The underlying mechanisms of semantic memory loss in Alzheimer's disease and semantic dementia
Introduction
Semantic memory is a distinct part of the declarative memory system (Tulving, 1972) comprising knowledge of facts, vocabulary, and concepts acquired through everyday life (Squire, 1987). Deficits of semantic memory are prominent in both Alzheimer's disease (AD; Chertkow & Bub, 1990; Hodges & Patterson, 1995; Hodges, Patterson, Oxbury, & Funnell, 1992; Hodges, Salmon, & Butters, 1992; Martin & Fedio, 1983) and semantic dementia (SD; Hodges et al., 1992a, Hodges et al., 1992b; Snowden, Goulding, & Neary, 1989). AD patients often demonstrate a progressive decline in performance on tasks that are dependent upon semantic memory, including word finding and picture naming (Hodges & Patterson, 1995; Hodges et al., 1992a, Hodges et al., 1992b; Rogers, Ivanoiu, Patterson, & Hodges, 2006). Patients with SD, the temporal variant of frontotemporal dementia, generally present with a more severe progressive impairment on such tasks (Hodges et al., 1992a, Hodges et al., 1992b, Hodges et al., 1994; Rogers et al., 2006).
Over the past two decades, there has been documentation of considerable impairment in performance on semantic memory-dependent tasks in AD patients (Chertkow & Bub, 1990; Chertkow, Bub, & Seidenberg, 1989; Hodges et al., 1992a, Hodges et al., 1992b). This semantic task impairment can occur with a sparing of other linguistic abilities, such as phonology, prosody, and syntax, and only minor perceptual problems (Chertkow & Bub, 1990; Chertkow et al., 1989). Another neurological condition that impairs explicit semantic memory performance is semantic dementia, which presents initially as an isolated loss of semantic knowledge. Like the semantic deficit seen in AD, language functions such as syntax, phonology and prosody are initially unaffected in patients with SD.
Two primary theories have been proposed to explain the semantic deficits observed in patients with AD and patients with SD, on semantic memory tests such as the Hodges Battery (Hodges et al., 1992a, Hodges et al., 1992b). Impairment on explicit semantic tests such as these could be linked to either a degradation of the internal semantic network, or to a failure to retrieve the information from that network. That is, it is possible that failure on explicit semantic tests may be the result not of impaired semantic representations per se, but of impairment in the conscious strategic processing needed to access those representations (Nebes, 1992). The integrity of the semantic representations themselves can be better assessed via an implicit processing task, such as priming, which does not require the use of such conscious strategic processing (Chertkow et al., 1989; Glosser & Friedman, 1991; Glosser, Friedman, Grugan, Lee, & Grossman, 1998; Nakamura, Nakanishi, Hamanaka, Nakaaki, & Yoshida, 2000; Ober & Shenaut, 1988). Shallice (1988) states, “On a degraded store deficit, if an item cannot be identified, it should not be possible to prime it.” But, if the semantic representations are not degraded but rather are inaccessible, semantic priming will be intact. Thus, to conclude that a semantic deficit is the result of damage to the semantic representations within the network, one must evaluate both implicit and explicit semantic processing.
Some researchers propose that the semantic deficit in Alzheimer's disease reflects a degradation of the semantic network itself (Chertkow & Bub, 1990; Hodges & Patterson, 1995; Hodges et al., 1992a, Hodges et al., 1992b; Rogers et al., 2006), while others attribute the deficit to impaired retrieval from the network (Nebes, 1992; Nebes, Martin, & Horn, 1984). The most prevalent argument in support of semantic network damage is the consistency of impairment across a variety of semantic tasks (Chertkow & Bub, 1990; Hodges & Patterson, 1995; Hodges et al., 1992a, Hodges et al., 1992b). The similarity of deficient performance on the same semantic items in multiple tasks is attributed to the degraded representations of those specific objects. Hodges and Patterson (1995) furthered this argument by illustrating the impairment of visual semantic performance as well. The impaired abilities of AD patients on the PPT suggest that the overall task impairment extends beyond verbal semantic tasks. Hodges and Patterson (1995) argue that a retrieval deficit is unlikely to extend across differing modes of input and output. However, it could be argued that a retrieval deficit might cross modalities if it is caused by some impairment in a common mechanism, or mechanisms responsible for the conscious, effortful retrieval of semantic information from the network. For instance, Rich, Park, Dopkins, and Brandt (2002) discovered that task structure affects the semantic performance of AD patients. AD patients required guidance and explicitly stated categories in order to properly sort pictures. The authors concluded that the “free-sorting” task required a greater degree of strategic processing, which is limited in AD patients. Possibly, AD patients could not strategically limit their search of the semantic system to only retrieve specific information without category information as a guide. This conclusion has been supported by the results of other studies (Moreaud, David, Charnallet, & Pellat, 2001; Nebes, 1992), which suggest that processing limitations could impede semantic performance on explicit tasks independently of any actual network damage. Moreaud et al. (2001) found that a large proportion of seemingly semantic errors in AD resulted from the inability to retrieve the phonological word form. Lastly, Cronin-Golomb, Keane, Kokodis, Corkin, and Growdon (1992) reached a similar conclusion. In that study, AD patients were able to accurately rank the typicality of category exemplars, but were far slower than controls. The results suggested that unspecified factors were limiting the retrievabilty of intact semantic items.
