Analysis of Glial Fibrillary Acidic Protein and Ubiquitin C-Terminal Hydrolase L1 in Postmortem Serum and Cerebrospinal Fluid in Traumatic Cerebral Deaths
Year 2022,
, 242 - 248, 30.03.2022
Ayşe Kurtuluş Dereli
,
Mücahit Seçme
,
Kemalettin Acar
Abstract
Objective: There is a growing body of research aimed at identifying biological markers that could indicate traumatic cerebral deaths such as traumatic brain damage in the postmortem period. In the event of astrocytic and neuronal injury, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) are released into cerebrospinal fluid and blood. In the postmortem identification of traumatic brain injury, the present research explores the ability of GFAP and UCH-L1.
Methods: Cerebrospinal fluid and blood samples were obtained from medicolegal autopsies, 17 cases with severe head trauma, 9 cases with the non-lethal head trauma group and 18 control cases. UCH-L1 and GFAP levels in postmortem cerebrospinal fluid and serum were determined
from an enzyme-linked immunosorbent assay (ELISA).
Results: GFAP level in cerebrospinal fluid and serum was 2.68±0.67 ng/ml and 0.79±0.92 ng/ml in the lethal head trauma group, 2.74±0.64 ng/ml and 1.05±0.68 ng/ml the non-lethal head trauma group and 2.49±0.55 ng/ml and 1.05±0.89 ng/ml in the control group, respectively.
UCH-L1 level in cerebrospinal fluid and serum was 3.02±0.68 ng/ml and 2.69±0.77 ng/ml in the lethal head trauma group, 3.34±0.70 ng/ml and 2.59±0.65 ng/ml the non-lethal head trauma group and 3.28±0.33 ng/ml and 2.74±0.34 ng/ml in the control group, respectively. Elevated cerebrospinal fluid and serum UCH-L1 and GFAP levels were observed in all cases, although absence of statistically significant difference between the trauma and control groups (p>0.05).
Conclusion: Further studies are needed to assess whether postmortem serum and CSF GFAP and UCH-L1 concentrations increase regardless of the cause of death.
Supporting Institution
Scientific Research Coordination Unit of Pamukkale University
Project Number
2018HZDP017
Thanks
This study was supported by Scientific Research Coordination Unit of Pamukkale University under the project number 2018HZDP017.
References
- [1] Knight B, Saukko P. Knight’s Forensic Pathology. London: E
Arnold, 2004: 98-135.
- [2] Werner C, Engelhard K. Pathophysiology of traumatic brain
injury. Br J Anaesth. 2007 Jul;99(1):4-9.
- [3] Olczak M, Niderla-Bielińska J, Kwiatkowska M, Samojłowicz D,
Tarka S, Wierzba-Bobrowicz T. Tau protein (MAPT) as a possible
biochemical marker of traumatic brain injury in postmortem
examination. Forensic Sci Int. 2017;280:1-7.
- [4] Diaz-Arrastia R, Wang KK, Papa L, Sorani MD, Yue JK, Puccio AM,
McMahon PJ, Inoue T, Yuh EL, Lingsma HF, Maas AIR, Valadka
AB, Okonkwo DO, Manley GT, TRACK-TBI Investigators. Acute
biomarkers of traumatic brain injury: relationship between
plasma levels of ubiquitin C-terminal hydrolase-L1 and glial
fibrillary acidic protein. J Neurotrauma 2014;31(1):19-25.
- [5] Jones A, Jarvis P. Review of the potential use of blood neurobiomarkers
in the diagnosis of mild traumatic brain injury. Clin
Exp Emerg Med. 2017;4(3):121-127.
- [6] Zetterberg H, Blennow K. Fluid markers of traumatic brain
injury. Mol Cell Neurosci 2015; 66: 99-102.
- [7] Olczak M, Kwiatkowska M, Niderla-Bielińska J, Chutorański
D, Tarka S, Wierzba-Bobrowicz T. Brain-originated peptides
as possible biochemical markers of traumatic brain injury
in cerebrospinal fluid post-mortem examination. Folia
Neuropathol. 2018;56(2):97-103.
- [8] Breitling B, Brunkhorst R, Verhoff M, Foerch C. Post-mortem
serum concentrations of GFAP correlate with agony time but
do not indicate a primary cerebral cause of death. PLoS One
2018;13(10):1-11.
