The human perirhinal cortex and semantic memory

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1 EJN 3710 European Journal of Neuroscience, pp. 1 7, 2004 ª Federation of European Neuroscience Societies The human perirhinal cortex and semantic memory R. R. Davies, 1 Kim S. Graham, 2 John H. Xuereb, 3 Guy B. Williams 4 and John R. Hodges 1,2 1 Department of Clinical Neurosciences,University of Cambridge, Cambridge, UK 2 MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 5EF, UK 3 Department of Pathology, University of Cambridge, Cambridge, UK 4 Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, UK Keywords: Alzheimer s disease, entorhinal cortex, semantic dementia, volumetric MRI Abstract Studies in macaque monkeys indicate that the perirhinal cortex in the temporal lobe participates in object memory. This function may be analogous to aspects of human semantic memory (knowledge of objects, concepts, faces and words). To date, the status of perirhinal cortex has not specifically been investigated in patients with semantic deficits as seen in semantic dementia, the temporal lobe variant of frontotemporal dementia. High-resolution three-dimensional magnetic resonance imaging was performed in subjects with semantic dementia and Alzheimer s disease (characterized in its early stages by selective episodic memory impairment) and in healthy age-matched controls. Hippocampal, perirhinal, temporopolar and entorhinal cortex volumes were measured by outlining areas on successive scan slices according to recognized landmarks. The entorhinal and hippocampal regions were further subdivided into anterior and posterior parts. In keeping with the hypothesized contribution of the perirhinal cortex to semantic memory function, we found greater involvement of this region, together with the temporopolar and anterior entorhinal cortices, in semantic dementia than in either Alzheimer s disease patients or control subjects. Performance on a range of semantic tests also correlated with perirhinal volume. Bilateral reduction in hippocampal volume compared with controls was seen in Alzheimer s disease. In conclusion, atrophy of the human perirhinal cortex, and of directly connected areas, was associated with semantic memory impairment but not episodic memory impairment, as predicted from the primate work. Introduction The dichotomy of episodic and semantic memory forms the most widely accepted model of human declarative memory (Tulving, 2001). It is well established that lesions of the hippocampus (HPC) and closely related structures produce lasting deficits in the acquisition of episodic memory (memories specific in time and place) (Squire & Zola, 1996). By contrast, the neural basis of semantic memory (knowledge of objects, people and word-meanings) is uncertain. Early Alzheimer s disease (AD) is typified by episodic memory impairment linked to pathology in the entorhinal cortex (ERC) and the HPC itself (Braak & Braak, 1991; Van Hoesen et al., 1991). Neuroimaging supports this association, showing atrophy of ERC and or HPC in patients with incipient AD (Killiany et al., 2002). Breakdown of semantic memory is a well-recognized symptom in AD; in the early stages, however, patients often perform normally on standard semantic tests (Hodges & Patterson, 1995). Semantic dementia (SD), temporal lobe variant frontotemporal dementia, provides a model of semantic memory impairment (Hodges et al., 1992; Hodges & Miller, 2001). Aspects of episodic memory are retained in SD with normal performance on recognition-based memory tests involving visual material and relative preservation of recent autobiographical memory (Graham & Hodges, 1997; Hodges & Graham, 2001; Simons et al., 2002). The early syndromes of SD and Correspondence: Professor J. R. Hodges, 2 MRC Cognition and Brain Sciences Unit, as above. john.hodges@mrc-cbu.cam.ac.uk AD are therefore complementary: (i) episodic memory impairment with relatively preserved semantic memory in AD and (ii) semantic memory impairment with relatively preserved episodic memory in SD. The perirhinal cortex (PRC), lying in the anteromedial temporal lobe, corresponds to Brodmann areas (BA) 35 and 36. Medially, it borders the ERC (BA 28) and anterolaterally, the temporopolar cortex (TPC) (Amaral & Insausti, 1990; Insausti et al., 1998). Although traditionally referred to as BA 38, the ventromedial aspect of the temporal pole has come to be regarded as an extension of BA 36 (Suzuki & Amaral, 1994a,b; Saleem & Tanaka, 1996), and hence part of the total perirhinal cortex (Insausti et al., 1998). Lesion studies in non-human primates indicate that PRC plays a critical role in processes comparable with the non-verbal aspects of human semantic memory (Murray & Bussey, 1999). Little is known, however, about the PRC in human diseases affecting semantic memory. Magnetic resonance imaging (MRI) studies have shown left temporal lobe atrophy in SD patients (Chan et al., 2001b; Galton et al., 2001): dividing the temporal lobe by sulci, atrophy is most pronounced in the fusiform and inferior temporal gyri. The status of the hippocampus has also been controversial: early reports suggested sparing of the HPC but further studies have shown left HPC atrophy equivalent to that in AD, although the distribution is often different, with more anterior HPC involvement in SD (Chan et al., 2001a). Here, volumetric MRI was employed to measure medial temporal lobe regions defined by reference to cytoarchitectonics. The patterns of volume loss were analysed in three subject groups with differing semantic and episodic memory profiles: SD, AD and controls. Received 27 April 2004, revised 12 August 2004, accepted 18 August 2004 doi: /j x E J N B Dispatch: Journal: EJN CE: Blackwell Journal Name Manuscript No. Author Received: No. of pages: 7 PE: Vijaya

