Brain (2002), 125, 2044±2057
The dynamic time course of semantic memory impairment in Alzheimer's disease: clues from hyperpriming and hypopriming effects BeÂneÂdicte Giffard,1 BeÂatrice Desgranges,1 Florence Nore-Mary,1,2 Catherine LaleveÂe,1 HeÂleÁne Beaunieux,1,3 Vincent de la Sayette,1 Florence Pasquier2 and Francis Eustache1,4 E0218±Universite de Caen, Laboratoire de Neuropsychologie, CHU CoÃte de Nacre, 2Clinique Neurologique, Centre de la MeÂmoire, CHRU, HoÃpital Roger Salengro, Lille, 3Laboratoire de Psychologie Cognitive et Pathologique, Universite de Caen, 4Ecole Pratique des Hautes Etudes, Universite Rene Descartes, Paris, France 1Inserm
Summary
The nature of semantic memory de®cit in Alzheimer's disease is still a matter of controversy. To clarify this issue, we examined the evolution of semantic memory impairment in 24 Alzheimer's disease patients by means of a longitudinal study. We used two semantic tasks, one explicit and the other implicit, to evaluate the integrity of the same concepts. The explicit task was a semantic knowledge task composed of naming and questions, involving superordinate and attribute knowledge of concepts. The implicit task, a lexical decision task, assessed semantic priming and allowed a very pure measurement of semantic memory. In this task, related pairs of words had coordinate (e.g. `tiger±lion') or attribute (`tiger±stripe') relationships. In the coordinate
Correspondence to: Prof. Francis Eustache, Inserm E0218±Universite de Caen, Laboratoire de Neuropsychologie, CHU CoÃte de Nacre, 14033 Caen Cedex, France E-mail:
[email protected]
relation between two words, the semantic priming performances were at ®rst paradoxical: they increased abnormally (hyperpriming) before falling down, whereas in the attribute condition, the priming effects were ®rst normal and then started to decrease in the ®nal sessions (hypopriming). Compared with the semantic knowledge performance, these apparently disconcerting results re¯ect a coherent pattern of semantic memory degradation in Alzheimer's disease that is a progressive deterioration starting with speci®c attribute information. The data reveal in an astonishing yet striking manner the dynamic semantic memory degradation in Alzheimer's disease through the apparently paradoxical semantic priming effects.
Keywords: Alzheimer's disease; longitudinal study; semantic memory; semantic priming Abbreviations: DRS = dementia rating scale; MMSE = mini-mental state examination; SOA = stimulus-onset asynchrony
Introduction
Numerous studies have shown that semantic memory impairments may occur relatively early in the course of Alzheimer's disease. Mildly demented patients with Alzheimer's disease have been shown to be impaired on tests of object naming (Martin and Fedio, 1983; Huff et al., 1986; Hodges et al., 1992), verbal ¯uency (Ober et al., 1986; Troster et al., 1989; Bayles et al., 1990; Hodges and Patterson, 1995; Salmon et al., 1999) or de®nitions (Hodges et al., 1996; Lambon Ralph et al., 1997). Nevertheless, the nature of the cognitive dysfunction responsible for these semantic processing impairments is still a matter of controversy. Some investigators (Chertkow et al., 1989, 1994; Chertkow and Bub, 1990; Hodges et al., 1992; Martin, 1992; ã Guarantors of Brain 2002
Chan et al., 1993, 1995; Randolph et al., 1993; Binetti et al., 1995) argue that the semantic de®cit stems from a gradual breakdown in the hierarchical organization of semantic knowledge (Collins and Quillian, 1969) as Alzheimer's disease progresses. That is, whereas Alzheimer's disease patients may retain semantic information about a given concept, they progressively lose knowledge of the concept's speci®c attributes that constitute its meaning (Hodges et al., 1992). Another point of view (Ober and Shenaut, 1988; Nebes, 1989, 1992, 1994; Nebes et al., 1989; Bayles et al., 1991; Hartman, 1991) is that the store of semantic memory remains relatively intact in Alzheimer's disease, and that the de®cit is related to a decreased ability to access semantic
Semantic memory deterioration in Alzheimer's disease information. However, many of the tasks used to explore semantic memory require sustained attention, active searching, working memory and overt retrieval in addition to the more basic processes of accessing and using information from semantic memory. Most importantly, these tasks lack sensitivity and do not allow one to establish accurately how and when the structure of semantic memory deteriorates. Therefore, one of the methods used to investigate the organization of semantic memory with more precision is the single-word semantic priming paradigm. In this study, semantic priming refers speci®cally to a short-lived phenomenon that is usually considered a measure of semantic knowledge integrity. It does not refer to repetition priming with a delay between study and test that demands the participation of long-term memory in new learning. This paradigm allows one to assess semantic memory implicitly and thus minimizes non-semantic cognitive processes. Semantic