Deciphering amyotrophic lateral sclerosis: What phenotype, neuropathology and genetics are telling us about pathogenesis

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

Volumn 14, Issue SUPPL1, 2013, Pages 5-18

  Ravits, John ^a   Appel, Stanley ^b   Baloh, Robert H ^c   Barohn, Richard ^d   Rix Brooks, Benjamin ^e   Elman, Lauren ^f   Floeter, Mary Kay ^g   Henderson, Christopher ^h   Lomen Hoerth, Catherine ⁱ   MacKlis, Jeffrey D ^j   McCluskey, Leo ^f   Mitsumoto, Hiroshi ^h   Przedborski, Serge ^h   Rothstein, Jeffrey ^k   Trojanowski, John Q ^l   Van Den Berg, Leonard H ^m   Ringel, Steven ⁿ  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b HOUSTON METHODIST RESEARCH INSTITUTE   (United States)

^c CEDARS SINAI MEDICAL CENTER   (United States)

^d UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF NORTH CAROLINA AT CHARLOTTE   (United States)

^f PENNSYLVANIA HOSPITAL   (United States)

^g NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE   (United States)

^h NewYork Presbyterian Hospital   (United States)

ⁱ UNIVERSITY OF CALIFORNIA   (United States)

^j HARVARD UNIVERSITY   (United States)

^k JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^l UNIVERSITY OF PENNSYLVANIA   (United States)

^m UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

ⁿ UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

more..

Author keywords

ALS; FTD; Motor neuron disease; PLS; PMA

Indexed keywords

ALPHA SYNUCLEIN; RIBONUCLEOPROTEIN; DNA BINDING PROTEIN; PROTEIN TDP-43;

AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; BRAIN DEVELOPMENT; BULBAR PARALYSIS; CELL DEATH; CELL INCLUSION; CELL INTERACTION; DOMINANT GENE; FRONTOTEMPORAL DEMENTIA; GENE MUTATION; HUMAN; MOTONEURON; NERVE DEGENERATION; NEUROPATHOLOGY; PATHOGENESIS; PHENOTYPE; PRIMARY LATERAL SCLEROSIS; PRIORITY JOURNAL; PROGRESSIVE MUSCULAR ATROPHY; PSEUDOBULBAR PALSY; RNA PROCESSING; TDP 43 PROTEINOPATHY; DISEASE COURSE; GENETICS; LIMB; MUTATION; PATHOLOGY; PATHOPHYSIOLOGY;

AMYOTROPHIC LATERAL SCLEROSIS; DISEASE PROGRESSION; DNA-BINDING PROTEINS; EXTREMITIES; HUMANS; MOTOR NEURONS; MUTATION; PHENOTYPE;

EID: 84877871521     PISSN: 21678421     EISSN: 21679223     Source Type: Journal    
DOI: 10.3109/21678421.2013.778548     Document Type: Article

References (128)

