, Volume 14, Issue 1, pp 119–134 | Cite as

Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis



Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.


ALS Biomarkers Prognostic Diagnostic Clinical Preclinical 

Supplementary material

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  1. 1.
    Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet 2011;377(9769):942-955.PubMedCrossRefGoogle Scholar
  2. 2.
    Cleveland DW, Rothstein J. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2001;2:806-819.PubMedCrossRefGoogle Scholar
  3. 3.
    Bensimon G, Lacomblez L, Meininger V, Group ARS. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994;330:585-591.PubMedCrossRefGoogle Scholar
  4. 4.
    Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V, II ARSG. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996;347:1425-1431.Google Scholar
  5. 5.
    Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012(3):CD001447.Google Scholar
  6. 6.
    Bowser R, Turner MR, Shefner J. Biomarkers in amyotrophic lateral sclerosis: oppportunities and limitations. Nat Rev Neurol 2011;7:631-638.PubMedCrossRefGoogle Scholar
  7. 7.
    Bruijn LI, Miller TM, Cleveland DW. Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 2004;27:723-749.PubMedCrossRefGoogle Scholar
  8. 8.
    Shaw PJ. Molecular and cellular pathways of neurodegeneration in motor neurone disease. J Neurol Neurosurg Psychiatry 2005;76(8):1046-1057.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sabatelli M, Conte A, Zollino M. Clinical and genetic heterogeneity of amyotrophic lateral sclerosis. Clin Genet 2013;83(5):408-416.PubMedCrossRefGoogle Scholar
  10. 10.
    Collins MA, An J, Hood BL, Conrads TP, Bowser RP. Label-free LC-MS/MS proteomic analysis of cerebrospinal fluid identifies protein/pathway alterations and candidate biomarkers for amyotrophic lateral sclerosis. J Proteome Res 2015;14(11):4486-4501.PubMedCrossRefGoogle Scholar
  11. 11.
    Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphan J Rare Dis 2009;4:3.CrossRefGoogle Scholar
  12. 12.
    Rutkove SB. Clinical measures of disease progression in amyotrophic lateral sclerosis. Neurotherapeutics 2015;12(2):384-393.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Cudkowicz ME, Titus S, Kearney M, et al. Safety and efficacy of ceftriaxone for amyotrophic lateral sclerosis: a multi-stage, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014;13(11):1083-1091.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Cudkowicz ME, Van den Berg LH, Shefner JM, et al. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomized, double-blind, phase 3 trial. Lancet Neurol 2013;12(11):1059-1067.PubMedCrossRefGoogle Scholar
  15. 15.
    Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocyline in patients with amyotrophic lateral sclerosis: a phase III randomized trial. Lancet Neurol 2007;6(12):1045-1053.PubMedCrossRefGoogle Scholar
  16. 16.
    Mitsumoto H, Brooks BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 2014;13(11):1127-1138.PubMedCrossRefGoogle Scholar
  17. 17.
    Nicholson KA, Cudkowicz ME, Berry JD. Clinical trial designs in amyotrophic lateral sclerosis: does one design fit all? Neurotherapeutics 2015;12(2):376-383.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mendez EF, Sattler R. Biomarker development for C9orf72 repeat expansion in ALS. Brain Res 2015;1607:26-35.Google Scholar
  19. 19.
    Turner MR, Kiernan MC, Leigh NP, Talbot K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 2009;8:94-109.PubMedCrossRefGoogle Scholar
  20. 20.
    Su XW, Simmons Z, Mitchell RM, Kong L, Stephens HE, Connor JR. Biomarker-based predictive models for prognosis in amyotrophic lateral sclerosis. JAMA Neurol 2013;70(12):1505-1511.PubMedGoogle Scholar
  21. 21.
    Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69(3):89-95.CrossRefGoogle Scholar
  22. 22.
    Kruger T, Lautenschlager J, Grosskreutz J, Rhode H. Proteome analysis of body fluids for amyotrophic lateral sclerosis biomarker discovery. Proteomics Clin Appl 2013;7:123-135.PubMedCrossRefGoogle Scholar
  23. 23.
    Hu S, Loo JA, Wong DT. Human body fluid proteome analysis. Proteomics 2006;6(23):6326-6353.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Rohlff C. Proteomics in molecular medicine: applications in central nervous systems disorders. Electrophoresis 2000;21:1227-1234.PubMedCrossRefGoogle Scholar
  25. 25.