priming effects refer to the modi®cation of a stimulus processing behind the presentation of a related stimulus. These effects depend on semantic memory (Tulving, 1995) and require a semantic processing of the prime stimulus and/or a semantic relation between the prime and the target. Generally, in lexical decision or pronunciation tasks, a word (e.g. `chair') is recognized faster if it is preceded by a semantically related word (`table') than by an unrelated word (`horse') (Meyer and Schvaneveldt, 1971; Fischler, 1977; Neely, 1977). This processing facilitation would depend on the automatic spreading activation through the semantic network (Collins and Loftus, 1975): the presentation of a prime activates its node in memory and this activation automatically spreads to related nodes, thus momentarily increasing their accessibility. Semantic priming studies have yielded contradictory results in Alzheimer's disease patients. Some authors have reported less-than-normal priming (hypopriming) in Alzheimer's disease patients compared with controls (Ober and Shenaut, 1988; Salmon et al., 1988; Silveri et al., 1996), while others have found equivalent priming (Nebes et al., 1984; Ober et al., 1991) or even paradoxical increased priming effects (hyperpriming) in Alzheimer's disease patients (Chertkow et al., 1989, 1994; Nebes et al., 1989; Balota and Duchek, 1991; Hartman, 1991; Balota et al., 1999; Bell et al., 2001). These diametrically opposed results may re¯ect not only differences in the methods used, but also clinical heterogeneity in the population samples studied. For example, the severity of dementia, and therefore of semantic de®cits, differed from one study to another, and even within individual studies. Interestingly, some authors reported a combination of no priming and intact priming (e.g. Albert and Milberg, 1989; Bushell and Martin, 1997; Glosser et al., 1998) or both intact priming and hyperpriming (e.g. Margolin et al., 1996; Shenaut and Ober, 1996; Giffard et al., 2001). The aim of the present study was, therefore, to investigate further the structure of semantic memory impairment in a sample of Alzheimer's disease patients and to assess the relationships between semantic priming effects and semantic
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memory de®cits by means of a longitudinal investigation, in which we were able to follow their subsequent evolution. Our approach relies on the fact that semantic memory is found to deteriorate progressively throughout the course of Alzheimer's disease (Chan et al., 1997) as a result of the degradation of the neocortical association areas that are presumed to store the semantic representations. Loss of semantic knowledge is often con®ned to a limited number of items during the early stages of the disorder and then spreads as the disease progresses. This progressive deterioration of semantic information over time bears on the claim that conceptual structure is hierarchically organized (Collins and Quillian, 1969) from superordinate (e.g. `a canary is an animal') to basic-level category (`a canary, like a swallow or a raven, is a bird') to speci®c features (`a canary is yellow and can ¯y'). However, this traditional framework of hierarchical organization has been largely challenged. Computational models of semantic memory (Masson, 1995; Plaut, 1995; McRae et al., 1997) assume that conceptual knowledge is represented in a widely distributed network of low-level representational units (semantic features). In such models, concepts are represented by an overlap of features, and domain and category structure is based on similarity, captured in the degree to which semantic properties overlap rather than being distinctly encoded at a separate level (Devlin et al., 1998; Tyler and Moss, 2001). Nevertheless, to make the study more straightforward, the protocol has been realized within the framework of hierarchical conceptual structure, distinguishing several semantic levels. We made the assumption that the semantic memory deteriorates in a sequential manner, at a subordinate level ®rst and at a superordinate level thereafter (Warrington, 1975). For this reason, we combined two dimensions in the present study: the semantic level (subordinate versus superordinate) and time (longitudinal evaluation). Furthermore, we made the assumption that at the onset of the disease loss of semantic knowledge results in concepts becoming less well de®ned as their distinguishing attributes are eliminated, and later on there is a weakening of the formerly strong associations between related concepts in the semantic network. To assess semantic memory in an Alzheimer's disease group with mild-to-moderate dementia, we compared performances for both an implicit and an explicit task. These two tasks used the same stimuli targets. The implicit semantic memory task, a lexical decision task, assessed the semantic priming effects. In order to explore the hierarchical semantic hypothesis in the case of a conceptual degradation (Warrington and Shallice, 1979), we used two types of word pairs in the lexical decision task. Some word pairs shared a coordinate relationship (e.g. `tiger±lion'), i.e. the prime and the target belonged to the same semantic category and shared the same semantic level. Other word pairs were related according to an attribute condition (`tiger±stripe'), i.e. the target was a speci®c attribute of the prime concept. The cognitive slowing process is characteristic of Alzheimer's
