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Review

Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

, , , &
Pages 1669-1682 | Received 08 Mar 2016, Accepted 14 Jun 2016, Published online: 04 Jul 2016

References

  • Logroscino G, Traynor BJ, Hardiman O, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry. 2008 Jan;79(1):6–11.
  • Ingre C, Roos PM, Piehl F, et al. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015;7:181–193.
  • Bakkar N, Boehringer A, Bowser R. Use of biomarkers in ALS drug development and clinical trials. Brain Res. 2015 May;1607(1607):94–107.
  • Pradat P-F, Kabashi E, Desnuelle C. Deciphering spreading mechanisms in amyotrophic lateral sclerosis: clinical evidence and potential molecular processes. Curr Opin Neurol. 2015 Oct;28(5):455–461.
  • Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994 Mar 3; 330(9):585–591.
  • Lacomblez L, Bensimon G, Leigh PN, et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996 May 25; 347(9013):1425–1431.
  • Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology. 2006 Mar 14;66(5):647–653.
  • Logroscino G, Traynor BJ, Hardiman O, et al. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):385–390.
  • Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013 Nov;9(11):617–628.
  • Alonso A, Logroscino G, Jick SS, et al. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. ‎Eur J Neurol: Official J Eur Fed Neuroll Soc. 2009 Jun;16(6):745–751.
  • 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 Dec;1(5):293–299.
  • Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13;73(15):1218–1226.
  • Traynor BJ, Alexander M, Corr B, et al. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996–2000. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1258–1261.
  • Rowland LP. The quality of neurological care, 1997. Arch Neurol. 1997 Nov;54(11):1327–1328.
  • Andersen PM, Nilsson P, Forsgren L, et al. CuZn-superoxide dismutase, extracellular superoxide dismutase, and glutathione peroxidase in blood from individuals homozygous for Asp90Ala CuZu-superoxide dismutase mutation. J Neurochem. 1998 Feb;70(2):715–720.
  • Andersen PM. The genetics of amyotrophic lateral sclerosis (ALS). Suppl Clin Neurophysiol. 2004;57:211–227.
  • Bruijn LI, Houseweart MK, Kato S, et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science. 1998 Sep 18;281(5384):1851–1854.
  • 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 Oct 20;72(2):257–268.
  • 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 Oct 20;72(2):245–256.
  • Gijselinck I, Van Langenhove T, van der Zee J, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2012 Jan;11(1):54–65.
  • Belzil VV, Bauer PO, Prudencio M, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 2013 Dec;126(6):895–905.
  • Yokoseki A, Shiga A, Tan CF, et al. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008 Apr;63(4):538–542.
  • Rutherford NJ, Zhang YJ, Baker M, et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 2008;4(9):e1000193.
  • Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130–133.
  • Marangi G, Traynor BJ. Genetic causes of amyotrophic lateral sclerosis: new genetic analysis methodologies entailing new opportunities and challenges. Brain Res. 2015 May;1607(1607):75–93.
  • Lattante S, Ciura S, Rouleau GA, et al. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet. 2015 May;31(5):263–273.
  • 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 Nov;13(11):1127–1138.
  • Vucic S, Rothstein JD, Kiernan MC. Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies. Trends Neurosci. 2014 Aug;37(8):433–442.
  • Babin PJ, Goizet C, Raldua D. Zebrafish models of human motor neuron diseases: advantages and limitations. Prog Neurobiol. 2014 Jul;118:36–58.
  • Tsao W, Jeong YH, Lin S, et al. Rodent models of TDP-43: recent advances. Brain Research. 2012 Jun 26;1462:26–39.
  • Lanson NA Jr., Pandey UB. FUS-related proteinopathies: lessons from animal models. Brain Res. 2012 Jun;26(1462):44–60.
  • Perrin S. Preclinical research: make mouse studies work. Nature. 2014 Mar 27;507(7493):423–425.
  • Hedges EC, Mehler VJ, Nishimura AL. The use of stem cells to model amyotrophic lateral sclerosis and frontotemporal dementia: from basic research to regenerative medicine. Stem Cells Int. 2016;2016:9279516.
  • Nishimura AL, Shum C, Scotter EL, et al. Allele-specific knockdown of ALS-associated mutant TDP-43 in neural stem cells derived from induced pluripotent stem cells. PLoS One. 2014;9(3):e91269.
  • Wray S, Self M, Lewis PA, et al. Creation of an open-access, mutation-defined fibroblast resource for neurological disease research. PLoS One. 2012;7(8):e43099.
