Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy
Chain is Higher in Converting Clinically Isolated Syndrome
and Correlates with CAMP Response Element-Binding Protein
Concentration

Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration

Öz:

Introduction: Prevision of conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS) is required to avoid unnecessary use of immunomodulating agents and to recognize patients with high disease activity. Our aim was to evaluate the value of phosphorylated neurofilament heavy chain (pNFH, a marker for neuroaxonal degeneration) and Cyclic adenosine monophosphate response element‑binding protein (cAMP response element‑binding protein [CREB], a marker for neuroregeneration) levels in the prediction of conversion from CIS to MS. Methods: Twenty‑three consecutively recruited treatment‑naïve CIS patients were followed for 36 months. pNFH and CREB levels were measured in the first episode cerebrospinal fluid (CSF) and the serum of 12 converting (CIS‑MS) and 11 nonconverting CIS patients (CIS‑CIS) by enzyme‑linked immunosorbent assay. Results: Baseline CSF but not serum samples of CIS‑CIS patients displayed significantly lower pNFH levels compared to patients with CIS‑MS. The analysis of receiver operating characteristic curve presented a high specificity for the prediction of MS conversion for the CSF pNFH cut‑off level of 730.9 pg/ml. CSF pNFH levels significantly correlated with serum and CSF CREB levels. Higher baseline CSF pNFH and CREB levels were associated with more rapid progression to MS or increased disability scores. Conclusion: CSF pNFH measurement may potentially determine MS patients with unfavorable clinical progression after the first attack. pNFH and CREB appear to be increased in parallel in CSF of CIS patients with higher disease activity. These results suggest that neurofilaments are not only indicators of axonal degeneration but also partly a marker of neuronal differentiation and new axon regeneration mediated by CREB signaling pathway.