- [9] Missler U, Wiesmann M, Wittmann G, Magerkurth O,
Hagenstrom H. Measurement of glial fibrillary acidic protein
in human blood: analytical method and preliminary clinical
results. Clin Chem 1999;45(1):138–141.
- [10] Foerch C, Niessner M, Back T, Bauerle M, De Marchis GM,
Ferbert A, Grehl H, Hamann GF, Jacobs A, Kastrup A, Klimpe
S, Palm F, Thomalla G, Worthmann H, Sitzer M, BE FAST Study
Group. Diagnostic accuracy of plasma glial fibrillary acidic
protein for differentiating intracerebral hemorrhage and
cerebral ischemia in patients with symptoms of acute stroke.
Clin Chem. 2012;58(1):237-245.
- [11] Helwig K, Seeger F, Hölschermann H, Lischke V, Gerriets T,
Niessner M, Foerch C. Elevated Serum Glial Fibrillary Acidic
Protein (GFAP) is Associated with Poor Functional Outcome
After Cardiopulmonary Resuscitation. Neurocrit Care
2017;27(1):68-74.
- [12] Herrmann M, Vos P, Wunderlich MT, de Bruijn CH, Lamers
KJ. Release of glial tissue-specific proteins after acute
stroke: A comparative analysis of serum concentrations
of protein S-100B and glial fibrillary acidic protein. Stroke
2000;31(11):2670-2677.
- [13] Doran JF, Jackson P, Kynoch PA, Thompson RJ. Isolation of PGP
9.5, a new human neurone-specific protein detected by highresolution
two-dimensional electrophoresis. J Neurochem.
1983;40(6):1542-1547.
- [14] Day IN, Thompson RJ. UCHL1 (PGP 9.5): neuronal biomarker
and ubiquitin system protein. Prog Neurobiol. 2010;90(3):327-
362.
- [15] Paul Bishop, Dan Rocca, Jeremy M. Henley. Ubiquitin
C-terminal hydrolase L1 (UCH-L1): structure, distribution and
roles in brain function and dysfunction. Biochem J. 2016;
473(16): 2453–2462.
- [16] Papa L, Akinyi L, Liu MC, Pineda JA, Tepas JJ, Oli MW, Zheng
W, Robinson G, Robicsek SA, Gabrielli A, Heaton SC, Hannay
HJ, Demery JA, Brophy GM, Layon J, Robertson CS, Hayes RL,
Wang KK. Ubiquitin C-terminal hydrolase is a novel biomarker
in humans for severe traumatic brain injury. Crit Care Med.
2010;38(1):138-144.
- [17] Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L,
Singh I, Deane R, Nedergaard M. Impairment of glymphatic
pathway function promotes tau pathology after traumatic
brain injury. J Neurosci. 2014; 34 (49): 16180-16193.
- [18] Plog BA, Dashnaw ML, Hitomi E, Peng W, Liao Y, Lou N, Rashid
Deane R, Nedergaard M. Biomarkers of traumatic injury are
transported from brain to blood via the glymphatic system. J
Neurosci. 2015;35(2):518-526.
- [19] Fraser DD, Close TE, Rose KL, Ward R, Mehl M, Farrell C,
Lacroix J, Creery D, Kesselman M, Stanimirovic D, Hutchison
JS, Canadian Critical Care Translational Biology Group. Severe
traumatic brain injury in children elevates glial fibrillary acidic
protein in cerebrospinal fluid and serum. Pediatr Crit Care
Med. 2011;12(3):319-324.
- [20] 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(3):R156.
- [21] Hausmann R, Riess R, Fieguth A, Betz P. Immunohistochemical
investigations on the course of astroglial GFAP expression
following human brain injury. Int J Legal Med. 2000;113(2):70–
75.
- [22] Hozumi I, Aquino DA, Norton WT. GFAP mRNA levels following
stab wound in rat brain. Brain Res. 1990;534(1-2):291–294
- [23] Lescuyer P, Allard L, Zimmermann-Ivol CG, Burgess JA,
Hughes-Frutiger S, Burkhard PR, Sanchez JC, Hochstrasser DF.
Identification of post-mortem cerebrospinal fluid proteins as
potential biomarkers of ischemia and neurodegeneration.
Proteomics 2004;4(8):2234-2241.
