ischemic events. There is also evidence correlating S-100 β levels with the severity of long-term neurological impairment as well as Glasgow outcome scores. Similar results have been observed with ventricular cerebrospinal fluid (CSF) S-100 β concentrations. There is significant evidence to suggest that S-100 β in CSF may show a superior correlation with CT and single-photon emission CT findings in addition to being predictive for outcome in patients with cerebral aneurysm[43-46].


As an isoenzyme of enolase enzyme involved in glycolysis, NSE was thought to be a relevant marker of neuronal injury[47]. However, it has also concurrently evolved as a marker for neuro-endocrine malignancies such as small cell lung cancer and neuroblastoma and hence it specificity for neural tissues is doubtful[48]. Serum levels are in the range of 5-12 ng/mL and CSF levels normally are less than 2 ng/mL[49].

NSE in TBI: In experimental model studies on cortical contusion, the highest concentration of NSE was observed at around 7.5 h following injury. This coincides with the primary mechanism of injury to the brain parenchyma and could be explained on the basis of extrusion of the cytoplasmic protein into the CSF from damaged neural and glial tissue. A secondary peak in the NSE levels was observed at around 1.5 d and in all probability reflects secondary ischemic damage to the contused brain[29]. An experimental TBI model in rats clearly demonstrated that CSF NSE is a more accurate motor of ongoing neuronal damage than serum NSE levels[50].

There have been a plethora of studies on the correlation of serum and CSF NSE levels with head injury as well as their prediction of long-term outcome[33,37,39,40,51-54]. Serum NSE levels showed a significant correlation with an identifiable contusion on CT scan and also predicted the incidence of long-term mortality and persistent vegetative state in patients with TBI[51].


NSE in SAH patients had been found to be an excellent predictor of delayed cerebral ischemic events and poor perioperative outcome. However, the correlation of serum NSE levels with the clinical grade of SAH patients at the time of admission is a contentious issue with various studies giving different levels[55-57].

NSE in stroke

Experimental studies in cerebral ischemia models and animal studies have unequivocally demonstrated that NSE levels in CSF correlate with the degree of severity of cerebral ischemia. In addition they have been found to be increased before irreversible brain cell damage, hence offering the promise of being used as a marker of guidance of cerebro-protective measures in stroke[58-60]. In human studies examining the correlation of CSF with serum NSE levels, NSE has been found to have a positive correlation with infarct size and volume[61-66]. In a study by Cunningham et al[67], serum NSE levels in patients with ischemic stroke were higher when compared with hemorrhagic stroke, and the highest levels in ischemia was observed at 48 to 96 h. NSE had also been found to correlate with and help in differentiation between reversible and irreversible brain damage in survivors of cardiac arrest[68-71]. In such patients, serum NSE levels post resuscitation care are a reliable predictor of neurologic outcome and they also aid in prognostication of such patients.


Of the three isoenzymic forms of creatinine phosphokinase, the CPK-BB isoform is found in the brain[48]. CPK-BB levels in various pathological entities of brain injury such as stroke, TBI, post cardiac arrest and SAH have shown a correlation with the extent of injury and have also shown to be able to predict outcome[72-78].


MBP originates from oligodendroglial cells and binds with myelin[79]. In TBI it is released into CSF and serves as a useful marker predicting the clinical course and outcome[52,80-84].

In addition there are various other proteins which are less established via-a-vis their role in predicting severity and outcome in the brain injured states.


Tau is a protein arising from the microtubules, which offers theoretical promise as a marker of brain injury and has been especially studied in TBI states[85,86]. However, recent evidence has been very conflicting and the evidence on the diagnostic and prognostic value of tau protein and its correlation with abnormal CT findings in TBI has been very limited[87-90].


As a major component of astroglia, glial fibrillary acidic protein (GFAP) offers the promise of exclusivity to the central nervous system[91-93]. There have been numerous studies in TBI sub-population such as severe or moderate TBI wherein GFAP concentration has shown a positive correlation with severity of injury, outcomes as well as CT and MRI findings[94-98]. In a study comparing GFAP and S-100 β, GFAP exhibited characteristics of being a more sensitive marker of neural injury. It also had higher value for predicting return to work via-a-vis S-100 β especially in patients with severe head injury[99].


Ubiquitin c terminal hydrolase (UCH-L1) is a neuron specific protein comprising 1%-5% of total brain protein, which has been implicated in neuron repair in pathological and degenerative conditions of the brain[100-102]. There is a release of UCH-L1 into CSF and blood in brain injury and elevated levels have exhibited a correlation with severity and outcome in TBI populations[103].


The preceding discussion indicates that the different biomarkers in brain injury do not exactly fit into the “one size fits all” algorithm. Evidence in the field is an evolving process and it seems increasingly probable that neuro-clinicians will rely more and more on a combination of different biomarkers as an aid in diagnosis, severity scoring, prognostication and interventional decisions in brain injured patients[101,104]. S-100, GFAP and UCH-L1 are early biomarkers of neuronal injury and have the potential to aid in clinical decision-making in the initial management of patients presenting with an acute neuronal crisis such as stroke, TBI and SAH. The other biomarkers are of value in predicting long-term complications and prognosis in such patients.


While CSF levels of biomarkers reflecting CNS injury are more accurate, in acute settings such as TBI and stroke, collection of blood samples represents a more convenient and practical approach. In recent times there have been enormous strides in the field of standardization of methods by which samples are being collected for the measurement of the neuronal biomarkers[105,106]. Recently there have been attempts to isolate the aforementioned biomarkers from urine and saliva of patients to preclude non-invasiveness and ease collection[107].


The widespread use of neuro-pathological markers is limited by variability and discrepancies in the values indicating significant levels of these biomarkers. The results of various studies paint a very inconsistent picture and this could be attributed to flaws and variation in study design as well as non-standardization of techniques in collection, handling and assay of such biomarkers. To summarize, the data till date on biomarkers of the injured brain can be described as a work in progress. There is a need for robust multicentric studies which will go a long way in the determination of reference points for guidance of care in patients presenting with neurological injury.


In addition to serum and CSF assays of biomarkers of brain injury, there has been a variety of neuro-chemical methods which have been of use in brain tissue biochemistry. These methods have gradually progressed from analysis of post mortem samples to advent of newer and sophisticated methods such as cerebral microdialysis (CMD).