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disease patients and of older subjects in general. In the present study, we controlled for the effects of this slowing with the help of a measurement expressed as a percentage of the priming effects. Moreover, we used the following automaticity criteria to minimize the intervention of attentional mechanisms, such as prelexical expectancy or postlexical semantic matching processes (for a review see Neely, 1991): (i) low proportion of related words (20%); (ii) short stimulusonset asynchrony (SOA; 250 ms); (iii) low attention to the prime (the subject had just to answer the target); and (iv) the same proportion of word targets and non-word targets (Posner and Snyder, 1975; Neely, 1991). The explicit semantic memory test (a semantic knowledge task) was inspired by Martin (1987) and Desgranges et al. (1996). This task required decisions that involved conscious exploration in semantic memory and was designed to probe for knowledge across the hierarchy of semantic memory from the superordinate to the ®ne-grained subordinate level. Our primary goal was to examine the hypothesis that the pro®le of semantic priming effects evolves in a dynamic manner as the semantic memory deterioration advances (see Chertkow et al., 1990), hence the interest in the longitudinal assessment of these two components. This evolution of priming effects in Alzheimer's disease could account for the variety of pro®les of semantic priming observed in the literature. It was, therefore, necessary to take into account the Alzheimer's disease semantic de®cit variability, which can hide different semantic priming pro®les (see Albert and Milberg, 1989); a study that takes into account the performance levels with semantic knowledge could allow a better understanding of the observed priming effects. The hypothesis of this longitudinal study suggests at least three stages in the evolution of priming. (i) When semantic memory is still intact, semantic priming effects in patients and age-matched controls should be equivalent in both coordinate and attribute conditions, because semantic priming depends on semantic memory. (ii) When the speci®c attributes of concepts begin to be lostÐwhereas superordinate information is well preserved (e.g. the tiger and the lion are still known to be wild animals, but knowledge about their stripes and mane is lost)Ðthe ability to distinguish between two very similar concepts is impaired. In the case of a coordinate relationship (`tiger± lion'), priming effects do not only existÐsince the words are semantically related through membership in their preserved superordinate classÐbut they are greater than in a control group (hyperpriming): speci®c attributes that characterize each concept are lost, hence a confusion, an overlapping between the two coordinate concepts (both are wild animals and also both have fur and are dangerous). Therefore, as suggested by Martin (1992), the semantic priming (`tiger± lion') would be treated by the patient as repetition priming (`wild animal±wild animal'), the magnitude of which is greater than in the former. In the attribute condition (`tiger± stripe'), at the same semantic deterioration level, the priming effect should decrease because knowledge of the speci®c attributes (`stripe') grows weaker. So, for the patient, the link
between the words `tiger' and `stripe' is attenuated. This hypothesis has been con®rmed by the study of Giffard and colleagues (Giffard et al., 2001) in a large sample of patients. (iii) As semantic memory deteriorates even more, not only the speci®c attributes, but also the concepts themselves, are lost. This is the reason why, in the attribute as well as in the coordinate condition, the semantic priming effects should decrease, because not even coordinate links between words will be remembered. The ®rst time that such a longitudinal investigation was conducted was in a study by Giffard and colleagues (Giffard et al., 2001). In that initial study, 20 normal control subjects and 53 Alzheimer's disease patients were examined. In the present study, the normal control group's scores are the same as those in the study of Giffard and colleaguesÐhence, control subjects have been examined once onlyÐand the 24 patients examined through the four sessions were selected from the 53 Alzheimer's disease patients. For statistical reasons, only patients who received the four sessions were included in the longitudinal analysis.
Material and methods
The methodology used was similar to that employed in our previous study (Giffard et al., 2001) and will, therefore, be described brie¯y.
