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Stages of pTDP‐43 pathology in amyotrophic lateral sclerosis

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Brettschneider, Johannes, Del Tredici, Kelly, Toledo, Jon B., Robinson, John L., Irwin, David J., Grossman, Murray, Suh, EunRan, Van Deerlin, Vivianna M. +12 more·2013·Annals of Neurology
DOI 10.1002/ana.23937PMC PMC3785076
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Abstract

Objective: To see whether the distribution patterns of phosphorylated 43kDa TAR DNA‐binding protein (pTDP‐43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages. Methods: pTDP‐43 immunohistochemistry was performed on 70μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background. Results: ALS cases with the lowest burden of pTDP‐43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X–XII, and spinal cord α‐motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP‐43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP‐43 lesions showed pTDP‐43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP‐43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP‐43 pathology. Interpretation: pTDP‐43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP‐43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP‐43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS. Ann Neurol 2013;74:20–38

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  1. [2]Neumann M Sampathu DM Kwong LK Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science 6 10 2006 314 5796 130 3 17023659
  2. [3]Lee EB Lee VM Trojanowski JQ Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration Nature reviews Neuroscience 1 2012 13 1 38 50 PMC3285250 22127299
  3. [4]Braak H Thal DR Ghebremedhin E Del Tredici K Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years Journal of neuropathology and experimental neurology 11 2011 70 11 960 969 22002422 This is the correct reference and not Braak et al. 2006.
  4. [5]Braak H Del Tredici K Where, when, and in what form does sporadic Alzheimer’s disease begin? Current opinion in neurology 12 2012 25 6 708 14 23160422
  5. [6]Braak H Del Tredici K Rüb U de Vos RA Jansen Steur EN Braak E Staging of brain pathology related to sporadic Parkinson’s disease Neurobiology of aging Mar-Apr 2003 24 2 197 211 12498954
  6. [10]Mougenot AL Bencsik A Nicot S Transmission of prion strains in a transgenic mouse model overexpressing human A53T mutated alpha-synuclein Journal of neuropathology and experimental neurology 5 2011 70 5 377 85 21487306
  7. [11]Volpicelli-Daley LA Luk KC Patel TP Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death Neuron 6 10 2011 72 1 57 71 21982369 PMC3204802
  8. [12]Luk KC Kehm VM Zhang B O’Brien P Trojanowski JQ Lee VM Intracerebral inoculation of pathological alpha-synuclein initiates a rapidly progressive neurodegenerative alpha-synucleinopathy in mice The Journal of experimental medicine 7 5 2012 209 5 975 86 22508839 PMC3348112
  9. [13]Luk KC Kehm V Carroll J Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice Science 16 11 2012 338 6109 949 53 23161999 PMC3552321
  10. [14]Cushman M Johnson BS King OD Gitler AD Shorter J Prion-like disorders: blurring the divide between transmissibility and infectivity Journal of cell science 15 4 2010 123 Pt 8 1191 201 20356930 PMC2848109
  11. [15]Brooks BR Miller RG Swash M Munsat TL El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders: official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 12 2000 1 5 293 9 11464847
  12. [18]Xie SX Baek Y Grossman M Building an integrated neurodegenerative disease database at an academic health center Alzheimer’s & dementia: the journal of the Alzheimer’s Association 7 2011 7 4 e84 93 PMC3145967 21784346
  13. [19]Kanouchi T Ohkubo T Yokota T Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation? Journal of neurology, neurosurgery, and psychiatry 7 2012 83 7 739 45 PMC3368493 22544947
  14. [20]Neary D Snowden JS Gustafson L Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria Neurology 12 1998 51 6 1546 54 9855500
  15. [21]Rascovsky K Hodges JR Knopman D Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia Brain: a journal of neurology 9 2011 134 Pt 9 2456 77 21810890 PMC3170532
