What Is Semantic Dementia? a Cohort Study of Diagnostic Features and Clinical Boundaries

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- tions were frequent in SD (54.1%) but phonological er- hort of patients with semantic dementia (SD) that high- rors were absent, in contrast to progressive nonfluent lights important, sometimes overlooked features and to aphasia with the opposite pattern. All but 3 patients with compare it with similar entities. probable SD questioned the meaning of words. Patients with SD had significantly lower naming and comprehen- Design: Cohort study. sion scores, and their fluency was between progressive nonfluent aphasia and Alzheimer disease or behavioral Setting: A cognitive neurology clinic. frontotemporal dementia. Behavior was abnormal in 94.6% of patients with probable SD. Patients: A population of 48 patients clinically diagnosed with SD was contrasted with 52 patients with pro- Conclusions: Semantic dementia is distinguishable from gressive nonfluent aphasia, 42 patients with a behav- other presentations of frontotemporal dementia and Alz- ioral variety of frontotemporal dementia, and 105 patients heimer disease, not only by fluent speech and impaired with Alzheimer disease on speech output characteristics, comprehension, naming, and repetition subtests of comprehension without loss of episodic memory, syn- the Western Aphasia Battery, the Frontal Behavioral In- tax, and phonology but also by empty, garrulous speech ventory, and other cognitive tests. Neuroimaging was vi- with thematic perseverations, semantic paraphasias, and sually analyzed, and 6 patients with SD had autopsy. poor category fluency. Questioning the meaning of words (eg, “What is steak?”) is an important diagnostic clue not Results: Of 37 patients with probable SD, 48.6% had se- seen in other groups, and behavior change is prevalent. mantic jargon; 21.6%, excessive garrulous output; and 75.7%, some pragmatic disturbance. Semantic substitu- Arch Neurol. 2010;67(4):483-489

EMANTIC DEMENTIA (SD) Snowden et al1 and has been adopted by designates a progressive cog- others,9 including the consensus criteria nitive and language deficit, of Neary et al,13 as a variety of frontotem- primarily involving compre- poral dementia (FTD). The incidence of hension of words and related SD is estimated by one clinic to be 25% in semanticS processing.1 These patients lose their patients with FTD.12 the meaning of words, usually nouns, but Semantic dementia has been equated retain fluency, phonology, and syntax. with fluent progressive aphasia.9,14 Flu- Author Affiliations: Pick2 described similar patients as hav- ent aphasia, however, is common in Alz- Department of Clinical 15 Neurological Sciences, ing “pure word deafness” in association heimer disease (AD) and, at the onset, University of Western Ontario with left temporal atrophy. Transcortical all patients with progressive aphasia are (Dr Kertesz), and Cognitive sensory aphasia was used for similar cases.3 fluent, even those who become nonflu- Neurology and Alzheimer Semantic aphasia was a term used by Head4 ent later.16,17 The fluency-nonfluency dis- Research Centre, St Joseph’s in war-injured patients for a 2-way distinction is often arbitrary and rarely quan- Hospital, London, Ontario, turbance of comprehension and naming. titated. Primary progressive aphasia is Canada (Dr Kertesz and The condition was called gogi (meaning) subdivided variably and sometimes in- Ms Jesso); University of aphasia in Japan.5 Some patients were con- cludes SD. Here we used the term pro- Gdan´ sk, Gdan´ sk, Poland sidered to have loss of semantic memory6 gressive nonfluent aphasia (PNFA) for a (Dr Harciarek); Concordia and others a language impairment.7,8 Se- comparison group. Semantic deficits, con- University, Montreal, Canada 18 (Mr Blair); and the Department mantic dementia has been further elabo- sidered basic to SD, also appear in AD. of Neurology, Royal Victoria rated as the degradation of a single cen- Because of these overlapping features from Hospital, Belfast, Northern tral network of conceptual knowledge.9-12 different clinical and biological entities, the Ireland (Dr McMonagle). The definition of SD originates from diagnostic boundaries remain uncertain.

