Frontotemporal dementia Recent advances

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1 Frontotemporal dementia Recent advances Dr Jonathan Rohrer MRC Clinician Scientist Honorary Consultant Neurologist The problem of UCL Institute of Neurology National Hospital for Neurology and Neurosurgery Tau Ubi 1

2 Tau GRN MAPT Tau TDP C9ORF72 TDP UPS Ubi UPS Ubi Genetics Ta u CBD A typi cal GRN VCP SQSTM1 MAPT C9ORF72 TDP Tau MAPT GRN TIA1 PI C K S MAPT TDP-43 A B parki nsoni sm CBS S TARDBP TBK1 CCNF TIA1 CHMP2B UPS Ubi C9ORF72 TBK1 SQ STM 1 TBK1 VCP C D aftld U PPA PN FA NIFID Genetics Pathological subtype unclear for TARDBP,, CHCHD1, and CCNF mutations BI BD - Genetics The clinical syndromes of The syndromes commonly overlap PPA CBS LPA PPA- NOS CBS 2

3 The syndromes commonly overlap The syndromes commonly overlap Uncommon CBS A LS Diagnosing in clinic how useful is Bv: frontotemporal atrophy but variable MRI Probably the most useful imaging modality Frontal atrophy can be difficult to see on CT when subtle and can be overcalled sometimes Temporal-predominant Frontal-predominant Semantic dementia Early Middle Late Semantic dementia Early Middle Late 3

4 12/4/17 Semantic dementia Early Middle Progressive nonfluent aphasia Late Early Progressive nonfluent aphasia Early Middle Progressive nonfluent aphasia Early Diagnosing in clinic how useful is Middle Late The pathology of CSF? Exclude AD pathology e.g. in PPA syndromes, frontal AD Frontotemporal lobar degeneration (FTLD) Raised tau NOT a marker of tau pathology Tau-positive PET scan? FDG-PET/SPECT no large advantage over volumetric MRI and much less knowledge about variability in different subtypes although can be abnormal when MR looks normal in some cases Amyloid (Florbetapir): available to help exclude AD pathology (alternative to CSF if available) Tau: experimental and unlikely to be available soon DaT scan? Ubiquitin-positive, tau-negative (FTLD-U) 4R 4R +/- 3R 3R FTLD-TDP FTLD- FTLD-UPS 1. CBD 6. Pick s disease 7.Type A 12. aftldu MAPT mutations 8.Type B 13. NIFID 15. CHMP2B mutations 3. AGD 6. NTD 9.Type C 14. BIBD 4. GGT 1.Type D 11. Other Probably not can be positive; no help in differentiating -P vs other parkinsonian disorders (and can be negative in ) 4

5 The pathology of Why focus on genetic? The helpful bits Commonest pathologies TDP ~ Ta u > > Some clear associations: syndrome very commonly pathology most commonly TDP type C -MND most commonly TDP type B V young onset sporadic disease (<4) associated with pathology The unhelpful bits No one-to-one correlations CBS can have multiple pathologies including most of the tau types and TDP type A ( and AD) more commonly tau pathology if there is a motor speech disorder but variable has very variable pathology A substantial proportion of patients with have a genetic form Able to accurately define the molecular pathology of the disease TDP-43 in GRN, C9orf72, TBK1 Tau in MAPT Allows study of the disease from a very early stage by investigating at-risk family members How heritable is? Which are the genes involved? Modified Goldman score 1 = autosomal dominant (14%) 2 = familial aggregation (11%) 3 = one first degree-relative under 65 (7%) 3.5 = one first-degree relative over 65 (9%) 4 = no family history (59%) 1998 Microtubule-associated protein tau (MAPT) 24 Valosin-containing protein (VCP) 25 Charged multivesicular body protein 2B (CHMP2B) 26 Progranulin (GRN) 28 TA R-DNA binding protein (TARDBP) 29 Fused-in-sarcoma () 211 Chromosome 9 open reading frame 72 (C9ORF72) 212 Sequestosome 1 (SQSTM1) 214 Coiled-coiled-helix-coiled-coiled-helix domain containing 1 (CHCHD1) 215 TA NK -binding kinase 1 (TBK1) 216 Cyclin F (CCNF) 217 T cell-restricted intracellular antigen (TIA1) gene frequency in UK Risk of carrying a genetic mutation 1998 Microtubule-associated protein tau (MAPT) = 1% 24 Valosin-containing protein (VCP) =.5% 25 Charged multivesicular body protein 2B (CHMP2B) 26 Progranulin (GRN) = 8% 28 TA R-DNA binding protein (TARDBP) 29 Fused-in-sarcoma () 211 Chromosome 9 open reading frame 72 (C9ORF72) = 9% 212 Sequestosome 1 (SQSTM1) = 1% 214 Coiled-coiled-helix-coiled-coiled-helix domain containing 1 (CHCHD1) 215 TA NK -binding kinase 1 (TBK1) = 1% 216 Cyclin F (CCNF) 217 T cell-restricted intracellular antigen (TIA1) For as a whole (based on modified Goldman score): 1: 88% 2: 53% 3: 5% 3.5: 12% 4: 7% Risk: > -MND > > CBS >> >> For (45% risk overall): 1: 87% 2: 64% 3: 6% 3.5: 25% 4: 13% 5