    Rothstein JD. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol 2009;65(Suppl. 1):S3-S9.PubMedCrossRefGoogle Scholar
  26. 26.
    Xu Z, Cork LC, Griffin JW, Cleveland DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell 1993;73(1):23-33.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee MK, Marszalek JR, Cleveland DW. A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron 1994;13(4):975-988.PubMedCrossRefGoogle Scholar
  28. 28.
    Brettschneider J, Petzold A, Sussmuth SD, Ludolph AC, Tumani H. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology 2006;66(6):852-856.PubMedCrossRefGoogle Scholar
  29. 29.
    Reijn TS, Abdo WF, Schelhaas HJ, Verbeek MM. CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol 2009;256:615-619.PubMedCrossRefGoogle Scholar
  30. 30.
    Ganesalingam J, An J, Bowser R, Andersen PM, Shaw CE. pNfH is a promising biomarker for ALS. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(2):146-149.PubMedCrossRefGoogle Scholar
  31. 31.
    Ganesalingam J, An J, Shaw CE, Shaw G, Lacomis D, Bowser R. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem 2011;117:528-537.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Lehnert S, Costa J, de Carvalho M, et al. Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:344-350.PubMedCrossRefGoogle Scholar
  33. 33.
    Oeckl P, Jardel C, Salachas F, et al. Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS. Amyotroph Lateral Scler Frontotemporal Degener 2016;17(5-6):1-10.CrossRefGoogle Scholar
  34. 34.
    Boylan KB, Glass JD, Crook JE, et al. Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013;84(4):467-472.PubMedCrossRefGoogle Scholar
  35. 35.
    Rosengren LE, Karlsson J-E, Karlsson J-O, Persson LI, Wikkelsø C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 1996;67(5):2013-2018.PubMedCrossRefGoogle Scholar
  36. 36.
    Tortelli R, Ruggieri M, Cortese R, et al. Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 2012;19(12):1561-1567.PubMedCrossRefGoogle Scholar
  37. 37.
    Tortelli R, Copetti M, Ruggieri M, et al. Cerebrospinal fluid neurofilament light chain levels: marker of progression to generalized amyotrophic lateral sclerosis. Eur J Neurol 2015;22(1):215-218.PubMedCrossRefGoogle Scholar
  38. 38.
    Lu CH, Macdonald-Wallis C, Gray E, et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology 2015;84(22):2247-2257.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Menke RA, Gray E, Lu CH, et al. CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol 2015;2(7):748-755.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Steinacker P, Feneberg E, Weishaupt J, et al. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry 2016;87:12-20.PubMedCrossRefGoogle Scholar
  41. 41.
    Van Geel WJ, Rosengren LE, Verbeek MM. An enzyme immunoassay to quantify neurofilament light chain in cerebrospinal fluid. J Immunol Methods 2005;296:179-185.PubMedCrossRefGoogle Scholar
  42. 42.
    Goldstein ME, Sternberger NH, Sternberger LA. Phosphorylation protects neurofilaments against proteolysis. J Neuroimmunol 1987;14(2):149-160.PubMedCrossRefGoogle Scholar
  43. 43.
    McCombe PA, Pfluger C, Singh P, Lim CY, Airey C, Hernderson RD. Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis. J Neurol Sci 2015;353:122-129.PubMedCrossRefGoogle Scholar
  44. 44.
    Weydt P, Oeckl P, Huss A, et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol 2016;79(1):152-158.PubMedCrossRefGoogle Scholar
  45. 45.
    Ransohoff RM. How neuroinflammation contributes to neurodegeneration. Science 2016;353(6301):777-783.PubMedCrossRefGoogle Scholar
  46. 46.
    McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 2002;26(4):459-470.PubMedCrossRefGoogle Scholar
  47. 47.