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Sex/Age at Onset, y/ Duration of Memory Questioning Visual Face Surface Speech Neurological Autopsy 1st Syndrome Illness, yb for Names Words Agnosia Agnosia Pragmatics Artc Dyslexia Output Image Findings F/60/SD 4 1 1 1 1 1 . . . 1 Empty LTA FTLD-U F/56/bvFTD 4 1 1 1 1 1 . . . 1 Stereotypy RTAϾLF FTLD-U M/61/bvFTD 6 1 ...... 1 . . . 1 Semantic jargon LTA FTLD-U M/46/SD 1 1 1 1 . . . 1 1 1 Empty LTA FTLD-U M/38/bvFTD 2 1 ...... 1 ...... Semantic jargon, perseverative LTA FTLD-U F/64/bvFTD 1 1 1 ...... Perseverative FTA DLDH F/51/bvFTD 7 1 1 1 0 1 . . . 1 Semantic jargon Diffuse . . . F/68/bvFTD 3 . . . 1 1 1 1 ...... Semantic jargon RϾLTA ... F/56/SD 3 . . . 1 ...... 1 1 1 Semantic jargon LTA . . . F/65/SD 2 1 1 1 ...... 0 Tangential LϾRTA ... 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 LϾRTA ... 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 LϾRTFA ... 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 LϾR ... 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 RϾLFTA . . . M/69/SD 5 1 1 ...... 1 1 1 Semantic jargon LϾRTA ... F/62/bvFTD 6 1 1 1 1 1 ...... Garrulous, perseverative LϾRTA ... M/59/SD 4 1 1 ...... 1 . . . 1 Semantic jargon LϾRTA ... 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 LϾRTA ... M/64/SD 3 1 1 . . . 0 1 1 1 Perseverative LϾRTA ... F/66/SD 4 1 1 ...... 1 . . . Normal, fluent LϾRTA ... M/59/bvFTD 10 1 1 ...... 1 1 . . . Semantic jargon LϾRTFA ... 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. a 0 indicates that a symptom does not exist; 1, symptom exists. b Years from onset of illness to first clinical visit. c Indicates an obsession with painting or jigsaw puzzles. d For 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.

Some features of SD such as distinctive speech output 361 patients with FTD or Pick complex. Patients with SD had characteristics, impaired pragmatics (the study of the give- progressive loss of naming and comprehension, with preserved and-take and efficiency of communication), “What is...” syntax, phonology, fluency, and relatively preserved episodic 20 questioning of meaning, and behavioral abnormality are memory. They were followed up at yearly intervals, but only relatively unexplored. We aimed to study SD in a cog- the results of the first examination were used for the statistical nitive neurology clinic population of patients in an at- analyses in this study. Thirty-seven patients were considered to have probable SD (Table 1). This group had prominent com- tempt to delineate the syndrome from the behavioral pre- prehension and word-finding difficulty, either from the begin- sentation of patients with FTD (bvFTD), PNFA, and AD. ning of the illness or by the first time they were seen. Patients In addition to comparing neurocognitive features with with possible SD (n=11) were cases with atypical features and related conditions, we characterized the pragmatics of were not included in the statistical analysis. One patient had epi- speech and quantitated language, including fluency and sodic memory loss and 2 had confused close relatives as strang- the behavioral abnormality. In view of a recent sugges- ers (the Capgras delusion), which raised the suspicion of pos- tion associating a specific pathology with SD,19 the study sible AD.21 One patient had significant vascular disease and of clinical boundaries of SD is even more relevant. We another panic attacks. Five possible cases had predominant be- report autopsy confirmation in 6 of 48 patients. 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- METHODS sented with mainly behavioral or personality disturbance, ful- filling Neary and colleagues’ criteria,13 and no significant lan- The target population was 48 patients with SD who were diag- guage impairment was evident on the first examination. Patients nosed clinically using the Neary et al criteria13 from a cohort of with PNFA had an initial deficit of language output and pres-

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Mean (SD)

Variable SD bvFTD AD PFNA P Value 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: 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 30) .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 with PNFA and bvFTD with AD).

