Advertisement

Molecular Diagnosis & Therapy

, Volume 13, Issue 2, pp 115–125 | Cite as

Biomarkers in Amyotrophic Lateral Sclerosis

Facts and Future Horizons
  • Pierre-François PradatEmail author
  • Michel Dib
Neurodegenerative Disorders

Abstract

The only specific marker of sporadic amyotrophic lateral sclerosis (ALS) is neuropathologic, namely the presence of inclusions staining positively for ubiquitin and TAR DNA-binding protein (TARDBP, also known as TDP-43) in degenerating motor neurons. Abnormalities in various physiopathologic pathways associated with ALS, such as oxidative stress, inflammation, and excitotoxicity, have been reported in blood, cerebrospinal fluid, and muscle biopsies. A number of studies in ALS patients have indicated that nuclear magnetic resonance (NMR) spectroscopy and diffusion tensor magnetic resonance imaging (MRI) can detect corticospinal lesions. However, because of their relative lack of sensitivity and specificity, these techniques are currently inadequate for use as diagnostic tools in individual patients. Recently, there has been much interest in the use of high-throughput techniques such as transcriptomics, proteomics, and metabolomics for the detection of biomarkers. In the future, a combination of biologic, radiologic, and electrophysiologic markers, rather than a single marker, may prove a useful tool for the diagnosis and follow-up of ALS patients. This article provides an overview of recently described biologic and radiologic markers of the disease.

Keywords

Amyotrophic Lateral Sclerosis Motor Neuron Fractional Anisotropy Diffusion Tensor Imaging Spinal Muscular Atrophy 
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.

