CNS Drugs

, Volume 25, Issue 9, pp 783–799 | Cite as

Targeting Progressive Neuroaxonal Injury

Lessons from Multiple Sclerosis
  • Amit Bar-Or
  • Peter RieckmannEmail author
  • Anthony Traboulsee
  • V. Wee Yong
Review Article


Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), are characterized by progressive neuroaxonal injury, suggesting a common pathophysiological pathway. Identification and development of neuroprotective therapies for such diseases has proven a major challenge, particularly because of an already substantial neuroaxonal compromise at the time of initial onset of clinical symptoms. Methods for early identification of neurodegeneration are therefore vital to ensure that neuroprotective therapies are applied as early as possible. Recent investigations have enhanced our understanding of the role of neuroaxonal injury in multiple sclerosis (MS). As MS generally manifests earlier in life and can be diagnosed much earlier in the course of the disease than the above-mentioned ‘classic’ neurodegenerative diseases, it is possible that MS could be used as a model disease to study degeneration and regeneration of the CNS. The mechanism of neuroaxonal injury in MS is believed to be inflammation-led neurodegeneration; however, the reverse may also be true (i.e. neuroaxonal degeneration may precede inflammation). Animal models of PD, AD and ALS have shown that it is likely that most cases of disease are due to initial inflammation, followed by a degenerative process, providing a parallel between MS and the classic neurodegenerative diseases. Other common factors between MS and the neurodegenerative diseases include iron and mitochondrial dysregulation, abnormalities in α-synuclein and tau protein, and a number of immune mediators. Conventional MRI techniques, using markers such as T2-weighted lesions, gadolinium-enhancing lesions and T1-weighted hypointensities, are readily available and routinely used in clinical practice; however, the utility of these MRI measures to predict disease progression in MS is limited. More recently, MRI techniques that provide more pathology-specific data have been applied in MS studies, including magnetic resonance spectroscopy, magnetization transfer ratio and myelin water imaging. Optical coherence tomography (OCT) is a non-MRI technique that quantifies optic nerve integrity and retinal ganglion cell loss as markers of neuroaxonal injury; more research is needed to evaluate whether information obtained from OCT is a reliable marker of axonal injury and long-term disability in MS. Using these advanced techniques, it may become possible to follow degeneration and regeneration longitudinally in patients with MS and to better differentiate the effects of drugs under investigation. Currently available immune-directed therapies that are approved by the US FDA for the first-line treatment of MS (interferon-β and glatiramer acetate) have been shown to decelerate the inflammatory process in MS; however, such therapy is less effective in preventing the progression of the disease and neuroaxonal injury. The use of MS as a clinical model to study modulation of neuroaxonal injury in the brain could have direct implications for the development of treatment strategies in neurodegenerative diseases such as AD, PD and ALS.


Multiple Sclerosis Amyotrophic Lateral Sclerosis Optical Coherence Tomography Nerve Growth Factor Expand Disability Status Scale 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Gibb WR. Neuropathology of Parkinson’s disease and related syndromes. Neurol Clin 1992 May; 10 (2): 361–76PubMedGoogle Scholar
  2. 2.
    Sperling R, Johnson K. Pro: can biomarkers be gold standards in Alzheimer’s disease [abstract]? Alzheimers Res Ther 2010 Jun 25; 2 (3): 17PubMedCrossRefGoogle Scholar
  3. 3.
    Pahwa R, Lyons KE. Early diagnosis of Parkinson’s disease: recommendations from diagnostic clinical guidelines. Am J Manag Care 2010 Mar; 16 Suppl Implications: S94–9PubMedGoogle Scholar
  4. 4.
    Olanow CW, Schapira AH, LeWitt PA, et al. TCH346 as a neuroprotective drug in Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2006 Dec; 5 (12): 1013–20PubMedCrossRefGoogle Scholar
  5. 5.
    Pardridge WM. CNS drug design based on principles of blood-brain barrier transport. J Neurochem 1998 May; 70 (5): 1781–92PubMedCrossRefGoogle Scholar
  6. 6.
    Kieburtz K. Issues in neuroprotection clinical trials in Parkinson’s disease. Neurology 2006 May 23; 66 (10 Suppl. 4): S50–7PubMedCrossRefGoogle Scholar
  7. 7.