ervation of comprehension, memory, and visuospatial ability. Patients with SD and bvFTD were younger than those with Patients with additional memory and comprehension prob- AD and PNFA (Table 2). The sex distribution was 16 women lems in their history were excluded as having possible PNFA. to 21 men in the SD group, 13 to 29 in bvFTD group, 32 to 22 in Alzheimer disease was diagnosed when the primary deficit was the PNFA group, and 41 to 64 in the AD group. ␹2 analysis showed (episodic) memory impairment and the patients fulfilled the that the PNFA group had significantly more women than the National Institute of Neurological and Communicative Disor- bvFTD (␹2=7.7; P=.006) and AD groups (␹2=5.9; P=.02). The ders and Stroke/Alzheimer’s Disease and Related Disorders As- time from onset of illness to first examination was longer in pa- sociation (NINCDS/ADRDA) criteria. tients with SD. The institutional review board of University of The patients were grouped on the basis of a clinical inter- Western Ontario approved the study of human subjects. view and neurological examination, independently of the neu- ropsychological assessment to avoid circularity. The Mini- Mental State Examination, Dementia Rating Scale, Clock RESULTS Drawing Test, and Category fluency (animals per minute) tests measured cognition. Language testing was performed with the COGNITION Western Aphasia Battery (WAB). The aphasia quotient repre- sents a total score and overall measure of the severity of language impairment; major subtests are fluency, speech con- Table 2 shows the results of comparison of all groups on tent, comprehension of nouns and sentences, repetition, naming, cognitive and behavioral tests. Analyses of variance and reading, and writing. A subset of patients with SD was also ex- Tukey post hoc tests showed significantly better perfor- amined for the supplementary reading and writing of irregu- mance by the bvFTD group when compared with the lar words. The clinical description of conversational speech char- PNFA and AD groups on the Mini-Mental State Exami- acteristics was additional to formal language assessment with nation and the Dementia Rating Scale. Patients with SD the WAB. Behavior and personality change was rated on the were also better, but not significantly. The animal flu- Frontal Behavioral Inventory, with higher score indicating greater ency task revealed that patients with SD performed sig- behavioral change.22 The side and lobar locations of prominent atrophy or hypometabolism on magnetic resonance imaging nificantly worse than those with AD and bvFTD. Not only or computed tomography and hexylmethylpropylene amineox- was visuospatial function preserved in our SD cohort, but ine–single-photon emission computed tomography was re- we also observed a heightened, at times obsessive, incli- viewed by A. K. and P. M. (Table 1) but the radiological fea- nation to paint and complete jigsaw puzzles in 9 pa- tures were not used in patient grouping. tients with SD (Table 1). Visual object agnosia (13 of 37

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50 Score, % 40

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

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 Ͻ .05; significant difference from semantic dementia.

patients) and prosopagnosia (15 of 37 patients) was ob- the SD group (n=31) with the bvFTD (n=17), PNFA vious enough to be observed by the caregivers or the ex- (n=52), and AD groups (n=105). Analysis of variance aminer (Table 1). showed a significant difference between the groups as measured by the aphasia quotient; the AD and bvFTD groups SPEECH OUTPUT had significantly less language deficit than the SD group. The AD group was significantly more fluent than the SD Speech output in patients with SD was fluent (WAB flu- group, and patients with PNFA were significantly less fluency rating of 6 or higher) in all cases. Eighteen of the 37 ent than the bvFTD and AD groups but not significantly patients had semantic jargon, defined as speech that is mean- different from the SD group. Auditory (single noun) word ingless and irrelevant but grammatically and phonologi- recognition and sequential commands (sentence com- cally correct, consisting of real words. Empty speech is simi- prehension) were significantly lower in SD than AD pa- lar, but has