    Chen Y, Liu XH, Wu JJ, et al. Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis. Exp Ther Med 2016;11(6):2095-2106.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Varghese AM, Sharma A, Mishra P, et al. Chitotriosidase—a putative biomarker for sporadic amyotrophic lateral sclerosis. Clin Proteomics 2013;10(1):19.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Chen X, Chen Y, Wei Q, et al. Assessment of a multiple biomarker panel for diagnosis of amyotrophic lateral sclerosis. BMC Neurol 2016;16:173.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Moreau C, Gosset P, Brunaud-Danel V, et al. CSF profiles of angiogenic and inflammatory factors depend on the respiratory status of ALS patients. Amyotroph Lateral Scler 2009;10(3):175-181.PubMedCrossRefGoogle Scholar
  51. 51.
    Almer G, Teismann P, Stevic Z, et al. Increased levels of the pro-inflammatory prostaglandin PGE2 in CSF from ALS patients. Neurology 2002;58:1277-1279.PubMedCrossRefGoogle Scholar
  52. 52.
    Ilzecka J. Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients. Acta Neurol Scand 2003;108(2):125-129.PubMedCrossRefGoogle Scholar
  53. 53.
    Mitchell RM, Freeman WM, Randazzo WT, et al. A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis. Neurology 2009;72:14-19.PubMedCrossRefGoogle Scholar
  54. 54.
    Moreau C, Devos D, Brunaud-Danel V, et al. Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia? Neurology 2005;65(12):1958-1960.PubMedCrossRefGoogle Scholar
  55. 55.
    Kuhle J, Lindberg RL, Regeniter A, et al. Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis. Eur J Neurol 2009;16:771-774.PubMedCrossRefGoogle Scholar
  56. 56.
    Lind AL, Wu D, Freyhult E, et al. A multiplex protein panel applied to cerebrospinal fluid reveals three new biomarker candidates in ALS but none in neuropathic pain patients. PLOS ONE 2016;11(2):e0149821.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Liu J, Gao L, Zang D. Elevated levels of IFN-gamma in CSF and serum of patients with amyotrophic lateral sclerosis. PLOS ONE 2015;10(9):e0136937.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Beers DR, Henkel JS, Zhao W, et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 2011;134(5):1293-1314.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Butovsky O, Siddiqui S, Gabriely G, et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J Clin Invest 2012;122:3063-3087.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J 2014;33(1):7-22.PubMedCrossRefGoogle Scholar
  61. 61.
    Smith R, Myers K, Ravits J, Bowser R. Amyotrophic lateral sclerosis: Is the spinal fluid pathway involved in seeding and spread? Med Hypotheses 2015;85(5):576-583.PubMedCrossRefGoogle Scholar
  62. 62.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72(2):245-256.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257-268.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cleary JD, Ranum LPW. Repeat-associated non-ATG (RAN) translation in neurological disease. Hum Mol Genet 2013;22:R45-R51.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Ash PE, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77(4):639-646.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Mori K, Weng S-M, Arzberger T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335-1338.PubMedCrossRefGoogle Scholar
  67. 67.
    Wen X, Tan W, Westergard T, et al. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 2014;84:1213-1225.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Westergard T, Jensen BK, Wen X, et al. Cell-to-cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep 2016;17:645-652.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mackenzie I, Arzberger T, Kremmer E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 2013;126(6):859-879.PubMedCrossRefGoogle Scholar
  70. 70.
    Lee KH, Zhang P, Kim HJ, et al. C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 2016;167(3):774-788.PubMedCrossRefGoogle Scholar
  71. 71.
    Anderson P, Kedersha N. RNA granules: post-transcriptional and epigenetic modulators of gene expression. Nat Rev Mol Cell Biol 2009;10(6):430-436.PubMedCrossRefGoogle Scholar
  72. 72.
    Gendron Tania F, Van Blitterswijk M, Bieniek KF, et al. Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol 2015;130:559-573.Google Scholar
  73. 73.
    Su Z, Zhang Y, Gendron TF, et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 2014;83(5):1043-1050.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    King AE, Woodhouse A, Kirkcaldie MTK, Vickers JC. Excitotoxicity in ALS: overstimulation, or overreaction? Exp Neurol 2016;275:162-171.PubMedCrossRefGoogle Scholar
  75. 75.
    Blasco H, Mavel S, Corcia P, Gordon PH. The glutamate hypothesis in ALS: pathophysiology and drug development. Curr Med Chem 2014;21(31):3551-3575.PubMedCrossRefGoogle Scholar
  76. 76.