    Slikkker W, Youdim M, Palmer GC, et al. The future of neuroprotection. Ann N Y Acad Sci 1999; 890: 529–33PubMedCrossRefGoogle Scholar
  8. 8.
    Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain 2006 Mar; 129 (Pt 3): 595–605PubMedCrossRefGoogle Scholar
  9. 9.
    Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006 Mar; 129 (Pt 3): 606–16PubMedCrossRefGoogle Scholar
  10. 10.
    Bar-Or A. The immunology of multiple sclerosis. Semin Neurol 2008 Feb; 28 (1): 29–45PubMedCrossRefGoogle Scholar
  11. 11.
    Hemmer B, Nessler S, Zhou D, et al. Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pract Neurol 2006 Apr; 2 (4): 201–11PubMedCrossRefGoogle Scholar
  12. 12.
    Martino G, Adorini L, Rieckmann P, et al. Inflammation in multiple sclerosis: the good, the bad, and the complex. Lancet Neurol 2002 Dec; 1 (8): 499–509PubMedCrossRefGoogle Scholar
  13. 13.
    McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007 Sep; 8 (9): 913–9PubMedCrossRefGoogle Scholar
  14. 14.
    Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005 Nov; 128 (Pt 11): 2705–12PubMedCrossRefGoogle Scholar
  15. 15.
    Li DK, Zhao GJ, Paty DW. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 2001 Jun 12; 56 (11): 1505–13PubMedCrossRefGoogle Scholar
  16. 16.
    Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: clinical results. Neurology 2001 Jun 12; 56(11): 1496–504CrossRefGoogle Scholar
  17. 17.
    Truyen L, van Waesberghe JH, van Walderveen MA, et al. Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 1996 Dec; 47 (6): 1469–76PubMedCrossRefGoogle Scholar
  18. 18.
    Filippi M, Rovaris M, Rocca MA, et al. Glatiramer acetate reduces the proportion of new MS lesions evolving into “black holes”. Neurology 2001 Aug 28; 57 (4): 731–3PubMedCrossRefGoogle Scholar
  19. 19.
    Chard DT, Griffin CM, McLean MA, et al. Brain metabolite changes in cortical grey and normal-appearing white matter in clinically early relapsing-remitting multiple sclerosis. Brain 2002 Oct; 125 (Pt 10): 2342–52PubMedCrossRefGoogle Scholar
  20. 20.
    De Stefano N, Narayanan S, Francis SJ, et al. Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability. Arch Neurol 2002 Oct; 59 (10): 1565–71PubMedCrossRefGoogle Scholar
  21. 21.
    Bjartmar C, Kidd G, Mork S, et al. Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 2000 Dec; 48 (6): 893–901PubMedCrossRefGoogle Scholar
  22. 22.
    Sepulcre J, Sastre-Garriga J, Cercignani M, et al. Regional gray matter atrophy in early primary progressive multiple sclerosis: a voxel-based morphometry study. Arch Neurol 2006 Aug; 63 (8): 1175–80PubMedCrossRefGoogle Scholar
  23. 23.
    Rashid W, Davies GR, Chard DT, et al. Increasing cord atrophy in early relapsing-remitting multiple sclerosis: a 3 year study. J Neurol Neurosurg Psychiatry 2006 Jan; 77(1): 51–5PubMedCrossRefGoogle Scholar
  24. 24.
    Martino G. How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders. Lancet Neurol 2004 Jun; 3 (6): 372–8PubMedCrossRefGoogle Scholar
  25. 25.
    Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008; 31: 247–69PubMedCrossRefGoogle Scholar
  26. 26.
    Dhib-Jalbut S, Arnold DL, Cleveland DW, et al. Neurodegeneration and neuroprotection in multiple sclerosis and other neurodegenerative diseases. J Neuroimmunol 2006 Jul; 176(1–2): 198–215PubMedCrossRefGoogle Scholar
  27. 27.
    Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009; 8: 280–91PubMedCrossRefGoogle Scholar
  28. 28.
    Craner MJ, Newcombe J, Black JA, et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc Natl Acad Sci U S A 2004 May 25; 101 (21): 8168–73PubMedCrossRefGoogle Scholar
  29. 29.
