584
Views
1
CrossRef citations to date
0
Altmetric
Review

Current and emerging ALS biomarkers: utility and potential in clinical trials

&
Pages 871-886 | Received 19 Jun 2018, Accepted 28 Sep 2018, Published online: 08 Oct 2018

References

  • Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330:585–591.
  • Writing G, Edaravone ALSSG. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:505–512.
  • Center for Drug Evaluation and Research FaDA, US Department of Health and Human Services. Guidance for industry and FDA staff: qualification process for drug development tools. 2014
  • Huynh W, Simon NG, Grosskreutz J, et al. Assessment of the upper motor neuron in amyotrophic lateral sclerosis. Clin Neurophysiol. 2016;127:2643–2660.
  • Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013;9:617–628.
  • Fujimura-Kiyono C, Kimura F, Ishida S, et al. Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2011;82:1244–1249.
  • Roche JC, Rojas-Garcia R, Scott KM, et al. A proposed staging system for amyotrophic lateral sclerosis. Brain. 2012;135:847–852.
  • Chio A, Logroscino G, Hardiman O, et al. Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler. 2009;10:310–323.
  • Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293–299.
  • Balendra R, Jones A, Jivraj N, et al. Use of clinical staging in amyotrophic lateral sclerosis for phase 3 clinical trials. J Neurol Neurosurg Psychiatry. 2015;86:45–49.
  • Baumann F, Henderson RD, Morrison SC, et al. Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11:194–202.
  • Medical Research Council. Aids to the examination of the peripheral nervous system. London. Her Majesty's Stationery Office; 1976
  • Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 2013;12:368–380.
  • Zou ZY, Zhou ZR, Che CH, et al. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017;88:540–549.
  • Williams KL, Fifita JA, Vucic S, et al. Pathophysiological insights into ALS with C9ORF72 expansions. J Neurol Neurosurg Psychiatry. 2013;84:931–935.
  • Andersen PM. Genetics of sporadic ALS. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001;2(Suppl 1):S37–41.
  • Cudkowicz ME, McKenna-Yasek D, Sapp PE, et al. Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997;41:210–221.
  • Al-Chalabi A, van Den Berg LH, Veldink J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat Rev Neurol. 2017;13:96–104.
  • Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388:3017–3026.
  • 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;12:435–442.
  • Jiang J, Zhu Q, Gendron TF, et al. Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs. Neuron. 2016;90:535–550.
  • Shepheard SR, Chataway T, Schultz DW, et al. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. PLoS One. 2014;9:e87398.
  • Ono S, Imai T, Matsubara S, et al. Decreased urinary concentrations of type IV collagen in amyotrophic lateral sclerosis. Acta Neurol Scand. 1999;100:111–116.
  • 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;13:975–988.
  • Brettschneider J, Petzold A, Sussmuth SD, et al. Axonal damage markers in cerebrospinal fluid are increased in ALS. Neurology. 2006;66:852–856.
  • Gaiottino J, Norgren N, Dobson R, et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One. 2013;8:e75091.
  • Lu CH, Macdonald-Wallis C, Gray E, et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015;84:2247–2257.
  • Xu Z, Henderson RD, David M, et al. Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: a Systematic Review and Meta-Analysis. PLoS One. 2016;11:e0164625.
  • Ganesalingam J, An J, Bowser R, et al. pNfH is a promising biomarker for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14:146–149.
  • Oeckl P, Jardel C, Salachas F, et al. Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:404–413.
  • Poesen K, De Schaepdryver M, Stubendorff B, et al. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology. 2017;88:2302–2309.
  • Feneberg E, Oeckl P, Steinacker P, et al. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis. Neurology. 2018;90:e22–e30.
  • Rossi D, Volanti P, Brambilla L, et al. CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis. J Neurol. 2018;265:510–521.
  • Ganesalingam J, An J, Shaw CE, et al. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem. 2011;117:528–537.
  • McCombe PA, Pfluger C, Singh P, et al. Serial measurements of phosphorylated neurofilament-heavy in the serum of subjects with amyotrophic lateral sclerosis. J Neurol Sci. 2015;353:122–129.
  • 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;111:1182–1191.
  • De Schaepdryver M, Jeromin A, Gille B, et al. Comparison of elevated phosphorylated neurofilament heavy chains in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2018;89:367–373.
  • 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.
  • 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;19:1561–1567.
  • Gaiani A, Martinelli I, Bello L, et al. Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: neurofilament Light Chain Levels in Definite Subtypes of Disease. JAMA Neurol. 2017;74:525–532.
