Hostname: page-component-77f85d65b8-grvzd Total loading time: 0 Render date: 2026-04-21T17:21:18.844Z Has data issue: false hasContentIssue false
  • English
  • Français

Pathogenic Mechanisms in Sporadic Amyotrophic Lateral Sclerosis

Published online by Cambridge University Press:  18 September 2015

Eisen Andrew  and
Krieger Charles
Eisen Andrew*
Affiliation:
Neuromuscular Diseases Unit, The Vancouver General Hospital and the University of British Columbia, Vancouver
Krieger Charles
Affiliation:
Neuromuscular Diseases Unit, The Vancouver General Hospital and the University of British Columbia, Vancouver
*
The Neuromuscular Diseases Unit, The Vancouver General Hospital, 855 West 12th Avenue, Vancouver, British Columbia, Canada V5Z IM9
Rights & Permissions [Opens in a new window]

Abstract:

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the 'Save PDF' action button.

In recognition of the 100th anniversary of Charcot’s death we have reviewed possible pathogenic mechanisms in amyotrophic lateral sclerosis (ALS). Advances in the last 5 years in molecular biology and genetics have identified mutations in the cytosolic dismutase (SODI) gene in some patients with familial ALS raising the possibility that oxidative stress may be involved in the pathogenesis. An excitotoxic pathogenesis has been implicated based on elevated plasma and CSF levels of amino acids and altered contents of amino acids in the nervous system of ALS patients and changes in the number of excitatory amino acid receptors. ALS sera containing antibodies to L-type calcium channels and the development of immune mediated lower and upper and lower motor neuron models have revitalized research efforts focusing on an immune basis for ALS. Other pathogenic mechanisms which have been the subject of recent research include elemental toxicity, apoptosis and programmed cell death and possibly a deficiency or abnormality in growth factors. Pathogenic processes for ALS must account for an increasing incidence of ALS, male preponderance, and the selective vulnerability of the corticomotoneuronal system.

Information

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 20 , Issue 4 , November 1993 , pp. 286 - 296
Copyright
Copyright © Canadian Neurological Sciences Federation 1993

References

REFERENCES

1.Charcot, JM. Sclerose des cordons latéraux de la moelle épinère chez femme hysterique atteinte de contracture permanente des quatre membres. Bull Soc Med Hop Paris. 1865; 2 (Suppi 2): 24–42.Google Scholar
2.Charcot, JM, Joffroy, A. Deux cas datrophie musculaire progressive avec lesions de la substance grise et des faisceaux anteriolatéraux de la moelle épinère. Arch Physiol Norm Pathol 1869; 2: 354–367, 629–649, 744–760.Google Scholar
3.Gaffney, JS, Sufit, RL, Hartmann, H, et al. Clinical diagnosis of amyotrophic lateral sclerosis (ALS): a clinicopathological study of “El Escorial” working group criteria in 36 autopsied patients. Neurology 1992; 42 (Suppl 3): 455p.Google Scholar
4.Li, TM, Swash, M, Alberman, E, Day, SJ. Diagnosis of motor neu ron disease by neurologists: a study in three countries. J Neurol Neurosurg Psychiatry 1991; 54: 980–983.Google Scholar
5.Daube, J.Electrophysiological studies in the diagnosis and prognosis of motor neuron diseases. Neurol Clin 1985; 3: 473–493.Google Scholar
6.Eisen, A, McComas, AJ. Motor neuron disorders. In: Clinical Electromyography, Second Edition, Brown, WF, Bolton, CF, eds. Boston, Butterworth-Heinemann, 1993; 427–450.Google Scholar
7.Younger, DS, Chou, S, Hays, AP, et al. Primary lateral sclerosis. A clinical diagnosis reemerges. Arch Neurol 1988; 45: 1304–1307.Google Scholar
8.Pringle, CE, Hudson, AJ, Munoz, DG, et al. Primary lateral sclero sis. Clinical features, neuropathology and diagnostic criteria. Brain 1992; 115: 495–520.Google Scholar
9.Brown, WF, Ebers, GC, Hudson, AJ, et al. Motor-evoked responses in primary lateral sclerosis. Muscle Nerve 1992; 15: 626–629.CrossRefGoogle ScholarPubMed
