Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;13(1):10–22. doi: 10.1111/j.1750-3639.2003.tb00002.x

Neuropathology with Clinical Correlations of Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and 2000

Yue‐Shan Piao 1, Koichi Wakabayashi 3, Akiyoshi Kakita 1,2, Mitsunori Yamada 1, Shintaro Hayashi 1, Takashi Morita 4, Fusahiro Ikuta 5, Kiyomitsu Oyanagi 6, Hitoshi Takahashi 1,✉
PMCID: PMC8095891  PMID: 12580541

Abstract

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbar‐onset form (30 cases) than for the limb‐onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower‐motor‐predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido‐nigro‐luysian degeneration (2 cases). The age at onset was significantly higher for lower‐motor‐predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin‐immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin‐immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin‐immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar‐onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar‐onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS.

Full Text

The Full Text of this article is available as a PDF (579.2 KB).

References

  • 1. Abrahams S, Goldstein LH, Kew JJM, Brooks DJ, Lloyd CM, Frith CD, Leigh PN (1996) Frontal lobe dysfunction in amyotrophic lateral sclerosis. A PET study. Brain 119:2105–2120. [DOI] [PubMed] [Google Scholar]
  • 2. Anderson VER, Cairns NJ, Leigh PN (1995) Involvement of the amygdala, dentate and hippocampus in motor neuron disease. J Neurol Sci 129 (Suppl):75–78. [DOI] [PubMed] [Google Scholar]
  • 3. Bergmann M (1993) Motor neuron disease/amyotrophic lateral sclerosis—lessons from ubiquitin. Pathol Res Pract 189:902–912. [DOI] [PubMed] [Google Scholar]
  • 4. Bergmann M, Kuchelmeister K, Migheli A, Schiffer D, Gullotta F (1993) Motor neuron disease with pallido‐luysio‐nigral atrophy. Acta Neuropathol 86:105–108. [DOI] [PubMed] [Google Scholar]
  • 5. Brownell B, Oppenheimer DR, Hughes JT (1970) The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatry 33:338–357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Chou SM (1979) Pathognomy of intraneuronal inclusions in ALS In: Amyotrophic Lateral Sclerosis, Tsubaki T, Toyokura Y (eds.), PP. 135–176, University of Tokyo Press: Tokyo . [Google Scholar]
  • 7. Dagi TF, Tarkington MA, Leech JJ (1987) Tandem lumbar and cervical stenosis. Natural history, prognostic indices, and results after surgical decompression. J Neurosurg 66:842–849. [DOI] [PubMed] [Google Scholar]
  • 8. Gray F, De Baecque C, Serdaru M, Escourolle R (1981) Pallido‐luyso‐nigral atrophy and amyotrophic lateral sclerosis. Acta Neuropathol (Suppl VII):348–351. [DOI] [PubMed] [Google Scholar]
  • 9. Gray F, Eizenbaum JF, Gherardi R, Degos JD, Poirier J (1985) Luyso‐pallido‐nigral atrophy and amyotrophic lateral sclerosis. Acta Neuropathol 66:78–82. [DOI] [PubMed] [Google Scholar]
  • 10. Hardy J, Gwinn‐Hardy K (1998) Genetic classification of primary neurodegenerative disease. Science 282:1075–1079. [DOI] [PubMed] [Google Scholar]
  • 11. Hasegawa K, Kowa H, Yagishita S (1992) Extrapyramidal system involvement in motor neuron disease. J Neurol Sci 108:137–148. [DOI] [PubMed] [Google Scholar]
  • 12. Hayashi H, Kato S (1989) Total manifestations of amyotrophic lateral sclerosis. ALS in the totally locked‐in state. J Neurol Sci 93:19–35. [DOI] [PubMed] [Google Scholar]
  • 13. Hirano A, Donnenfeld H, Sasaki S, Nakano I, Bartfeld H (1984) The fine structure of motor neurone disease In: Research Progress in Motor Neuron Disease, Rose FC (ed.), PP. 328–348, Pitman: London . [Google Scholar]