    Smith KJ, McDonald WI. The pathophysiology of multiple sclerosis: the mechanisms underlying the production of symptoms and the natural history of the disease. Philos Trans R Soc Lond B Biol Sci 1999 Oct 29; 354 (1390): 1649–73PubMedCrossRefGoogle Scholar
  30. 30.
    Hohlfeld R. Biotechnological agents for the immunotherapy of multiple sclerosis: principles, problems and perspectives. Brain 1997 May; 120 (Pt 5): 865–916PubMedCrossRefGoogle Scholar
  31. 31.
    Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol 2008 Oct; 22 (5): 453–64PubMedCrossRefGoogle Scholar
  32. 32.
    Wu DC, Re DB, Nagai M, et al. The inflammatory NADPH oxidase enzyme modulates motor neuron degeneration in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci U S A 2006 Aug 8; 103 (32): 12132–7PubMedCrossRefGoogle Scholar
  33. 33.
    Akiyama H, Barger S, Barnum S, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging 2000 May–Jun; 21 (3): 383–421PubMedCrossRefGoogle Scholar
  34. 34.
    Owens T. The enigma of multiple sclerosis: inflammation and neurodegeneration cause heterogeneous dysfunction and damage. Curr Opin Neurol 2003 Jun; 16 (3): 259–65PubMedCrossRefGoogle Scholar
  35. 35.
    Lu JQ, Fan Y, Mitha AP, et al. Association of alpha-synuclein immunoreactivity with inflammatory activity in multiple sclerosis lesions. J Neuropathol Exp Neurol 2009 Feb; 68 (2): 179–89PubMedCrossRefGoogle Scholar
  36. 36.
    Holtzer R, Irizarry MC, Sanders J, et al. Relation of quantitative indexes of concurrent alpha-synuclein abnormalities to clinical outcome in autopsy-proven Alzheimer disease. Arch Neurol 2006 Feb; 63 (2): 226–30PubMedCrossRefGoogle Scholar
  37. 37.
    Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J 2005 Apr; 19 (6): 533–42PubMedCrossRefGoogle Scholar
  38. 38.
    Hedegaard CJ, Chen N, Sellebjerg F, et al. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP. Immunology 2009 Sep; 128 (1 Suppl.): e451–61PubMedCrossRefGoogle Scholar
  39. 39.
    Kellner A, Matschke J, Bernreuther C, et al. Autoantibodies against beta-amyloid are common in Alzheimer’s disease and help control plaque burden. Ann Neurol 2009 Jan; 65 (1): 24–31PubMedCrossRefGoogle Scholar
  40. 40.
    Couratier P, Yi FH, Preud’homme JL, et al. Serum autoantibodies to neurofilament proteins in sporadic amyotrophic lateral sclerosis. J Neurol Sci 1998 Feb 5; 154 (2): 137–45PubMedCrossRefGoogle Scholar
  41. 41.
    Papachroni KK, Ninkina N, Papapanagiotou A, et al. Autoantibodies to alpha-synuclein in inherited Parkinson’s disease. J Neurochem 2007 May; 101 (3): 749–56PubMedCrossRefGoogle Scholar
  42. 42.
    Haacke EM, Makki M, Ge Y, et al. Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging 2009 Mar; 29 (3): 537–44PubMedCrossRefGoogle Scholar
  43. 43.
    Collingwood JF, Chong RK, Kasama T, et al. Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer’s plaque core material. J Alzheimers Dis 2008 Jun; 14 (2): 235–45PubMedGoogle Scholar
  44. 44.
    Jeong SY, Rathore KI, Schulz K, et al. Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis. J Neurosci 2009 Jan 21; 29 (3): 610–9PubMedCrossRefGoogle Scholar
  45. 45.
    Bartzokis G, Lu PH, Tishler TA, et al. Myelin breakdown and iron changes in Huntington’s disease: pathogenesis and treatment implications. Neurochem Res 2007 Oct; 32 (10): 1655–64PubMedCrossRefGoogle Scholar
  46. 46.
    Wallis LI, Paley MN, Graham JM, et al. MRI assessment of basal ganglia iron deposition in Parkinson’s disease. J Magn Reson Imaging 2008 Nov; 28 (5): 1061–7PubMedCrossRefGoogle Scholar
  47. 47.
