semantic knowledge in mild cognitive impairment and mild alzheimer's disease

INTRODUCTION

The semantic memory impairment in Alzheimer’sdisease (AD) is well documented (Chertkow andBub, 1990; Hodges and Patterson, 1995; Hodges etal., 1991, 1992, 1996; Lambon Ralph et al., 1997),yet much of the research has tended to focus on theunderlying cause of the deficit rather than how earlyon in the disease process semantics are affected.

A study of patients with presumed early AD,scoring above 23 on the MiniMental StateExamination (MMSE) (Folstein et al., 1975),revealed a subgroup with impairment on a range ofsemantic memory tasks, as well as a subgroup thatperformed flawlessly on these tasks (Hodges andPatterson, 1995). In a more recent study, using thesame MMSE cut-off, Perry et al. (2000), reportedimpairments on the category fluency task from theCambridge Semantic Battery and the picturecondition of the Pyramid and Palm Trees test(Howard and Patterson, 1992).

The development of cholinergic therapies for ADhas highlighted the importance of early diagnosisand fuelled interest in so-called Mild CognitiveImpairment (also referred to as Minimal AD,Questionable AD and Isolated Memory Deficit),which is regarded as the predementia prodrome ofAD (Grundman et al., 2004; Petersen et al., 2001).Episodic memory and attentional deficits have beenthe focus of much of the research, with few studiesincluding any assessment of semantic memory. In arecent study by Chen et al. (2001) subjects withdeficits in the domain of episodic memory, but not

fulfilling the criteria for AD, were found to beimpaired on a category fluency task. These resultsconcur with those of our previous studies, whichfound category fluency to be a very sensitiveassessment of semantic impairment (Hodges andPatterson, 1995; Hodges et al., 1996; Perry et al.,2000). In contrast, Albert et al. (2001) reportednormal performance on naming and category fluencyin a group of patients categorized as .5 on the clinicaldementia rating (CDR) scale (Hughes et al., 1982).These studies highlight the need for furtherinvestigation, using a well-defined criteria for mildcognitive impairment (MCI) and a morecomprehensive battery of semantic assessments.

We previously reported impairments in semanticknowledge of object use in patients with semanticdementia (SD), a disorder associated with bilateral,but typically asymmetrical, pathology affecting thetemporal pole, anteromedial and inferolateraltemporal lobes (Galton et al., 2000; Davies et al.,2004), with greater impairment on this test comparedto more traditional tests of semantic memory (Bozeatet al., 2002). This suggests that object-based tests ofsemantic knowledge may be more sensitive thanmost traditional semantic memory measures [e.g.,naming, word-picture matching, Pyramids and PalmTrees (Howard and Patterson, 1992)]. The object-based knowledge test requires the individuals toassociate a picture of an object to another picturerelating to its function, recipient or action (see Figure1). Deficits in knowledge of object use have beenreported previously in patients with AD (Buxbaumet al., 1997; Dumont et al., 2000; Kempler, 1988;

Cortex, (2006) 42, 675-684

RESEARCH REPORT

SEMANTIC KNOWLEDGE IN MILD COGNITIVE IMPAIRMENT AND MILDALZHEIMER’S DISEASE

Anna-Lynne R. Adlam1, Sasha Bozeat1, Robert Arnold1, Peter Watson1 and John R. Hodges1,2

(1Cognition and Brain Sciences Unit, Medical Research Council, Cambridge, UK; 2University Neurology Unit,Addenbrooke’s Hospital, Cambridge, UK)

ABSTRACT

The aim of this study was to investigate memory in patients with mild cognitive impairment (MCI) and mildAlzheimer’s disease (AD). Ten patients with MCI, 11 with AD and a group of age and education matched healthy controlparticipants were assessed on a comprehensive battery of semantic memory tests, including traditional semantic memorymeasures and a non-verbal test of knowledge of object use. The MCI group was impaired on tests of category fluency andall three conditions of an object knowledge test (matching to recipient, function and action), plus a difficult object-namingtest. The mild AD group showed additional impairments on traditional measures of semantic memory, including naminghigh frequency items, comprehension and semantic association. Together these findings suggest that semantic memoryimpairments occur early in the course of AD, more specifically in patients with “amnesic” MCI, and provide furtherevidence that impaired category fluency reflects semantic breakdown.

Key words: semantic memory, Alzheimer’s disease, mild cognitive impairment

Ochipa et al., 1992; Rapcsak et al., 1989), as well aspost stroke patients with conceptual or ideational-type apraxia (e.g., De Renzi and Lucchelli, 1988).This is, however, the first study to investigatesemantic knowledge very early in the course of AD.

The aim of the current study was to investigatesemantic memory in patients with MCI and mild ADusing traditional measures and a test of semanticknowledge of object use.

METHODS

A total of 51 subjects took part in this study: 21patients, and 30 controls. The patients presented tothe Memory Clinic at Addenbrooke’s Hospital,

Cambridge where they were seen by a seniorneurologist (J.R.H.), a psychiatrist and a clinicalneuropsychologist. In addition to a clinicalassessment, all patients were given a number ofstandard psychiatric rating scales to exclude majorfunctional psychiatric disorders such as depressionand schizophrenia. Brain magnetic resonanceimaging scans were either normal or showed a milddegree of medial temporal atrophy.

Patients were divided into two groups: MCI(n = 10) and mild AD (n = 11). Patients with MCIpresented with complaints of poor memory,substantiated by a spouse/family member, withpreservation of activities of daily life.