  • Reijn TS, Abdo WF, Schelhaas HJ, et al. CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol. 2009;256:615–619.
  • Gille B, De Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis. Neuropathol Appl Neurobiol. 2018;1–14.
  • Gong ZY, Lv GP, Gao LN, et al. Neurofilament Subunit L Levels in the Cerebrospinal Fluid and Serum of Patients with Amyotrophic Lateral Sclerosis. Neurodegener Dis. 2018;18:165–172.
  • Menke RA, Gray E, Lu CH, et al. CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol. 2015;2:748–755.
  • Brettschneider J, Van Deerlin VM, Robinson JL, et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 2012;123:825–839.
  • 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;84:467–472.
  • 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;22:215–218.
  • Weydt P, Oeckl P, Huss A, et al. Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol. 2016;79:152–158.
  • 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.
  • 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.
  • Mackenzie IR, Arzberger T, Kremmer E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 2013;126:859–879.
  • 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.
  • Crisp MJ, Mawuenyega KG, Patterson BW, et al. In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest. 2015;125:2772–2780.
  • Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–133.
  • Mackenzie IR, Bigio EH, Ince PG, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61:427–434.
  • Chen-Plotkin AS, Lee VM, Trojanowski JQ. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol. 2010;6:211–220.
  • Verstraete E, Kuiperij HB, van Blitterswijk MM, et al. TDP-43 plasma levels are higher in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012;13:446–451.
  • Kasai T, Tokuda T, Ishigami N, et al. Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol. 2009;117:55–62.
  • 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;65:1481–1487.
  • 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;130:49–61.
  • Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–233.
  • Hawley ZCE, Campos-Melo D, Droppelmann CA, et al. MotomiRs: miRNAs in Motor Neuron Function and Disease. Front Mol Neurosci. 2017;10:127.
  • Hoye ML, Koval ED, Wegener AJ, et al. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci. 2017;37:5574–5586.
  • Campos-Melo D, Droppelmann CA, He Z, et al. Altered microRNA expression profile in Amyotrophic Lateral Sclerosis: a role in the regulation of NFL mRNA levels. Mol Brain. 2013;6:26.
  • Benigni M, Ricci C, Jones AR, et al. Identification of miRNAs as Potential Biomarkers in Cerebrospinal Fluid from Amyotrophic Lateral Sclerosis Patients. Neuromolecular Med. 2016;18:551–560.
  • Freischmidt A, Muller K, Ludolph AC, et al. Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol Commun. 2013;1:42.
  • 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;15:243–253.
  • Freischmidt A, Muller K, Zondler L, et al. Serum microRNAs in sporadic amyotrophic lateral sclerosis. Neurobiol Aging. 2015;36(2660):e15–20.
  • Takahashi I, Hama Y, Matsushima M, et al. Identification of plasma microRNAs as a biomarker of sporadic Amyotrophic Lateral Sclerosis. Mol Brain. 2015;8:67.
  • Jia R, Shepheard S, Jin J, et al. Urinary Extracellular Domain of Neurotrophin Receptor p75 as a Biomarker for Amyotrophic Lateral Sclerosis in a Chinese cohort. Sci Rep. 2017;7:5127.
  • Shepheard SR, Wuu J, Cardoso M, et al. Urinary p75(ECD): a prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology. 2017;88:1137–1143.
  • Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43–53.
  • Chen Y, Liu XH, Wu JJ, et al. Proteomic analysis of cerebrospinal fluid in amyotrophic lateral sclerosis. Exp Ther Med. 2016;11:2095–2106.
  • Ehrhart J, Smith AJ, Kuzmin-Nichols N, et al. Humoral factors in ALS patients during disease progression. J Neuroinflammation. 2015;12:127.
  • Houi K, Kobayashi T, Kato S, et al. Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosis. Acta Neurol Scand. 2002;106:299–301.
  • Lu CH, Allen K, Oei F, et al. Systemic inflammatory response and neuromuscular involvement in amyotrophic lateral sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e244.
  • Cereda C, Baiocchi C, Bongioanni P, et al. TNF and sTNFR1/2 plasma levels in ALS patients. J Neuroimmunol. 2008;194:123–131.
  • Lunetta C, Lizio A, Maestri E, et al. Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis. JAMA Neurol. 2017;74:660–667.
  • Miller RG, Block G, Katz JS, et al. Randomized phase 2 trial of NP001-a novel immune regulator: safety and early efficacy in ALS. Neurol Neuroimmunol Neuroinflamm. 2015;2:e100.