    Turner MR, Bowser R, Bruijn L, et al. Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2013;14(Suppl. 1):19-32.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Cid C, Alvarez-Cermeno JC, Regidor I, Salinas M, Alcazar A. Low concentrations of glutamate induce apoptosis in cultured neurons: implications for amyotrophic lateral sclerosis. J Neurol Sci 2003;206(1):91-95.PubMedCrossRefGoogle Scholar
  78. 78.
    Spreux-Varoquaux O, Bensimon G, Lacomblez L, et al. Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci 2002;193(2):73-78.PubMedCrossRefGoogle Scholar
  79. 79.
    Yanez M, Galan L, Matias-Guiu J, Vela A, Guerrero A, Garcia AG. CSF from amyotrophic lateral sclerosis patients produces glutamate independent death of rat motor brain cortical neurons: protection by resveratrol but not riluzole. Brain Res 2011;1423:77-86.PubMedCrossRefGoogle Scholar
  80. 80.
    Shaw PJ, Forrest V, Ince PG, Richardson JP, Wastell HJ. CSF and plasma amino acid levels in motor neuron disease: elevation of CSF glutamate in a subset of patients. Neurodegeneration 1995;4(2):209-216.PubMedCrossRefGoogle Scholar
  81. 81.
    Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990;28(1):18-25.PubMedCrossRefGoogle Scholar
  82. 82.
    Rothstein JD, Kuncl R, Chaudhry V, et al. Excitatory amino acids in amyotrophic lateral sclerosis: an update. Ann Neurol 1991;30(2):224-225.PubMedCrossRefGoogle Scholar
  83. 83.
    Perry TL, Krieger C, Hansen S, Eisen A. Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. Ann Neurol 1990;28(1):12-17.PubMedCrossRefGoogle Scholar
  84. 84.
    Blin O, Samuel D, Nieoullon A, Serratice G. Changes in CSF amino acid concentrations during the evolution of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1994;57(1):119-120.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Tikka TM, Vartiainen NE, Goldsteins G, et al. Minocycline prevents neurotoxicity induced by cerebrospinal fluid from patients with motor neurone disease. Brain 2002;125(Pt 4):722-731.PubMedCrossRefGoogle Scholar
  86. 86.
    Wuolikainen A, Moritz T, Marklund SL, Antti H, Andersen PM. Disease-related changes in the cerebrospinal fluid metabolome in amyotrophic lateral sclerosis detected by GC/TOFMS. PLOS ONE 2011;6(4):e17947.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Wuolikainen A, Jonsson P, Ahnlund M, et al. Multi-platform mass spectrometry analysis of the CSF and plasma metabolomes of rigorously matched amyotrophic lateral sclerosis, Parkinson's disease and control subjects. Mol Biosyst 2016;12:1287-1298.PubMedCrossRefGoogle Scholar
  88. 88.
    Bozik ME, Mitsumoto H, Brooks BR, et al. A post hoc analysis of subgroup outcomes and creatinine in the phase III clinical trial (EMPOWER) of dexpramipexole in ALS. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(5-6):406-413.PubMedCrossRefGoogle Scholar
  89. 89.
    Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314(5796):130-133.PubMedCrossRefGoogle Scholar
  90. 90.
    Arai T, Hasegawa M, Akiyama H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006;351:602-611.PubMedCrossRefGoogle Scholar
  91. 91.
    Lagier-Tourenne C, Cleveland DW. Rethinking ALS: The FUS about TDP-43. Cell 2009;136:1001-1004.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Noto Y, Shibuya K, Sato Y, et al. Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: Specificity, sensitivity, and a possible prognostic value. Amyotroph Lateral Scler 2011;12(2):140-143.PubMedCrossRefGoogle Scholar
  93. 93.
    Kasai T, Tokuda T, Ishigami N, et al. Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol 2009;117(1):55-62.PubMedCrossRefGoogle Scholar
  94. 94.
    Junttila A, Kuvaja M, Hartikainen P, et al. Cerebrospinal fluid TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis patients with and without the C9ORF72 hexanucleotide expansion. Dement Geriatr Cogn Disord Extra 2016;6:142-149.CrossRefGoogle Scholar
  95. 95.