CMD was a modification of the push-pull cannula technique and was invented by Delgado et al[108] with subsequent modifications and popularization by Ludvig et al[109] and Ungerstedt et al[110]. It is a novel way of monitoring brain tissue biochemical metabolites such as glucose, lactate, pyruvate, glutamate and glycerol wherein the monitoring of each component gives an idea about the severity and type of pathologic process in the brain. Table 1 summarizes all the commonly used serum and CSF biomarkers of cerebral injury with their clinical implications[111-120]. Table 2 summarizes components monitored by cerebral microdialysis and their clinical implications[121-125].

Table 1 Serum and cerebrospinal fluid biomarkers of cerebral injury.
Structure effectedFindings in brain injury
Cerebro spinal fluidBlood/serum
Tau proteinAxonLevels peak 4-8 d after injury[111,112]Elevated levels in hypoxic injury[113,114]
Myelin basic proteinAxonPrecise measurement difficult[115]Elevated levels in brain injury[116]
γ-enolaseNeuronConfounded by blood contaminated CSF[117]Serum levels are very sensitive to lysis of RBC in blood contaminated CSF[117], elevated levels in brain injury[116]
S-100 βAstrolglial cellsElevated levels but less sensitive[108]Confounded by release from extracerebral tissue[118]
GFAPAstroglial cellsElevated levels but less sensitive[107,108]Serum levels correlate with changes in brain imaging[119], no extracerebral sources detected[120]
UCH-L1NeuronNAOnly one pilot study[98]
Table 2 The components monitored by cerebral microdialysis and their clinical implications.
VariableNormal levels (at a flow rate of 0.3 μL/min)Clinical implications
Lactate2.9 ± 0.9 mmol/LIncreased levels seen in ischemia and hyperglycolysis[121-123]
Pyruvate166 ± 47 μmol/LDecreased levels seen in ischemia and hypoxic conditions[124,125]
L/P ratioNormal value-20Value > 25 - metabolic crisis[124]
Type 1-lactate increased, pyruvate decreased, signifying ischemia
Type 2-raised LPR due to primarily decreased pyruvate level, seen in glycolysis failure or shunting of glucose to alternative metabolic pathways[125]
Glycerol82 ± 4 μmol/LOne of the constituents of the cell membranes
An increase in levels signifies cell damage[124]
Glutamate16 ± 16 μmol/LMarker of excitotoxicity[124]
Glucose1.7 ± 0.9 mmol/LChanges in blood flow or metabolism cause disproportionate changes in brain glucose
Affected by ischaemia, hyperaemia, hyperglycaemia, hypermetabolism and hypometabolism[124]

CMD is being increasingly used as a research tool and as a component of multi-modality monitoring in the brain injured states such as TBI, SAH, brain tumors, stroke and epilepsy. Table 3 illustrates the clinical implications of cerebral microdialysis in various scenarios[126-151].

Table 3 Cerebral microdialysis implications in clinical scenarios.
Clinical conditionCMD implications
Traumatic brain injuryHelpful in optimising therapy in neuro-ICUs as a component of multi-modality monitoring
Helpful in indivisualising management on the basis of cerebral perfusion pressure targets and assessment of response to medical and surgical interventions[126,127]
Predictor of severity, neurological outcome and long-term anatomical aberrations in the injured brain[128-130]
Detection and management of glycemic perturbations of the injured brain[131,132]
Predicting long-term anatomical alteration[133]
Subarachnoid haemorrhageDetection of ischemic changes during aneurysm clipping[134]
Specific for the detection of delayed ischaemic neurological deficit[135-138]
Prognostication of SAH patients[139,140]
Acute ischaemic strokeDetecting development of oedema of the infarcted tissue[141]
Monitoring effects of decompression hemicraniectomy and hypothermia in stroke patients[142,143]
Brain tumoursNeurobiochemistry of brain tumours[144,145]
Biochemical changes during treatment
Drug pharmacokinetics study[146]
Monitoring of drug effect
Development of tumor drug delivery systems[147,148]
EpilepsyStudy of biochemical milieu of epileptic focus[149]
Other applicationsStudy of the perihaemorrhagic zone in intracranial hemorrhage[150,151]
Study of biochemical changes and novel therapeutic options in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease

Proteomic analysis of potential new CSF biomarkers for TBI has not yet identified any such markers that can be used in clinically useful tests[152]. A number of proteomic studies on potential biomarkers of TBI in peripheral blood have been published. These studies have replicated the findings from targeted analyses of specific candidate biomarkers, but as yet none of the novel biomarker profiles identified in these studies as being associated with TBI has been validated in independent studies using unrelated, non-proteomic or genomic techniques[153]. Exciting preliminary data on the expression profiles of small non-coding RNAs in peripheral blood mononuclear cells from military personnel exposed to mild TBI have been reported; three small RNAs seem to be primarily associated with mild TBI, but the results require replication[154].


To conclude, biochemical markers of brain injury have witnessed major developments in acquisition and processing of samples, with cerebral microdialysis and expression of non-coding RNAs being the most recent modality to analyze such changes. Use of such biomarkers, while not as popular as their cardiac counterparts, is slowly but surely being established both in the realms of basic research as well as in management, severity scoring and prognostication of patients with neurological injury. There is abundant potential in the regular use of such biomarkers and efforts are underway to integrate such biomarkers into clinical practice in TBI, SAH and stroke.


Manuscript source: Invited manuscript

Specialty type: Biochemistry and molecular biology

Country of origin: India

Peer-review report classification

Grade A (Excellent): A

Grade B (Very good): 0

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P- Reviewer: Tian YF S- Editor: Qiu S L- Editor: Wang TQ E- Editor: Li D