Notes

Acknowledgments

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    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: 293–9PubMedCrossRefGoogle Scholar
  2. 2.
    Pradat PF, Bruneteau G. Quels sont les critères cliniques de la sclérose latérale amyotrophique en fonction des formes cliniques? Rev Neurol (Paris) 2006; 162(2): 4S29–33Google Scholar
  3. 3.
    Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med 2001; 344: 1688–700PubMedCrossRefGoogle Scholar
  4. 4.
    Swash M. Clinical features and diagnosis of amyotrophic lateral sclerosis. In: Brown Jr RH, Meininger V, Swash M, editors. Amyotrophic lateral sclerosis. London: Martin Dunitz, 2000: 3–30Google Scholar
  5. 5.
    Forman MS, Trojanowski JQ, Lee VM. TDP-43: a novel neurodegenerative proteinopathy. Curr Opin Neurobiol 2007; 17: 548–55PubMedCrossRefGoogle Scholar
  6. 6.
    Pradat PF, Bruneteau G. Quels sont les signes cliniques, classiques et inhabituels, devant faire évoquer une sclérose latérale amyotrophique? Rev Neurol (Paris) 2006; 162(2): 4S17–24Google Scholar
  7. 7.
    de Carvalho M, Dengler R, Eisen A, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008; 119: 497–503PubMedCrossRefGoogle Scholar
  8. 8.
    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: 427–34PubMedCrossRefGoogle Scholar
  9. 9.
    Shankar SK, Yanagihara R, Garruto RM, et al. Immunocytochemical characterization of neurofibrillary tangles in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Ann Neurol 1989; 25: 146–51PubMedCrossRefGoogle Scholar
  10. 10.
    Traynor BJ, Codd MB, Corr B, et al. Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch Neurol 2000; 57: 109–13PubMedCrossRefGoogle Scholar
  11. 11.
    Beghi E, Millul A, Micheli A, et al. Incidence of ALS in Lombardy, Italy. Neurology 2007; 68: 141–5PubMedCrossRefGoogle Scholar
  12. 12.
    Beghi E, Mennini T, Bendotti C, et al. The heterogeneity of amyotrophic lateral sclerosis: a possible explanation of treatment failure. Curr Med Chem 2007; 14: 3185–200PubMedCrossRefGoogle Scholar
  13. 13.
    Logroscino G, Traynor BJ, Hardiman O, et al. Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues. J Neurol Neurosurg Psychiatry 2008; 79: 6–11PubMedCrossRefGoogle Scholar
  14. 14.
    Iwasaki Y, Ikeda K, Ichikawa Y, et al. The diagnostic interval in amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2002; 104: 87–9PubMedCrossRefGoogle Scholar
  15. 15.
    Zoccolella S, Beghi E, Palagano G, et al. Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients: a population-based study. J Neurol Sci 2006; 250: 45–9PubMedCrossRefGoogle Scholar
  16. 16.
    Chio A, Mora G, Leone M, et al. Early symptom progression rate is related to ALS outcome: a prospective population-based study. Neurology 2002; 59: 99–103PubMedCrossRefGoogle Scholar
  17. 17.
    Traynor BJ, Codd MB, Corr B, et al. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol 2000; 57: 1171–6PubMedCrossRefGoogle Scholar
  18. 18.
    Riviere M, Meininger V, Zeisser P, et al. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol 1998; 55: 526–8PubMedCrossRefGoogle Scholar
  19. 19.
    Paillisse C, Lacomblez L, Dib M, et al. Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole. Amyotroph Lateral Scler Other Motor Neuron Disord 2005; 6: 37–44PubMedCrossRefGoogle Scholar
  20. 20.
    Kunst CB. Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 2004; 75: 933–47PubMedCrossRefGoogle Scholar
  21. 21.
    Camu W. Sclerose latérale amyotrophique: des formes monogéniques aux formes multigéniques. Neurologies 2003; 6: 517–20Google Scholar
  22. 22.
    Kabashi E, Valdmanis PN, Dion P, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008; 40: 572–4PubMedCrossRefGoogle Scholar
  23. 23.
    Kwiatkowski Jr TJ, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009; 323: 1205–8PubMedCrossRefGoogle Scholar
  24. 24.
    Vance C, Rogelj B, Hortobagyi T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 2009; 323: 1208–11PubMedCrossRefGoogle Scholar