- [24] Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L,
Comabella M, Franciotta D, Frederiksen J L, Fleming J O, Furlan
R, Hintzen R Q, Hughes S G, Johnson M H, Krasulova E, Kuhle
J, Magnone M C, Rajda C, Rejdak K, Schmidt H K, Pesch V van,
Waubant E, Wolf C, Giovannoni G, Hemmer B, Tumani H,
Deisenhammer F. A consensus protocol for the standardization
of cerebrospinal fluid collection and biobanking. Neurology
2009;73(22):1914-1922.
- [25] Gul SS, Huesgen KW, Wang KK, Mark K, Tyndall JA. Prognostic
utility of neuroinjury biomarkers in post out-of-hospital
cardiac arrest (OHCA) patient management. Med Hypotheses
2017;105:34-47.
- [26] Chalak LF, Sánchez PJ, Adams-Huet B, Laptook AR, Heyne RJ,
Rosenfeld CR. Biomarkers for severity of neonatal hypoxicischemic
encephalopathy and outcomes in newborns receiving
hypothermia therapy. J Pediatr. 2014;164(3):468-474.
- [27] Liu MC, Akinyi L, Scharf D, Mo J, Larner SF, Muller U, Oli MW,
Zheng W, Kobeissy F, Papa L, Lu XC, Dave JR, Tortella FC,
Hayes RL, Wang KKW. Ubiquitin C-terminal hydrolase-L1 as a
biomarker for ischemic and traumatic brain injury in rats. Eur J
Neurosci. 2010;31(4):722–732.
- [28] Papa L, Brophy GM, Welch RD, Lewis LM, Braga CF, Tan CN,
Ameli NJ, Lopez MA, Haeussler CA, Giordano DIM, Silvestri S,
Giordano P, Weber KD, Hill-Pryor C, Hack DC. Time course and
diagnostic accuracy of glial and neuronal blood biomarkers
GFAP and UCH-L1 in a large cohort of trauma patients with
and without mild traumatic brain injury. JAMA Neurology
2016;73(5):551–560.
- [29] Mondello S, Linnet A, Buki A, Robicsek S, Gabrielli A, Tepas
J, Papa L, Brophy GM, Tortella F, Hayes RL, Wang KK. Clinical
utility of serum levels of ubiquitin C-terminal hydrolase as a
biomarker for severe traumatic brain injury. Neurosurgery
2012;70(3):666-675.
- [30] Fink EL, Berger RP, Clark RS, Watson RS, Angus DC, Panigrahy
A, Richichi R, Callaway CW, Bell MJ, Mondello S, Hayes RL,
Kochanek PM. Exploratory study of serum ubiquitin carboxylterminal
esterase L1 and glial fibrillary acidic protein for
outcome prognostication after pediatric cardiac arrest.
Resuscitation 2016;101:65-70.
- [31] Siman R, Roberts VL, McNeil E, Dang A, Bavaria JE, Ramchandren
S, McGarvey M. Biomarker evidence for mild central nervous
system injury after surgically-induced circulation arrest. Brain
Res. 2008;1213: 1-11
- [32] Piette MH, Pieters SE, De Letter EA. Evaluation of the agonal
stress: can immunohistochemical detection of ubiquitin in the
locus coeruleus be useful? Int J Legal Med. 2011;125(3):333-
340.
Year 2022,
, 242 - 248, 30.03.2022
Ayşe Kurtuluş Dereli
,
Mücahit Seçme
,
Kemalettin Acar
Project Number
2018HZDP017
References
- [1] Knight B, Saukko P. Knight’s Forensic Pathology. London: E
Arnold, 2004: 98-135.
- [2] Werner C, Engelhard K. Pathophysiology of traumatic brain
injury. Br J Anaesth. 2007 Jul;99(1):4-9.
- [3] Olczak M, Niderla-Bielińska J, Kwiatkowska M, Samojłowicz D,
Tarka S, Wierzba-Bobrowicz T. Tau protein (MAPT) as a possible
biochemical marker of traumatic brain injury in postmortem
examination. Forensic Sci Int. 2017;280:1-7.
- [4] Diaz-Arrastia R, Wang KK, Papa L, Sorani MD, Yue JK, Puccio AM,
McMahon PJ, Inoue T, Yuh EL, Lingsma HF, Maas AIR, Valadka
AB, Okonkwo DO, Manley GT, TRACK-TBI Investigators. Acute
biomarkers of traumatic brain injury: relationship between
plasma levels of ubiquitin C-terminal hydrolase-L1 and glial
fibrillary acidic protein. J Neurotrauma 2014;31(1):19-25.