1.  Patel PM, Drummond JC, Lemkuil BP. Cerebral physiology and the effects of anaesthetic drugs. Miller’s Anaesthesia. Philadelphia: Elsevier;; 2015;387-409.  [PubMed]  [DOI]
2.  Finlay JM, Smith GS. A Critical Analysis of Neurochemical Methods for Monitoring Transmitter Dynamics in the Brain, 2000.  Available from: http://www.acnp.org/g4/GN401000004/CH004.html.  [PubMed]  [DOI]
3.  Schoenemann PT. Evolution of the size and functional areas of the human brain. Annu Rev Anthropol. 2006;35:379-406.  [PubMed]  [DOI]
4.  Allsopp G, Gamble HJ. An electron microscopic study of the pericytes of the developing capillaries in human fetal brain and muscle. J Anat. 1979;128:155-168.  [PubMed]  [DOI]
5.  Ballabh P, Braun A, Nedergaard M. Anatomic analysis of blood vessels in germinal matrix, cerebral cortex, and white matter in developing infants. Pediatr Res. 2004;56:117-124.  [PubMed]  [DOI]
6.  Cristante E, McArthur S, Mauro C, Maggioli E, Romero IA, Wylezinska-Arridge M, Couraud PO, Lopez-Tremoleda J, Christian HC, Weksler BB. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci USA. 2013;110:832-841.  [PubMed]  [DOI]
7.  Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86-98.  [PubMed]  [DOI]
8.  Yin B, Loike JD, Kako Y, Weinstock PH, Breslow JL, Silverstein SC, Goldberg IJ. Lipoprotein lipase regulates Fc receptor-mediated phagocytosis by macrophages maintained in glucose-deficient medium. J Clin Invest. 1997;100:649-657.  [PubMed]  [DOI]
9.  Seyfried TN, Kiebish MA, Marsh J, Shelton LM, Huysentruyt LC, Mukherjee P. Metabolic management of brain cancer. Biochim Biophys Acta. 2011;1807:577-594.  [PubMed]  [DOI]
10.  Marieb EN, Hoehn K. Human Anatomy & Physiology, 8th ed. San Francisco, CA: Benjamin Cummings; 2010;385-428.  [PubMed]  [DOI]
11.  Murai T, Müller U, Werheid K, Sorger D, Reuter M, Becker T, von Cramon DY, Barthel H. In vivo evidence for differential association of striatal dopamine and midbrain serotonin systems with neuropsychiatric symptoms in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 2001;13:222-228.  [PubMed]  [DOI]
12.  Hajjawi OS. Human Brain Biochemistry. Ame J BioS. 2014;2:122-134.  [PubMed]  [DOI]
13.  Sherwood L. Human Physiology from Cells to Systems. Stamford, CT: Cengage Learning; 2012;105-115.  [PubMed]  [DOI]
14.  Marois R, Ivanoff J. Capacity limits of information processing in the brain. Trends Cogn Sci. 2005;9:296-305.  [PubMed]  [DOI]
15.  Crick FHC. The Astonishing Hypothesis: The Scientific Search for the Soul. New York, NY: Macmillan Publishing Company; 1994;81-90.  [PubMed]  [DOI]
16.  Kass IS, Cottrell JE, Lei B. Brain metabolism, the pathophysiology of brain injury, and potential beneficial agents and techniques. In: Cottrell JE, Young WL. Cottrell and Young’s Neuroanesthesia. Philadelphia: Elsevier, 2010: 1-16. Philadelphia: Elsevier; 2010;1-16.  [PubMed]  [DOI]
17.  Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol. 1986;19:105-111.  [PubMed]  [DOI]
18.  Choi DW. Excitotoxic cell death. J Neurobiol. 1992;23:1261-1276.  [PubMed]  [DOI]
19.  Zola-Morgan S, Squire LR, Amaral DG. Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci. 1986;6:2950-2967.  [PubMed]  [DOI]
20.  Wang J, Lei B, Popp S, Meng F, Cottrell JE, Kass IS. Sevoflurane immediate preconditioning alters hypoxic membrane potential changes in rat hippocampal slices and improves recovery of CA1 pyramidal cells after hypoxia and global cerebral ischemia. Neuroscience. 2007;145:1097-1107.  [PubMed]  [DOI]
21.  Lawrence T, Helmy A, Bouamra O, Woodford M, Lecky F, Hutchinson PJ. Traumatic brain injury in England and Wales: prospective audit of epidemiology, complications and standardised mortality. BMJ Open. 2016;6:e012197.  [PubMed]  [DOI]
22.  Prough DS. Management of head trauma. 1997 Annual Refresher Course Lectures. Ame Soc Anest. 1997;253: 1-7.  [PubMed]  [DOI]
23.  Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66-73.  [PubMed]  [DOI]
24.  Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S, Ringleb PA. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8:141-150.  [PubMed]  [DOI]
25.  Bakay RA, Sweeney KM, Wood JH. Pathophysiology of cerebrospinal fluid in head injury: Part 2. Biochemical markers for central nervous system trauma. Neurosurgery. 1986;18:376-382.  [PubMed]  [DOI]
26.  Ingebrigtsen T, Waterloo K, Jacobsen EA, Langbakk B, Romner B. Traumatic brain damage in minor head injury: relation of serum S-100 protein measurements to magnetic resonance imaging and neurobehavioral outcome. Neurosurgery. 1999;45:468-475; discussion 475-476.  [PubMed]  [DOI]
27.  Nygaard O, Langbakk B, Romner B. Age- and sex-related changes of S-100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder. Clin Chem. 1997;43:541-543.  [PubMed]  [DOI]
28.  Wiesmann M, Missler U, Hagenström H, Gottmann D. S-100 protein plasma levels after aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien). 1997;139:1155-1160.  [PubMed]  [DOI]
29.  Hårdemark HG, Ericsson N, Kotwica Z, Rundström G, Mendel-Hartvig I, Olsson Y, Påhlman S, Persson L. S-100 protein and neuron-specific enolase in CSF after experimental traumatic or focal ischemic brain damage. J Neurosurg. 1989;71:727-731.  [PubMed]  [DOI]
30.  Ingebrigtsen T, Romner B, Kongstad P, Langbakk B. Increased serum concentrations of protein S-100 after minor head injury: a biochemical serum marker with prognostic value? J Neurol Neurosurg Psychiatry. 1995;59:103-104.  [PubMed]  [DOI]