  25. 25.
    Schymick JC, Talbot K, Traynor BJ. Genetics of sporadic amyotrophic lateral sclerosis. Hum Mol Genet 2007; 16(2): R233–42PubMedCrossRefGoogle Scholar
  26. 26.
    Simpson EP, Henry YK, Henkel JS, et al. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden. Neurology 2004; 62: 1758–65PubMedCrossRefGoogle Scholar
  27. 27.
    Ilzecka J, Stelmasiak Z, Dobosz B. Transforming growth factor-beta 1 (tgf-beta 1) in patients with amyotrophic lateral sclerosis. Cytokine 2002; 20: 239–43PubMedCrossRefGoogle Scholar
  28. 28.
    Spreux-Varoquaux O, Bensimon G, Lacomblez L, et al. Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci 2002; 193: 73–8PubMedCrossRefGoogle Scholar
  29. 29.
    Baron P, Bussini S, Cardin V, et al. Production of monocyte chemoattractant protein-1 in amyotrophic lateral sclerosis. Muscle Nerve 2005; 32: 541–4PubMedCrossRefGoogle Scholar
  30. 30.
    Kuzma M, Jamrozik Z, Baranczyk-Kuzma A. Activity and expression of glutathione S-transferase pi in patients with amyotrophic lateral sclerosis. Clin Chim Acta 2006; 364: 217–21PubMedCrossRefGoogle Scholar
  31. 31.
    Ihara Y, Nobukuni K, Takata H, et al. Oxidative stress and metal content in blood and cerebrospinal fluid of amyotrophic lateral sclerosis patients with and without a Cu, Zn-superoxide dismutase mutation. Neurol Res 2005; 27: 105–8PubMedCrossRefGoogle Scholar
  32. 32.
    Sohmiya M, Tanaka M, Suzuki Y, et al. An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients. J Neurol Sci 2005; 228: 49–53PubMedCrossRefGoogle Scholar
  33. 33.
    Ferri A, Nencini M, Battistini S, et al. Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosis patients. J Neurochem 2004; 90: 1237–42PubMedCrossRefGoogle Scholar
  34. 34.
    Ilzecka J, Stelmasiak Z. Serum bilirubin concentration in patients with amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2003; 105: 237–40PubMedCrossRefGoogle Scholar
  35. 35.
    Nygren I, Larsson A, Johansson A, et al. VEGF is increased in serum but not in spinal cord from patients with amyotrophic lateral sclerosis. Neuroreport 2002; 13: 2199–201PubMedCrossRefGoogle Scholar
  36. 36.
    Houi K, Kobayashi T, Kato S, et al. Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2002; 106: 299–301PubMedCrossRefGoogle Scholar
  37. 37.
    Ilzecka J. Decreased serum endoglin level in patients with amyotrophic lateral sclerosis: a preliminary report. Scand J Clin Lab Invest 2008; 68: 348–51PubMedCrossRefGoogle Scholar
  38. 38.
    Ilzecka J. Increased serum CNTF level in patients with amyotrophic lateral sclerosis. Eur Cytokine Netw 2003; 14: 192–4PubMedGoogle Scholar
  39. 39.
    Ilzecka J. Decreased serum-soluble TRAIL levels in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2008; 117: 343–6PubMedCrossRefGoogle Scholar
  40. 40.
    Ilzecka J. Prostaglandin E2 is increased in amyotrophic lateral sclerosis patients. Acta Neurol Scand 2003; 108: 125–9PubMedCrossRefGoogle Scholar
  41. 41.
    Demestre M, Parkin-Smith G, Petzold A, et al. The pro and the active form of matrix metalloproteinase-9 is increased in serum of patients with amyotrophic lateral sclerosis. J Neuroimmunol 2005; 159: 146–54PubMedCrossRefGoogle Scholar
  42. 42.
    Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008; 70: 1004–9PubMedCrossRefGoogle Scholar
  43. 43.
    Steele AJ, al Chalabi A, Ferrante K, et al. Detection of serum reverse transcriptase activity in patients with ALS and unaffected blood relatives. Neurology 2005; 64: 454–8PubMedCrossRefGoogle Scholar
  44. 44.
    Lacomblez L, Doppler V, Beucler I, et al. APOE: a potential marker of disease progression in ALS. Neurology 2002; 58: 1112–4PubMedCrossRefGoogle Scholar
  45. 45.
    Boll MC, Alcaraz-Zubeldia M, Montes S, et al. Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients. Neurochem Res 2003; 28: 699–703PubMedCrossRefGoogle Scholar
  46. 46.
    Kaufmann E, Boehm BO, Sussmuth SD, et al. The advanced glycation end-product N epsilon-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Neurosci Lett 2004; 371: 226–9PubMedCrossRefGoogle Scholar