2 2 R. R. Davies et al. Materials and methods Twenty-four consenting subjects participated in the study (eight SD, eight AD and eight controls). The patients were attending the Memory Clinic at Addenbrooke s Hospital in Cambridge, forming part of a longitudinal study linked to the clinic. The SD cases met recent international consensus criteria (Neary et al., 1998) and the AD cases fulfilled criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer s Disease and Related Disorders Association. Both groups underwent a comprehensive neuropsychological evaluation, which included the Mini Mental State Examination (MMSE) (Folstein et al., 1975), the Addenbrooke s Cognitive Examination (ACE) (Mathuranath et al., 2000), tests of episodic and semantic memory, and visuospatial and perceptual ability, as previously described in detail (Hodges et al., 1999; Perry & Hodges, 2000). Everyday functioning was assessed using the Clinical Dementia Rating Scale (CDR) (Hughes et al., 1982). Controls were healthy subjects from the volunteer panel at the MRC Cognition and Brain Sciences Unit. Imaging was performed with 1.5T GE Signa equipment (GE Medical Systems, Milwaukee, WI, USA). The examination comprised a dual echo axial FSE, T1 axial SE and three-dimensional (3D) volume aquisition in the coronal plane using FSPGR TIW (inversion recovery preparation 650 ms, matrix , NEX 1). Volumetric analysis was performed on the 3D MR series in all subjects by the same observer (R.R.D.). The regions of interest were traced manually on coronal slices orientated perpendicular to the anterior commissure posterior commissure axis with ANALYSE software (Biomedical Imaging Resource, Mayo Clinic, Rochester, MN, USA). Three of the regions, the TPC, PRC and ERC, were defined according to the Insausti protocol (Insausti et al., 1998). The hippocampus was outlined according to the Mayo Clinic method (Watson et al., 1997). ERC and HPC volumes were further subdivided simply by measuring separately the slices anterior and posterior to the midpoint of those regions. The volumes were corrected for intracranial volume estimated from cross-sectional area at the level of the anterior commissure. Repeated measurements were taken in a sample of cases (22 measurements) to ensure reliability. SSPS 10 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. The primary approach consisted of a multifactorial analysis of variance (anova) with diagnosis as the fixed factor and the regional volumes as dependent variables. Games Howell post-hoc testing was used (suitable for unequal variances). To explore further the rostral caudal pattern of atrophy within the HPC and ERC we performed an analysis based on the mean difference between logarithms to the base 10 of the anterior and posterior subregions. This is a classical mathematical tool for obtaining a ratio of two values (log A log B ¼ log {A B}). This step was followed by one-way anovas and post-hoc Games Howell tests. Pearson correlation coefficients (with one-tailed significance tests) were calculated for regional volumes in SD vs. semantic test scores. Repeatability was assessed for TPC, PRC, ERC and HPC using Pearson correlation coefficients and paired Student s t-tests. Demographic and neuropsychological data were also compared using t-tests (unpaired). Results The three groups were well matched for age (mean age SD 60.9 ± 8.1 years, ad 64.9 ± 4.6 years, controls 63.8 ± 6.0 years; one-way anova, F ¼ 0.84, P ¼ 0.45). There were equal numbers of men and women in the SD and control groups but six females and 1two males in the AD group. As shown in Table 1, disease severity in Table 1. Mean neuropsychological testing scores in the patient groups Test (maximum score) SD AD t-test MMSE (30) 25.9 ± ± * ACE (100) 63.0 ± ± CDR 0.5 ± ± Rey copy (36) 32.9 ± ± Rey recall (36) 16.7 ± ± 3.0 < 0.01* Animal fluency 9 ± ± Naming (64) 37.3 ± ± PPT (52) 43.0 ± ± SD, semantic dementia; AD, Alzheimer s disease; MMSE, Mini Mental State Examination (Folstein et al., 1975); ACE, Addenbrooke s Cognitive Examination (Mathuranath et al., 2000); CDR, Clinical Dementia Rating (Hughes et al., 1982); PPT, Pyramids and Palm Trees (Howard & Patterson, 1992). Rey copy: see Osterrieth, 1944; Rey recall: see Osterrieth, *Significantly higher score in SD, significantly higher score in AD. the SD and AD groups was equivalent as measured by