Semantic Dementia asa Disorder of Memory

John R. Hodges

MRC-CBU Cambridge and University ofCambridge

MRC CBU

A Brief History

z 1890s Arnold Pick: amnestic aphasia inpatients with left temporal atrophy

A Brief History

z 1975 Warrington: “Selective loss ofsemantic memory”

z 1982 Mesulam “Primary progressiveaphasia”

z 1989 Snowden et al “Semantic dementia”

z 1992 Hodges et al. “Semantic dementia:progressive fluent aphasia with lefttemporal lobe atrophy”

Classification of FTD(Neary et al. 1998 Neurology 51, 1546-54)

Disinhibited variant Apathetic variant

FTD Semantic dementia Prog nonfluent aphasia

FTLD

Semantic dementia(Neary et al. 1998)

z Insidious onset and gradual progressionz Language disorder characterised by

y Fluent empty spontaneous speechy Loss of word meaning: impaired comprehension and namingy Semantic paraphasias

z Perceptual disorder characterised byy Prosopagnosia and/ory Associative agnosia

z Preserved matching and drawingz Preserved single word reading

Semantic dementia: Our view

z Progressive loss of verbal and non-verbal semanticmemory

Semantic dementia

z Progressive loss of verbal and non-verbal semanticmemory

z Preservation of other cognitive domains (e.g.., workingmemory, visuo-spatial ability, non-verbal problemsolving ability, phonology & syntax)

Semantic dementia

z Progressive loss of verbal and non-verbal semanticmemory

z Preservation of other cognitive domains (e.g., workingmemory, visuo-spatial ability, non-verbal problemsolving ability, phonology & syntax)

z Good orientation and recall of recent events

Semantic dementia

z Progressive loss of verbal and non-verbal semanticmemory

z Preservation of other cognitive domains (e.g., workingmemory, visuo-spatial ability, non-verbal problemsolving ability, phonology & syntax)

z Good orientation and recall of recent events

z Atrophy to the infero-lateral temporal neocortex withrelative preservation of the hippocampus early in thedisease

Three cases of semanticdementia

z Case A: mild

z Case B: moderate

z Case C: severe

Patient A

z 50 year-old woman, university education

z 24 months word finding difficulty and “lossof memory for words”

z No impairment in conversationalcomprehension

z Intact everyday activities

Patient A

z Verbal fluency reduced for living andmanmade items: 50% of normal

z Easy naming test: 92%

z Hard (Graded) naming test: 30%Semantic errors

Semantic BatteryGraded Naming Test

Easy Hard

Patient A

z Verbal fluency reduced for living and manmadeitems: 50% of normal

z Easy naming test: 92%z Hard (Graded) naming test: 30% Semantic

errorsz Word-picture matching and pyramids and

palmtrees: 100%z Visuo-spatial skills, problem solving, non-verbal

memory: all normal

Patient A

z MRI: anteriorleft TL atrophy

Diagnosis: Primary progressive aphasia: purelyanomic?

Patient A: Is comprehensionnormal?

z Synonym judgement impairedy Rogue scoundrel polka gasket

y Humour whiff wit carbon

y Impetus equity motivationmisconception

WP-Matching Level 0 WP-Matching Level 1

WP-Matching Level 2 WP-Matching Level 3

Mean effect of semantic distanceon Word-to-Picture Matching

0.3

0.35

0.4

0.45

0.5

0.55

0.6

L0 L1 L2 L3

Patient A: Is comprehensionnormal?

z Synonym judgement impaired

z Definitions of word meaning also impaired

z Word comprehension deficits are present iftested using harder tests

z Still PPA: fluent type?

Patient B

z 48 months word finding difficulty and “lossof memory for words”

z Spouse noted impairment incomprehension

z Intact everyday activities

z Becoming rigid and rather obsessional

Patient B

z Verbal fluency reduced for living andmanmade items: 20% of normal

z Easy naming test: 41%

z Hard (Graded) naming test: 0%

Patient B

z Verbal fluency reduced for living and manmadeitems: 20% of normal

z Easy naming test: 41%z Hard (Graded) naming test: 0%z Word-picture matching: 80%z Visuo-spatial skills, problem solving, non-verbal

memory: all normalz Normal use of objects in everyday life

Patient B

z Left anteriorTL atrophy &FDG-PET

z Progressive aphasia with marked wordcomprehension deficit

Patient B: Is it just language?

z Impaired on pyramids and palmtrees(80%) and even more on Camel and cacti(60%)

Examples from Camel & Cacti Test Patient B: Is it just language?

z Impaired on pyramids and palmtrees(80%) and even more on Camel and cacti(60%)

z Unusual objects battery: markedimpairment in matching tasks and objectusage

Object Matching and Usage Battery

Recipient Action

Function

Object Matching Tests

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scor

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patients controls

functionrecipientaction

Real Object Use

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hold movement orientation

patientscontrols

Naming and Word-to-PictureMatching

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AN JC KH AT D S DC BW JH patientmean

controlmean

namingwpm

Knowledge and Object Use

00.10.20.30.40.50.60.70.80.9

1

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1knowledge

obje

ct u

se

Patient B: Is it just language?

z Impaired on pyramids and palmtrees (80%) andeven more on Camel and cacti (60%)

z Unusual objects battery: marked impairment inmatching tasks and object usage

z Markedly impaired knowledge of object colour

Colouring line drawings...