some coherence and conversational relevance tients. In naming objects, the SD group was signifi- (n=4). Nine patients had significant thematic or semantic cantly worse than all others. perseveration (stereotypy), and 8 patients were garrulous, Using the WAB classification criteria, our patients with with excessive output that incorporated some of the above SD were classified as follows at baseline: 24, anomic; 4, features. Altogether, pragmatic difficulties including fail- transcortical sensory; and 3, Wernicke’s aphasia. The last ure of topic maintenance, perseveration, and failure to switch visit classification changed to mostly Wernicke’s and trans- speaker roles, were present in 35 of 37 patients (Table 1). cortical sensory aphasia. Surface dyslexia and dys- Semantic substitutions in spontaneous speech were fre- graphia (patients retain phonological processing and regu- quent in SD (54.1%) when compared with PNFA (7.5%; larize words when they cannot read or write them by ␹2=24.9; P=.001) but phonological paraphasias were ab- meaning), elicited by reading and writing irregular words, sent in SD and frequent in PNFA (41.5%; ␹2=20.3; P=.001), was observed in 18 of 19 patients with SD (Table 1). a significant double dissociation. Fifteen of the patients with PNFA were nonfluent, scoring 5 or less on the standard- BEHAVIOR ized fluency rating of the WAB. Another 10 had aphemia, stuttering, or apraxia of speech; some were only anomic Only 6 cases presented with relatively pure SD without and logopenic at the time of first examination but none had behavioral change. All but 2 of these cases developed the clinically significant comprehension or semantic diffi- behavioral features eventually. One died of motor neu- culty. Questioning the meaning of words heard in conver- ron disease a year after being seen; the other was lost to sation was typical and occurred in 34 of 37 of the patients follow-up. In 16 of 37 patients, the behavioral symp- with SD. This feature was recorded in 4 of 6 of the autop- toms were noticed first (Table 1). On the Frontal Behav- sied SD cases and was not seen in any other groups (Table 1). ioral Inventory, the bvFTD and SD groups scored significantly higher (more behavioral abnormality) than the LANGUAGE PNFA and AD groups.22 Item analysis of the Frontal Be- havioral Inventory that compared the SD and bvFTD The Figure shows the results of the quantitative as- groups is summarized in Table 3. Only apathy, aspon- pects of language performance on the WAB, comparing taneity (closely related), and personal neglect differed sig-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 nificantly between the two groups. These are all negative items (deficiency behaviors). When all of the negative Table 3. Scores of Patients With SD and bvFTD on Items (Table 3) items are combined in a subscale, the SD group of the Frontal Behavioral Inventory scored significantly lower (better) than bvFTD group Ͻ Mean (SD) (t63=−3.945; P .001; effect size [d]=0.97), a large effect. P Whereas, on the positive subscale (disinhibition or ex- FBI Item SD bvFTD Value cess behaviors, the other 12 items), the difference be- Apathya 1.16 (1.24) 2.09 (1.06) .002 a tween the groups was moderate (t63=−2.050; P=.04; Aspontaneity 1.20 (1.30) 2.24 (0.92) Ͻ.001 d=0.51). Indifference 1.13 (1.23) 1.85 (1.08) .01 Inflexibility 1.61 (1.31) 1.85 (1.02) .41 Personal neglecta 0.87 (1.06) 1.91 (1.08) Ͻ.001 COMMENT Disorganization 1.94 (1.03) 2.50 (0.79) .02 Inattention 2.06 (1.06) 2.21 (1.01) .58 Loss of insight 1.35 (1.36) 2.09 (1.11) .02 The diagnosis of SD is far from unequivocally defined or Perseverations/obsessions 1.87 (1.20) 2.09 (1.03) .44 universally practiced. Numerous studies have ap- Irritability 1.13 (1.15) 1.68 (1.25) .07 proached theoretical issues exploring semantic memory Jocularity 0.84 (1.13) 0.97 (1.17) .65 using a few patients with SD at a time. We focused on Poor judgment/impulsivity 1.42 (1.20) 1.57 (0.98) .57 the clinical features and quantitation of language and be- Inappropriateness 1.71 (1.32) 2.03 (1.03) .28 Restlessness/roaming 1.10 (1.16) 1.44 (1.28) .26 havior in a larger cohort. Although the language results Aggression 0.84 (1.16) 1.00 (1.23) .59 could be considered circular, because SD was defined by Hyperorality 0.84 (1.10) 1.71 (1.24) .004 fluent speech and