    Steinacker P, Hendrich C, Sperfeld AD, et al. TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 2008;65(11):1481-1487.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Xiao S, Sanelli T, Chiang H, et al. Low molecular weight species of TDP-43 generated by abnormal splicing form inclusions in amyotrophic lateral sclerosis and result in motor neuron death. Acta Neuropathol 2015;130(1):49-61.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Ranganathan S, Williams E, Ganchev P, et al. Proteomic profiling of cerebrospinal fluid identifies biomarkers for amyotrophic lateral sclerosis. J Neurochem 2005;95:1461-1471.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ryberg H, An J, Darko S, et al. Discovery and verification of amyotrophic lateral sclerosis biomarkers by mass spectrometry based proteomics. Muscle Nerve 2010;42:104-111.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Pasinetti GM, Ungar LH, Lange DJ, et al. Identification of potential CSF biomarkers in ALS. Neurology 2006;66:1218-1222.PubMedCrossRefGoogle Scholar
  100. 100.
    Tsuji-Akimoto S, Yabe I, Niino M, Kikuchi S, Sasaki H. Cystatin C in cerebrospinal fluid as a biomarker of ALS. Neurosci Lett 2009;452(1):52-55.PubMedCrossRefGoogle Scholar
  101. 101.
    Paraoan L, Grierson I. Focus on molecules: cystatin C. Exp Eye Res 2007;84:1019-1020.PubMedCrossRefGoogle Scholar
  102. 102.
    Nagai A, Terashima M, Sheikh AM, et al. Involvement of cystatin C in pathophysiology of CNS diseases. Front Biosci 2008;13:3470-3479.PubMedCrossRefGoogle Scholar
  103. 103.
    Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A. Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti-cystatin C serum. Neurosci Lett 1993;162(1-2):125-128.PubMedCrossRefGoogle Scholar
  104. 104.
    Mori F, Tanji K, Miki Y, Wakabayashi K. Decreased cystatin C immunoreactivity in spinal motor neurons and astrocytes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2009;68(11):1200-1206.PubMedCrossRefGoogle Scholar
  105. 105.
    Wilson ME, Boumaza I, Bowser R. Cystatin C: A candidate biomarker for amyotrophic lateral sclerosis. PLOS ONE 2010;5(12):e15133.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Wilson ME, Boumaza I, Bowser R. Measurement of cystatin C functional activity in the cerebrospinal fluid of amyotrophic lateral sclerosis and control subjects. Fluids Barriers CNS 2013;10:15.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-297.PubMedCrossRefGoogle Scholar
  108. 108.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009;136:215-233.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Eitan C, Hornstein E. Vulnerability of microRNA biogenesis in FTD-ALS. Brain Res 2016;1647:105-111.Google Scholar
  110. 110.
    Kocerha J, Kauppinen S, Wahlestedt C. microRNAs in CNS disorders. Neuromol Med 2009;11(3):162-172.CrossRefGoogle Scholar
  111. 111.
    Weinberg MS, Wood MJ. Short non-coding RNA biology and neurodegenerative disorders: novel disease targets and therapeutics. Hum Mol Genet 2009;18(R1):R27-R39.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Goodall EF, Heath PR, Bandmann O, Kirby J, Shaw PJ. Neuronal dark matter: the emerging role of microRNAs in neurodegeneration. Front Cell Neurosci 2013;7:178.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Haramati S, Chapnik E, Sztainberg Y, et al. miRNA malfunction causes spinal motor neuron disease. Proc Natl Acad Sci U S A 2010;107(29):13111-13116.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Campos-Melo D, Droppelmann CA, He Z, Volkening K, Strong MJ. Altered microRNA expression profile in amyotrophic lateral sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain 2013;6:26.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Emde A, Eitan C, Liou LL, et al. Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS. EMBOJ 2015;34:2633-2651.CrossRefGoogle Scholar
  116. 116.
    Benigni M, Ricci C, Jones AR, Giannini F, Al-Chalabi A, Battistini S. Identification of miRNAs as potential biomarkers in cerebrospinal fluid from amyotrophic lateral sclerosis patients. Neuromolecular Med 2016;18:551-560.PubMedCrossRefGoogle Scholar
  117. 117.
    Freischmidt A, Muller K, Ludolph AC, Weishaupt JH. Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol Commun 2013;1:42.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    De Felice B, Annunziata A, Fiorentino G, et al. miR-338-3p is over-expressed in blood, CFS, serum and spinal cord from sporadic amyotrophic lateral sclerosis patients. Neurogenetics 2014;15(4):243-253.PubMedCrossRefGoogle Scholar
  119. 119.