31.  Ingebrigtsen T, Romner B. Serial S-100 protein serum measurements related to early magnetic resonance imaging after minor head injury. Case report. J Neurosurg. 1996;85:945-948.  [PubMed]  [DOI]
32.  Ingebrigtsen T, Romner B, Trumpy JH. Management of minor head injury: the value of early computed tomography and serum protein S-100 measurements. J Clin Neurosci. 1997;4:29-33.  [PubMed]  [DOI]
33.  Raabe A, Grolms C, Keller M, Döhnert J, Sorge O, Seifert V. Correlation of computed tomography findings and serum brain damage markers following severe head injury. Acta Neurochir (Wien). 1998;140:787-791; discussion 791-792.  [PubMed]  [DOI]
34.  Raabe A, Menon DK, Gupta S, Czosnyka M, Pickard JD. Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: a pilot study. J Neurol Neurosurg Psychiatry. 1998;65:930-932.  [PubMed]  [DOI]
35.  Raabe A, Grolms C, Sorge O, Zimmermann M, Seifert V. Serum S-100B protein in severe head injury. Neurosurgery. 1999;45:477-483.  [PubMed]  [DOI]
36.  Raabe A, Seifert V. Fatal secondary increase in serum S-100B protein after severe head injury. Report of three cases. J Neurosurg. 1999;91:875-877.  [PubMed]  [DOI]
37.  Waterloo K, Ingebrigtsen T, Romner B. Neuropsychological function in patients with increased serum levels of protein S-100 after minor head injury. Acta Neurochir (Wien). 1997;139:26-31; discussion 31-32.  [PubMed]  [DOI]
38.  Woertgen C, Rothoerl RD, Holzschuh M, Metz C, Brawanski A. Comparison of serial S-100 and NSE serum measurements after severe head injury. Acta Neurochir (Wien). 1997;139:1161-1164; discussion 1165.  [PubMed]  [DOI]
39.  Rothoerl RD, Woertgen C, Holzschuh M, Metz C, Brawanski A. S-100 serum levels after minor and major head injury. J Trauma. 1998;45:765-767.  [PubMed]  [DOI]
40.  Herrmann M, Curio N, Jost S, Wunderlich MT, Synowitz H, Wallesch CW. Protein S-100B and neuron specific enolase as early neurobiochemical markers of the severity of traumatic brain injury. Restor Neurol Neurosci. 1999;14:109-114.  [PubMed]  [DOI]
41.  Herrmann M, Jost S, Kutz S, Ebert AD, Kratz T, Wunderlich MT, Synowitz H. Temporal profile of release of neurobiochemical markers of brain damage after traumatic brain injury is associated with intracranial pathology as demonstrated in cranial computerized tomography. J Neurotrauma. 2000;17:113-122.  [PubMed]  [DOI]
42.  Raabe A, Grolms C, Seifert V. Serum markers of brain damage and outcome prediction in patients after severe head injury. Br J Neurosurg. 1999;13:56-59.  [PubMed]  [DOI]
43.  Persson L, Hårdemark H, Edner G, Ronne E, Mendel-Hartvig I, Påhlman S. S-100 protein in cerebrospinal fluid of patients with subarachnoid haemorrhage: a potential marker of brain damage. Acta Neurochir (Wien). 1988;93:116-122.  [PubMed]  [DOI]
44.  Hårdemark HG, Almqvist O, Johansson T, Påhlman S, Persson L. S-100 protein in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage: relation to functional outcome, late CT and SPECT changes, and signs of higher cortical dysfunction. Acta Neurochir (Wien). 1989;99:135-144.  [PubMed]  [DOI]
45.  Takayasu M, Shibuya M, Kanamori M, Suzuki Y, Ogura K, Kageyama N, Umekawa H, Hidaka H. S-100 protein and calmodulin levels in cerebrospinal fluid after subarachnoid hemorrhage. J Neurosurg. 1985;63:417-420.  [PubMed]  [DOI]
46.  Satoh H, Ikeda Y, Ohashi K. Measurement of S-100b in cerebrospinal fluid among SAH cases: prediction of outcome. 29th Annual Meeting of Japanese Society of Surgery for Stroke, 2000. .  [PubMed]  [DOI]
47.  Schoerkhuber W, Kittler H, Sterz F, Behringer W, Holzer M, Frossard M, Spitzauer S, Laggner AN. Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke. 1999;30:1598-1603.  [PubMed]  [DOI]
48.  Ikeda Y, Mochizuki Y, Nakamura Y, Dohi K, Matsumoto H, Jimbo H, Hayashi M, Matsumoto K, Yoshikawa T, Murase H. Protective effect of a novel vitamin E derivative on experimental traumatic brain edema in rats--preliminary study. Acta Neurochir Suppl. 2000;76:343-345.  [PubMed]  [DOI]
49.  Marangos PJ, Schmechel DE. Neuron specific enolase, a clinically useful marker for neurons and neuroendocrine cells. Annu Rev Neurosci. 1987;10:269-295.  [PubMed]  [DOI]
50.  Uzan M, Hanci M, Güzel O, Sarioğlu AC, Kuday C, Ozlen F, Kaynar MY. The significance of neuron specific enolase levels in cerebrospinal fluid and serum after experimental traumatic brain damage. Acta Neurochir (Wien). 1995;135:141-143.  [PubMed]  [DOI]
51.  Kuroiwa T, Tanabe H, Takatsuka H, Arai M, Nagasawa S, Ohta T. [Significance of serum neuron-specific enolase levels after head injury]. No Shinkei Geka. 1993;21:1021-1024.  [PubMed]  [DOI]
52.  Yamazaki Y, Yada K, Morii S, Kitahara T, Ohwada T. Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury. Surg Neurol. 1995;43:267-270; discussion 270-271.  [PubMed]  [DOI]
53.  Ross SA, Cunningham RT, Johnston CF, Rowlands BJ. Neuron-specific enolase as an aid to outcome prediction in head injury. Br J Neurosurg. 1996;10:471-476.  [PubMed]  [DOI]
54.  Ergün R, Bostanci U, Akdemir G, Beşkonakli E, Kaptanoğlu E, Gürsoy F, Taşkin Y. Prognostic value of serum neuron-specific enolase levels after head injury. Neurol Res. 1998;20:418-420.  [PubMed]  [DOI]
