Deterioration of the memory for historic events in patients with mild cognitive impairment and early Alzheimer's disease

Neuropsychologia 48 (2010) 4093–4101

Contents lists available at ScienceDirect

Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Deterioration of the memory for historic events in patients with mild cognitive impairment and early Alzheimer’s disease Thomas Leyhe a,b,∗ , Stephan Müller a,b , Gerhard W. Eschweiler a,b , Ralf Saur a,c a b c

Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstraße 24, 72076 Tübingen, Germany Geriatric Center at the University Hospital of Tübingen, Osianderstraße 24, 72076 Tübingen, Germany Section of Experimental Magnetic Resonance of CNS, Department of Neuroradiology, University of Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany

a r t i c l e

i n f o

Article history: Received 30 March 2010 Received in revised form 27 August 2010 Accepted 6 October 2010 Available online 13 October 2010 Keywords: Temporal gradient Cognitive impairment Dementia Neurodegeneration Cortical Reallocation Theory Multiple Trace Theory

a b s t r a c t Retrograde memory decline in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) has been evaluated using tests of past public knowledge, such as famous personalities and events, and tests of autobiographical memory. Reports of temporal gradients (TG) in retrograde amnesia have been inconclusive. Here, we compared the remembrance of famous historic events by patients with amnesic MCI and early AD using the newly developed Historic Events Test (HET). The HET demands knowledge about famous public events of the past 60 years divided into five time segments, and consists of three tasks, Recognition, Dating Accuracy, and Contextual Memory. In both patient groups, the performance was worse than in healthy controls. Memory performance of all time segments was uniformly affected by this kind of retrograde amnesia. There was no evidence of a TG, and memory decline was similar in all three tasks of the HET. In contrast, for the same patients tested at the same time, we had previously found a TG for autobiographical memory with better preservation of remote than recent memories (Leyhe, Müller, Milian, Eschweiler, & Saur, 2009). We propose that recall of more frequently retrieved remote autobiographical facts and incidents has become independent of the hippocampus, whereas more seldomly retrieved recent autobiographical memory and knowledge of famous events remain dependent on the hippocampus and will thereby be susceptible to the early neurodegenerative damage of the hippocampus in AD. Our assumption may reconcile the Cortical Reallocation Theory and the Multiple Trace Theory. © 2010 Elsevier Ltd. All rights reserved.

1. Introduction Assessment of retrograde memory is an essential part of evaluating patients with amnesia. Because memory disorders are cardinal symptoms of Alzheimerˇıs disease (AD), retrograde memory in AD has been investigated using tests of past public knowledge, such as famous personalities and events, and tests of autobiographical memory. Two major theories exist that explain storage and retrieval of memories differently: the Cortical Reallocation Theory (CRT; Alvarez & Squire, 1994; Meeter & Murre, 2004; Squire, 2004) and the Multiple Trace Theory (MTT; Moscovitch et al., 2005; Nadel & Moscovitch, 1997). The CRT is also referred to as the Standard Model of Memory Consolidation. The CRT (Alvarez & Squire, 1994; Meeter & Murre, 2004; Squire, 2004) implicates a temporary role for the hippocampus for mem-

∗ Corresponding author at: Department of Psychiatry and Psychotherapy, University of Tübingen, Osianderstraße 24, 72076 Tübingen, Germany. Tel.: +49 07071 2982311; fax: +49 07071 294141. E-mail address: [email protected] (T. Leyhe). 0028-3932/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2010.10.011

ory trace formation and consolidation, especially for memories concerning personally experienced past (autobiographical) events, including spatial and temporal contexts (i.e., the so-called episodic memory). According to the CRT, immediately after storage, memories depend on the medial temporal lobe memory system for their retrieval. After a critical time period, memories become independent of this system and resistant to hippocampal disruption due to consolidation in the neocortex (Alvarez & Squire, 1994; McClelland, McNaughton, & O’Reilly, 1995; Meeter & Murre, 2004; Meeter, Murre, & Janssen, 2005; Squire & Alvarez, 1995; Squire, Cohen, & Nadel, 1984). Therefore, damage to medial temporal lobe structures would affect only more recent memories, leading to a temporal gradient (TG) of amnesia with better preservation of remote remembrance. The MTT (Moscovitch et al., 2005; Nadel & Moscovitch, 1997) provides another explanation for the graded memory decline of episodic memory in amnesia. According to this theory, the hippocampal complex updates and enriches memories of autobiographical episodes throughout life and forms memory traces that include both hippocampal and neocortical neurons. In this model, each time a memory is retrieved, a new hippocampally mediated trace is created. Thus, frequently repeated remote memories are

4094

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

represented by more and stronger hippocampal-neocortical traces than recent ones, making them less susceptible to disruption by brain damage. Consequently, the extent and severity of retrograde amnesia as well as the slope of the TG are related to the extent and location of damage to the extended hippocampal system. A number of studies have been reported that document impairment of the remembrance of public events, the identification of famous faces, and autobiographical memory domains in patients with retrograde amnesia. Reports of TGs in retrograde amnesia have been variable. Some investigators found more preserved earlier remote memories compared to later memories in patients with Korsakoff’s syndrome, Parkinson’s Disease (PD), or AD, as well as in patients suffering from encephalitis or closed head injuries, whereas others did not (for review see Brown, 2002; Meeter, Eijsackers, & Mulder, 2006). Beatty, Salmon, Butters, Heindel, and Granholm (1988) used a Famous Faces and Public Events Recall Questionnaire to compare retrograde amnesia in patients with AD and Huntington’s disease (HD). The Famous Faces portion consisted of photographs of persons who were best known during the five decades from 1940 to 1980. The Public Events Recall Questionnaire demanded knowledge about events in the same time period. Overall performance of the patients with AD was poorer than that of the patients with HD. Both groups recalled less information from recent times than from the more distant past. This effect was significantly greater for patients with AD than for those with HD. Sagar, Cohen, Sullivan, Corkin, and Growdon (1988) assessed remote memory for public and personal events in patients with AD and PD using a series of recall and recognition tests. Participants were shown newspaper pictures depicting famous public events from the 1940s to the 1980s. The aim was to examine different aspects of knowledge related to content and date of these past events. For the recall of the content of personal and public events, both groups showed a gradient of deficits in which remote events were affected less than recent ones. Gradient effects were not evident in the recall of dates and were less marked in the recognition of content or dates. Wilson, Kaszniak, and Fox (1981) evaluated patients with dementia and healthy controls with two tests of memory for persons and events that were famous between 1930 and 1975. They found that the patient group had significantly more difficulty recalling information than the healthy control group, but the patients did not show a TG. Leplow et al. (1997) investigated remote memory for public events in patients with AD using a famous events questionnaire and found that remote memory impairments extended 30–40 years without any temporally graded memory loss. Dorrego et al. (1999) examined the presence of deficits in memory for autobiographical events and famous people in patients with AD. They found that even patients with very mild AD had significantly more severe deficits in memory for public events than healthy controls, but no significant TG was found. In contrast, patients with AD showed a significant TG of autobiographical memory with better recall of remote memories than more recent ones. Starkstein, Boller, and Garau (2005) examined long-term changes in autobiographical and public remote memory in patients with AD and age-matched healthy controls at baseline and 24–36 months later. Both groups were assessed using the Autobiographical Memory Scale, which consists of questions from personal history, and the Remote Memory Scale, which assesses memories (free recall and recognition) for famous people and well-known events from four decades (1950s–1980s). They found a significant recall gradient on the public remote memory test at follow-up, suggesting that the presence of a TG is related to the stage of illness (Dorrego et al., 1999; Nestor, Graham, Bozeat, Simons, & Hodges, 2002). They also found a significant recall gradient on the autobio-

