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. 2005 Sep;76(9):1279–1285. doi: 10.1136/jnnp.2004.054429

Abnormal cortical excitability in sporadic but not homozygous D90A SOD1 ALS

M Turner 1, A Osei-Lah 1, A Hammers 1, A Al-Chalabi 1, C Shaw 1, P Andersen 1, D Brooks 1, P Leigh 1, K Mills 1
PMCID: PMC1739803  PMID: 16107368

Abstract

Background: Excitotoxicity is one pathogenic mechanism proposed in amyotrophic lateral sclerosis (ALS), and loss of cortical inhibitory influence may be contributory. Patients with ALS who are homozygous for the D90A superoxide dismutase-1 (SOD1) gene mutation (homD90A) have a unique phenotype, associated with prolonged survival compared with patients with sporadic ALS (sALS). In this study, transcranial magnetic stimulation (TMS) was used to explore cortical excitation and inhibition. Flumazenil binds to the benzodiazepine subunit of the GABAA receptor, and 11C-flumazenil positron emission tomography (PET) was used as a marker of cortical neuronal loss and/or dysfunction, which might in turn reflect changes in cortical inhibitory GABAergic mechanisms.

Methods: Cortical responses to single and paired stimulus TMS were compared in 28 patients with sALS and 11 homD90A patients versus 24 controls. TMS measures included resting motor threshold, central motor conduction time, silent period, intracortical inhibition (ICI), and facilitation. 11C-flumazenil PET of the brain was performed on 20 patients with sALS and nine with homD90A. Statistical parametric mapping was used to directly compare PET images from the two patient groups to identify those areas of relatively reduced cortical 11C-flumazenil binding that might explain differences in cortical excitability seen using TMS.

Results: Increased cortical excitability, demonstrated by reduction in ICI, was seen in the patients with sALS but not the homD90A patients. A relative reduction in cortical 11C-flumazenil binding was found in the motor and motor association regions of the superior parietal cortices of the patients with sALS.

