Abstract
Background and aims
Most patients with multiple sclerosis presenting with a relapsing–remitting disease course at diagnosis transition to secondary progressive multiple sclerosis (SPMS) 1–2 decades after onset. SPMS is characterized by predominant neurodegeneration and atrophy. These pathogenic hallmarks result in unsatisfactory treatment response in SPMS patients. Therefore, early diagnosis of SPMS is necessary for prompt treatment decisions. The aim of this review was to assess neurophysiological and fluid biomarkers that have the potential to monitor disease progression and support early SPMS diagnosis.
Methods
We performed a systematic review of studies that analyzed the role of neurophysiological techniques and fluid biomarkers in supporting SPMS diagnosis using the preferred reporting items for systematic reviews and meta-analyses statement.
Results
From our initial search, we selected 24 relevant articles on neurophysiological biomarkers and 55 articles on fluid biomarkers.
Conclusion
To date, no neurophysiological or fluid biomarker is sufficiently validated to support the early diagnosis of SPMS. Neurophysiological measurements, including short interval intracortical inhibition and somatosensory temporal discrimination threshold, and the neurofilament light chain fluid biomarker seem to be the most promising. Cross-sectional studies on an adequate number of patients followed by longitudinal studies are needed to confirm the diagnostic and prognostic value of these biomarkers. A combination of neurophysiological and fluid biomarkers may be more sensitive in detecting SPMS conversion.
Similar content being viewed by others
Abbreviations
- BAEPs :
-
Brainstem auditory evoked potentials
- CCL :
-
Chemokine ligand
- CHI3L1 :
-
Chitinase 3 Like 1
- CIS :
-
Clinically isolated syndrome
- CNS :
-
Central nervous system
- CSF :
-
Cerebrospinal fluid
- cTBS :
-
Continuous theta burst stimulation
- CXC :
-
Chemokine CXC motif ligand
- DMTs :
-
Disease-modifying treatments
- EDSS :
-
Expanded disability status scale
- EGF :
-
Epidermal growth factor
- EPs :
-
Evoked potentials
- FOXP3 :
-
Forkhead box P3
- GEPS :
-
Global evoked potential score
- GFAP :
-
Glial fibrillary acidic protein
- HCs :
-
Healthy controls
- HGF :
-
Hepatocyte growth factor
- ICF :
-
Intracortical facilitation
- IFN :
-
Interferon
- IL :
-
Interleukin
- ISI :
-
Interstimulus interval
- iTBS :
-
Intermittent theta burst stimulation
- LAG-3:
-
Lymphocyte activation gene 3
- LICI :
-
Long interval intracortical inhibition
- LTD :
-
Long-term depression
- LTP :
-
Long-term potentiation
- mEPS :
-
Multimodal evoked potential scores
- MEPs :
-
Motor evoked potentials
- miRNA :
-
Micro RNA
- mRAGE :
-
Membrane receptor for advanced glycation end products
- MRI :
-
Magnetic resonance imaging
- MS :
-
Multiple sclerosis
- MSSS :
-
Multiple sclerosis severity scale
- M1 :
-
Primary motor cortex
- NAWM :
-
Normal-appearing white matter
- NfH :
-
Neurofilament heavy chain
- NfL :
-
Neurofilament light chain
- NfM :
-
Neurofilament medium chain
- OCBs :
-
Oligoclonal bands
- PAS :
-
Paired associative stimulation
- PBMCs :
-
Peripheral blood mononuclear cells
- PPMS :
-
Primary progressive multiple sclerosis
- PRISMA :
-
Preferred reporting items for systematic reviews and metanalyses
- RRMS :
-
Relapsing–remitting multiple sclerosis
- SEPs :
-
Sensory evoked potentials
- SICF :
-
Short-interval intracortical facilitation
- SICI :
-
Short-interval intracortical inhibition
- Simoa :
-
Single molecule array technique
- SPMS :
-
Secondary progressive multiple sclerosis
- STDT :
-
Somatosensory temporal discrimination threshold
- TBS :
-
Theta burst stimulation
- TGF :