55.  Kacira T, Kemerdere R, Atukeren P, Hanimoglu H, Sanus GZ, Kucur M, Tanriverdi T, Gumustas K, Kaynar MY. Detection of caspase-3, neuron specific enolase, and high-sensitivity C-reactive protein levels in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007;60:674-679; discussion 679-680.  [PubMed]  [DOI]
56.  Kuroiwa T, Tanabe H, Arai M, Ohta T. [Measurement of serum neuron-specific enolase levels after subarachnoid hemorrhage and intracerebral hemorrhage]. No Shinkei Geka. 1994;22:531-535.  [PubMed]  [DOI]
57.  Hårdemark HG, Persson L, Bolander HG, Hillered L, Olsson Y, Påhlman S. Neuron-specific enolase is a marker of cerebral ischemia and infarct size in rat cerebrospinal fluid. Stroke. 1988;19:1140-1144.  [PubMed]  [DOI]
58.  Horn M, Seger F, Schlote W. Neuron-specific enolase in gerbil brain and serum after transient cerebral ischemia. Stroke. 1995;26:290-296; discussion 296-297.  [PubMed]  [DOI]
59.  Barone FC, Clark RK, Price WJ, White RF, Feuerstein GZ, Storer BL, Ohlstein EH. Neuron-specific enolase increases in cerebral and systemic circulation following focal ischemia. Brain Res. 1993;623:77-82.  [PubMed]  [DOI]
60.  Steinberg R, Gueniau C, Scarna H, Keller A, Worcel M, Pujol JF. Experimental brain ischemia: neuron-specific enolase level in cerebrospinal fluid as an index of neuronal damage. J Neurochem. 1984;43:19-24.  [PubMed]  [DOI]
61.  Royds JA, Davies-Jones GA, Lewtas NA, Timperley WR, Taylor CB. Enolase isoenzymes in the cerebrospinal fluid of patients with diseases of the nervous system. J Neurol Neurosurg Psychiatry. 1983;46:1031-1036.  [PubMed]  [DOI]
62.  Hay E, Royds JA, Davies-Jones GA, Lewtas NA, Timperley WR, Taylor CB. Cerebrospinal fluid enolase in stroke. J Neurol Neurosurg Psychiatry. 1984;47:724-729.  [PubMed]  [DOI]
63.  Jacobi C, Reiber H. Clinical relevance of increased neuron-specific enolase concentration in cerebrospinal fluid. Clin Chim Acta. 1988;177:49-54.  [PubMed]  [DOI]
64.  Kawasaki H, Wakayama Y, Okayasu H, Takahashi1 H, Shibuya S. Levels of serum and cerebrospinal fluid enolase in patients with cerebral vascular disease and other neurological diseases. Stroke. 1988;10:313-318.  [PubMed]  [DOI]
65.  Vermuyten K, Lowenthal A, Karcher D. Detection of neuron specific enolase concentrations in cerebrospinal fluid from patients with neurological disorders by means of a sensitive enzyme immunoassay. Clin Chim Acta. 1990;187:69-78.  [PubMed]  [DOI]
66.  Mokuno K, Kato K, Kawai K, Matsuoka Y, Yanagi T, Sobue I. Neuron-specific enolase and S-100 protein levels in cerebrospinal fluid of patients with various neurological diseases. J Neurol Sci. 1983;60:443-451.  [PubMed]  [DOI]
67.  Cunningham RT, Watt M, Winder J, McKinstry S, Lawson JT, Johnston CF, Hawkins SA, Buchanan KD. Serum neurone-specific enolase as an indicator of stroke volume. Eur J Clin Invest. 1996;26:298-303.  [PubMed]  [DOI]
68.  Dauberschmidt R, Zinsmeyer J, Mrochen H, Meyer M. Changes of neuron-specific enolase concentration in plasma after cardiac arrest and resuscitation. Mol Chem Neuropathol. 1991;14:237-245.  [PubMed]  [DOI]
69.  Stelzl T, von Bose MJ, Hogl B, Fuchs HH, Flugel KA. A comparison of the prognostic value of neuron-specific enolase serum levels and somatosensory evoked potentials in 13 reanimated patients. Eur J Emerg Med. 1995;2:24-27.  [PubMed]  [DOI]
70.  Martens P, Raabe A, Johnsson P. Serum S-100 and neuron-specific enolase for prediction of regaining consciousness after global cerebral ischemia. Stroke. 1998;29:2363-2366.  [PubMed]  [DOI]
71.  Fogel W, Krieger D, Veith M, Adams HP, Hund E, Storch-Hagenlocher B, Buggle F, Mathias D, Hacke W. Serum neuron-specific enolase as early predictor of outcome after cardiac arrest. Crit Care Med. 1997;25:1133-1138.  [PubMed]  [DOI]
72.  Tirschwell DL, Longstreth WT, Rauch-Matthews ME, Chandler WL, Rothstein T, Wray L, Eng LJ, Fine J, Copass MK. Cerebrospinal fluid creatine kinase BB isoenzyme activity and neurologic prognosis after cardiac arrest. Neurology. 1997;48:352-357.  [PubMed]  [DOI]
73.  Pfeiffer FE, Homburger HA, Yanagihara T. Creatine kinase BB isoenzyme in CSF in neurologic diseases. Measurement by radioimmunoassay. Arch Neurol. 1983;40:169-172.  [PubMed]  [DOI]
74.  Ikeda Y, Nakazawa S, Tsuji Y, Mori H. [Sequential changes in serum creatine phosphokinase isoenzyme activity and correlation with prognosis in patients with acute head injuries]. Neurol Med Chir (Tokyo). 1987;27:90-96.  [PubMed]  [DOI]
75.  Cooper PR, Chalif DJ, Ramsey JF, Moore RJ. Radioimmunoassay of the brain type isoenzyme of creatine phosphokinase (CK-BB): a new diagnostic tool in the evaluation of patients with head injury. Neurosurgery. 1983;12:536-541.  [PubMed]  [DOI]
76.  Skogseid IM, Nordby HK, Urdal P, Paus E, Lilleaas F. Increased serum creatine kinase BB and neuron specific enolase following head injury indicates brain damage. Acta Neurochir (Wien). 1992;115:106-111.  [PubMed]  [DOI]
77.  Coplin WM, Longstreth WT, Lam AM, Chandler WL, Mayberg TS, Fine JS, Winn HR. Cerebrospinal fluid creatine kinase-BB isoenzyme activity and outcome after subarachnoid hemorrhage. Arch Neurol. 1999;56:1348-1352.  [PubMed]  [DOI]
78.  Bell RD, Khan M. Cerebrospinal fluid creatine kinase-BB activity: a perspective. Arch Neurol. 1999;56:1327-1328.  [PubMed]  [DOI]
79.  Johnsson P. Markers of cerebral ischemia after cardiac surgery. J Cardiothorac Vasc Anesth. 1996;10:120-126.  [PubMed]  [DOI]