Subjects
Twenty-four patients with probable Alzheimer's disease and 20 elderly normal controls participated in the study. All subjects gave informed consent to the neuropsychological procedure, which was approved by the Ethical Committee of the University of Caen. Diagnosis of patients, who were all right-handed, was made according to the criteria of McKhann and colleagues (McKhann et al., 1984). At the time of the ®rst session, all patients [mean age (6 SD) 71 6 5 years, range 61±78 years; six males and 18 females] underwent a neurological examination, standard laboratory studies, EEG and an extensive routine neuropsychological assessment. No abnormality, other than atrophy, was found on the CT scan or on MRI. The patients had no previous neurological or psychiatric history. The scores for the mini-mental state examination (MMSE; Folstein et al., 1975) and the dementia rating scale (Mattis, 1976) for the whole group are presented in Table 1. At the ®rst session, the Alzheimer's disease group was divided into two subgroups, A (n = 15) and B (n = 9), on the basis of their semantic knowledge impairment. A detailed explanation of this subdivision is addressed below. Control subjects (mean age 71 6 6 years, range 63±86 years; eight males and 12 females) received the same examinations as the patients but once only (see Giffard et al., 2001). They were recruited in clubs for retired people and had no neurological or psychiatric disorders. The score for the MMSE was 27±30, and for the DRS it was 135±143 (means and standard deviations are presented in Table 1). The
SD = standard deviation; MMSE = mini-mental state examination; DRS = dementia rating scale; UnRT = response times in the unrelated condition; SPE Co = semantic priming effects in the coordinate condition; SPE At = semantic priming effects in the attribute condition; GK = general knowledge; SK = speci®c knowledge; NS = not signi®cant.
0.015 0.08 (NS) 0.0002 0.001 0.16 (NS) 1 SD of the mean of the control group (patients without semantic de®cits, subgroup A). The second subgroup was composed of nine patients with performances that exceeded >1 SD of the control group (patients with semantic de®cits, subgroup B). We opted for this threshold of 1 SD below the mean of the control group, because the semantic knowledge task was not very sensitive, with a ceiling effect easily reached in controls. This subdivision of the Alzheimer's disease group allows a more detailed understanding of the effect of the semantic de®cits on semantic priming effects. During the follow-up period, we used the same subdivision to test and detect a
contrast in the evolution of semantic priming effects and semantic memory de®cits in each subgroup.
Demographic data
An ANOVA performed at the ®rst session between the three groups of subjects (one control group and the two Alzheimer's disease subgroups) showed no signi®cant differences in terms of age [F(2,41) = 0.20, P = 0.82], education level [F(2,41) = 1.68, P = 0.20] or sex distribution [F(2,41) = 0.57, P = 0.57]. The performances of the two Alzheimer's disease subgroups in MMSE and DRS tasks through the four sessions are shown in Table 2. Results of inter-subgroup (subgroup A versus subgroup B) analyses for cross-sectional comparisons (non-paired Student t-tests) and results of intrasubgroup analyses for longitudinal comparisons (one-way ANOVAs with repeated measures) are also shown.
Semantic knowledge task
The performances on the semantic knowledge task of the three groups of subjects are shown in Fig. 1. In the categorical knowledge subtest, to compare the scores between the three groups of subjects (control, subgroup A and subgroup B) through the four sessions, the performances were submitted to four one-factor ANOVAs. The analyses showed no group effect in any session. A two-way ANOVA with repeated measures of two Alzheimer's disease subgroups (subgroups A and B) 3 sessions 1±4 showed neither effect of group [F(1, 22) = 0.667, P = 0.42] nor effect of period [F(3,66) = 0.19, P = 0.90], and the interaction group 3 period was not signi®cant [F(3,66) = 1.78, P = 0.16]. On the contrary, in the attribute knowledge test, group effect was signi®cant in each session (P < 0.0001). At time 1, the subgroup B had signi®cantly worse attribute knowledge performances than the subgroup A and control group (because the two Alzheimer's disease subgroups were divided on this basis). Post hoc comparisons (Bonferroni/ Dunn's test) showed that at times 2, 3 and 4 of the study, both subgroup A and subgroup B had worse scores than the control group, and differences between the two Alzheimer's disease subgroups were no more signi®cant. A two-way ANOVA with repeated measures of two Alzheimer's disease subgroups (subgroups A and B) 3 sessions 1±4 showed a signi®cant effect of group [F(1,22) = 10.23, P = 0.004] and a signi®cant effect of session [F(2,43) = 5.52, P = 0.002], but no signi®cant interaction between group and session [F(2,43) = 0.78, P = 0.50]. In subgroup A, post hoc analysis (Bonferroni/Dunn's test) indicated a signi®cant difference between attribute knowledge scores at time 1 and time 4 (P = 0.0047).
Lexical decision task
The mean response times of the three groups of subjects in the lexical decision task in each of the test sessions are shown in
648.0 (78.3) 629.7 (82.7) 697.1 (89.3)
RT = response times. Subgroup A: patients without semantic de®cits at the ®rst session but with some from the second session (n = 15). Subgroup B: patients with semantic de®cits from the beginning of the evaluation (n = 9).