-
Transforming growth factor
- TGM6 :
-
Transglutaminase-6
- Th :
-
T helper
- TIM-3 :
-
T-cell immunoglobulin and mucin domain-containing 3
- TMS :
-
Transcranial magnetic stimulation
- TNF :
-
Tumor necrosis factor
- Treg :
-
Regulatory T cells
- T25FWT :
-
Timed 25-foot walk test
- VEGF :
-
Vascular endothelial growth factor
- VEPs :
-
Visual evoked potentials
- 9HPT :
-
9-Hole peg test
References
Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343(13):938–952. https://doi.org/10.1056/nejm200009283431307
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O'Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stuve O, Waubant E, Polman CH (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83(3):278–286. https://doi.org/10.1212/wnl.0000000000000560
Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17(2):162–173. https://doi.org/10.1016/s1474-4422(17)30470-2
Inojosa H, Proschmann U, Akgun K, Ziemssen T (2019) A focus on secondary progressive multiple sclerosis (SPMS): challenges in diagnosis and definition. J Neurol. https://doi.org/10.1007/s00415-019-09489-5
Scalfari A, Neuhaus A, Daumer M, Muraro PA, Ebers GC (2014) Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry 85(1):67–75. https://doi.org/10.1136/jnnp-2012-304333
Brown JWL, Coles A, Horakova D, Havrdova E, Izquierdo G, Prat A, Girard M, Duquette P, Trojano M, Lugaresi A, Bergamaschi R, Grammond P, Alroughani R, Hupperts R, McCombe P, VanPesch V, Sola P, Ferraro D, Grand'Maison F, Terzi M, Lechner-Scott J, Flechter S, Slee M, Shaygannejad V, Pucci E, Granella F, Jokubaitis V, Willis M, Rice C, Scolding N, Wilkins A, Pearson OR, Ziemssen T, Hutchinson M, Harding K, Jones J, McGuigan C, Butzkueven H, Kalincik T, Robertson N (2019) Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA 321(2):175–187. https://doi.org/10.1001/jama.2018.20588
Lassmann H (2018) Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol 9:3116. https://doi.org/10.3389/fimmu.2018.03116
De Angelis F, Plantone D, Chataway J (2018) Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs 32(6):499–526. https://doi.org/10.1007/s40263-018-0538-0
Katz Sand I, Krieger S, Farrell C, Miller AE (2014) Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. Mult Scler 20(12):1654–1657. https://doi.org/10.1177/1352458514521517
Ontaneda D, Cohen JA, Amato MP (2017) Clinical outcome measures for progressive MS trials. Mult Scler 23(12):1627–1635. https://doi.org/10.1177/1352458517729465
Bosma L, Kragt JJ, Polman CH, Uitdehaag BM (2013) Walking speed, rather than expanded disability status scale, relates to long-term patient-reported impact in progressive MS. Mult Scler 19(3):326–333. https://doi.org/10.1177/1352458512454346
Cadavid D, Cohen JA, Freedman MS, Goldman MD, Hartung HP, Havrdova E, Jeffery D, Kapoor R, Miller A, Sellebjerg F, Kinch D, Lee S, Shang S, Mikol D (2017) The EDSS-plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis. Mult Scler 23(1):94–105. https://doi.org/10.1177/1352458516638941
Enzinger C, Barkhof F, Ciccarelli O, Filippi M, Kappos L, Rocca MA, Ropele S, Rovira A, Schneider T, de Stefano N, Vrenken H, Wheeler-Kingshott C, Wuerfel J, Fazekas F (2015) Nonconventional MRI and microstructural cerebral changes in multiple sclerosis. Nat Rev Neurol 11(12):676–686. https://doi.org/10.1038/nrneurol.2015.194
Filippi M, Preziosa P, Rocca MA (2017) Microstructural MR imaging techniques in multiple sclerosis. Neuroimaging Clin N Am 27(2):313–333. https://doi.org/10.1016/j.nic.2016.12.004
Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1. https://doi.org/10.1186/2046-4053-4-1