80.  Bakay RA, Sweeney KM, Wood JH. Pathophysiology of cerebrospinal fluid in head injury: Part 1. Pathological changes in cerebrospinal fluid solute composition after traumatic injury. Neurosurgery. 1986;18:234-243.  [PubMed]  [DOI]
81.  Noseworthy TW, Anderson BJ, Noseworthy AF, Shustack A, Johnston RG, Petruk KC, McPherson TA. Cerebrospinal fluid myelin basic protein as a prognostic marker in patients with head injury. Crit Care Med. 1985;13:743-746.  [PubMed]  [DOI]
82.  Thomas DG, Palfreyman JW, Ratcliffe JG. Serum-myelin-basic-protein assay in diagnosis and prognosis of patients with head injury. Lancet. 1978;1:113-115.  [PubMed]  [DOI]
83.  Thomas DG, Rabow L, Teasdale G. Serum myelin basic protein, clinical responsiveness, and outcome of severe head injury. Acta Neurochir Suppl (Wien). 1979;28:93-95.  [PubMed]  [DOI]
84.  Alling C, Karlsson B, Vällfors B. Increase in myelin basic protein in CSF after brain surgery. J Neurol. 1980;223:225-230.  [PubMed]  [DOI]
85.  Zemlan FP, Rosenberg WS, Luebbe PA, Campbell TA, Dean GE, Weiner NE, Cohen JA, Rudick RA, Woo D. Quantification of axonal damage in traumatic brain injury: affinity purification and characterization of cerebrospinal fluid tau proteins. J Neurochem. 1999;72:741-750.  [PubMed]  [DOI]
86.  Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WS, Speciale SG, Zuccarello M. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res. 2002;947:131-139.  [PubMed]  [DOI]
87.  Bazarian JJ, Zemlan FP, Mookerjee S, Stigbrand T. Serum S-100B and cleaved-tau are poor predictors of long-term outcome after mild traumatic brain injury. Brain Inj. 2006;20:759-765.  [PubMed]  [DOI]
88.  Bulut M, Koksal O, Dogan S, Bolca N, Ozguc H, Korfali E, Ilcol YO, Parklak M. Tau protein as a serum marker of brain damage in mild traumatic brain injury: preliminary results. Adv Ther. 2006;23:12-22.  [PubMed]  [DOI]
89.  Ma M, Lindsell CJ, Rosenberry CM, Shaw GJ, Zemlan FP. Serum cleaved tau does not predict postconcussion syndrome after mild traumatic brain injury. Am J Emerg Med. 2008;26:763-768.  [PubMed]  [DOI]
90.  Kavalci C, Pekdemir M, Durukan P, Ilhan N, Yildiz M, Serhatlioglu S, Seckin D. The value of serum tau protein for the diagnosis of intracranial injury in minor head trauma. Am J Emerg Med. 2007;25:391-395.  [PubMed]  [DOI]
91.  Eng LF, Vanderhaeghen JJ, Bignami A, Gerstl B. An acidic protein isolated from fibrous astrocytes. Brain Res. 1971;28:351-354.  [PubMed]  [DOI]
92.  Missler U, Wiesmann M, Wittmann G, Magerkurth O, Hagenström H. Measurement of glial fibrillary acidic protein in human blood: analytical method and preliminary clinical results. Clin Chem. 1999;45:138-141.  [PubMed]  [DOI]
93.  Webster MJ, Knable MB, Johnston-Wilson N, Nagata K, Inagaki M, Yolken RH. Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression. Brain Behav Immun. 2001;15:388-400.  [PubMed]  [DOI]
94.  Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T, Edwards M, Rosmalen CF, Vissers JL. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology. 2010;75:1786-1793.  [PubMed]  [DOI]
95.  Mondello S, Papa L, Buki A, Bullock MR, Czeiter E, Tortella FC, Wang KK, Hayes RL. Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study. Crit Care. 2011;15:R156.  [PubMed]  [DOI]
96.  Vos PE, Lamers KJ, Hendriks JC, van Haaren M, Beems T, Zimmerman C, van Geel W, de Reus H, Biert J, Verbeek MM. Glial and neuronal proteins in serum predict outcome after severe traumatic brain injury. Neurology. 2004;62:1303-1310.  [PubMed]  [DOI]
97.  Pelinka LE, Kroepfl A, Leixnering M, Buchinger W, Raabe A, Redl H. GFAP versus S100B in serum after traumatic brain injury: relationship to brain damage and outcome. J Neurotrauma. 2004;21:1553-1561.  [PubMed]  [DOI]
98.  Papa L, Lewis LM, Falk JL, Zhang Z, Silvestri S, Giordano P, Brophy GM, Demery JA, Dixit NK, Ferguson I. Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Ann Emerg Med. 2012;59:471-483.  [PubMed]  [DOI]
99.  Metting Z, Wilczak N, Rodiger LA, Schaaf JM, van der Naalt J. GFAP and S100B in the acute phase of mild traumatic brain injury. Neurology. 2012;78:1428-1433.  [PubMed]  [DOI]
100.  Lincoln S, Vaughan J, Wood N, Baker M, Adamson J, Gwinn-Hardy K, Lynch T, Hardy J, Farrer M. Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson’s disease. Neuroreport. 1999;10:427-429.  [PubMed]  [DOI]
101.  Larsen CN, Price JS, Wilkinson KD. Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues. Biochemistry. 1996;35:6735-6744.  [PubMed]  [DOI]
102.  Kobeissy FH, Ottens AK, Zhang Z, Liu MC, Denslow ND, Dave JR, Tortella FC, Hayes RL, Wang KK. Novel differential neuroproteomics analysis of traumatic brain injury in rats. Mol Cell Proteomics. 2006;5:1887-1898.  [PubMed]  [DOI]
103.  Papa L, Lewis LM, Silvestri S, Falk JL, Giordano P, Brophy GM, Demery JA, Liu MC, Mo J, Akinyi L. Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention. J Trauma Acute Care Surg. 2012;72:1335-1344.  [PubMed]  [DOI]
104.  Mondello S, Jeromin A, Buki A, Bullock R, Czeiter E, Kovacs N, Barzo P, Schmid K, Tortella F, Wang KK. Glial neuronal ratio: a novel index for differentiating injury type in patients with severe traumatic brain injury. J Neurotrauma. 2012;29:1096-1104.  [PubMed]  [DOI]
105.  Manley GT, Diaz-Arrastia R, Brophy M, Engel D, Goodman C, Gwinn K, Veenstra TD, Ling G, Ottens AK, Tortella F. Common data elements for traumatic brain injury: recommendations from the biospecimens and biomarkers working group. Arch Phys Med Rehabil. 2010;91:1667-1672.  [PubMed]  [DOI]
