Frontotemporal dementia

John Hodges

FRONTIERPrince of Wales Medical Research

Institute

Causes of Early Onset Dementia

ADVASCULARFTDDLBOTHER

Prevalence per100, 000Total: 81 - 98AD: 11 - 41FTD: 4 - 15

City of 4 million= 3 to 4,000 EOD500-1000 FTD

Frontotemporal Dementia

Behavioural form

PNFA semantic demen

Language form(Primary progressive apha

FTD or FTLD

FTD: overlap Disorders

• FTD with motor neurone

diseaseChanges in personality and social behaviour

and/or aphasia typically precede bulbar type MND

Selective deficit in verb processing (Bak et al 2001)

High rate of psychosis and rapid progression

Frontotemporal Dementia

Behavioural form

PNFA semantic demen

Language form(Primary progressive apha

FTD or FTLDMND

Frontotemporal Dementia: overlaps

• Extrapyramidal

features are common in FTD (parkinsonism etc). Some cases develop severe apraxia

--> corticobasal

degeneration (CBD)

syndrome. Also cases with CBD commonly become aphasic.

Frontotemporal Dementia

Behavioural form

PNFA semantic demen

Language form(Primary progressive apha

FTD or FTLDCorticobasaldegeneration MND

Pathological heterogeneity

Molecular Genetic:MAPTProgranulinCHMP2B

So far < 20% cases

Clinical classification

Forms of FTD with tau

FTD with TDP43Several patternsLentiform (cat’s eye) charcteristic of PGRN mutations

FTD: Diagnosis

• Presenting/early features NOT JUST FRONTAL FEATURES WHICH OCCUR IN MANY DEMENTIAS AT LATE STAGE

• Patient and carer assessment with neuropsychological testing and imaging

• Distinct clinical profiles with matching changes on imaging

• Must exclude other potential causes of dementia

FTD: Clinical variants

• Frontal variant FTD: orbital and mesial

frontalChanges in personality and social behaviour

• Semantic dementia (progressive fluent aphasia): polar & inferior temporal lobeAnomia, impaired comprehension & loss of knowledge

• Progressive nonfluent aphasia: perisylvianDisrupted speech output, phonological deficits

• 65 year-old man, skilled craftsman

• 24 months word finding difficulty and “loss of memory for words”

• Impaired comprehension of word meaning

• Intact everyday activities

• Good day-to-day memory

Typical Semantic Dementia

As time goes by

1998 2001 2003dog √ √ √horse √ √ creaturezebra √ horse creaturekangaro o

koala australia n

creature

eagle pigeon bird d.k.

Semantic DementiaA distinct clinico-anatomical- (pathological) syndrome

Semantic Dementia: clues

• Very anomic• Poor word definitions• Good repetition: word alienation• Surface dyslexic: Pint; soot etc• Impaired person identification RIGHT CASES• Excellent visuospatial skills and attention• Good autobiographical but poor verbal memory!!!!

• ACE-R very sensitive with big MMSE-ACE discrepancy

• Early behavioural changes: obsessions, jigsaws. Eating, empathy loss

ACE-R• Incorporates MMSE takes 15 minutes• Sensitive to early AD and FTD• Five domains:

Orientation/attentionEpisodic memoryFluency P words and animalsLanguage: naming 12 line drawings, repetition & comprehensionVisuospatial

skills

• SD; good orientation/attention, very poor fluency and naming, good visuospatial skills

• Used in >30 countries, Australian versions, cut- offs (88 and 82)

Progressive Non-Fluent Aphasia

• Markedly reduced conversational speech with preserved word knowledge

• Far more varied than SD but are there clear subtypes?

• Speech apraxia

= motor speech disorderSpeech dysfluent, halting, distortedPhonetic errors in spontaneous speechVery poor repetition of single words

e-lec-trick-ery (electricity)

Unable to repeat strings of syllables “PA, TA, KA”

• Grammatical errors and impaired sentence comprehensionIf the lion ate the tiger, who survived?