1. Ravits J, Laurie P, Fan Y, Moore DH. Implications of ALS focality: rostral-caudal distribution of lower motor neuron loss post mortem. Neurology. 2007; 68: 1576-82. Epub 2007/05/09.
2. Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primar y Lateral Sclerosis-Clinical Features, Neuropathology and Diagnostic Criteria. Brain. 1992; 115: 495-520.
3. Rowland LP. Primary lateral sclerosis: disease, syndrome, both or neither? J Neurol Sci. 1999; 170: 1-4.
4. Swash M, Desai J, Misra VP. What is primary lateral sclerosis? J Neurol Sci. 1999; 170: 5-10.
5. Le Forestier N, Maisonobe T, Piquard A, Rivaud S, Crevier-Buchman L, Salachas F, et al. Does primary lateral sclerosis exist? A study of 20 patients and a review of the literature. Brain. 2001; 124: 1989-99.
6. Zhai P, Pagan F, Statland J, Butman JA, Floeter MK. Primary lateral sclerosis: a heterogeneous disorder composed of different subtypes? Neurology. 2003; 60: 1258-65.
7. Singer MA, Kojan S, Barohn RJ, Herbelin L, Nations SP, Trivedi JR, et al. Primary Lateral Sclerosis: clinical and laboratory features in 25 Patients. Journal of Clinical Neu-romuscular Disease. 2005; 7: 1-9. Epub 2005/09/01.
8. Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, Mitsumoto H, et al. The natural history of primary lateral sclerosis. Neurology. 2006; 66: 647-53.
9. Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle & Nerve. 2007; 35: 291-302. Epub 2007/01/11.
10. Tartaglia MC, Rowe A, Findlater K, Orange JB, Grace G, Strong MJ. Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up. Archives of Neurology. 2007; 64: 232-6.
11. Gordon PH, Cheng B, Katz IB, Mitsumoto H, Rowland LP. Clinical features that distinguish PLS, upper motor neuron-dominant ALS, and typical ALS. Neurology. 2009; 72: 1948-52.
12. Floeter MK, Mills R. Progression in primary lateral sclerosis: a prospective analysis. Amyotrophic lateral sclerosis: offi cial publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2009; 10: 339-46. Epub 2009/11/20.
13. Soraru G, Ermani M, Logroscino G, Palmieri A, D'Ascenzo C, Orsetti V, et al. Natural history of upper motor neurondominant ALS. Amyotrophic lateral sclerosis: offi cial publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2010; 11: 424-9. Epub 2009/11/26.
14. Grace GM, Orange JB, Rowe A, Findlater K, Freedman M, Strong MJ. Neuropsychological functioning in PLS: a comparison with ALS. The Canadian Journal of Neurological Sciences. 2011; 38: 88-97. Epub 2010/12/16.
15. Brugman F, Veldink JH, Franssen H, de Visser M, de Jong JM, Faber CG, et al. Differentiation of hereditary spastic paraparesis from primary lateral sclerosis in sporadic adult-onset upper motor neuron syndromes. Archives of Neurology. 2009; 66: 509-14. Epub 2009/04/15.
16. Visser J, van den Berg Vos RM, Franssen H, van den Berg LH, Wokke JH, de Jong JMV, et al. Disease course and prognostic factors of progressive muscular atrophy. Archives of Neurology. 2007; 64: 522-8.
17. Kim WK, Liu X, Sandner J, Pasmantier M, Andrews J, Rowland LP, et al. Study of 962 patients indicates progressive muscular atrophy is a form of ALS. Neurology. 2009; 73: 1686-92. Epub 2009/11/18.
18. van den Berg-Vos RM, Visser J, Kalmijn S, Fischer K, de Visser M, de Jong V, et al. A Long-term Prospective Study of the Natural Course of Sporadic Adult-Onset Lower Motor Neuron Syndromes. Archives of Neurology. 2009; 66: 751-7.
19. Wijesekera LC, Mathers S, Talman P, Galtrey C, Parkinson MH, Ganesalingam J, et al. Natural history and clinical features of the fl ail arm and fl ail leg ALS variants. Neurology. 2009; 72: 1087-94. Epub 2009/03/25.
20. Raaphorst J, de Visser M, van Tol MJ, Linssen WHJP, van der Kooi AJ, de Haan RJ, et al. Cognitive dysfunction in lower motor neuron disease: executive and memory defi cits in progressive muscular atrophy. J Neurol Neurosur Ps. 2011; 82: 170-5.
21. Cosottini M, Giannelli M, Siciliano G, Lazzarotti G, Michelassi MC, del Corona A, et al. Diffusion-tensor MR imaging of corticospinal tract in amyotrophic lateral sclerosis and progressive muscular atrophy. Radiology. 2005; 237: 258-64. Epub 2005/09/27.