10.Younger, DS, Rowland, LP, Latov, N, et al. Lymphoma, motor neu ron diseases and amyotrophic lateral sclerosis. Ann Neurol 1991: 29: 78–86.CrossRefGoogle Scholar
11.Parry, GJ, Sumner, AJ. Multifocal motor neuropathy. Neurol Clin 1992; 10: 671–684.CrossRefGoogle ScholarPubMed
12.Hudson, AJ. Amyotrophic lateral sclerosis and its association with dementia, Parkinsonism and other neurological disorders: a review. Brain 1981; 104: 217–247.Google Scholar
13.Eisen, A, Calne, D. Amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease: phylogenetic disorders of the human neocortex sharing many characteristics. Can J Neurol Sci 1992; 19 (Suppi 1): 117–123.Google Scholar
14.Burrow, JNC, Blumbergs, PC. Substantia nigra degeneration in motor neurone disease: a quantitative study. Aust NZ J Med 1992; 22: 469–472.Google Scholar
15.Hasegawa, K, Kowa, H, Yagishita, S. Extrapyramidal system involvement in motor neuron disease. J Neurol Sci 1992; 108: 137–148.Google Scholar
16.Hawkes, CH, Graham, AJ. National UK motor neuron disease twin study using the death discordant approach. Ann Neurol 1992; 32: 272–273.Google Scholar
17.Siddique, T, Figlewicz, DA, Pericak-Vance, MA, et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of a genetic-locus heterogeneity. N Engl J Med 1991; 324: 1381–1384.Google Scholar
18.Rosen, DR, Siddique, T, Patterson, D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362: 59–62.Google Scholar
19.Monti, D, Troiano, L, Tropea, F, et al. Apoptosis-programmed cell death: a role in the aging process? Am J Clin Nutrition 1992; 55 (Suppl 6): 1208–1214.Google Scholar
20.Fahn, S, Cohen, G. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 1992; 32: 804–812.Google Scholar
21.Eubanks, JH, Puranam, RS, Kleckner, NW, et al. The gene encoding the glutamate receptor subunit GluR5 is located on human chromosome 21q21.1-22.1 in the vicinity of the gene for familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 1993: 90: 178–182.Google Scholar
22.Couratier, P, Hugon, J, Sindu, P, Vallat, JM, Dumas, M. Cell culture evidence for neuronal degeneration in amyotrophic lateral scierosis being linked to glutamate AMPA/kainate receptors. Lancet 1993; 341: 265–268.Google Scholar
23.Jokelainen, M. Amyotrophic lateral sclerosis in Finland. Adv Exp Med Biol 1987; 209: 341–344.Google Scholar
24.Lilienfeld, DE, Chan E, Ehlandet al. Increasing mortality from motor neuron disease in the United States during the past two decades. Lancet 1989; 1: 710–713.Google Scholar
25.Durrleman, S, Alprerovitch, A. Increasing trend of ALS in France and elsewhere: are changes real? Neurology 1989; 29: 1306–1309.Google Scholar
26.Gunnarsson, L, Lindberg, G, Soderfelt, B, et al. The mortality of motor neuron disease on Sweden. Arch Neurol 1990; 47: 42–46.CrossRefGoogle ScholarPubMed
27.Kurtzke, JF. Risk factors in amyotrophic lateral sclerosis. In: Advances in Neurology, Vol 56: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. Rowland, LP, ed. Raven Press Ltd. 1991; 245–270.Google Scholar
28.Chio, A, Meineri, P, Tribolo, A, Schiffer, D. Risk factors in motor neuron disease: a case control study. Neuroepidemiology 1991; 10: 174–184.Google Scholar
29.Gallagher, JP, Talbert, OR.Motor neuron syndrome after electric shock. Acta Neurologica Scand 1991; 83: 79–82.Google Scholar
30.Sirdofsky, MD, Hawley, RJ, Manz, H.Progressive motor neuron disease associated with electrical injury. Muscle Nerve 1991; 14: 997–980.Google Scholar
31.Gregoire, N, Serratrice, G.Risk factors in amytotrophic lateral scierosis. Initial results apropos of 35 cases. Revue Neurol 1991; 147: 706–713.Google Scholar
32.Longstreth, WT, Nelson, LM, Koepsell, TD, van Belle, G.Hypotheses to explain the association between vigorous physical activity and amyotrophic lateral sclerosis. Medical Hypotheses 1991; 34: 144–148.Google Scholar
33.Currier, RD, Conwill, DE, Jackson, MS.Is amyotrophic lateral scierosis caused by influenza and physical activity? Results of a twin study. Ann Neurol 1988; 24: 148p.Google Scholar