- [5] Jones A, Jarvis P. Review of the potential use of blood neurobiomarkers
in the diagnosis of mild traumatic brain injury. Clin
Exp Emerg Med. 2017;4(3):121-127.
- [6] Zetterberg H, Blennow K. Fluid markers of traumatic brain
injury. Mol Cell Neurosci 2015; 66: 99-102.
- [7] Olczak M, Kwiatkowska M, Niderla-Bielińska J, Chutorański
D, Tarka S, Wierzba-Bobrowicz T. Brain-originated peptides
as possible biochemical markers of traumatic brain injury
in cerebrospinal fluid post-mortem examination. Folia
Neuropathol. 2018;56(2):97-103.
- [8] Breitling B, Brunkhorst R, Verhoff M, Foerch C. Post-mortem
serum concentrations of GFAP correlate with agony time but
do not indicate a primary cerebral cause of death. PLoS One
2018;13(10):1-11.
- [9] Missler U, Wiesmann M, Wittmann G, Magerkurth O,
Hagenstrom H. Measurement of glial fibrillary acidic protein
in human blood: analytical method and preliminary clinical
results. Clin Chem 1999;45(1):138–141.
- [10] Foerch C, Niessner M, Back T, Bauerle M, De Marchis GM,
Ferbert A, Grehl H, Hamann GF, Jacobs A, Kastrup A, Klimpe
S, Palm F, Thomalla G, Worthmann H, Sitzer M, BE FAST Study
Group. Diagnostic accuracy of plasma glial fibrillary acidic
protein for differentiating intracerebral hemorrhage and
cerebral ischemia in patients with symptoms of acute stroke.
Clin Chem. 2012;58(1):237-245.
- [11] Helwig K, Seeger F, Hölschermann H, Lischke V, Gerriets T,
Niessner M, Foerch C. Elevated Serum Glial Fibrillary Acidic
Protein (GFAP) is Associated with Poor Functional Outcome
After Cardiopulmonary Resuscitation. Neurocrit Care
2017;27(1):68-74.
- [12] Herrmann M, Vos P, Wunderlich MT, de Bruijn CH, Lamers
KJ. Release of glial tissue-specific proteins after acute
stroke: A comparative analysis of serum concentrations
of protein S-100B and glial fibrillary acidic protein. Stroke
2000;31(11):2670-2677.
- [13] Doran JF, Jackson P, Kynoch PA, Thompson RJ. Isolation of PGP
9.5, a new human neurone-specific protein detected by highresolution
two-dimensional electrophoresis. J Neurochem.
1983;40(6):1542-1547.
- [14] Day IN, Thompson RJ. UCHL1 (PGP 9.5): neuronal biomarker
and ubiquitin system protein. Prog Neurobiol. 2010;90(3):327-
362.
- [15] Paul Bishop, Dan Rocca, Jeremy M. Henley. Ubiquitin
C-terminal hydrolase L1 (UCH-L1): structure, distribution and
roles in brain function and dysfunction. Biochem J. 2016;
473(16): 2453–2462.
- [16] Papa L, Akinyi L, Liu MC, Pineda JA, Tepas JJ, Oli MW, Zheng
W, Robinson G, Robicsek SA, Gabrielli A, Heaton SC, Hannay
HJ, Demery JA, Brophy GM, Layon J, Robertson CS, Hayes RL,
Wang KK. Ubiquitin C-terminal hydrolase is a novel biomarker
in humans for severe traumatic brain injury. Crit Care Med.
2010;38(1):138-144.
- [17] Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L,
Singh I, Deane R, Nedergaard M. Impairment of glymphatic
pathway function promotes tau pathology after traumatic
brain injury. J Neurosci. 2014; 34 (49): 16180-16193.
- [18] Plog BA, Dashnaw ML, Hitomi E, Peng W, Liao Y, Lou N, Rashid
Deane R, Nedergaard M. Biomarkers of traumatic injury are
transported from brain to blood via the glymphatic system. J
Neurosci. 2015;35(2):518-526.