graphical memory scale at baseline and follow-up (i.e., significantly better recall of earlier than later decades). Patients with amnesic mild cognitive impairment (aMCI) have memory deficits, and in some cases, these deficits are present in combination with other cognitive impairments. The presence of aMCI increases the risk for dementia, with rates of conversion to AD of 10–15% per year (Gauthier et al., 2006; Petersen et al., 2001). Bizzozero, Lucchelli, Saetti, and Spinnler (2009) reported retrograde amnesia for public events in patients with aMCI. In their study they used an enquiry of media-mediated events that consists of questions concerning famous public events that occurred from 1976 to 2000, subdivided into five 5-year segments. There was evidence of a TG in about half of the patients with aMCI, and a better recall of remote events in comparison to more recent ones was observed. Joubert et al. (2008) examined whether patients with aMCI show semantic deficits on tasks that require the identification of common objects, famous people, and famous public events. The MCI group showed significantly lower performance compared to healthy controls on all tasks and significantly better performance on the object identification test than on the tests of famous people and famous events. Retrieving specific semantic information about persons or events with distinctive and unique features may be more affected by brain damage than knowledge of common objects, which share greater interconnected features with similar objects of the same category. Autobiographical memory is a mental representation of personal events and facts that allows retrieval of both personal semantic data and remembrance of incident or episodic memories. Impairment in autobiographical memory is consistently found in AD. There have been different findings concerning the effects of AD on the TG, as well as on semantic and episodic remembrance of autobiographical memory. Using the Autobiographical Memory Interview (AMI), Kopelman and colleagues found significant deficits in patients with AD. These deficits were more pronounced for recent time periods than for remote ones (Kopelman, Wilson, & Baddeley, 1989). Similar results have been reported by others (Hou, Bruce, Kramer, & Kramer, 2005; Nestor et al., 2002; Snowden, Griffiths, & Neary, 1996). Greene, Hodges, and Baddeley (1995) examined autobiographical memory in a cohort of patients with early AD and found a slight TG in the incident component, but not in the personal semantic component of the AMI (Kopelman, Wilson, & Baddeley, 1990). Ivanoiu, Cooper, Shanks, and Venneri (2004) compared episodic and semantic memory in patients with AD and semantic dementia, and healthy elderly individuals, and they did not show a clear TG for episodic autobiographical memory. They did, however, report a modest gradient for semantic autobiographical memory in the AD group. In contrast, other studies of patients with AD found no TG in autobiographical memory (Dall’Ora, della Sala, & Spinnler, 1989; Meeter et al., 2006). In a recent study (Leyhe et al., 2009), we compared autobiographical memory performance among healthy controls, patients with early AD, and patients with aMCI over three time spans (childhood, early adult life, and recent years) using a German version of the AMI (Kopelman et al., 1990). The AMI is a semi-structured interview consisting of two parts that independently test recall of the two components of autobiographical memory: autobiographical incidents and personal semantic information. By covering the entire lifespan, the AMI assesses the ability to recall detailed specific events in time and space (autobiographical incidents) and facts (personal semantic information) from childhood, early adult life, and recent life. In both the aMCI and the AD groups, we found a decline in recall of autobiographical incidents and semantic information with a better recall of remote than recent memories. In patients with AD, both components of autobiographical memory showed a clear TG,

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

with better preservation of memories of childhood than those of early adulthood and recent life. In contrast to patients with AD, those with aMCI exhibited impaired recall of personal facts and autobiographical incidents relating only to recent life. The TG of autobiographical memory decline in patients with AD is more compatible with the CRT than with the MTT of memory consolidation. Because memory consolidation depends on hippocampal integrity (Maguire, 2001; Svoboda, McKinnon, & Levine, 2006), disturbances in the consolidation of autobiographical incidents can occur early during hippocampal degeneration, which is associated with early AD (DeToledo-Morrell, Goncharova, Dickerson, Wilson, & Bennett, 2000). Because the disease typically starts late in life, degradation of autobiographical incident memory is most pronounced for recent events. According to the CRT, episodic memory of early adulthood and childhood are better preserved, because these memories have been consolidated and stored in the neocortex, and are thus independent of the hippocampus. The significant decline in autobiographical memory for recent life that occurs in patients with aMCI suggests that deterioration of consolidation of personal facts and events begins with commencement of functional impairment in the hippocampus. There are several studies that found substantial retrograde deficits in memory for public events concerning free recall, recognition, content, or date in AD (Beatty et al., 1988; Dorrego et al., 1999; Fama et al., 2000; Leplow et al., 1997; Meeter et al., 2006; Sagar et al., 1988; Starkstein et al., 2005; Wilson et al., 1981) and in aMCI (Bizzozero et al., 2009; Joubert et al., 2008). In these studies, only memory performance related to a specific event was investigated. To our knowledge, memory performance for personal contextual information about one’s own situation by taking notice of an event has not been investigated. In this study, we compared patients with aMCI, patients with early AD, and healthy controls using the newly developed Historic Events Test (HET). All participants were from the same sample investigated in our previous study using the AMI (Leyhe et al., 2009). The HET consists of three tasks: Recognition, Dating Accuracy, and Contextual Memory. While the Dating Accuracy task demands more semantic knowledge, the Contextual Memory task, which requires remembrance about the situation by taking notice of the events, has more episodic characteristics. We examined whether patients with aMCI and those with early AD showed impairment in memory for public events concerning recognition, dates, and contextual information and whether we could show differences between these tasks in the pattern of memory decline. Moreover, we investigated whether more distant memories were better preserved than more recent ones (i.e., whether we could show a TG of the memory about famous public events). We discuss the results in comparison with results from the same group using the AMI (Leyhe et al., 2009). According to the results of the reviewed previous studies we hypothesized that patients with aMCI and early AD would show impairment in the memory of historic events. As for the autobiographical memory we expected to show a TG with remote historic events being better preserved than recent ones. Moreover, we hypothesized that we could find differences in the three tasks of the HET in the pattern of memory decline. 2. Methods 2.1. Participants From September to December 2006, 60 participants (32 females and 28 males) with a mean age of 73.1 years (standard deviation [SD] 6.6 years) participated in this study. Patients were consecutively recruited from the Memory Clinic of the Department of Psychiatry and Psychotherapy of the University Hospital of Tübingen. The study population was divided into healthy controls (HCs) (N = 20), patients with aMCI (N = 20), and patients with early AD (N = 20). The HC group consisted of relatives or friends of the patients. All participants were initially tested with the Mini Mental State Examination (MMSE; Folstein, Folstein, & McHugh, 1975).