34.Armon, C, Kurland, LT, Daube, JR, O’Brien, PC. Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology 1991; 41: 1077–1084.Google Scholar
35.Kurland, LT, Radhakrishnan, K, Smith, GE, et al. Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiological evidence. J Neurol Sci 1992; 113: 133–143.CrossRefGoogle Scholar
36.Olivares, L, San Esteban, E, Alter, M.Mexican ‘resistance’ to amyotrophic lateral sclerosis. Arch Neurol 1972; 27: 397–402.Google Scholar
37.Annegers, JF, Appel, S, Lee, JR, Perkins, P.Incidence and preva lence of amytrophic lateral sclerosis in Harris County, Texas, 1985–1988. Arch Neurol 1991; 481: 589–593.Google Scholar
38.Williams, DB, Steele, J, Craig, UKet al. Changing prevelance of amyotrophic lateral sclerosis and Parkinsonism-dementia complex on Guam and the Northern Mariana Islands. Ann Neurol 1992; 32: 252p.Google Scholar
39.Kato, S, Hirano, A, Llena, JF.et al. Ultrastructural identification of neurofibrillary tangles in the spinal cords of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia complex on Gaum. Acta Neuropath 1992; 83: 277–282.Google Scholar
40.Sienko, DG, Davis, JP, Taylor, JA, Brooks, BR.Amyotrophic lateral sclerosis. A case-control study following detection of a cluster in a small Wisconsin community. Arch Neurol 1990; 47: p38–41.Google Scholar
41.Taylor, JA, Davis, JP.Evidence for clustering of amyotrophic later al sclerosis in Wisconsin. J Clin Epidemiol 1989; 42: 569–575.Google Scholar
42.Proctor, SP, Feldman, RG, Wolf, PA, et al. A perceived cluster of amyotrophic lateral sclerosis cases in a Massachusetts community. NeuroepidemioIogy 1992; 11: 277–281.Google Scholar
43.Appel, SH.Unifying hypothesis for the cause of amyotrophic lateral sclerosis, Parkinsonism and Alzheimer disease. Ann Neurol 1981; 10: 499–505.Google Scholar
44.Chou, SM, Norris, FH.Amyotrophic lateral sclerosis: the lower motor neuron hypothesis. Muscle & Nerve 1993; 16: (in press).Google Scholar
45.Charcot, JM.Clinical Lectures on Diseases of the Nervous System. Vol III (translated by Savili, T), The New Sydenham Society. London, 1889; 164–182.Google Scholar
46.Hudson, AJ, Kiernan, JA.Letter to the Lancet. Lancet 1988; 1: 652.Google Scholar
47.Eisen, A, Kim, S, Pant, B.Amyotrophic lateral sclerosis (ALS): a phylogenetic disease of the corticomotoneuron. Muscle Nerve 1992; 15: 219–228.Google Scholar
48.Rapport, MM.Implications of altered brain ganglioside profiles in amyotrophic lateral sclerosis (ALS). Acta Neurobiol Experiment 1990; 50: 505–513.Google Scholar
49.Oba, H, Araki, T, Monzawa, S, et al. MR imaging of amyotrophic lateral sclerosis. Nippon Acta Radiol 1992; 52: 427–435.Google Scholar
50.Ishikawa, K, Nagura, H, Yokota, T, Yamanouchi, H.Signal loss in the motor cortex on magnetic: Images in amyotrophic lateral sclerosis. Ann Neurol 1993; 33: 218–222.Google Scholar
51.Kiernan, JA, Hudson, AJ.Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain 1991; 114: 843–853.Google Scholar
52.Porter, R.Corticomotoneuronal projections: synaptic events related to skilled movement. Proc R Soc Lond (Biol) 1987: 231: 147–168.Google ScholarPubMed
53.Sillevis-Smitt, PAE, de Jong, JMBV.Animal models of amyotrophic lateral sclerosis and the spinal muscular atrophies. J Neurol Sci 1989; 91: 231–258.Google Scholar
54.Cote, F, Collard, JF, Julien, JPProgressive neuronopathy in trans-genie mice expressing the human neurofilament heavy gene: a mouse model of amyotrophic lateral sclerosis. Cell 1993; 73: 35–46.Google Scholar
55.Iwatsubo, T, Kuzuhara, S, Kanemitsu, A, et al. Corticofugal projections to the motor nuclei of the brainstem and spinal cord in humans. Neurology 1990; 40: 309–312.Google Scholar
56.Kihira, T, Yoshida, S, Uebayashi, Y, et al. Involvement of Onuf’s nucleus in ALS. Demonstration of intraneuronal conglomerate inclusions and Bunina bodies. J Neurol Sci 1991; 104: 119–128.Google Scholar
57.Okamoto, K, Hirai, S, Ishiguro, K, et al. Light and electron micro 293 scopic and immunohistochemical observations of Onuf’s nucleus of amyotrophic lateral sclerosis. Acta Neuropathol 1991; 81: 610–614.Google Scholar