Neuropsychological assessment revealedimpairment (< 2 SDs) on at least one test of

676 Anna-Lynne R. Adlam and Others

Fig. 1 – A) An example from the matching to function test. B) An example from the matching to recipient test. C) An example fromthe matching to action test.

A B

C

episodic memory but normal performance on arange of other routine tests of language,visuospatial and executive function administered inthe memory clinic (Hodges et al., 2000a) and ascore on the MMSE of > 24 (range: 25-29). Thissubgroup met the criteria for MCI (Grundman etal., 2004; Petersen et al., 2001) and corresponds tothat described as minimal dementia of theAlzheimer type (DAT) in our earlier publications(Hodges and Patterson, 1995; Perry et al., 2000).Patients with mild AD fulfilled NINCDS-ADRDA(National Institute of Neurological andCommunicative Diseases and Stroke-Alzheimer’sDisease and Related Disorders Association) criteria(McKhann et al., 1984) and had evidence ofimpaired memory plus deficits in at least one othercognitive domain, MMSE scores < 24 (range: 14-24) and impairments in activities of daily living.

Patients with a history of transient ischaemicevents in stroke, focal neurological signs, and/orsignificant white matter changes on magneticresonance imaging (MRI) to suggest cerebrovasculardisease were excluded.

Thirty age and education matched controls (p >.05) were selected from the Medical ResearchCouncil Cognition and Brain Sciences Unit’sparticipant panel (see Table I). Twenty controlsparticipated in the general neuropsychology studyand ten controls participated in the object knowledgestudy. The Addenbrooke’s Local Ethics Committee(LEC) approved these studies, and written informedconsent was obtained from all participants.

GENERAL NEUROPSYCHOLOGY

The following battery of neuropsychological testswas administered: the MMSE as a general measureof cognitive impairment (Folstein et al., 1975);verbal fluency for the letters F, A, S to test executivefunction; visuospatial function was assessed usingthe copy of the Rey Complex Figure (Rey, 1941) andvarious subtests from the Visual Object and SpacePerception battery (Warrington and James, 1991);the logical memory subtest of the Wechsler MemoryScale Revised (WMS-R; Wechsler, 1987) and recallof the Rey Complex Figure were used to assessepisodic memory.

GENERAL SEMANTIC ASSESSMENTS

The participants were also given a selection oftasks from the updated version of the CambridgeSemantic Battery, which is a collection of tests thatuse the same set of stimulus items to assess semanticknowledge systematically across different input andoutput modalities (Hodges and Patterson, 1995). Itcontains 64 items representing three categories ofliving things (animals, birds and fruit) and threecategories of artifacts (household items, tools andvehicles). The following subtests from the semanticbattery were administered: category fluency, inwhich the subject is asked to produce as manyexemplars as possible in one minute for each of thesix categories (three living and three man-made);basic-level naming of the 64 line drawings; andspoken word-to-picture matching using picturearrays containing the target plus nine within-categoryfoils.

Two other semantic assessments were alsoadministered: the concrete and abstract wordsynonym test (Warrington et al., 1998) whichrequires the subject to choose one of two words thatis similar in meaning to the target word, and thePyramid and Palm Trees test of associative semanticknowledge (Howard and Patterson, 1992). In thislatter assessment, subjects are asked to choose oneof two items that is most closely associated with thetarget (e.g., for the target pyramid, the choice isbetween palm tree and pine tree). The stimuli arepresented as either pictures or written words.

OBJECT KNOWLEDGE

A multiple component battery was constructedwith the purpose of assessing associativeinformation, functional knowledge and use of 36household objects (Bozeat et al., 2002). These werederived from three categories – tools, kitchenimplements and stationery items and ranged in ratedfamiliarity.

Matching Tasks

Conceptual knowledge for the 36 objects wasassessed in a series of matching tasks, which

Semantic knowledge in MCI 677

TABLE I

Mean (range) age and education (years:months), and gender for each group. MCI n = 10, AD n = 11, general neuropsychologycontrol group n = 20, object-knowledge control group n = 10*

Group Age at test Years of education Gender

General neuropsychology control 71:10 (62-80) 10:09 (9-13) 10 male, 10 female

Object knowledge control 62:08 (54-72) 12:11 (10-16) 5 male, 5 female

MCI 69:01 (54-79) 12:07 (9-16) 5 male, 5 femaleMild AD 69:08 (59-80) 10:06 (9-16) 6 male, 5 female

*MCI = mild cognitive impairment; AD = Alzheimer’s Disease.

consisted of digital photographs of the target andfour possible matches (see Figure 1). A picture of thetarget object was located at the top of the page andthe subject was asked to choose one of four responsealternatives as the best match according to one ofthree types of relationship, described below. Theorder of items was randomized across tasks and eachwas preceded by four practice trials.

Every effort was made to ensure comprehensionof the task. Data were not included if there wasany doubt about the patients’ ability to comprehendthe instructions, which occurred in two mild ADpatients when they were asked to match accordingto the action used when manipulating the targetobject.

Matching to Function

In this test, subjects were asked to choose one offour objects that could be used for the same purposeas the target item. The foils were chosen to be eithervisually similar to, or from the same category as, thetarget (e.g., for the target potato masher, the choiceis between fork, mallet, iron and potato peeler, seeFigure 1A).

Matching to Recipient

Subjects were asked to choose the correctrecipient for the target object. The foils were chosento be visually similar to the correct match orsemantically related (e.g., for the target potatomasher, the choice is between potato, pepper,flowerbed and cheese, see Figure 1B).