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1. De Lury A, Bisulca J, Coyle PK, Peyster R, Bangiyev L, Duong TQ. MRI features associated with rapid disease activity in clinically isolated syndrome patients at high risk for multiple sclerosis. Mult Scler Relat Disord 2020;41:101985.
2. Bittner S, Oh J, Havrdová EK, Tintoré M, Zipp F. The potential of serum neurofilament as biomarker for multiple sclerosis. Brain 2021:awab241. doi: 10.1093/brain/awab241.
3. Gordon BA. Neurofilaments in disease: What do we know? Curr Opin Neurobiol 2020;61:105‑15.
4. Ferreira‑Atuesta C, Reyes S, Giovanonni G, Gnanapavan S. The evolution of neurofilament light chain in multiple sclerosis. Front Neurosci 2021;15:642384.
5. Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, et al. Neurofilament light chain in cerebrospinal fluid and prediction of disease activity in clinically isolated syndrome and relapsing‑remitting multiple sclerosis. Eur J Neurol 2017;24:703‑12.
6. Petzold A, Eikelenboom MI, Keir G, Polman CH, Uitdehaag BM, Thompson EJ, et al. The new global multiple sclerosis severity score (MSSS) correlates with axonal but not glial biomarkers. Mult Scler 2006;12:325‑8.
7. Wang H, Wang C, Qiu W, Lu Z, Hu X, Wang K. Cerebrospinal fluid light and heavy neurofilaments in neuromyelitis optica. Neurochem Int 2013;63:805‑8.
8. Ljubisavljevic S, Stojanovic I, Basic J, Pavlovic DA. The validation study of neurofilament heavy chain and 8‑hydroxy‑2’‑deoxyguanosine as plasma biomarkers of clinical/paraclinical activity in first and relapsing‑remitting demyelination acute attacks. Neurotox Res 2016;30:530‑8.
9. Herrera MI, Kölliker‑Frers RA, Otero‑Losada M, Perez Lloret S, Filippo M, Tau J, et al. A pilot cross‑sectional study to investigate the biomarker potential of phosphorylated neurofilament‑H and immune mediators of disability in patients with 5 year relapsing‑remitting multiple sclerosis. Front Neurol 2019;10:1046.
10. Gresle MM, Liu Y, Dagley LF, Haartsen J, Pearson F, Purcell AW, et al. Serum phosphorylated neurofilament‑heavy chain levels in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2014;85:1209‑13.
11. Pasol J, Feuer W, Yang C, Shaw G, Kardon R, Guy J. Phosphorylated neurofilament heavy chain correlations to visual function, optical coherence tomography, and treatment. Mult Scler Int 2010;2010:542691.
12. Schmierer K, Parkes HG, So PW, An SF, Brandner S, Ordidge RJ, et al. High field (9.4 Tesla) magnetic resonance imaging of cortical grey matter lesions in multiple sclerosis. Brain 2010;133:858‑67.
13. Kular L, Needhamsen M, Adzemovic MZ, Kramarova T, Gomez‑Cabrero D, Ewing E, et al. Neuronal methylome reveals CREB‑associated neuro‑axonal impairment in multiple sclerosis. Clin Epigenetics 2019;11:86.
14. Liu W, Ye Q, Xi W, Li Y, Zhou X, Wang Y, et al. The ERK/CREB/PTN/syndecan‑3 pathway involves in heparin‑mediated neuro‑protection and neuro‑regeneration against cerebral ischemia‑reperfusion injury following cardiac arrest. Int Immunopharmacol 2021;98:107689.
15. Taherian N, Vaezi G, Neamati A, Etemad L, Hojjati V, Gorji‑Valokola M. Vitamin B12 and estradiol benzoate improve memory retrieval through activation of the hippocampal AKT, BDNF, and CREB proteins in a rat model of multiple sclerosis. Iran J Basic Med Sci 2021;24:256‑63.
16. Alghamdi BS, AboTaleb HA. Melatonin improves memory defects in a mouse model of multiple sclerosis by up‑regulating cAMP‑response element‑binding protein and synapse‑associated proteins in the prefrontal cortex. J Integr Neurosci 2020;19:229‑37.
17. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292‑302.
18. Hendricks R, Baker D, Brumm J, Davancaze T, Harp C, Herman A, et al. Establishment of neurofilament light chain Simoa assay in cerebrospinal fluid and blood. Bioanalysis 2019;11:1405‑18.
19. Gencer M, Akbayır E, Şen M, Arsoy E, Yılmaz V, Bulut N, et al. Serum orexin‑A levels are associated with disease progression and motor impairment in multiple sclerosis. Neurol Sci 2019;40:1067‑70.
20. Lam KY, Chen J, Lam CT, Wu Q, Yao P, Dong TT, et al. Asarone from Acori Tatarinowii Rhizoma potentiates the nerve growth factor‑induced neuronal differentiation in cultured PC12 cells: A signaling mediated by protein kinase A. PLoS One 2016;11:e0163337.
21. Liao KK, Wu MJ, Chen PY, Huang SW, Chiu SJ, Ho CT, et al. Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERK‑ and PKC‑dependent pathways. J Agric Food Chem 2012;60:433‑43.
22. Won JH, Ahn KH, Back MJ, Ha HC, Jang JM, Kim HH, et al. DA‑9801 promotes neurite outgrowth via ERK1/2‑CREB pathway in PC12 cells. Biol Pharm Bull 2015;38:169‑78.
23. Zheng Q, Liu L, Liu H, Zheng H, Sun H, Ji J, et al. The Bu Shen Yi Sui formula promotes axonal regeneration via regulating the neurotrophic factor BDNF/TrkB and the downstream PI3K/Akt signaling pathway. Front Pharmacol 2019;10:796.
24. Hernandez JB, Chang C, LeBlanc M, Grimm D, Le Lay J, Kaestner KH, et al. The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nat Commun 2015;6:7216.
25. Jana M, Ghosh S, Pahan K. Upregulation of myelin gene expression by a physically‑modified saline via phosphatidylinositol 3‑kinase‑mediated activation of CREB: Implications for multiple sclerosis. Neurochem Res 2018;43:407‑19.

