Differing neuropsychological and neuroanatomical correlates of abnormal reading in early-stage semantic dementia and dementia of the Alzheimer type
Introduction
Semantic dementia (the temporal variant of frontotemporal dementia; FTD) and dementia of the Alzheimer type (DAT) are clinically overlapping diseases sharing features such as insidious onset and gradual deterioration of comprehension and word finding ability, among other impairments. Despite clinical similarities, SD is pathologically distinct from DAT (Hodges, Garrard, & Patterson, 1998; Neary et al., 1998; see also Kertesz, Hudson, Mackenzie, & Munoz, 1994). Because treatments are increasingly likely to target specific neurodegenerative mechanisms, it is important to determine whether neuropsychological markers can differentiate SD from DAT early in the course of dementia, when intervention may be most effective.
Semantic dementia (SD) is the variant of FTD involving initially focal degeneration of one or both temporal lobes (Hodges, Patterson, Oxbury, & Funnell, 1992; Neary et al., 1998; Snowden, Goulding, & Neary, 1989; see also Warrington, 1975). SD is similar to the fluent variety of primary progressive aphasia (Mesulam, 1982) with additional impairment of non-verbal semantic knowledge (Hodges et al., 1992, Mesulam, 2001). Distinguishing early forms of SD from DAT neuropsychologically presents a challenge because DAT can also involve deficits on semantic processing tasks (Huff, Corkin, & Growden, 1986; Kertesz, Appell, & Fisman, 1986; Martin & Fedio, 1983) even relatively early in the disease (Chertkow & Bub, 1990; Hodges & Patterson, 1995). Similarly, although episodic memory impairment is a hallmark of early DAT, simple tests of verbal episodic memory such as logical paragraph recall cannot distinguish between the two dementias because both types of patients perform poorly, SD patients due primarily to impaired language and DAT patients due primarily to impaired memory (Hodges et al., 1999). Importantly, though, semantic impairment is variable in early DAT (Hodges & Patterson, 1995) and visuospatial and attentional-executive functioning are preserved in early SD (Hodges et al., 1992, Neary et al., 1998), suggesting that SD and DAT can be distinguished early in the dementia process. For example, Hodges et al. (1999) found that a relatively early SD group (mean mini-mental state exam (MMSE) = 20) was distinguished from an early DAT group (mean MMSE = 23) by significantly better performance on a test of picture reproduction.
A related cognitive domain, which may be preserved in SD compared to DAT is picture recognition memory. Recent evidence suggests that recognition memory for pictures is preserved in the majority of SD patients (Graham, Becker, & Hodges, 1997; Graham, Simons, Pratt, Patterson, & Hodges, 2000a; Simons, Graham, & Hodges, 2002a; Simons et al., 2002b). This stands in contrast to the marked picture naming deficits in SD relative to DAT. An outstanding issue in this area involves the timing of the emergence of the picture naming/recognition memory double dissociation between SD and DAT. If naming is impaired and picture recognition memory is preserved in early SD, and the reverse dissociation is evident in early DAT, then tests of picture naming/recognition memory might provide an important and relatively simple neuropsychological tool aiding differential diagnosis. A picture naming/recognition memory experiment was conducted to explore this issue.
The identification of an early SD group provided the opportunity to inform models of reading by exploring the influence of isolated lexical semantic impairment on reading words with regular spelling-to-sound correspondences. Individuals with SD show marked impairment in reading irregular words (e.g., glove) (Graham, Hodges, & Patterson, 1994; Graham, Patterson, & Hodges, 2000b; Patterson & Hodges, 1992), but the available data indicate little or no impairment in reading regular words (Graham et al., 1994, Graham et al., 2000b; Patterson & Hodges, 1992). Little research in this area has examined latencies of SD reading (naming). Latency may provide a sensitive index of subtle reading abnormalities that may exist in reading regular words in early SD and DAT. In particular, the apparently graded degrees of lexical semantic memory retention between healthy older individuals (retained), individuals with DAT (less retained), and individuals with SD (least retained), raises interesting questions about potential for differing influences of lexical and sublexical variables in reading between groups. Such effects have the potential to inform models of reading.
Finally, to identify neuroanatomical correlates of potentially differing reading patterns between groups, structural MRI was conducted and automated brain volume analyses and a sensitive cortical thickness technique were used to compare group differences in brain volume and local mean cortical thickness in vivo (Dale, Fischl, & Sereno, 1999; Fischl & Dale, 2000; Fischl, Liu, & Dale, 2001; Fischl, Sereno, & Dale, 1999a; Fischl, Sereno, Tootell, & Dale, 1999b).
Section snippets
Subjects
Three groups consisting of a total of 30 individuals participated in the study: six with early SD (four males and two females), 10 with early DAT (seven males and three females) and 14 non-demented (eight males and six females). Subjects were recruited from the Washington University's Alzheimer's Disease Research Center (ADRC) and screened for depression, severe hypertension and other medical factors described previously (Berg et al., 1998). Potential SD subjects were identified either
Multimodal semantic assessment
A battery of tests was used to assess semantic knowledge across input and output modalities and verbal and pictorial domains (similar to Chertkow & Bub, 1990; Hodges et al., 1992). A core component of the battery was a set of 64 line drawings from the Snodgrass and Vanderwart (1980) corpus, normed for frequency and prototypicality across six semantic categories: animals, birds, fruit, household items, tools, and vehicles (Bozeat, Lambon Ralph, Patterson, Garrard, & Hodges, 2000). The following
Results
Mean demographic information and scores representing estimated global dementia severity for SD, DAT and control groups are listed in Table 1. ANOVA revealed no significant age differences between the three groups (F(2,27) = 2.13, P = 0.14). The SD group was significantly younger than the DAT group (t(14) = 2.49, P < 0.05). DAT and control groups did not differ in age (P = 0.46). The three groups were matched for level of education. Patient groups were matched for general global severity of dementia as
Discussion
Our results demonstrate that SD can be differentiated neuropsychologically from DAT at very mild-to-mild stages of dementia severity. In particular, the large effect sizes in the direction of better picture recognition memory than picture naming observed consistently across SD individuals demonstrates that tests of picture naming/recognition memory constitutes one simple, powerful probe for early differentiation of SD from DAT. The identification of an early SD group provided the opportunity to
Conclusions
In conclusion, SD can be differentiated from DAT at mild dementia stages. While clinical overlap exists, the characteristic profile of relatively isolated multi-modal, multi-domain breakdown of semantic knowledge appears early in the course of SD, distinguishing it from DAT. The pattern of SD and DAT scores on picture naming and picture recognition memory tests suggest that these measures represent a simple, powerful probe for early differentiation of SD from DAT. In terms of reading, the
Acknowledgements
We thank the control subjects and the patients and their caregivers for volunteering their time for this research project. We also thank clinicians at ADRC for helping to identify patients, Drs. Andrew Kertesz, Martha Storandt, Jon Simons, Max Coltheart, and two anonymous reviewers for helpful discussion and Dr. Matt Lambon Ralph for allowing us to use several tests. Finally, we thank Laura Williams, Daniella Van Hooren, and Jeff Templeton for help with data collection. The research was
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