Matching to Action

In this test, subjects were asked to choose one offour objects that is manipulated/moved in the sameway as the target. The objects were not necessarilyheld in the same way. The foils were chosen to bevisually similar or semantically related to the target(e.g., for the target potato masher, the choice isbetween pizza cutter, bottle opener, wallpaperscraper and plunger, see Figure 1C).

Naming

The subjects were shown pictures of each of the36 objects individually and asked to produce thespecific name.

STATISTICAL ANALYSIS

The data were analyzed using separate analysesof variance (p < .05). Significant main effects wereanalyzed using Tukey’s honestly significantdifference (HSD), and simple main effects, followingsignificant interactions, were analyzed using t-testswith corrections for multiple comparisons(Bonferroni correction, .05/3 = p ≤ .017). Onoccasions where the data violated the assumptions ofparametric tests Kruskal-Wallis analyses of variancewere conducted, and significant main effects wereanalyzed using Mann-Whitney U tests (corrected formultiple comparisons, p ≤ .017).

RESULTS

General Neuropsychology

The means and standard deviations of eachgroup’s performance on the general neuropsychologymeasures and a summary of the statistical analysesare shown in Table II. Only the mild AD groupshowed impairments on a measure of letter fluency,both relative to controls and the MCI group. Bothpatient groups were impaired relative to controls onimmediate and delayed story recall. Consistent withthe increased forgetting of verbal material bothpatient groups showed increased forgetting of theRey Complex Figure. Performance on the copy of theRey Complex Figure and various subtests of theVisual Object and Space Perception battery werewithin the normal range for the MCI group indicatingpreservation of visuospatial skills. In contrast, themild AD group showed impairments relative tocontrols on the copy condition of the Rey ComplexFigure and two of three subtests of the Visual Object


TABLE II

General neuropsychology (a) represents significantly impaired compared to control group, (b) represents significant difference betweenMCI and mild AD. All statistical analyses are reported at p < .05 (Tukey’s HSD). MCI n = 10, AD n = 11, Control n = 10*

Test (maximum score) MCI mean (SD) Mild AD mean (SD) Control mean (SD)

MMSE (30) 27.40 (1.43) 20.09 (3.39)a,b 28.80 (1.01)Letter fluency (total: FAS) 42.78 (13.08) 26.75 (13.92)a,b 41.65 (12.38)Logical memoryImmediate recall (24) 4.75 (2.06)a 1.44 (1.13)a 10.27 (4.33)Delayed recall (24) 3.95 (5.05)a .20 (.42)a 8.26 (4.15)Rey figureCopy (36) 32.20 (3.82) 26.22 (6.38)a,b 33.95 (1.64)Delayed recall (36) 8.50 (7.42)a 3.31 (2.12)a 18.35 (5.95)VOSPIncomplete letters (20) 19.50 (.71) 17.20 (2.50)a,b 19.30 (.80)Dot counting (10) 9.50 (.85) 9.50 (.97) 9.95 (.22)Cube analysis (10) 9.20 (1.14) 6.00 (3.40)a,b 9.65 (.93)

*MCI = Mild Cognitive Impairment; AD = Alzheimer’s Disease; VOSP = Visual Object and Space Perception battery.

and Space Perception battery. Furthermore, the mildAD group was impaired relative to the MCI group onthese tests.

General Semantic Assessments

The means and standard deviations of eachgroup’s performance on the general semanticassessments and a summary of the statisticalanalyses are shown in Table III. Unlike theirperformance on the letter fluency task (see Table II),the MCI group was impaired relative to controls onthe category fluency task but was less impaired thanthe mild AD group. The MCI group did not differsignificantly from controls on any other semanticmemory measure. In contrast the mild AD groupshowed additional impairments on the naming test,word-picture matching test, both conditions of theword synonyms test and the word condition of thePyramids and Palm Trees test (the picturescondition was not included in the analysis). Themild AD group was also impaired relative to theMCI group on these tests, and the pictures but notthe word condition of the Pyramids and Palm Treestest. These findings suggest greater semanticmemory impairments in mild AD compared to MCI,with the category fluency test being the mostsensitive to mild semantic memory impairments.

Tests of Object Knowledge

Matching Tasks

Performance on the object use task is shown inFigure 2. A mixed-design analysis of variance(ANOVA) with a between-subject factor of Group(MCI, AD, control) and a within-subjects factor ofCondition (function, recipient, action) revealed:significant main effects of Group [F (2,26) = 30.95,p < .05] and Condition [F (2,52) = 52.66, p < .05],and a significant Group by Condition interaction [F(4,52) = 5.83, p < .05]. Post-hoc analyses revealedthat both the MCI and AD groups were impairedrelative to controls on all three conditions [MCI:

function, t (9.74) = 4.49, p < .017; recipient, t (13.45)= 3.11, p < .017; action, t (18) = 3.48, p < .017; AD:function, t (14.59) = 17.59, p < .017; recipient, t(11.87) = 6.24, p < .017; action, t (17) = 5.94, p <.017], but the AD group was only impaired relativeto the MCI group on the recipient [t (19) = 3.71, p <.017] and function [t (11.94) = 3.17, p < .017]matching conditions. Further analysis revealed thatthe groups showed different effects of task difficulty:the control group performed better on the recipientand function conditions compared to the actionmatching condition [recipient vs. action: t (9) = 4.47,p < .017; function vs. action: t (9) = 3.35, p < .017]but there was no significant difference inperformance on the function and recipient condition;the MCI group performed better on the recipientcondition compared to the action and functionconditions [recipient vs. action: t (9) = 6.74, p < .017;recipient vs. function: t (9) = 4.93, p < .017] but therewas no significant difference in performance on thefunction and action conditions; and this same patternof task difficulty was shown in the mild AD group[recipient vs. action: t (8) = 4.39, p < .017; recipientvs. function: t (10) = 8.32, p < .017]. Together thesefindings suggest that, although the MCI groupoutperformed the mild AD group on both therecipient and function matching conditions, unlikecontrols, both patient groups performed better on therecipient matching condition than any of the otherconditions.