Barro C, Leocani L, Leppert D, Comi G, Kappos L, Kuhle J (2017) Fluid biomarker and electrophysiological outcome measures for progressive MS trials. Mult Scler 23(12):1600–1613. https://doi.org/10.1177/1352458517732844
Leocani L, Rovaris M, Boneschi FM, Medaglini S, Rossi P, Martinelli V, Amadio S, Comi G (2006) Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study. J Neurol Neurosurg Psychiatry 77(9):1030–1035. https://doi.org/10.1136/jnnp.2005.086280
Jung P, Beyerle A, Ziemann U (2008) Multimodal evoked potentials measure and predict disability progression in early relapsing–remitting multiple sclerosis. Mult Scler 14(4):553–556. https://doi.org/10.1177/1352458507085758
Invernizzi P, Bertolasi L, Bianchi MR, Turatti M, Gajofatto A, Benedetti MD (2011) Prognostic value of multimodal evoked potentials in multiple sclerosis: the EP score. J Neurol 258(11):1933–1939. https://doi.org/10.1007/s00415-011-6033-x
Ramanathan S, Lenton K, Burke T, Gomes L, Storchenegger K, Yiannikas C, Vucic S (2013) The utility of multimodal evoked potentials in multiple sclerosis prognostication. J Clin Neurosci 20(11):1576–1581. https://doi.org/10.1016/j.jocn.2013.01.020
Schlaeger R, Schindler C, Grize L, Dellas S, Radue EW, Kappos L, Fuhr P (2014) Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years. Mult Scler 20(10):1348–1354. https://doi.org/10.1177/1352458514525867
Kallmann BA, Fackelmann S, Toyka KV, Rieckmann P, Reiners K (2006) Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis. Mult Scler 12(1):58–65. https://doi.org/10.1191/135248506ms1244oa
Giffroy X, Maes N, Albert A, Maquet P, Crielaard JM, Dive D (2016) Multimodal evoked potentials for functional quantification and prognosis in multiple sclerosis. BMC Neurol 16:83. https://doi.org/10.1186/s12883-016-0608-1
Schlaeger R, D'Souza M, Schindler C, Grize L, Kappos L, Fuhr P (2014) Prediction of MS disability by multimodal evoked potentials: investigation during relapse or in the relapse-free interval? Clin Neurophysiol 125(9):1889–1892. https://doi.org/10.1016/j.clinph.2013.12.117
Mori F, Kusayanagi H, Monteleone F, Moscatelli A, Nicoletti CG, Bernardi G, Centonze D (2013) Short interval intracortical facilitation correlates with the degree of disability in multiple sclerosis. Brain Stimul 6(1):67–71. https://doi.org/10.1016/j.brs.2012.02.001
Conte A, Lenzi D, Frasca V, Gilio F, Giacomelli E, Gabriele M, Bettolo CM, Iacovelli E, Pantano P, Pozzilli C, Inghilleri M (2009) Intracortical excitability in patients with relapsing–remitting and secondary progressive multiple sclerosis. J Neurol 256(6):933–938. https://doi.org/10.1007/s00415-009-5047-0
Vucic S, Burke T, Lenton K, Ramanathan S, Gomes L, Yannikas C, Kiernan MC (2012) Cortical dysfunction underlies disability in multiple sclerosis. Mult Scler 18(4):425–432. https://doi.org/10.1177/1352458511424308
Zeller D, Aufm Kampe K, Biller A, Stefan K, Gentner R, Schutz A, Bartsch A, Bendszus M, Toyka KV, Rieckmann P, Classen J (2010) Rapid-onset central motor plasticity in multiple sclerosis. Neurology 74(9):728–735. https://doi.org/10.1212/WNL.0b013e3181d31dcfZeller
Zeller D, Dang SY, Weise D, Rieckmann P, Toyka KV, Classen J (2012) Excitability decreasing central motor plasticity is retained in multiple sclerosis patients. BMC Neurol 12:92. https://doi.org/10.1186/1471-2377-12-92
Mori F, Rossi S, Piccinin S, Motta C, Mango D, Kusayanagi H, Bergami A, Studer V, Nicoletti CG, Buttari F, Barbieri F, Mercuri NB, Martino G, Furlan R, Nistico R, Centonze D (2013) Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis. J Neurosci 33(49):19112–19119. https://doi.org/10.1523/jneurosci.2536-13.2013
Conte A, Li Voti P, Pontecorvo S, Quartuccio ME, Baione V, Rocchi L, Cortese A, Bologna M, Francia A, Berardelli A (2016) Attention-related changes in short-term cortical plasticity help to explain fatigue in multiple sclerosis. Mult Scler 22(10):1359–1366. https://doi.org/10.1177/1352458515619780