954.5 (406.4) 1000.5 (487.0) 1054.9 (527.0) 846.2 (293.9) 873.5 (342.8) 926.2 (335.8) 826.8 (213.1) 840.4 (241.5) 927.8 (283.9) 796.7 (185.0) 832.1 (193.7) 920.9 (231.7) 810.7 (131.2) 826.3 (148.3) 873.8 (150.9) 794.2 (136.5) 791.8 (179.6) 853.5 (160.6) 794.0 (185.2) 822.8 (213.0) 893.6 (212.9)
Session 3 Session 2
Coordinate Attribute Unrelated
837.4 (202.3) 853.3 (226.5) 924.3 (228.5)
Session 4 Session 3 Session 2 Session 1 Session 1
Session 4
Subgroup B Subgroup A
Alzheimer's disease patients Controls RT condition
Table 3 Mean lexical decision response times (in ms) to word targets for the control group and the two Alzheimer's disease subgroups in each session (standard deviations in parentheses)
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Table 3. Four two-way ANOVAs comparing response times in the four sessions [three groups (control, subgroup A, subgroup B) 3 three conditions (coordinate, attribute, unrelated)] showed signi®cant effects of group and condition in the four analyses. The interactions group 3 condition were also signi®cant, but only in the ®rst and second sessions (P = 0.0025 and P = 0.01, respectively). Post hoc analyses (Bonferroni/Dunn's test) showed that in the three conditions and for each session, response times of the two subgroups of patients were similar and signi®cantly greater than those obtained by the controls. In the two subgroups of patients, a repeated measures ANOVA of Alzheimer's disease subgroup (subgroup A and subgroup B) 3 condition of response times (coordinate, attribute, unrelated) 3 session 1±4 revealed a signi®cant main effect of condition of response times [F(1,31) = 49.56, P = 0.0002], but no signi®cant main effect of group [F(1,22) = 0.40, P = 0.53] and session [F(1,32) = 2.37, P = 0.12]. There were no signi®cant group 3 condition of response times [F(1,31) = 0.87, P = 0.39], group 3 session [F(1,32) = 3.26, P = 0.07], condition of response times 3 session [F(6,132) = 1.26, P = 0.28], and group 3 condition of response times 3 session [F(6,132) = 0.51, P = 0.80] interaction effects. The coordinate and attribute priming effects of the two subgroups of patients (subgroups A and B) through the four sessions of testing are shown in Fig. 2. In the coordinate condition, to compare the semantic priming effects between the three groups of subjects (control, subgroup A, subgroup B) through the four sessions, the performances were submitted to four, one-factor ANOVAs. The analyses showed signi®cant differences between the three groups at the ®rst and second sessions [F(2,41) = 5.24, P = 0.009 and F(2,41) = 3.86, P = 0.029, respectively], but not at the third and fourth assessments. At time 1, post hoc analysis indicated that subgroup B obtained signi®cantly greater semantic priming effects than controls (hyperpriming) (P = 0.0025). In the second session of testing, while subgroup A began to show semantic de®cits, this Alzheimer's disease subgroup revealed a signi®cant hyperpriming effect (P = 0.011 between subgroup A and the control group); the difference between subgroup B and controls was no longer signi®cant (P = 0.09). At the third and fourth assessments, there were no longer signi®cant differences between the three groups of subjects. In the two Alzheimer's disease subgroups, in order to detect a period effect between the performances, the semantic priming effects were submitted to two-way ANOVAs with repeated measures. The analysis of the two Alzheimer's disease subgroups (subgroups A and B) 3 sessions 1±4 showed no effect of group [F(1,22) = 0.78, P = 0.39], but a signi®cant effect of period [F(3,63) = 4.14, P = 0.01]. The interaction group 3 session [F(3,63) = 0.993, P = 0.40] was not signi®cant. In subgroup A, post hoc analyses showed signi®cant differences between time 2 and time 3 (P = 0.0199), and between the second and the ®nal assessment (P = 0.034). The post hoc analysis in the subgroup B indicated a
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Fig. 2 Semantic priming effects in percentage (mean 6 standard deviation) for the two Alzheimer's disease subgroups [subgroup A (patients without semantic de®cits at the ®rst session) and subgroup B (patients with semantic de®cits from the ®rst session)] in the coordinate and attribute conditions through the four sessions of testing. For each session, the performances of the two subgroups were compared with those of the controls (represented by black straight lines) in both conditions. A hyperpriming phenomenon was shown at the ®rst session for subgroup B and at the second session for subgroup A, in the coordinate condition only. A hypopriming effect was evident at the fourth session in the attribute condition for both subgroups of patients. **P < 0.01 and *P < 0.05 compared with the control group. The black curves follow the semantic priming performances obtained by subgroup B. The dotted curves represent our hypotheses about semantic priming scores in the subgroup B before the beginning of the assessment (not yet hyperpriming in the coordinate condition, and equivalent priming in the attribute condition) and after the ®nal session (decrease of the semantic priming effects in both conditions).