  47. 47.
    Kuncl RW, Bilak MM, Bilak SR, et al. Pigment epithelium-derived factor is elevated in CSF of patients with amyotrophic lateral sclerosis. J Neurochem 2002; 81: 178–84PubMedCrossRefGoogle Scholar
  48. 48.
    Devos D, Moreau C, Lassalle P, et al. Low levels of the vascular endothelial growth factor in CSF from early ALS patients. Neurology 2004; 62: 2127–9PubMedCrossRefGoogle Scholar
  49. 49.
    Ilzecka J. Cerebrospinal fluid vascular endothelial growth factor in patients with amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2004; 106: 289–93PubMedCrossRefGoogle Scholar
  50. 50.
    Ilzecka J. Cerebrospinal fluid Flt3 ligand level in patients with amyotrophic lateral sclerosis. Acta Neurol Scand 2006; 114: 205–9PubMedCrossRefGoogle Scholar
  51. 51.
    Tanaka M, Kikuchi H, Ishizu T, et al. Intrathecal upregulation of granulocyte colony stimulating factor and its neuroprotective actions on motor neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2006; 65: 816–25PubMedCrossRefGoogle Scholar
  52. 52.
    Ilecka J. Decreased cerebrospinal fluid cGMP levels in patients with amyotrophic lateral sclerosis. J Neural Transm 2004; 111: 167–72PubMedCrossRefGoogle Scholar
  53. 53.
    Fischer LR, Culver DG, Tennant P, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 2004; 185: 232–40PubMedCrossRefGoogle Scholar
  54. 54.
    Jokic N, Gonzalez de Aguilar JL, Dimou L, et al. The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep 2006; 7: 1162–7PubMedCrossRefGoogle Scholar
  55. 55.
    Rouaux C, Panteleeva I, Rene F, et al. Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci 2007; 27: 5535–45PubMedCrossRefGoogle Scholar
  56. 56.
    Dupuis L, Gonzalez de Aguilar JL, Di Scala F, et al. Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol Dis 2002; 10: 358–65PubMedCrossRefGoogle Scholar
  57. 57.
    Pradat PF, Bruneteau G, Gonzalez de Aguilar JL, et al. Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes. Ann Neurol 2007; 62: 15–20PubMedCrossRefGoogle Scholar
  58. 58.
    Jokic N, Gonzalez de Aguilar JL, Pradat PF, et al. Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Ann Neurol 2005; 57: 553–6PubMedCrossRefGoogle Scholar
  59. 59.
    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; 169: 13–21PubMedCrossRefGoogle Scholar
  60. 60.
    Wojcik S, Engel WK, Askanas V. Increased expression of Noga-A in ALS muscle biopsies is not unique for this disease. Acta Myol 2006; 25: 116–8PubMedGoogle Scholar
  61. 61.
    Wojcik S, Engel WK, Yan R, et al. NOGO is increased and binds to BACE1 in sporadic inclusion-body myositis and in AbetaPP-overexpressing cultured human muscle fibers. Acta Neuropathol 2007; 114: 517–26PubMedCrossRefGoogle Scholar
  62. 62.
    Pradat PF, Gonzalez de Aguilar JL, Bruneteau G, et al. Specificity for amyotrophic lateral sclerosis of Nogo-A muscle expression [author reply]. Ann Neurol 2008; 62: 676–7Google Scholar
  63. 63.
    Pasinetti GM, Ungar LH, Lange DJ, et al. Identification of potential CSF biomarkers in ALS. Neurology 2006; 66: 1218–22PubMedCrossRefGoogle Scholar
  64. 64.
    Gonzalez de Aguilar JL, Niederhauser-Wiederkehr C, Halter B, et al. Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol Genomics 2008; 32: 207–18PubMedGoogle Scholar
  65. 65.
    Pradat PF, Bruneteau G. Quels sont les diagnostics différentiels et les formes frontières de SLA? Rev Neurol (Paris) 2006; 162(2): 4S81–90Google Scholar
  66. 66.
    Oba H, Araki T, Ohtomo K, et al. Amyotrophic lateral sclerosis: T2 shortening in motor cortex at MR imaging. Radiology 1993; 189: 843–6PubMedGoogle Scholar
  67. 67.
    Cheung G, Gawel MJ, Cooper PW, et al. Amyotrophic lateral sclerosis: correlation of clinical and MR imaging findings. Radiology 1995; 194: 263–70PubMedGoogle Scholar
  68. 68.
    Comi G, Rovaris M, Leocani L. Review neuroimaging in amyotrophic lateral sclerosis. Eur J Neurol 1999; 6: 629–37PubMedCrossRefGoogle Scholar