  • 14. Holton JL, Révész T, Crooks R, Scaravilli F (2002) Evidence for pathological involvement of the spinal cord in motor neuron disease‐inclusion dementia. Acta Neuropathol 103:221–227. [DOI] [PubMed] [Google Scholar]
  • 15. Hudson AJ (1981) Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain 104:217–247. [DOI] [PubMed] [Google Scholar]
  • 16. Ince PG, Lowe J, Shaw PJ (1998) Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol 24:104–117. [DOI] [PubMed] [Google Scholar]
  • 17. Ito T, Oyanagi K, Takahashi H, Takahashi HE, Ikuta F (1996) Cervical spondylotic myelopathy. Clinicopathologic study on the progression pattern and thin myelinated fibers of the lesions of seven patients examined during complete autopsy. Spine 21:827–833. [DOI] [PubMed] [Google Scholar]
  • 18. Iwanaga K, Hayashi S, Oyake M, Horikawa Y, Hayashi T, Wakabayashi M, Kondo H, Tsuji S, Takahashi H (1997) Neuropathology of sporadic amyotrophic lateral sclerosis of long duration. J Neurol Sci 146:139–143. [DOI] [PubMed] [Google Scholar]
  • 19. Iwanaga K, Wakabayashi K, Honma Y, Takahashi H (1997) Amyotrophic lateral sclerosis:occurrence of Bunina bodies in the locus ceruleus pigmented neurons. Clin Neuropathol 16:23–26. [PubMed] [Google Scholar]
  • 20. Jackson M, Lennox G, Lowe J (1996) Motor neuron disease‐inclusion dementia. Neurodegeneration 5:339–350. [DOI] [PubMed] [Google Scholar]
  • 21. Kakita A, Oyanagi K, Nagai H, Takahashi H (1997) Eosinophilic intranuclear inclusions in the hippocampal pyramidal neurons of a patient with amyotrophic lateral sclerosis. Acta Neuropathol 93:532–536. [DOI] [PubMed] [Google Scholar]
  • 22. Kato T, Katagiri T, Hirano A, Kawanami T, Sasaki H (1989) Lewy body‐like hyaline inclusions in sporadic motor neuron disease are ubiquitinated. Acta Neuropathol 77:391–396. [DOI] [PubMed] [Google Scholar]
  • 23. Kato S, Oda M, Murahashi M, Suda N (1995) Motor neuron disease with involvement of the pallido‐luysio‐nigral system and mesencephalic tegmentum. Clin Neuropathol 14:241–244. [PubMed] [Google Scholar]
  • 24. Kawashima T, Doh‐ura K, Kikuchi H, Iwaki T (2001) Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent‐shaped ubiquitinated intraneuronal inclusions in the parahippocampal gyrus and amygdala, but not in the neostriatum. Acta Neuropathol 102:467–472. [DOI] [PubMed] [Google Scholar]
  • 25. Kawashima T, Kikuchi H, Takita M, Doh‐ura K, Ogomori K, Oda M, Iwaki T (1998) Skein‐like inclusions in the neostriatum from a case of amyotrophic lateral sclerosis with dementia. Acta Neuropathol 96:541–545. [DOI] [PubMed] [Google Scholar]
  • 26. Kurland LT, Radhakrishnan K, Smith GE, Armon C, Nemetz PN (1992) Mechanical trauma as a risk factor in classic amyotrophic lateral sclerosis: lack of epidemiologic evidence. J Neurol Sci 113:133–143. [DOI] [PubMed] [Google Scholar]
  • 27. Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier‐Buchman L, Salachas F, Pradat P‐F, Lacomblez L, Meininger V (2001) Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature. Brain 124:1989–1999. [DOI] [PubMed] [Google Scholar]
  • 28. Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM (1988) Ubiquitin deposits in anterior horn cells in motor neurone disease. Neurosci Lett 93:197–203. [DOI] [PubMed] [Google Scholar]
  • 29. Leigh PN, Whitwell H, Garofalo O, Buller J, Swash M, Martin JE, Gallo JM, Weller RO, Anderton BH (1991) Ubiquitin‐immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity. Brain 114:775–788. [DOI] [PubMed] [Google Scholar]
  • 30. Lowe J (1994) New pathological findings in amyotrophic lateral sclerosis. J Neurol Sci 124:38–51. [DOI] [PubMed] [Google Scholar]