    Rasmussen S, Wang Y, Kivisakk P, et al. Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing-remitting experimental autoimmune encephalomyelitis. Brain 2007 Nov; 130 (Pt 11): 2816–29PubMedCrossRefGoogle Scholar
  48. 48.
    Streit WJ. Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev 2005 Apr; 48 (2): 234–9PubMedCrossRefGoogle Scholar
  49. 49.
    Sargsyan SA, Monk PN, Shaw PJ. Microglia as potential contributors to motor neuron injury in amyotrophic lateral sclerosis. Glia 2005 Sep; 51 (4): 241–53PubMedCrossRefGoogle Scholar
  50. 50.
    Dutta R, McDonough J, Yin X, et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol 2006 Mar; 59 (3): 478–89PubMedCrossRefGoogle Scholar
  51. 51.
    Leuner K, Pantel J, Frey C, et al. Enhanced apoptosis, oxidative stress and mitochondrial dysfunction in lymphocytes as potential biomarkers for Alzheimer’s disease. J Neural Transm Suppl 2007; 72: 207–15PubMedCrossRefGoogle Scholar
  52. 52.
    Oliveira JM, Jekabsons MB, Chen S, et al. Mitochondrial dysfunction in Huntington’s disease: the bioenergetics of isolated and in situ mitochondria from transgenic mice. J Neurochem 2007 Apr; 101 (1): 241–9PubMedCrossRefGoogle Scholar
  53. 53.
    Stack EC, Ferro JL, Kim J, et al. Therapeutic attenuation of mitochondrial dysfunction and oxidative stress in neurotoxin models of Parkinson’s disease. Biochim Biophys Acta 2008 Mar; 1782 (3): 151–62PubMedCrossRefGoogle Scholar
  54. 54.
    Anderson JM, Hampton DW, Patani R, et al. Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain 2008 Jul; 131 (Pt 7): 1736–48PubMedCrossRefGoogle Scholar
  55. 55.
    Terzi M, Birinci A, Cetinkaya E, et al. Cerebrospinal fluid total tau protein levels in patients with multiple sclerosis. Acta Neurol Scand 2007 May; 115 (5): 325–30PubMedCrossRefGoogle Scholar
  56. 56.
    Hampel H, Teipel SJ, Fuchsberger T, et al. Value of CSF beta-amyloid 1–42 and tau as predictors of Alzheimer’s disease in patients with mild cognitive impairment. Mol Psychiatry 2004 Jul; 9 (7): 705–10PubMedGoogle Scholar
  57. 57.
    Gohar M, Yang W, Strong W, et al. Tau phosphorylation at threonine-175 leads to fibril formation and enhanced cell death: implications for amyotrophic lateral sclerosis with cognitive impairment. J Neurochem 2009 Feb; 108 (3): 634–43PubMedCrossRefGoogle Scholar
  58. 58.
    Berg D, Youdim MB. Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 2006 Feb; 17 (1): 5–17PubMedCrossRefGoogle Scholar
  59. 59.
    Rego AC, Oliveira CR. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res 2003 Oct; 28 (10): 1563–74PubMedCrossRefGoogle Scholar
  60. 60.
    Venkateswaran S, Banwell B. Pediatric multiple sclerosis. Neurologist 2010 Mar; 16 (2): 92–105PubMedCrossRefGoogle Scholar
  61. 61.
    Dev KK, Hofele K, Barbieri S, et al. Part II: alpha-synuclein and its molecular pathophysiological role in neurodegenerative disease. Neuropharmacology 2003 Jul; 45 (1): 14–44PubMedCrossRefGoogle Scholar
  62. 62.
    Williams DR. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern Med J 2006 Oct; 36 (10): 652–60PubMedCrossRefGoogle Scholar
  63. 63.
    Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 2008 Sep; 4 (9): 491–8PubMedCrossRefGoogle Scholar
  64. 64.
    Neumann H, Kotter MR, Franklin RJ. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009 Feb; 132 (Pt 2): 288–95PubMedCrossRefGoogle Scholar
  65. 65.
    Bakshi R, Thompson AJ, Rocca MA, et al. MRI in multiple sclerosis: current status and future prospects. Lancet Neurol 2008 Jul; 7 (7): 615–25PubMedCrossRefGoogle Scholar
  66. 66.