  • Simon NG, Turner MR, Vucic S, et al. Quantifying disease progression in amyotrophic lateral sclerosis. Ann Neurol. 2014 Nov;76(5):643–657.
  • Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1–2):13–21.
  • Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Jan 24;66(2):265–267.
  • Berry JD, Miller R, Moore DH, et al. The Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical trials. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan;14(3):162–168.
  • Rudnicki SA, Berry JD, Ingersoll E, et al. Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a Phase II study: subgroup analysis of demographic and clinical characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan;14(1):44–51.
  • Goonetilleke A, De Belleroche J, Guiloff RJ. Motor neurone disease. Essays Biochem. 1994;28:27–45.
  • Andres PL, Skerry LM, Thornell B, et al. A comparison of three measures of disease progression in ALS. J Neurol Sci. 1996 Aug;139(Suppl):64–-70.
  • Andres PL, Hedlund W, Finison L, et al. Quantitative motor assessment in amyotrophic lateral sclerosis. Neurology. 1986 Jul;36(7):937–941.
  • Czaplinski A, Yen AA, Appel SH. Forced vital capacity (FVC) as an indicator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):390–392.
  • Baumann F, Rose SE, Nicholson GA, et al. Biomarkers of disease in a case of familial lower motor neuron ALS. Amyotroph Lateral Scler. 2010 Oct;11(5):486–489.
  • Fitting JW, Paillex R, Hirt L, et al. Sniff nasal pressure: a sensitive respiratory test to assess progression of amyotrophic lateral sclerosis. Ann Neurol. 1999 Dec;46(6):887–893.
  • Ludolph AC, Bendotti C, Blaugrund E, et al. Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph Lateral Scler. 2010;11(1–2):38–45.
  • Schoenfeld DA, Cudkowicz M. Design of phase II ALS clinical trials. Amyotroph Lateral Scler. 2008;9(1):16–23.
  • Turner MR, Kiernan MC, Leigh PN, et al. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 2009 Jan;8(1):94–109.
  • Otto M, Bowser R, Turner M, et al. Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS. Amyotroph Lateral Scler. 2012 Jan;13(1):1–10.
  • Gordon PH, Meininger V. How can we improve clinical trials in amyotrophic lateral sclerosis? Nat Rev Neurol. 2011 Nov;7(11):650–654.
  • Menke RA, Gray E, Lu CH, et al. CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol. 2015 Jul;2(7):748–755.
  • Chen H, Qian K, Du Z, et al. Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell. 2014 Jun 5;14(6):796–809.
  • Lu CH, Petzold A, Kalmar B, et al. 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.
  • Ganesalingam J, An J, Shaw CE, et al. Combination of neurofilament heavy chain and complement C3 as CSF biomarkers for ALS. J Neurochem. 2011 May;117(3):528–537.
  • 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 Dec;111(5):1182–1191.
  • Reijn TS, Abdo WF, Schelhaas HJ, et al. CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol. 2009 Apr;256(4):615–619.
  • Zhuo JM, Wang H, Pratico D. Is hyperhomocysteinemia an Alzheimer’s disease (AD) risk factor, an AD marker, or neither? Trends Pharmacol Sci. 2011 Sep;32(9):562–571.
  • 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 Nov;65(11):1481–1487.
  • Sjogren M, Gustafson L, Wikkelso C, et al. Frontotemporal dementia can be distinguished from Alzheimer’s disease and subcortical white matter dementia by an anterior-to-posterior rCBF-SPET ratio. Dement Geriatr Cogn Disord. 2000 Sep–Oct;11(5):275–285.
  • Brettschneider J, Petzold A, Sussmuth SD, et al. Neurofilament heavy-chain NfH(SMI35) in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes. Mov Disord. 2006 Dec;21(12):2224–2227.
  • Ganesalingam J, Bowser R. The application of biomarkers in clinical trials for motor neuron disease. Biomark Med. 2010 Apr;4(2):281–297.
  • Shevchenko G, Konzer A, Musunuri S, et al. Neuroproteomics tools in clinical practice. Biochim Biophys Acta. 2015 Jul;1854(7):705–717.
  • Okamoto K, Mizuno Y, Fujita Y. Bunina bodies in amyotrophic lateral sclerosis. Neuropathology. 2008 Apr;28(2):109–115.
  • Mendonca DM, Pizzati L, Mostacada K, et al. Neuroproteomics: an insight into ALS. Neurol Res. 2012 Dec;34(10):937–943.