58.Shaw, PJ, Ince, PG, Johnson, M, et al. The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human brainstem in relation to motor neuron disease. Brain Res 1992; 572: 276–280.Google Scholar
59Carpenter, S.Proximal axonal enlargement in motor neuron disease. Neurology 1968; 18: 841–851.Google Scholar
60.Delisle, MB, Carpenter, S.Neurofibrillary axonal swellings and amyotrophic lateral sclerosis. J Neurol Sci 1984; 63: 241–252.Google Scholar
61.Okamoto, K, Hirai, S, Shoji, M, et al. Axonal swellings in the corticospinal tracts in amyotrophic Lateral Sclerosis. Acta Neuropathol 1990; 80: 222–226.Google Scholar
62.Sasaki, S, Maruyama, S. Increase in diameter of the axonal initial segment is an early change in amyotrophic Lateral Sclerosis. J Neurol Sci 1992; 110: 114–120.Google Scholar
63.Leigh, PN, Dodson, A, Swash, M, et al. Cytoskeletal abnormalities in motor neuron disease: an immunocytochemical study. Brain 1989; 112: 521–535.Google Scholar
64.Breuer, AC, Atkinson, MB, Margolis, RL.The neuronal cytoskeleton and axonal transport abnormalities in motor neuron disease. In: Smith, RA, ed. Handbook of Amyotrophic Lateral Sclerosis. New York: Marcel Dekker Inc., 1992: 503–517.Google Scholar
65.Leigh, PN, Swash, M. Cytoskeletal pathology in motor neuron dis eases. In: Advances in Neurology. Vol 56: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. Rowland, LP, ed. Raven Press Ltd, 1991; 115–124.Google Scholar
66.Hirano, A. Cytopathology of amyotrophic lateral sclerosis. In: Rowland, LP, ed. Adv. Neurology, vol 56. New York: Raven Press, 1991: 91–102.Google ScholarPubMed
67.Brady, ST. Motor neurons and neurofilaments in sickness and in health. Cell 1993; 73: 1–3.Google Scholar
68.Monteiro, MJ, Hoffman, PN, Gearhart, JD, Cleveland, DW. Expression of NF-L in both neuronal and nonneuronal cells of transgenic mice: increased neurofilament density in axons without affecting caliber. J Cell Biol 1990; 111: 1543–1557.Google Scholar
69.Xu, Z, Cork, LC, Griffin, JW, Cleveland, DW. Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell 1993; 73: 23–33.Google Scholar
70.Mitsumoto, H, Bradley, WG. Murine motor neuron disease (the wobbler mouse). Brain 1982; 105: 811–834.Google Scholar
71.Messer, A, Strominger, NL, Mazurkiewicz, JE. Histopathology of the late-onset motor neuron degeneration (Mnd) mutant in the mouse. J Neurogenet 1987; 4: 201–213.Google Scholar
72.Karpati, G, Carpenter, S, Durham, H. A hypothesis for the pathogenesis of amyotrophic lateral sclerosis. Rev Neurol 1988; 144: 672–675.Google Scholar
73.Parhad, IM, Oishi, R, Clark, AW. GAP-43 gene expression is increased in anterior horn cells of amyotrophic lateral sclerosis. Ann Neurol 1992; 31: 593–597.Google Scholar
74.Wakayama, I. Morphometry of spinal motor neurons in amyotrophic lateral sclerosis with special reference to chromatolysis and intracytoplasmic inclusion bodies. Brain Res 1992; 586: 12–18.Google Scholar
75.Lowe, J, Aldridge, F, Lennox, G, et al.Inclusion bodies in motor cortex and brainstem of patients with motor neurone disease are detected by immunocytochemical localization of ubiquitin. Neurosci Lett 1989; 105: 7–13.Google Scholar
76.Garofalo, OKennedy, PG, Swash, M, et al. Ubiquitin and heat shock protein expression in amyotrophic lateral sclerosis. Neuropathol Appi Neurobiol 1991; 17: 39–45.Google Scholar
77.Leigh, PN, Whitwell, H, Garofalo, O. et al. Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution and specificity. Brain 1991; 114: 775–788.Google Scholar
78.Murayama, S, Bouldin, TW, Suzuki, K. Immunocytochemical and ultrastructural studies of upper motor neurons in amyotrophic lateral sclerosis. Acta Neuropathol 1992; 83: 518–524.Google Scholar
79.Okamoto, K. Hirai, S, Yamazaki, T, et al. New ubiquitin-positive intraneuronal inclusions in the extra-motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 1991; 129: 233–236.Google Scholar
80.Matsumoto, S, Hirano, A, Goto, S. Ubiquitin-immunoreactive filaments inclusions in anterior horn cells of Guamanian amyotrophic lateral sclerosis. Acta Neuropathol 1990; 80: 233–238.Google Scholar