    Schuff N, Woerner N, Boreta L, et al. MRI of hippocampal volume loss in early Alzheimer’s disease in relation to ApoE genotype and biomarkers. Brain 2009 Apr; 132 (Pt 4): 1067–77PubMedCrossRefGoogle Scholar
  67. 67.
    Fisher E, Rudick RA, Simon JH, et al. Eight-year follow-up study of brain atrophy in patients with MS. Neurology 2002 Nov 12; 59 (9): 1412–20PubMedCrossRefGoogle Scholar
  68. 68.
    Khan O. Can clinical outcomes be used to detect neuroprotection in multiple sclerosis? Neurology 2007 May 29; 68 (22 Suppl. 3): S64–71; discussion S91–6PubMedCrossRefGoogle Scholar
  69. 69.
    Daumer M, Neuhaus A, Morrissey S, et al. MRI as an outcome in multiple sclerosis clinical trials. Neurology 2009 Feb 24; 72 (8): 705–11PubMedCrossRefGoogle Scholar
  70. 70.
    Sormani MP, Bonzano L, Roccatagliata L, et al. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol 2009 Mar; 65 (3): 268–75PubMedCrossRefGoogle Scholar
  71. 71.
    Laule C, Kozlowski P, Leung E, et al. Myelin water imaging of multiple sclerosis at 7 T: correlations with histopathology. Neuroimage 2008 May 1; 40 (4): 1575–80PubMedCrossRefGoogle Scholar
  72. 72.
    Chen JT, Collins DL, Atkins HL, et al. Magnetization transfer ratio evolution with demyelination and remyelination in multiple sclerosis lesions. Ann Neurol 2008 Feb; 63 (2): 254–62PubMedCrossRefGoogle Scholar
  73. 73.
    Geurts JJ, Barkhof F. Grey matter pathology in multiple sclerosis. Lancet Neurol 2008 Sep; 7 (9): 841–51PubMedCrossRefGoogle Scholar
  74. 74.
    Kutzelnigg A, Lassmann H. Cortical demyelination in multiple sclerosis: a substrate for cognitive deficits? J Neurol Sci 2006 Jun 15; 245 (1–2): 123–6PubMedCrossRefGoogle Scholar
  75. 75.
    Simmons A, Westman E, Muehlboeck S, et al. MRI measures of Alzheimer’s disease and the AddNeuroMed study. Ann N Y Acad Sci 2009 Oct; 1180: 47–55PubMedCrossRefGoogle Scholar
  76. 76.
    Beyer MK, Janvin CC, Larsen JP, et al. A magnetic resonance imaging study of patients with Parkinson’s disease with mild cognitive impairment and dementia using voxel-based morphometry. J Neurol Neurosurg Psychiatry 2007 Mar; 78 (3): 254–9PubMedCrossRefGoogle Scholar
  77. 77.
    Reetz K, Gaser C, Klein C, et al. Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson’s disease. Mov Disord 2009 Jan 15; 24 (1): 99–103PubMedCrossRefGoogle Scholar
  78. 78.
    Agosta F, Rocca MA, Valsasina P, et al. A longitudinal diffusion tensor MRI study of the cervical cord and brain in amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry 2009 Jan; 80 (1): 53–5PubMedCrossRefGoogle Scholar
  79. 79.
    Grosskreutz J, Peschel T, Unrath A, et al. Whole brain-based computerized neuroimaging in ALS and other motor neuron disorders. Amyotroph Lateral Scler 2008 Aug; 9 (4): 238–48PubMedCrossRefGoogle Scholar
  80. 80.
    Ginestroni A, Battaglini M, Della Nave R, et al. Early structural changes in individuals at risk of familial Alzheimer’s disease: a volumetry and magnetization transfer MR imaging study. J Neurol 2009 Jun; 256 (6): 925–32PubMedCrossRefGoogle Scholar
  81. 81.
    Kiefer C, Brockhaus L, Cattapan-Ludewig K, et al. Multiparametric classification of Alzheimer’s disease and mild cognitive impairment: the impact of quantitative magnetization transfer MR imaging. Neuroimage 2009 Dec; 48 (4): 657–67PubMedCrossRefGoogle Scholar
  82. 82.