4095

HC individuals had no history of neurological or psychiatric disease and no signs of cognitive decline, as confirmed by a clinical interview. Moreover all participants in the HC group had a MMSE score of 29 or 30. Patients with AD and aMCI underwent physical, neurological, and psychiatric examinations as well as electroencephalography and computed tomography or magnetic resonance imaging of the brain. Routine laboratory tests included Lues (syphilis) serology as well as analysis of vitamin B12, folic acid, and thyroid-stimulating hormone levels. In all patients, neuropsychological testing was performed using the “Consortium to Establish a Registry for Alzheimer’s Disease” test battery (CERAD) by Morris et al. (1989) extended by the Trail Making test and a phonemic fluency task (CERAD-Plus; Memory Clinic Basel, 2005). Activities of daily living were assessed using the Nurses’ Observation Scale for Geriatric Patients (NOSGER; Spiegel et al., 1991). The diagnosis of aMCI was defined by the Mayo criteria (Petersen et al., 1999), which include the presence of a memory complaint (corroborated by an informant), impaired memory function for age and education (delayed word recall score > 1 standard deviation below normal age- and education-matched mean for older adults), preserved general cognitive function, intact activities of daily living, and the absence of dementia. In some patients with aMCI, a slight decrease in executive function was detected. Deteriorated performance was found in seven of the 20 aMCI patients regarding Trail Making test (TMT) B and TMT-B-A scores. Five of them showed additionally deficits in a verbal fluency task. No other cognitive impairments were detected with neuropsychological testing. All patients with AD met the diagnostic criteria of probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994), the ICD-10 Classification of Mental and Behavioural Disorders (World Health Organization, 1992), and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (McKhann et al., 1984). All patients with AD had a score of four on the Global Deterioration Scale (Reisberg, Ferris, De Leon, & Crook, 1982). All study participants had normal or corrected-to-normal visual acuity and sufficient hearing ability. None of the participants had a physical handicap that affected their ability to perform the required tasks or any indication of neurological or psychiatric disorders unrelated to their diagnosis. The study was approved by the local Ethics Committee, and written informed consent was obtained from each individual. 2.2. Historic Events Test The HET (see Appendix A) consists of 20 items concerning famous public events that occurred between 1945 and 2005. The HET was developed to investigate the ability to retrieve famous events and the contextual information about the situation by taking notice of the events. The event items were selected after a pre-test with healthy adults older than 60 years of age (Saur & Leyhe, 2006). Sixty famous events were initially chosen by exploring Wikipedia, a free online encyclopedia (http://www.wikipedia.org), for public events for the time period from 1945 to 2005. Most events concerned political news, crime, natural disasters, and sports events. The 60-year period was subdivided into five time segments: A (1945–1959); B (1960–1974); C (1975–1989); D (1990–1999); and E (2000–2005). For each time segment, four famous events were required. For the pre-test, each event was presented as a catchphrase, and the participants had to rate their memory quality for the event on a rating scale from 1 meaning no remembrance to 4 meaning vivid recollection. The participants also had to rate emotional arousal and valence for the time when they took notice of the event. Based on this information, four items from each time segment were selected that received a rating on the memory quality scale of at least 2 (meaning little remembrance) or higher in at least 70% of participants. Furthermore, for each decade, one positive high arousal, one negative high arousal, and two events with modest arousal were chosen. This procedure ensured that the influence of the emotional arousal was balanced for the five time periods. The resulting 20 items are presented in Appendix A. The 20 events were arranged in a random (i.e., non-chronological) order. For each event, the participants had to perform three tasks. In the Recognition task, they were asked whether they knew the event. The Dating Accuracy task required knowledge of the year of the event. In the Contextual Memory task, knowledge of details of the event and the contextual information were required. Initially, the participants were confronted with catchphrases of the events (i.e., “Germany wins the soccer world championship for the first time.”). The Recognition task was scored with one point when the participant registered the event. Zero points were given when the participant was not able to remember that the event happened at all. For each period, a maximum score of four points could be scored. Dating Accuracy was rated with three points for correctly stating the year, with two points for a deviation of less than 5 years, one point for a deviation of 5–10 years, and zero points for a deviation of more than 10 years. For each period, the maximum score was 12. In the Contextual Memory task, three points were given for fully exhaustive answers (i.e., answers produced spontaneously and reflecting a correct memory specific in time and place of the situation when the participants were hearing about or experiencing the event). Two points were given for a personal but non-specific

4096

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

memory or a specific memory for which time and place were not recalled. One point was awarded for a vague personal memory. A score of zero corresponded either to failure to provide an answer or statement of either a wrong answer or general, unspecific statements, or a response based on semantic memory. For each period, the maximum score was 12. Informants, such as spouses or life-long companions, were asked to verify the accuracy and details of the responses. Only general prompting (such as “Try again” or “Do you remember something else?”) was allowed, but specific suggestions were not permitted. There was no time limit. Each participant was examined in a single session, lasting 1–2 h.

Table 1 Demographic data, cognitive status and disease duration. Characteristic

Participant group

Number Female/male Age (years): mean (SD) Education (years): mean (SD) MMSE (max. 30): mean (SD) Disease duration (m): mean (SD)

HC

aMCI

AD

20 14/6 71.6 (6.5) 11.8 (2.8) 29.7 (0.5) –

20 8/12 72.6 (6.8) 10.2 (5.2) 26.7 (3.3) 18.0 (10.8)

20 10/10 76.9 (5.5) 10.4 (3.8) 20.3 (5.9) 39.00 (15.5)

2.3. Data analysis The SPSS-14 statistical package for Windows was used for data analysis. Differences in age, education, and MMSE score were assessed using a one-way analysis of variance (ANOVA), followed by a post hoc Scheffé test. The chi-square test was used to detect differences in gender distribution. Differences of the CERAD-Plus subscores and the disease duration in the patient groups were assessed using t-tests for independent samples. Two-way ANOVAs were used to examine the main effects of group and time segments as well as the interaction effect on the performance of the Recognition, Dating Accuracy, and Contextual Memory tasks. A group–time segment interaction effect was indicative of a TG when the memory recall of a patient group became progressively worse with periods that were more recent, relative to that of HCs. Subsequent ANOVAs were used to test for TG separately in the two patient groups. Between-group differences within each time segment were examined with a one-way ANOVA, followed by a post hoc Scheffé test. To test for a substantial influence of age, two-way analyses of covariance (ANCOVA), with age as a covariate, were used to examine the main effects of group and time segments, as well as an interaction effect on the performance of recognition, dating accuracy, and contextual information. To control for the influence of executive functions, correlations between the Trail Making Test (TMT) from the CERAD-Plus and the results of the HET in the patients groups were evaluated using the Spearman-rank correlation test. To validate the influence of the stage of illness correlations between the MMSE and the results of the HET in the patients groups were evaluated using the Spearman-rank correlation test.