81.Brooks, BR. The role of axonal transport in neurodegenerative dis ease spread: meta-analysis of experimental and clinical poliomyelitis compared with amyotrophic lateral sclerosis. Can J Neurol Sci 1991; 18 (Suppi) 435–438.Google Scholar
82.Sar, M, Stumpf, WE. Androgen concentration in motor neurons of cranial nerves and spinal cord. Science 1992; 197: 77–80.Google Scholar
83.Sheridan, PJ, Weaker, FJ. Androgen receptor systems in the brain stem of the primate. Brain Res 1987; 406: 62–72.Google Scholar
84.Warner, CL, Griffin, JE, Wilson, JD, et al. X-linked spinomuscular atrophy: a kindred with associated abnormal androgen receptor binding. Neurology 1992; 42: 2181–2184.Google Scholar
85.Igarashi, S, Tanno, Y, Onodera, O, et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 1992; 42: 2300–2302.Google Scholar
86.Ono, S, Yamauchi, M. Collagen cross-linking of skin in patients with amyotrophic lateral sclerosis. Ann Neurol 1992; 31: 305–310.Google Scholar
87.Ono, S, Yamauchi, M. Amyotrophic lateral sclerosis: increased solubility of skin collagen. Neurology 1992; 42: 1535–1539.Google Scholar
88.Shaw, PJ. Excitatory amino acid receptors, excitotoxicity, and the human nervous system. Current Opinion in Neurology and Neurosurgery 1993; 6: 414–422.Google Scholar
89.Choi, DW. Glutamate Neurotoxicity and Diseases of the Nervous System. Neuron 1988; 1: 623–634.Google Scholar
90.Choi, DW, Rothman, SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann Rev Neurosci 1990; 13: 171–182.Google Scholar
91.Rothman, SM. Excitotoxins: Possible mechanisms of action. NY Acad Sci 1992; 648: 132–138.Google Scholar
92.Nicotera, P, Orrenius, S. Ca2+ and cell death. NY Acad Sci 1992; 648: 17–27.Google Scholar
93.Konnerth, A, Keller, BU, Lev-Tov, A. Patch clamp analysis of excitatory synapses in mammalian spinal cord slices. Pflugers Arch 1990; 417: 285–290.Google Scholar
94.Ziskind-Conhaim, L. NMDA receptors mediate poly- and mono-synaptic potentials in motoneurons of rat embryos. J Neurosci 1990; 10: 125–135.Google Scholar
95.Cornell-Bell, AH, Finkbeiner, SM, Cooper, MS, Smith, SJ. Glutamate induces calcium waves in cultured astrocytes: longrange glial signalling. Science 1990; 247: 470–473.Google Scholar
96.Plaitakis, A, Caroscio, JT. Abnormal glutamate metabolism in amyotrophic lateral sclerosis. Ann Neurol 1987; 22: 575–579.CrossRefGoogle ScholarPubMed
97.Plaitakis, A. Glutamate dysfunction and selective motor neuron degeneration in amyotrophic lateral sclerosis: A hypothesis. Ann Neurol 1990; 28: 3–8.Google Scholar
98.Spencer, PS, Nunn, PB, Hugon, J, et al. Guam amyotrophic lateral sclerosis-Parkinsonism-dementia linked to a plant excitant neurotoxin. Science 1987; 237: 517–522.Google Scholar
99.Rothstein, JD, Tsai, G, Kuncl, RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 1990; 28: 18–25.Google Scholar
100.Rothstein, JD, Kuncl, R, Chaudhry, V, et al. Excitatory amino acids in amyotrophic lateral sclerosis: An update. Ann Neurol 1991; 30: 224–225.Google Scholar
101.Heafield, MT, Fearn, S, Steventon, RH, et al. Plasma cysteine and sulphate levels in patients with motor neurone, Parkinson’s and Alzheimer’s disease. Neurosci Lett 1990; 110: 216–220.Google Scholar
102.Perry, TL, Krieger, C, Hansen, S, Eisen, A. Amyotrophic lateral sclerosis: amino acid levels in plasma and cerebrospinal fluid. Ann Neurol 1990; 28: 12–17.Google Scholar
103.Perry, TL, Krieger, C, Hansen, S, Tabatabaei, A. Amyotrophic lateral sclerosis: fasting plasma levels of cysteine and inorganic sulfate are normal, as are brain contents of cysteine. Neurology 1991; 41: 487–490.Google Scholar
104.Cottell, E, Hutchinson, M, Simon, J, Harrington, MG. Plasma glutamate levels in normal subjects and in patients with amyotrophic lateral sclerosis. Biochem Soc Trans 1990; 18: 283.Google Scholar
105.Spink, DC, Martin, DL. Excitatory amino acids in amyotrophic Lateral sclerosis. Ann Neurol 1991; 29: 110.Google Scholar
