1. Semantic Dementia Temporal variant of Frontotemporal dementia Progressive atrophy of one or both temporal lobes Regions of significant gray matter density reduction relative to age-matched controls, as measured by voxel-based morphometry (Mummery et al., 2000). Cognitive Profile Recent experiments suggest better retrieval of recent autobiographical memories compared to those from the distant past (e.g., Graham & Hodges, 1997). This implies that learning of new material may be relatively preserved in semantic dementia Semantic Memory (all modalities of input and output) Phonology, syntax Problem solving Visuospatial Perception ImpairedPreserved Study Test Recognition Memory We have investigated episodic learning in semantic dementia using objects, faces, and line drawings as stimuli (Graham et al., 2000; Simons et al., 2001). Mean No. Correct * Typically, patients with semantic dementia (SD) show intact recognition memory for these kinds of pictures. Patients with early Alzheimer’s disease (AD), however, exhibit marked impairment. Analysis of Individual Patients with Semantic Dementia 30 40 50 60 70 80 90 100 Percent Correct GCBKHDMMBDCJHDEFM Patients with Semantic Dementia Control Mean Most patients with semantic dementia have highly accurate recognition memory. But at advanced stages of the disease, evidence of emerging deficit? What could be causing this recognition memory impairment at late stages of semantic dementia? Investigate relative contributions of recollection and familiarity (Mandler, 1980). –Recollection: ‘Remembering’ item with associated context –Familiarity: ‘Knowing’ that item has been experienced Using: Source monitoring task Associative memory test Relate memory performance to measures of atrophic disruption in associated neural regions (e.g., medial temporal lobe, prefrontal cortex) The Present Study Aims: Source Monitoring Task 10 min delay Study Phase 1 30 line drawings Study Phase 2 30 different drawings Test Phase “Did you see the picture in Set 1, Set 2, or not at all?” 120 drawings: 30 from Set 1, 30 Set 2, 60 New Associative Memory Test Study Phase 32 door and sofa pairs “Were these items paired together at study?” Test Phase 48 door and sofa pairs: 16 old, paired together at study 16 old, re-paired since study 16 new, not seen at study Recollection and the Hippocampus ‘Recollection’ supported by hippocampal system ‘Familiarity’ supported by perirhinal cortex system Aggleton & Brown (1999): Selective bilateral hippocampal damage impairs recall but spares recognition memory Vargha-Khadem et al. (1997): Much evidence links the hippocampus with recollection-based memory. For example: Volumetric MRI Analysis Volumetric analysis of the hippocampus (and other temporal lobe regions) conducted by manually tracing on 1.5mm contiguous coronal MRI slices using Analyze software on a Sun Sparcstation 20. Areas totalled to produce a volume for each region, corrected for total brain volume by dividing by whole brain cross-sectional area. Hippocampus and Source Memory HC Volume Z-Score r=-.4, n.s. Source Discrimination No significant positive correlation between bilateral hippocampal volume and source memory. This is despite significant correlations for other regions (e.g., between inferior temporal lobe and semantic memory). Suggests that, in semantic dementia at least, hippocampal atrophy is not the explanation for the pattern of recollection-based memory performance. Background Recollection and the Prefrontal Cortex Source memory correlates highly with scores on frontal lobe tests in healthy adults. Schacter et al. (1984), Glisky et al. (1995): Source memory impairment prominent feature of frontal lobe damage. Schacter et al. (1984), Shimamura et al. (1990): Currently no volumetric protocol for the prefrontal cortex, so two methods of testing this: Compare recollection-based memory with performance on frontal lobe tests in patients with semantic dementia. Examine source memory ability of patients with the frontal variant of frontotemporal dementia. Wisconsin Card Sorting Test Tower of London WMS-R Digit Span WMS-R Spatial Span Computerized Spatial Span Computerized N-Back Composite Frontal Score 1) Battery of Frontal Lobe Tasks Tests chosen to reflect different aspects of frontal lobe function, such as temporal sequencing, planning, holding and manipulating within working memory. Z-scores for each individual patient calculated for each frontal test, relative to mean performance of healthy controls. Composite frontal score then computed for each patient by taking the average of the frontal test z-scores. Frontal Battery and Recollective Memory Associative Memory Composite Frontal Score r=.69, p=.056 Source Discrimination Composite Frontal Score r=.72, p<.05 Composite frontal score correlates significantly with both source discrimination and associative memory. 