106.  Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L, Comabella M, Franciotta D, Frederiksen JL, Fleming JO, Furlan R. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology. 2009;73:1914-1922.  [PubMed]  [DOI]
107.  Hallén M, Karlsson M, Carlhed R, Hallgren T, Bergenheim M. S-100B in serum and urine after traumatic head injury in children. J Trauma. 2010;69:284-289.  [PubMed]  [DOI]
108.  Delgado JM, DeFeudis FV, Roth RH, Ryugo DK, Mitruka BM. Dialytrode for long term intracerebral perfusion in awake monkeys. Arch Int Pharmacodyn Ther. 1972;198:9-21.  [PubMed]  [DOI]
109.  Ludvig N, Potter PE, Fox SE. Simultaneous single-cell recording and microdialysis within the same brain site in freely behaving rats: a novel neurobiological method. J Neurosci Methods. 1994;55:31-40.  [PubMed]  [DOI]
110.  Ungerstedt U. Measurement of neurotransmitter release by intracranial dialysis. In: Marsden CA, ed. Measurement of Neurotransmitter Release In Vivo. IBRO Handbook Series: Methods in the Neurosciences. New York: John Wiley & Sons Ltd, 1984: 81-105. .  [PubMed]  [DOI]
111.  Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, Edman A, Popa C, Rasulzada A, Wahlund LO. Neurochemical aftermath of amateur boxing. Arch Neurol. 2006;63:1277-1280.  [PubMed]  [DOI]
112.  Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLoS One. 2012;7:e33606.  [PubMed]  [DOI]
113.  Mörtberg E, Zetterberg H, Nordmark J, Blennow K, Catry C, Decraemer H, Vanmechelen E, Rubertsson S. Plasma tau protein in comatose patients after cardiac arrest treated with therapeutic hypothermia. Acta Anaesthesiol Scand. 2011;55:1132-1138.  [PubMed]  [DOI]
114.  Randall J, Mörtberg E, Provuncher GK, Fournier DR, Duffy DC, Rubertsson S, Blennow K, Zetterberg H, Wilson DH. Tau proteins in serum predict neurological outcome after hypoxic brain injury from cardiac arrest: results of a pilot study. Resuscitation. 2013;84:351-356.  [PubMed]  [DOI]
115.  Gupta MK. Myelin basic protein and demyelinating diseases. Crit Rev Clin Lab Sci. 1987;24:287-314.  [PubMed]  [DOI]
116.  Borg K, Bonomo J, Jauch EC, Kupchak P, Stanton EB, Sawadsky B. Serum Levels of Biochemical Markers of Traumatic Brain Injury. ISRN Emergency Medicine. 2012;2012.  [PubMed]  [DOI]
117.  Ramont L, Thoannes H, Volondat A, Chastang F, Millet MC, Maquart FX. Effects of hemolysis and storage condition on neuron-specific enolase (NSE) in cerebrospinal fluid and serum: implications in clinical practice. Clin Chem Lab Med. 2005;43:1215-1217.  [PubMed]  [DOI]
118.  Fazio V, Bhudia SK, Marchi N, Aumayr B, Janigro D. Peripheral detection of S100beta during cardiothoracic surgery: what are we really measuring? Ann Thorac Surg. 2004;78:46-53.  [PubMed]  [DOI]
119.  Pelinka LE, Kroepfl A, Leixnering M, Buchinger W, Raabe A, Redl H. GFAP Versus S100B in Serum after Traumatic Brain Injury: Relationship to Brain Damage and Outcome. J Neurotr. 2004;21:1553-1561.  [PubMed]  [DOI]
120.  Mayer CA, Brunkhorst R, Niessner M, Pfeilschifter W, Steinmetz H, Foerch C. Blood Levels of Glial Fibrillary Acidic Protein (GFAP) in Patients with Neurological Diseases. Kleinschnitz C, ed. PLoS ONE. 2013;8:e62101.  [PubMed]  [DOI]
121.  Bergsneider M, Hovda DA, Shalmon E, Kelly DF, Vespa PM, Martin NA, Phelps ME, McArthur DL, Caron MJ, Kraus JF. Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg. 1997;86:241-251.  [PubMed]  [DOI]
122.  Reinstrup P, Ståhl N, Mellergård P, Uski T, Ungerstedt U, Nordström CH. Intracerebral microdialysis in clinical practice: baseline values for chemical markers during wakefulness, anesthesia, and neurosurgery. Neurosurgery. 2000;47:701-709; discussion 709-710.  [PubMed]  [DOI]
123.  Tisdall MM, Smith M. Cerebral microdialysis: research technique or clinical tool. Br J Anaesth. 2006;97:18-25.  [PubMed]  [DOI]
124.  Ungerstedt U, Rostami E. Microdialysis in neurointensive care. Curr Pharm Des. 2004;10:2145-2152.  [PubMed]  [DOI]
125.  Hillered L, Persson L, Nilsson P, Ronne-Engstrom E, Enblad P. Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis. Curr Opin Crit Care. 2006;12:112-118.  [PubMed]  [DOI]
126.  Timofeev I, Czosnyka M, Carpenter KL, Nortje J, Kirkpatrick PJ, Al-Rawi PG, Menon DK, Pickard JD, Gupta AK, Hutchinson PJ. Interaction between brain chemistry and physiology after traumatic brain injury: impact of autoregulation and microdialysis catheter location. J Neurotrauma. 2011;28:849-860.  [PubMed]  [DOI]
127.  Timofeev I, Carpenter KL, Nortje J, Al-Rawi PG, O’Connell MT, Czosnyka M, Smielewski P, Pickard JD, Menon DK, Kirkpatrick PJ. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain. 2011;134:484-494.  [PubMed]  [DOI]
128.  Sala N, Suys T, Zerlauth JB, Bouzat P, Messerer M, Bloch J, Levivier M, Magistretti PJ, Meuli R, Oddo M. Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2013;33:1815-1822.  [PubMed]  [DOI]
129.  Sahuquillo J, Merino MA, Sánchez-Guerrero A, Arikan F, Vidal-Jorge M, Martínez-Valverde T, Rey A, Riveiro M, Poca MA. Lactate and the lactate-to-pyruvate molar ratio cannot be used as independent biomarkers for monitoring brain energetic metabolism: a microdialysis study in patients with traumatic brain injuries. PLoS One. 2014;9:e102540.  [PubMed]  [DOI]