Gorno-Tempini, et al. Annals Neurol, 2004

Behavioural variant FTD • Slowly progressive insidious onset• No insight• Alterations in personality and behaviour• Apathy• Disinhibition• Loss of empathy and warmth• Alterations in eating habits and preferences• Strange obsessions and rituals• Poor planning and organisation• Mental rigidity• Decline in self-care

John• 53 M• Left school at age 16• Head boy• Diploma engineering• joined family firm• Married, 2 children• No FH of dementia

• Age 38 Marital dysharmony, alcohol excess• Age 53 Psychiatric referral then to memory clinic

– Family firm bankrupt– Disastrous financial decisions for 5 yrs

progressive personality change• Lack of thought for family• No empathy• Emotionally cold• e.g., failed to attend daughter’s graduation• Apathetic

– High scores on Cambridge Behavioural Inventory

Modelled on Neuropsychiatric InventoryPlus cognitive and ADL sections80 questions cover:

MoodAbnormal beliefsChallenging behavioursDisinhibitionAppetite and eatingStereotypic behavioursMotivation

Cambridge Behavioural Inventory

Tests: Undecided• Memory good

• Language and semantics good

• Executive FunctionWisconsin card sorting normalFAS letter fluency 30BADS Normal

John:

• Next 4 years progressive decline• Euphoric, giggling inappropriately• Poor self-care• Grandiose, no insight

– Disinhibited• begging, stealing

– Preoccupied counting, checking• doors, locks, car suspension

– Excessive food consumption• sweet foods, hoarding chocolates

• Died suddenly

Orbitofrontal atrophy

Amygdala atrophy

(JH 104) Neuropathology

Emotion Processing

Motivation

Behavioural Regulation

DLPFCExecutive functions, working memory

Faux pas test

Jeanette bought her friend Ann a crystal bowl for a wedding gift. Ann had a big wedding and there were a lot of presents to keep track

of.

About a year later, Jeanette was over one night at Anne’s for dinner. Jeanette dropped a wine bottle by accident on the crystal bowl, and the bowl shattered. “I’m really sorry, I’ve broken the bowl”

said

Jeanette. “Don’t worry”

said Anne “I never liked it anyway. Someone gave it to me for my wedding”

Faux Pas

bv-FTD Controls0.00

0.25

0.50

0.75

1.00

Com

posi

te S

core

Gregory et al. Brain 2000

TASIT Results

Judgement of social scenarios by FTD patients

Sincere Sarcastic-5

-4

-3

-2

-1

0

1Z

-Sco

re

Onset –

slow to presentGradual change in behaviourDisinhibited, stereotypicEating habits; sweet foodsApatheticLack of insight

CBI-

69

ACE –

90, MMSE 29

2 yrs rapid downhill courseTo nursing homeACE fell proressively

Onset –

slow to presentGradual change in behaviourDisinhibited, rigidPoor financial judgementApathetic, lacked empathyLack of insight

CBI-

70 (high)

ACE –

89, MMSE 30

10 yrs follow-upNo changeVariable performance on frontal TasksACE normal after 10 yrs

Case 1 Case 2

bv-FTD

8 years

2 years

The FTD phenocopy syndrome: a mystery solved ?

What is the bvFTD-phenocopy syndrome?

• Neurodegenerative: very slow progress?

• Undiagnosed autism spectrum

• Psychiatric• Depression• Mania• Schizophrenia

• Mid-life regression in vulnerable personality

Olivier PiguetClement LoyPatricia LilloBeatrice GarcinEneida MioshiMichael HornbergerWendy KelsoSharpley HsiehSharon SavageEmma SchofieldSarah Homewood

Pathology: Glenda Halliday and Jill Kril

Imaging: Lindy Rae and Steven Rose

Website

www.ftdrg.org