Exploration of the patient data revealed that asingle mild AD patient performed significantlyabove the group mean on this task. The criticaleffects remained significant with this outlierremoved.

Naming

The performance of the three groups on thenaming tasks is shown in Figure 3. A Kruskal-Wallisanalysis of variance revealed a main effect of Group(X(2) = 20.91, p < .05). Post-hoc analysis revealedthat despite performing within the normal range onthe naming test from the Cambridge Semantic


TABLE III

Assessment of semantics (a) represents significantly impaired compared to control group, (b) represents significant difference between MCIand mild AD. All statistical analyses are reported at p < .05 (Tukey’s HSD). MCI n = 10, AD n = 11, Control n = 10*

Test (maximum score) MCI mean (SD) Mild AD mean (SD) Control mean (SD)

Category fluency Living 44.20 (9.40)a 24.40 (9.62)a,b 63.55 (11.87)Manmade 36.10 (6.56)a 21.90 (10.14)a,b 55.0 (11.44)Naming (64) 61.10 (2.77) 54.60 (10.13)a,b 62.35 (1.81)Word-picture matching (64) 63.70 (.48) 59.1 (6.94)a,b 63.85 (.37)Word synonymsConcrete (25) 22.70 (2.00) 20.71 (2.43)a 23.80 (1.24)Abstract (25) 22.00 (3.23) 20.71 (2.56)a 23.35 (1.66)Pyramids and palm treesWords (52) 50.33 (1.22) 49.20 (1.81)a 48.30 (2.06)b

Pictures (52) 50.44 (1.81) 51.60 (1.47) not administered

*MCI = Mild Cognitive Impairment; AD = Alzheimer’s Disease.


Fig. 3 – The mean number of correct responses on the object naming test for each group (maximum = 36). Standard error meansare shown for each group. MCI n = 10, AD n = 11, Control n = 10. MCI represents Mild Cognitive Impairment; AD representsAlzheimer’s Disease.

Fig. 2 – The mean number of correct responses on the three tests of visual associative knowledge for each group (maximum = 36).Standard error means are shown for each group. MCI n = 10, AD n = 11 (n = 9 action matching), Control n = 10. MCI represents MildCognitive Impairment; AD represents Alzheimer’s Disease.

Battery (see Table III), the MCI patients achievedsignificantly lower scores than the control subjectswhen asked to name the 36 objects (U = 11.00, p <.017). The mild AD group also performedsignificantly worse than the control group (U < 1, p< .017), and the MCI group (U = 14.5, p < .017).

Naming and Object Matching Consistency

Previous studies have shown that the semanticmemory impairment profile associated with AD isconsistent with a storage degradation hypothesis asopposed to a loss of access to semantic knowledge(Hodges et al., 1992). To examine the consistencybetween naming and object knowledge, wecompared the individuals’ performance at namingthe objects with their object-function, -recipient and-action matching ability for the same items usingsubjects’ z scores (see Table IV). There was astriking correspondence across the tests. Of note isthe finding that only two patients with MCIperformed within the normal range on the namingtask, while between two and four patients performedwithin the normal range on the matching subtests.The two patients with normal naming also performedwell on the majority of the matching tasks,suggesting a high concordance between naming,matching to function and matching to recipient.Matching to action may draw upon differentcognitive processes (see Discussion). None of theAD patients performed within the normal range onnaming and only one performed within the normalrange on one of the matching tasks (matching toaction). This suggests that as severity of diseaseincreases (as estimated by MMSE score),impairments in naming and object knowledgeincrease.

DISCUSSION

The main aim of this study was to investigatesemantic memory in patients with MCI and mild AD,using a combination of traditional semantic memorymeasures and a non-verbally based test of semanticknowledge of object use.

Consistent with the pattern of diagnosis andprevious research (Hodges and Patterson, 1995;Grundman et al., 2004; Perry et al., 2000; Petersenet al., 2001), both the MCI and mild AD groups wereimpaired relative to controls on episodic memorymeasures including story recall and recall of the ReyComplex Figure. Consistent with previous literature,only the mild AD group showed impairments onmeasures of visuo-perceptual abilities (e.g., Caineand Hodges, 2001).

On the Cambridge Semantic Battery, the mildAD group showed widespread impairments ontraditional semantic memory measures of naming,word-picture matching, word synonym judgementand category fluency, with greater impairmentsrelative to the MCI group on most of thesemeasures. In contrast, the MCI group did not differsignificantly from controls, except on categoryfluency. The interpretation of an isolated deficit incategory fluency is controversial. Many authorsinterpret this as a sign of early semantic degradation(Albert et al., 2001; Chen et al., 2001; Hodges andPatterson, 1995; Hodges et al., 1996; Perry et al.,2000), even though executive and phonologicalprocesses play a role in the task. One of the keyfindings has been disproportionate impairment incategory fluency relative to letter based fluency,especially since the latter is particularly sensitive tofrontal and subcortical pathology (Hodges, 1995;Rosser and Hodges, 1994). In keeping with previous


