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Bodian silver method Neuropathology of the Dementia Spectrum
Charles Duyckaerts
Escourolle Neuropathology Lab Alzheimer-Prion team ICM
Pitié-Salpêtrière Senile plaquePitié-Salpêtrière Neurofibrillary tangle 12
Aβ accumulation + tauopathy = Alzheimer disease
(please note: no neuronal loss in criteria)
Pitié-Salpêtrière Pitié-Salpêtrière 34
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BRAAK STAGES : tau pathology THAL PHASES : Aβ pathology
I II
1 23
III IV
4 5 V VI Braak and Braak. Acta Neuropathol 1991 Thal et al. Neurology 2002
Pitié-Salpêtrière Pitié-Salpêtrière 56
Pick’s circumscribed atrophy
Pitié-Salpêtrière α-synuclein IHC Pitié-Salpêtrière 78
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Dementia (~1920)
Alzheimer disease Pick disease (Pick circumscribed atrophy)
Alzheimer A (1911) Uber eigenartige Krankheitsfälle des späteren Alters. Zentralblatt Gesam Neurol Psychiat 4: 356- Pitié-Salpêtrière Pitié-Salpêtrière 385 910
Pick disease
Pick disease (Pick body disease) is also a tauopathy
Tau IHC Pitié-Salpêtrière Pitié-Salpêtrière 11 12
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Fronto-temporal dementia with 1- behavioral changes 2- semantic dementia 3- progressive non-fluent aphasia
Pick disease (with Pick bodies) « Pick without Pick body » R. Escourolle. 1957 & S. Brion
Type C of Tissot, Constantinidis & Richard, 1975 Previously « Atypical Pick disease »
Knopman DS, Mastri AR, Frei WH, Sung JH, Rustan T (1990) Dementia lacking distinctive histologic feature: a common non-Alzheimer degenerative dementia. Neurology 40: 251-256
Pitié-Salpêtrière Pitié-Salpêtrière 13 14
Mutations in the tau gene in frontotemporal dementia and parkinsonism linked to Frontotemporal dementia and parkinsonism chromosome 17 (FTDP-17). linked to chromosome 17 Foster et al. 1997 •Irish family 1 •Pallido-ponto-nigral degeneration •Familial multiple system tauopathy with presenile dementia •Seattle family A or BK •Dutch family 1 •Duke university family 1684 •Hereditary dysphasic disinhibition dementia family 2 •Australian family •Familial progressive subcortical dementia
© Oxford University Press 2000 Pitié-Salpêtrière Pitié-Salpêtrière 15 16
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Dementia
Alzheimer disease Fronto-temporal dementia
Tauopathy
Pick disease Tau mutation
P301L MAPT Mutation
Pitié-Salpêtrière Pitié-Salpêtrière 17 18
Cortico-basal degeneration
pTau AT8 pTau AT8
pTau AT8 Pitié-Salpêtrière Pitié-Salpêtrière 19 20
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PSP DCB
Pitié-Salpêtrière Pitié-SalpêtrièreM. Tolnay & A. Probst Neuropathol Appl Neurobiol 1999; 25:171-187 21 22
Dementia Dementia
Alzheimer disease Fronto-temporal dementia Alzheimer disease Fronto-temporal dementia
Tauopathy Tauopathy Ubiquitin positive inclusions Pick disease Tau mutation Pick disease Tau mutation ? With Parkinson sd With Parkinson sd -PSP -PSP -CBD -CBD
Pitié-Salpêtrière Pitié-Salpêtrière 23 24
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M. Neumann et al. Science, 2006 Isolation of insoluble proteins TAR DNA-binding protein 43 (TDP-43)
Injection to mouse; Selection of antibodies that Binds DNA & RNA production of monoclonal label inclusions on section Plays the role of a transcription factor antibodies 2 D Gel
Mass spectrometry
Pitié-Salpêtrière Pitié-Salpêtrière 25 26
TDP-43 IHC Pitié-Salpêtrière Pitié-Salpêtrière 27 28
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Pitié-Salpêtrière Pitié-Salpêtrière 29 30
RANT Traduction non conventionnelle
Mori et al., Science 2013 Repeat-Associated Non-ATG (RAN) Translation GG Mori et al., Science 2013 Repeat-Associated Non-ATG (RAN) Translation GG G GG G G Anterior horn Cerebellum GGlyG G G CCGlyCC CCCGlyC GAlaGG GProG GArg P62 + P62 + G Poly-(Gly-Ala) + TDP43 + TDP43 - C Pitié-Salpêtrière C Pitié-Salpêtrière 31 32
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« Harmonized classification of FTLD-TDP » Type A: cytoplasm + Mackenzie et al. 2011 short neurites + layer 2 predominance Type A Type B Type C Type D GRN mutation
Type B : intranuclear + cytoplasmic inclusions; no layer predominance Multisystemic protéinopathies Inclusion bodies myopathy Paget disease of the bone C9ORF72 hexanucleotide repeat •FTD, ALS
Mutations of: • VCP Valosin-Containing-Protein • hnRNP A2B1 & A1, GRN « prion-like » domain C9ORF72 Kim et al., Nature 2013 +/- C9ORF72 Type C: long neurites •SQSTM1 (p62) (semantic dementia) <1% familial FTLD
Pitié-Salpêtrière Pitié-Salpêtrière 33 34
Dementia Dementia
Alzheimer disease Fronto-temporal dementia Alzheimer disease Fronto-temporal dementia
Tauopathy Tauopathy TDP-43 inclusions TDP-43 inclusions
Pick disease Tau mutation Pick disease Tau mutation D D A C A C B B
Pitié-Salpêtrière Pitié-Salpêtrière 35 36
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Anti-neurofilament
Pitié-Salpêtrière Pitié-Salpêtrière 37 38
Neuronal death
Protein accumulation
(role and dysfunction of accumulated proteins: unknown)
Pitié-Salpêtrière FUS IHC Pitié-Salpêtrière 39 40
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The Neurodegenerative Disease
neurodegenerative diseases
Pitié-Salpêtrière Pitié-Salpêtrière 41 42
How do lesions progress ?