Mori F, Nistico R, Mandolesi G, Piccinin S, Mango D, Kusayanagi H, Berretta N, Bergami A, Gentile A, Musella A, Nicoletti CG, Nicoletti F, Buttari F, Mercuri NB, Martino G, Furlan R, Centonze D (2014) Interleukin-1beta promotes long-term potentiation in patients with multiple sclerosis. Neuromolecular Med 16(1):38–51. https://doi.org/10.1007/s12017-013-8249-7
Baione V, Belvisi D, Cortese A, Cetta I, Tartaglia M, Millefiorini E, Berardelli A, Conte A (2019) Cortical M1 plasticity and metaplasticity in patients with multiple sclerosis. Mult Scler Relat Disord 38:101494. https://doi.org/10.1016/j.msard.2019.101494
Brooks JB, Jardim MR, Papais-Alvarenga RM, Fragoso YD (2015) There is still a role for the blink reflex in the diagnosis and follow-up of multiple sclerosis. Clin Neurophysiol 126(4):743–747. https://doi.org/10.1016/j.clinph.2014.06.050
Degirmenci E, Erdogan C, Bir LS (2013) Correlation between blink reflex abnormalities and magnetic resonance imaging findings in patients with multiple sclerosis. Acta Neurol Belg 113(3):265–269. https://doi.org/10.1007/s13760-012-0175-1
Cabib C, Llufriu S, Martinez-Heras E, Saiz A, Valls-Sole J (2014) Abnormal control of orbicularis oculi reflex excitability in multiple sclerosis. PLoS ONE 9(8):e103897. https://doi.org/10.1371/journal.pone.0103897
Klissurski M, Novachkova S, Tzvetanov P, Alexiev F (2009) Orbicularis oculi reflex abnormalities in patients with multiple sclerosis: a clinical, EMG, and MRI investigation. Electromyogr Clin Neurophysiol 49(1):59–63
Conte A, Gianni C, Belvisi D, Cortese A, Petsas N, Tartaglia M, Cimino P, Millefiorini E, Berardelli A, Pantano P (2019) Deep grey matter involvement and altered sensory gating in multiple sclerosis. Mult Scler 1352458519845287. doi: https://doi.org/10.1177/1352458519845287
Rocchi L, Conte A, Bologna M, Li Voti P, Millefiorini E, Cortese A, Pontecorvo S, Berardelli A (2016) Somatosensory temporal discrimination threshold is impaired in patients with multiple sclerosis. Clin Neurophysiol 127(4):1940–1941. https://doi.org/10.1016/j.clinph.2016.01.010
Pryce G, Baker D (2018) Oligoclonal bands in multiple sclerosis; functional significance and therapeutic implications. Does the specificity matter? Mult Scler Relat Disord 25:131–137. https://doi.org/10.1016/j.msard.2018.07.030
Joseph FG, Hirst CL, Pickersgill TP, Ben-Shlomo Y, Robertson NP, Scolding NJ (2009) CSF oligoclonal band status informs prognosis in multiple sclerosis: a case control study of 100 patients. J Neurol Neurosurg Psychiatry 80(3):292–296. https://doi.org/10.1136/jnnp.2008.150896
Lourenco P, Shirani A, Saeedi J, Oger J, Schreiber WE, Tremlett H (2013) Oligoclonal bands and cerebrospinal fluid markers in multiple sclerosis: associations with disease course and progression. Mult Scler 19(5):577–584. https://doi.org/10.1177/1352458512459684
Gresle MM, Liu Y, Dagley LF, Haartsen J, Pearson F, Purcell AW, Laverick L, Petzold A, Lucas RM, Van der Walt A, Prime H, Morris DR, Taylor BV, Shaw G, Butzkueven H (2014) Serum phosphorylated neurofilament-heavy chain levels in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 85(11):1209–1213. https://doi.org/10.1136/jnnp-2013-306789
Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-Simmelink MJ, Schepens M, Bouwman F, Twaalfhoven HA, Blom HJ, Jakobs C, Dijkstra CD (2009) Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology 72(15):1322–1329. https://doi.org/10.1212/WNL.0b013e3181a0fe3f