  69. 69.
    Ellis CM, Simmons A, Jones DK, et al. Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology 1999; 53: 1051–8PubMedCrossRefGoogle Scholar
  70. 70.
    Goodin DS, Rowley HA, Olney RK. Magnetic resonance imaging in amyotrophic lateral sclerosis. Ann Neurol 1988; 23: 418–20PubMedCrossRefGoogle Scholar
  71. 71.
    Hecht MJ, Fellner F, Fellner C, et al. MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1-and proton-density-weighted images. J Neurol Sci 2001; 186: 37–44PubMedCrossRefGoogle Scholar
  72. 72.
    Hofmann E, Ochs G, Pelzl A, et al. The corticospinal tract in amyotrophic lateral sclerosis: an MRI study. Neuroradiology 1998; 40: 71–5PubMedCrossRefGoogle Scholar
  73. 73.
    Kato Y, Matsumura K, Kinosada Y, et al. Detection of pyramidal tract lesions in amyotrophic lateral sclerosis with magnetization-transfer measurements. AJNR Am J Neuroradiol 1997; 18: 1541–7PubMedGoogle Scholar
  74. 74.
    Mirowitz S, Sartor K, Gado M, et al. Focal signal-intensity variations in the posterior internal capsule: normal MR findings and distinction from pathologic findings. Radiology 1989; 172: 535–9PubMedGoogle Scholar
  75. 75.
    Tanabe JL, Vermathen M, Miller R, et al. Reduced MTR in the corticospinal tract and normal T2 in amyotrophic lateral sclerosis. Magn Reson Imaging 1998; 16: 1163–9PubMedCrossRefGoogle Scholar
  76. 76.
    Thorpe JW, Moseley IF, Hawkes CH, et al. Brain and spinal cord MRI in motor neuron disease. J Neurol Neurosurg Psychiatry 1996; 61: 314–7PubMedCrossRefGoogle Scholar
  77. 77.
    Waragai M. MRI and clinical features in amyotrophic lateral sclerosis. Neuroradiology 1997; 39: 847–51PubMedCrossRefGoogle Scholar
  78. 78.
    Graham JM, Papadakis N, Evans J, et al. Diffusion tensor imaging for the assessment of upper motor neuron integrity in ALS. Neurology 2004; 63: 2111–9PubMedCrossRefGoogle Scholar
  79. 79.
    Winhammar JM, Rowe DB, Henderson RD, et al. Assessment of disease progression in motor neuron disease. Lancet Neurol2005; 4: 229–38PubMedCrossRefGoogle Scholar
  80. 80.
    Valsasina P, Agosta F, Benedetti B, et al. Diffusion anisotropy of the cervical cord is strictly associated with disability in ALS. J Neurol Neurosurg Psychiatry 2006; 78: 480–4PubMedCrossRefGoogle Scholar
  81. 81.
    Pohl C, Block W, Karitzky J, et al. Proton magnetic resonance spectroscopy of the motor cortex in 70 patients with amyotrophic lateral sclerosis. Arch Neurol 2001; 58: 729–35PubMedCrossRefGoogle Scholar
  82. 82.
    Sarchielli P, Pelliccioli GP, Tarducci R, et al. Magnetic resonance imaging and 1H-magnetic resonance spectroscopy in amyotrophic lateral sclerosis. Neuroradiology 2001; 43: 189–97PubMedCrossRefGoogle Scholar
  83. 83.
    Suhy J, Miller RG, Rule R, et al. Early detection and longitudinal changes in amyotrophic lateral sclerosis by (1)H MRSI. Neurology 2002; 58: 773–9PubMedCrossRefGoogle Scholar
  84. 84.
    Gredal O, Rosenbaum S, Topp S, et al. Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy. Neurology 1997; 48: 878–81PubMedCrossRefGoogle Scholar
  85. 85.
    Pioro EP, Antel JP, Cashman NR, et al. Detection of cortical neuron loss in motor neuron disease by proton magnetic resonance spectroscopic imaging in vivo. Neurology 1994; 44: 1933–8PubMedCrossRefGoogle Scholar
  86. 86.
    Kalra S, Hanstock CC, Martin WR, et al. Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy. Arch Neurol 2006; 63: 1144–8PubMedCrossRefGoogle Scholar
  87. 87.
    Sach M, Winkler G, Glauche V, et al. Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis. Brain 2004; 127: 340–50PubMedCrossRefGoogle Scholar
  88. 88.
    Sage CA, Peeters RR, Gorner A, et al. Quantitative diffusion tensor imaging in amyotrophic lateral sclerosis. Neuroimage 2007; 34: 486–99PubMedCrossRefGoogle Scholar
  89. 89.
    Thivard L, Pradat PF, Lehericy S, et al. Diffusion tensor imaging and voxel based morphometry study in amyotrophic lateral sclerosis: relationships with motor disability. J Neurol Neurosurg Psychiatry 2007; 78: 889–92PubMedCrossRefGoogle Scholar