    Ridha BH, Tozer DJ, Symms MR, et al. Quantitative magnetization transfer imaging in Alzheimer disease. Radiology 2007 Sep; 244 (3): 832–7PubMedCrossRefGoogle Scholar
  83. 83.
    van Es AC, van der Flier WM, Admiraal-Behloul F, et al. Lobar distribution of changes in gray matter and white matter in memory clinic patients: detected using magnetization transfer imaging. Am J Neuroradiol 2007 Nov–Dec; 28 (10): 1938–42PubMedCrossRefGoogle Scholar
  84. 84.
    Anik Y, Iseri P, Demirci A, et al. Magnetization transfer ratio in early period of Parkinson disease. Acad Radiol 2007 Feb; 14 (2): 189–92PubMedCrossRefGoogle Scholar
  85. 85.
    Eckert T, Sailer M, Kaufmann J, et al. Differentiation of idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, and healthy controls using magnetization transfer imaging. Neuroimage 2004 Jan; 21 (1): 229–35PubMedCrossRefGoogle Scholar
  86. 86.
    Tambasco N, Pelliccioli GP, Chiarini P, et al. Magnetization transfer changes of grey and white matter in Parkinson’s disease. Neuroradiology 2003 Apr; 45 (4): 224–30PubMedGoogle Scholar
  87. 87.
    Andjus PR, Bataveljic D, Vanhoutte G, et al. In vivo morphological changes in animal models of amyotrophic lateral sclerosis and Alzheimer’s-like disease: MRI approach. Anat Rec (Hoboken) 2009 Dec; 292 (12): 1882–92CrossRefGoogle Scholar
  88. 88.
    Santillo AF, Skoglund L, Lindau M, et al. Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation. Alzheimer Dis Assoc Disord 2009 Jul–Sep; 23 (3): 298–300PubMedCrossRefGoogle Scholar
  89. 89.
    Frohman EM, Fujimoto JG, Frohman TC, et al. Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat Clin Pract Neurol 2008 Dec; 4 (12): 664–75PubMedCrossRefGoogle Scholar
  90. 90.
    Costello F, Hodge W, Pan YI, et al. Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography. Mult Scler 2008 Aug; 14 (7): 893–905PubMedCrossRefGoogle Scholar
  91. 91.
    Inglese M, Mancardi GL, Pagani E, et al. Brain tissue loss occurs after suppression of enhancement in patients with multiple sclerosis treated with autologous haematopoietic stem cell transplantation. J Neurol Neurosurg Psychiatry 2004 Apr; 75 (4): 643–4PubMedGoogle Scholar
  92. 92.
    Boutros T, Croze E, Yong VW. Interferon-beta is a potent promoter of nerve growth factor production by astrocytes. J Neurochem 1997 Sep; 69 (3): 939–46PubMedCrossRefGoogle Scholar
  93. 93.
    Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010 Jul; 9 (7): 681–8PubMedCrossRefGoogle Scholar
  94. 94.
    Barkhof F, Hulst HE, Drulovic J, et al. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology 2010 Mar 30; 74 (13): 1033–40PubMedCrossRefGoogle Scholar
  95. 95.
    Antel JP, Miron VE. Central nervous system effects of current and emerging multiple sclerosis-directed immuno-therapies. Clin Neurol Neurosurg 2008 Nov; 110 (9): 951–7PubMedCrossRefGoogle Scholar
  96. 96.
    Weber MS, Hohlfeld R, Zamvil SS. Mechanism of action of glatiramer acetate in treatment of multiple sclerosis. Neurotherapeutics 2007 Oct; 4 (4): 647–53PubMedCrossRefGoogle Scholar
  97. 97.
    Iarlori C, Gambi D, Lugaresi A, et al. Reduction of free radicals in multiple sclerosis: effect of glatiramer acetate (Copaxone). Mult Scler 2008 Jul; 14 (6): 739–48PubMedCrossRefGoogle Scholar
  98. 98.
    Wolinsky JS, Narayana PA, O’Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007 Jan; 61 (1): 14–24PubMedCrossRefGoogle Scholar
  99. 99.
    Sajja BR, Narayana PA, Wolinsky JS, et al. Longitudinal magnetic resonance spectroscopic imaging of primary progressive multiple sclerosis patients treated with glatiramer acetate: multicenter study. Mult Scler 2008 Jan; 14 (1): 73–80PubMedCrossRefGoogle Scholar
  100. 100.