3. Results 3.1. Characteristics of HCs, and patients with aMCI and AD The demographic data and the mean MMSE scores of the three groups as well as the disease duration of the patient groups are shown in Table 1. One-way ANOVA of the mean age (F[2,57] = 3.601; P = .059) and education (F[2,57] = .954; P = .391) did not detect any significant group differences. The three groups did also not differ in gender distribution (chi2 [3] = 2.67, P = .606). As expected, a one-way ANOVA revealed highly significant differences in the MMSE (F[2,57] = 38.60; P < .001). HCs had higher mean MMSE scores than patients with aMCI (P < .05) and AD (P < .001). Moreover, mean MMSE scores of patients with aMCI were higher than those of patients with AD (P < .001). There was a significant longer disease duration in the AD patients than in the aMCI group (t[38] = 4.961; P < .001). In Table 2 the results of the patient groups in the CERAD-Plus test battery are shown. In all subtests except for TMT B performance

HC, healthy controls; aMCI, patients with amnesic mild cognitive impairment; AD, patients with early Alzheimer’s disease; MMSE, Mini Mental State Examination; max., maximum; m, month; SD, standard deviation.

of the AD patients was significantly worse compared to the aMCI group (all P < .05).

3.2. Recognition task Analysis of recognition performance revealed a significant main effect for group (F[2,57] = 52.733; P < .001). Post hoc Scheffé tests showed that recognition was poorer in patients with AD than in HCs (P < .001) and patients with aMCI (P < .001). Performance of the aMCI group was worse than that of the HCs (P < .001). The other main factor, time period, was also significant (F[4,228] = 3.472; P < .05). To explore whether a TG existed in the recognition of past events, we tested the interaction between time segment and group and found no significant interaction (F[8,228] = 0.410; P = .687). Fig. 1 shows the recognition performance of the individual groups. Further analyses showed that patients with AD performed worse than the HC group on the Recognition task over all time segments (A–E) (P < .001). Patients with AD performed worse than the aMCI group in recognition of events in segments B (P < .001), C (P < .01), D (P < .01), and E (P < .01). No differences were found in segment A (P < .140). Significant differences were also seen when comparing the aMCI and HC groups. The patients with aMCI performed worse than HCs in recognition of events in segments A (P < .01), D (P < .05), and E (P < .01). No significant differences were found in segments B (P < .074) and C (P < .055), although a clear trend was noted. To control for a possible influence of age, we performed a two-way ANCOVA, with age as a covariate. Again, we found a significant main effect of group (F[2,56] = 43.505; P < .001) but no significant interaction effect between time segment and group (F[8,224] = 0.972; P = .459). There was no main effect of the factor time segment (F[4,224] = 1.459; P = .216) and the covariate factor age (F[1,56] = 1.066; P = .306). Table 3 summarizes the scores for the Recognition task.

Table 2 Scores of the CERAD-Plus subtests. Subtest

Word List Learning (max. 30) Word List Recall (max. 10) Word List Recognition (max. 100%) Verbal fluency (Animals) Verbal fluency (S-Words) Modified Boston Naming Test (max. 15) Constructional Praxis (max. 11) Recall of Constructional Praxis (max. 11) Trail Making Test A (max. 180 s) Trail Making Test B (max. 300 s)

Participant group aMCI

AD

16.1 (3.7; 7–23) 3.6 (1.8; 0–7) 87.8 (14.6; 50–100) 16.8 (5.1; 8–28) 13.9 (6.3; 6–31) 13.7 (1.4; 9–15) 10.1 (1.4; 7–11) 6.2 (3.1; 0–11) 67.3 (36.2; 23–145) 126.2 (33.1; 84–181)

10.0 (3.9; 1–19) 1.5 (1.7; 0–5) 71.8 (14.4; 50–90) 10.5 (4.7; 2–20) 10.1 (4.7; 0–19) 12.3 (2.2; 7–15) 8.4 (3.1; 4–11) 2.2 (2.6; 0–9) 94.8 (42.1; 42–180) 184.6 (63.1; 101–234)

Scores are shown as mean (standard deviation; range); CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; aMCI, patients with amnesic mild cognitive impairment; AD, patients with early Alzheimer’s disease; max., maximum.

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

mance and TMT B-A scores in the patient groups (r scores ranged from −0.222 to 0.312; all P > .5). Correlation analysis with the MMSE showed high correlations with the total score of the Recognition task of the HET (r = 0.820; P < .001) as well as with the scores for each of the time segments (r scores ranged from 0.627 to 0.710; all P < .001).

100

Recognition performance (in %)

4097

80

60

3.3. Dating Accuracy task 40

HC

20

MCI AD

0

A

B

C

D

E

Time segment Fig. 1. Performance in the Recognition task of the Historic Events Test across time segments in healthy controls (HC), patients with amnesic mild cognitive impairment (MCI), and early Alzheimer’s disease (AD). Segment A (1945–1959); B (1960–1974); C (1975–1989); D (1990–1999); E (2000–2005).

To control for a possible influence of executive function, we correlated the results of the TMT from the CERAD (Morris et al., 1989) with the results of recognition performance in the patient groups. We did not find any significant correlations (r scores ranged from −0.366 to 0.109; all P > .5) between recognition performance and either TMT A or TMT B. Because TMT B scores reflect not only executive function but also attention, we computed TMT B-A scores by subtracting TMT A scores (indicating attentional speed) from TMT B scores (indicating the more executive aspect of divided attention). There were no significant correlations between recognition perfor-

Analysis of factual knowledge about the year when the event happened revealed a significant main effect for group (F[2,57] = 51.924; P < .001). Post hoc Scheffé tests showed that dating accuracy was worse in patients with AD than in HCs (P < .001) and patients with aMCI (P < .001). Performance of the aMCI group was worse than that of the HCs (P < .001). The other main factor, time period, was also significant (F[4,228] = 3.658; P < .01). To explore whether a TG existed in the dating accuracy for past events, we tested the interaction between time segment and group and found no significant interaction (F[8,228] = 0.456; P = .886). Fig. 2 shows the dating accuracy performance in the individual groups. Further analyses showed that patients with AD performed worse than the HC group on the Dating Accuracy task over all time segments (A–E) (P < .001). Patients with AD performed worse than the aMCI group in segments B and C (P < .001), and in segment D (P < .01). No differences were found in segments A (P < .057) or E (P < .061), although a clear trend was noted. Significant differences were also found when comparing the aMCI and HC groups. Patients with aMCI performed worse than HCs in segments A (P < .05), B, and C (P < .01), and in segments D and E (P < .05). To control for a possible influence of age, we performed a two-way ANCOVA, with age as a covariate. We again found a significant main effect of group (F[2,56] = 33.569; P < .001) but no