  • Zecca L, Youdim MB, Riederer P, et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004 Nov;5(11):863–873.
  • Von Neuhoff N, Oumeraci T, Wolf T, et al. Monitoring CSF proteome alterations in amyotrophic lateral sclerosis: obstacles and perspectives in translating a novel marker panel to the clinic. PLoS One. 2012;7(9):e44401.
  • Brettschneider J, Lehmensiek V, Mogel H, et al. Proteome analysis reveals candidate markers of disease progression in amyotrophic lateral sclerosis (ALS). Neurosci Lett. 2010 Jan 1;468(1):23–27.
  • Ryberg H, Bowser R. Protein biomarkers for amyotrophic lateral sclerosis. Expert Rev Proteomics. 2008 Apr;5(2):249–262.
  • Lerman BJ, Hoffman EP, Sutherland ML, et al. Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Brain Behav. 2012 Sep;2(5):563–575.
  • Paez-Colasante X, Figueroa-Romero C, Sakowski SA, et al. Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era. Nat Rev Neurol. 2015 May;11(5):266–279.
  • Trushina E, Mielke MM. Recent advances in the application of metabolomics to Alzheimer’s Disease. Biochim Biophys Acta. 2013 Jun;1842(8):1232–1239.
  • Zoccolella S, Beghi E, Palagano G, et al. Predictors of long survival in amyotrophic lateral sclerosis: a population-based study. J Neurol Sci. 2008 May 15;268(1–2):28–32.
  • Testa D, Lovati R, Ferrarini M, et al. Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Dec;5(4):208–212.
  • Shimizu T, Nagaoka U, Nakayama Y, et al. Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: a multicenter study in Japan. Amyotroph Lateral Scler. 2012 Jun;13(4):363–366.
  • Scotton WJ, Scott KM, Moore DH, et al. Prognostic categories for amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012 Oct;13(6):502–508.
  • Millul A, Beghi E, Logroscino G, et al. Survival of patients with amyotrophic lateral sclerosis in a population-based registry. Neuroepidemiology. 2005;25(3):114–119.
  • Magnus T, Beck M, Giess R, et al. Disease progression in amyotrophic lateral sclerosis: predictors of survival. Muscle Nerve. 2002 May;25(5):709–714.
  • Louwerse ES, Visser CE, Bossuyt PM, et al. Amyotrophic lateral sclerosis: mortality risk during the course of the disease and prognostic factors. The Netherlands ALS Consortium. J Neurol Sci. 1997 Oct;152(Suppl 1):S10–7.
  • Kollewe K, Mauss U, Krampfl K, et al. ALSFRS-R score and its ratio: a useful predictor for ALS-progression. J Neurol Sci. 2008 Dec 15;275(1–2):69–73.
  • Gordon PH, Salachas F, Lacomblez L, et al. Predicting survival of patients with amyotrophic lateral sclerosis at presentation: a 15-year experience. Neurodegener Dis. 2013;12(2):81–90.
  • Del Aguila MA, Longstreth WT Jr., McGuire V, et al. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology. 2003 Mar 11;60(5):813–819.
  • Czaplinski A, Yen AA, Appel SH. Amyotrophic lateral sclerosis: early predictors of prolonged survival. J Neurol. 2006 Nov;253(11):1428–1436.
  • Gordon PH, Salachas F, Lacomblez L, et al. Predicting survival of patients with amyotrophic lateral sclerosis at presentation: a 15-Year experience. Neurodegener Dis. 2012 Aug;12(2):81–90.
  • Gordon PH, Miller RG, Moore DH. Alsfrs-R. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004 Sep;Suppl 5(1):90–93.
  • Gordon PH, Corcia P, Lacomblez L, et al. Defining survival as an outcome measure in amyotrophic lateral sclerosis. Arch Neurol. 2009 Jun;66(6):758–761.
  • Gordon PH, Cheung YK. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006 Oct 10;67(7):1314–1315. author reply 14-5.
  • Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain. 1995 Jun;118(Pt 3):707–719.
  • Bede P, Hardiman O. Lessons of ALS imaging: pitfalls and future directions - A critical review. Neuroimage Clin. 2014;4:436–443.
  • Pradat PF, El Mendili MM. Neuroimaging to investigate multisystem involvement and provide biomarkers in amyotrophic lateral sclerosis. Biomed Res Int. 2014;2014:467560.