  16. [22]Gorno-Tempini ML Hillis AE Weintraub S Classification of primary progressive aphasia and its variants Neurology 15 3 2011 76 11 1006 14 21325651 PMC3059138
  17. [23]Duda JE Giasson BI Mabon ME Lee VM Trojanowski JQ Novel antibodies to synuclein show abundant striatal pathology in Lewy body diseases Annals of neurology 8 2002 52 2 205 10 12210791
  18. [24]Neumann M Kwong LK Lee EB Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies Acta neuropathologica 2 2009 117 2 137 49 19125255 PMC2693625
  19. [25]Lee EB Leng LZ Zhang B Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice The Journal of biological chemistry 17 2 2006 281 7 4292 9 16361260
  20. [26]Uryu K Nakashima-Yasuda H Forman MS Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies Journal of neuropathology and experimental neurology 6 2008 67 6 555 64 18520774 PMC3659339
  21. [27]Geser F Brandmeir NJ Kwong LK Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis Arch Neurol 5 2008 65 5 636 41 18474740
  22. [28]Feldengut S Del Tredici K Braak H Paraffin sections of 70-100 μm: A novel technique and its benefits for studying the nervous system Journal of neuroscience methods 25 3 2013 doi:10.1016/j.neumeth.2013.03.010. [Epub ahead of print] 23537935 · DOI
  23. [29]Brettschneider J Van Deerlin VM Robinson JL Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion Acta neuropathologica 6 2012 123 6 825 39 22426854 PMC3521561
  24. [30]Deng HX Chen W Hong ST Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature 8 9 2011 477 7363 211 5 21857683 PMC3169705
  25. [31]Van Deerlin VM Leverenz JB Bekris LM TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis Lancet neurology 5 2008 7 5 409 16 18396105 PMC3546119
  26. [32]Braak H Rüb U Del Tredici K Involvement of precerebellar nuclei in multiple system atrophy Neuropathology and applied neurobiology 2 2003 29 1 60 76 12581341
  27. [33]Braak H Braak E Neuronal types in the striatum of man Cell and tissue research 11 1982 227 2 319 342 6185228
  28. [34]Schmidt S Braak E Braak H Parvalbumin-immunoreactive structures of the adult human entorhinal and transentorhinal region Hippocampus 10 1993 3 4 459 70 8269037
  29. [36]Ozawa T Paviour D Quinn NP The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations Brain: a journal of neurology 12 2004 127 Pt 12 2657 71 15509623
  30. [37]Ravits JM La Spada AR ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration Neurology 8 9 2009 73 10 805 11 19738176 PMC2739608
  31. [38]Ravits J Paul P Jorg C Focality of upper and lower motor neuron degeneration at the clinical onset of ALS Neurology 8 5 2007 68 19 1571 5 17485643
  32. [39]Ravits J Laurie P Fan Y Implications of ALS focality: rostral-caudal distribution of lower motor neuron loss postmortem Neurology 8 5 2007 68 19 1576 82 17485644
  33. [40]Nishihira Y Tan CF Hoshi Y Sporadic amyotrophic lateral sclerosis of long duration is associated with relatively mild TDP-43 pathology Acta neuropathologica 1 2009 117 1 45 53 18923836
  34. [41]Brettschneider J Libon DJ Toledo JB Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis Acta neuropathologica 1 1 2012 PMC3595560 22210083
  35. [42]Mori F Tanji K Zhang HX Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia Acta neuropathologica 8 2008 116 2 193 203 18560845
  36. [44]Philips T Bento-Abreu A Nonneman A Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis Brain: a journal of neurology 2 2013 136 Pt 2 471 82 23378219 PMC3572934
  37. [45]Mackenzie IR Bigio EH Ince PG Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology 5 2007 61 5 427 34 17469116
  38. [46]Hirano A Neuropathology of ALS: an overview Neurology 10 1996 47 4 Suppl 2 S63 6 8858053
  39. [47]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 9 2012 124 3 339 52 22903397
  40. [48]Okamoto K Hirai S Amari M Oculomotor nuclear pathology in amyotrophic lateral sclerosis Acta neuropathologica 1993 85 5 458 62 8493857
  41. [49]Lawyer T Jr. Netsky MG Amyotrophic lateral sclerosis AMA archives of neurology and psychiatry 2 1953 69 2 171 92 13007227
  42. [50]Sharma R Hicks S Berna CM Kennard C Talbot K Turner MR Oculomotor dysfunction in amyotrophic lateral sclerosis: a comprehensive review Arch Neurol 7 2011 68 7 857 61 21747027
  43. [51]Büttner-Ennever JA The extraocular motor nuclei: organization and functional neuroanatomy Progress in brain research 2006 151 95 125 16221587