Table 3 Scores for the Recognition task. Participant group

HC MCI AD Significant group differences

Time segment A (1945–1959)

B (1960–1974)

C (1975–1989)

D (1990–1999)

E (2000–2005)

88.75 (12.76) 61.25 (29.77) 45.00 (29.91)

96.25 (9.15) 82.50 (16.42) 48.75 (26.25) AD < HC*** AD < MCI*** MCI < HC†

97.50 (7.69) 81.25 (19.65) 50.00 (29.24) AD
93.75 (13.75) 73.75 (24.96) 45.00 (28.79) AD < HC*** AD < MCI** MCI < HC*

100.00 (.00) 75.00 (28.09) 46.25 (25.99) AD < HC*** AD < MCI** MCI < HC**

AD < HC*** MCI < HC**

Note: Scores are expressed as mean percentage (standard deviation). Maximum score = 100%. HC, healthy controls; MCI, patients with amnesic mild cognitive impairment; AD, patients with early Alzheimer’s disease. † P < .10. * P < .05. ** P < .01. *** P < .001. Table 4 Scores for the Dating Accuracy task. Participant group

HC MCI AD Significant group differences

Time segment A (1945–1959)

B (1960–1974)

C (1975–1989)

D (1990–1999)

E (2000–2005)

7.15 (2.45) 4.65 (2.88) 2.65 (2.34) AD < HC*** AD < MCI† MCI < HC*

6.70 (1.62) 4.75 (2.22) 2.05 (1.19) AD < HC*** AD < MCI*** MCI < HC**

7.95 (1.53) 5.55 (2.64) 2.60 (1.66) AD < HC*** AD < MCI*** MCI < HC**

6.65 (1.56) 4.85 (2.08) 2.50 (1.73) AD < HC*** AD < MCI** MCI < HC*

8.00 (2.36) 5.40 (3.11) 3.30 (2.67) AD < HC*** AD < MCI† MCI < HC*

Note: Scores are expressed as mean (standard deviation). Maximum score = 12. HC, healthy controls; MCI, patients with amnesic mild cognitive impairment; AD, patients with early Alzheimer’s disease. † P < .10. * P < .05. ** P < .01. *** P < .001.

4098

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

12

12

Dating accuracy (max. = 12)

10

Contextual memory retrieval (max. = 12)

HC MCI AD 8

6

4

2

0 A

B

C

D

HC AD 8

6

4

2

0

E

MCI

10

A

Time segment

B

C

D

E

Time segment

Fig. 2. Performance in the Dating Accuracy task of the Historic Events Test across time segments in healthy controls (HC), patients with amnesic mild cognitive impairment (MCI), and early Alzheimer’s disease (AD). Segment A (1945–1959); B (1960–1974); C (1975–1989); D (1990–1999); E (2000–2005).

Fig. 3. Performance in the Contextual Memory task of the Historic Events Test across time segments in healthy controls (HC), patients with amnesic mild cognitive impairment (MCI), and early Alzheimer’s disease (AD). Segment A (1945–1959); B (1960–1974); C (1975–1989); D (1990–1999); E (2000–2005).

significant interaction effect between time segment and group (F[8,224] = 0.950; P = .476). There was also no main effect of the factor time segment (F[4,224] = 1.442; P = .221) and of the covariate factor age (F[1,56] = 3.082; P = .085). Table 4 summarizes the dating accuracy scores. To control for a possible influence of executive function, we correlated the results of the TMT from the CERAD (Morris et al., 1989) with the results of dating accuracy performance in the patient groups. We found no significant correlations (r scores ranged from −0.394 to 0.171; all P > .5) between dating accuracy and either TMT A or TMT B. We computed TMT B-A scores and found no significant correlations between dating accuracy performance and TMT B-A scores in the patient groups (r scores ranged from −0.383 to 0.324; all P > .5). Correlation analysis with the MMSE showed high correlations with the total score of the Dating Accuracy task of the HET (r = 0.798; P < .001) as well as with the scores for each of the time segments (r scores ranged from 0.604 to 0.757; all P < .001).

(P < .001). The other main factor, time period, was also significant (F[4,228] = 5.580; P < .001). To explore whether a TG existed in the recollection of personal episodic memories, we tested the interaction between time segment and group and found no significant interaction (F[8,228] = 0.982; P = .451). Fig. 3 shows the performance in the Contextual Memory task of the individual groups. Further analyses showed that patients with AD performed worse than the HC group over all time segments (A–E) (P < .001). Patients with AD performed worse than the aMCI group in segments B and C (P < .01), and in segments D (P < .001) and E (P < .01). No differences were found in segment A (P < .165). Significant differences were also found when comparing the aMCI and HC groups. Patients with aMCI performed worse than HCs in segments A (P < .001), B, C (P < .01), D (P < .001), and E (P < .01). To control for a possible influence of age, we performed a two-way ANCOVA, with age as a covariate. We again found a significant main effect of group (F[2,56] = 39.129; P < .001) but no significant interaction effect between time segment and group (F[8,224] = 1.138; P = .339). There was no main effect of the factor time segment (F[4,224] = 1.377; P = .243) and the covariate factor age (F[1,56] = 1.183; P = .281). Table 5 summarizes scores for the retrieval of contextual information. To control for a possible influence of executive function, we correlated the results of the TMT from the CERAD (Morris et al., 1989) with the results of contextual memory retrieval in the patient groups. We found no significant correlations (r scores ranged from

3.4. Contextual Memory task Analysis of the retrieval of contextual information linked with the circumstances of the events revealed a significant main effect for group (F[2,57] = 57.291; P < .001). Post hoc Scheffé tests showed that the retrieval of contextual information was worse in patients with AD than in HCs (P < .001) and patients with aMCI (P < .001). Performance of the aMCI group was worse than that of the HCs Table 5 Scores for the Contextual Memory task. Participant group

HC MCI AD Significant group differences

Time segment A (1945–1959)

B (1960–1974)

C (1975–1989)

D (1990–1999)

E (2000–2005)

7.65 (2.56) 4.20 (2.91) 2.65 (2.08)

8.60 (1.60) 5.90 (2.78) 2.70 (1.83) AD < HC*** AD < MCI*** MCI < HC**

8.90 (1.86) 6.00 (2.75) 2.80 (2.30) AD < HC*** AD < MCI*** MCI < HC**

7.80 (1.79) 4.45 (2.46) 2.10 (1.51) AD < HC*** AD < MCI** MCI < HC***

7.75 (1.86) 5.15 (2.68) 2.55 (1.76) AD < HC*** AD < MCI** MCI < HC**

AD < HC*** MCI < HC***

Note: Scores are expressed as mean (standard deviation). Maximum score = 12. HC, healthy controls; aMCI, patients with amnesic mild cognitive impairment; AD, patients with early Alzheimer’s disease. ** P < .01. *** P < .001.