6 12/4/17 Is it possible to predict which patient has which mutation? Clinical syndrome : any of the genes (C9orf72 if odd delusions) -MND: C9orf72 : GRN >>C9orf72 When and what to test? Next generation sequencing allows us to test all the genes at the same time (except C9orf72) dementia panel available at NHNN (but long wait ). CBS: MAPT > GRN mutations syndrome: rare cases of MAPT mutations Imaging But multiple variants in same person what s pathogenic? Some people carry double mutations e.g. in C9orf72 and GRN The problem of and all neurodegenerative disease Theoretical changes in biomarkers Abnormal Presymptomatic disease Clinical disease CSF/s er um Biomarker Pr otein-binding PET Functional MRI; FDG-PET Str uctur al MRI Ps ychology tests Social cognitionand behaviour Function Normal Time The Genetic Initiative Multicentre consortiu m for tracking evolution of genetic with comm on meth od ological platf orm f or assessment of biomarkers Now 25 centres across E urope and C an ada with >75 recruited (target 1 by summer 218) Recruiting presymptomatic an d affected member s of families with a known p ath ogenic mutati on in GRN or MAPT or an expansion in C9orf72 TORONTO LONDON ONTARIO QUEBEC CITY MONTREAL STOCKHOLM LONDON (UCL) CAMBRIDGE MANCHESTER OXFORD ROTTERDAM/AMSTERDAM MILANO (UNIMI/INCB) BRESCIA (UNIBS/FBF) FIRENZ E BARCELONA SAN SEBASTIAN LISBOA COIMBRA PARIS ROUEN LEUVEN Standardi zed asse ssments: clinical, function al, neuropsychological, MRI, blood and CSF assessments TUBINGEN ULM MUNCHEN 6

7 GENFI structural imaging Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis Jonathan D Rohrer, Jennifer M Nicholas, David M Cash, John van Swieten, Elise Dopper, Lize Jiskoot, Rick van Minkelen, Serge A Rombouts, M Jorge Cardoso, Shona Clegg, Miklos Espak, Simon Mead, David L Thomas, Enrico De Vita, Mario Masellis, Sandra E Black, Morris Freedman, Ron Keren, Bradley J MacIntosh, Ekaterina Rogaeva, David Tang-Wai, Maria Carmela Tartaglia, Robert Laforce Jr, Fabrizio Tagliavini, Pietro Tiraboschi, Veronica Redaelli, Sara Prioni, Marina Grisoli, Barbara Borroni, Alessandro Padovani, Daniela Galimberti, Elio Scarpini, Andrea Arighi, Giorgio Fumagalli, James B Rowe, Ian Coyle-Gilchrist, Caroline Graff, Marie Fallström, Vesna Jelic, Anne Kinhult Ståhlbom, Christin Andersson, Håkan Thonberg, Lena Lilius, Giovanni B Frisoni, Michela Pievani, Martina Bocchetta, Luisa Benussi, Roberta Ghidoni, Elizabeth Finger, Sandro Sorbi, Benedetta Nacmias, Gemma Lombardi, Cristina Polito, Jason D Warren, Sebastien Ourselin, Nick C Fox, Martin N Rossor

8 Occipital Occipital Occipital p<.5 p<.1 p<.1 p<.1 Frontal Temporal Occipital Hippocampus Amygdala Striatum Thalamus Cerebellum All mutation carriers 46 Phase 3: LMTM (TauRx) FAILED clinical trials Phase 2: HDAC inhibitor (FORUM) GRN mutation carriers?failed Phase 1: AADVAC (Axon) MAPT mutation carriers ASOs (Ionis) C9orf72 mutation carriers/mapt mutation carriers ASO (Wave) C9orf72 mutation carriers 2 nd generation HDAC inhibitor/gene therapy GRN mutation carriers The future still a clinical diagnosis supported by neuroimaging Poor clinico-pathological correlation Genetic testing worth doing in and certain other circumstances FPI Prevention Initiative We h ave yet to have adequate biomarkers either to indicate when best to start treatment or how to monitor disease progression. Clinical trials are now happening: Prevention Initiative joining worldwide studies. 8

9 Acknowledgments To a ll the pa rtic ipants, carers and family members who take part in the GENFI study Cambridge: James Rowe Brescia FBF: Giovanni Frisoni Brescia UNIBS: Barbara Borroni Milano UNIMI: Daniela Galimberti Milano INCB: Pietro Tiraboschi Toronto: Mario Maselis London Ontario: Liz Finger Rotterdam: John van Swieten Firenze: Sandro Sorbi Stockholm: Caroline Graff Quebec: Robert Laforce Lisboa: AlexandreMendonca Manchester: Alex Gerhard Oxford: Chris Butler Barcelona: Raquel Sanchez-Val l e San Sebastian: Fe rmi n Moreno Paris: Alexis Brice Lille: Florence Pasquier Rouen: Olivier Martinaud Ulm: Markus Otto Tubingen: MatthisSynofzik Munchen: Johannes Levin Leuven: Rik Vandenberghe Montreal: Simon Ducharme Coimbra: Isabel Santana Jason Warren Nick Fox Martin Ros s or Jonathan Schott Cath Mummery Seb Crutch Sebastien Ourselin Henrik Zetterberg Adrian Isaacs Simon Mead Selina Wray Ta mma r yn Lashley Tamas Revesz John Hardy Raffaele Ferrari Rita Guerreiro Jose Bras Katrina Dick Ione Woollacott Elizabeth Gordon Lucy Russell Martina Bocchetta Carolin Heller Martha Foiani Mica Clarke Tess Verneuil Rhian Convery Caroline Greaves Dave Cash Dave Thomas Jorge Cardoso Marc Modat Jennifer Nicholas Charlie Marshal Chris Hardy Rebecca Bond FUNDING: thank you to the MRC, Bluefield Project, ARUK, Alzheimer s Society 9