TABLE IV

The performance of patients relative to controls on the object knowledge tasks (matching and naming). Z-scores are relative to thecontrol mean and the asterisks indicate performance less than 2 standard deviations below the control mean (i.e., performance

within the normal range)*

MMSE Naming Function Recipient Action

MCI1 29 – .7* .0* .7* -– 4.1MCI2 29 – 5.1 – 7.1 – .7* – .1*MCI3 29 – 2.5 – 3.5 – 2.7 – 1.5*MCI4 28 – 6.0 – 4.9 – .7* – 2.9MCI5 28 1.1* – .7* .0* – 2.1MCI6 27 – 8.6 – 7.1 – 3.4 – 2.9MCI7 27 – 4.2 – 9.9 – 2.0 – 2.9MCI8 26 – 13.9 – 14.1 – 4.0 – 7.7MCI9 26 – 4.2 – 13.4 – 3.4 .8*MCI10 25 – 9.5 – 10.6 – 5.4 – 2.7AD1 24 – 6.9 – 12.0 – 4.0 – 5.0AD2 23 – 4.2 – 8.5 – 2.0 – .1*AD3 23 – 12.2 – 15.6 – 7.4 – 2.9AD4 23 – 20.1 – 13.4 – 8.0 – 5.8AD5 22 – 9.5 – 10.6 – 2.0 – 3.2AD6 22 – 13.0 – 10.6 – 5.4 – 3.5AD7 18 – 26.2 – 12.7 – 10.1 not administeredAD8 18 – 20.1 – 14.1 – 8.7 – 3.5AD9 18 – 13.0 – 11.3 – 6.7 not administeredAD10 16 – 18.3 – 14.8 – 13.4 – 4.7AD11 14 – 11.3 – 13.4 – 6.0 – 5.3

*MCI = Mild Cognitive Impairment; AD = Alzheimer’s Disease; MMSE = Mini-Mental State Examination.

studies we also found normal letter fluency in MCI.In contrast to their performance on the more

traditional measures of semantic associations (e.g.,Pyramids and Palm Trees tests) and naming, the MCIgroup showed impairments relative to the controlgroup on all three matching conditions of the objectuse task and when asked to name the 36 objects. Thispattern of impairment was reasonably consistentacross the group, with only two patients performingwithin the normal range on naming, and all patientsperforming more than two standard deviations belowthe control mean on at least one matching task.

The deficit on the object-matching tasks relativeto the Pyramids and Palm Trees test of semanticassociation suggests that this task is more difficultthan the traditional measure. Indeed, theperformance of the control group on the three object-matching conditions suggests this to be the case.

The object-naming task presented here requiresspecific-level naming of items that are of lowerwritten and spoken frequency (CELEX lexicaldatabase; Baayen et al., 1993) than those used in the64-item naming assessment. In our previous findingsof patients with SD we have shown that naming isparticularly affected by item frequency andfamiliarity, where lower frequency item naming ismore disrupted early in the course of the disease(Lambon Ralph et al., 1998; Patterson and Hodges,1992).

Together, these results suggest that semanticmemory is impaired in MCI, providing furtherevidence of semantic breakdown very early on in thecourse of AD, and that tests of object use knowledgeand object naming are more sensitive to this deficitthat the more traditional measures.

The mild AD patients were also impaired on allconditions of the object matching task and on objectnaming, relative to the control group, and were moreimpaired than the MCI group on recipient andfunction matching, and object naming. Thesefindings are consistent with their greater deficits onthe more traditional measures of semantic memorysuggesting a more general decline in cognitiveperformance with disease severity.

A further finding of interest relates to taskdifficulty effects in the conditions of the object usetask. It appeared that the groups showed differentpatterns of task difficulty. The control groupperformed better on the recipient and functionmatching conditions compared to the actionmatching condition showing no significantdifference in performance on the function andrecipient matching conditions. In contrast, the twopatient groups performed better on the recipientmatching condition compared to the action andfunction matching conditions showing no significantdifference in performance on these two conditions.Consistent with these findings, a previous studyreported better performance on the recipientmatching condition in patients with SD and theircontrols (this was only significant in controls)

relative to the other conditions (Bozeat et al., 2002).This same study found that the presence of arecipient improved the performance of the patientswith SD on measures of object praxis (hold,movement). Moreover, this effect was modulated bythe degree of semantic impairment, such that thepatients with a moderate level of conceptualimpairment demonstrated better use with therecipient present, whereas the patients with mild andsevere impairments showed no effect. The authorssuggested that the presence of the recipient provideda level of context, and, therefore, access to furtherconceptual knowledge, and provided a clue to theultimate use of the object. In contrast, Buxbaum etal. (1997), reported better function than recipientmatching in a patient with SD (D.M.) and a patientwith suspected AD (H.B.). Their tests were, however,different to those reported here in that real objectswere presented instead of photographs.

There is a continued debate in the literatureregarding the cognitive architecture of the semanticsystem, particularly whether action-semantics form aseparable system (see Hodges et al., 2000b).Although a full discussion is beyond the scope ofthis paper, it is worth considering briefly how ourfindings of impairment in object use knowledgemight contribute to this debate. The present studydid not assess pantomiming the use of objects, whichis thought to require access to the conceptual andproduction praxis systems (Roy and Square, 1985)but presents considerable difficulty with thestandardization of scores. Two types of conceptualpraxis knowledge were, however, tested; namely,knowledge of function and knowledge of action.Consistent with previous reports of object useknowledge in AD (Kempler, 1988; Ochipa et al.,1992), our patients were impaired on theseconditions. We have extended this finding to showthat breakdown in object use knowledge, at moresevere stages of the disease, occurs in parallel toimpairments in naming the same objects. Thesefindings support the hypothesis of the degradation ofa central, unitary, semantic system (Caramazza et al.,1990; Hodges et al., 1992).