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

−0.347 to 0.083; all P > .5) between contextual memory retrieval and either TMT A or TMT B. We computed TMT B-A scores and observed no significant correlations between contextual memory retrieval and TMT B-A scores in the patient groups (r scores ranged from −0.277 to 0.143; all P > .5). Correlation analysis with the MMSE showed high correlations with the total score of the Contextual Memory task of the HET (r = 0.820; P < .001) as well as with the scores for each of the time segments (r scores ranged from 0.638 to 0.763; all P < .001).

4. Discussion The data in this study show impairment of the remembrance of public events in patients with aMCI and early AD according to our initial hypothesis. Both groups recognized fewer famous public events from the past 60 years than controls. Dating accuracy was also significantly worse in the patients. Moreover, the retrieval of contextual information about the situation when taking notice of the events was diminished. Our results are in accordance with other studies showing deterioration of the remembrance of famous public events in MCI (Bizzozero et al., 2009; Joubert et al., 2008) and AD (Beatty et al., 1988; Dorrego et al., 1999; Fama et al., 2000; Leplow et al., 1997; Meeter et al., 2006; Sagar et al., 1988; Starkstein et al., 2005; Wilson et al., 1981). In contrast to our expectation we did not find a TG in this type of retrograde amnesia. No TG was detected in the patients with aMCI or early AD for recognition of public events, dating accuracy, or retrieval of contextual information. In all three memory tasks, retrograde amnesia in both patient groups showed a uniform performance level over the five time segments encompassing famous public events of the last 60 years as surveyed with our HET. Conflicting results exist regarding a TG in the remembrance of public events or the identification of famous faces in both patients with AD and those with aMCI. Some authors showed a clear TG in these types of retrograde amnesia with better recall of remote memories than more recent ones in AD (for example, Sagar et al., 1988; Starkstein et al., 2005) and aMCI (Bizzozero et al., 2009), but others did not (for example, Dorrego et al., 1999; Fama et al., 2000; Leplow et al., 1997). One hypothesis is that the occurrence of a TG depends on the stage of the illness (Dorrego et al., 1999; Nestor et al., 2002; Starkstein et al., 2005). In contrast to our previous study (Leyhe et al., 2009) in which we found a clear TG in recall of autobiographical incidents and semantic information with a better recall of remote than recent memories, we did not detect a TG for the remembrance of public events in the same patients with AD at the same time in our current study. Moreover, the same patients with aMCI that exhibited impaired recall of personal facts and autobiographical incidents relating only to recent life (Leyhe et al., 2009), revealed uniform impairment of the remembrance of public events throughout all five time segments tested with the HET. Different explanations are possible for our findings. First, in contrast with autobiographical memory, remembrance of famous events may depend on an intact hippocampal complex throughout an individual’s entire life. Thus, incipient hippocampal damage in aMCI and early AD uniformly affects all time segments examined with our HET, whereas remote autobiographical memory stored independently of the hippocampus in the neocortex is intact at the commencement of AD in which mainly the mediotemporal cortex is impaired. Second, storage of the remembrance of famous events may be much weaker than storage of more important autobiographical knowledge. Thus, there are fewer hippocampal-neocortical memory traces leading to an early disruption of the necessary network with uniform loss of this kind of knowledge, whereas the frequently

4099

retrieved remote autobiographical memory is more resistant to hippocampal damage. Third, there may be different pathways of consolidation of autobiographical memory and non-personal public events. In contrast to our initial hypothesis we could not find differences in the three tasks of the HET. The pattern of memory decline of famous events did not differ between the more semantic tasks of the HET (Recognition and Dating Accuracy tasks) and the episodic Contextual Memory task. Similarly, autobiographical semantic memory decline resembled that of autobiographical incident memory decline in the same patients with aMCI and early AD (Leyhe et al., 2009). Given that the lateral temporal cortex (mainly on the left) is especially involved in the retrieval of semantic memory (Fujii, Moscovitch, & Nadel, 2000), the initial hippocampal damage associated with AD should not affect the memory of semantic facts. One possible explanation for our findings is an early spread of the disease to the lateral temporal cortex, as has been shown with neuroimaging (Whitwell et al., 2007). However, a more likely explanation is that the consolidation of semantic facts depends on the hippocampus (Nadel & Moscovitch, 1997; Squire, 1992; Squire & Alvarez, 1995) and, thus, is also susceptible to early hippocampal damage. Integrating our results and the findings of other authors into one theoretical framework would require reconciliation of the CRT and the MTT. Consolidation of all subtypes of memory initially depends on the hippocampus (Bayley & Squire, 2005; Gabrieli, Cohen, & Corkin, 1988; Hamann & Squire, 1995; Nadel & Moscovitch, 1997, 2001; Westmacott, Leach, Freedman, & Moscovitch, 2001). Retrieval of encoded information depends on the hippocampus as long as the cortical network is not strong enough to store the information independent of the hippocampus. Thus, more seldomly recalled information of public events will usually depend on the hippocampus, whereas more frequently retrieved remote autobiographical knowledge will have become separated from the hippocampus and thus less susceptible to the early hippocampal damage of AD. Our explanation is different to the assumption of the MTT. According to MTT each time a memory is retrieved, a new hippocampally mediated trace is created. Thus, frequently repeated memories are represented by more and stronger hippocampalneocortical traces than less often retrieved ones. In contrast, we propose that more frequent retrieved memories will become independent of the hippocampus and stored in the neocortex. This assumption is in line with the CRT. However, in contrast to this theory we propose that retrieval frequency and not remoteness of a memory is crucial for its independence of the hippocampus. Each time detailed memories of public events are retrieved, the autobiographical context experienced at the time of their occurrence serves as an index point necessary for recall of the information about such events. This kind of autobiographic knowledge that assists in retrieval of information of public events is likely less important and therefore more seldomly recalled than information about autobiographic information concerning closer life circumstances. As a consequence, the cortical network is not strong enough to store the information independent of the hippocampus. As hippocampal atrophy is increasing from healthy controls to patients with aMCI and further to AD (Pihlajamäki, Jauhiainen, & Soininen, 2009; Whitwell et al., 2008), memory performance for public events should be related to the stage of illness. In line with this assumption we could show high correlations between the MMSE scores of the participants and their performances in the HET. Possibly information used frequently in a certain time period and therefore stored in a cortical network separate from the hippocampus must be once more consolidated by the hippocampus when the information has not been retrieved for a longer time and the cortical network has been weakened again.