poor comprehension, patient selec- Hypersexuality 0.45 (0.96) 0.59 (1.08) .59 tion was based on caregiver history and neurocognitive Utilization 0.52 (0.89) 0.59 (1.02) .76 examination; language and behavioral quantitation, neu- Incontinence 0.23 (0.68) 0.62 (1.04) .09 ropsychological tests, and imaging were performed in- Hoarding 0.89 (0.89) 1.08 (1.08) .24 dependently. Abbreviations: bvFTD, behavioral frontotemporal dementia; FBI, Frontal Semantic dementia should be suspected when a pa- Behavioral Inventory; SD, semantic dementia. tient with progressive aphasia has significant or early dif- a Indicates significant difference after Bonferroni corrections; PϽ.002. ficulty with single-word comprehension.1,12,23 The semantic loss becomes clinically evident when the patient questions the meaning of words, usually nouns in con- erature; one has increasing loss of word meaning while versation. The “What is...?”questioning was fre- the other has significant loss of syntax.12,25 We also docu- quently observed in the population with SD, and it ap- mented the high frequency of surface dyslexia, confirm- pears to be a highly diagnostic feature because it was ing the loss of reading of irregular words by the seman- absent in all other patient groups. This is even more strik- tic route.12,26 ing considering patients demonstrated preserved repeti- The fluency-nonfluency distinction is controversial and tion and phonological competence, eg, “Gorilla? . . . go- rarely based on a standardized, scorable scale such as in rilla...what is gorilla?” Naming was the worst in our our study. A recent editorial warned against such an over- SD group, confirming that it is a major, albeit less spe- simplified dichotomy of progressive aphasia.27 There are cific, feature.1,12,23 Patients with AD also forget words early, different definitions of fluency28,29 or logopenia.29 Fur- perform poorly on naming tests, and substitute words from thermore, fluency is stage related,16,20 and4of6ofour the same semantic or superordinate category. autopsied patients with SD were recorded to be nonflu- A most remarkable feature in our SD cohort was the ent or mute eventually. Particularly problematic is the severe pragmatic disturbance with garrulous, excessive, inclusion of all fluent aphasics as having SD, potentially disinhibited output, stereotypic thematic perseveration, resulting in including patients with early PNFA or AD and semantic jargon. Persevering with their own agenda in SD groups. Recent usage includes SD under the pri- and not stopping to listen are features that distinguish mary progressive aphasia umbrella, in addition to PNFA early SD from PNFA and AD. Others have explored sin- and logopenic progressive aphasia, which turns out to gular aspects of pragmatics such as coherence in SD.24 be aphasic AD in many cases.29-31 Some ambiguous cases The conversational peculiarity appears early but the ca- have been called mixed progressive aphasia.31 This cat- sual observer may not notice it. Later it may be com- egory is similar to our designation of possible SD in this pounded, even overshadowed by the altered personality study or possible primary progressive aphasia previ- and unacceptable behavior, although it contributes sig- ously.20 Semantic paraphasias were characteristic of SD nificantly to the social handicap. and phonological ones of PNFA, confirming other stud- A comprehensive yet practical-length language test ies12,28 and demonstrating a double dissociation. Phono- such as the WAB is helpful to quantify fluency, compre- logical paraphasias, however, are also a feature of logo- hension, repetition, naming, reading, and writing and to penic progressive aphasia29 and develop in later stages follow the course of the illness.17 Formal testing of com- of AD.15 prehension with the WAB or verbal intelligence tests may In our study, one-third of our patients with SD alert the examiner to SD. Word comprehension was un- (Table 1) had clinically evident visual object use agno- impaired in PNFA initially. Sentence comprehension was sia and prosopagnosia in addition to the language defi- impaired in both patients with SD and PNFA but each cit. Caregivers often described loss of object recognition may have different mechanisms, as suggested in the lit- beyond word finding or naming impairment, usually