- [19] Fraser DD, Close TE, Rose KL, Ward R, Mehl M, Farrell C,
Lacroix J, Creery D, Kesselman M, Stanimirovic D, Hutchison
JS, Canadian Critical Care Translational Biology Group. Severe
traumatic brain injury in children elevates glial fibrillary acidic
protein in cerebrospinal fluid and serum. Pediatr Crit Care
Med. 2011;12(3):319-324.
- [20] 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(3):R156.
- [21] Hausmann R, Riess R, Fieguth A, Betz P. Immunohistochemical
investigations on the course of astroglial GFAP expression
following human brain injury. Int J Legal Med. 2000;113(2):70–
75.
- [22] Hozumi I, Aquino DA, Norton WT. GFAP mRNA levels following
stab wound in rat brain. Brain Res. 1990;534(1-2):291–294
- [23] Lescuyer P, Allard L, Zimmermann-Ivol CG, Burgess JA,
Hughes-Frutiger S, Burkhard PR, Sanchez JC, Hochstrasser DF.
Identification of post-mortem cerebrospinal fluid proteins as
potential biomarkers of ischemia and neurodegeneration.
Proteomics 2004;4(8):2234-2241.
- [24] Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L,
Comabella M, Franciotta D, Frederiksen J L, Fleming J O, Furlan
R, Hintzen R Q, Hughes S G, Johnson M H, Krasulova E, Kuhle
J, Magnone M C, Rajda C, Rejdak K, Schmidt H K, Pesch V van,
Waubant E, Wolf C, Giovannoni G, Hemmer B, Tumani H,
Deisenhammer F. A consensus protocol for the standardization
of cerebrospinal fluid collection and biobanking. Neurology
2009;73(22):1914-1922.
- [25] Gul SS, Huesgen KW, Wang KK, Mark K, Tyndall JA. Prognostic
utility of neuroinjury biomarkers in post out-of-hospital
cardiac arrest (OHCA) patient management. Med Hypotheses
2017;105:34-47.
- [26] Chalak LF, Sánchez PJ, Adams-Huet B, Laptook AR, Heyne RJ,
Rosenfeld CR. Biomarkers for severity of neonatal hypoxicischemic
encephalopathy and outcomes in newborns receiving
hypothermia therapy. J Pediatr. 2014;164(3):468-474.
- [27] Liu MC, Akinyi L, Scharf D, Mo J, Larner SF, Muller U, Oli MW,
Zheng W, Kobeissy F, Papa L, Lu XC, Dave JR, Tortella FC,
Hayes RL, Wang KKW. Ubiquitin C-terminal hydrolase-L1 as a
biomarker for ischemic and traumatic brain injury in rats. Eur J
Neurosci. 2010;31(4):722–732.
- [28] Papa L, Brophy GM, Welch RD, Lewis LM, Braga CF, Tan CN,
Ameli NJ, Lopez MA, Haeussler CA, Giordano DIM, Silvestri S,
Giordano P, Weber KD, Hill-Pryor C, Hack DC. Time course and
diagnostic accuracy of glial and neuronal blood biomarkers
GFAP and UCH-L1 in a large cohort of trauma patients with
and without mild traumatic brain injury. JAMA Neurology
2016;73(5):551–560.
- [29] Mondello S, Linnet A, Buki A, Robicsek S, Gabrielli A, Tepas
J, Papa L, Brophy GM, Tortella F, Hayes RL, Wang KK. Clinical
utility of serum levels of ubiquitin C-terminal hydrolase as a
biomarker for severe traumatic brain injury. Neurosurgery
2012;70(3):666-675.
- [30] Fink EL, Berger RP, Clark RS, Watson RS, Angus DC, Panigrahy
A, Richichi R, Callaway CW, Bell MJ, Mondello S, Hayes RL,
Kochanek PM. Exploratory study of serum ubiquitin carboxylterminal
esterase L1 and glial fibrillary acidic protein for
outcome prognostication after pediatric cardiac arrest.
Resuscitation 2016;101:65-70.
- [31] Siman R, Roberts VL, McNeil E, Dang A, Bavaria JE, Ramchandren
S, McGarvey M. Biomarker evidence for mild central nervous
system injury after surgically-induced circulation arrest. Brain
Res. 2008;1213: 1-11
- [32] Piette MH, Pieters SE, De Letter EA. Evaluation of the agonal
stress: can immunohistochemical detection of ubiquitin in the
locus coeruleus be useful? Int J Legal Med. 2011;125(3):333-
340.