4100

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101

As limitations of this study the lack of neuroanatomical data of the participants and the lack of an operationalisation of the retrieval frequency of the memories are to be mentioned. Future investigations of remote memory should involve an examination of the association between retrieval frequency, memory performance and neuroimaging results. The remembrance of autobiographical episodes and facts as well as famous events or faces should be investigated in other amnesic patients with well characterized brain lesions. Retrieval frequency might be of importance in the clinical assessment as it could explain differences of the extent and quality of patients’ retrograde amnesia. In summary, in this study, we showed impairment of the remembrance of famous events in patients with aMCI and early AD using the newly developed HET. In both groups, this kind of retrograde amnesia uniformly affected memory of all time segments surveyed by the HET. No TG was detected, and memory decline was similar in the more semantic and the episodic tasks of the HET. In the same patients tested at the same time with the AMI, we had found a TG in autobiographical memory with better preservation of remote than recent remembrance. Thus, we propose that recall of more frequently retrieved remote autobiographical facts and incidents have become independent of the hippocampus, whereas more seldomly retrieved recent autobiographical memory and knowledge of famous events remain dependent on the hippocampus and will thereby be susceptible to the early neurodegenerative damage of the hippocampus in AD. Our assumption may reconcile the CRT and the MTT. Appendix A. Year Segment A (1945–1959) Atomic bombing of Hiroshima (Atombombenabwurf über Hiroshima) Coronation of Queen Elizabeth II (Krönung von Elisabeth II) Germany wins the soccer world championship the first time (Deutschland wird zum ersten Mal Fußballweltmeister) Implementation of conscription in Germany (Einführung der Wehrpflicht in Deutschland) Segment B (1960–1974) John F. Kennedy assassination (Ermordung von John F. Kennedy) First human spaceflight to land on the moon with the Apollo 11 mission (Erste bemannte Mondlandung von Apollo 11) Olympic summer games in Munich (Olympische Sommerspiele in München) Willy Brandt’s resignation as federal chancellor (Rücktritt von Willy Brandt als Bundeskanzler) Segment C (1975–1989) Lowering the age of consent (Senkung des Volljährigkeitsalters von 21 auf 18 Jahre) Wedding of Prince Charles and Lady Diana (Hochzeit von Prinz Charles mit Lady Diana) Chernobyl nuclear reactor disaster (Kernreaktorunfall in Tschernobyl) The fall of the Berlin Wal (Fall der Berliner Mauer) Segment D (1990–1999) Introduction of a five-digit postal code system (Einführung fünfstelliger Postleitzahlen) Eschede ICE train disaster (ICE-Zugunglück in Eschede) Gerhard Schröder becomes federal chancellor (Gerhard Schröder wird Bundeskanzler) The last total solar eclipse in Germany (Die letzte Sonnenfinsternis in Deutschland) Segment E (2000–2005) Saddam Hussein is captured (Festnahme von Saddam Hussein) The Indian Ocean Tsunami (Tsunami/Flutkatastrophe im indischen Ozean) Wedding of Prince Charles and Camilla (Hochzeit von Prinz Charles und Camilla) Joseph Alois Ratzinger becomes pope (Joseph Alois Ratzinger wird Papst)

1945 1953 1954 1956

1963 1969 1972 1974

1975 1981 1986 1989 1993 1998 1998 1999

2003 2004 2005 2005

References Alvarez, R., & Squire, L. R. (1994). Memory consolidation and the medial temporal lobe: A simple network model. Proceedings of the National Academy of Sciences, 91, 7041–7045.

American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th ed.). Washington: American Psychiatric Association. Bayley, P. J., & Squire, L. R. (2005). Failure to acquire new semantic knowledge in patients with large medial temporal lobe lesions. Hippocampus, 15(2), 273–280. Beatty, W. W., Salmon, D. P., Butters, N., Heindel, W. C., & Granholm, E. A. (1988). Retrograde amnesia in patients with Alzheimer’s disease or Huntington’s disease. Neurobiology of Aging, 9, 181–186. Bizzozero, I., Lucchelli, F., Saetti, M. C., & Spinnler, H. J. (2009). Mild cognitive impairment does entail retrograde amnesia for public events. Journal of Clinical and Experimental Neuropsychology, 31(1), 48–56. Brown, A. S. (2002). Consolidation theory and retrograde amnesia in humans. Psychonomic Bulletin & Review, 9, 403–425. Dall’Ora, P., della Sala, S., & Spinnler, H. (1989). Autobiographical memory: Its impairment in amnesic syndromes. Cortex, 25, 197–217. DeToledo-Morrell, L., Goncharova, I., Dickerson, B., Wilson, R. S., & Bennett, D. A. (2000). From health aging to early Alzheimer’s disease: In vivo detection of entorhinal cortex atrophy. Annals of the New York Academy of Sciences, 911, 240–253. Dorrego, M. F., Sabe, L., García-Cuerva, A., Kuzis, G., Tiberti, C., Boller, F., et al. (1999). Remote memory in Alzheimer’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 11(4), 490–497. Fama, R., Sullivan, E. V., Shear, P. K., Cahn-Weiner, D. A., Marsh, L., Lim, K. O., et al. (2000). Structural brain correlates of verbal and nonverbal fluency measures in Alzheimer’s disease. Neuropsychology, 14(1), 29–40. 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. Journal of Psychiatric Research, 12, 189–198. Fujii, T., Moscovitch, M., & Nadel, L. (2000). Consolidation, retrograde amnesia, and the temporal lobe. In F. Boller, J. Grafman, & L. S. Cermak (Eds.), The handbook of neuropsychology (2nd ed., Vol. 4, pp. 223–250). Amsterdam, The Netherlands: Elsevier. Gabrieli, J. D., Cohen, N. J., & Corkin, S. (1988). The impaired learning of semantic knowledge following bilateral medial temporal-lobe resection. Brain and Cognition, 7, 157–177. Gauthier, S., Reisberg, B., Zaudig, M., Petersen, R. C., Ritchie, K., Broich, K., et al. (2006). Mild cognitive impairment. Lancet, 367, 1262–1270. Greene, J. D. W., Hodges, J. R., & Baddeley, A. D. (1995). Autobiographical memory and executive function in early dementia of Alzheimer type. Neuropsychologia, 33, 1647–1670. Hamann, S. B., & Squire, L. R. (1995). On the acquisition of new declarative knowledge in amnesia. Behavioral Neuroscience, 109, 1027–1044. Hou, C. E., Bruce, L., Kramer, M., & Kramer, H. (2005). Patterns of autobiographical memory loss in dementia. International Journal of Geriatric Psychiatry, 20, 809–815. Ivanoiu, A., Cooper, J. M., Shanks, M. F., & Venneri, A. (2004). Retrieval of episodic and semantic autobiographical memories in early Alzheimer’s disease and semantic dementia. Cortex, 40, 173–175. Joubert, S., Felician, O., Barbeau, E. J., Didic, M., Poncet, M., & Ceccaldi, M. (2008). Patterns of semantic memory impairment in mild cognitive impairment. Behavioural Neurology, 19(1–2), 35–40. Kopelman, M. D., Wilson, B. A., & Baddeley, A. D. (1989). The autobiographical memory interview: A new assessment of autobiographical and personal semantic memory in amnesic patients. Journal of Clinical and Experimental Neuropsychology, 11, 724–744. Kopelman, M. D., Wilson, B. A., & Baddeley, A. D. (1990). The autobiographical memory interview. Bury St. Edmunds: Thames Valley Test. Leplow, B., Dierks, C., Herrmann, P., Pieper, N., Annecke, R., & Ulm, G. (1997). Remote memory in Parkinson’s disease and senile dementia. Neuropsychologia, 35(4), 547–557. Leyhe, T., Müller, S., Milian, M., Eschweiler, G. W., & Saur, R. (2009). Impairment of episodic and semantic autobiographical memory in patients with mild cognitive impairment and early Alzheimer’s disease. Neuropsychologia, 35(4), 547–557. Maguire, E. A. (2001). Neuroimaging, memory and the human hippocampus. Revue Neurologique, 57(8–9), 791–794. McClelland, J. L., McNaughton, B. L., & O’Reilly, R. C. (1995). Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 102, 419–457. McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease: Report of the NINCDS-ADRDA workgroup under the auspices of the Department of Health and Human Services taskforce on Alzheimer’s disease. Neurology, 34, 939–944. Meeter, M., Eijsackers, E. V., & Mulder, J. L. (2006). Retrograde amnesia for autobiographical memories and public events in mild and moderate Alzheimer’s disease. Journal of Clinical and Experimental Neuropsychiatry, 28, 914–927. Meeter, M., & Murre, J. M. J. (2004). Consolidation of long-term memory: Evidence and alternatives. Psychological Bulletin, 130, 843–857. Meeter, M., Murre, J. M. J., & Janssen, S. M. (2005). Remembering the news: Modeling retention data from a study with 14,000 participants. Memory and Cognition, 33(5), 793–810. Memory Clinic Basel. (2005). CERAD-Plus: The Consortium to Establish a Registry for Alzheimerˇıs Disease. Basel: Universitätsspital. Morris, J. C., Heyman, A., Mohs, R. C., Hughes, J. P., van Belle, G., Fillenbaum, G., et al. (1989). The consortium to establish a registry for Alzheimer’s disease (CERADNP). Part 1. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39, 1159–1165.