the ACE (Mathuranath et al., 2000) and CDR (Hughes et al., 1982) although on the MMSE (Folstein et al., 1975) the difference between the groups just reached significance, reflecting the greater degree of disorientation among the AD patients. Results from further neuropsychological tests are also shown in Table 1, demonstrating the double dissociation between episodic and semantic memory in the two groups. The AD group were significantly more impaired on tests of visual memory (recall of the Rey complex figure; Osterrieth, 1944) whereas the SD group performance was significantly worse on tests of production (animal category fluency, and picture naming) and comprehension [the Pyramids and Palm trees (PPT) test; Howard & Patterson, 1992]. With regard to the structural data, correlation coefficients and comparison of means between the original and second data sets demonstrated excellent repeatability: TPC (r ¼ 0.98, t-test P ¼ 0.57, n ¼ 6); PRC (r ¼ 1.00, t-test P ¼ 0.16, n ¼ 5); ERC (r ¼ 0.96, t-test P ¼ 0.78, n ¼ 6); HPC (r ¼ 0.98, t-test P ¼ 0.49, n ¼ 5). To compare volumes of the measured regions across the groups, a multifactorial anova was performed. As shown in Table 2, there were significant group effects for all regions assessed but post-hoc pair-wise comparisons revealed very different profiles in the two patient groups. The TPC, PRC and anterior ERC were found to be significantly smaller bilaterally in SD than in AD or normal controls (NC), whereas these regions were not significantly affected in AD (i.e. NC ¼ AD > SD). The left, but not the right, posterior ERC was also more atrophic in SD than in controls. Although the ERC was reduced in volume bilaterally in AD in comparison with controls, the difference did not reach significance in this small series. Anterior and posterior HPC regions were significantly atrophic in both the AD and the SD groups compared with controls (NC > AD ¼ SD), with the exception of the left posterior HPC in SD. In addition, there was one significant intergroup difference: the left anterior HPC was significantly smaller in SD than in AD (NC > AD > SD). The relative severity of atrophy in SD and AD across regions from lateral to medial (PRC fi ERC fi HPC) is illustrated in Fig. 1 as volume proportional to controls. Profound atrophy of left and right total perirhinal volume (i.e. TPC + PRC volume) in SD is clearly shown. Similar profiles are seen on the left and right. On the right and on the left, atrophy in SD involved the more lateral regions to a greater extent than the medial. The converse was true in AD. It was noted that the mean anterior ERC volumes were smaller than the corresponding posterior ERC volumes in SD but that the reverse was true in AD. The main anova, however, did not establish a

3 Human perirhinal cortex and semantic memory 3 Table 2. Regional volumes corrected for intracranial volume with statistical analyses Medial temporal lobe region Volume (mm 3 ) SD AD Controls anova P-value Post-hoc tests(games Howell) SD vs AD SD vs. controls AD vs. controls TPC Left 902 ± ± ± ** 0.002** Right 1253 ± ± ± * 0.011* PRC Left 853 ± ± ± ** 0.001** Right 1152 ± ± ± * 0.007* ERC (anterior) Left 252 ± ± ± ** 0.001** Right 368 ± ± ± * 0.008* ERC (posterior) Left 299 ± ± ± ** Right 404 ± ± ± HPC (anterior) Left 1317 ± ± ± * 0.000** 0.007* Right 1744 ± ± ± ** 0.000** HPC (posterior) Left 964 ± ± ± * Right 977 ± ± ± * 0.001** Volumes are presented as mean ± standard deviation. SD, semantic dementia; AD, Alzheimer s disease; TPC, temporopolar cortex; PRC, perirhinal cortex; ERC, entorhinal cortex; HPC, hippocampus; *Statistically significant at 0.05 level; **statistically significant at level. Fig. 1. Temporal lobe regional atrophy in semantic dementia (black) and Alzheimer s disease (grey): values shown are means with standard deviations of regional volumes as a percentage of the corresponding mean control volume. TPRC, temporopolar perirhinal cortex; ERC, entorhinal cortex; HPC, hippocampus; A, anterior; P, posterior. Table 3. Post-hoc significance data after one-way anovas of differences in logarithms to the base 10 of anterior and posterior of medial temporal lobe regions Medial temporal lobe region Mean difference in logarithm to the base 10 between anterior and posterior subregions anova SD AD Controls P-value SD vs. AD Post-hoc tests (Games Howell) SD vs. controls AD vs. controls ERC Left ) * 0.001** Right ) * 0.047* HPC Left * 0.018* Right *P < 0.05; **P < statistically significant difference between the two disease groups. By comparing logarithms of anterior and posterior ERC and HPC subvolumes we could establish the degree of atrophy occurring anteriorly and posteriorly in SD and AD with the obscuring effect of 2 absolute volumes removed (Table 3). The subsequent one-way anovas and pair-wise post-hoc tests confirmed greater anterior hippocampal atrophy in SD (on the left but not on the right) together with parallel involvement of the anterior ERC (bilaterally). This finding contrasts with that in AD in which the volumes were in proportion to the control anterior posterior volumes, suggesting more uniform involvement of ERC and HPC. Correlational analyses of combined left and right total PRC volume against semantic test scores in the eight SD cases formed a further exploration of the data. Significant positive correlations were found with performance on animal category fluency (r ¼ 0.73, t-test P ¼ 0.02) and naming (r ¼ 0.64, t-test P ¼ 0.04). The remaining semantic task, PPT, approached statistical significance (r ¼ 0.53, t-test