  90. 90.
    Mitsumoto H, Ulug AM, Pullman SL, et al. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology 2007; 68: 1402–10PubMedCrossRefGoogle Scholar
  91. 91.
    Wong JC, Concha L, Beaulieu C, et al. Spatial profiling of the corticospinal tract in amyotrophic lateral sclerosis using diffusion tensor imaging. J Neuroimaging 2007; 17: 234–40PubMedCrossRefGoogle Scholar
  92. 92.
    Schimrigk SK, Bellenberg B, Schluter M, et al. Diffusion tensor imaging-based fractional anisotropy quantification in the corticospinal tract of patients with amyotrophic lateral sclerosis using a probabilistic mixture model. AJNR Am J Neuroradiol 2007; 28: 724–30PubMedGoogle Scholar
  93. 93.
    Blain CRV, Williams VC, Johnston C, et al. A longitudinal study of diffusion tensor MRI in ALS. Amyotroph Lateral Scler 2007; 8: 348–55PubMedCrossRefGoogle Scholar
  94. 94.
    Abe O, Yamada H, Masutani Y, et al. Amyotrophic lateral sclerosis: diffusion tensor tractography and voxel-based analysis. NMR Biomed 2004; 17: 411–6PubMedCrossRefGoogle Scholar
  95. 95.
    Ciccarelli O, Behrens TE, Altmann DR, et al. Probabilistic diffusion tractography: a potential tool to assess the rate of disease progression in amyotrophic lateral sclerosis. Brain 2006; 129: 1859–71PubMedCrossRefGoogle Scholar
  96. 96.
    Grosskreutz J, Kaufmann J, Fradrich J, et al. Widespread sensorimotor and frontal cortical atrophy in amyotrophic lateral sclerosis. BMC Neurol 2006; 6: 17PubMedCrossRefGoogle Scholar
  97. 97.
    Waragai M, Takaya Y, Hayashi M. Serial MRI and SPECT in amyotrophic lateral sclerosis: a case report. J Neurol Sci 1997; 148: 117–20PubMedCrossRefGoogle Scholar
  98. 98.
    Waldemar G, Vorstrup S, Jensen TS, et al. Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d,l-HMPAO SPECT study. J Neurol Sci 1992; 107: 19–28PubMedCrossRefGoogle Scholar
  99. 99.
    Abe K, Yorifuji S, Nishikawa Y. Reduced isotope uptake restricted to the motor area in patients with amyotrophic lateral sclerosis. Neuroradiology 1993; 35: 410–1PubMedCrossRefGoogle Scholar
  100. 100.
    Kalra S, Arnold D. Neuroimaging in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 243–8PubMedCrossRefGoogle Scholar
  101. 101.
    Habert MO, Lacomblez L, Maksud P, et al. Brain perfusion imaging in amyotrophic lateral sclerosis: extent of cortical changes according to the severity and topography of motor impairment. Amyotroph Lateral Scler 2007; 8: 9–15PubMedCrossRefGoogle Scholar
  102. 102.
    Hoffman JM, Mazziotta JC, Hawk TC, et al. Cerebral glucose utilization in motor neuron disease. Arch Neurol 1992; 49: 849–54PubMedCrossRefGoogle Scholar
  103. 103.
    Hatazawa J, Brooks RA, Dalakas MC, et al. Cortical motor-sensory hypometabolism in amyotrophic lateral sclerosis: a PET study. J Comput Assist Tomogr 1988; 12: 630–6PubMedCrossRefGoogle Scholar
  104. 104.
    Turner MR, Rabiner EA, Hammers A, et al. [11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. Brain 2005; 128: 896–905PubMedCrossRefGoogle Scholar
  105. 105.
    Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis 2004; 15: 601–9PubMedCrossRefGoogle Scholar
  106. 106.
    Kew JJ, Leigh PN, Playford ED, et al. Cortical function in amyotrophic lateral sclerosis: a positron emission tomography study. Brain 1993; 116 (Pt 3): 655–80PubMedCrossRefGoogle Scholar
  107. 107.
    Konrad C, Henningsen H, Bremer J, et al. Pattern of cortical reorganization in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study. Exp Brain Res 2002; 143: 51–6PubMedCrossRefGoogle Scholar
  108. 108.
    Unrath A, Ludolph AC, Kassubek J. Brain metabolites in definite amyotrophic lateral sclerosis: a longitudinal proton magnetic resonance spectroscopy study. J Neurol 2007; 254: 1099–106PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Fédération des Maladies du Système NerveuxCentre Référent Maladie Rare SLA, Hôpital de la Pitié-SalpêtrièreParisFrance

Personalised recommendations