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 manifesting as difficulty finding an object in their sight Greater left than right temporal atrophy has been pre- or not knowing how to use it. Visual, face, and sound viously described as characteristic of SD1,12,37; our data agnosia as well as the behavioral abnormality have been confirm this. Marked temporal atrophy should alert the associated with right temporal involvement and language- clinician to the diagnosis. There are exceptions, how- predominant symptoms with left temporal atrophy.32 Vi- ever, suggesting that neuroimaging should be used as an sual agnosia can also be a feature of posterior cortical at- adjunct rather than primary diagnostic criterion. Neu- rophy, which most often has AD pathology but the roimaging is also stage related and, eventually, both tem- apperceptive deficit and the presence of Balint syn- poral lobes and frontal areas become involved.40 drome distinguished that condition from SD.33 The underlying pathology is most often ubiquitin The association of SD with the behavioral manifesta- positive.19,37,41 In our series, 5 of 6 autopsies had tions of FTD occurred with few exceptions. This has been ubiquitin-positive, tau-negative inclusions and 1 had previously recognized to a variable extent34,35 but, in our dementia that lacked distinctive histopathology. Recent opinion, it has not received enough emphasis. In some studies suggested an association with more neuritic studies, SD often appears as a separate syndrome and little, ubiquitin deposits with few cytoplasmic inclusions.19 So if any, mention is made of the behavioral abnormalities. far we do not have sufficient data to confirm or contra- We have previously shown that the presence of more than dict this correlation. one Pick complex syndrome (eg, disinhibition plus apha- In conclusion, the cardinal diagnostic features of SD sia) is associated with FTD rather than other pathology based on our findings are (1) the questioning of the mean- at autopsy.36 In another study of SD, the presence of being of words, which is a striking manifestation of the com- havioral change also seemed to correspond to the pres- prehension deficit of single nouns (SD may be called the ence of FTD pathology.37 Others consider the behav- “Whatis...?”disease after this singularly characteris- ioral abnormalities in SD to be distinct from those of tic clue); (2) garrulous, empty, fluent speech output with bvFTD.34 For example, patients with SD have food fads thematic perseveration and semantic jargon; and (3) the and are social seekers, while patients with bvFTD have strong association between SD and bvFTD—the two pre- gluttony and social avoidance.34 We also found on item sentations often converge. analysis that negative symptoms such as apathy and per- The equation with all fluent aphasia is an overinclu- sonal neglect were more severe in bvFTD, but the dis- sive dilution of a clinically and possibly biologically disinhibition items were involved more similarly. This sug- tinct presentation. The overlap with aphasic AD, logo- gests a different involvement of the medial frontal penic progressive aphasia, and early PNFA creates cingulate and the anterior temporal orbitofrontal cir- diagnostic uncertainties until the characteristic features cuits earlier in the disease. Semantic dementia without of SD emerge. Nevertheless, the identification of SD is behavioral impairment may appear early in the illness. valuable, particularly in view of the recent advances in On the other hand, SD often appears secondarily to bvFTD pathology and molecular biology of FTD that suggest a and remains underdiagnosed. From our longitudinal co- potential for specific treatment of different varieties of hort study of FTD,20 only patients with bvFTD devel- the presentation. oped SD later (approximately 20%). Conversely, more patients with SD (76%) developed bvFTD as a second- Accepted for Publication: July 15, 2009. ary syndrome compared with other presentations, sug- Correspondence: Andrew Kertesz, MD, Department of gesting an association of bvFTD with SD.20 In the pres- Cognitive Neurology, University of Western Ontario, 268 ent study, the Frontal Behavioral Inventory, as expected, Grosvenor St, London, ON N6A 4V2 (andrew.kertesz showed the greatest behavior impairment