Romme Christensen J, Bornsen L, Khademi M, Olsson T, Jensen PE, Sorensen PS, Sellebjerg F (2013) CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis. Mult Scler 19(7):877–884. https://doi.org/10.1177/1352458512466929
Preziosa P, Rocca MA, Filippi M (2020) Current state-of-art of the application of serum neurofilaments in multiple sclerosis diagnosis and monitoring. Expert Rev Neurother. https://doi.org/10.1080/14737175.2020.1760846
Bhan A, Jacobsen C, Myhr KM, Dalen I, Lode K, Farbu E (2018) Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler 24(10):1301–1307. https://doi.org/10.1177/1352458518782005
Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28(6):595–599. https://doi.org/10.1038/nbt.1641
Ferraro D, Guicciardi C, De Biasi S, Pinti M, Bedin R, Camera V, Vitetta F, Nasi M, Meletti S, Sola P (2020) Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients. Acta Neurol Scand 141(1):16–21. https://doi.org/10.1111/ane.13152
Salzer J, Svenningsson A, Sundstrom P (2010) Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 16(3):287–292. https://doi.org/10.1177/1352458509359725
Gil-Perotin S, Castillo-Villalba J, Cubas-Nunez L, Gasque R, Hervas D, Gomez-Mateu J, Alcala C, Perez-Miralles F, Gascon F, Dominguez JA, Casanova B (2019) Combined cerebrospinal fluid neurofilament light chain protein and chitinase-3 like-1 levels in defining disease course and prognosis in multiple sclerosis. Front Neurol 10:1008. https://doi.org/10.3389/fneur.2019.01008
Sellebjerg F, Royen L, Soelberg Sorensen P, Oturai AB, Jensen PEH (2019) Prognostic value of cerebrospinal fluid neurofilament light chain and chitinase-3-like-1 in newly diagnosed patients with multiple sclerosis. Mult Scler 25(11):1444–1451. https://doi.org/10.1177/1352458518794308
Martin SJ, McGlasson S, Hunt D, Overell J (2019) Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: a meta-analysis of case–control studies. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2018-319190
Bridel C, van Wieringen WN, Zetterberg H, Tijms BM, Teunissen CE, Alvarez-Cermeno JC, Andreasson U, Axelsson M, Backstrom DC, Bartos A, Bjerke M, Blennow K, Boxer A, Brundin L, Burman J, Christensen T, Fialova L, Forsgren L, Frederiksen JL, Gisslen M, Gray E, Gunnarsson M, Hall S, Hansson O, Herbert MK, Jakobsson J, Jessen-Krut J, Janelidze S, Johannsson G, Jonsson M, Kappos L, Khademi M, Khalil M, Kuhle J, Landen M, Leinonen V, Logroscino G, Lu CH, Lycke J, Magdalinou NK, Malaspina A, Mattsson N, Meeter LH, Mehta SR, Modvig S, Olsson T, Paterson RW, Perez-Santiago J, Piehl F, Pijnenburg YAL, Pyykko OT, Ragnarsson O, Rojas JC, Romme Christensen J, Sandberg L, Scherling CS, Schott JM, Sellebjerg FT, Simone IL, Skillback T, Stilund M, Sundstrom P, Svenningsson A, Tortelli R, Tortorella C, Trentini A, Troiano M, Turner MR, van Swieten JC, Vagberg M, Verbeek MM, Villar LM, Visser PJ, Wallin A, Weiss A, Wikkelso C, Wild EJ (2019) Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2019.1534
Pasquali L, Lucchesi C, Pecori C, Metelli MR, Pellegrini S, Iudice A, Bonuccelli U (2015) A clinical and laboratory study evaluating the profile of cytokine levels in relapsing remitting and secondary progressive multiple sclerosis. J Neuroimmunol 278:53–59. https://doi.org/10.1016/j.jneuroim.2014.12.005
Tejera-Alhambra M, Casrouge A, de Andrés C, Seyfferth A, Ramos-Medina R, Alonso B, Vega J, Fernández-Paredes L, Albert ML, Sánchez-Ramón S (2015) Plasma biomarkers discriminate clinical forms of multiple sclerosis. PLoS ONE 10(6):e0128952. https://doi.org/10.1371/journal.pone.0128952
Khademi M, Kockum I, Andersson ML, Iacobaeus E, Brundin L, Sellebjerg F, Hillert J, Piehl F, Olsson T (2011) Cerebrospinal fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease course. Mult Scler 17(3):335–343. https://doi.org/10.1177/1352458510389102