22. Sach M, Winkler G, Glauche V, Lieper t J, Heimbach B, Koch MA, et al. Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis. Brain. 2004; 127: 340-50.
23. van der Graaff MM, Sage CA, Caan MWA, Akkerman EM, Lavini C, Majoie CB, et al. Upper and extra-motor neuron involvement in early motor neuron disease: a diffusion tensor imaging study. Brain. 2011; 134: 1211-28.
24. Kaufmann P, Pullman SL, Shungu DC, Chan S, Hays AP, Del Bene ML, et al. Objective tests for upper motor neuron involvement in amyotrophic lateral sclerosis (ALS). Neurology. 2004; 62: 1753-7. Epub 2004/05/26.
25. Mitsumoto H, Ulug AM, Pullman SL, Gooch CL, Chan S, Tang MX, et al. Quantitative objective markers for upper and lower motor neuron dysfunction in ALS. Neurology. 2007; 68: 1402-10.
26. Floyd AG, Yu QP, Piboolnurak P, Tang MX, Fang Y, Smith W A, et al. Transcranial magnetic stimulation in ALS: utility of central motor conduction tests. Neurology. 2009; 72: 498-504. Epub 2009/02/11.
27. Turner MR, Scaber J, Goodfellow JA, Lord ME, Marsden R, Talbot K. The diagnostic pathway and prognosis in bul-bar-onset amyotrophic lateral sclerosis. J Neurol Sci. 2010; 294: 81-5.
28. Aydogdu I, Tanriverdi Z, Ertekin C. Dysfunction of bulbar central pattern generator in ALS patients with dysphagia during sequential deglutition. Clin Neurophysiol. 2011; 122: 1219-28.
29. Kollewe K, Munte TF, Samii A, Dengler R, Petri S, Mohammadi B. Patterns of cortical activity differ in ALS patients with limb and/or bulbar involvement depending on motor tasks. Journal of Neurology. 2011; 258: 804-10. Epub 2010/12/04.
30. Katz JS, Wolfe GI, Andersson PB, Saperstein DS, Elliott JL, Nations SP, et al. Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder. Neurology. 1999; 53: 1071-6.
31. Rosenfeld J, Chang SW, Jackson CE, Elchami Z, Barohn RJ. Lower Extremity Amyotrophic Diplegia (LAD): a new clinical entity in the spectrum of motor neuron disease. Neurology. 2002; 58: 411-2.
32. Muzyka IM, Dimachkie MM, Barohn RJ, Katz JS, Jackson CE, Wang YX, et al. Lower Extemity Amyotrophic Diplegia (LAD): Prevalence and Pattern of Weakness. Neurology. 2010; 74: 467.
33. Turner MR, Gerhard A, Al-Chalabi A, Shaw CE, Hughes RAC, Banati RB, et al. Mills'and other isolated upper motor neuron syndromes: in vivo study with C-11-(R)-PK11195 PET. J Neurol Neurosur Ps. 2005; 76: 871-4.
34. Kiernan JA, Hudson AJ. Frontal lobe atrophy in motor neuron diseases. Brain. 1994; 117: 747-57. Epub 1994/08/01.
35. Abe K, Fujimura H, Toyooka K, Sakoda S, Yorifuji S, Yanagihara T. Cognitive function in amyotrophic lateral sclerosis. J Neurol Sci. 1997; 148: 95-100. Epub 1997/05/01.
36. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002; 59: 1077-9.
37. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. Are amyotrophic lateral sclerosis patients cognitively normal? Neurology. 2003; 60: 1094-7.
38. Strong MJ, Grace GM, Freedman M, Lomen-Hoerth C, Woolley S, Goldstein LH, et al. Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis: offi cial publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2009; 10: 131-46. Epub 2009/05/23.
39. Gordon PH, Goetz RR, Rabkin JG, Dalton K, McElhiney M, Hays AP, et al. A prospective cohort study of neuropsy-chological test performance in ALS. Amyotrophic lateral sclerosis: offi cial publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 2010; 11: 312-20. Epub 2010/03/17.
40. Olney RK, Murphy J, Forshew D, Garwood E, Miller BL, Langmore S, et al. The effects of executive and behavioral dysfunction on the course of ALS. Neurology. 2005; 65: 1774-7.
41. Farnikova K, Kanovsky P, Nestrasil I, Otruba P. Coexistence of Parkinsonism, dementia and upper motor neuron syndrome in four Czech patients. J Neurol Sci. 2010; 296: 47-54. Epub 2010/07/14.
42. Gamez J, Corbera-Bellalta M, Mila M, Lopez-Lisbona R, Boluda S, Ferrer I. Chorea-ballism associated with familial amyotrophic lateral sclerosis. A clinical, genetic, and neu-ropathological study. Movement disorders: offi cial journal of the Movement Disorder Society. 2008; 23: 434-8. Epub 2007/12/12.