106.Hugon, J, Vallat, JM, Spencer, PS, et al. Kainie acid induces early and delayed degenerative neuronal changes in rat spinal cord. Neurosci Lett 1989; 104: 258–262.Google Scholar
107.Urea, G, Urca, R. Neurotoxic effects of excitatory amino acids in the mouse spinal cord: quisqualate and kainate but not N-methyl-D-aspartate induce permanent neural damage. Brain Res 1990; 529: 7–15.Google Scholar
108.Teitelbaum, JS, Zatorre, RJ, Carpenter, S, et al. Neurological sequelae of domic acid intoxication due to the ingestion of contaminated mussels. N Engl J Med 1990; 322: 1781–1787.Google Scholar
109.Debonnel, G, Beauchesne, L, de Montigny, C. Domoic acid, the alleged “mussel toxin”, might produce its neurotoxic effect through kainate receptor activation: an electrophysiological study in the dorsal hippocampus. Can J Phys Pharm 1989; 67: 29–33.Google Scholar
110.Perry, TL, Hansen, S, Jones, K. Brain glutamate deficiency in amyotrophic lateral sclerosis. Neurology 1987; 37: 1845–1848.Google Scholar
111.Malessa, S, Leigh, PN, Bertel, Oet al. Amyotrophic lateral sclerosis: glutamate dehydrogenase and transmitter amino acids in spinal cord. J Neurol Neurosurg Psychiatry 1991; 54: 984–988.Google Scholar
112.Plaitakis, A, Constantakakis, E, Smith, J. The neuroexcitotoxic amino acids glutamate and aspartate are altered in the spinal cord and brain in amyotrophic lateral sclerosis. Ann Neurol 1988; 24: 446–449.Google Scholar
113.Tsai, GC, Stauch-Slusher, B, Sim, L, et al. Reduction in acidic amino and N-acetylaspartylglutamate in amyotrophic lateral sclerosis CNS. Brain Res 1991; 556: 151–156.Google Scholar
114.Allaoua, H, Chaudieu, I, Krieger, O, et. al. Alterations in spinal cord excitatory amino acid receptors in amyotrophic lateral sclerosis patients. Brain Res 1992: 579: 169–172.Google Scholar
115.Shaw, PJInce, PG, Johnson, M, et al. The quantitative autoradiographic distribution of [3H]MK-801 binding sites in the normal human spinal cord. Brain Res 1991; 539: 164–168.Google Scholar
116.Rothstein, JD, Martin, LJ, Kuncl, RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992; 326: 1464–1468.Google Scholar
117.Young, AB, Fagg, GE. Excitatory amino acid receptors in the brain: membrane binding and receptor autoradiographic approaches. Trends Phann Sci 1990; 11: 126–133.Google Scholar
118.Whitehouse, PJWalmsley, JK, Zarbin, MA, et al. Amyotrophic lateral sclerosis: alterations in neurotransmitter receptors. Ann Neurol 1983; 14: 8–16.Google Scholar
119.Krieger, C, Perry, TL, Hansen, S, Mitsumoto, H, Honoré, T. Excitatory amino acid receptor antagonist in murine motoneuron disease (the wobbler mouse). Can J Neurol Sci 1992; 19: 462–465.Google Scholar
120.Pestronk, A. Invited review: motor neuropathies, motor neuron disorders and antiglycolipid antibodies. Muscle Nerve 1991; 14: 297–936.Google Scholar
121.Krieger, C. Perry, TL, Ziltener, HJ. Amyotrophic lateral sclerosis: interleukin-6 levels in cerebrospinal fluid. Can J Neurol Sci 1992; 19: 357–359.Google Scholar
122.Drachman, DB, Kuncl, RW. Amyotrophic lateral sclerosis: an unconventional autoimmune disease? Neurol 1989; 26: 269–274.Google Scholar
123.McGeer, PL, McGeer, EG, Kawamata, T, et al. Reactions of the immune system in chronic degenerative neurological diseases. Can J Neurol Sci 1991; 18 (Suppl): 376–379.Google Scholar
124.Engelhardt, JI, Appel, SH. IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. Arch Neurol 1990: 47: 1210–1216.Google Scholar
125.Lampson, LA, Kushner, PD, Sobel, RA. Major histocompatibility complex antigen expression in the affected tissues in amyotrophic lateral sclerosis. Ann Neurol 1990; 28: 365–372.CrossRefGoogle ScholarPubMed
126.Kawamata, T, Akiyama, HYamada, T, McGeer, PL. Immunologic reactions in amyotrophic lateral sclerosis brian and spinal cord tissue. Am J Path 1992; 140: 691–707.Google Scholar
127.Murayama, S, Inoue, K, Kawakami, H, et al. A unique pattern of astrocytosis in the primary motor area in amyotrophic lateral sclerosis. Acta Neuropathol 1991; 82: 456–461.Google Scholar