Ma X, Zhou J, Zhong Y, Jiang L, Mu P, Li Y, Singh N, Nagarkatti M, Nagarkatti P (2014) Expression, regulation and function of microRNAs in multiple sclerosis. Int J Med Sci 11(8):810–818. https://doi.org/10.7150/ijms.8647
Sondergaard HB, Hesse D, Krakauer M, Sorensen PS, Sellebjerg F (2013) Differential microRNA expression in blood in multiple sclerosis. Mult Scler 19(14):1849–1857. https://doi.org/10.1177/1352458513490542
Gandhi R, Healy B, Gholipour T, Egorova S, Musallam A, Hussain MS, Nejad P, Patel B, Hei H, Khoury S, Quintana F, Kivisakk P, Chitnis T, Weiner HL (2013) Circulating microRNAs as biomarkers for disease staging in multiple sclerosis. Ann Neurol 73(6):729–740. https://doi.org/10.1002/ana.23880
Mancuso R, Hernis A, Agostini S, Rovaris M, Caputo D, Clerici M (2015) MicroRNA-572 expression in multiple sclerosis patients with different patterns of clinical progression. J Transl Med 13:148. https://doi.org/10.1186/s12967-015-0504-2
Haghikia A, Hellwig K, Baraniskin A, Holzmann A, Decard BF, Thum T, Gold R (2012) Regulated microRNAs in the CSF of patients with multiple sclerosis: a case–control study. Neurology 79(22):2166–2170. https://doi.org/10.1212/WNL.0b013e3182759621
Vistbakka J, Elovaara I, Lehtimaki T, Hagman S (2017) Circulating microRNAs as biomarkers in progressive multiple sclerosis. Mult Scler 23(3):403–412. https://doi.org/10.1177/1352458516651141
Ebrahimkhani S, Vafaee F, Young PE, Hur SSJ, Hawke S, Devenney E, Beadnall H, Barnett MH, Suter CM, Buckland ME (2017) Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep 7(1):14293. https://doi.org/10.1038/s41598-017-14301-3
Romme Christensen J, Bornsen L, Ratzer R, Piehl F, Khademi M, Olsson T, Sorensen PS, Sellebjerg F (2013) Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS ONE 8(3):e57820. https://doi.org/10.1371/journal.pone.0057820
Venken K, Hellings N, Hensen K, Rummens JL, Medaer R, D'Hooghe MB, Dubois B, Raus J, Stinissen P (2006) Secondary progressive in contrast to relapsing–remitting multiple sclerosis patients show a normal CD4+CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 83(8):1432–1446. https://doi.org/10.1002/jnr.20852
Sternberg Z, Chiotti A, Tario J, Chichelli T, Patel N, Chadha K, Yu J, Karmon Y (2016) Reduced expression of membrane-bound (m)RAGE is a biomarker of multiple sclerosis disease progression. Immunobiology 221(2):193–198. https://doi.org/10.1016/j.imbio.2015.09.007
Lavon I, Heli C, Brill L, Charbit H, Vaknin-Dembinsky A (2019) Blood Levels of co-inhibitory-receptors: a biomarker of disease prognosis in multiple sclerosis. Front Immunol 10:835. https://doi.org/10.3389/fimmu.2019.00835
Iacobaeus E, Amoudruz P, Strom M, Khademi M, Brundin L, Hillert J, Kockum I, Malmstrom V, Olsson T, Tham E, Piehl F (2011) The expression of VEGF-A is down regulated in peripheral blood mononuclear cells of patients with secondary progressive multiple sclerosis. PLoS ONE 6(5):e19138. https://doi.org/10.1371/journal.pone.0019138
Ingram G, Hakobyan S, Hirst CL, Harris CL, Pickersgill TP, Cossburn MD, Loveless S, Robertson NP, Morgan BP (2010) Complement regulator factor H as a serum biomarker of multiple sclerosis disease state. Brain 133(Pt 6):1602–1611. https://doi.org/10.1093/brain/awq085
DeMarshall C, Goldwaser EL, Sarkar A, Godsey GA, Acharya NK, Thayasivam U, Belinka BA, Nagele RG (2017) Autoantibodies as diagnostic biomarkers for the detection and subtyping of multiple sclerosis. J Neuroimmunol 309:51–57. https://doi.org/10.1016/j.jneuroim.2017.05.010
Cristofanilli M, Gratch D, Pagano B, McDermott K, Huang J, Jian J, Bates D, Sadiq SA (2017) Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes. Mult Scler 23(13):1707–1715. https://doi.org/10.1177/1352458516684022