in the bvFTD @sjhc.london.on.ca). group. Nonetheless, the SD group also obtained higher Author Contributions: Study concept and design: Kertesz. scores (more behavioral abnormalities) compared with Acquisition of data: Kertesz, Jesso, Harciarek, Blair, and AD and PNFA. McMonagle. Analysis and interpretation of data: Kertesz, In this study, patients with SD and PNFA performed Jesso, Blair, and McMonagle. Drafting of the manuscript: worse than the other groups on the Mini-Mental State Kertesz, Jesso, Harciarek, and McMonagle. Critical revi- Examination and the Dementia Rating Scale because these sion of the manuscript for important intellectual content: tests have significant language components. Clinically, Kertesz, Harciarek, Blair, and McMonagle. Statistical analy- these patients are more aphasic than demented. Al- sis: Kertesz, Jesso, Harciarek, and Blair. Obtained funding: though episodic and nonverbal visuospatial memory is Kertesz. Administrative, technical, and material support: preserved in SD,12 family reports of forgetfulness of names Kertesz, Jesso, and McMonagle. Study supervision: Kertesz. were common (28 of 37 in Table 1). Poor performance Funding/Support: This study was supported by the Law- on verbal memory tests related to verbal semantic loss son Research Institute and the Medical Research Coun- and reversal of the temporal gradient for episodic memory cil of Canada Cohort study (ACCORD); and a START in SD has been observed by others.38,39 The present study scholarship from the Foundation for Polish Science (Dr also indicates that the category fluency is significantly Harciarek). worse in the SD group, likely owing to lexicosemantic Financial Disclosure: Dr Kertesz reports receiving grants rather than executive dysfunction. The incidence of SD for pharmaceutical trials by Janssen-Ortho (Galan- was estimated in one clinic as 25% in the FTD popula- tamine in Frontotemporal dementia), for clinical trials tion12 vs 10% in ours. This may reflect differences in se- in Alzheimer disease by Pfizer, Myriad, Lundbeck, and lection or referral but incidence data from a well- GlaxoSmithKline, and serving on the advisory board of designed epidemiological study are lacking. Pfizer.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 22. Kertesz A, Davidson W, Fox H. Frontal behavioral inventory: diagnostic criteria REFERENCES for frontal lobe dementia. Can J Neurol Sci. 1997;24(1):29-36. 23. Mesulam MM, Grossman M, Hillis A, Kertesz A, Weintraub S. The core and halo 1. Snowden JS, Goulding PJ, Neary D. Semantic dementia: a form of circum- of primary progressive aphasia and semantic dementia. Ann Neurol. 2003; scribed cerebral atrophy. Behav Neurol. 1989;2:167-182. 54(suppl 5):S11-S14. 2. Pick A. Über primäre progressive Demenz bei Erwachsenen [About primary pro- 24. Ash S, Moore P, Antani S, McCawley G, Work M, Grossman M. Trying to tell a gressive dementia in adults]. Prag Med Wochenschr. 1904;29:417. tale: discourse impairments in progressive aphasia and frontotemporal dementia. 3. Henschen SE, Schaller WF. Clinical and anatomical contributions on brain pathology. Neurology. 2006;66(9):1405-1413. Arch Neurol Psychiatry. 1925;13(2):226-249. 25. Grossman M, Moore P. A longitudinal study of sentence comprehension diffi- 4. Head H. Aphasia and Kindred Disorders of Speech. New York, NY: MacMillan culty in primary progressive aphasia. J Neurol Neurosurg Psychiatry. 2005; Co; 1926. 76(5):644-649. 5. Sasanuma S, Monoi H. The syndrome of gogi (word meaning) aphasia: selec- 26. Wilson SM, Brambati SM, Henry RG, et al. The neural basis of surface dyslexia tive impairment of kanji processing. Neurology. 1975;25(7):627-632. in semantic dementia. Brain. 2009;132(pt 1):71-86. 6. Warrington EK. The selective impairment of semantic memory. Q J Exp Psychol. 27. Hillis AE. Lost for words. Neurology. 2008;71(16):1218-1219. 1975;27(4):635-657. 28. Clark DG, Charuvastra A, Miller BL, Shapira JS, Mendez MF. Fluent versus non- 7. Basso A, Capitani E, Laiacona M. Progressive language impairment without de- fluent primary progressive aphasia: a comparison of clinical and functional neu- mentia: a case with isolated category specific semantic defect. J Neurol Neuro- roimaging features. Brain Lang. 2005;94(1):54-60. surg Psychiatry. 1988;51(9):1201-1207. 