Corruptive protein templating (M. Jucker)
Pitié-Salpêtrière Pitié-Salpêtrière 43 44
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Misfolded protein APP23 mouse
Interaction between normal and misfolded protein
Conversion of normal to misfolded protein
Accumulation of misfolded protein
Pitié-Salpêtrière Pitié-Salpêtrière 45 46
Laboratoire de Neuropathologie Raymond Escourolle Hôpital de La Salpêtrière Equipe Alzheimer/Prion CRICM
Maï Panchal Kunie Ando Mounir Belkouch Adina Lazar
Charles Duyckaerts Benoît Delatour Marie-Claude Potier
Pitié-Salpêtrière Pitié-Salpêtrière 47 48
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Bogaert L van 1925 Les troubles mentaux de la sclérose latérale amyotrophique. Encéphale 20: 27-47 Lowe J, Lennox G, Jefferson D, Morrell K,
Von Braunmühl A 1932 Picksche Krankheit und amyotrophische Lateralsklerose McQuire D, Gray T, Landon M, Doherty FJ, Mayer Allg Z Psychiat 96: 364-366 RJ (1988) Wechsler IS et Davison C 1932 Amyotrophic lateral sclerosis with mental symptoms: a clinico-pathologic study. Arch Neurol Psychiat 27: 859-880 A filamentous inclusion body within anterior horn Delay J, Brion S, Escourolle R, Marty R 1959 Sclérose latérale amyotrophique et démence 100:191-204 neurones in motor neurone disease defined by
Castaigne P, Lhermitte F, Cambier J, Escourolle R, Le Bigot P 1972 Etude immunocytochemical localisation of ubiquitin. neuropathologique de 61 observations de sclérose latérale amyotrophique Rev Neurol (Paris) 127: 401-414 Neurosci Lett 94 (1-2):203-210
Pitié-Salpêtrière Pitié-Salpêtrière 49 50
Kato S, Oda M, Hayashi H, Kawata A, Shimizu T (1994)
Participation of the limbic system and its associated areas in the dementia of amyotrophic lateral sclerosis.
J Neurol Sci 126 (1):62-69.
Tolnay M, Probst A (1995)
Frontal lobe degeneration: novel ubiquitin-immunoreactive neurites within frontotemporal cortex.
Neuropathol Appl Neurobiol 21 (6):492-497. Ubiquitine; corne antérieure
Pitié-Salpêtrière Pitié-Salpêtrière 51 52
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Ubiquitin
Ubiquitin is a small (8.7kD) protein
Attaches to proteins
Labels them for destruction by the proteasome
Aaron Ciechanover, Aaron Ciechanover, Avram Hershko, and Irwin Rose. Nobel Ubiquitin P62 Prize, 2004
Pitié-Salpêtrière Pitié-Salpêtrière 53 54
ALS Dementia
ALS - Dementia
Pitié-Salpêtrière Pitié-Salpêtrière 55 56
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Pedigrees of Belgian FTDP-17u families DR2 (A) and DR8 (B)
Lund et Manchester (1994) : ‘dégénérescence du lobe frontal’, ‘type Pick’, ‘maladie du motoneurone’
‘démence sans signe histologique distinctif’ [Knopman, 1990]
van der Zee, J. et al. Brain 2006 129:841-852; doi:10.1093/brain/awl029 Brain. 2006 Apr;129(Pt 4):830-1. A Belgian ancestral haplotype harbours a highly Pitié-Salpêtrière prevalentPitié-Salpêtrière mutation for 17q21-linked tau-negative FTLD. 57 58
Ubiquitine
Pirici D, Vandenberghe R, Rademakers R, Dermaut B, Cruts M, Vennekens K, Cuijt I, Lubke U, Ceuterick C, Martin JJ, Van Broeckhoven C, Kumar-Singh S (2006)
Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family.