    La Mantia L, Munari LM, Lovati R. Glatiramer acetate for multiple sclerosis. Cochrane Database Syst Rev 2010; 5: CD004678PubMedGoogle Scholar
  101. 101.
    Gordon PH, Doorish C, Montes J, et al. Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology 2006 Apr 11; 66 (7): 1117–9PubMedCrossRefGoogle Scholar
  102. 102.
    Meininger V, Drory VE, Leigh PN, et al. Glatiramer acetate has no impact on disease progression in ALS at 40mg/day: a double-blind, randomized, multicentre, placebo-controlled trial. Amyotroph Lateral Scler 2009 Oct-Dec; 10 (5–6): 378–83PubMedCrossRefGoogle Scholar
  103. 103.
    Laurie C, Reynolds A, Coskun O, et al. CD4+ T cells from Copolymer-1 immunized mice protect dopaminergic neurons in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neuroimmunol 2007 Feb; 183 (1–2): 60–8PubMedCrossRefGoogle Scholar
  104. 104.
    Frenkel D, Maron R, Burt DS, et al. Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest 2005 Sep; 115 (9): 2423–33PubMedCrossRefGoogle Scholar
  105. 105.
    Butovsky O, Koronyo-Hamaoui M, Kunis G, et al. Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 2006 Aug 1; 103 (31): 11784–9PubMedCrossRefGoogle Scholar
  106. 106.
    Correale J, Villa A. The blood-brain-barrier in multiple sclerosis: functional roles and therapeutic targeting. Autoimmunity 2007 Mar; 40 (2): 148–60PubMedCrossRefGoogle Scholar
  107. 107.
    Veldhuis WB, Derksen JW, Floris S, et al. Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat. J Cereb Blood Flow Metab 2003 Sep; 23 (9): 1029–39PubMedCrossRefGoogle Scholar
  108. 108.
    Biernacki K, Antel JP, Blain M, et al. Interferon beta promotes nerve growth factor secretion early in the course of multiple sclerosis. Arch Neurol 2005 Apr; 62 (4): 563–8PubMedCrossRefGoogle Scholar
  109. 109.
    Leary SM, Miller DH, Stevenson VL, et al. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003 Jan 14; 60 (1): 44–51PubMedCrossRefGoogle Scholar
  110. 110.
    Montalban X, Sastre-Garriga J, Tintore M, et al. A single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis. Mult Scler 2009 Oct; 15 (10): 1195–205PubMedCrossRefGoogle Scholar
  111. 111.
    Rojas JI, Romano M, Ciapponi A, et al. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev 2010; (1): CD006643Google Scholar
  112. 112.
    Andersen O, Elovaara I, Farkkila M, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004 May; 75 (5): 706–10PubMedCrossRefGoogle Scholar
  113. 113.
    Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002 Sep 10; 59 (5): 679–87PubMedCrossRefGoogle Scholar
  114. 114.
    Kappos L, Polman C, Pozzilli C, et al. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology 2001 Dec 11; 57 (11): 1969–75PubMedCrossRefGoogle Scholar
  115. 115.
    Panitch H, Miller A, Paty D, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004 Nov 23; 63 (10): 1788–95PubMedCrossRefGoogle Scholar
  116. 116.
    Beghi E, Chio A, Inghilleri M, et al. A randomized controlled trial of recombinant interferon beta-1a in ALS: Italian Amyotrophic Lateral Sclerosis Study Group. Neurology 2000 Jan 25; 54 (2): 469–74PubMedCrossRefGoogle Scholar

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Authors and Affiliations

  • Amit Bar-Or
    • 1
  • Peter Rieckmann
    • 2
    Email author
  • Anthony Traboulsee
    • 3
  • V. Wee Yong
    • 4
  1. 1.Department of Neurology and Neurosurgery and Microbiology and ImmunologyMcGill University, Neuroimmunology UnitMontrealCanada
  2. 2.Multiple Sclerosis Society of Canada Research Chair, Division of Neurology, Brain Research CenterUniversity of British ColumbiaVancouverCanada
  3. 3.Multiple Sclerosis/Magnetic Resonance Imaging Research GroupUniversity of British ColumbiaVancouverCanada
  4. 4.Hotchkiss Brain Institute and the Department of Clinical NeurosciencesUniversity of CalgaryCanada

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