29. Gorno-Tempini ML, Dronkers NF, Rankin KP, et al. Cognition and anatomy in 8. Kertesz A, Davidson W, McCabe P. Primary progressive semantic aphasia: a case three variants of primary progressive aphasia. Ann Neurol. 2004;55(3):335- study. J Int Neuropsychol Soc. 1998;4(4):388-398. 346. 9. Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia: progressive 30. Rabinovici GD, Jagust WJ, Furst AJ, et al. Abeta amyloid and glucose metabo- fluent aphasia with temporal lobe atrophy. Brain. 1992;115(pt 6):1783-1806. lism in three variants of primary progressive aphasia. Ann Neurol. 2008;64 10. Hodges JR, Garrard P, Patterson K. Semantic dementia. In: Kertesz A, Munoz (4):388-401. GD, eds. Pick’s Disease and Pick Complex. New York, NY: Wiley-Liss; 1998:83- 31. Mesulam M, Wicklund A, Johnson N, et al. Alzheimer and frontotemporal pa- 104. thology in subsets of primary progressive aphasia. Ann Neurol. 2008;63(6): 11. Hodges JR, Bozeat S, Lambon Ralph MA, Patterson K, Spatt J. The role of con- 709-719. ceptual knowledge in object use: evidence from semantic dementia. Brain. 2000; 32. Seeley WW, Bauer AM, Miller BL, et al. The natural history of temporal variant 123(pt 9):1913-1925. frontotemporal dementia. Neurology. 2005;64(8):1384-1390. 12. Hodges JR, Patterson K. Semantic dementia: a unique clinicopathological syndrome. Lancet Neurol. 2007;6(11):1004-1014. 33. McMonagle P, Deering F, Berliner Y, Kertesz A. The cognitive profile of posterior 13. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a cortical atrophy. Neurology. 2006;66(3):331-338. consensus on clinical diagnostic criteria. Neurology. 1998;51(6):1546-1554. 34. Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D. Distinct 14. Adlam AL, Patterson K, Rogers TT, et al. Semantic dementia and fluent primary behavioural profiles in frontotemporal dementia and semantic dementia. J Neu- progressive aphasia: two sides of the same coin? Brain. 2006;129(pt 11):3066- rol Neurosurg Psychiatry. 2001;70(3):323-332. 3080. 35. Rosen HJ, Allison SC, Ogar JM, et al. Behavioral features in semantic dementia 15. Appell J, Kertesz A, Fisman M. A study of language functioning in Alzheimer patients. vs other forms of progressive aphasias. Neurology. 2006;67(10):1752-1756. Brain Lang. 1982;17(1):73-91. 36. Kertesz A, Blair M, Davidson W, McMonagle P, Munoz DG. The evolution and 16. Kertesz A, Davidson W, McCabe P, Takagi K, Munoz D. Primary progressive apha- pathology of frontotemporal dementia. Brain. 2005;128:1996-2005. sia: diagnosis, varieties, evolution. J Int Neuropsychol Soc. 2003;9(5):710-719. 37. Davies RR, Hodges JR, Kril JJ, Patterson K, Halliday GM, Xuereb JH. The patho- 17. Blair M, Marczinski CA, Davis-Faroque N, Kertesz A. A longitudinal study of lan- logical basis of semantic dementia. Brain. 2005;128(pt 9):1984-1995. guage decline in Alzheimer’s disease and frontotemporal dementia. J Int Neu- 38. Snowden JS, Griffiths HL, Neary D. Semantic-episodic memory interactions in ropsychol Soc. 2007;13(2):237-245. semantic dementia: implications for retrograde memory function. Cogn 18. Chertkow H, Bub D. Semantic memory loss in dementia of Alzheimer’s type: what Neuropsychol. 1996;13(8):1101-1139. do various measures measure? Brain. 1990;113(pt 2):397-417. 39. Hodges JR, Graham KS. A reversal of the temporal gradient for famous person 19. Mackenzie IR, Baborie A, Pickering-Brown S, et al. Heterogeneity of ubiquitin knowledge in semantic dementia: implications for the neural organisation of long- pathology in frontotemporal lobar degeneration: classification and relation to clini- term memory. Neuropsychologia. 1998;36(8):803-825. cal phenotype. Acta Neuropathol. 2006;112(5):539-549. 40. Rohrer JD, McNaught E, Foster J, et al. Tracking progression in frontotemporal 20. Kertesz A, Blair M, McMonagle P, Munoz DG. The diagnosis and course of fron- lobar degeneration: serial MRI in semantic dementia. Neurology. 2008;71(18): totemporal dementia. Alzheimer Dis Assoc Disord. 2007;21(2):155-163. 1445-1451. 21. Harciarek M, Kertesz A. The prevalence of misidentification syndromes in neu- 41. Knibb JA, Xuereb JH, Patterson K, Hodges JR. Clinical and pathological charac- rodegenerative diseases. Alzheimer Dis Assoc Disord. 2008;22(2):163-169. terization of progressive aphasia. Ann Neurol. 2006;59(1):156-165.

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