J Neuropathol Exp Neurol 65 (3):289-301
Pitié-Salpêtrière Pitié-Salpêtrière 59 60
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Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Baker et al Nature. 2006 Aug 24;442(7105):916-9. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Cruts et al. Nature. 2006 Aug 24;442(7105):920-4.
CA2-3 CA1 gène muté codon stop
Moins de progranuline (haploinsuffisance) Pitié-Salpêtrière Pitié-Salpêtrière 61 62
An intronic hexanucleotide repeat expansion in theC9ORF72 gene (GGGGCC) has recently been shown to be the genetic cause of chromosome 9p21- linked ALS-FTLD, and accounts for 30– 40 % of familial ALS and a similar portion of familial FTLD,
[behavioral variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia, and semantic dementia (SD)], progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS).
Accumulation of tau protein
Pitié-Salpêtrière Pitié-Salpêtrière 63 64
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Dementia
Alzheimer disease Fronto-temporal dementia
Genetics of frontotemporal lobar Tauopathy Other degeneration Ubiquitin inclusions
PM Aswathy, PS Jairani, PS Mathuranath Pick disease Tau mutation
Pitié-Salpêtrière Pitié-Salpêtrière 65 66
Topography of the lesions Topography of the lesions determines clinical signs determines clinical signs & symptoms & symptoms
Cortical blindness Cortical blindness
Amnesia Amnesia
Hemiplegia Hemiplegia
Apraxia Apraxia Frontal syndrome Frontal syndrome Visual agnosia Visual agnosia
Klüver-Bucy syndrome Klüver-Bucy syndrome Prosopagnosia Prosopagnosia
Pitié-Salpêtrière Pitié-Salpêtrière 67 68
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Topography of the lesions Topography of the lesions determines clinical signs determines clinical signs & symptoms & symptoms
Cortical blindness Cortical blindness
Amnesia Amnesia
Hemiplegia Hemiplegia
Apraxia Apraxia Frontal syndrome Frontal syndrome Visual agnosia Visual agnosia
Klüver-Bucy syndrome Klüver-Bucy syndrome Prosopagnosia Prosopagnosia
Pitié-Salpêtrière Pitié-Salpêtrière 69 70
Topography of the lesions Topography of the lesions determines clinical signs determines clinical signs & symptoms & symptoms
Cortical blindness Cortical blindness
Amnesia Amnesia
Hemiplegia Hemiplegia
Apraxia Apraxia Frontal syndrome Frontal syndrome Visual agnosia Visual agnosia
Klüver-Bucy syndrome Klüver-Bucy syndrome Prosopagnosia Prosopagnosia
Pitié-Salpêtrière Pitié-Salpêtrière 71 72
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Topography of the lesions determines clinical signs & symptoms
Cortical blindness
Amnesia
Hemiplegia
Apraxia Frontal syndrome Visual agnosia
Klüver-Bucy syndrome Prosopagnosia
Pitié-Salpêtrière Pitié-Salpêtrière 73 74
Dysfunction of isocortex/ hippocampus
Dementia
Pitié-Salpêtrière Pitié-Salpêtrière 75 76
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Topography of the lesions determines clinical signs Lesions Disease & symptoms
Cortical blindness
Amnesia
Hemiplegia Dysfunction
Apraxia Frontal syndrome Visual agnosia Symptoms
Klüver-Bucy syndrome Prosopagnosia
Pitié-Salpêtrière Pitié-Salpêtrière 77 78
Pitié-Salpêtrière Pitié-Salpêtrière 79 80
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Pitié-Salpêtrière Pitié-Salpêtrière 81 82
NFT NFT Anti-Aβ antibody (6F3D)
CoronaPitié-Salpêtrière of the senile plaque Neuropil thread Pitié-Salpêtrière 83 84
21 08/11/2019
“Neuropil threads” = both dendrites and axons
Senile plaque: a composite lesion Anti-Aβ (6F3D) Anti-Tau (AT8)
IHC tau (AT8 antibody)
Pitié-Salpêtrière Pitié-Salpêtrière 85 86
Alzheimer disease
Goedert M Brain 2009;132:1102-1111 O. Fischer 1907.
W. Spielmeyer. Histopathologie des Nervensystems (Histopathology of the Nervous System). Erster Band: Allgemeiner Teil. Berlin, J. Springer, 1922.
Pitié-Salpêtrière 87
22