  • 31. Lowe J, Aldridge F, Lennox G, Doherty F, Jefferson D, Landon M, Mayer RJ (1989) Inclusion bodies in motor cortex and brainstem of patients with motor neuron disease are detected by immunocytochemical localisation of ubiquitin. Neurosci Lett 105:7–13. [DOI] [PubMed] [Google Scholar]
  • 32. Lowe J, Lennox G, Jefferson D, Morrell K, McQuire D, Gray T, Landon M, Doherty FJ, Mayer RJ (1988) A filamentous inclusion body within anterior horn neurones in motor neurone disease defined by immunocytochemical localisation of ubiquitin. Neurosci Lett 94:203–210. [DOI] [PubMed] [Google Scholar]
  • 33. Lowe J, Lennox G, Leigh PN (1997) Disorders of movement and system degeneration In: Greenfield's Neuropathology, Vol 2, 6th Edition, Graham DI, Lantos PL (eds.), Chapter 6, pp. 320–330, Arnord: London , Sydney , Auckxland . [Google Scholar]
  • 34. Lowe J, Mayer J, Landon M, Layfield R (2001) Ubiquitin and the molecular pathology of neurodegenerative diseases. Adv Exp Med Biol 487:169–186. [DOI] [PubMed] [Google Scholar]
  • 35. Matsumoto S, Kusaka H, Ito H, Imai T (1996) Golgi apparatus and intraneuronal inclusions of anterior horn cells in amyotrophic lateral sclerosis: an immunohistochemical study. Acta Neuropathol 91:603–607. [DOI] [PubMed] [Google Scholar]
  • 36. McGuire V, Longstreth WT, Koepsell TD, van Belle G (1996) Incidence of amyotrophic lateral sclerosis in three counties in western Washington state. Neurology 47:571–573. [DOI] [PubMed] [Google Scholar]
  • 37. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ (2001) Clinical and pathological diagnosis of frontotemporal dementia. Report of the work group on frontotemporal dementia and Pick's disease. Arch Neurol 58:1803–1809. [DOI] [PubMed] [Google Scholar]
  • 38. Mitsuyama Y (1984) Presenile dementia with motor neuron disease in Japan: clinicopathological review of 26 cases. J Neurol Neurosurg Psychiatry 47:953–959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Mizusawa H, Nakamura H, Wakayama I, Yen S‐HC, Hirano A (1991) Skein‐like inclusions in the anterior horn cells in motor neuron disease. J Neurol Sci 105:14–21. [DOI] [PubMed] [Google Scholar]
  • 40. Murayama S, Mori H, Ihara Y, Bouldin TW, Suzuki K, Tomonaga M (1990) Immunocytochemical and ultrastructural studies of lower motor neurons in amyotrophic lateral sclerosis. Ann Neurol 27:137–148. [DOI] [PubMed] [Google Scholar]
  • 41. Nakano I (1993) Temporal lobe lesions in amyotrophic lateral sclerosis with or without dementia: a neuropathological study. Neuropathology 13:215–227. [Google Scholar]
  • 42. Nakano I (2000) Frontotemporal dementia with motor neuron disease (amyotrophic lateral sclerosis with dementia). Neuropathology 20:68–75. [DOI] [PubMed] [Google Scholar]
  • 43. Nakano I, Donnenfeld H, Hirano A (1983) A neuropathological study of amyotrophic lateral sclerosis. With special reference to central chromatolysis and spheroid in the spinal anterior horn and some pathological changes of the motor cortex. Shinkeinaika 18:136–144. [Google Scholar]
  • 44. Nakano I, Hashizume Y, Tomonaga M (1990) Bunina bodies in neurons of the medullary reticular formation in a case of amyotrophic lateral sclerosis. Acta Neuropathol 79:689–691. [DOI] [PubMed] [Google Scholar]
  • 45. Nakano I, Iwatsubo T, Hashizume Y, Mizutani T, Mannen T (1992) Amyotrophic lateral sclerosis with dementia. Lesions in the apical cortex and some deeper structures of the temporal lobes. Neuropathology 12:69–77. [Google Scholar]
  • 46. Nakano I, Shibata T, Uesaka Y (1993) On the possibility of autolysosomal processing of skein‐like inclusions. Electron microscopic observation in a case of amyotrophic lateral sclerosis. J Neurol Sci 120:54–59. [DOI] [PubMed] [Google Scholar]