128.Engelhardt, JL, Appel, SH, Killian, JM. Experimental autoimmune motorneuron disease. Ann Neurol 1989; 26: 368–376.Google Scholar
129.Engelhardt, JL, Appel, SH, Killian, JM. Motor neuron destruction in guinea pigs immunized with bovine spinal cord ventral horn homogenate: experimental autoimmune gray matter disease. J Neuroimmunol 1990; 27: 21–31.Google Scholar
130.Uchitel, OD, Scornik, F, Protti, DA, et al. Long-term neuromuscular dysfunction produced by passive transfer of amyotrophic lateral sclerosis immunoglobulins. Neurology 1992; 42: 2175–2180.Google Scholar
131.Delbono, O, Garcia, J, Appel, SH, Stefani, E. IgG from amyotrophic lateral sclerosis affects tubular calcium channels of skeletal muscle. Am J Physiol 1991: 260: 1347–1351.Google Scholar
132.Smith, RG. Hamilton, S, Hofmann, F, Schneider, T. el al. Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis. N Engl J Med 1992; 327: 1721–1728.Google Scholar
133.Rowland, LP. Amyotrophic lateral sclerosis and autoimmunity. N Engl J Med 1992; 327: 1752–1753.Google Scholar
134.Ince, P, Stout, N, Slade, J, Shaw, PJ. Calcium binding protein immunoreactivity in human motor system and in motor neurone disease. Proc 1st Intl ALS/MND meeting, Birmingham, U.K., 1991.Google Scholar
135.Barry, MA, Eastman, A. Endonucleuse activation during apoptosis: the role of cytosolic Ca2+ and pH. Biochem Biophysical Res Comm 1992; 186: 782–789.Google Scholar
136.Franceschi, C. Cell proliferation, cell death and aging. Aging 1992; 1: 1–13.Google Scholar
137.Altman, J. Programmed cell death: the paths to suicide. Trends Neurosci 1992; 15.Google Scholar
138.Alsion, MR, Sarraf, CE. Apoptosis: a gene-directed programme of cell death. J Roy Coll Physcians Lond 1992; 26: 25–35.Google Scholar
139.Trump, BF, Berezesky, IK. The role of cytosolic Ca2+ in cell injury, necrosis and apoptosis. Current Opinion Cell Biol 1992; 4: 227–232.Google Scholar
140.Stewart, SS, Appel, SH. Trophic factors in neurological disease. Ann Rev Med 1988; 39: 193–201.Google Scholar
141.Oppenheim, RW. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci 1989; 12: 252–255.Google Scholar
142.Barde, YA. Trophic factors and neuronal survival. Neuron 1989; 2: 1525–1534.Google Scholar
143.Oppenheim, RW. Cell death during development of the nervous system. Ann Rev Neurosci 1991; 14: 453–501.Google Scholar
144.Kim, SU, Krieger, C, Eisen, A.Human and rodent spinal cord neu rons in culture. In: Rowland, LP, ed. Advances in Neurology, Vol 56: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. Raven Press Ltd. 1991; 57–67.Google Scholar
145.Dohrmann, U, Edgar, D, Thoenen, H. Distinct neurotrophic factors from skeletal muscle and the central nervous system interact synergistically to support the survival of cultured embryonic spinal motor neurons. Dev Biol 1987: 124: 145–152.Google Scholar
146.Arakawa, Y, Sendtner, M, Thoenen, H. Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J Neurosci 1990; 10: 3507–3515.Google Scholar
147.Martinou, J-C, Martinou, I, Kato, AC. Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motoneurons in vitro. Neuron 1992; 8: 737–744.Google Scholar
148.Oppenheim, RW, Prevette, D, Yin, QW, et al. Control of embryogenie motorneuron survival in vivo by ciliary neurotrophic factor. Science 1991; 251: 1616–1618.Google Scholar
149.Davis, S, Aldrich, TH, Valenzuela, DM, et al. The receptor for ciliary neurotrophic factor. Science 1991; 253: 59–63.Google Scholar
150.Ip, NY, Nye, SH, Boulton, TG, et al. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transucing receptor component gp130. Cell 1992: 69: 1121–1132.Google Scholar
151.Ip, NY, McClain, J. Barrezueta, NX, et al. The component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 1993; 10: 89–102.Google Scholar
152.Stockli, KALillien, LE, Naher-Noe, M, et al. Regional distribution, developmental changes and cellular localization of CNTF-mRNA and protein in the rat brain. J Cell Biol 1991; 115: 447–459.Google Scholar