signi®cant difference between the ®rst and the ®nal session (P = 0.032). In order to detect changing patterns of priming effects in the coordinate condition between the two subgroups of patients between sessions one and two, we conducted a twoway ANOVA with repeated measures (two groups 3 two sessions). There was no signi®cant group effect [F(1,22) = 0.63, P = 0.43] and no signi®cant session effect [F(1,22) = 0.27, P = 0.61], but the interaction group 3 session [F(1,22) = 4.65, P = 0.042] was signi®cant. In the attribute condition, the analyses of variance showed signi®cant differences between the three groups of subjects, but only at the ®nal testing period [F(2,41) = 4.75, P = 0.014]. Post hoc analyses indicated that, at this session, the priming effects of the two Alzheimer's disease subgroups were signi®cantly smaller than those of the control group (subgroup A, P = 0.0148; subgroup B, P = 0.0148). Nevertheless, at the third session, the scores of subgroup B tended to be smaller than that observed for the priming effects in the control group (P = 0.045). In the two Alzheimer's disease subgroups, a two-way ANOVA with repeated measures of two groups (subgroups A and B) 3 sessions 1±4 indicated that there was neither a signi®cant group effect [F(1,22) = 0.006, P = 0.94] nor a session effect [F(3, 66) =
2.56, P = 0.06], and the interaction group 3 session was not signi®cant [F(3,66) = 0.621, P = 0.60].
Discussion
The results of the present longitudinal study show changing patterns of semantic priming effects over the course of Alzheimer's disease. Moreover, the evolution of the priming effect does not always follow a linear curve. The experimental procedure allowed us to reveal a dissociation according to the condition (coordinate versus attribute): the priming effect observed in the attribute condition declines in a linear progression over the course of the disease, whereas in the coordinate condition the priming performance increases abnormally (hyperpriming) before falling. Furthermore, at the initial assessment of the study, the subdivision of the Alzheimer's disease group according to the severity of the speci®c attribute de®cits revealed that subgroup A (patients without semantic de®cits at the ®rst session, but with semantic de®cits from the second session) shows exactly the same longitudinal pro®les of evolution as that of subgroup B (patients with semantic de®cits from the beginning of the evaluation), but with one session interval.
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Fig. 3 Schematic evolution of the semantic priming effects in Alzheimer's disease. Semantic priming effects evolve with the semantic memory de®cits. The dotted lines illustrate our hypothesis about semantic priming effects in the coordinate and attribute conditions (see Introduction for the three hypothetical stages of semantic deterioration in Alzheimer's disease). The solid black lines illustrate the patterns of semantic priming obtained by the patients in the coordinate and attribute conditions (see Results section). Note the difference between the initial hypothesis and the pattern of results actually obtained. As expected, the patients showed a hyperpriming effect in the coordinate condition and a progressive semantic priming decrease in the attribute condition. But, contrary to initial expectation based upon hierarchical models of semantic memory, the semantic priming decrease in the attribute condition does not occur at the same time as hyperpriming in the coordinate condition, but later. This unexpected pattern is explained by computational models (see text).