43. Gilbert RM, Fahn S, Mitsumoto H, Rowland LP. Parkin-sonism and motor neuron diseases: 27 patients with diverse overlap syndromes. Movement disorders: offi cial journal of the Movement Disorder Society. 2010; 25: 1868-75. Epub 2010/07/30.
44. Knirsch UI, Bachus R, Gosztonyi G, Zschenderlein R, Ludolph AC. Clinicopathological study of atypical motor neuron disease with vertical gaze palsy and ballism. Acta Neuropathologica. 2000; 100: 342-6. Epub 2000/08/31.
45. Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, et al. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Movement disorders: offi cial journal of the Movement Disorder Society. 2009; 24: 1843-7. Epub 2009/07/18.
46. Pradat PF, Salachas F, Cartalat-Carel S, Lacomblez L, Patte N, Leforestier N, et al. Association of chorea and motor neuron disease. Movement Disord. 2002; 17: 419-20.
47. Inoue A, Kumon Y, Fujiwara S, Watanabe H, Fukumoto SY, Ohue S, et al. A case of emergency carotid endarterec-tomy for severe stenosis of the cervical internal carotid artery presenting with progressing stroke: importance of managing blood pressure postoperatively. Neurol Surg Tokyo. 2006; 34: 289-95.
48. Averbuch-Heller L, Helmchen C, Horn AKE, Leigh RJ, Buttner-Ennever JA. Slow vertical saccades in motor neuron disease: correlation of structure and function. Ann Neurol. 1998; 44: 641-8.
49. Palmowski A, Jost WH, Osterhage J, Prudlo J, Kasmann B, Schimrigk K, et al. Disorders of eye movement in amyo-trophic lateral sclerosis: report of two patients. Klinische Monatsblatter fur Augenheilkunde. 1995; 206: 170-2. Epub 1995/03/01.
50. Okuda B, Yamamoto T, Yamasaki M, Maya K, Imai T. Motor Neuron Disease with Slow Eye Movements and Vertical Gaze Palsy. Acta Neurologica Scandinavica. 1992; 85: 71-6.
51. Donaghy C, Thurtell MJ, Pioro EP, Gibson JM, Leigh RJ. Eye movements in amyotrophic lateral sclerosis and its mimics: a review with illustrative cases. Journal of Neurology, Neurosurgery, and Psychiatry. 2011; 82: 110-6. Epub 2010/11/26.
52. Grosskreutz J, Kaufmann J, Fradrich J, Dengler R, Heinze HJ, Peschel T. Widespread sensorimotor and frontal cortical atrophy in amyotrophic lateral sclerosis. BMC Neurology. 2006; 6: 17. Epub 2006/04/28.
53. van der Graaff MM, de Jong JM, Baas F, de Visser M. Upper motor neuron and extra-motor neuron involvement in amyotrophic lateral sclerosis: a clinical and brain imaging review. Neuromuscular Disorders. 2009; 19: 53-8. Epub 2008/12/17.
54. Dupuis L, Pradat PF, Ludolph AC, Loeffl er JP. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurology. 2011; 10: 75-82. Epub 2010/11/03.
55. McCluskey LF, Elman LB, Martinez-Lage M, van Deerlin V, Yuan WX, Clay D, et al. Amyotrophic Lateral Sclerosis-Plus Syndrome With TAR DNA-Binding Protein-43 Pathology. Archives of Neurology. 2009; 66: 121-4.
56. Ince PG, Evans J, Knopp M, Forster G, Hamdalla HHM, Wharton SB, et al. Corticospinal tract degeneration in the progressive muscular atrophy variant of ALS. Neurology. 2003; 60: 1252-8.
57. Geser F, Stein B, Partain M, Elman LB, McCluskey LF, Xie SX, et al. Motor neuron disease clinically limited to the lower motor neuron is a diffuse TDP-43 proteinopathy. Acta Neuropathologica. 2011; 121: 509-17. Epub 2011/01/13.
58. Kobayashi Z, Tsuchiya K, Arai T, Yokota O, Yoshida M, Shimomura Y, et al. Clinicopathological characteristics of FTLD-TDP showing corticospinal tract degeneration but lacking lower motor neuron loss. J Neurol Sci. 2010; 298: 70-7. Epub 2010/09/03.
59. Kosaka T, Fu YJ, Shiga A, Ishidaira H, Ta n CF, Tani T, et al. Primary lateral sclerosis: upper motor-predominant amyotrophic lateral sclerosis with frontotemporal lobar degeneration: immunohistochemical and biochemical analyses of TDP-43. Neuropathology: offi cial journal of the Japanese Society of Neuropathology. 2012; 32: 373-84. Epub 2011/11/22.
60. Leigh PN, Anderton BH, Dodson A, Gallo JM, Swash M, Power DM. Ubiquitin Deposits in Anterior Horn Cells in Motor Neuron Disease. Neuroscience Letters. 1988; 93: 197-203.