Tests of implicit semantic priming have been used to discriminate between possible causes of impaired semantic ability in AD as well. Nebes et al. (1984), in finding semantic priming effects in AD patients, suggest that the impairment witnessed on explicit semantic tasks must be limited to the conscious retrieval of semantic information from an intact network (Chertkow & Bub, 1990; Chertkow et al., 1989) found intact priming effects in AD patients, as did Ober et al. (Ober & Shenaut, 1988; Ober, Shenaut, Jagust, & Stillman, 1991). Glosser et al. (1998) evaluated the semantic priming of different categorical semantic relationships and showed that AD patients retained priming for the higher-level, superordinate category labels (“daughter” priming “relative”) even though priming of category coordinates (“cousin” priming “nephew”) was absent. This result demonstrates a loss of priming for concepts with presumably weaker semantic connections and less overlap in attributes within the semantic network, and is suggestive of another issue to be considered in the examination of the semantic networks of AD patients: the nature of attribute storage. The “bottom-up” or “attribute-first” loss of semantic information was originally proposed by Warrington (1975) and has been supported in numerous studies since (Glosser et al., 1998; Martin & Fedio, 1983). The results from Glosser et al. (1998) appear to be an instance of such bottom-up loss, where only the highest-level superordinate connections are still intact. However, the study by Glosser et al. did not indicate the level of explicitly observable semantic impairment of their AD patients. Additionally, Glosser et al. (1998) did not test priming of specific attributes, the theoretical weakest link of the semantic network. Perhaps priming of attributes in demented patients would be reduced compared to either category labels or category coordinates.
An important variable that has not been adequately controlled in past priming experiments of AD is the degree of impairment on explicit semantic tasks. Both types of underlying impairments – network degradation and access/retrieval impairment – are expected to affect explicit tasks, while only degradation should impact on implicit tasks. Thus, to determine the contribution of a retrieval deficit, performance on both explicit and implicit tasks must be evaluated.
As is the case with AD, patients with SD demonstrate a high degree of impairment on all explicit semantic tasks (Hodges et al., 1992a, Hodges et al., 1992b). Additionally, a consistency of specific item loss has been noted across different explicit tasks (Hodges et al., 1992a, Hodges et al., 1992b, Hodges et al., 1994; Tyler & Moss, 1998). Hodges et al., 1992a, Hodges et al., 1992b state that if one particular semantic item (e.g. mouse) is consistently impaired across all tasks, then that item's internal representation within the network is probably lost. Even before SD was clinically defined, Warrington (1975) concluded that her three anomic patients, later identified as having SD, suffered from a semantic network disruption that was responsible for their pervasive loss of semantic knowledge. She reached this conclusion based on the patients’ thorough loss of semantic knowledge as observed through explicit semantic questions. While numerous studies have attributed the semantic memory loss in SD to semantic network degradation (Hodges et al., 1992a, Hodges et al., 1992b, Hodges et al., 1994; Nakamura et al., 2000, Rogers et al., 2006; Tyler & Moss, 1998; Warrington, 1975), there have not been reports linking the semantic task impairment in SD to a retrieval deficit, similar to what is suggested for AD.
As noted earlier, if the representation of a particular item within the semantic network is degraded, then the activation that can be spread through its connections will be degraded as well. Thus, a priming effect should not be found. Some support for this conclusion comes from the study by Tyler and Moss (1998), who examined one SD patient and found that, even early in the disease's progression, priming on a lexical-decision task was absent for semantically related words with low degrees of lexical association. The absence of semantic priming was shown for superordinate relationships, as well as for priming across category members and attributes. Thus, consistent with the conclusion of a semantic network disruption in SD (Hodges et al., 1992a, Hodges et al., 1992b; Warrington, 1975), the impairment on explicit semantic memory tests seen on the Hodges et al., 1992a, Hodges et al., 1992b battery was accompanied by a significant deficit in implicit semantic processing as well. While the trend of these results supports the notion of a degradation of the semantic network in SD, there is a reason to treat this conclusion with caution, as only one patient was evaluated. Therefore, while the Tyler and Moss (1998) study points to the nature of the semantic impairment in SD, further studies are required.