  44. [52]Suzuki L Coulon P Sabel-Goedknegt EH Ruigrok TJ Organization of cerebral projections to identified cerebellar zones in the posterior cerebellum of the rat The Journal of neuroscience: the official journal of the Society for Neuroscience 8 8 2012 32 32 10854 69 22875920 PMC6621006
  45. [53]Gilbert RM Fahn S Mitsumoto H Rowland LP Parkinsonism and motor neuron diseases: twenty-seven patients with diverse overlap syndromes Movement disorders: official journal of the Movement Disorder Society 15 9 2010 25 12 1868 75 20669307
  46. [54]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 1 2011 82 1 110 6 21097546
  47. [55]Leveille A Kiernan J Goodwin JA Antel J Eye movements in amyotrophic lateral sclerosis Arch Neurol 11 1982 39 11 684 6 7125995
  48. [56]Phukan J Pender NP Hardiman O Cognitive impairment in amyotrophic lateral sclerosis Lancet neurology 11 2007 6 11 994 1003 17945153
  49. [57]Strong MJ Grace GM Orange JB Leeper HA Menon RS Aere C A prospective study of cognitive impairment in ALS Neurology 10 11 1999 53 8 1665 70 10563610
  50. [58]Jeong Y Park KC Cho SS Pattern of glucose hypometabolism in frontotemporal dementia with motor neuron disease Neurology 22 2 2005 64 4 734 6 15728305
  51. [59]Ludolph AC Langen KJ Regard M Frontal lobe function in amyotrophic lateral sclerosis: a neuropsychologic and positron emission tomography study Acta neurologica Scandinavica 2 1992 85 2 81 9 1574993
  52. [60]Fang PC Stepniewska I Kaas JH Ipsilateral cortical connections of motor, premotor, frontal eye, and posterior parietal fields in a prosimian primate, Otolemur garnetti The Journal of comparative neurology 26 9 2005 490 3 305 33 16082679
  53. [61]Wu CW Bichot NP Kaas JH Converging evidence from microstimulation, architecture, and connections for multiple motor areas in the frontal and cingulate cortex of prosimian primates The Journal of comparative neurology 17 7 2000 423 1 140 77 10861543
  54. [62]Matsumura M Kubota K Cortical projection to hand-arm motor area from post-arcuate area in macaque monkeys: a histological study of retrograde transport of horseradish peroxidase Neuroscience letters 3 1979 11 3 241 6 117403
  55. [63]Muakkassa KF Strick PL Frontal lobe inputs to primate motor cortex: evidence for four somatotopically organized ‘premotor’ areas Brain research 9 11 1979 177 1 176 82 115545
  56. [64]Tokuno H Tanji J Input organization of distal and proximal forelimb areas in the monkey primary motor cortex: a retrograde double labeling study The Journal of comparative neurology 8 7 1993 333 2 199 209 8393892
  57. [65]Lu MT Preston JB Strick PL Interconnections between the prefrontal cortex and the premotor areas in the frontal lobe The Journal of comparative neurology 15 3 1994 341 3 375 92 7515081
  58. [66]Piao YS Wakabayashi K Kakita A Neuropathology with clinical correlations of sporadic ayotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000 Brain Pathol 1 2003 13 1 10 22 12580541 PMC8095891
  59. [67]Matheson JK Harrington HJ Hallett M Abnormalities of multimodality evoked potentials in amyotrophic lateral sclerosis Arch Neurol 4 1986 43 4 338 40 3954617
  60. [68]Radtke RA Erwin A Erwin CW Abnormal sensory evoked potentials in amyotrophic lateral sclerosis Neurology 6 1986 36 6 796 801 3703285
  61. [69]Thiebaut de Schotten M Dell’Acqua F Valabregue R Catani M Monkey to human comparative anatomy of the frontal lobe association tracts Cortex; a journal devoted to the study of the nervous system and behavior 1 2012 48 1 82 96 22088488
  62. [70]Kawamura K Naito J Corticocortical projections to the prefrontal cortex in the rhesus monkey investigated with horseradish peroxidase techniques Neuroscience research 4 1984 1 2 89 103 6536892
  63. [71]Zhang H Tan CF Mori F TDP-43-immunoreactive neuronal and glial inclusions in the neostriatum in amyotrophic lateral sclerosis with and without dementia Acta neuropathologica 1 2008 115 1 115 22 17786458
  64. [72]Miki Y Mori F Nunomura J Sporadic amyotrophic lateral sclerosis with pallido-nigro-luysian degeneration: a TDP-43 immunohistochemical study Neuropathology: official journal of the Japanese Society of Neuropathology 4 2010 30 2 149 53 19703266
  65. [73]Nambu A A new dynamic model of the cortico-basal ganglia loop Progress in brain research 2004 143 461 6 14653188