61. Lowe J, Lennox G, Jefferson D, Morrell K, Mcquire D, Gray T, et al. A Filamentous Inclusion Body within Anterior Horn Neurons in Motor Neuron Disease Defi ned by Immunocytochemical Localization of Ubiquitin. Neuroscience Letters. 1988; 94: 203-10.
62. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314: 130-3.
63. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Bioph Res Co. 2006; 351: 602-11.
64. Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, et al. Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Archives of Neurology. 2008; 65: 636-41. Epub 2008/05/14.
65. Andersen PM, Al-Chalabi A. Clinical genetics of amyo-trophic lateral sclerosis: what do we really know? Nature reviews. Neurology. 2011; 7: 603-15. Epub 2011/10/13.
66. Corcia P, Valdmanis P, Millecamps S, Lionnet C, Blasco H, Mouzat K, et al. Phenotype and genotype analysis in amyo-trophic lateral sclerosis with TARDBP gene mutations. Neurology. 2012; 78: 1519-26. Epub 2012/04/28.
67. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, van den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathologica. 2012; 124: 339-52. Epub 2012/08/21.
68. Mackenzie IRA, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007; 61: 427-34.
69. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, et al. p62 positive, TDP-43-negative, neuronal cyto-plasmic and intranuclear inclusions in the cerebellum and hippocampus defi ne the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathologica. 2011; 122: 691-702. Epub 2011/11/22.
70. Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklos L, Bell C, et al. An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neu-ropathology: offi cial journal of the Japanese Society of Neu-ropathology. 2011. Epub 2011/12/21.
71. Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, Strong MJ, et al. Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the signifi cance of glial pathology. Acta Neu-ropathologica. 2011; 122: 657-71.
72. Cudkowicz ME, McKenna-Yasek D, Chen C, Hedley-Whyte ET, Brown RH Jr. Limited corticospinal tract involvement in amyotrophic lateral sclerosis subjects with the A4V mutation in the copper/zinc superoxide dismutase gene. Ann Neurol. 1998; 43: 703-10. Epub 1998/06/18.
73. Ince PG, Tomkins J, Slade JY, Thatcher NM, Shaw PJ. Amyotrophic lateral sclerosis associated with genetic abnormalities in the gene encoding Cu/Zn superoxide dismutase: molecular pathology of fi ve new cases, and comparison with previous reports and 73 sporadic cases of ALS. J Neuropath Exp Neur. 1998; 57: 895-904.
74. Forsberg K, Jonsson PA, Andersen PM, Bergemalm D, Graffmo KS, Hultdin M, et al. Novel Antibodies Reveal Inclusions Containing Non-Native SOD1 in Sporadic ALS Patients. PloS One. 2010; 5.
75. Bosco DA, Morfi ni G, Karabacak NM, Song YY, Gros-Louis F, Pasinelli P, et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010; 13: 1396-1403.
76. Liu HN, Sanelli T, Horne P, Pioro EP, Strong MJ, Rogaeva E, et al. Lack of Evidence of Monomer/Misfolded Superoxide Dismutase-1 in Sporadic Amyotrophic Lateral Sclerosis. Ann Neurol. 2009; 66: 75-80.
77. Kerman A, Liu HN, Croul S, Bilbao J, Rogaeva E, Zinman L, et al. Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form. Acta Neuropathologica. 2010; 119: 335-44.
78. Brotherton TE, Li YJ, Cooper D, Gearing M, Julien JP, Rothstein JD, et al. Localization of a toxic form of superoxide dismutase-1 protein to pathologically affected tissues in familial ALS. P Natl Acad Sci USA. 2012; 109: 5505-10.
79. Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, Manavis J, et al. FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosur Ps. 2010; 81: 639-45.
80. Mackenzie IRA, Ansorge O, Strong M, Bilbao J, Zinman L, Ang LC, et al. Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neu-ropathologica. 2011; 122: 87-98.
81. Baumer D, Hilton D, Paine SML, Turner MR, Lowe J, Talbot K, et al. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology. 2010; 75: 611-8.