130.  Bullock R, Zauner A, Woodward JJ, Myseros J, Choi SC, Ward JD, Marmarou A, Young HF. Factors affecting excitatory amino acid release following severe human head injury. J Neurosurg. 1998;89:507-518.  [PubMed]  [DOI]
131.  Rostami E. Glucose and the injured brain-monitored in the neurointensive care unit. Front Neurol. 2014;5:91.  [PubMed]  [DOI]
132.  Oddo M, Schmidt JM, Carrera E, Badjatia N, Connolly ES, Presciutti M, Ostapkovich ND, Levine JM, Le Roux P, Mayer SA. Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: a microdialysis study. Crit Care Med. 2008;36:3233-3238.  [PubMed]  [DOI]
133.  Marcoux J, McArthur DA, Miller C, Glenn TC, Villablanca P, Martin NA, Hovda DA, Alger JR, Vespa PM. Persistent metabolic crisis as measured by elevated cerebral microdialysis lactate-pyruvate ratio predicts chronic frontal lobe brain atrophy after traumatic brain injury. Crit Care Med. 2008;36:2871-2877.  [PubMed]  [DOI]
134.  Bhatia R, Hashemi P, Razzaq A, Parkin MC, Hopwood SE, Boutelle MG, Strong AJ. Application of rapid-sampling, online microdialysis to the monitoring of brain metabolism during aneurysm surgery. Neurosurgery. 2006;58:ONS-313-ONS-20; discussion ONS-321.  [PubMed]  [DOI]
135.  Unterberg AW, Sakowitz OW, Sarrafzadeh AS, Benndorf G, Lanksch WR. Role of bedside microdialysis in the diagnosis of cerebral vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg. 2001;94:740-749.  [PubMed]  [DOI]
136.  Ulrich CT, Fung C, Vatter H, Setzer M, Gueresir E, Seifert V, Beck J, Raabe A. Occurrence of vasospasm and infarction in relation to a focal monitoring sensor in patients after SAH: placing a bet when placing a probe? PLoS One. 2013;8:e62754.  [PubMed]  [DOI]
137.  Sarrafzadeh AS, Sakowitz OW, Kiening KL, Benndorf G, Lanksch WR, Unterberg AW. Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients? Crit Care Med. 2002;30:1062-1070.  [PubMed]  [DOI]
138.  Skjøth-Rasmussen J, Schulz M, Kristensen SR, Bjerre P. Delayed neurological deficits detected by an ischemic pattern in the extracellular cerebral metabolites in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg. 2004;100:8-15.  [PubMed]  [DOI]
139.  Sarrafzadeh A, Haux D, Küchler I, Lanksch WR, Unterberg AW. Poor-grade aneurysmal subarachnoid hemorrhage: relationship of cerebral metabolism to outcome. J Neurosurg. 2004;100:400-406.  [PubMed]  [DOI]
140.  Schmidt JM, Ko SB, Helbok R, Kurtz P, Stuart RM, Presciutti M, Fernandez L, Lee K, Badjatia N, Connolly ES. Cerebral perfusion pressure thresholds for brain tissue hypoxia and metabolic crisis after poor-grade subarachnoid hemorrhage. Stroke. 2011;42:1351-1356.  [PubMed]  [DOI]
141.  Berger C, Annecke A, Aschoff A, Spranger M, Schwab S. Neurochemical monitoring of fatal middle cerebral artery infarction. Stroke. 1999;30:460-463.  [PubMed]  [DOI]
142.  Berger C, Kiening K, Schwab S. Neurochemical monitoring of therapeutic effects in large human MCA infarction. Neurocrit Care. 2008;9:352-356.  [PubMed]  [DOI]
143.  Berger C, Schäbitz WR, Georgiadis D, Steiner T, Aschoff A, Schwab S. Effects of hypothermia on excitatory amino acids and metabolism in stroke patients: a microdialysis study. Stroke. 2002;33:519-524.  [PubMed]  [DOI]
144.  Roslin M, Henriksson R, Bergström P, Ungerstedt U, Bergenheim AT. Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis. J Neurooncol. 2003;61:151-160.  [PubMed]  [DOI]
145.  Xu W, Mellergård P, Ungerstedt U, Nordström CH. Local changes in cerebral energy metabolism due to brain retraction during routine neurosurgical procedures. Acta Neurochir (Wien). 2002;144:679-683.  [PubMed]  [DOI]
146.  Blakeley J, Portnow J. Microdialysis for assessing intratumoral drug disposition in brain cancers: a tool for rational drug development. Expert Opin Drug Metab Toxicol. 2010;6:1477-1491.  [PubMed]  [DOI]
147.  Ronquist G, Hugosson R, Sjölander U, Ungerstedt U. Treatment of malignant glioma by a new therapeutic principle. Acta Neurochir (Wien). 1992;114:8-11.  [PubMed]  [DOI]
148.  Bergenheim AT, Roslin M, Ungerstedt U, Waldenström A, Henriksson R, Ronquist G. Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB). J Neurooncol. 2006;80:285-293.  [PubMed]  [DOI]
149.  Ronne-Engström E, Hillered L, Flink R, Spännare B, Ungerstedt U, Carlson H. Intracerebral microdialysis of extracellular amino acids in the human epileptic focus. J Cereb Blood Flow Metab. 1992;12:873-876.  [PubMed]  [DOI]
150.  Qureshi AI, Ali Z, Suri MF, Shuaib A, Baker G, Todd K, Guterman LR, Hopkins LN. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med. 2003;31:1482-1489.  [PubMed]  [DOI]
151.  Orakcioglu B, Kentar MM, Schiebel P, Uozumi Y, Unterberg A, Sakowitz OW. Perihemorrhagic ischemia occurs in a volume-dependent manner as assessed by multimodal cerebral monitoring in a porcine model of intracerebral hemorrhage. Neurocrit Care. 2015;22:133-139.  [PubMed]  [DOI]
152.  Ottens AK, Kobeissy FH, Golden EC, Zhang Z, Haskins WE, Chen SS, Hayes RL, Wang KK, Denslow ND. Neuroproteomics in neurotrauma. Mass Spectrom Rev. 2006;25:380-408.  [PubMed]  [DOI]
153.  Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KK. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn. 2011;11:65-78.  [PubMed]  [DOI]
154.  Pasinetti GM, Ho L, Dooley C, Abbi B, Lange G. Select non-coding RNA in blood components provide novel clinically accessible biological surrogates for improved identification of traumatic brain injury in OEF/OIF Veterans. Am J Neurodegener Dis. 2012;1:88-98.  [PubMed]  [DOI]