• 15 SD patients asked tocolour 40 line drawingsof common objects

• Objects includedanimals, fruits andvegetables, body parts,and artifacts withconventional colours

• 2 patients coloured allobjects, the rest pointedto the colours theywould use

Correlation with word-picture matching

Patient C

z 60 months word finding difficulty and “lossof memory for word”

z Marked impairment in comprehension

z Restricted everyday abilities, good withnumbers, able to cook, still driving!

z Strange habits

Patient C: Spontaneous Speech

JH: What kind of job did you do?

Patient: I did things, you know.. In the house

JH: Do you have any hobbies?

Patient: Hobbies, what are they? That’s just myproblem I don’t know words

JH: Things you like to do.

Patient: Oh, I like to play golf.

Patient C: Is she demented?

z Fluency: “what’s an animal”

z Naming: zero

z Word-picture matching: chance

z Pyramids and palmtrees: very poor

z Preserved: digit span, visuospatial skills,recognition memory for pictures

Patients A, B and C are one!

z Patient A = W.M in 1998

z Patient B = W.M. in 2001

z Patient C = W.M in 2003

z Typical longitudinal course in semanticdementia

Change in naming errors

d.k.birdpigeoneagle

creatureaustraliankoalakangaroo

creaturehorse+zebra

creature++horse

+++dog

200320011998

Naming in SD: effects ofdifficulty in patient W.M.

0102030405060708090

100

1998 1999 2000 2001 2002 2003

Naming: easyNaming: hard

Fluency, naming andcomprehension in SD: patient W.M.

0102030405060708090

100

1998 1999 2000 2001 2002 2003

FluencyNamingW-P matching

Comprehension in SD: effects ofstimuli in patient W.M.

30

40

50

60

70

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90

100

1998 1999 2000 2001 2002 2003

PPT: picturesCCT: picturesSoundsColour knowledge

Progression in semanticdementia

z Fluency and naming low freq and atypicalexemplars. Word definition tests.

z Impairment on comprehension testsrequiring specific “low level” knowledge

z Particular problems where the mapping ofstimulus to meaning is arbitraryy Words ->sounds ->pictures ->objects

What is semantic dementia?

z Insidious onset and gradual progressionz Language disorder characterised by

y Fluent empty spontaneous speechy Loss of word meaning: impaired comprehension and

namingy Semantic paraphasias

z Perceptual disorder characterised byy Prosopagnosia and/ory Associative agnosia

z Preserved matching and drawingz Preserved single word reading

Longitudinal MRIs in W.M.

16-12-99 18-08-00+246 days

27-06-01+559 days

Neural basis of concept knowledge?

From McClelland and Rogers (2003)

Semantics

Visual VerbalAuditory Haptic

Vision Hearing Touch Taste Smell

• Local reps ofwords

• Local reps ofvisual features

namesdescriptors

A computational implementationA computational implementation

Voxel BasedMorphometryin Semantic dementia

Mummery et al. 2000

VBM Correlation with semantic loss in FTD/SDseries

Semantic and Episodic Memory

SemanticMemory

task

EpisodicMemory

task

-35

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core

W M KH AT GCB SL JH DC IF M S FM A M DE

Episodic Memory

Semantic Memory

Patients with Semantic Dementia

Performance of SD Patients

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PL IH R W M C VJ V A S C RB HM ATy

Episodic Memory

Semantic Memory

Patients with Alzheimer's Disease

Performance of AD Patients

Temporal source memory testTemporal source memory testStudy Phase 1Study Phase 1

Simons et al. Brain 2002

Study Phase 2Study Phase 2

“Did you see the picture in Set 1, Set 2, or not at all?”

Test PhaseTest Phase

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Item

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Item Detection: SD cases ranked by severity

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Source discrimination: SD cases ranked by severity

CANTAB PAL task

z Visuospatial Associative memory; subjects must learn location of novelvisual stimuli

z Difficulty increases from 1-2-3-6-8 stimuliz Subjects have 10 chances to learn each problem

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0 SD fvFTD DAT CON

Group

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Errors at 6 pattern stage of the PAL (Lee et al., 2003)

The circuit of Papez

Thalamus

Hippocampus

Mammillarybody

Medio-dorsal N.

Lateral-dorsal N.Anterior N.

PosteriorCingulate

Entorhinalcortex

NB: each of these nodeshas been implicated ascausing amnesia in focallesion studies

Method

z Regions of interest traced onto3T volumetric MRI.

z FDG-PET co-registered ontoMRI

z CMRglc calculated

z Normalised to cerebellum

z 3-compartment partial volumecorrection

FDG-PET findings in AD and MCI

MCI AD

Early PETchanges

Early pathologicalinvolvement

Mammillary bodies andthalamus

FDG-PET changes in MCI/AD

Hippocampal complex

0.4

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C AD SD C AD SD

* †

* P<0.05 v Controls † P<0.01 v Controls

LeftRight

†

Hippocampal complex in AD and SD

* SPM P(corr)=0.05

FDG-PET FindingsIn series of SD cases

Posterior Cingulate

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LeftRight

Posterior Cingulate in AD and SD

† †

Mammillary Bodies

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0.55

0.6

0.65

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0.75

0.8

0.85

0.9

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Control AD SD

†

Mamillary bodies in AD and SDSummary of metabolicchanges

AD SD

HC HCMB MBThalamus ThalamusPC PCAmygdala Amygdala

Kim GrahamKaralyn Patterson

Jon SimonsPeter NestorRhys Davies Clare Galton

Mieke Verfaeille Tim Rogers

Andy lee