Nishihara H, Shimizu F, Kitagawa T, Yamanaka N, Akada J, Kuramitsu Y, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Nakamura K, Kanda T (2017) Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis. Mult Scler 23(3):382–394. https://doi.org/10.1177/1352458516655217
Axelsson M, Malmestrom C, Nilsson S, Haghighi S, Rosengren L, Lycke J (2011) Glial fibrillary acidic protein: a potential biomarker for progression in multiple sclerosis. J Neurol 258(5):882–888. https://doi.org/10.1007/s00415-010-5863-2
Burman J, Svenningsson A (2016) Cerebrospinal fluid concentration of galectin-9 is increased in secondary progressive multiple sclerosis. J Neuroimmunol 292:40–44. https://doi.org/10.1016/j.jneuroim.2016.01.008
Barbour C, Kosa P, Komori M, Tanigawa M, Masvekar R, Wu T, Johnson K, Douvaras P, Fossati V, Herbst R, Wang Y, Tan K, Greenwood M, Bielekova B (2017) Molecular-based diagnosis of multiple sclerosis and its progressive stage. Ann Neurol 82(5):795–812. https://doi.org/10.1002/ana.25083
Dickens AM, Larkin JR, Griffin JL, Cavey A, Matthews L, Turner MR, Wilcock GK, Davis BG, Claridge TD, Palace J, Anthony DC, Sibson NR (2014) A type 2 biomarker separates relapsing-remitting from secondary progressive multiple sclerosis. Neurology 83(17):1492–1499. https://doi.org/10.1212/wnl.0000000000000905
Teunissen CE, Koel-Simmelink MJ, Pham TV, Knol JC, Khalil M, Trentini A, Killestein J, Nielsen J, Vrenken H, Popescu V, Dijkstra CD, Jimenez CR (2011) Identification of biomarkers for diagnosis and progression of MS by MALDI-TOF mass spectrometry. Mult Scler 17(7):838–850. https://doi.org/10.1177/1352458511399614
Herman S, Akerfeldt T, Spjuth O, Burman J, Kultima K (2019) Biochemical differences in cerebrospinal fluid between secondary progressive and relapsing–remitting multiple sclerosis. Cells 8(2):84. https://doi.org/10.3390/cells8020084
Ottervald J, Franzen B, Nilsson K, Andersson LI, Khademi M, Eriksson B, Kjellstrom S, Marko-Varga G, Vegvari A, Harris RA, Laurell T, Miliotis T, Matusevicius D, Salter H, Ferm M, Olsson T (2010) Multiple sclerosis: identification and clinical evaluation of novel CSF biomarkers. J Proteomics 73(6):1117–1132. https://doi.org/10.1016/j.jprot.2010.01.004
Herman S, Khoonsari PE, Tolf A, Steinmetz J, Zetterberg H, Åkerfeldt T, Jakobsson PJ, Larsson A, Spjuth O, Burman J, Kultima K (2018) Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis. Theranostics 8(16):4477–4490. https://doi.org/10.7150/thno.26249
Gencer M, Akbayir E, Sen M, Arsoy E, Yilmaz V, Bulut N, Tuzun E, Turkoglu R (2019) Serum orexin-A levels are associated with disease progression and motor impairment in multiple sclerosis. Neurol Sci 40(5):1067–1070. https://doi.org/10.1007/s10072-019-3708-z
Scarisbrick IA, Linbo R, Vandell AG, Keegan M, Blaber SI, Blaber M, Sneve D, Lucchinetti CF, Rodriguez M, Diamandis EP (2008) Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration. Biol Chem 389(6):739–745. https://doi.org/10.1515/bc.2008.085
Oliveira SR, Kallaur AP, Reiche EMV, Kaimen-Maciel DR, Panis C, Lozovoy MAB, Morimoto HK, Maes M, Dichi I, Simao ANC (2017) Albumin and protein oxidation are predictors that differentiate relapsing–remitting from progressive clinical forms of multiple sclerosis. Mol Neurobiol 54(4):2961–2968. https://doi.org/10.1007/s12035-016-9860-z
Benesova Y, Vasku A, Novotna H, Litzman J, Stourac P, Beranek M, Kadanka Z, Bednarik J (2009) Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis. Mult Scler 15(3):316–322. https://doi.org/10.1177/1352458508099482