82. Deng HX, Zhai H, Bigio EH, Yan J, Fecto F, Ajroud K, et al. FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol. 2010; 67: 739-48. Epub 2010/06/03.
83. Ravits JM, La Spada AR. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology. 2009; 73: 805-11.
84. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology. 2007; 68: 1571-5. Epub 2007/05/09.
85. van den Heuvel MP, Mandl RCW, Kahn RS, Pol HEH. Functionally Linked Resting-State Networks Refl ect the Underlying Structural Connectivity Architecture of the Human Brain. Hum Brain Mapp. 2009; 30: 3127-41.
86. Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative Diseases Target Large-Scale Human Brain Networks. Neuron. 2009; 62: 42-52.
87. Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting Regional Neurodegeneration from the Healthy Brain Functional Connectome. Neuron. 2012; 73: 1216-27.
88. Douaud G, Filippini N, Knight S, Talbot K, Turner MR. Integration of structural and functional magnetic resonance imaging in amyotrophic lateral sclerosis. Brain. 2011; 134: 3470-9. Epub 2011/11/15.
89. Verstraete E, Veldink JH, Mandl RCW, van den Berg LH, van den Heuvel MP. Impaired Structural Motor Connec-tome in Amyotrophic Lateral Sclerosis. PloS One. 2011; 6.
90. Mohammadi B, Kollewe K, Samii A, Dengler R, Munte TF. Functional Neuroimaging at Different Disease Stages Reveals Distinct Phases of Neuroplastic Changes in Amyo-trophic Lateral Sclerosis. Hum Brain Mapp. 2011; 32: 750-8.
91. Turner MR, Brockington A, Scaber J, Hollinger H, Marsden R, Shaw PJ, et al. Pattern of spread and prognosis in lower limb-onset ALS. Amyotroph Lateral Scler. 2010; 11: 369-73.
92. Korner S, Kollewe K, Fahlbusch M, Zapf A, Dengler R, Krampfl K, et al. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis. Muscle & Nerve. 2011; 43: 636-42. Epub 2011/04/13.
93. Chio A, Calvo A, Moglia C, Mazzini L, Mora G, group Ps. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. Journal of Neurology, Neurosur-gery, and Psychiatry. 2011; 82: 740-6. Epub 2011/03/16.
94. Fujimura-Kiyono C, Kimura F, Ishida S, Nakajima H, Hosokawa T, Sugino M, et al. Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. 2011; 82: 1244-9. Epub 2011/09/17.
95. Gargiulo-Monachelli GM, Janota F, Bettini M, Shoesmith CL, Strong MJ, Sica RE. Regional spread pattern predicts survival in patients with sporadic amyotrophic lateral sclerosis. European journal of neurology: the offi cial journal of the European Federation of Neurological Societies. 2012; 19: 834-41. Epub 2012/01/18.
96. Kanouchi T, Ohkubo T, Yokota T. Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? J Neurol Neurosur Ps. 2012; 83: 739-45.
97. Ganesalingam J, Stahl D, Wijesekera L, Galtrey C, Shaw CE, Leigh PN, et al. Latent cluster analysis of ALS phenotypes identifi es prognostically differing groups. PloS One. 2009; 4: 7107. Epub 2009/09/23.
98. Yang WC, Strong MJ. Widespread neuronal and glial hyper-phosphorylated tau deposition in ALS with cognitive impairment. Amyotroph Lateral Scler. 2012; 13: 178-93.
99. Desport JC, Torny F, Lacoste M, Preux PM, Couratier P. Hypermetabolism in ALS: correlations with clinical and paraclinical parameters. Neuro-degenerative Diseases. 2005; 2: 202-7. Epub 2006/08/16.
100. Muller FL, Song W, Jang YC, Liu Y, Sabia M, Richardson A, et al. Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am J Physiol-Reg I. 2007; 293: 1159-68.
101. Bogdanov M, Brown RH, Matson W, Smart R, Hayden D, O'Donnell H, et al. Increased oxidative damage to DNA in ALS patients. Free Radical Bio Med. 2000; 29: 652-8.
102. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, et al. Wild-type non-neuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science. 2003; 302: 113-7. Epub 2003/10/04.
103. Yamanaka K, Boillee S, Roberts EA, Garcia ML, McAlonis-Downes M, Mikse OR, et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. P Natl Acad Sci USA. 2008; 105: 7594-9.
104. Rothstein JD, Martin LJ, Kuncl RW. Decreased Glutamate Transport by the Brain and Spinal-Cord in Amyotrophic Lateral Sclerosis. New Engl J Med. 1992; 326: 1464-8.