  • Smith R, Myers K, Ravits J, et al. Amyotrophic lateral sclerosis: is the spinal fluid pathway involved in seeding and spread? Med Hypotheses. 2015;85:576–583.
  • 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.
  • Chiu IM, Chen A, Zheng Y, et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A. 2008;105:17913–17918.
  • Beers DR, Zhao W, Wang J, et al. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017;2:e89530.
  • Sheean RK, McKay FC, Cretney E, et al. Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. JAMA Neurol. 2018;75:681–689.
  • Thonhoff JR, Beers DR, Zhao W, et al. Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. Neurol Neuroimmunol Neuroinflamm. 2018;5:e465.
  • Brites D, Vaz AR. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front Cell Neurosci. 2014;8:117.
  • Steinacker P, Verde F, Fang L, et al. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression. J Neurol Neurosurg Psychiatry. 2018;89:239–247.
  • Martinez-Merino L, Iridoy M, Galbete A, et al. Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis. Neurodegener Dis. 2018;18:208–215.
  • Thompson AG, Gray E, Thezenas ML, et al. Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis. Ann Neurol. 2018;83:258–268.
  • Pagliardini V, Pagliardini S, Corrado L, et al. Chitotriosidase and lysosomal enzymes as potential biomarkers of disease progression in amyotrophic lateral sclerosis: a survey clinic-based study. J Neurol Sci. 2015;348:245–250.
  • Tefera TW, Borges K. Metabolic Dysfunctions in Amyotrophic Lateral Sclerosis Pathogenesis and Potential Metabolic Treatments. Front Neurosci. 2016;10:611.
  • Zoccolella S, Simone IL, Capozzo R, et al. An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis. J Neurol. 2011;258:238–243.
  • Ascherio A, LeWitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009;66:1460–1468.
  • Auinger P, Kieburtz K, McDermott MP. The relationship between uric acid levels and Huntington’s disease progression. Mov Disord. 2010;25:224–228.
  • Keizman D, Ish-Shalom M, Berliner S, et al. Low uric acid levels in serum of patients with ALS: further evidence for oxidative stress? J Neurol Sci. 2009;285:95–99.
  • Ikeda K, Hirayama T, Takazawa T, et al. Relationships between disease progression and serum levels of lipid, urate, creatinine and ferritin in Japanese patients with amyotrophic lateral sclerosis: a cross-sectional study. Intern Med. 2012;51:1501–1508.
  • Zach N, Ennist DL, Taylor AA, et al. Being PRO-ACTive: what can a Clinical Trial Database Reveal About ALS? Neurotherapeutics. 2015;12:417–423.
  • Atassi N, Berry J, Shui A, et al. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014;83:1719–1725.
  • Chio A, Calvo A, Bovio G, et al. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study. JAMA Neurol. 2014;71:1134–1142.
  • Paganoni S, Deng J, Jaffa M, et al. Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle Nerve. 2011;44:20–24.
  • Marin B, Desport JC, Kajeu P, et al. Alteration of nutritional status at diagnosis is a prognostic factor for survival of amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry. 2011;82:628–634.
  • Wills AM, Hubbard J, Macklin EA, et al. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014;383:2065–2072.
  • 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;15:362–370.
  • Konrad C, Kawamata H, Bredvik KG, et al. Fibroblast bioenergetics to classify amyotrophic lateral sclerosis patients. Mol Neurodegener. 2017;12:76.
  • Wainger BJ, Kiskinis E, Mellin C, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014;7:1–11.
  • Richard JP, Maragakis NJ. Induced pluripotent stem cells from ALS patients for disease modeling. Brain Res. 2015;1607:15–25.
  • Tagerud S, Libelius R, Magnusson C. Muscle Nogo-A: a marker for amyotrophic lateral sclerosis or for denervation? Ann Neurol. 2007;62:676.
  • Meininger V, Pradat PF, Corse A, et al. Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS One. 2014;9:e97803.
  • Cornblath DR, Kuncl RW, Mellits ED, et al. Nerve conduction studies in amyotrophic lateral sclerosis. Muscle Nerve. 1992;15:1111–1115.
  • Neuwirth C, Nandedkar S, Stalberg E, et al. Motor unit number index (MUNIX): a novel neurophysiological technique to follow disease progression in amyotrophic lateral sclerosis. Muscle Nerve. 2010;42:379–384.
  • Shefner JM, Watson ML, Simionescu L, et al. Multipoint incremental motor unit number estimation as an outcome measure in ALS. Neurology. 2011;77:235–241.