Conclusions: A cortical inhibitory deficit in sALS was not demonstrable in a homogeneous genetic ALS population of similar disability, suggesting a distinct cortical vulnerability. 11C-flumazenil PET demonstrated that neuronal loss/dysfunction in motor and motor association areas may underlie this difference. The corollary, that there may be relative preservation of neuronal function in these areas in the homD90A group, has implications for understanding the slower progression of disease in these patients.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Al-Chalabi A., Andersen P. M., Chioza B., Shaw C., Sham P. C., Robberecht W., Matthijs G., Camu W., Marklund S. L., Forsgren L. Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum Mol Genet. 1998 Dec;7(13):2045–2050. doi: 10.1093/hmg/7.13.2045. [DOI] [PubMed] [Google Scholar]
  2. Andersen P. M., Forsgren L., Binzer M., Nilsson P., Ala-Hurula V., Keränen M. L., Bergmark L., Saarinen A., Haltia T., Tarvainen I. Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients. Brain. 1996 Aug;119(Pt 4):1153–1172. doi: 10.1093/brain/119.4.1153. [DOI] [PubMed] [Google Scholar]
  3. Andersen Peter M., Sims Katherine B., Xin Winnie W., Kiely Rosemary, O'Neill Gilmore, Ravits John, Pioro Erik, Harati Yadollah, Brower Richard D., Levine Johanan S. Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):62–73. doi: 10.1080/14660820310011700. [DOI] [PubMed] [Google Scholar]
  4. Brooks B. R., Miller R. G., Swash M., Munsat T. L., World Federation of Neurology Research Group on Motor Neuron Diseases 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. doi: 10.1080/146608200300079536. [DOI] [PubMed] [Google Scholar]
  5. Cahn Seth D., Herzog Andrew G., Pascual-Leone Alvaro. Paired-pulse transcranial magnetic stimulation: effects of hemispheric laterality, gender, and handedness in normal controls. J Clin Neurophysiol. 2003 Sep-Oct;20(5):371–374. doi: 10.1097/00004691-200309000-00009. [DOI] [PubMed] [Google Scholar]
  6. Cedarbaum J. M., Stambler N., Malta E., Fuller C., Hilt D., Thurmond B., Nakanishi A. 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. doi: 10.1016/s0022-510x(99)00210-5. [DOI] [PubMed] [Google Scholar]
  7. Cunningham V. J., Jones T. Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab. 1993 Jan;13(1):15–23. doi: 10.1038/jcbfm.1993.5. [DOI] [PubMed] [Google Scholar]
  8. Desiato M. T., Caramia M. D. Towards a neurophysiological marker of amyotrophic lateral sclerosis as revealed by changes in cortical excitability. Electroencephalogr Clin Neurophysiol. 1997 Feb;105(1):1–7. doi: 10.1016/s0924-980x(96)96582-0. [DOI] [PubMed] [Google Scholar]
  9. Desiato M. T., Palmieri M. G., Giacomini P., Scalise A., Arciprete F., Caramia M. D. The effect of riluzole in amyotrophic lateral sclerosis: a study with cortical stimulation. J Neurol Sci. 1999 Oct 31;169(1-2):98–107. doi: 10.1016/s0022-510x(99)00225-7. [DOI] [PubMed] [Google Scholar]
  10. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999 Mar;81(3):163–221. doi: 10.1016/s0163-7258(98)00042-4. [DOI] [PubMed] [Google Scholar]
  11. Eisen A., Pant B., Stewart H. Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci. 1993 Feb;20(1):11–16. doi: 10.1017/s031716710004734x. [DOI] [PubMed] [Google Scholar]
  12. Eisen A., Shytbel W., Murphy K., Hoirch M. Cortical magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve. 1990 Feb;13(2):146–151. doi: 10.1002/mus.880130211. [DOI] [PubMed] [Google Scholar]
  13. Ellis C. M., Simmons A., Jones D. K., Bland J., Dawson J. M., Horsfield M. A., Williams S. C., Leigh P. N. Diffusion tensor MRI assesses corticospinal tract damage in ALS. Neurology. 1999 Sep 22;53(5):1051–1058. doi: 10.1212/wnl.53.5.1051. [DOI] [PubMed] [Google Scholar]
  14. Friston K. J., Frith C. D., Liddle P. F., Frackowiak R. S. Comparing functional (PET) images: the assessment of significant change. J Cereb Blood Flow Metab. 1991 Jul;11(4):690–699. doi: 10.1038/jcbfm.1991.122. [DOI] [PubMed] [Google Scholar]