    Freischmidt A, Muller K, Zondler L, et al. Serum microRNAs in sporadic amyotrophic lateral sclerosis. Neurobiol Aging 2015;36(9):2660.PubMedCrossRefGoogle Scholar
  120. 120.
    Takahashi I, Hama Y, Matsushima M, et al. Identification of plasma microRNAs as a biomarker of sporadic amyotrophic lateral sclerosis. Mol Brain 2015;8(1):67.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Bunton-Stasyshyn RK, Saccon RA, Fratta P, Fisher EM. SOD1 function and its implications for amyotrophic lateral sclerosis pathology: new and renascent themes. Neuroscientist 2015;21(5):519-529.PubMedCrossRefGoogle Scholar
  122. 122.
    Andersen PM, Sims KB, Xin WW, et al. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord 2003;4(2):62-73.PubMedCrossRefGoogle Scholar
  123. 123.
    Kaur SJ, McKeown SR, Rashid S. Mutant SOD1 mediated pathogenesis of amyotrophic lateral sclerosis. Gene 2016;577(2):109-118.PubMedCrossRefGoogle Scholar
  124. 124.
    Frutiger K, Lukas TJ, Gorrie G, Ajroud-Driss S, Siddique T. Gender difference in levels of Cu/Zn superoxide dismutase (SOD1) in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2008;9(3):184-187.PubMedCrossRefGoogle Scholar
  125. 125.
    Miller TM, Kaspar BK, Kops GJ, et al. Virus-delivered small RNA silencing sustains strength in amyotrophic lateral sclerosis. Ann Neurol 2005;57(5):773-776.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ralph GS, Radcliffe PA, Day DM, et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat Med 2005;11(4):429-433.PubMedCrossRefGoogle Scholar
  127. 127.
    Lange DJ, Andersen PM, Remanan R, Marklund S, Benjamin D. Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: a phase I pilot study. Amyotroph Lateral Scler Frontotemporal Degener 2013;14:199-204.PubMedCrossRefGoogle Scholar
  128. 128.
    Winer L, Srinivasan D, Chun S, et al. SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol 2013;70:201-207.PubMedCrossRefGoogle Scholar
  129. 129.
    Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12(5):435-442.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Johanson CE, Stopa EG, McMillan PN. The blood-cerebrospinal fluid barrier: structure and functional significance. Methods Mol Biol 2011;686:101-131.PubMedCrossRefGoogle Scholar
  131. 131.
    Spector R, Keep RF, Robert Snodgrass S, Smith QR, Johanson CE. A balanced view of choroid plexus structure and function: focus on adult humans. Exp Neurol 2015;267:78-86.PubMedCrossRefGoogle Scholar
  132. 132.
    Boylan K, Yang C, Crook J, et al. Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J Neurochem 2009;111(5):1182-1191.PubMedCrossRefGoogle Scholar
  133. 133.
    de Andrade HM, de Albuquerque M, Avansini SH, et al. MicroRNAs-424 and 206 are potential prognostic markers in spinal onset amyotrophic lateral sclerosis. J Neurol Sci 2016;368:19-24.PubMedCrossRefGoogle Scholar
  134. 134.
    Ehrhart J, Smith AJ, Kuzmin-Nichols N, et al. Humoral factors in ALS patients during disease progression. J Neuroinflammation 2015;12:127.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Houi K, Kobayashi T, Kato S, Mochio S, Inoue K. Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2002;106(5):299-301.PubMedCrossRefGoogle Scholar
  136. 136.
    Ilzecka J, Stelmasiak Z, Dobosz B. Transforming growth factor-Beta 1 (tgf-Beta 1) in patients with amyotrophic lateral sclerosis. Cytokine 2002;20(5):239-243.PubMedCrossRefGoogle Scholar
  137. 137.
    Lu CH, Allen K, Oei F, et al. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflammation 2016;3(4):e244.CrossRefGoogle Scholar
  138. 138.
    Cereda C, Baiocchi C, Bongioanni P, et al. TNF and sTNFR1/2 plasma levels in ALS patients. J Neuroimmunol 2008;194(1-2):123-131.PubMedCrossRefGoogle Scholar
  139. 139.