2) Frontal Variant FTD Frontal variant of Frontotemporal dementia Progressive atrophy primarily affecting frontal lobes Earliest signs are changes in behavior and personality, followed by cognitive impairment (attention, executive function, etc.) Recognition memory deficit rarely observed, unless atrophy has spread to involve posterior cortical regions Performance on the Source Monitoring Task Patients with frontal variant FTD had little difficulty with familiarity-based item memory. Item Detection Source Discrimination But all patients tested were severely impaired at recollection- based source memory. Item memory normal in most patients with semantic dementia; the most severe patients may be impaired. Source discrimination normal in some patients, impaired in others. –Source memory not related to bilateral hippocampal volume –Strong association with performance on frontal lobe tasks –Patients with frontal variant FTD very impaired on source In seeking to understand the neural substrates of long-term memory, we should not forget the important role played by the prefrontal cortex.Conclusions References Aggleton, J.P. & Brown, M.W. (1999). Behavioral and Brain Sciences, 22, 425-489. Glisky, E.L., Polster, M.R., & Routhieaux, B.C. (1995). Neuropsychology, 9, 229-235. Graham, K.S. & Hodges, J.R. (1997). Neuropsychology, 11, 77- 89. Graham, K.S., Simons, J.S., et al. (2000). Neuropsychologia, 38, 313-324. Mandler, G. (1980). Psychological Review, 87, 252-271. Mummery, C.J., Patterson, K., et al. (2000). Annals of Neurology, 47, 36-45. Schacter, D.L., Harbluk, J.L., & McLachlan, D.R. (1984). Journal of Verbal Learning and Verbal Behavior, 23, 593-611. Shimamura, A.P., Janowsky, J.S., & Squire, L.R. (1990). Neuropsychologia, 28, 803-813. Simons, J.S., Graham, K.S., et al. (2001). Neuropsychology, 15, 101-114. Simons, J.S., Graham, K.S., & Hodges, J.R. (submitted). Journal of Memory and Language. Vargha-Khadem, F., Gadian, D.G., et al. (1997). Science, 277, 376-380. Familiarity-Based Memory Just like before, as a group, the patients were not impaired relative to controls at familiarity-based item memory, F 1,20 = 2.3, n.s. Also similar to before, three patients at advanced stages of semantic dementia did show a significant deficit. Previous studies indicate that this pattern is not due to: –Degraded semantic knowledge –Disrupted perceptual processes But can be attributed to atrophy Item Detection Control group confidence interval Patient confidence interval (no overlap indicates impairment) Key: Patients (increasing severity ) affecting medial temporal lobe regions such as the perirhinal cortex (Simons et al., submitted). Recollection-Based Memory Recollection-based source memory of seven patients not significantly impaired relative to controls (although two, WM and IF, are borderline). Three patients (JP, DS, and JW) significantly impaired. No obvious link between this deficit and disease severity. Again, pattern not related to degraded semantic knowledge. Possible explanations? Atrophy progressing to affect the function of: Source Discrimination *** Patients (increasing severity ) Hippocampus? Prefrontal Cortex? Recollection-Based Memory in Frontotemporal Dementia Jon S. Simons 1 *, Mieke Verfaellie 2, Kim S. Graham 1, Clare J. Galton 3, Karalyn Patterson 1, and John R. Hodges 1,3 1. MRC Cognition and Brain Sciences Unit, Cambridge, UK 2. Memory Disorders Research Center, Boston University School of Medicine 3. University Neurology Unit, Addenbrooke’s Hospital, Cambridge, UK * Now at the Department of Psychology, Harvard University, Rm 860, William James Hall, 33 Kirkland St, Cambridge, MA 02138 E-mail: jss@wjh.harvard.edu ***