It should be noted, however, that the issue of lossversus impaired access to knowledge remains a topicof considerable controversy. The criteria ofconsistency, both across testing sessions and acrossdifferent modes of testing, has been criticized,particularly in the context of AD, where implicittasks have sometimes suggested that semanticrepresentations are relatively intact despite impairedperformance on explicit tasks (Multhaup et al., 2003;Ober, 2002; Perri et al., 2003; Rich et al., 2002).

Although we have designated the object basedtests as non-verbal, it is possible that subjects useverbal strategies to perform the matching tasks andthat the deficit reflects, therefore, a breakdown inverbal knowledge. This seems unlikely given thefindings in SD where a wide range of non-verballybased tasks have shown substantial deficits (Bozeat


et al., 2000, 2002, 2003; Hodges et al., 2000b;Rogers et al., 2003), although these findings may notgeneralize across dementias. Resolution of this issuerequires further work using other non-verbally basedtests of semantic memory.

The anatomical basis of the semantic deficit inAD is still under debate. The finding of semanticmemory impairments early in the course of AD isconsistent with the pathological changes associatedwith AD, which involves parahippocampal regionsfrom early in the course of the disease (Braak andBraak, 1991). In the recent study of SD by Galton etal. (2001) performance on semantic tasks was foundto correlate most closely with atrophy of the anteriorfusiform gyrus which is immediately lateral to thecollateral sulcus. The banks of the collateral sulcuscontain perirhinal cortex (Brodmann areas 35/36),which is continuous rostrally with the temporopolarcortex (Brodmann area 38) (Insausti et al., 1998), thearea typically associated with SD (Mummery et al.,1999, 2000). Recent studies in non-human primateshave suggested that the perirhinal cortex contains anetwork of object feature representations analogousto semantic knowledge in man (Murray and Bussey,1999). Furthermore, recent studies of patients with aform of amnesia that occurs in early childhood haveassociated their relatively preserved semanticmemory with the integrity of this region (Gadian etal., 2000; Mishkin et al., 1998; Vargha-Khadem etal., 1997). The perirhinal cortex is in close proximityto the entorhinal cortex, which is severely damagedvery early in the course of AD (Gomez-Isla et al.,1996). It seems highly likely, therefore, that semanticimpairment in AD reflects encroachment ofpathology into the perirhinal and/or more lateraltemporal regions, which are present to a subtledegree at an extremely early stage of disease. Itshould be stressed that the degree of semanticmemory impairment is mild compared to that seen inSD (see Bozeat et al., 2002 for a comparison).

CONCLUSIONS

All of the patients involved in this study wereimpaired relative to controls on non-verbal tests ofsemantic knowledge of object use, indicating thatsemantic memory is affected early in the course ofAD. The mild AD patients were more impaired thanthe MCI group on category fluency, 64-item naming,word-picture matching, object naming and objectrecipient and function matching, and showedadditional impairments relative to controls ontraditional semantic memory measures, consistentwith the greater severity of their disease. Despiteperforming well on most traditional assessments ofsemantic memory, as a group the MCI patients wereimpaired on category fluency, naming the objectsand all of the object associative knowledge tasks.Together these findings suggest that tests of categoryfluency, object knowledge and low frequency

naming are sensitive to semantic memory deficits inMCI and mild AD. These findings are relevant to theongoing debate about the purity of the amnesicdeficit in MCI. Our patients correspond to amnesiaMCI (Grundman et al., 2004; Petersen et al., 2001),yet showed deficits in naming when tested using amore stringent task requiring the production ofspecific level/low frequency terms as well as on asemantic task of object use. This casts doubt on theappropriateness of the label “amnesic MCI” andsuggests that MCI might not be all that mild if thebreadth of deficits is taken into account.

Acknowledgments. We thank the participants and theirfamilies for their continued support with our research. Wealso thank Margaret Tillson for her help in preparing thismanuscript. This research was funded by the MedicalResearch Council.

REFERENCES

ALBERT MS, MOSS MB, TANZI R and JONES K. Preclinicalprediction of AD using neuropsychological tests. Journal ofInternational Neuropsychological Society, 7: 631-639, 2001.

BAAYEN RH, PIEPENBROCK R and VAN RIJN H. The CELEX LexicalDatabase. Linguistic Data Consortium, University ofPennsylvania, 1993.

BOZEAT S, LAMBON RALPH MA, GRAHAM KS, PATTERSON K, WIKINH, ROWLAND J, ROGERS TT and HODGES JR. A duck with fourlegs: Investigating the structure of conceptual knowledgeusing picture drawing in semantic dementia. CognitiveNeuropsychology, 20: 27-47, 2003.

BOZEAT S, LAMBON RALPH MA, PATTERSON K, GARRARD P andHODGES JR. Non-verbal semantic impairment in semanticdementia. Neuropsychologia, 38: 1207-1215, 2000.

BOZEAT S, LAMBON RALPH MA, PATTERSON K and HODGES JR.When objects lose their meaning: What happens to their use.Cognitive, Affective and Behavioural Neuroscience, 2: 236-251, 2002.

BRAAK H and BRAAK E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathologica, 82: 239-259, 1991.

BUXBAUM LJ, SCHWARTZ MF and CAREW TG. The role of semanticmemory in object use. Cognitive Neuropsychology, 14: 219-254, 1997.