    Zonder L, Muller K, Khalaji S, et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol 2016;132(3):391-411.CrossRefGoogle Scholar
  140. 140.
    Henkel JS, Beers DR, Wen S, et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med 2013;5:64-79.PubMedCrossRefGoogle Scholar
  141. 141.
    Verstraete E, Kuiperij HB, van Blitterswijk MM, et al. TDP-43 plasma levels are higher in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012;13(5):446-451.PubMedCrossRefGoogle Scholar
  142. 142.
    Suarez-Calvet M, Dols-Icardo O, Llado A, et al. Plasma phosphorylated TDP-43 levels are elevated in patients with frontotemporal dementia carrying a C9orf72 repeat expansion or a GRN mutation. J Neurol Neurosurg Psychiatry 2014;85(6):684-691.PubMedCrossRefGoogle Scholar
  143. 143.
    De Marco G, Lupino E, Calvo A, et al. Cytoplasmic accumulation of TDP-43 in circulating lymphomonocytes of ALS patients with and without TARDBP mutations. Acta Neuropathol 2011;121(5):611-622.PubMedCrossRefGoogle Scholar
  144. 144.
    Cecchi M, Messina P, Airoldi L, et al. Plasma amino acids patterns and age of onset of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(5-6):371-375.PubMedCrossRefGoogle Scholar
  145. 145.
    Andreadou E, Kapaki E, Kokotis P, et al. Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis. In Vivo 2008;22(1):137-141.PubMedGoogle Scholar
  146. 146.
    Andreadou E, Kapaki E, Kokotis P, et al. Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: the effect of riluzole treatment. Clin Neurol Neurosurg 2008;110(3):222-226.PubMedCrossRefGoogle Scholar
  147. 147.
    Niebroj-Dobosz I, Janik P, Kwiecinski H. Effect of Riluzole on serum amino acids in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2002;106(1):39-43.PubMedCrossRefGoogle Scholar
  148. 148.
    Paganoni S, Zhang M, Quiroz Zarate A, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol 2012;259(9):1923-1928.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Lawton KA, Brown MV, Alexander D, et al. Plasma metabolomic biomarker panel to distinguish patients with amyotrophic lateral sclerosis from disease mimics. Amyotroph Lateral Scler Frontotemporal Degener 2014;15(5-6):362-370.PubMedCrossRefGoogle Scholar
  150. 150.
    Schutzer SE, Liu T, Natelson BH, et al. Establishing the proteome of normal human cerebrospinal fluid. PLOS ONE 2010;5(6):e10980.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Zhang J, Goodlett DR, Peskind ER, et al. Quantitative proteomic analysis of age-related changes in human cerebrospinal fluid. Neurobiol Aging 2005;26(2):207-227.PubMedCrossRefGoogle Scholar
  152. 152.
    Shepheard SR, Chataway T, Schultz DW, Rush RA, Rogers ML. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. PLOS ONE 2014;9(1):9.CrossRefGoogle Scholar
  153. 153.
    Ono S, Shimizu N, Imai T, Rodriguez GP. Urinary collagen metabolite excretion in amyotrophic lateral sclerosis. Muscle Nerve 2001;24:821-825.PubMedCrossRefGoogle Scholar
  154. 154.
    Ono S, Imai T, Matsubara S, et al. Decreased urinary concentrations of type IV collagen in amyotrophic lateral sclerosis. Acta Neurol Scand 1999;100(2):111-116.PubMedCrossRefGoogle Scholar
  155. 155.
    Bogdanov M, Brown RH, Matson WR, et al. Increased oxidative damage to DNA in ALS patients. Free Radical Biol Med 2000;29(7):652-658.CrossRefGoogle Scholar
  156. 156.
    Mitsumoto H, Santella RM, Liu X, et al. Oxidative stress biomarkers in sporadic ALS. Amyotroph Lateral Scler 2008;9(3):177-183.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Ono S, Imai T, Munakata S, et al. Collagen abnormalities in the spinal cord from patients with amyotrophic lateral sclerosis. J Neurol Sci 1998;160(2):140-147.PubMedCrossRefGoogle Scholar
  158. 158.