153.Sendtner, M, Schmalbruch, H, Stoekli, KA. et al. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive motor neuronopathy. Nature 1992: 358: 501–504.Google Scholar
154.Friedman, B, Scherer, SS, Rudge, JS, Helgren, M, et al. Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cells in vivo. Neuron 1992; 9: 295–305.Google Scholar
155.Mitsumoto, H, lkeda, K. Ciliary neurotrophic factor (CNTF) 295 improves neuromuscular function and muscle strength following onset of motor neuron disease in the wobbler mouse. Neurolgy 1993; 43 (Suppl): 415p.Google Scholar
156.Ikeda, K, Mitsumoto, H. Morphological changes correlate with functional improvement following ciliary neurotrophic factor (CNTF) treatment of motor neuron disease in the wobbler mouse. Neurology 1993; 43 (Suppl): 321p.Google Scholar
157.ALS CNTF Treatment Study (ACTS) Phase I-II Study Group. Recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis (ALS) patients: phase I-II safety, tolerability and pharmacokinetic studies. Neurology 1993; 43 (Suppl): 416p.Google Scholar
158.Bloch-Gallego, E, Huchet, M, El, M’Hamdi, et al. Survival in vitro of motoneurons identified or purified by novel antibody-based methods is selectively enhanced by muscle-derived factors. Development 1991; 111: 221–232.Google Scholar
159.Jubelt, B. Viruses and motor neuron disease. In: Rowland, LP, ed. Advances in Neurology, Vol. 56: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases. Raven Press Ltd. 1991; 463–472.Google Scholar
160.Salazar, AM, Masters, CL, Gajdusek, DC, Gibbs, CJ Jr. Syndromes of amyotrophic lateral sclerosis and dementia: relation to transmissible Creutzfeldt-Jakob disease. Ann Neurol 1983; 14: 17–26.Google Scholar
161.Melchers, W, de Visser, M, Jongen, P, et al. The postpolio syndrome: no evidence for poliovirus persistence. Ann Neurol 1992; 32: 728–732.Google Scholar
162.Mitchell, JD. Anterior horn cell diseases. In: Diseases of the Spinal Cord. Critchley, E, Eisen, A, eds. Springer-Verlag, London, 1991; 235–253.Google Scholar
163.Gajdusek, DC, Salazar, AM. Amyotrophic lateral sclerosis and parkinsonian syndromes in high incidence among Auyu and Jakai people of West New Guinea. Neurology 1982; 32: 107–126.Google Scholar
164.Yanagihara, RT, Garrulo, RM, Gajdusek, DC, et al. Calcium and vitamin D metabolism in Guamian Chamorrros with amyotrophic lateral sclerosis and parkinsonism-dementia. Ann Neurol 1984; 15: 42–48.Google Scholar
165.Yasui, M, Yase, Y, Ota, K, Garruto, RM. Aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula of Japan. Neurotoxicology 1991; 12: 615–620.Google ScholarPubMed
166.Yoshida, S, Yase, Y, Mizumoto, Y, Iwata, S. Aluminum deposition and Ca-hydroxyapatite formation in frontal cortex tissue of amyotrophic lateral sclerosis. Clin Neurol 1989; 29: 421–426.Google Scholar
167.Mitchell, JD, East, BW, Harris, IA, Pentland, B. Manganese, sele nium and other trace elements in spinal cord, liver and bone in motor neurone disease. Eur Neurol 1991; 31: 7–11.Google Scholar
168.Yasui, M, Yase, Y, Ota, K, Mukoyama, M, Adachi, K. High aluminum deposition in the central nervous system of patients with amyotrophic lateral sclerosis from the Kii Peninsula, Japan: two cases. Neurotoxicology 1991; 12: 277–283.Google Scholar
169.Garruto, RM, Shankar, SK, Yanaguhara, R, et al. Low-calcium, high aluminum diet-induced motor neuron pathology in cynomolgus monkeys. Acta Neuropathol (Beri) 1989; 78: 210–219.Google Scholar
170.Strong, MJ, Gamto, RM. Potentiation in the neurotoxic induction of experimental chronic neurodegenerative disorders: N-butyl benzenesulfonamide and aluminum chloride. Neurotoxicology 1991; 12: 415–425.Google Scholar
171.Brodie, MJ. Drug profiles: lamotrigine. Lancet 1992; 339: 1397–1400.Google Scholar
172.Eisen, A, Stewart, H, Schulzer, M, Cameron, D. Anti-Glutamate therapy in amyotrophic lateral sclerosis: a trial using Iamotrigine. Can J Neurol Sci (in press).Google Scholar
173.Asmark, H, Aquilonius, SM, Gillberg, PG, et al. A pilot trial of dex-tromethorphan in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1993; 56: 197–200.Google Scholar