T. Leyhe et al. / Neuropsychologia 48 (2010) 4093–4101 Moscovitch, M., Rosenbaum, R. S., Gilboa, A., Addis, D. R., Westmacott, R., Grady, C., et al. (2005). Functional neuroanatomy of remote episodic, semantic and spatial memory: A unified account based on multiple trace theory. Journal of Anatomy, 207(1), 35–66. Nadel, L, & Moscovitch, M. (1997). Memory consolidation, retrograde amnesia and the hippocampal complex. Current Opinion in Neurobiology, 7, 217–227. Nadel, L., & Moscovitch, M. (2001). The hippocampal complex and longterm memory revisited. Trends in Cognitive Sciences, 5, 228–230. Nestor, P. J., Graham, K. S., Bozeat, S., Simons, J. S., & Hodges, J. R. (2002). Memory consolidation and the hippocampus: Further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia. Neuropsychologia, 40, 633–654. Petersen, R. C., Doody, R., Kurz, A., Mohs, R. C., Morris, J. C., Rabins, P. V., et al. (2001). Current concepts in mild cognitive impairment. Archives of Neurology, 58, 1985–1992. Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild cognitive impairment: Clinical characterization and outcome. Archives of Neurology, 56, 303–308. Pihlajamäki, M., Jauhiainen, A. M., & Soininen, H. (2009). Structural and functional MRI in mild cognitive impairment. Current Alzheimer Research, 6, 179–185. Reisberg, B., Ferris, S. H., De Leon, M. J., & Crook, T. (1982). The global deterioration scale for assessment of primary degenerative dementia. American Journal of Psychiatry, 139, 1136–1139. Sagar, H. J., Cohen, N. J., Sullivan, E. V., Corkin, S., & Growdon, J. H. (1988). Remote memory function in Alzheimer’s disease and Parkinson’s disease. Brain, 111, 185–206. Saur, R., & Leyhe, T. (2006). Development of a new famous events test for exploring episodic memory in patients with dementia. Journal of the International Neuropsychological Society, 12(Suppl. S2), 1–93. Snowden, J. S., Griffiths, H. L., & Neary, D. (1996). Semantic–episodic memory interactions in semantic dementia: Implications for retrograde memory function. Cognitive Neuropsychology, 13, 1101–1137. Spiegel, R., Brunner, C., Ermini-Fünfschilling, D., Monsch, A., Notter, M., Puxty, J., et al. (1991). A new behavioural assessment scale for geriatric out- and in-patients:

4101

The NOSGER (Nurses’ Observation Scale for Geriatric Patients). Journal of the American Geriatrics Society, 39(4), 339–347. Squire, L. R. (1992). Memory and the hippocampus: A synthesis from findings with rats, monkeys, and humans. Psychological Review, 99, 195–231. Squire, L. R. (2004). Memory systems of the brain: A brief history and current perspective. Neurobiology of Learning and Memory, 82, 171–177. Squire, L. R., & Alvarez, P. (1995). Retrograde amnesia and memory consolidation: A neurobiological perspective. Current Opinion in Neurobiology, 5, 169–177. Squire, L. R., Cohen, N. J., & Nadel, L. (1984). The medial temporal region and memory consolidation: A new hypothesis. In H. Weingartner, & E. Parker (Eds.), Memory Consolidation (pp. 185–210). Hillsdale, N.J.: Erlbaum. Starkstein, S. E., Boller, F., & Garau, L. (2005). A two-year follow-up study of remote memory in Alzheimer’s disease. Journal of Neuropsychiatry and Clinical Neurosciences, 17, 336–341. Svoboda, E., McKinnon, M. C., & Levine, B. (2006). The functional neuroanatomy of autobiographical memory: A meta-analysis. Neuropsychologia, 44, 2189– 2208. Westmacott, R., Leach, L., Freedman, M., & Moscovitch, M. (2001). Different patterns of autobiographical memory loss in semantic dementia and medial temporal lobe amnesia: A challenge to consolidation theory. Neurocase, 7(1), 37– 55. Whitwell, J. L., Przybelski, S. A., Weigand, S. D., Knopman, D. S., Boeve, B. F., Petersen, R. C., et al. (2007). 3D maps from multiple MRI illustrate changing atrophy patterns as subjects’ progress from mild cognitive impairment to Alzheimer’s disease. Brain, 130, 1777–1786. Whitwell, J. L., Shiung, M. M., Przybelski, S. A., Weigand, S. D., Knopman, D. S., Boeve, B., et al. (2008). MRI patterns of atrophy associated with progression to AD in amnestic mild cognitive impairment. Neurology, 70, 512–520. Wilson, R. S., Kaszniak, A. W., & Fox, J. H. (1981). Remote memory in senile dementia. Cortex, 17(1), 41–48. World Health Organization. (1992). Mental and behavioural disorders (including disorders of psychological development) (Chapter 5) (F). In Clinical descriptions and diagnostic guidelines. Tenth revision of the International Classification of Diseases. Geneva: World Health Organization.