    Obayashi K, Sato K, Shimazaki R, et al. Salivary chromogranin A: useful and quantitative biochemical marker of affective state in patients with amyotrophic lateral sclerosis. Intern Med 2008;47(21):1875-1879.PubMedCrossRefGoogle Scholar
  159. 159.
    Roozendaal B, Kim S, Wolf OT, Kim MS, Sung KK, Lee S. The cortisol awakening response in amyotrophic lateral sclerosis is blunted and correlates with clinical status and depressive mood. Psychoneuroendocrinology 2012;37(1):20-26.PubMedCrossRefGoogle Scholar
  160. 160.
    Maier A, Deigendesch N, Muller K, et al. Interleukin-1 antagonist anakinra in amyotrophic lateral sclerosis—a pilot study. PLOS ONE 2015;10(10):e0139684.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Fiala M, Mizwicki MT, Weitzman R, Magpantay L, Nishimoto N. Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients. Am J Neurodegener Dis 2013;2(2):129-139.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Mizwicki MT, Fiala M, Magpantay L, et al. Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis 2012;1(3):305-315.PubMedPubMedCentralGoogle Scholar
  163. 163.
    Lu CH, Petzold A, Kalmar B, Dick J, Malaspina A, Greensmith L. Plasma neurofilament heavy chain levels correlate to markers of late stage disease progression and treatment response in SOD1(G93A) mice that model ALS. PLOS ONE 2012;7(7):e40998.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Stommel EW, Cohen JA, Fadul CE, et al. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler 2009;10(5-6):393-404.PubMedCrossRefGoogle Scholar
  165. 165.
    Levine TD, Bowser R, Hank N, Saperstein D. A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotroph Lateral Scler 2010;11(6):514-519.PubMedCrossRefGoogle Scholar
  166. 166.
    Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006;60(1):22-31.PubMedCrossRefGoogle Scholar
  167. 167.
    Bakkar N, Boehringer A, Bowser R. Use of biomarkers in ALS drug development and clinical trials. Brain Res 2015;1607:94-107.Google Scholar
  168. 168.
    Sussmuth SD, Sperfeld AD, Hinz A, et al. CSF glial markers correlate with survival in amyotrophic lateral sclerosis. Neurology 2010;74:982-987.PubMedCrossRefGoogle Scholar
  169. 169.
    Lu CH, Petzold A, Topping J, et al. Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study. J Neurol Neurosurg Psychiatry 2015;86(5):565-573.PubMedCrossRefGoogle Scholar
  170. 170.
    Blasco H, Patin F, Madji Hounoum B, et al. Metabolomics in amyotrophic lateral sclerosis: how far can it take us? Eur J Neurol 2016;23(3):447-454.PubMedCrossRefGoogle Scholar
  171. 171.
    Gray E, Larkin JR, Claridge TD, Talbot K, Sibson NR, Turner MR. The longitudinal cerebrospinal fluid metabolomic profile of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2015;16(7-8):456-463.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Blasco H, Corcia P, Pradat PF, et al. Metabolomics in cerebrospinal fluid of patients with amyotrophic lateral sclerosis: an untargeted approach via high-resolution mass spectrometry. J Proteome Res 2013;12(8):3746-3754.Google Scholar
  173. 173.
    Lawton KA, Cudkowicz ME, Brown MV, et al. Biochemical alterations associated with ALS. Amyotroph Lateral Scler 2012;13(1):110-118.PubMedCrossRefGoogle Scholar
  174. 174.
    Kumar A, Bala L, Kalita J, et al. Metabolomic analysis of serum by (1) H NMR spectroscopy in amyotrophic lateral sclerosis. Clin Chim Acta 2010;411(7-8):563-567.PubMedCrossRefGoogle Scholar
  175. 175.
    Dettmer K, Aronov PA, Hammock BD. Mass spectrometry-based metabolomics. Mass Spectrom Rev 2007;26(1):51-78.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Wishart DS, Jewison T, Guo AC, et al. HMDB 3.0—The Human Metabolome Database in 2013. Nucl Acids Res 2013;41:D801-D807.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2016

Authors and Affiliations

  1. 1.Department of NeurologyBarrow Neurological Institute, St. Joseph’s Hospital and Medical CenterPhoenixUSA
  2. 2.Department of NeurobiologyBarrow Neurological Institute, St. Joseph’s Hospital and Medical CenterPhoenixUSA

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