  • Blasco H, Nadal-Desbarats L, Pradat PF, et al. Untargeted 1H-NMR metabolomics in CSF: toward a diagnostic biomarker for motor neuron disease. Neurology. 2014 Apr 1;82(13):1167–1174.
  • Hardiman O. Symptomatic treatment of respiratory and nutritional failure in amyotrophic lateral sclerosis. J Neurol. 2000 Apr;247(4):245–251.
  • Hardiman O. Management of respiratory symptoms in ALS. J Neurol. 2011 Mar;258(3):359–365.
  • O’Doherty LJ, Hickey A, Hardiman O. Measuring life quality, physical function and psychological well-being in neurological illness. Amyotroph Lateral Scler. 2010 Oct;11(5):461–468.
  • Lacomblez L, Bensimon G, Leigh PN, et al. Long-term safety of riluzole in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Mar;3(1):23–29.
  • Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006 Jul 11;67(1):20–27.
  • 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(5):e97803.
  • Hey SP, Kimmelman J. The risk-escalation model: a principled design strategy for early-phase trials. Kennedy Inst Ethics J. 2014 Jun;24(2):121–139.
  • Gordon PH, Cheng B, Montes J, et al. Outcome measures for early phase clinical trials. Amyotroph Lateral Scler. 2007 Oct;8(5):270–273.
  • Nanasi PP, Jednakovits A Multilateral in vivo and in vitro protective effects of the novel heat shock protein coinducer, bimoclomol: results of preclinical studies. Cardiovasc Drug Rev. Summer 2001;19(2):133–151.
  • Welch WJ. The role of heat-shock proteins as molecular chaperones. Curr Opin Cell Biol. 1991 Dec;3(6):1033–1038.
  • Hargitai J, Lewis H, Boros I, et al. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1. Biochem Biophys Res Commun. 2003 Aug 1;307(3):689–695.
  • Kieran D, Kalmar B, Dick JR, et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med. 2004 Apr;10(4):402–405.
  • Kalmar B, Novoselov S, Gray A, et al. Late stage treatment with arimoclomol delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS. J Neurochem. 2008 Oct;107(2):339–350.
  • Cudkowicz ME, Shefner JM, Simpson E, et al. Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve. 2008 Jul;38(1):837–844.
  • Hemendinger RA, Armstrong EJ 3rd, Brooks BR. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death. Toxicol Appl Pharmacol. 2011 Mar 15;251(3):217–225.
  • Ikeda K, Iwasaki Y, Kaji R. Neuroprotective effect of ultra-high dose methylcobalamin in wobbler mouse model of amyotrophic lateral sclerosis. J Neurol Sci. 2015 Jul 15;354(1–2):70–74.
  • Pratt AJ, Getzoff ED, Perry JJ. Amyotrophic lateral sclerosis: update and new developments. Degener Neurol Neuromuscul Dis. 2012 Feb;2012(2):1–14.
  • Izumi Y, Kaji R. Clinical trials of ultra-high-dose methylcobalamin in ALS. Brain Nerve. 2007 Oct;59(10):1141–1147.
  • Watanabe T, Kaji R, Oka N, et al. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci. 1994 Apr;122(2):140–143.
  • Kaji R, Kodama M, Imamura A, et al. Effect of ultrahigh-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve. 1998 Dec;21(12):1775–1778.
  • Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist–a review of preclinical data. Neuropharmacology. 1999 Jun;38(6):735–767.
  • Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317–324.
  • Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600–607.
  • van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):136–143.
  • Reisberg B, Doody R, Stoffler A, et al. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006 Jan;63(1):49–54.
  • Aarsland D, Ballard C, Walker Z, et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009 Jul;8(7):613–618.
  • Wilcock G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002 Nov;17(6):297–305.
  • Orgogozo JM, Rigaud AS, Stoffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002 Jul;33(7):1834–1839.
  • Johnson JW, Glasgow NG, Povysheva NV. Recent insights into the mode of action of memantine and ketamine. Curr Opin Pharmacol. 2015 Feb;20:54–63.
  • Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry. 1997 Jan 15;41(2):135–144.
  • Kornhuber J, Quack G. Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett. 1995 Aug 4;195(2):137–139.
  • Bormann J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur J Pharmacol. 1989 Aug 3;166(3):591–592.
  • Parsons CG, Gruner R, Rozental J, et al. Patch clamp studies on the kinetics and selectivity of N-methyl-D-aspartate receptor antagonism by memantine (1-amino-3,5-dimethyladamantan). Neuropharmacology. 1993 Dec;32(12):1337–1350.