  • Cheah BC, Vucic S, Krishnan AV, et al. Neurophysiological index as a biomarker for ALS progression: validity of mixed effects models. Amyotroph Lateral Scler. 2011;12:33–38.
  • Neuwirth C, Nandedkar S, Stalberg E, et al. Motor Unit Number Index (MUNIX): a novel neurophysiological marker for neuromuscular disorders; test-retest reliability in healthy volunteers. Clin Neurophysiol. 2011;122:1867–1872.
  • Felice KJ. A longitudinal study comparing thenar motor unit number estimates to other quantitative tests in patients with amyotrophic lateral sclerosis. Muscle Nerve. 1997;20:179–185.
  • Shefner JM, Cudkowicz ME, Schoenfeld D, et al. A clinical trial of creatine in ALS. Neurology. 2004;63:1656–1661.
  • Rutkove SB, Aaron R, Shiffman CA. Localized bioimpedance analysis in the evaluation of neuromuscular disease. Muscle Nerve. 2002;25:390–397.
  • Rutkove SB, Lee KS, Shiffman CA, et al. Test-retest reproducibility of 50 kHz linear-electrical impedance myography. Clin Neurophysiol. 2006;117:1244–1248.
  • Rutkove SB, Caress JB, Cartwright MS, et al. Electrical impedance myography correlates with standard measures of ALS severity. Muscle Nerve. 2014;49:441–443.
  • Rutkove SB, Caress JB, Cartwright MS, et al. Electrical impedance myography as a biomarker to assess ALS progression. Amyotroph Lateral Scler. 2012;13:439–445.
  • Wang LL, Spieker AJ, Li J, et al. Electrical impedance myography for monitoring motor neuron loss in the SOD1 G93A amyotrophic lateral sclerosis rat. Clin Neurophysiol. 2011;122:2505–2511.
  • Kanai K, Kuwabara S, Misawa S, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006;129:953–962.
  • Vucic S, Lin CS, Cheah BC, et al. Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain. 2013;136:1361–1370.
  • Geevasinga N, Menon P, Ng K, et al. Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:580–588.
  • Kanai K, Shibuya K, Kuwabara S. [Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis]. Rinsho Shinkeigaku. 2011;51:1118–1119.
  • Vucic S, Kiernan MC. Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain. 2006;129:2436–2446.
  • Vucic S, Nicholson GA, Kiernan MC. Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain. 2008;131:1540–1550.
  • Floyd AG, Yu QP, Piboolnurak P, et al. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology. 2009;72:498–504.
  • Mills KR. The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain. 2003;126:2558–2566.
  • Park SB, Vucic S, Cheah BC, et al. Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial. EBioMedicine. 2015;2:1916–1922.
  • Whitwell JL. Voxel-based morphometry: an automated technique for assessing structural changes in the brain. J Neurosci. 2009;29:9661–9664.
  • Menke RA, Korner S, Filippini N, et al. Widespread grey matter pathology dominates the longitudinal cerebral MRI and clinical landscape of amyotrophic lateral sclerosis. Brain. 2014;137:2546–2555.
  • Agosta F, Pagani E, Rocca MA, et al. Voxel-based morphometry study of brain volumetry and diffusivity in amyotrophic lateral sclerosis patients with mild disability. Hum Brain Mapp. 2007;28:1430–1438.
  • Shen D, Cui L, Fang J, et al. Voxel-Wise Meta-Analysis of Gray Matter Changes in Amyotrophic Lateral Sclerosis. Front Aging Neurosci. 2016;8:64.
  • Agosta F, Gorno-Tempini ML, Pagani E, et al. Longitudinal assessment of grey matter contraction in amyotrophic lateral sclerosis: A tensor based morphometry study. Amyotroph Lateral Scler. 2009;10:168–174.
  • Schuster C, Kasper E, Machts J, et al. Focal thinning of the motor cortex mirrors clinical features of amyotrophic lateral sclerosis and their phenotypes: a neuroimaging study. J Neurol. 2013;260:2856–2864.
  • Walhout R, Schmidt R, Westeneng HJ, et al. Brain morphologic changes in asymptomatic C9orf72 repeat expansion carriers. Neurology. 2015;85:1780–1788.
  • Verstraete E, Veldink JH, Hendrikse J, et al. Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012;83:383–388.
  • Schuster C, Kasper E, Machts J, et al. Longitudinal course of cortical thickness decline in amyotrophic lateral sclerosis. J Neurol. 2014;261:1871–1880.
  • Agosta F, Pagani E, Petrolini M, et al. Assessment of white matter tract damage in patients with amyotrophic lateral sclerosis: a diffusion tensor MR imaging tractography study. AJNR Am J Neuroradiol. 2010;31:1457–1461.