  66. [74]Delwaide PJ Parkinsonian rigidity Functional neurology Apr-Jun 2001 16 2 147 56 11495420
  67. [75]Saper CB Role of the cerebral cortex and striatum in emotional motor response Progress in brain research 1996 107 537 50 8782541
  68. [76]Boxer AL Mackenzie IR Boeve BF Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family Journal of neurology, neurosurgery, and psychiatry 2 2011 82 2 196 203 PMC3017222 20562461
  69. [77]Kew JJ Leigh PN Playford ED Cortical function in amyotrophic lateral sclerosis. A positron emission tomography study Brain: a journal of neurology 6 1993 116 (Pt 3 655 80 8513396
  70. [78]Lee SJ Desplats P Sigurdson C Tsigelny I Masliah E Cell-to-cell transmission of non-prion protein aggregates Nature reviews Neurology 12 2010 6 12 702 6 PMC4996353 21045796
  71. [79]Baker HF Ridley RM Duchen LW Crow TJ Bruton CJ Induction of beta (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Comparison with transmission of spongiform encephalopathy Molecular neurobiology 2 1994 8 1 25 39 8086126
  72. [80]Kane MD Lipinski WJ Callahan MJ Evidence for seeding of beta -amyloid by intracerebral infusion of Alzheimer brain extracts in beta -amyloid precursor protein-transgenic mice The Journal of neuroscience: the official journal of the Society for Neuroscience 15 5 2000 20 10 3606 11 10804202 PMC6772682
  73. [81]Mougenot AL Nicot S Bencsik A Prion-like acceleration of a synucleinopathy in a transgenic mouse model Neurobiology of aging 1 8 2011 21813214
  74. [83]Chia R Tattum MH Jones S Collinge J Fisher EM Jackson GS Superoxide dismutase 1 and tgSOD1 mouse spinal cord seed fibrils, suggesting a propagative cell death mechanism in amyotrophic lateral sclerosis PloS one 2010 5 5 e10627 20498711 PMC2869360
  75. [84]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 The Journal of biological chemistry 27 5 2011 286 21 18664 72 21454603 PMC3099683
  76. [85]Fallini C Bassell GJ Rossoll W The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth Human molecular genetics 15 8 2012 21 16 3703 18 22641816 PMC3406762
  77. [88]Byrne S Elamin M Bede P Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study Lancet neurology 3 2012 11 3 232 40 22305801 PMC3315021

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Authors
Brettschneider, J., Del Tredici, K., Toledo, J. B., Robinson, J. L., Irwin, D. J., Grossman, M., Suh, E., Van Deerlin, V. M., Wood, E. M., Baek, Y., Kwong, L., Lee, E. B., Elman, L., McCluskey, L., Fang, L., Feldengut, S., Ludolph, A. C., Lee, V. M. ‐., Braak, H., & Trojanowski, J. Q.
Affiliations
  • Universität Ulm (DE)
  • Clinical Neuroanatomy Section Department of Neurology Center for Biomedical Research University of Ulm Ulm Germany
  • University of Pennsylvania (US)
  • Center for Neurodegenerative Disease Research University of Pennsylvania School of Medicine Philadelphia PA
Corresponding author
Trojanowski, John Q.
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2013-06-19
Volume
74
Issue
1
Pages
20-38
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.23937
PMC
PMC3785076
OpenAlex
W1503916499
Cited by
1,065
References
12
Citations by year
2026: 73 · 2025: 86 · 2024: 85 · 2023: 101 · 2022: 94 · 2021: 85 · 2020: 94 · 2019: 77 · 2018: 91 · 2017: 81 · 2016: 74 · 2015: 64 · 2014: 45 · 2013: 14
FWCI
41.71
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (AG033101, AG-010124, P30AG010124, AG039510, P01AG017586, AG032953, K08AG039510, K08AG033101, AG-017586, P01AG032953, T32AG000255)
  • National Institute of Neurological Disorders and Stroke (NS044266, R01NS044266)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
amyotrophic lateral sclerosis, intraneuronal inclusions, neuropathological staging, C9orf72 repeat expansion, disease progression, prefrontal cortex, hippocampus, motor cortex, brainstem motor nuclei, striatum, executive dysfunction
MeSH terms
Autophagy-Related Proteins, C9orf72 Protein, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Brain, Cross-Sectional Studies, DNA-Binding Proteins, Female, Genetic Testing, Humans, Male, Middle Aged, Mutation, Neuroglia, Neurons, Proteins, Spinal Cord, Ubiquitins, Disease Progression, Cell Cycle Proteins, Adaptor Proteins, Signal Transducing, TDP-43 Proteinopathies

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