  • 47. Neilson S, Gunnarsson L‐G, Robinson I (1994) Rising mortality from motor neurone disease in Sweden 1961–1990: the relative role of increased population life expectancy and environmental factors. Acta Neurol Scand 90:150–159. [DOI] [PubMed] [Google Scholar]
  • 48. Neilson S, Robinson I, Alperovitch A (1994) Rising amyotrophic lateral sclerosis mortality in France 1968–1990: increased life expectancy and inter‐disease competition as an explanation. J Neurol 241:448–455. [DOI] [PubMed] [Google Scholar]
  • 49. Neilson S, Robinson I, Nymoen EH (1994) Longitudinal analysis of amyotrophic lateral sclerosis mortality in Norway, 1966–1989: evidence for a susceptible subpopulation. J Neurol Sci 122:148–154. [DOI] [PubMed] [Google Scholar]
  • 50. Okamoto K, Hirai S, Amari M, Watanabe M, Sakurai A (1993) Bunina bodies in amyotrophic lateral sclerosis immunostained with rabbit anti‐cystatin C serum. Neurosci Lett 162:125–128. [DOI] [PubMed] [Google Scholar]
  • 51. Okamoto K, Hirai S, Yamazaki T, Sun X, Nakazato Y (1991) New ubiquitin‐positive intraneuronal inclusions in the extra‐motor cortices in patients with amyotrophic lateral sclerosis. Neurosci Lett 129:233–236. [DOI] [PubMed] [Google Scholar]
  • 52. Okamoto K, Hirano A (1982) Bunina bodies in amyotrophic lateral sclerosis. Shinkeinaika 17:259–265. [Google Scholar]
  • 53. Okamoto K, Morimatsu M, Hirai S, Ishida Y (1980) Intracytoplasmic inclusions (Bunina bodies) in amyotrophic lateral sclerosis. Acta Pathol Jpn 30:591–597. [DOI] [PubMed] [Google Scholar]
  • 54. Okamoto K, Yamazaki T, Yamaguchi H, Shooji M, Hirai S (1988) Pathology of Clarke's nucleus in sporadic amyotrophic lateral sclerosis. Rinsho Shinkeigaku 28:536–542. [PubMed] [Google Scholar]
  • 55. Oyanagi K, Makifuchi T, Ikuta A (1983) A topographic and quantitative study of neurons in human spinal gray matter, with special reference to their changes in amyotrophic lateral sclerosis. Biomed Res 4:211–224. [Google Scholar]
  • 56. Prusiner SB (2001) Neurodegenerative diseases and prions. N Engl J Med 344:1516–1526. [DOI] [PubMed] [Google Scholar]
  • 57. Riggs JE (1996) Amyotrophic lateral sclerosis, heterogeneous susceptibility, trauma, and epidemiology. Arch Neurol 53:225–227. [DOI] [PubMed] [Google Scholar]
  • 58. Rossor MN, Revesz T, Lantos PL, Warrington EK (2000) Semantic dementia with ubiquitin‐positive tau‐negative inclusion bodies. Brain 123:267–276. [DOI] [PubMed] [Google Scholar]
  • 59. Rowland LP (1998) Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 160 (Suppl 1):S6–24. [DOI] [PubMed] [Google Scholar]
  • 60. Sasaki S, Maruyama S (1993) Ultrastructural study of Bunina bodies in the anterior horn neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett 154:117–120. [DOI] [PubMed] [Google Scholar]
  • 61. Sasaki S, Maruyama S (1994) Immunocytochemical and ultrastructural studies of the motor cortex in amyotrophic lateral sclerosis. Acta Neuropathol 87:578–585. [DOI] [PubMed] [Google Scholar]
  • 62. Schiffer D, Autilio‐Gambetti L, Chiò A, Gambetti P, Giordana MT, Gullotta F, Migheli A, Vigliani MC (1991) Ubiquitin in motor neuron disease: study at the light and electron microscope. J Neuropathol Exp Neurol 50:463–473. [DOI] [PubMed] [Google Scholar]
  • 63. Stieber A, Chen Y, Wei S, Mourelatos Z, Gonatas J, Okamoto K, Gonatas NK (1998) The fragmented neuronal Golgi apparatus in amyotrophic lateral sclerosis includes the trans‐Golgi‐network: functional implications. Acta Neuropathol 95:245–253. [DOI] [PubMed] [Google Scholar]
  • 64. Takahashi H, Ikuta F (1992) Bunina body in amyotrophic lateral sclerosis. No To Shinkei 44:525–532 (in Japanese). [PubMed] [Google Scholar]