  • van der Graaff MM, Sage CA, Caan MW, et al. Upper and extra-motoneuron involvement in early motoneuron disease: a diffusion tensor imaging study. Brain. 2011;134:1211–1228.
  • Chapman MC, Jelsone-Swain L, Johnson TD, et al. Diffusion tensor MRI of the corpus callosum in amyotrophic lateral sclerosis. J Magn Reson Imaging. 2014;39:641–647.
  • Zhang Y, Schuff N, Woolley SC, et al. Progression of white matter degeneration in amyotrophic lateral sclerosis: a diffusion tensor imaging study. Amyotroph Lateral Scler. 2011;12:421–429.
  • Keil C, Prell T, Peschel T, et al. Longitudinal diffusion tensor imaging in amyotrophic lateral sclerosis. BMC Neurosci. 2012;13:141.
  • El Mendili MM, Cohen-Adad J, Pelegrini-Issac M, et al. Multi-parametric spinal cord MRI as potential progression marker in amyotrophic lateral sclerosis. PLoS One. 2014;9:e95516.
  • Cardenas-Blanco A, Machts J, Acosta-Cabronero J, et al. Structural and diffusion imaging versus clinical assessment to monitor amyotrophic lateral sclerosis. Neuroimage Clin. 2016;11:408–414.
  • Foerster BR, Dwamena BA, Petrou M, et al. Diagnostic accuracy of diffusion tensor imaging in amyotrophic lateral sclerosis: a systematic review and individual patient data meta-analysis. Acad Radiol. 2013;20:1099–1106.
  • Bowen BC, Pattany PM, Bradley WG, et al. MR imaging and localized proton spectroscopy of the precentral gyrus in amyotrophic lateral sclerosis. AJNR Am J Neuroradiol. 2000;21:647–658.
  • Pyra T, Hui B, Hanstock C, et al. Combined structural and neurochemical evaluation of the corticospinal tract in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11:157–165.
  • Unrath A, Ludolph AC, Kassubek J. Brain metabolites in definite amyotrophic lateral sclerosis. A longitudinal proton magnetic resonance spectroscopy study. J Neurol. 2007;254:1099–1106.
  • Pohl C, Block W, Traber F, et al. Proton magnetic resonance spectroscopy and transcranial magnetic stimulation for the detection of upper motor neuron degeneration in ALS patients. J Neurol Sci. 2001;190:21–27.
  • Pagani M, Chio A, Valentini MC, et al. Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology. 2014;83:1067–1074.
  • Van Laere K, Vanhee A, Verschueren J, et al. Value of 18fluorodeoxyglucose-positron-emission tomography in amyotrophic lateral sclerosis: a prospective study. JAMA Neurol. 2014;71:553–561.
  • Zurcher NR, Loggia ML, Lawson R, et al. Increased in vivo glial activation in patients with amyotrophic lateral sclerosis: assessed with [(11)C]-PBR28. Neuroimage Clin. 2015;7:409–414.
  • Levine TD, Bowser R, Hank N, et al. A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotroph Lateral Scler. 2010;11:514–519.
  • Gomeni R, Fava M. Pooled Resource Open-Access ALSCTC. Amyotrophic lateral sclerosis disease progression model. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:119–129.
  • Berry JD, Taylor AA, Beaulieu D, et al. Improved stratification of ALS clinical trials using predicted survival. Ann Clin Transl Neurol. 2018;5:474–485.
  • Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol. 2006;60:22–31.
  • 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;10:393–404.
  • Benatar M, Wuu J, Andersen PM, et al. Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018;90:e565–e74.
  • Fiala M, Mizwicki MT, Weitzman R, et al. Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients. Am J Neurodegener Dis. 2013;2:129–139.
  • Lange DJ, Andersen PM, Remanan R, et al. 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.
  • 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;15:406–413.
  • Maier A, Deigendesch N, Muller K, et al. Interleukin-1 Antagonist Anakinra in Amyotrophic Lateral Sclerosis–A Pilot Study. PLoS One. 2015;10:e0139684.
  • Macchi Z, Wang Y, Moore D, et al. A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: possible mitochondrial biomarker target engagement. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16:345–352.
  • Fournier CN, Schoenfeld D, Berry JD, et al. An open label study of a novel immunosuppression intervention for the treatment of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:242–249.
  • Berry JD, Paganoni S, Atassi N, et al. Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability. Muscle Nerve. 2017;56:1077–1084.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.