4 4 R. R. Davies et al. P ¼ 0.09). There was no evidence of a significant association between any of the semantic scores and either HPC or ERC volume. The converse correlational analysis between regional volumes and Rey recall scores in the AD group was not possible as most patients performed close to baseline level (see Table 1). Discussion This study represents the first documentation of volume loss in the human PRC in a syndrome of semantic memory impairment. The structural comparisons showed significant atrophy of PRC in SD but not in AD (Fig. 2) and the correlational analyses confirmed that the degree of PRC volume loss positively associated with performance on tests of semantic memory. It was also established that brain areas closely related to the PRC (TPC and anterior ERC) are severely atrophic in SD, whereas the nearby posterior ERC is less consistently affected. The definition of the TPC used corresponds to the ventromedial temporal pole, often regarded as an extension of BA 36, and hence functionally part of a wider PRC region (Saleem & Tanaka, 1996; Insausti et al., 1998). The anterior part of the ERC receives its major input from the PRC whereas it is the posterior parahippocampal cortex that projects to posterior ERC. Thus, TPC and anterior, but not posterior, ERC are intimately related to PRC. By contrast to the findings in SD, measurements in our AD cohort showed bilateral hippocampal atrophy, as predicted. They also suggested atrophy of anterior and posterior ERC in comparison with controls. It seems likely that this region would have been significantly atrophic if a larger series of AD cases been assessed. The focus of this study was the medial temporal lobe: lateral temporal areas were not measured. There is little doubt that these lateral regions tend to be more atrophic in SD than in AD or controls and this, more widespread, atrophy is likely to contribute to the loss of function. It should be recalled, however, that studies employing automated techniques to assess whole brain volume in SD consistently show greatest atrophy in anterior, not lateral, temporal lobe regions (Mummery et al., 2000). A volumetric study also found that superolateral temporal regions were not significantly atrophic in SD compared with controls (Galton et al., 2001). Measuring areas lateral to the PRC would have required, as in previous studies, delineation along gyral lines (Chan et al., 2001b; Galton et al., 2001): there is no equivalent to the Insausti protocol to provide landmarks for the cytoarchitectonic boundaries occurring outside the collateral sulcus (Insausti et al., 1998). The studies of Chan and Galton indicate that temporal lobe atrophy in SD has an anteromedial emphasis. The key finding of the present study is that, using the method most closely approximating identification of borders in individual cases through microscopic work performed in parallel, atrophy in SD maps onto a theoretically cohesive group of anteromedial regions. Comparison with AD indicates that the extent of the medial atrophy in SD corresponds to the location of the PRC as traditionally defined, the anterior extension of PRC over the temporal pole and its main projection area, the anterior ERC. The early pathological involvement of the ERC and HPC by neurofibrillary pathology in AD is well established (Braak & Braak, 1991); such neuropathological findings have been replicated using a range of modern imaging techniques (Killiany et al., 2002). This pattern of medial temporal lobe involvement is reflected in the profound impairment in episodic memory consistently found from the very earliest clinical stages of AD (Perry & Hodges, 2000). The pathological basis of SD is varied but all cases reported to date have represented one of the manifestations of frontotemporal dementia. Fig. 2. Coronal MR images of (A) semantic dementia and (B) Alzheimer s disease brains with regions marked: left entorhinal cortex (red) and left perirhinal cortex (blue). Some cases have had classic Pick s pathology with silver- and taupositive intraneuronal inclusions, others have shown ubiquitin-positive inclusions and the remainder have had severe focal neuronal loss lacking a specific immunohistochemical signature (Garrard & Hodges, 2000; Rossor et al., 2000; Hodges & Miller, 2001). In contrast to AD, there has been virtually no detailed mapping of the distribution of pathology within the temporal lobe at post-mortem. A single case with semantic deficits that underwent detailed neuropathological assessment, in fact, had predominantly posterior temporal lobe abnormalities (Harasty et al., 1996). COLOUR FIG.