These data corroborate the ®ndings of a transversal study performed by Giffard and colleagues (Giffard et al., 2001) in that hyperpriming is observed in the coordinate condition when semantic memory begins to deteriorate. In addition to this initial work, the present longitudinal study suggests that the hyperpriming phenomenon is not a set manifestation of semantic de®cits, but just occurs when the semantic attributes start to be lost. Thereafter, in the coordinate condition, this paradoxical effect disappears: semantic priming effects decrease progressively along with semantic memory deterioration, which concerns not only speci®c attributes but actual concepts themselves. Furthermore, contrary to the present work, the transversal study was not able to reveal a hypopriming effect in the attribute condition since this semantic priming decrease appears later as the semantic memory deteriorates. Our very controlled methodology, which was always the same during the longitudinal follow-up, allows us to consider that these patterns of semantic priming re¯ect changes in semantic memory de®cits exclusively. Therefore, our ®nding calls into question many interpretations in studies showing normal priming effects or hyperpriming in Alzheimer's disease. Some researchers (Nebes et al., 1984; Ober and Shenaut, 1995) consider that normal priming effects in Alzheimer's disease re¯ect intact semantic knowledge. Nevertheless, this intuitively plausible hypothesis is right in part, but does not take into account the complexity of the conceptual structure (Moss et al., 1995; Nakamura et al., 2000; Giffard et al., 2001). Partial semantic degradation can still allow apparently normal priming effects: damage to stored representation may result in loss of some, but not all, of the speci®c attribute information. In this case, semantic
priming effects, supported by the remaining intact features only, can be observed. At time interval 4 of our longitudinal investigation, in subgroup B we observed equivalent semantic priming as controls in the coordinate condition, whereas performance was inferior in the attribute condition (hypopriming). If knowledge of speci®c attributes had remained intact over the sessions, we would have observed equivalent semantic priming as that of controls in both conditions. Concerning the paradoxical hyperpriming phenomenon, con¯icting hypotheses have been advanced to explain this effect. According to Nebes and colleagues (Nebes et al., 1989), hyperpriming means that the semantic memory is intact and would just re¯ect an artefact of general slowing in Alzheimer's disease: the slower the patient responds, the larger semantic priming effects he/she shows. The results of our longitudinal investigation contradict the explanation of Nebes and colleagues: we did not observe in the Alzheimer's disease group a signi®cant effect of session on response times in the lexical decision task, whereas the semantic priming effects changed signi®cantly over time. We have also observed equivalent priming effects even though the patients responded signi®cantly more slowly than the controls. Moreover, Pearson correlations indicated the absence of signi®cant relationship between the magnitude of priming effects and response times, except at the fourth assessment in the coordinate condition (but the patients did not show hyperpriming at this time). Furthermore, in our study, semantic priming effects are expressed as a percentage of the unrelated condition response times, which minimizes any effect of slowing on the size of the priming effect. According to others (Hartman, 1991; Ober et al., 1991; Silveri et al., 1996; Bell et al., 2001) hyperpriming may occur
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only in some experimental conditions that incite the subject to develop attentional strategies (pre-lexical expectancy or postlexical semantic matching processes). These attentional strategies are de®cient in Alzheimer's disease. Ober and Shenaut (1995) observed in a meta-analysis that hyperpriming mainly occurs in paradigms, bringing into play these attentional processes (long SOAs, high proportions of related word pairs, high proportions of non-words). Thus, the hyperpriming effect would be the result of Alzheimer's disease strategic de®cits in semantic priming tasks. Attentional processes involve divided attention and working memory. Patients with Alzheimer's disease have considerable dif®culty in dividing attention between concurrently running cognitive operations. Thus, when semantic priming tasks involve long SOAs and a high proportion of related pairs, the patients (like normal subjects) are attempting to divide their attention among generate, search and decision processes. However, these multiple cognitive operations `hamper' their impaired working memory, especially for the pairs in which words are unrelated and in which the potential targets will have to be inhibited. This will probably create for the patient a doubt about the decision asked (`yes' the target is a word or `yes' the target is related to the prime). This confusion is expressed by a magni®ed difference between the response times in unrelated targets and in targets related to the prime (due mainly to increased slowing for unrelated pairs) for Alzheimer's disease patients compared with controls. In our study, the adjustment of the protocol (SOA = 250 ms, 20% of related words, response on the target only, same proportion of target words and target non-words) did not incite the subjects to engage expectancy or post-lexical processes. Therefore, the hyperpriming effect observed in our study was not the result of the intervention of such strategies. Moreover, with this same protocol, we have observed inferior, equivalent and superior semantic priming effects than with a control group. Our results show that when semantic memory is still entirely preserved (subgroup A at the ®rst session), semantic priming effects are similar in patients and their controls in both coordinate and attribute conditions, because semantic priming depends on semantic memory. Thereafter, a hyperpriming effect is encountered in the coordinate condition at the beginning of the semantic de®cit only (subgroup B at the ®rst session and subgroup A at the second session). These results agree with those of Chertkow et al. (1989) concerning words sharing a coordinate relation, where a hyperpriming effect is observed for the degraded items only. In our study, the hyperpriming effect re¯ects a deterioration of semantic memory and, more speci®cally, a storage de®cit for speci®c attribute information: from the onset of the dementia, semantic representations deteriorate progressively, affecting the speci®c attributes ®rst, with preservation of general knowledge (Martin and Fedio, 1983). The distinction between coordinate concepts is therefore more and more dif®cult because their speci®c attributes, which allow them to be distinguished, are lost. Without being exactly the same,