  • Chen HS, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem. 2006 Jun;97(6):1611–1626.
  • Van Den Bosch L, Van Damme P, Bogaert E, et al. The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006 Nov–Dec;1762(11–12):1068–1082.
  • Blasco H, Mavel S, Corcia P, et al. The glutamate hypothesis in ALS: pathophysiology and drug development. Curr Med Chem. 2014;21(31):3551–3575.
  • Sonkusare SK, Kaul CL, Ramarao P. Dementia of Alzheimer’s disease and other neurodegenerative disorders–memantine, a new hope. Pharmacol Res. 2005 Jan;51(1):1–17.
  • Yanez M, Matias-Guiu J, Arranz-Tagarro JA, et al. The neuroprotection exerted by memantine, minocycline and lithium, against neurotoxicity of CSF from patients with amyotrophic lateral sclerosis, is antagonized by riluzole. Neurodegener Dis. 2014;13(2–3):171–179.
  • Wenk GL, Zajaczkowski W, Danysz W. Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B. Behav Brain Res. 1997 Feb;83(1–2):129–133.
  • Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, et al. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1–40). Brain Res. 2002 Dec 20;958(1):210–221.
  • Wang R, Zhang D. Memantine prolongs survival in an amyotrophic lateral sclerosis mouse model. Eur J Neurosci. 2005 Nov;22(9):2376–2380.
  • Joo IS, Hwang DH, Seok JI, et al. Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Clin Neurol. 2007 Dec;3(4):181–186.
  • De Carvalho M, Pinto S, Costa J, et al. A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010 Oct;11(5):456–460.
  • 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 Dec;11(6):514–519.
  • Takahashi R. Edaravone in ALS. Exp Neurol. 2009 Jun;217(2):235–236.
  • Ito H, Wate R, Zhang J, et al. Treatment with edaravone, initiated at symptom onset, slows motor decline and decreases SOD1 deposition in ALS mice. Exp Neurol. 2008 Oct;213(2):448–455.
  • Aoki M, Warita H, Mizuno H, et al. Feasibility study for functional test battery of SOD transgenic rat (H46R) and evaluation of edaravone, a free radical scavenger. Brain Res. 2011 Mar 25;1382:321–325.
  • Ikeda K, Iwasaki Y. Edaravone, a free radical scavenger, delayed symptomatic and pathological progression of motor neuron disease in the Wobbler Mouse. PLoS One. 2015;10(10):e0140316.
  • Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler. 2006 Dec;7(4):241–245.
  • Abe K, Itoyama Y, Sobue G, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Dec;15(7–8):610–617.
  • Yang YM, Gupta SK, Kim KJ, et al. A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS. Cell Stem Cell. 2013 Jun 6;12(6):713–726.
  • Bordet T, Buisson B, Michaud M, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007 Aug;322(2):709–720.
  • Sunyach C, Michaud M, Arnoux T, et al. Olesoxime delays muscle denervation, astrogliosis, microglial activation and motoneuron death in an ALS mouse model. Neuropharmacology. 2012 Jun;62(7):2346–2352.
  • Lenglet T, Lacomblez L, Abitbol JL, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol. 2014 Mar;21(3):529–536.
  • Solling C. Organ-protective and immunomodulatory effects of erythropoietin–an update on recent clinical trials. Basic Clin Pharmacol Toxicol. 2012 Feb;110(2):113–121.
  • Siren AL, Fratelli M, Brines M, et al. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA. 2001 Mar 27;98(7):4044–4049.
  • Mennini T, De Paola M, Bigini P, et al. Nonhematopoietic erythropoietin derivatives prevent motoneuron degeneration in vitro and in vivo. Mol Med. 2006 Jul–Aug;12(7–8):153–160.
  • Chung YH, Joo KM, Kim YS, et al. Enhanced expression of erythropoietin in the central nervous system of SOD1(G93A) transgenic mice. Brain Res. 2004 Aug 6;1016(2):272–280.
  • Grunfeld JF, Barhum Y, Blondheim N, et al. Erythropoietin delays disease onset in an amyotrophic lateral sclerosis model. Exp Neurol. 2007 Mar;204(1):260–263.
  • Janik P, Kwiecinski H, Sokolowska B, et al. Erythropoietin concentration in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis. J Neural Transm. 2010 Mar;117(3):343–347.
  • Lauria G, Dalla Bella E, Antonini G, et al. Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study. J Neurol Neurosurg Psychiatry. 2015 Aug;86(8):879–886.