5 Human perirhinal cortex and semantic memory 5 Our findings suggest that the main locus of pathology in SD centres upon the TPC PRC anterior ERC complex. It is interesting to note that although the cognitive profiles of the two disorders, AD and SD, are distinct, the regions affected within the temporal lobe lie close together and may form an overarching medial temporal lobe long-term memory system. Within this system, individual components may have specialized roles. The PRC may be a central region for the storage of long-term knowledge representations, whereas the acquisition of new knowledge might depend on the interaction between the HPC and PRC (Vargha-Khadem et al., 1997; Hodges & Graham, 2001). The hippocampal atrophy in SD, which on the left exceeded that found in AD, confirms the findings of two recent volumetric studies (Chan et al., 2001b; Galton et al., 2001). This result, and the finding of atrophy to anterior ERC in SD compared with AD, raises a number of issues concerning the neural basis of the preserved episodic memory in SD. The asymmetric nature of the pathology in SD, along both right left and anterior posterior axes, may be a critical factor. Presumably, the HPC and ERC regions that are still preserved are sufficient to support the episodic memory capacity described in SD. Lack of damage to the limbic circuit outside the medial temporal lobe may also be relevant. Although hypometabolism in the limbic circuit (specifically, the retrosplenial cortex) has been demonstrated in very early AD (Nestor et al., 2003), such findings have not been reported in SD. An exploration of the contrasting memory impairments in SD and AD is crucial to the study. The pathological processes resulting in volume loss, however, differ between the two diseases: equivalence of volume loss across the groups need not imply pathological or functional equivalence. Anterior posterior comparisons of ERC and HPC volume in individual SD and AD cases permitted an examination of the effects of a given disease process at different brain locations. Combining the SD cases and then the AD cases corroborated the distribution of semantic regions within the medial temporal lobe suggested by the main analysis. Selective perirhinal lesions in macaque monkeys cause severe deficits on classic delayed-matching-to-sample tasks (Meunier et al., 1993; Baxter & Murray, 2001). Although initially interpreted within a framework of episodic-type memory, more recent work suggests that the deficits may also be attributed to problems with perceptual processing. Thus, lesions to the fornix or hippocampus, structures implicated in episodic memory, produce only slight impairments in performance on such object-recognition tasks (Shaw & Aggleton, 1993; Murray & Mishkin, 1998). Crucially, monkeys with perirhinal lesions exhibit, under certain conditions, deficits on matching when there is minimal memory demand, e.g. in simultaneous and zerosecond delay conditions, and have particular difficulties on tasks that require discrimination between items with high degrees of feature overlap (Meunier et al., 1993; Buckley et al., 2001; Bussey et al., 2002). The implication is that the PRC represents complex conjunctions of object features in a fashion parallel to current concepts of human semantic memory (Murray & Bussey, 1999) and in keeping with the description of deficits experienced by SD patients as the inability to generalize to and from specific exemplars. It may be that cytoarchitectonic similarities between human and macaque PRC are not reflected in similarity of function. Whereas humans with SD lose long-established factual knowledge, macaques with PRC lesions display impaired acquisition of new object-based knowledge. The linguistic aspect of human semantics is clearly distinct from PRC function in monkeys: extrapolation from the nonhuman literature necessarily requires a change in emphasis away from the verbal aspects of any cognitive domain. A recent functional study emphasized the links between object names and physical attributes (Wise et al., 2000): the region of the PRC showed increased activation with increased noun imageability. Returning to non-verbal semantics, the absence of deficits on the straightforward object-recognition tasks in SD patients contrasts with poor performance in PRC-lesion monkeys (Hodges & Graham, 2001). Notably, however, recognition memory for items such as faces that require configural processing is affected in SD (Simons et al., 2001). The challenge of finding criteria for PRC reflecting a cytoarchitectonic, or indeed functional, unit was central to the study. Insausti et al. (1998) define PRC for volumetric measurement as the grey matter in the lateral bank of the collateral sulcus from the midpoint of the medial bank of the collateral sulcus to its lateral edge with specific allowances for extremes in sulcal depth. The Insausti approach is more physiological than subdividing along gyral lines. However, marked baseline variation in collateral sulcus conformation is certainly a factor in the data (Pruessner et al., 2002). For instance, a shallow collateral sulcus found in the shrivelled SD temporal lobe would arbitrarily extend the defined PRC laterally onto the surface of the fusiform gyrus. That the data support the hypothesis despite this confounding influence may be regarded as reassuring. Equally, the severe temporal lobe distortion in SD and the modest sizes of the regions to be measured would be considerable obstacles to acquiring volume data by automated methods. A more basic concern is that the borders of the PRC are not irrefutably defined. The medial border of the PRC is accepted as being its junction with the ERC pyramidalis externa cells. The lateral border is less distinctive although associated with the emergence of sixlayered isocortex. Undulations in the cortical surface frequently distort the basic laminar pattern so that none of the borders is consistently clear even on microscopy and much of the boundary may be oblique in any given case. Although the regional delineations are based on a systematic study of 49 post-mortem brain specimens (Insausti et al., 31998), extrapolation from MR images should be undertaken with caution even greater than that required in histological studies. In conclusion, there is strong evidence implicating macaque PRC in mnemonic and perceptual processing of objects. From this study in neurodegenerative disease, we can postulate a parallel role for human PRC. Although static lesion patients whose lesions are thought to encompass PRC are known to perform better on conventional semantic tasks than SD patients (Levy et al., 2004), recent studies in both non-progressive and progressive (SD) patients with involvement of perirhinal cortex find deficits in the two patient groups when stimuli that necessitate configural processing are utilized (Lee et al., 2004). These studies are highly consistent with recent investigations in non-human primates (Buckley et al., 2001; Bussey et al., 2002). Fundamental questions that remain include: (i) are current structural definitions of PRC functionally the most relevant? and (ii) are PRC functions optimally described in terms of current models of memory and perception? It seems unlikely, for instance, that either episodic or semantic memory is conceptually coterminous with the function of the PRC although this study suggests that a semantic memory model of PRC function may be the more plausible of the two. Further conclusions will emerge from the convergence of structural and functional brain imaging with neuropathological studies. Acknowledgements Wellcome Trust Training Fellowship (R.R.D.); Medical Research Council (K.G. and J.R.H.). We wish to thank Professor Hilkka Soininen, Dr Mikko Laakso and Dr Corina Penannen of the Department of Neurolgy, Kuopio University, Finland, for valuable guidance on the volumetric method. We also thank Dr Nagui Antoun, Consultant Neuroradiologist, Addenbrooke s Hospital, for much practical assistance and Dr Ian Nimmo-Smith and Dr Andy Lee of the MRC-CBU for statistical advice.