hyperpriming could be close to a repetition priming (in which the prime and the target are the same) in which the intensity is greater than semantic priming (Martin, 1992). Hyperpriming does not appear to be an artefact of overall slowing or the result of attentional processes intervention, but rather, as argued here and by Giffard et al. (2001), it may well be a direct consequence of degraded semantic representations. However, according to our hypothesis, semantic priming effects in both conditions should have decreased at the same time as general knowledge deterioration. In the categorical knowledge test, we did not observe in either of the Alzheimer's disease subgroups, a signi®cant difference compared with control subjects at any session. This absence of difference may be explained by the fact that semantic memory de®cits are measured with a task composed of yes/no and multiple choice questions and for which the answers are very straightforward, and therefore a ceiling effect is quickly reached. This task would therefore not be sensitive enough to detect general knowledge de®cits. However, we can suppose that as semantic memory deteriorates even more, semantic priming effects in both coordinate and attribute conditions would continue to decrease (see Fig. 2, dotted lines). Otherwise, we made the assumption that at the beginning of the semantic deterioration, while patients showed hyperpriming in the coordinate condition, we should have observed simultaneously a semantic priming decrease in the attribute condition, when in fact the performances were still normal (Fig. 3). To explain this pattern, we can suppose that in Alzheimer's disease, features of concepts would not be lost in an all-or-none manner, but the loss could be progressive and incomplete at the start of the disease. Computational models based upon distributed networks, in which each concept is represented by an overlap of features (e.g. the concept `tiger' is represented by the features `animal', `wild', `four legs', `fur' and `stripes'), could allow a better understanding of our results than the traditional framework of hierarchical organization (Collins and Quillian, 1969) does. Such connectionist models assume that category structure is based on similarity, captured in the degree to which semantic properties overlap. Thus, `tiger' and `lion' belong to the same category (animal) and are semantically close because they share a large number of category-relevant properties (`wild', `four legs', `fur'). However, they can be distinguished by some speci®c features (for example, the stripes of the tiger and the mane of the lion). Therefore, there would exist two kinds of attributes: those that are common to lots of concepts and that also tend to cooccur across exemplars, and those that are speci®c to one concept and that usually occur in isolation. In Alzheimer's disease, common features would be preserved longer than distinctive features (Devlin et al., 1998). Following such a conception, the hyperpriming effect observed in the coordinate condition could just be caused by a loss of those distinctive features. The representations of the tiger and the lion would therefore only be characterized by attributes like `four legs', `wild' and `fur', which are shared by the two concepts. Thus, these two concepts would become
Semantic memory deterioration in Alzheimer's disease synonyms at that point of the semantic deterioration. In the attribute condition, semantic priming effects would still be normal because the pairs in this condition are mainly composed of common features. Thereafter, as semantic memory deteriorates even more, not only the distinctive attributes, but also those shared by the two concepts, would be progressively altered. These two concepts would then become even less close. This could explain why, in the coordinate and attribute conditions, we observed a decrease in semantic priming effects. The present study demonstrates that the presence of semantic priming effects in Alzheimer's disease does not necessarily prove integrity of the semantic memory, and that on the contrary, considering models of semantic memory we can interpret the paradoxical evolution of semantic priming effects as a progressive deterioration of semantic memory. Following hierarchical models, increased semantic priming (hyperpriming) re¯ects the loss of speci®c information represented at lower hierarchical levels in spite of the integrity of general knowledge represented at a higher level. Considering computational models, hyperpriming re¯ects progressive loss of semantic features, to start with by distinctive features and thereafter by shared properties. Therefore, the results of this longitudinal study suggest that the pro®le of semantic priming effects in Alzheimer's disease evolves in a dynamic manner and is dependent on the level of semantic memory deterioration. The longitudinal pro®les observed might explain in part the con¯icting results noted in the literature. This method of investigation leads to a very precise and accurate measurement of semantic de®cits in patients with Alzheimer's disease. Overall, our ®ndings are an example of a way in which a disease may temporarily result in a `supra-normal' performance on speci®c tests, through a modular loss of function within an organized cognitive system.
Acknowledgements
We wish to thank Drs O. Letortu and S. Schaeffer for the recruitment of the patients, Dr J. Segui, Professor F. Viader, Professor J. C. Baron and Mrs J. Lambert for their methodological advice, Professor S. Faure, Drs P. Piolino and S. Rossi for their statistical advice, and Dr A. R. Young for revising the English style. This work was supported by the FranceAlzheimer association and by a grant from the MinisteÁre de l'Education Nationale de la Recherche et de la Technologie.
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