  15. Hanajima R., Ugawa Y. Impaired motor cortex inhibition in patients with ALS: evidence from paired transcranial magnetic stimulation. Neurology. 1998 Dec;51(6):1771–1772. doi: 10.1212/wnl.51.6.1771. [DOI] [PubMed] [Google Scholar]
  16. Hanajima R., Ugawa Y., Terao Y., Ogata K., Kanazawa I. Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders. J Neurol Sci. 1996 Sep 1;140(1-2):109–116. doi: 10.1016/0022-510x(96)00100-1. [DOI] [PubMed] [Google Scholar]
  17. Kew J. J., Leigh P. N., Playford E. D., Passingham R. E., Goldstein L. H., Frackowiak R. S., Brooks D. J. Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study. Brain. 1993 Jun;116(Pt 3):655–680. doi: 10.1093/brain/116.3.655. [DOI] [PubMed] [Google Scholar]
  18. Leigh P. N., Meldrum B. S. Excitotoxicity in ALS. Neurology. 1996 Dec;47(6 Suppl 4):S221–S227. doi: 10.1212/wnl.47.6_suppl_4.221s. [DOI] [PubMed] [Google Scholar]
  19. Liepert J., Schwenkreis P., Tegenthoff M., Malin J. P. The glutamate antagonist riluzole suppresses intracortical facilitation. J Neural Transm (Vienna) 1997;104(11-12):1207–1214. doi: 10.1007/BF01294721. [DOI] [PubMed] [Google Scholar]
  20. Lloyd C. M., Richardson M. P., Brooks D. J., Al-Chalabi A., Leigh P. N. Extramotor involvement in ALS: PET studies with the GABA(A) ligand [(11)C]flumazenil. Brain. 2000 Nov;123(Pt 11):2289–2296. doi: 10.1093/brain/123.11.2289. [DOI] [PubMed] [Google Scholar]
  21. Maekawa S., Al-Sarraj S., Kibble M., Landau S., Parnavelas J., Cotter D., Everall I., Leigh P. N. Cortical selective vulnerability in motor neuron disease: a morphometric study. Brain. 2004 May 6;127(Pt 6):1237–1251. doi: 10.1093/brain/awh132. [DOI] [PubMed] [Google Scholar]
  22. Mills K. R., Nithi K. A. Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve. 1997 Sep;20(9):1137–1141. doi: 10.1002/(sici)1097-4598(199709)20:9<1137::aid-mus7>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  23. Mills K. R., Nithi K. A. Peripheral and central motor conduction in amyotrophic lateral sclerosis. J Neurol Sci. 1998 Jul 15;159(1):82–87. doi: 10.1016/s0022-510x(98)00148-8. [DOI] [PubMed] [Google Scholar]
  24. Mills K. R. The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain. 2003 Aug 22;126(Pt 11):2558–2566. doi: 10.1093/brain/awg260. [DOI] [PubMed] [Google Scholar]
  25. Osei-Lah Abena D., Turner Martin R., Andersen Peter M., Leigh P. Nigel, Mills Kerry R. A novel central motor conduction abnormality in D90A-homozygous patients with amyotrophic lateral sclerosis. Muscle Nerve. 2004 Jun;29(6):790–794. doi: 10.1002/mus.20032. [DOI] [PubMed] [Google Scholar]
  26. Parton Matthew J., Broom Wendy, Andersen Peter M., Al-Chalabi Ammar, Nigel Leigh P., Powell John F., Shaw Christopher E., D90A SOD1 ALS Consortium D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. Hum Mutat. 2002 Dec;20(6):473–473. doi: 10.1002/humu.9081. [DOI] [PubMed] [Google Scholar]
  27. Peretti-Viton P., Azulay J. P., Trefouret S., Brunel H., Daniel C., Viton J. M., Flori A., Salazard B., Pouget J., Serratrice G. MRI of the intracranial corticospinal tracts in amyotrophic and primary lateral sclerosis. Neuroradiology. 1999 Oct;41(10):744–749. doi: 10.1007/s002340050836. [DOI] [PubMed] [Google Scholar]
  28. Petri Susanne, Krampfl Klaus, Hashemi Fariba, Grothe Claudia, Hori Akira, Dengler Reinhard, Bufler Johannes. Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol. 2003 Oct;62(10):1041–1051. doi: 10.1093/jnen/62.10.1041. [DOI] [PubMed] [Google Scholar]
  29. Prout A. J., Eisen A. A. The cortical silent period and amyotrophic lateral sclerosis. Muscle Nerve. 1994 Feb;17(2):217–223. doi: 10.1002/mus.880170213. [DOI] [PubMed] [Google Scholar]
  30. Rosen D. R., Siddique T., Patterson D., Figlewicz D. A., Sapp P., Hentati A., Donaldson D., Goto J., O'Regan J. P., Deng H. X. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Mar 4;362(6415):59–62. doi: 10.1038/362059a0. [DOI] [PubMed] [Google Scholar]