6 6 R. R. Davies et al. Abbreviations ACE, Addenbrooke s Cognitive Examination; AD, Alzheimer s disease; BA, Brodmann area; CDR, Clinical Dementia Rating Scale; ERC, entorhinal cortex; HPC, hippocampus; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; NC, normal control; PPT, Pyramids and Palm Trees; PRC, perirhinal cortex; SD, semantic dementia; TPC, temporopolar cortex. References Amaral, D.G. & Insausti, R. (1990) Hippocampal formation. In Paxinos, G. (Ed.), The Human Nervous System. Academic Press, Inc., San Diego, pp Baxter, M.G. & Murray, E.A. (2001) Impairments in visual discrimination learning and recognition memory produced by neurotoxic lesions of rhinal cortex in rhesus monkeys. Eur. J. Neurosci., 13, Braak, H. & Braak, E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. (Berlin), 82, Buckley, M.J., Booth, M.C., Rolls, E.T. & Gaffan, D. (2001) Selective perceptual impairments after perirhinal cortex ablation. J. Neurosci., 21, Bussey, T.J., Saksida, L.M. & Murray, E.A. (2002) Perirhinal cortex resolves feature ambiguity in complex visual discriminations. Eur. J. Neurosci., 15, Chan, D., Fox, N.C., Jenkins, R., Scahill, R.I., Crum, W.R. & Rossor, M.N. (2001a) Rates of global and regional cerebral atrophy in AD and frontotemporal dementia. Neurology, 57, Chan, D., Fox, N.C., Scahill, R.I., Crum, W.R., Whitwell, J.L., Leschziner, G., Rossor, A.M., Stevens, J.M., Cipolotti, L. & Rossor, M.N. (2001b) Patterns of temporal lobe atrophy in semantic dementia and Alzheimer s disease. Ann. Neurol., 49, Eacott, M.J., Gaffan, D. & Murray, E.A. (1994) Preserved recognition memory for small sets, and impaired stimulus identification for large sets, following 4 rhinal cortex ablations in monkeys. Eur. J. Neurosci., 6, Folstein, M.F., Folstein, S.E. & McHugh, P.R. (1975) Mini mental state. A practical method for grading the cognitive state of patients for the clinician. J. Psychol. Res., 12, Galton, C.J., Patterson, K., Graham, K., Lambon-Ralph, M.A., Williams, G., Antoun, N., Sahakian, B.J. & Hodges, J.R. (2001) Differing patterns of temporal atrophy in Alzheimer s disease and semantic dementia. Neurology, 57, Garrard, P. & Hodges, J.R. (2000) Semantic dementia: clinical, radiological and pathological perspectives. J. Neurol., 247, Graham, K.S. & Hodges, J.R. (1997) Differentiating the roles of the hippocampal complex and the neocortex in long-term memory storage: evidence from the study of semantic dementia and Alzheimer s disease. Neuropsychology, 11, Harasty, J.A., Halliday, G.M., Code, C. & Brooks, W.S. (1996) Quantification of cortical atrophy in a case of progressive fluent aphasia. Brain, 119, Hodges, J.R. & Graham, K.S. (2001) Episodic memory: insights from semantic dementia. Phil. Trans. R. Soc. Lond. B Biol. Sci., 356, Hodges, J.R. & Miller, B. (2001) The neuropsychology of frontal variant frontotemporal dementia and semantic dementia. Introduction to the special topic papers: Part II. Neurocase, 7, Hodges, J.R. & Patterson, K. (1995) Is semantic memory consistently impaired early in the course of Alzheimer s disease? Neuroanatomical and diagnostic implications. Neuropsychologia, 33, Hodges, J.R., Patterson, K., Oxbury, S. & Funnell, E. (1992) Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain, 115, Hodges, J.R., Patterson, K., Ward, R., Garrard, P., Bak, T., Perry, R. & Gregory, C. (1999) The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer s disease: a comparative neuropsychological study. Neuropsychology, 13, Howard, D. & Patterson, K. (1992) Pyramids and Palm Trees: a Test of Semantic Access from Pictures and Words. Thames Valley Test Company, Suffolk. Hughes, C.P., Berg, L., Danziger, W.L., Coben, L.A. & Martin, R.L. (1982) A new clinical scale for staging dementia. Br. J. Psychiatry, 140, Insausti, R., Juottonen, K., Soininen, H., Insausti, A.M., Partanen, K., Vainio, P., Laakso, M.P. & Pitkanen, A. (1998) MR volumetric analysis of the human entorhinal, perirhinal, and temporopolar cortices. Am. J. Neuroradiol., 19, Killiany, R.J., Hyman, B.T., Gomez-Isla, T., Moss, M.B., Kikinis, R., Jolesz, F., Tanzi, R., Jones, K. & Albert, M.S. (2002) MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology, 58, Lee, A.C.H., Bussey, T.J., Murray, E.A., Saksida, L.M., Epstein, R.A., Kapur, N., Hodges, J.R. & Graham, K.S. (2004) Perceptual