105. Rothstein JD, Martin L, Levey AI, Dykeshoberg M, Jin L, Wu D, et al. Localization of Neuronal and Glial Glutamate Transporters. Neuron. 1994; 13: 713-25.
106. Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyo-trophic lateral sclerosis (ALS). Proc Natl Acad Sci U S A. 2002; 99: 1604-9. Epub 2002/01/31.
107. Beers DR, Henkel JS, Xiao Q, Zhao WH, Wang JH, Yen AA, et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. P Natl Acad Sci U S A. 2006; 103: 16021-6.
108. Beers DR, Henkel JS, Zhao WH, Wang JH, Huang AL, Wen SX, et al. Endogenous regulatory T-lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain. 2011; 134: 1293-314.
109. Zhao WH, Beers DR, Henkel JS, Zhang W, Urushitani M, Julien JP, et al. Extracellular Mutant SOD1 Induces Micro-glial-Mediated Motoneuron Injury. Glia. 2010; 58: 231-43.
110. Buratti E, Baralle FE. Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Frontiers in Bioscience: a journal and virtual library. 2008; 13: 867-78. Epub 2007/11/06.
111. Lagier-Tourenne C, Polymenidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Human Molecular Genetics. 2010; 19: 46-64. Epub 2010/04/20.
112. Lagier-Tourenne C, Cleveland D W. Rethinking ALS: the FUS about TDP-43. Cell. 2009; 136: 1001-4. Epub 2009/03/24.
113. Nagai M, Abe K, Okamoto K, Itoyama Y. Identifi cation of alternative splicing forms of GLT-1 mRNA in the spinal cord of amyotrophic lateral sclerosis patients. Neuroscience Letters. 1998; 244: 165-8.
114. Rabin SJ, Kim JM, Baughn M, Libby RT, Kim YJ, Fan YX, et al. Sporadic ALS has compartment-specifi c aberrant exon splicing and altered cell-matrix adhesion biology. Human Molecular Genetics. 2010; 19: 313-28.
115. Lin CLG, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, et al. Aberrant RNA processing in a neurode-generative disease: the cause for absent EAAT2 a glutamate transporter, in amyotrophic lateral sclerosis. Neuron. 1998; 20: 589-602.
116. Aizawa H, Sawada J, Hideyama T, Yamashita T, Katayama T, Hasebe N, et al. TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2. Acta Neuropathologica. 2010; 120: 75-84.
117. Kawahara Y, Ito K, Sun H, Aizawa H, Kanazawa I, Kwak S. Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004; 427: 801.
118. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang XD, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010; 466: 1069-77.
119. Voigt A, Herholz D, Fiesel FC, Kaur K, Muller D, Karsten P, et al. TDP-43-Mediated Neuron Loss In Vivo Requires RNA-Binding Activity. PloS One. 2010; 5.
120. Polymenidou M, Cleveland D W. The seeds of neurodegen-eration: prion-like spreading in ALS. Cell. 2011; 147: 498-508. Epub 2011/11/01.
121. Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem. 2011; 286: 18664-72. Epub 2011/04/02.
122. Grad LI, Guest WC, Yanai A, Pokrishevsky E, O'Neill MA, Gibbs E, et al. Intermolecular transmission of superoxide dismutase-1 misfolding in living cells. Proc Natl Acad Sci U S A. 2011; 108: 16398-403. Epub 2011/09/21.
123. Munch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. P Natl Acad Sci U S A. 2011; 108: 3548-53.
124. Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A, et al. Exogenous alpha-synuclein fi brils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011; 72: 57-71. Epub 2011/10/11.
125. Ozdinler PH, Benn S, Yamamoto TH, Guzel M, Brown RH, Macklis JD. Corticospinal Motor Neurons and Related Subcerebral Projection Neurons Undergo Early and Specifi c Neurodegeneration in hSOD1(G93A) Trans-genic ALS Mice. Journal of Neuroscience. 2011; 31: 4166-77.
126. MacDonald JL, Fame RM, Azim E, Shnider SJ, Molyneaux BJ, Arlotta P, Macklis JD. Specifi cation of cortical projection neurons: transcriptional mechanisms. Developmental neuroscience: a comprehensive reference. 2012.
127. Molyneaux BJ, Arlotta P, Menezes JRL, Macklis JD. Neuronal subtype specifi cation in the cerebral cortex. Nature Reviews Neuroscience. 2007; 8: 427-37.
128. Woodworth MB, Custo Greig L, Kriegstein AR, Macklis JD. SnapShot: cortical development. Cell. 2012; 151: 918-918.e1.