APA	GENCER M, KORAL G, ŞANLI E, ÇIRAK S, AKBAYIR E, YÜCEER H, YILMAZ V, TÜZÜN E, KIZILAY T, YILDIZ R, YENTUR S, TÜRKOĞLU R (2021). Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . , 256 - 261. 10.4103/nsn.nsn_144_21
Chicago	GENCER Mehmet,KORAL Gizem,ŞANLI Elif,ÇIRAK Selen,AKBAYIR Ece,YÜCEER Hande,YILMAZ Vuslat,TÜZÜN Erdem,KIZILAY Tuğçe,YILDIZ Ruziye Erol,YENTUR Sibel Penbe,TÜRKOĞLU Recai Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . (2021): 256 - 261. 10.4103/nsn.nsn_144_21
MLA	GENCER Mehmet,KORAL Gizem,ŞANLI Elif,ÇIRAK Selen,AKBAYIR Ece,YÜCEER Hande,YILMAZ Vuslat,TÜZÜN Erdem,KIZILAY Tuğçe,YILDIZ Ruziye Erol,YENTUR Sibel Penbe,TÜRKOĞLU Recai Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . , 2021, ss.256 - 261. 10.4103/nsn.nsn_144_21
AMA	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . . 2021; 256 - 261. 10.4103/nsn.nsn_144_21
Vancouver	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . . 2021; 256 - 261. 10.4103/nsn.nsn_144_21
IEEE	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R "Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration ." , ss.256 - 261, 2021. 10.4103/nsn.nsn_144_21
ISNAD	GENCER, Mehmet vd. "Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration ". (2021), 256-261. https://doi.org/10.4103/nsn.nsn_144_21

APA	GENCER M, KORAL G, ŞANLI E, ÇIRAK S, AKBAYIR E, YÜCEER H, YILMAZ V, TÜZÜN E, KIZILAY T, YILDIZ R, YENTUR S, TÜRKOĞLU R (2021). Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . Neurological sciences and neurophysiology (Online), 38(4), 256 - 261. 10.4103/nsn.nsn_144_21
Chicago	GENCER Mehmet,KORAL Gizem,ŞANLI Elif,ÇIRAK Selen,AKBAYIR Ece,YÜCEER Hande,YILMAZ Vuslat,TÜZÜN Erdem,KIZILAY Tuğçe,YILDIZ Ruziye Erol,YENTUR Sibel Penbe,TÜRKOĞLU Recai Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . Neurological sciences and neurophysiology (Online) 38, no.4 (2021): 256 - 261. 10.4103/nsn.nsn_144_21
MLA	GENCER Mehmet,KORAL Gizem,ŞANLI Elif,ÇIRAK Selen,AKBAYIR Ece,YÜCEER Hande,YILMAZ Vuslat,TÜZÜN Erdem,KIZILAY Tuğçe,YILDIZ Ruziye Erol,YENTUR Sibel Penbe,TÜRKOĞLU Recai Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . Neurological sciences and neurophysiology (Online), vol.38, no.4, 2021, ss.256 - 261. 10.4103/nsn.nsn_144_21
AMA	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . Neurological sciences and neurophysiology (Online). 2021; 38(4): 256 - 261. 10.4103/nsn.nsn_144_21
Vancouver	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration . Neurological sciences and neurophysiology (Online). 2021; 38(4): 256 - 261. 10.4103/nsn.nsn_144_21
IEEE	GENCER M,KORAL G,ŞANLI E,ÇIRAK S,AKBAYIR E,YÜCEER H,YILMAZ V,TÜZÜN E,KIZILAY T,YILDIZ R,YENTUR S,TÜRKOĞLU R "Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration ." Neurological sciences and neurophysiology (Online), 38, ss.256 - 261, 2021. 10.4103/nsn.nsn_144_21
ISNAD	GENCER, Mehmet vd. "Cerebrospinal Fluid Level of Phosphorylated Neurofilament Heavy Chain is Higher in Converting Clinically Isolated Syndrome and Correlates with CAMP Response Element-Binding Protein Concentration ". Neurological sciences and neurophysiology (Online) 38/4 (2021), 256-261. https://doi.org/10.4103/nsn.nsn_144_21