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Bodian silver method Neuropathology of the Spectrum

Charles Duyckaerts

Escourolle Neuropathology Lab Alzheimer-Prion team ICM

Pitié-Salpêtrière Senile plaquePitié-Salpêtrière Neurofibrillary tangle 12

Aβ accumulation + = 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. 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

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 and 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

Klüver-Bucy syndrome Klüver-Bucy syndrome 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

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“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 ). Erster Band: Allgemeiner Teil. Berlin, J. Springer, 1922.

Pitié-Salpêtrière 87

22