The frontotemporal dementia spectrum what the general physician needs to know Dr Jonathan Rohrer

The frontotemporal dementia spectrum what the general physician needs to know Dr Jonathan Rohrer MRC Clinician Scientist Honorary Consultant Neurologist Dementia Research Centre, UCL Institute of Neurology National Hospital for Neurology and Neurosurgery

Outline of the talk: 10 things to know about FTD 1. FTD is more common than you might think 2. Research in FTD is increasing 3. FTD is not just one disease clinically 4. The most common form presents with behavioural symptoms but the language form is also seen frequently 5. FTD is not just one disease pathologically 6. FTD is commonly genetic 7. MR imaging is variable but can be helpful diagnostically 8. Other tests are less useful 9. Therapeutic drug trials are now starting 10. Support is available for these rare diseases

History First case was described by Arnold Pick in 1892 Non-AD inclusions (later known as Pick bodies) described by Alois Alzheimer in 1911 Concept of Pick s disease described later in 1925/1926 by Gans/Onari and Spatz Sparse case reports until 1980 s when resurgence of interest, although first diagnostic criteria ( frontotemporal dementia ) only described in 1994

1. FTD is more common than you think

Epidemiology Second most common young onset degenerative dementia almost as common as AD. Recent large epidemiological study (Coyle-Gilchrist et al, 2016) Prevalence: 10.8/100,000 Incidence: 1.6/100,000 person years Estimated lifetime risk: 1 in 742 Age-adjusted prevalence peaks between 65-69 at 42.6/100,000 Prevalence for people >65 is double that of 40-64

2. Research in FTD is increasing

Increasing interest in FTD over the years 2016 2014 2012 2010 2008 2006 2004 2002 2000 1998 1996 1994 1992 1990 69 41 46 35 28 22 21 18 107 111 205 202 194 292 264 255 341 470 470 465 460 430 426 570 568 630 Number of papers on FTD in Pubmed 0 100 200 300 400 500 600 700 800 900 815

3. FTD is not just one disease clinically

Clinical spectrum of FTD Frontotemporal dementia Behavioural Language Behavioural variant frontotemporal dementia (bvftd) Progressive nonfluent aphasia (PNFA) Semantic dementia (SD) Primary progressive aphasia (PPA)

Overlap with other conditions Atypical parkinsonian syndromes: Progressive supranuclear palsy (bvftd, PNFA) Corticobasal (degeneration) syndrome (bvftd, PNFA) Motor neurone disease/amyotrophic lateral sclerosis (bvftd >> PNFA and rare descriptions of SD)

4. The most common form presents with behavioural symptoms but the language form is also seen frequently

Consensus criteria Lund-Manchester criteria 1994 Neary criteria 1998 McKhann criteria 2001 Mesulam PPA criteria 1998/2001 New criteria: Rascovsky International bvftd Consortium criteria for bvftd Brain 2011

Behavioural variant FTD new criteria 1. Disinhibition Socially inappropriate behaviour Loss of manners or decorum Impulsive, rash or careless actions 2. Apathy/inertia 3. Loss of sympathy/empathy 4. Perseverative, stereotyped and compulsive behaviour Simple repetitive movements Complex, compulsive or ritualistic behaviours 5. Hyperorality/dietary changes Altered food preference sweet tooth, binge eating 6. Executive dysfunction

PPA subtypes New classification published in Neurology March 2011 3 (rather than 2) subtypes: SD PNFA LPA = logopenic aphasia (first described 2004)

Semantic dementia Multimodal loss of semantic knowledge: verbal initially then visual, auditory, olfactory, gustatory Fluent speech with semantic errors Anomia Single word comprehension problems Surface dyslexia Later, nonverbal impairment e.g. visual agnosia

Splitting the progressive aphasias Traditionally 2 subtypes SD = fluent aphasia PNFA = nonfluent aphasia Problem: PNFA very mixed Agrammatism Motor speech impairment: apraxia of speech Anomia Word-finding pauses New classification splits nonfluent patients into PNFA (more anterior tau > TDP-43 path) and LPA (more posterior AD path)