  • 65. Takahashi H, Ohama E, Ikuta F (1991) Are Bunina bodies of endoplamic reticulum origin? An ultrastructural study of subthalamic eosinophilic inclusions in a case of atypical motor neuron disease. Acta Pathol Jpn 41:889–894. [DOI] [PubMed] [Google Scholar]
  • 66. Takahashi H, Ohama E, Ikuta F (1991) Motor neuron disease: two forms of Bunina body revealed by a method for ultrastructural study of conventional histological sections In: Neuropathology in Brain Research, Ikuta F (ed.), PP. 127–132, Excerpta Medica: Amsterdam . [Google Scholar]
  • 67. Takahashi H, Ohama E, Ikuta F, Tokiguchi S (1991) An autopsy case of atypical motor neuron disease with Bunina bodies in the lower motor and subthalamic neurons. Acta Pathol Jpn 41:46–51. [DOI] [PubMed] [Google Scholar]
  • 68. Takahashi H, Oyanagi K, Ikuta F (1993) The intermediolateral nucleus in sporadic amyotrophic lateral sclerosis. Acta Neuropathol 86:190–192. [DOI] [PubMed] [Google Scholar]
  • 69. Takahashi H, Oyanagi K, Ohama E, Ikuta F (1992) Clarke's column in sporadic amyotrophic lateral sclerosis. Acta Neuropathol 84:465–470. [DOI] [PubMed] [Google Scholar]
  • 70. Tomonaga M, Saito M, Yoshimura M, Shimada H, Tohgi H (1978) Ultrastructure of the Bunina bodies in anterior horn cells of amyotrophic lateral sclerosis. Acta Neuropathol 42:81–86. [DOI] [PubMed] [Google Scholar]
  • 71. Tsuchiya K, Ikeda K, Haga C, Kobayashi T, Morimatsu Y, Nakano I, Matsushita M (2001) Atypical amyotrophic lateral sclerosis with dementia mimicking frontal Pick's disease: a report of an autopsy case with a clinical course of 15 years. Acta Neuropathol 101:625–630. [DOI] [PubMed] [Google Scholar]
  • 72. Yamada M, Piao Y‐S, Toyoshima Y, Tsuji S, Takahashi H (2000) Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral‐pallidoluysian atrophy contain expanded polyglutamine stretches. Acta Neuropathol 99:615–618. [DOI] [PubMed] [Google Scholar]
  • 73. Yoshida S, Mitani K, Wakayama I, Kihira T, Yase Y (1995) Bunina body formation in amyotrophic lateral sclerosis: a morphometric‐statistical and trace element study featuring aluminum. J Neurol Sci 130:88–94. [DOI] [PubMed] [Google Scholar]
  • 74. Yoshida M, Murakami N, Hashizume Y, Itoh E, Takahashi A (1992) A clinicopathological study of two respirator‐aided long‐survival cases of amyotrophic lateral sclerosis. Rinsho Shinkeigaku 32:259–265. [PubMed] [Google Scholar]
  • 75. Yuasa R (1964) On amyotrophic lateral sclerosis with dementia. Rinsho Shinkeigaku 4:529–533. [Google Scholar]
  • 76. Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M, Takahashi H (1998) Accumulation of a‐synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96:445–452. [DOI] [PubMed] [Google Scholar]
  • 77. Wakabayashi K, Horikawa Y, Oyake M, Suzuki S, Morita T, Takahashi H (1998) Sporadic motor neuron disease with severe sensory neuronopathy. Acta Neuropathol 95:426–430. [DOI] [PubMed] [Google Scholar]
  • 78. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/a‐synuclein‐positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson's disease brains. Acta Neuropathol 99:14–20. [DOI] [PubMed] [Google Scholar]
  • 79. Wakabayashi K, Piao Y‐S, Hayashi S, Kakita A, Yamada M, Takahashi H (2001) Ubiquitinated neuronal inclusions in the neostriatum in patients with amyotrophic lateral sclerosis with and without dementia—A study of 60 patients 31 to 87 years of age. Clin Neuropathol 20:47–52. [PubMed] [Google Scholar]
  • 80. Wightman G, Anderson VER, Martin J, Swash M, Anderton BH, Neary D, Mann D, Luthert P, Leigh PN (1992) Hippocampal and neocortical uniquitin‐immunoreactive inclusions in amyotrophic lateral sclerosis with dementia. Neurosci Lett 139:269–274. [DOI] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES