Kertesz

ORIGINAL CONTRIBUTION

What Is Semantic Dementia?

A Cohort Study of Diagnostic Features and Clinical Boundaries

Andrew Kertesz, MD; Sarah Jesso, BA; Michal Harciarek, PhD; Mervin Blair, MA; Paul McMonagle, MD

Objectives: To describe a large, clinically defined co-hort of patients with semantic dementia (SD) that high-lights important, sometimes overlooked features and tocompare it with similar entities.

Design: Cohort study.

Setting: A cognitive neurology clinic.

Patients: A population of 48 patients clinically diag-nosed with SD was contrasted with 52 patients with pro-gressive nonfluent aphasia, 42 patients with a behav-ioral variety of frontotemporal dementia, and 105 patientswith Alzheimer disease on speech output characteris-tics, comprehension, naming, and repetition subtests ofthe Western Aphasia Battery, the Frontal Behavioral In-ventory, and other cognitive tests. Neuroimaging was vi-sually analyzed, and 6 patients with SD had autopsy.

Results: Of 37 patients with probable SD, 48.6% had se-mantic jargon; 21.6%, excessive garrulous output; and75.7%, some pragmatic disturbance. Semantic substitu-

tions were frequent in SD (54.1%) but phonological er-rors were absent, in contrast to progressive nonfluentaphasia with the opposite pattern. All but 3 patients withprobable SD questioned the meaning of words. Patientswith SD had significantly lower naming and comprehen-sion scores, and their fluency was between progressivenonfluent aphasia and Alzheimer disease or behavioralfrontotemporal dementia. Behavior was abnormal in94.6% of patients with probable SD.

Conclusions: Semantic dementia is distinguishable fromother presentations of frontotemporal dementia and Alz-heimer disease, not only by fluent speech and impairedcomprehension without loss of episodic memory, syn-tax, and phonology but also by empty, garrulous speechwith thematic perseverations, semantic paraphasias, andpoor category fluency. Questioning the meaning of words(eg, “What is steak?”) is an important diagnostic clue notseen in other groups, and behavior change is prevalent.

Arch Neurol. 2010;67(4):483-489

S EMANTIC DEMENTIA (SD)designates a progressive cog-nitive and language deficit,primarily involving compre-hension of words and related

semantic processing.1 These patients losethe meaning of words, usually nouns, butretain fluency, phonology, and syntax.Pick2 described similar patients as hav-ing “pure word deafness” in associationwith left temporal atrophy. Transcorticalsensory aphasia was used for similar cases.3

Semantic aphasia was a term used by Head4

in war-injured patients for a 2-way dis-turbance of comprehension and naming.The condition was called gogi (meaning)aphasia in Japan.5 Some patients were con-sidered to have loss of semantic memory6

and others a language impairment.7,8 Se-mantic dementia has been further elabo-rated as the degradation of a single cen-tral network of conceptual knowledge.9-12

The definition of SD originates from

Snowden et al1 and has been adopted byothers,9 including the consensus criteriaof Neary et al,13 as a variety of frontotem-poral dementia (FTD). The incidence ofSD is estimated by one clinic to be 25% intheir patients with FTD.12

Semantic dementia has been equatedwith fluent progressive aphasia.9,14 Flu-ent aphasia, however, is common in Alz-heimer disease (AD)15 and, at the onset,all patients with progressive aphasia arefluent, even those who become nonflu-ent later.16,17 The fluency-nonfluency dis-tinction is often arbitrary and rarely quan-titated. Primary progressive aphasia issubdivided variably and sometimes in-cludes SD. Here we used the term pro-gressive nonfluent aphasia (PNFA) for acomparison group. Semantic deficits, con-sidered basic to SD, also appear in AD.18

Because of these overlapping features fromdifferent clinical and biological entities, thediagnostic boundaries remain uncertain.

Author Affiliations:Department of ClinicalNeurological Sciences,University of Western Ontario(Dr Kertesz), and CognitiveNeurology and AlzheimerResearch Centre, St Joseph’sHospital, London, Ontario,Canada (Dr Kertesz andMs Jesso); University ofGdansk, Gdansk, Poland(Dr Harciarek); ConcordiaUniversity, Montreal, Canada(Mr Blair); and the Departmentof Neurology, Royal VictoriaHospital, Belfast, NorthernIreland (Dr McMonagle).

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Some features of SD such as distinctive speech outputcharacteristics, impaired pragmatics (the study of the give-and-take and efficiency of communication), “What is . . . ”questioning of meaning, and behavioral abnormality arerelatively unexplored. We aimed to study SD in a cog-nitive neurology clinic population of patients in an at-tempt to delineate the syndrome from the behavioral pre-sentation of patients with FTD (bvFTD), PNFA, and AD.In addition to comparing neurocognitive features withrelated conditions, we characterized the pragmatics ofspeech and quantitated language, including fluency andthe behavioral abnormality. In view of a recent sugges-tion associating a specific pathology with SD,19 the studyof clinical boundaries of SD is even more relevant. Wereport autopsy confirmation in 6 of 48 patients.

METHODS

The target population was 48 patients with SD who were diag-nosed clinically using the Neary et al criteria13 from a cohort of

361 patients with FTD or Pick complex. Patients with SD hadprogressive loss of naming and comprehension, with preservedsyntax, phonology, fluency, and relatively preserved episodicmemory. They were followed up at yearly intervals,20 but onlythe results of the first examination were used for the statisticalanalyses in this study. Thirty-seven patients were considered tohave probable SD (Table 1). This group had prominent com-prehension and word-finding difficulty, either from the begin-ning of the illness or by the first time they were seen. Patientswith possible SD (n=11) were cases with atypical features andwere not included in the statistical analysis. One patient had epi-sodic memory loss and 2 had confused close relatives as strang-ers (the Capgras delusion), which raised the suspicion of pos-sible AD.21 One patient had significant vascular disease andanother panic attacks. Five possible cases had predominant be-havioral disturbance and only incipient SD by the first clinic visit,and 1 had mixed nonfluent and SD features.

Behavioral FTD was diagnosed clinically when a patient pre-sented with mainly behavioral or personality disturbance, ful-filling Neary and colleagues’ criteria,13 and no significant lan-guage impairment was evident on the first examination. Patientswith PNFA had an initial deficit of language output and pres-

Table 1. Clinical Features of Semantic Dementiaa

Sex/Ageat Onset, y/1st Syndrome

Duration ofIllness, yb

Memoryfor Names

QuestioningWords

VisualAgnosia

FaceAgnosia Pragmatics Artc

SurfaceDyslexia

SpeechOutput

NeurologicalImage

AutopsyFindings

F/60/SD 4 1 1 1 1 1 . . . 1 Empty LTA FTLD-UF/56/bvFTD 4 1 1 1 1 1 . . . 1 Stereotypy RTA�LF FTLD-UM/61/bvFTD 6 1 . . . . . . . . . 1 . . . 1 Semantic jargon LTA FTLD-UM/46/SD 1 1 1 1 . . . 1 1 1 Empty LTA FTLD-UM/38/bvFTD 2 1 . . . . . . 1 . . . . . . . . . Semantic jargon, perseverative LTA FTLD-UF/64/bvFTD 1 1 1 . . . . . . . . . . . . . . . Perseverative FTA DLDHF/51/bvFTD 7 1 1 1 0 1 . . . 1 Semantic jargon Diffuse . . .F/68/bvFTD 3 . . . 1 1 1 1 . . . . . . Semantic jargon R�LTA . . .F/56/SD 3 . . . 1 . . . . . . 1 1 1 Semantic jargon LTA . . .F/65/SD 2 1 1 1 . . . . . . 0 Tangential L�RTA . . .M/51/SD 6 1 1 1 1 . . . . . . 1 Empty LTA . . .M/63/SD 1 1 1 1 . . . 1 . . . . . . Semantic jargon, perseverative Diffuse . . .F/46/SD 4 1 1 1 1 . . . . . . 1 Semantic jargon L�RTA . . .F/48/SD 3 . . . . . . 1 1 1 . . . . . . Garrulous, semantic jargon LFTA . . .F/55/SD 1 1 1 . . . . . . 1 . . . 1 Semantic jargon LTA . . .M/48/SD 2 1 1 0 1 1 . . . 1 Dysarthric L�RTFA . . .F/47/bvFTD 4 1 1 1 1 1 . . . Garrulous LTPA . . .M/66/bvFTD 6 . . . 1 . . . . . . 1 . . . . . . Garrulous, stereotypy FTA . . .F/57/SD 3 1 1 0 . . . 1 Empty LTPA . . .F/72/bvFTD 5 . . . 1 1 0 1 . . . . . . Garrulous, abusive LTA . . .M/67/SD 3 1 1 . . . . . . 1 . . . . . . Semantic jargon LTA . . .M/60/bvFTD 1 0 1 1 0 1 . . . . . . Semantic jargon FTA L�R . . .M/72/SD 5 1 1 . . . . . . 1 . . . . . . Stereotypy FTA . . .M/58/bvFTD 5 . . . 1 . . . . . . 1 . . . . . . Semantic jargon LTPA . . .F/64/bvFTD 5 1 1 . . . . . . . . . . . . 1 Semantic jargon R�LFTA . . .M/69/SD 5 1 1 . . . . . . 1 1 1 Semantic jargon L�RTA . . .F/62/bvFTD 6 1 1 1 1 1 . . . . . . Garrulous, perseverative L�RTA . . .M/59/SD 4 1 1 . . . . . . 1 . . . 1 Semantic jargon L�RTA . . .F/63/SD 4 1 1 . . . . . . 1 . . . 1 Perseverative RFTA . . .F/54/SD 6 1 1 . . . 1 1 . . . 1 Garrulous LTA . . .F/58/SD 3 . . . 1 . . . 1 . . . 1 . . . Semantic jargon LTA . . .M/57/SD 5 1 1 . . . . . . 1 1 . . . Garrulous L�RTA . . .M/64/SD 3 1 1 . . . 0 1 1 1 Perseverative L�RTA . . .F/66/SD 4 1 1 . . . . . . . . . 1 . . . Normal, fluent L�RTA . . .M/59/bvFTD 10 1 1 . . . . . . 1 1 . . . Semantic jargon L�RTFA . . .M/52/bvFTD 9 . . . 1 0 1 1 1 1 Stereotypy, semantic jargon LTFA . . .F/41/bvFTD 2 1 1 1 1 1 . . . . . . Perseverative, garrulous RTFA . . .Totald 28 34 13 15 28 9 18

Abbreviations: A, atrophy; ellipses, not tested for; bvFTD, behavioral frontotemporal dementia; DLDH, dementia lacking distinctive histology; F, frontal;FTLD-U, frontotemporal lobar degeneration with ubiquitin-positive inclusions; L, left; P, parietal; R, right; SD, semantic dementia; T, temporal.

a0 indicates that a symptom does not exist; 1, symptom exists.bYears from onset of illness to first clinical visit.c Indicates an obsession with painting or jigsaw puzzles.dFor men, n=17; women, n=20; mean (SD) age, 58 (8.4) years; a total of 21 patients had SD; 16, bvFTD; the mean (SD) duration of illness was 4 (2.1) years.




ervation of comprehension, memory, and visuospatial ability.Patients with additional memory and comprehension prob-lems in their history were excluded as having possible PNFA.Alzheimer disease was diagnosed when the primary deficit was(episodic) memory impairment and the patients fulfilled theNational Institute of Neurological and Communicative Disor-ders and Stroke/Alzheimer’s Disease and Related Disorders As-sociation (NINCDS/ADRDA) criteria.

The patients were grouped on the basis of a clinical inter-view and neurological examination, independently of the neu-ropsychological assessment to avoid circularity. The Mini-Mental State Examination, Dementia Rating Scale, ClockDrawing Test, and Category fluency (animals per minute) testsmeasured cognition. Language testing was performed with theWestern Aphasia Battery (WAB). The aphasia quotient repre-sents a total score and overall measure of the severity of lan-guage impairment; major subtests are fluency, speech con-tent, comprehension of nouns and sentences, repetition, naming,reading, and writing. A subset of patients with SD was also ex-amined for the supplementary reading and writing of irregu-lar words. The clinical description of conversational speech char-acteristics was additional to formal language assessment withthe WAB. Behavior and personality change was rated on theFrontal Behavioral Inventory, with higher score indicating greaterbehavioral change.22 The side and lobar locations of promi-nent atrophy or hypometabolism on magnetic resonance imagingor computed tomography and hexylmethylpropylene amineox-ine–single-photon emission computed tomography was re-viewed by A. K. and P. M. (Table 1) but the radiological fea-tures were not used in patient grouping.

Patients with SD and bvFTD were younger than those withAD and PNFA (Table 2). The sex distribution was 16 womento 21 men in the SD group, 13 to 29 in bvFTD group, 32 to 22 inthe PNFA group, and 41 to 64 in the AD group. �2 analysis showedthat the PNFA group had significantly more women than thebvFTD (�2=7.7; P=.006) and AD groups (�2=5.9; P=.02). Thetime from onset of illness to first examination was longer in pa-tients with SD. The institutional review board of University ofWestern Ontario approved the study of human subjects.

RESULTS

COGNITION

Table 2 shows the results of comparison of all groups oncognitive and behavioral tests. Analyses of variance andTukey post hoc tests showed significantly better perfor-mance by the bvFTD group when compared with thePNFA and AD groups on the Mini-Mental State Exami-nation and the Dementia Rating Scale. Patients with SDwere also better, but not significantly. The animal flu-ency task revealed that patients with SD performed sig-nificantly worse than those with AD and bvFTD. Not onlywas visuospatial function preserved in our SD cohort, butwe also observed a heightened, at times obsessive, incli-nation to paint and complete jigsaw puzzles in 9 pa-tients with SD (Table 1). Visual object agnosia (13 of 37

Table 2. Demographics, Cognitive Screening, and Behavior

Variable

Mean (SD)

P ValueSD bvFTD AD PFNA

Age (n=37) (n=31) (n=105) (n=52)57.92 (8.38)a,b 58.48 (8.43)c,d 67.67 (8.62)b,d 64.37 (7.30)a,c .002a

.000b

.010c

.000d

Years ill (n=37) (n=42) (n=105) (n=52)4.0 (2.13)a,b,c 2.96 (2.92)c 2.59 (1.67)b 2.65 (1.43)a .009a

.001b

.019c

MMSE (n=29) (n=34) (n=35) (n=32)(max: 30) 21.48 (6.63) 25.03 (4.43)a,b 19.71 (7.26)b 19.44 (7.71)a .004a

.006b

FBI (n=32) (n=38) (n=28) (n=37)(max: 72, cutoff:

30)27.47 (15.35)a,b,c 36.84 (11.52)c,d,e 14.61 (10.40)b,e 16.86 (11.21)a,d .003a

.000b

.010c

.000d

.000e

DRS (n=25) (n=26) (n=95) (n=45)(max: 144) 101.40 (23.59)a 120.19 (25.75)a,b,c 105.33 (21.26)c 99.09 (30.16)b .034a

.003b

.034c

Clock drawing test (n=14) (n=19) (n=31) (n=10)(max: 10) 6.29 (2.86) 8.21 (1.87) 6.37 (3.03) 6.15 (3.38) No significant differences

Animal Fluency (n=32) (n=18) (n=105) (n=52)(normal above 12) 5.66 (3.80)a,b 11.67 (5.87)b,c 9.22 (4.44)a 7.83 (5.10)c .001a

.000b

.015c

Abbreviations: AD, Alzheimer disease; bvFTD, behavioral frontotemporal dementia; DRS, Dementia Rating Scale; FBI, Frontal Behavioral Inventory;max, maximum; MMSE, Mini-Mental State Examination; PFNA, progressive nonfluent aphasia; SD, semantic dementia.

a-eScores are significantly different in pairwise comparison (Tukey, post hoc) in each row (eg, in the MMSE row, only 2 comparisons are significant, bvFTD withPNFA and bvFTD with AD).




patients) and prosopagnosia (15 of 37 patients) was ob-vious enough to be observed by the caregivers or the ex-aminer (Table 1).

SPEECH OUTPUT

Speech output in patients with SD was fluent (WAB flu-ency rating of 6 or higher) in all cases. Eighteen of the 37patients had semantic jargon, defined as speech that is mean-ingless and irrelevant but grammatically and phonologi-cally correct, consisting of real words. Empty speech is simi-lar, but has some coherence and conversational relevance(n=4). Nine patients had significant thematic or semanticperseveration (stereotypy), and 8 patients were garrulous,with excessive output that incorporated some of the abovefeatures. Altogether, pragmatic difficulties including fail-ureof topicmaintenance,perseveration, and failure to switchspeaker roles, were present in 35 of 37 patients (Table 1).Semantic substitutions in spontaneous speech were fre-quent in SD (54.1%) when compared with PNFA (7.5%;�2=24.9; P=.001) but phonological paraphasias were ab-sent in SD and frequent in PNFA (41.5%; �2=20.3; P=.001),a significant double dissociation. Fifteen of the patients withPNFA were nonfluent, scoring 5 or less on the standard-ized fluency rating of the WAB. Another 10 had aphemia,stuttering, or apraxia of speech; some were only anomicand logopenic at the time of first examination but none hadclinically significant comprehension or semantic diffi-culty. Questioning the meaning of words heard in conver-sation was typical and occurred in 34 of 37 of the patientswith SD. This feature was recorded in 4 of 6 of the autop-sied SD cases and was not seen in any other groups (Table 1).

LANGUAGE

The Figure shows the results of the quantitative as-pects of language performance on the WAB, comparing

the SD group (n=31) with the bvFTD (n=17), PNFA(n=52), and AD groups (n=105). Analysis of varianceshowed a significant difference between the groups as mea-sured by the aphasia quotient; the AD and bvFTD groupshad significantly less language deficit than the SD group.The AD group was significantly more fluent than the SDgroup, and patients with PNFA were significantly less flu-ent than the bvFTD and AD groups but not significantlydifferent from the SD group. Auditory (single noun) wordrecognition and sequential commands (sentence com-prehension) were significantly lower in SD than AD pa-tients. In naming objects, the SD group was signifi-cantly worse than all others.

Using the WAB classification criteria, our patients withSD were classified as follows at baseline: 24, anomic; 4,transcortical sensory; and 3, Wernicke’s aphasia. The lastvisit classification changed to mostly Wernicke’s and trans-cortical sensory aphasia. Surface dyslexia and dys-graphia (patients retain phonological processing and regu-larize words when they cannot read or write them bymeaning), elicited by reading and writing irregular words,was observed in 18 of 19 patients with SD (Table 1).

BEHAVIOR

Only 6 cases presented with relatively pure SD withoutbehavioral change. All but 2 of these cases developed thebehavioral features eventually. One died of motor neu-ron disease a year after being seen; the other was lost tofollow-up. In 16 of 37 patients, the behavioral symp-toms were noticed first (Table 1). On the Frontal Behav-ioral Inventory, the bvFTD and SD groups scored sig-nificantly higher (more behavioral abnormality) than thePNFA and AD groups.22 Item analysis of the Frontal Be-havioral Inventory that compared the SD and bvFTDgroups is summarized in Table 3. Only apathy, aspon-taneity (closely related), and personal neglect differed sig-

100

80

90

70

60

50

40

30

20

10

0Aphasia Quotient Fluency Auditory Word Recognition Sequential Command Naming Objects Repetition

Scor

e, %

SD bvFTD PPA AD

Figure. Language function on the subtests of the Western Aphasia Battery comparing semantic dementia (SD) with behavioral frontotemporal dementia (bvFTD),primary progressive aphasia (PPA) (progressive nonfluent aphasia), and Alzheimer disease (AD). Raw scores are converted to percentages of the maximum score,usually achieved by controls. *P � .05; significant difference from semantic dementia.




nificantly between the two groups. These are all nega-tive items (deficiency behaviors). When all of the negative(Table 3) items are combined in a subscale, the SD groupscored significantly lower (better) than bvFTD group(t63=−3.945; P� .001; effect size [d]=0.97), a large effect.Whereas, on the positive subscale (disinhibition or ex-cess behaviors, the other 12 items), the difference be-tween the groups was moderate (t63=−2.050; P= .04;d=0.51).

COMMENT

The diagnosis of SD is far from unequivocally defined oruniversally practiced. Numerous studies have ap-proached theoretical issues exploring semantic memoryusing a few patients with SD at a time. We focused onthe clinical features and quantitation of language and be-havior in a larger cohort. Although the language resultscould be considered circular, because SD was defined byfluent speech and poor comprehension, patient selec-tion was based on caregiver history and neurocognitiveexamination; language and behavioral quantitation, neu-ropsychological tests, and imaging were performed in-dependently.

Semantic dementia should be suspected when a pa-tient with progressive aphasia has significant or early dif-ficulty with single-word comprehension.1,12,23 The se-mantic loss becomes clinically evident when the patientquestions the meaning of words, usually nouns in con-versation. The “What is . . . ?” questioning was fre-quently observed in the population with SD, and it ap-pears to be a highly diagnostic feature because it wasabsent in all other patient groups. This is even more strik-ing considering patients demonstrated preserved repeti-tion and phonological competence, eg, “Gorilla? . . . go-rilla . . . what is gorilla?” Naming was the worst in ourSD group, confirming that it is a major, albeit less spe-cific, feature.1,12,23 Patients with AD also forget words early,perform poorly on naming tests, and substitute words fromthe same semantic or superordinate category.

A most remarkable feature in our SD cohort was thesevere pragmatic disturbance with garrulous, excessive,disinhibited output, stereotypic thematic perseveration,and semantic jargon. Persevering with their own agendaand not stopping to listen are features that distinguishearly SD from PNFA and AD. Others have explored sin-gular aspects of pragmatics such as coherence in SD.24

The conversational peculiarity appears early but the ca-sual observer may not notice it. Later it may be com-pounded, even overshadowed by the altered personalityand unacceptable behavior, although it contributes sig-nificantly to the social handicap.

A comprehensive yet practical-length language testsuch as the WAB is helpful to quantify fluency, compre-hension, repetition, naming, reading, and writing and tofollow the course of the illness.17 Formal testing of com-prehension with the WAB or verbal intelligence tests mayalert the examiner to SD. Word comprehension was un-impaired in PNFA initially. Sentence comprehension wasimpaired in both patients with SD and PNFA but eachmay have different mechanisms, as suggested in the lit-

erature; one has increasing loss of word meaning whilethe other has significant loss of syntax.12,25 We also docu-mented the high frequency of surface dyslexia, confirm-ing the loss of reading of irregular words by the seman-tic route.12,26

The fluency-nonfluency distinction is controversial andrarely based on a standardized, scorable scale such as inour study. A recent editorial warned against such an over-simplified dichotomy of progressive aphasia.27 There aredifferent definitions of fluency28,29 or logopenia.29 Fur-thermore, fluency is stage related,16,20 and 4 of 6 of ourautopsied patients with SD were recorded to be nonflu-ent or mute eventually. Particularly problematic is theinclusion of all fluent aphasics as having SD, potentiallyresulting in including patients with early PNFA or ADin SD groups. Recent usage includes SD under the pri-mary progressive aphasia umbrella, in addition to PNFAand logopenic progressive aphasia, which turns out tobe aphasic AD in many cases.29-31 Some ambiguous caseshave been called mixed progressive aphasia.31 This cat-egory is similar to our designation of possible SD in thisstudy or possible primary progressive aphasia previ-ously.20 Semantic paraphasias were characteristic of SDand phonological ones of PNFA, confirming other stud-ies12,28 and demonstrating a double dissociation. Phono-logical paraphasias, however, are also a feature of logo-penic progressive aphasia29 and develop in later stagesof AD.15

In our study, one-third of our patients with SD(Table 1) had clinically evident visual object use agno-sia and prosopagnosia in addition to the language defi-cit. Caregivers often described loss of object recognitionbeyond word finding or naming impairment, usually

Table 3. Scores of Patients With SD and bvFTD on Itemsof the Frontal Behavioral Inventory

FBI Item

Mean (SD)P

ValueSD bvFTD

Apathya 1.16 (1.24) 2.09 (1.06) .002Aspontaneitya 1.20 (1.30) 2.24 (0.92) �.001Indifference 1.13 (1.23) 1.85 (1.08) .01Inflexibility 1.61 (1.31) 1.85 (1.02) .41Personal neglecta 0.87 (1.06) 1.91 (1.08) �.001Disorganization 1.94 (1.03) 2.50 (0.79) .02Inattention 2.06 (1.06) 2.21 (1.01) .58Loss of insight 1.35 (1.36) 2.09 (1.11) .02Perseverations/obsessions 1.87 (1.20) 2.09 (1.03) .44Irritability 1.13 (1.15) 1.68 (1.25) .07Jocularity 0.84 (1.13) 0.97 (1.17) .65Poor judgment/impulsivity 1.42 (1.20) 1.57 (0.98) .57Inappropriateness 1.71 (1.32) 2.03 (1.03) .28Restlessness/roaming 1.10 (1.16) 1.44 (1.28) .26Aggression 0.84 (1.16) 1.00 (1.23) .59Hyperorality 0.84 (1.10) 1.71 (1.24) .004Hypersexuality 0.45 (0.96) 0.59 (1.08) .59Utilization 0.52 (0.89) 0.59 (1.02) .76Incontinence 0.23 (0.68) 0.62 (1.04) .09Hoarding 0.89 (0.89) 1.08 (1.08) .24

Abbreviations: bvFTD, behavioral frontotemporal dementia; FBI, FrontalBehavioral Inventory; SD, semantic dementia.

a Indicates significant difference after Bonferroni corrections; P� .002.




manifesting as difficulty finding an object in their sightor not knowing how to use it. Visual, face, and soundagnosia as well as the behavioral abnormality have beenassociated with right temporal involvement and language-predominant symptoms with left temporal atrophy.32 Vi-sual agnosia can also be a feature of posterior cortical at-rophy, which most often has AD pathology but theapperceptive deficit and the presence of Balint syn-drome distinguished that condition from SD.33

The association of SD with the behavioral manifesta-tions of FTD occurred with few exceptions. This has beenpreviously recognized to a variable extent34,35 but, in ouropinion, it has not received enough emphasis. In somestudies, SD often appears as a separate syndrome and little,if any, mention is made of the behavioral abnormalities.We have previously shown that the presence of more thanone Pick complex syndrome (eg, disinhibition plus apha-sia) is associated with FTD rather than other pathologyat autopsy.36 In another study of SD, the presence of be-havioral change also seemed to correspond to the pres-ence of FTD pathology.37 Others consider the behav-ioral abnormalities in SD to be distinct from those ofbvFTD.34 For example, patients with SD have food fadsand are social seekers, while patients with bvFTD havegluttony and social avoidance.34 We also found on itemanalysis that negative symptoms such as apathy and per-sonal neglect were more severe in bvFTD, but the dis-inhibition items were involved more similarly. This sug-gests a different involvement of the medial frontalcingulate and the anterior temporal orbitofrontal cir-cuits earlier in the disease. Semantic dementia withoutbehavioral impairment may appear early in the illness.On the other hand, SD often appears secondarily to bvFTDand remains underdiagnosed. From our longitudinal co-hort study of FTD,20 only patients with bvFTD devel-oped SD later (approximately 20%). Conversely, morepatients with SD (76%) developed bvFTD as a second-ary syndrome compared with other presentations, sug-gesting an association of bvFTD with SD.20 In the pres-ent study, the Frontal Behavioral Inventory, as expected,showed the greatest behavior impairment in the bvFTDgroup. Nonetheless, the SD group also obtained higherscores (more behavioral abnormalities) compared withAD and PNFA.

In this study, patients with SD and PNFA performedworse than the other groups on the Mini-Mental StateExamination and the Dementia Rating Scale because thesetests have significant language components. Clinically,these patients are more aphasic than demented. Al-though episodic and nonverbal visuospatial memory ispreserved in SD,12 family reports of forgetfulness of nameswere common (28 of 37 in Table 1). Poor performanceon verbal memory tests related to verbal semantic lossand reversal of the temporal gradient for episodic memoryin SD has been observed by others.38,39 The present studyalso indicates that the category fluency is significantlyworse in the SD group, likely owing to lexicosemanticrather than executive dysfunction. The incidence of SDwas estimated in one clinic as 25% in the FTD popula-tion12 vs 10% in ours. This may reflect differences in se-lection or referral but incidence data from a well-designed epidemiological study are lacking.

Greater left than right temporal atrophy has been pre-viously described as characteristic of SD1,12,37; our dataconfirm this. Marked temporal atrophy should alert theclinician to the diagnosis. There are exceptions, how-ever, suggesting that neuroimaging should be used as anadjunct rather than primary diagnostic criterion. Neu-roimaging is also stage related and, eventually, both tem-poral lobes and frontal areas become involved.40

The underlying pathology is most often ubiquitinpositive.19,37,41 In our series, 5 of 6 autopsies hadubiquitin-positive, tau-negative inclusions and 1 haddementia that lacked distinctive histopathology. Recentstudies suggested an association with more neuriticubiquitin deposits with few cytoplasmic inclusions.19 Sofar we do not have sufficient data to confirm or contra-dict this correlation.

In conclusion, the cardinal diagnostic features of SDbased on our findings are (1) the questioning of the mean-ing of words, which is a striking manifestation of the com-prehension deficit of single nouns (SD may be called the“What is . . . ?” disease after this singularly characteris-tic clue); (2) garrulous, empty, fluent speech output withthematic perseveration and semantic jargon; and (3) thestrong association between SD and bvFTD—the two pre-sentations often converge.

The equation with all fluent aphasia is an overinclu-sive dilution of a clinically and possibly biologically dis-tinct presentation. The overlap with aphasic AD, logo-penic progressive aphasia, and early PNFA createsdiagnostic uncertainties until the characteristic featuresof SD emerge. Nevertheless, the identification of SD isvaluable, particularly in view of the recent advances inpathology and molecular biology of FTD that suggest apotential for specific treatment of different varieties ofthe presentation.

Accepted for Publication: July 15, 2009.Correspondence: Andrew Kertesz, MD, Department ofCognitive Neurology, University of Western Ontario, 268Grosvenor St, London, ON N6A 4V2 ([email protected]).Author Contributions: Study concept and design: Kertesz.Acquisition of data: Kertesz, Jesso, Harciarek, Blair, andMcMonagle. Analysis and interpretation of data: Kertesz,Jesso, Blair, and McMonagle. Drafting of the manuscript:Kertesz, Jesso, Harciarek, and McMonagle. Critical revi-sion of the manuscript for important intellectual content:Kertesz, Harciarek, Blair, and McMonagle. Statistical analy-sis: Kertesz, Jesso, Harciarek, and Blair. Obtained funding:Kertesz. Administrative, technical, and material support:Kertesz, Jesso, and McMonagle. Study supervision: Kertesz.Funding/Support: This study was supported by the Law-son Research Institute and the Medical Research Coun-cil of Canada Cohort study (ACCORD); and a STARTscholarship from the Foundation for Polish Science (DrHarciarek).Financial Disclosure: Dr Kertesz reports receiving grantsfor pharmaceutical trials by Janssen-Ortho (Galan-tamine in Frontotemporal dementia), for clinical trialsin Alzheimer disease by Pfizer, Myriad, Lundbeck, andGlaxoSmithKline, and serving on the advisory board ofPfizer.




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