CAINE D and HODGES JR. Heterogeneity of semantic andvisuospatial deficits in early Alzheimer’s disease.Neuropsychology, 15: 155-164, 2001.

CARAMAZZA A, HILLIS AE, RAPP BC and ROMANI C. The multiplesemantics hypothesis: Multiple confusions. CognitiveNeuropsychology, 7: 161-189, 1990.

CHEN P, RATCLIFF G, BELLE SH, CAULEY JA, DEKOSKY ST andGANGULI M. Patterns of cognitive decline in presymptomaticAlzheimer’s disease. Archives of General Psychiatry, 58: 853-858, 2001.

CHERTKOW H and BUB D. Semantic memory loss in dementia ofAlzheimer’s type. What do various measures measure? Brain,113: 397-417, 1990.

DAVIES RR, GRAHAM KS, XUEREB JH, WILLIAMS GB and HODGESJR. The human perirhinal cortex and semantic memory.European Journal of Neuroscience, 20: 2441-2446, 2004.

DE RENZI E and LUCCHELLI F. Ideational apraxia. Brain, 111: 1173-1185, 1988.

DUMONT C, SKA B and JOANETTE Y. Conceptual apraxia andsemantic memory deficit in Alzheimer’s disease: Two sides ofthe same coin? Journal of the InternationalNeuropsychological Society, 6: 693-703, 2000.

FOLSTEIN MF, FOLSTEIN SE and MCHUGH PR. “Mini-mental state”.A practical method for grading the cognitive state of patientsfor the clinician. Journal of Psychiatric Research, 12: 189-198, 1975.

GADIAN DG, AICARDI J, WATKINS KE, PORTER DA, MISHKIN M andVARGHA-KHADEM F. Developmental amnesia associated withearly hypoxic-ischaemic injury. Brain, 123: 499-507, 2000.

GALTON CJ, PATTERSON K, GRAHAM KS, LAMBON RALPH MA,WILLIAMS G, ANTOUN N, SAHAKIAN BJ and HODGES JR.Differing patterns of temporal atrophy in Alzheimer’s diseaseand semantic dementia. Neurology, 57: 216-225, 2001


GALTON CJ, PATTERSON K, XUEREB JH and HODGES JR. Atypicaland typical presentations of Alzheimer’s disease: A clinical,neuropsychological, neuroimaging and pathological study of13 cases. Brain, 123: 484-498, 2000.

GOMEZ-ISLA T, PRICE JL, MCKEEL DW, MORRIS JC, GROWDEN JHand HYMAN BT. Profound loss of layer II entorhinal cortexneurons occurs in very mild Alzheimer’s disease. Journal ofNeuroscience, 16: 4491-4500, 1996.

GRUNDMAN M, PETERSEN RC, FERRIS SH, THOMAS RG, AISEN PS,BENNETT DA, FOSTER NL, JACK CR JR, GALASKO DR, DOODYRS, KAYE J, SANO M, MOHS R, GAUTHIER S, KIM HT, JIN S,SCHULTZ AN, SCHAFER K, MULNARD R, VAN DYCK CH,MINTZER J, ZAMRINI EY, CAHN-WEINER D and THAL LJ. Mildcognitive impairment can be distinguished from Alzheimerdisease and normal aging for clinical trials. Archives ofNeurology, 61: 59-66, 2004.

HODGES JR. Verbal fluency in cortical and subcortical dementia –Reply. Journal of Neurology, Neurosurgery & Psychiatry, 58:521, 1995.

HODGES JR, BERRIOS GE and BREEN K. The multidisciplinarymemory clinic approach. In Berrios GE and Hodges JR (Eds),Memory Disorders in Psychiatric Practice. Cambridge:Cambridge University Press, 2000a.

HODGES JR, BOZEAT S, LAMBON RALPH MA, PATTERSON K andSPATT J. The role of conceptual knowledge in object use:Evidence from semantic dementia. Brain, 123: 1913-1925,2000b.

HODGES JR and PATTERSON K. Is semantic memory consistentlyimpaired early in the course of Alzheimer’s disease?Neuroanatomical and diagnostic implications.Neuropsychologia, 33: 441-459, 1995.

HODGES JR, PATTERSON KE, GRAHAM N and DAWSON K. Namingand knowing in dementia of Alzheimer’s type. Brain andLanguage, 54: 302-325, 1996.

HODGES JR, SALMON DP and BUTTERS N. The nature of the namingdeficit in Alzheimer’s and Huntington’s disease. Brain, 114:1547-1558, 1991.

HODGES JR, SALMON DP and BUTTERS N. Semantic memoryimpairment in Alzheimer’s disease: Failure of access ordegraded knowledge? Neuropsychologia, 30: 301-314, 1992.

HOWARD D and PATTERSON K. Pyramids and Palm Trees: A Test ofSemantic Access from Pictures and Words. Bury St Edmunds:Thames Valley Test Company, 1992.

HUGHES CP, BERG L, DANZIGER WL, COBEN LA and MARTIN RL.A new clinical scale for the staging of dementia. BritishJournal of Psychiatry, 140: 566-572, 1982.

INSAUSTI R, JUOTTONEN K, SOININEN H, INSAUSTI AM, PARTANENK, VAINIO P, LAAKSO MP and PITKANEN A. MR volumetricanalysis of the human entorhinal, perirhinal, and temporopolarcortices. American Journal of Neuroradiology, 19: 659-671,1998.

KEMPLER D. Lexical and pantomine abilities in Alzheimer’sdisease. Aphasiology, 2: 147-159, 1988.

