08/11/2019 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 1 08/11/2019 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 2 08/11/2019 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 3 08/11/2019 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 4 08/11/2019 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 5 08/11/2019 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 6 08/11/2019 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 7 08/11/2019 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 8 08/11/2019 « 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 9 08/11/2019 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 10 08/11/2019 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 11 08/11/2019 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 12 08/11/2019 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 13 08/11/2019 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 14 08/11/2019 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 15 08/11/2019 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 16 08/11/2019 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 17 08/11/2019 Topography of the lesions Topography of the lesions determines clinical