Muris AH, Rolf L, Broen K, Hupperts R, Damoiseaux J, Smolders J (2016) A low vitamin D status at diagnosis is associated with an early conversion to secondary progressive multiple sclerosis. J Steroid Biochem Mol Biol 164:254–257. https://doi.org/10.1016/j.jsbmb.2015.11.009
Regenold WT, Phatak P, Makley MJ, Stone RD, Kling MA (2008) Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression. J Neurol Sci 275(1–2):106–112. https://doi.org/10.1016/j.jns.2008.07.032
Guimaraes I, Cardoso MI, Sa MJ (2006) Tau protein seems not to be a useful routine clinical marker of axonal damage in multiple sclerosis. Mult Scler 12(3):354–356. https://doi.org/10.1191/1352458506ms1288sr
Koch MW, George S, Wall W, Wee Yong V, Metz LM (2015) Serum NSE level and disability progression in multiple sclerosis. J Neurol Sci 350(1–2):46–50. https://doi.org/10.1016/j.jns.2015.02.009
Malhotra S, Fissolo N, Tintore M, Wing AC, Castillo J, Vidal-Jordana A, Montalban X, Comabella M (2015) Role of high mobility group box protein 1 (HMGB1) in peripheral blood from patients with multiple sclerosis. J Neuroinflammation 12:48. https://doi.org/10.1186/s12974-015-0269-9
Teunissen CE, Killestein J, Kragt JJ, Polman CH, Dijkstra CD, Blom HJ (2008) Serum homocysteine levels in relation to clinical progression in multiple sclerosis. J Neurol Neurosurg Psychiatry 79(12):1349–1353. https://doi.org/10.1136/jnnp.2008.151555
Harirchian MH, Sahraian MA, Shirani A (2006) Serum prolactin level in patients with multiple sclerosis: a case control study. Med Sci Monit 12(4):Cr177–180
Berilgen MS, Bulut S, Ustundag B, Tekatas A, Ayar A (2005) Patients with multiple sclerosis have higher levels of serum ghrelin. Neuro Endocrinol Lett 26(6):819–822
Aeinehband S, Brenner P, Stahl S, Bhat M, Fidock MD, Khademi M, Olsson T, Engberg G, Jokinen J, Erhardt S, Piehl F (2016) Cerebrospinal fluid kynurenines in multiple sclerosis; relation to disease course and neurocognitive symptoms. Brain Behav Immun 51:47–55. https://doi.org/10.1016/j.bbi.2015.07.016
Pasquali L, Pecori C, Lucchesi C, LoGerfo A, Iudice A, Siciliano G, Bonuccelli U (2015) Plasmatic oxidative stress biomarkers in multiple sclerosis: relation with clinical and demographic characteristics. Clin Biochem 48(1–2):19–23. https://doi.org/10.1016/j.clinbiochem.2014.09.024
Eshaghi A, Prados F, Brownlee WJ, Altmann DR, Tur C, Cardoso MJ, De Angelis F, van de Pavert SH, Cawley N, De Stefano N, Stromillo ML, Battaglini M, Ruggieri S, Gasperini C, Filippi M, Rocca MA, Rovira A, Sastre-Garriga J, Vrenken H, Leurs CE, Killestein J, Pirpamer L, Enzinger C, Ourselin S, Wheeler-Kingshott C, Chard D, Thompson AJ, Alexander DC, Barkhof F, Ciccarelli O (2018) Deep gray matter volume loss drives disability worsening in multiple sclerosis. Ann Neurol 83(2):210–222. https://doi.org/10.1002/ana.25145
Latorre A, Rocchi L, Berardelli A, Bhatia KP, Rothwell JC (2019) The interindividual variability of transcranial magnetic stimulation effects: implications for diagnostic use in movement disorders. Mov Disord 34(7):936–949. https://doi.org/10.1002/mds.27736
Acknowledgements
We thank Melissa Kerr for the English language editing.
Funding
This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author information
Authors and Affiliations
Contributions
All authors equally contributed to this work.
Corresponding author
Ethics declarations
Conflicts of interest
No competing interests to declare.
Rights and permissions
About this article
Cite this article
Ferrazzano, G., Crisafulli, S.G., Baione, V. et al. Early diagnosis of secondary progressive multiple sclerosis: focus on fluid and neurophysiological biomarkers. J Neurol 268, 3626–3645 (2021). https://doi.org/10.1007/s00415-020-09964-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00415-020-09964-4