Perhaps the best way to gain insight into the semantic deficits of AD and SD patients is to examine them in parallel. In clinical testing, AD patients typically present with impaired episodic memory and later develop substantial impairments on explicit semantic memory tasks (Hodges et al., 1992a, Hodges et al., 1992b). In contrast, SD patients initially present with the impaired explicit semantic task performance, while having intact episodic memory (Perry & Hodges, 2000). Considering the substantial variation in temporal atrophy across the patient populations it would seem unlikely that the groups share the same mechanism of semantic memory loss. As stated previously, SD patients’ temporal damage closely coincides with the locus of the semantic network, while the medial temporal atrophy of AD patients is typically tied to their episodic memory loss. This suggests that the deficient impaired performance in SD might be the result of a degraded network, while the problem in AD may be based on retrieval difficulties in addition to a partially degraded semantic system. This would be consistent with prior priming studies, which found greatly reduced priming in SD (Tyler & Moss, 1998) and relatively intact semantic priming in AD (Ober & Shenaut, 1988; Ober et al., 1991).
Nakamura et al. (2000) examined this hypothesis and did find priming in AD but not in SD. Unfortunately, this study had a very small number of subjects, did not examine priming for various semantic relationships, and the AD and SD patients were not matched for level of basic impairment on explicit semantic tasks. Even though the findings of Nakamura et al. (2000) support the current hypothesis, the significantly worse explicit semantic performance in the SD group confounds the results. That study leaves open the possibility that the impairment observed in the two groups was caused by the same underlying deficit, but the SD patients were more advanced in their semantic network degradation, as was concluded by Rogers et al. (2006). Given the individual problems with this and other studies of priming, further investigation is required to further elucidate semantic priming in AD and SD patients.
As seen with the Nakamura et al. (2000) study, comparisons between AD and SD patients are difficult to interpret because SD patients appear to have a far more severe impairment of the semantic memory network than patients with AD. Perry and Hodges (2000) demonstrated a significant difference between the two patient populations, matched for MMSE scores and length of disease duration, on tasks of category fluency, picture naming and PPT. However, MMSE and length of disease duration are not the best variables on which to match the populations when considering the questions at hand. In posing questions about the comparative underlying impairments responsible for the observed explicit semantic deficits, it is crucial that the two groups be matched on degree of impairment on explicit semantic tasks. Only by matching the groups on tests of explicit semantic processing can we determine whether the performance deficits on these tasks stem from the same underlying impairments in AD and SD.
While no comparative studies have yet matched these two groups in this way, finding subsets of the two patient populations with equivalent explicit semantic task deficits is critical. Using the Hodges et al., 1992a, Hodges et al., 1992b battery as a guideline, an overlap can be found in the level of explicit semantic memory performance seen in the AD and SD patients documented in different studies (Bozeat, Lambon Ralph, Patterson, Garrard, & Hodges, 2000; Hodges & Patterson, 1995; Hodges et al., 1992a, Hodges et al., 1992b). The goal of this study is to examine AD and SD patients who have matching impairments on explicit semantic tasks, in order to explore the possibility of differences in the mechanisms of their semantic memory loss.
In this study, semantic priming is used to examine the implicit semantic processing of AD and SD patients who are matched for explicit semantic task performance. The priming effects for different levels within the semantic network (superordinate, coordinate, and attributes) are examined in order to support or refute the hypothesis of partial degradation of the semantic network in AD and the complete loss of the semantic network in SD. Finally, the results of the study are analyzed to determine which semantic model best explains the semantic priming results.
Section snippets
Participants
Each of the two patient groups consisted of 11 individuals, one group diagnosed with probable Alzheimer's disease (AD) and the other with semantic dementia (SD). The AD patient group was recruited from the Georgetown University Medical Center's (GUMC) Memory Disorders Clinic where they were diagnosed with probable Alzheimer's according to the NINCDS-ADRDA criteria (McKhann et al., 1984). SD patients were diagnosed in the University of Pennsylvania Department of Neurology using the established
Results
The measure of accuracy was percent correct oral responses (“yes” or no”) to the target word. Following the standard convention (Ober, 2002), the measure of the priming effect was the mean reaction time for the unprimed target words minus the mean reaction time for the primed target words.1
Discussion
The healthy control participants demonstrated priming effects in all four experimental conditions, affirming the implicit connections between words at both lexical and semantic levels. These findings are consistent with previously published results (Glosser & Friedman, 1991; Glosser et al., 1998) and further validate the need to examine semantic priming independently of lexical associative priming. Moreover, the control participants confirm that semantic priming effects can be obtained using
Acknowledgments
We would like to thank Paul Aisen, Ph.D., Murray Grossman, Ph.D., and every member of their labs, for assisting with patient testing, as well as Larry Muenz, Ph.D., for his statistical knowledge. This research was made possible by an NIDCD Fellowship 1F31DC05885 and an NIH Grant AG17586, awarded to Dr. Grossman.
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