deficits in amnesia: challenging the medial temporal lobe mnemonic view. Neuropsychologia, 5 in press. Levy, D.A., Bayley, P.J. & Squire, L.R. (2004) The anatomy of semantic knowledge: medial vs. lateral temporal lobe. Proc. Natl Acad. Sci. USA, 101, Mathuranath, P.S., Nestor, P.J., Berrios, G.E., Rakowicz, W. & Hodges, J.R. (2000) A brief cognitive test battery to differentiate Alzheimer s disease and frontotemporal dementia. Neurology, 55, Meunier, M., Bachevalier, J., Mishkin, M. & Murray, E.A. (1993) Effects on visual recognition of combined and separate ablations of the entorhinal and perirhinal cortex in rhesus monkeys. J. Neurosci., 13, Mummery, C.J., Patterson, K., Price, C.J., Ashburner, J., Frackowiak, R.S. & Hodges, J.R. (2000) A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory. Ann. Neurol., 47, Murray, E.A. & Bussey, T.J. (1999) Perceptual-mnemonic functions of the perirhinal cortex. Trends Cogn. Sci., 3, Murray, E.A. & Mishkin, M. (1998) Object recognition and location memory in monkeys with excitotoxic lesions of the amygdala and hippocampus. J. Neurosci., 18, Neary, D., Snowden, J.S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M., Kertesz, A., Robert, P.H., Albert, M., Boone, K., Miller, B.L., Cummings, J. & Benson, D.F. (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology, 51, Nestor, P.J., Fryer, T.D., Ikeda, M. & Hodges, J.R. (2003) Retrosplenial cortex (BA 29 30) hypometabolism in mild cognitive impairment (prodromal Alzheimer s disease). Eur. J. Neurosci., 18, Osterrieth, P.A. (1944) Le test de copie d une figure complexe: Contribution a l etude de la perception et de la memoire. Arch. Psychologie, 30, Perry, R.J. & Hodges, J.R. (2000) Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer s disease. Neurology, 54, Pruessner, J.C., Kohler, S., Crane, J., Pruessner, M., Lord, C., Byrne, A., Kabani, N., Collins, D.L. & Evans, A.C. (2002) Volumetry of temporopolar, perirhinal, entorhinal and parahippocampal cortex from high-resolution MR images: considering the variability of the collateral sulcus. Cereb. Cortex, 12, Rossor, M.N., Revesz, T., Lantos, P.L. & Warrington, E.K. (2000) Semantic dementia with ubiquitin-positive tau-negative inclusion bodies. Brain, 123, Saleem, K.S. & Tanaka, K. (1996) Divergent projections from the anterior inferotemporal area TE to the perirhinal and entorhinal cortices in the macaque monkey. J. Neurosci., 16, Shaw, C. & Aggleton, J.P. (1993) The effects of fornix and medial prefrontal lesions on delayed non-matching-to-sample by rats. Behav. Brain Res., 54, Simons, J.S., Graham, K.S., Galton, C.J., Patterson, K. & Hodges, J.R. (2001) Semantic knowledge and episodic memory for faces in semantic dementia. Neuropsychology, 15, Simons, J.S., Verfaellie, M., Galton, C.J., Miller, B.L., Hodges, J.R. & Graham, K.S. (2002) Recollection-based memory in frontotemporal dementia: implications for theories of long-term memory. Brain, 125, Squire, L.R. & Zola, S.M. (1996) Structure and function of declarative and nondeclarative memory systems. Proc. Natl Acad. Sci. USA, 93, Suzuki, W.A. & Amaral, D.G. (1994a) Topographic organization of the reciprocal connections between the monkey entorhinal cortex and the perirhinal and parahippocampal cortices. J. Neurosci., 14, Suzuki, W.A. & Amaral, D.G. (1994b) Perirhinal and parahippocampal cortices of the macaque monkey: cortical afferents. J. Comp. Neurol., 350, Tulving, E. (2001) Episodic memory and common sense: how far apart? Phil. Trans. R. Soc. Lond. B Biol. Sci., 356, Van Hoesen, G.W., Hyman, B.T. & Damasio, A.R. (1991) Entorhinal cortex pathology in Alzheimer s disease. Hippocampus, 1, 1 8. Vargha-Khadem, F., Gadian, D.G., Watkins, K.E., Connelly, A., Van Paesschen, W. & Mishkin, M. (1997) Differential effects of early hippocampal pathology on episodic and semantic memory. Science, 277,

7 Human perirhinal cortex and semantic memory 7 Watson, C., Jack, C.R. Jr & Cendes, F. (1997) Volumetric magnetic resonance imaging. Clinical applications and contributions to the understanding of temporal lobe epilepsy. Arch. Neurol., 54, Wise, R.J., Howard, D., Mummery, C.J., Fletcher, P., Leff, A., Buchel, C. & Scott, S.K. (2000) Noun imageability and the temporal lobes. Neuropsychologia, 38,

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