5. FTD is not just one disease pathologically

Pathological subtypes Frontotemporal lobar degeneration (FTLD) Tau-positive Ubiquitin-positive, tau-negative (FTLD-U) 4R 4R +/- 3R 3R FTLD-TDP FTLD-FUS FTLD-UPS 1. CBD 2. PSP 3. AGD 5. MAPT mutations 6. NTD 6. Pick s disease 7. Type A 8. Type B 9. Type C 12. aftldu 13. NIFID 14. BIBD 15. CHMP2B mutations 4. GGT 10. Type D 11. Other AD pathology:?10-20% of bvftd; PPA (LPA most and?<5% of SD and PNFA)

Tau CBD Atypical parkinsonism MAPT PSP PICK S MAPT CBS PSPS GRN TDP-43 A bvftd C9ORF72 B C D PPA PNFA FUS aftldu SD VCP NIFID BIBD FTD- ALS

6. FTD is commonly genetic

Genetics of FTD Up to 50% of patients with FTD describe a family history of a dementia But a smaller number have an autosomal dominant inheritance (~a third) And variable across clinical syndromes

Genetics of FTD Which are the genes involved in FTD? 1998 Microtubule-associated protein tau (MAPT) 2004 Valosin-containing protein (VCP) 2005 Charged multivesicular body protein 2B (CHMP2B) 2006 Progranulin (GRN) 2008 TAR-DNA binding protein (TARDP) 2009 Fused-in-sarcoma (FUS) 2011 Chromosome 9 open reading frame 72 (C9orf72) 2012 - Sequestosome 1 (SQSTM1)

When and what to test? On family history Autosomal dominant family history commonly present but not always On clinical syndrome: bvftd: any of the genes (C9orf72 if delusions) FTD-MND: C9orf72 PNFA: GRN >>C9orf72 CBS: MAPT > GRN PSP syndrome: rare cases of MAPT mutations

Risk of genetic mutation bvftd autosomal dominant family history: chance of finding a known mutation is ~90% with a single young onset (<65) first degree relative: risk is ~60% with a single older onset (>65) first degree relative: risk is ~25% no known family history: risk is ~10% PPA: risk is <5% This is mostly in patients with PNFA SD: risk is <1% (0 in UCL cohort) CBS: risk is 1% PSP: risk is <0.5%

When and what to test? Next generation sequencing will allow us to test all the genes at the same time (apart from C9orf72). But multiple variants in same person what s pathogenic? Some people carry double mutations e.g. in C9orf72 and GRN

7. MR imaging is variable but can be helpful diagnostically

Behavioural variant FTD 1. T > P/F 3. F > T 2. Mainly T 4. Mainly F Temporal-predominant Frontal-predominant

Behavioural variant FTD - phenocopy

Semantic dementia Early Middle Late

Early Progressive nonfluent aphasia

Progressive nonfluent aphasia Early Middle

Progressive nonfluent aphasia Early Middle Late

8. Other tests are less useful

How useful is CSF? Exclude AD pathology NB: raised tau NOT a marker of tau pathology PET scan? FDG-PET or SPECT no large advantage over volumetric MRI; less knowledge about variability in different subtypes Amyloid (AV45/Florbetapir) will become available to help exclude AD pathology in very specific circumstances Tau (e.g. AV1451) experimental and unlikely to be available soon DaTscan? Probably not

9. Therapeutic trials are now starting

Current and forthcoming trials in FTD TauRx: methylene blue Forum: HDAC inhibitor for GRN mutations Multiple tau trials (monoclonal antibodies, ASO, others ) for MAPT mutations/psp ASO trial for C9orf72

10. Support is available for these rare diseases

www.ftdtalk.org

Summary and the future FTD still a clinical diagnosis supported by neuroimaging Poor clinico-pathological correlation Genetic testing worth doing in certain circumstances Therapeutic trials now starting Patients and family members benefit from disease-specific support groups

Acknowledgements Patients and their families Dementia Research Centre Nick Fox Jason Warren Jonathan Schott Martin Rossor Cath Mummery Funding MRC NIHR ARUK Alzheimer s Society