  • Shefner JM, Watson ML, Meng L, et al. A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Dec;14(7–8):574–581.
  • Shefner JM, Wolff AA, Meng L. The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Dec;14(7–8):582–585.
  • Beal MF. Neuroprotective effects of creatine. Amino Acids. 2011 May;40(5):1305–1313.
  • Adhihetty PJ, Beal MF. Creatine and its potential therapeutic value for targeting cellular energy impairment in neurodegenerative diseases. Neuromolecular Med. 2008;10(4):275–290.
  • Pastula DM, Moore DH, Bedlack RS. Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2012;12:CD005225.
  • Pastula DM, Moore DH, Bedlack RS. Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2010;6:CD005225.
  • Folch J, Petrov D, Ettcheto M, et al. Masitinib for the treatment of mild to moderate Alzheimer’s disease. Expert Rev Neurother. 2015 Jun;15(6):587–596.
  • Calvo A, Moglia C, Balma M, et al. Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity? CNS Neurol Disord Drug Targets. 2010 Jul;9(3):325–330.
  • Malaspina A, Puentes F, Amor S. Disease origin and progression in amyotrophic lateral sclerosis: an immunology perspective. Int Immunol. 2015 Mar;27(3):117–129.
  • Salvado M, Vargas V, Vidal M, et al. Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient. World J Gastroenterol. 2015 Sep 28;21(36):10475–10479.
  • Lunn JS, Sakowski SA, Feldman EL. Stem cell therapies for amyotrophic lateral sclerosis: recent advances and prospects for the future. Stem Cells. 2014 Jan;32(5):1099–1109.
  • Papadeas ST, Maragakis NJ. Advances in stem cell research for Amyotrophic Lateral Sclerosis. Curr Opin Biotechnol. 2009 Oct;20(5):545–551.
  • Glass JD, Boulis NM, Johe K, et al. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells. 2012 Jun;30(6):1144–1151.
  • Feldman EL, Boulis NM, Hur J, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol. 2014 Mar;75(3):363–373.
  • Minguell JJ, Allers C, Lasala GP. Mesenchymal stem cells and the treatment of conditions and diseases: the less glittering side of a conspicuous stem cell for basic research. Stem Cells Dev. 2013 Jan 15;22(2):193–203.
  • Urushitani M, Ezzi SA, Julien JP. Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA. 2007 Feb 13;104(7):2495–2500.
  • Gros-Louis F, Soucy G, Lariviere R, et al. Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J Neurochem. 2010 Jun;113(5):1188–1199.
  • Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel. 2013;5(4):227–245.
  • Nicholson KA, Cudkowicz ME, Berry JD. Clinical Trial Designs in Amyotrophic Lateral Sclerosis: does One Design Fit All? Neurotherapeutics. 2015 Apr;12(2):376–383.
  • Gordon PH, Cheung YK, Levin B, et al. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph Lateral Scler. 2008 Aug;9(4):212–222.
  • Weckbach S, Losacco JT, Hahnhaussen J, et al. Challenging the dogma on inferiority of stainless steel implants for fracture fixation. An end of the controversy?. Unfallchirurg. 2012 Jan;115(1):75–79.
  • Gupta SK. Non-inferiority clinical trials: practical issues and current regulatory perspective. Indian J Pharmacol. 2011 Jul;43(4):371–374.
  • 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 Sep;15(5–6):406–413.
  • 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 May;12(5):435–442.
  • Fernandes SA, Douglas AG, Varela MA, et al. Oligonucleotide-Based Therapy for FTD/ALS Caused by the C9orf72 Repeat Expansion: a Perspective. J Nucleic Acids. 2013;2013:208245.
  • Roche JC, Rojas-Garcia R, Scott KM, et al. A proposed staging system for amyotrophic lateral sclerosis. Brain. 2012 Mar;135(Pt 3):847–852.
  • Balendra R, Jones A, Jivraj N, et al. Estimating clinical stage of amyotrophic lateral sclerosis from the ALS Functional Rating Scale. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Jun;15(3–4):279–284.
  • 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 Jan;86(1):45–49.
  • Berry JD, Cudkowicz ME, Shefner JM. Predicting success: optimizing phase II ALS trials for the transition to phase III. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Mar;15(1–2):1–8.
  • Geldenhuys WJ. Van der Schyf CJ. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr Med Chem. 2013;20(13):1662–1672.
  • Beghi E, Pupillo E, Bonito V, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013 Sep;14(5–6):397–405.
  • Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):739–745.

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