  31. Rossini P. M., Marciani M. G., Caramia M., Roma V., Zarola F. Nervous propagation along 'central' motor pathways in intact man: characteristics of motor responses to 'bifocal' and 'unifocal' spine and scalp non-invasive stimulation. Electroencephalogr Clin Neurophysiol. 1985 Oct;61(4):272–286. doi: 10.1016/0013-4694(85)91094-6. [DOI] [PubMed] [Google Scholar]
  32. Rowland L. P., Shneider N. A. Amyotrophic lateral sclerosis. N Engl J Med. 2001 May 31;344(22):1688–1700. doi: 10.1056/NEJM200105313442207. [DOI] [PubMed] [Google Scholar]
  33. Rösler K. M., Truffert A., Hess C. W., Magistris M. R. Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Clin Neurophysiol. 2000 Dec;111(12):2208–2218. doi: 10.1016/s1388-2457(00)00481-8. [DOI] [PubMed] [Google Scholar]
  34. Schwenkreis P., Liepert J., Witscher K., Fischer W., Weiller C., Malin J. P., Tegenthoff M. Riluzole suppresses motor cortex facilitation in correlation to its plasma level. A study using transcranial magnetic stimulation. Exp Brain Res. 2000 Dec;135(3):293–299. doi: 10.1007/s002210000532. [DOI] [PubMed] [Google Scholar]
  35. Sommer M., Tergau F., Wischer S., Reimers C. D., Beuche W., Paulus W. Riluzole does not have an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral sclerosis. J Neurol. 1999 Nov;246 (Suppl 3):III22–III26. doi: 10.1007/BF03161086. [DOI] [PubMed] [Google Scholar]
  36. Stefan K., Kunesch E., Benecke R., Classen J. Effects of riluzole on cortical excitability in patients with amyotrophic lateral sclerosis. Ann Neurol. 2001 Apr;49(4):536–539. [PubMed] [Google Scholar]
  37. Triggs W. J., Menkes D., Onorato J., Yan R. S., Young M. S., Newell K., Sander H. W., Soto O., Chiappa K. H., Cros D. Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology. 1999 Aug 11;53(3):605–611. doi: 10.1212/wnl.53.3.605. [DOI] [PubMed] [Google Scholar]
  38. Turazzini M., Manganotti P., Del Colle R., Silvestri M., Fiaschi A. Serum levels of carbamazepine and cortical excitability by magnetic brain stimulation. Neurol Sci. 2004 Jun;25(2):83–90. doi: 10.1007/s10072-004-0234-3. [DOI] [PubMed] [Google Scholar]
  39. Turner M. R., Cagnin A., Turkheimer F. E., Miller C. C. J., Shaw C. E., Brooks D. J., Leigh P. N., Banati R. B. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004 Apr;15(3):601–609. doi: 10.1016/j.nbd.2003.12.012. [DOI] [PubMed] [Google Scholar]
  40. Weber M., Eisen A., Stewart H. G., Andersen P. M. Preserved slow conducting corticomotoneuronal projections in amyotrophic lateral sclerosis with autosomal recessive D90A CuZn-superoxide dismutase mutation. Brain. 2000 Jul;123(Pt 7):1505–1515. doi: 10.1093/brain/123.7.1505. [DOI] [PubMed] [Google Scholar]
  41. Yokota T., Yoshino A., Inaba A., Saito Y. Double cortical stimulation in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1996 Dec;61(6):596–600. doi: 10.1136/jnnp.61.6.596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ziemann U., Winter M., Reimers C. D., Reimers K., Tergau F., Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology. 1997 Nov;49(5):1292–1298. doi: 10.1212/wnl.49.5.1292. [DOI] [PubMed] [Google Scholar]
  43. de Carvalho Mamede, Evangelista Teresinha, Sales-Luís M. L. The corticomotor threshold is not dependent on disease duration in amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Other Motor Neuron Disord. 2002 Mar;3(1):39–42. doi: 10.1080/146608202317576525. [DOI] [PubMed] [Google Scholar]
  44. de Carvalho Mamede, Turkman Antónia, Swash Michael. Motor responses evoked by transcranial magnetic stimulation and peripheral nerve stimulation in the ulnar innervation in amyotrophic lateral sclerosis: the effect of upper and lower motor neuron lesion. J Neurol Sci. 2003 Jun 15;210(1-2):83–90. doi: 10.1016/s0022-510x(03)00024-8. [DOI] [PubMed] [Google Scholar]

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