LAMBON RALPH M, GRAHAM KS, ELLIS A and HODGES JR. Namingin semantic dementia – What matters? Neuropsychologia, 36:775-784, 1998.

LAMBON RALPH MA, PATTERSON K and HODGES JR. Therelationship between naming and semantic knowledge fordifferent categories in dementia of Alzheimer’s type.Neuropsychologia, 35: 1251-1260, 1997.

MCKHANN G, DRACHMAN D, FOLSTEIN M, KATZMAN R, PRICE Dand STADLAN EM. Clinical diagnosis of Alzheimer’s disease:Report of the NINCDS-ADRDA Work Group under theauspices of Department of Health and Human Services TaskForce on Alzheimer’s Disease. Neurology, 34: 939-944, 1984.

MISHKIN M, VARGHA-KHADEM F and GADIAN DG. Amnesia andthe organization of the hippocampal system. Hippocampus, 8:212-216, 1998.

MULTHAUP KS, BALOTA DA and FAUST ME. Exploring semanticmemory by investigating buildup and release of proactiveinterference in healthy older adults and individuals withdementia of the Alzheimer type. Journal of International

Neuropsychological Society, 9: 830-838, 2003.MUMMERY CJ, PATTERSON K, PRICE CJ, ASHBURNER J, FRACKOWIAK

RS and HODGES JR. A voxel based morphometry study ofsemantic dementia: The relationship between temporal lobeatrophy and semantic dementia. Annals of Neurology, 47: 36-45, 2000.

MUMMERY CJ, PATTERSON K, WISE RJ, VANDENBERGHE R, PRICECJ and HODGES JR. Disrupted temporal lobe connections insemantic dementia. Brain, 122: 61-73, 1999.

MURRAY EA and BUSSEY TJ. Perceptual-mnemonic functions ofthe perirhinal cortex. Trends in Cognitive Sciences, 3: 142-151, 1999.

OBER BA. RT and non-RT methodology for semantic primingresearch with Alzheimer’s disease patients: A critical review.Journal of Clinical Experimental Neuropsychology, 24: 883-911, 2002

OCHIPA C, ROTHI LJ and HEILMAN KM. Conceptual apraxia inAlzheimer’s disease. Brain, 115: 1061-1071, 1992.

PATTERSON K and HODGES JR. Deterioration of word meaning:Implications for reading. Neuropsychologia, 30: 1025-1040,1992.

PERRI R, CARLESIMO GA, ZANNINO GD, MAURI M, MUOLO B,PETTENATI C and CALTAGIRONE C. Intentional and automaticmeasures of specific-category effect in the semanticimpairment of patients with Alzheimer’s disease.Neuropsychologia, 41: 1509-1522, 2003.

PERRY RJ, WATSON P and HODGES JR. The nature and staging ofattention dysfunction in early (minimal and mild) Alzheimer’sdisease: Relationship to episodic and semantic memoryimpairment. Neuropsychologia, 38: 252-271, 2000.

PETERSEN RC, DOODY R, KURZ A, MOHS RC, MORRIS JC, RABINSPV, RITCHIE K, ROSSOR M, THAL L and WINBLAD B. Currentconcepts in mild cognitive impairment. Archives of Neurology,58: 1985-1992, 2001.

RAPCSAK SZ, CROSWELL SC and RUBENS A. Apraxia in Alzheimer’sdisease. Neurology, 39: 664-668, 1989.

REY A. L’examen psychologique dans les cas d’encéphalopathietraumatique. Archives de Psychologie, 28: 286-340, 1941.

RICH JB, PARK NW, DOPKINS S and BRANDT J. What doAlzheimer’s disease patients know about animals? It dependson task structure and presentation format. Journal ofInternational Neuropsychological Society, 8: 83-94, 2002.

ROGERS TT, LAMBON RALPH MA, HODGES JR and PATTERSON K.Object recognition under semantic impairment: The effects ofconceptual regularities on perceptual decisions. Language andCognitive Processes, 18: 625-662, 2003.

ROSSER A and HODGES JR. Initial letter and semantic categoryfluency in Alzheimer’s disease, Huntington’s disease andprogressive supranuclear palsy. Journal of Neurology,Neurosurgery and Psychiatry, 57: 1389-1394, 1994.

ROY EA and SQUARE PA. Common considerations in the study oflimb, verbal and oral apraxia. In Roy EA (Ed),Neuropsychological Studies of Apraxia and Related Disorders.North Holland: Elsevier Science Publishers, 1985.

VARGHA-KHADEM F, GADIAN DG, WATKINS KE, CONNELLY A, VANPAESSCHEN W and MISHKIN M. Differential effects of earlyhippocampal pathology on episodic and semantic memory.Science, 277: 376-380, 1997.

WARRINGTON EK and JAMES M. The Visual Object and SpacePerception Battery. Bury St Edmunds: Thames Valley TestCompany, 1991.

WARRINGTON EK, MCKENNA P and ORPWOOD L. Single wordcomprehension: A concrete and abstract word synonym test.Neuropsychological Rehabilitation, 8: 143-154, 1998.

WECHSLER DA. Wechsler Memory Scale – Revised. San Antonio:Psychological Corporation, 1987.

Anna-Lynne R. Adlam, Cognition and Brain Sciences Unit, Medical Research Council,15 Chaucer Road, Cambridge, CB2 2EF, UK.e-mail: [email protected]


(Received 10 December 2004; reviewed 15 February 2005; revised 11 March 2005; accepted 29 April 2005;Action Editor Jordan Grafman)

semantic knowledge in mild cognitive impairment and mild alzheimer's disease

Documents