Elsevier

NeuroImage

Volume 54, Issue 2, 15 January 2011, Pages 1530-1539
NeuroImage

Fractionating verbal episodic memory in Alzheimer's disease

https://doi.org/10.1016/j.neuroimage.2010.09.005Get rights and content

Abstract

The aim of this study was to determine the neural correlates of different stages of episodic memory function and their modulation by Alzheimer's disease (AD). Several decades of work has supported the role of the medial temporal lobes (MTL) in episodic memory function. However, a more recent work, derived in part from functional neuroimaging studies, has suggested that other brain structures make up a large-scale network that appears to support successful encoding and retrieval of episodic memories. Furthermore, controversy exists as to whether dissociable MTL regions support qualitatively different aspects of memory (hippocampus: contextual memory or ‘recollection’; perirhinal/lateral entorhinal cortex: item memory or ‘familiarity’). There is limited neuropsychological support for these models and most work in AD only has examined free recall memory measures. We studied the relationship between performance on different stages of the Rey Auditory Verbal Learning Test (AVLT), a 15-item word list learning task, and structural MRI measures in mild AD patients. Structural measures included hippocampal volume and cortical thickness of several ROIs known to undergo atrophy in AD. Correlation and multiple regression analyses, controlling for age, education, and gender, were performed in 146 mild AD patients (MMSE 23.3 ± 2.0). To evaluate the robustness of these relationships, similar analyses were performed with additional standardized verbal memory measures. Early immediate recall trials (e.g. Trial 1 of the AVLT) were not associated with the size of MTL regions, but correlated most strongly with inferior parietal, middle frontal gyrus, and temporal pole ROIs. After repeated exposure (e.g. Trial 5 of the AVLT), immediate recall was correlated with both MTL and a similar distribution of isocortical structures, but most strongly the temporal pole. For delayed recall, only the hippocampus correlated with performance. In contrast, for delayed recognition discrimination, the perirhinal/entorhinal cortex correlated more strongly than the hippocampus; no other isocortical regions were strongly associated with performance. Convergent results were found for immediate and delayed trials of other memory tests. The current results suggest that a richer understanding of the memory deficits in AD can be gained by examining multiple measures, which tap different aspects of memory function. Furthermore, the present findings are consistent with models hypothesizing different stages of verbal list learning map onto dissociable brain regions. These data have implications for understanding the anatomic basis of processes underlying episodic memory, particularly related to a division of labor within the medial temporal lobes and within the large-scale MTL-cortical memory network.

Research Highlights

► Dissociable regions of atrophy correlate with different stages of memory processing. ► Early immediate memory trials correlate with working and semantic memory networks. ► Later immediate memory trials additionally correlate with MTL structures. ► Delayed memory is almost exclusively associated with MTL structures. ► Dissociable MTL regions correlate with disparate forms of delayed memory.

Introduction

Decades of research support the central role of the medial temporal lobes (MTL), particularly the hippocampus, in episodic memory function (Squire et al., 2004). Although the most profound forms of amnesia are associated with lesions to these structures (Scoville and Milner, 1957), a variety of other cortical regions also play important roles. For example, the prefrontal cortex contributes to controlled-strategic processing at encoding and retrieval, supporting accurate memory performance (Alexander et al., 2009, Blumenfeld & Ranganath, 2007). Working memory, which is in part subserved by frontal and parietal regions (Champod and Petrides, 2007), also generally modulates episodic memory performance by promoting efficient encoding of information to later be remembered. Additionally, the semantic memory system is involved in modulating the depth and organization of encoding, impacting the strength of a memory trace (Craik & Lockhart, 1972, Goldblum et al., 1998). While the left ventrolateral prefrontal cortex has been implicated as critical to semantic access at memory encoding (Logan et al., 2002, Otten et al., 2001), high level conceptual representations thought to be supported by the temporal pole (Lambon Ralph et al., 2009, Lambon Ralph et al, Patterson et al., 2007), are also likely essential to robust encoding.

Alzheimer's disease (AD) is the most common form of acquired amnesia. Given the early and profound involvement of neuropathology, particularly neurofibrillary tangles, in the MTL of AD patients (Arnold et al., 1991, Braak & Braak, 1991, Delacourte et al., 1999, Price et al., 1991), much of the work examining the anatomic basis of memory impairment in this condition has focused on the hippocampus and other MTL structures. However, AD pathology, as reflected in the clinical phenotype, involves multiple neural networks supporting other cognitive domains such as executive functioning, language, semantic memory, and visuospatial processing (Arnold et al., 1991). The influence of these additional domains of impairment is often neglected when considering episodic memory performance measures.

A variety of standardized episodic memory measures, frequently involving verbal list learning tasks, have been utilized for clinical diagnosis and monitoring of disease progression in AD. These tasks typically produce several memory measures, including immediate recall (commonly with repeated exposure), delayed free recall, and often recognition memory. However, much of the work in AD has focused on delayed free recall or treated these different measures as instances of a monolithic process. In fact, a number of studies have combined many of these measures into summary statistics to capture “episodic memory.” While such an approach is not unreasonable in that it may reduce the variability inherent in individual tests and may be useful in screening for any form of memory impairment, it reflects a process purity that is only approximate at best.

For example, a major debate in the memory literature is whether recollection, associated with detailed contextual retrieval of a prior event, is differentially represented in the MTL relative to familiarity, or an acontextual sense of prior encounter (Aggleton & Brown, 2006, Eichenbaum et al., 2007, Squire et al., 2007, Yonelinas, 2002). A variety of lines of research have supported an anatomic mapping of recollection to the hippocampus and familiarity to extrahippocampal MTL structures, particularly perirhinal and lateral entorhinal cortices [Bowles et al., 2007, Davachi et al., 2003, Fortin et al., 2004, Montaldi et al., 2006, Wolk et al., in press; for review, see Aggleton and Brown (2006)]. As free recall and recognition memory are likely differentially dependent on these memory processes, these measures may reflect differential localization of pathology within the MTL. Moreover, immediate recall after a single trial is likely related more to working memory than to so-called long-term memory processes involved in recall with repeated learning or after a delay. Thus, performance on an initial learning trial(s) would likely be predicted to relate to frontoparietal or other nodes of the working memory system.

Since one major goal of psychometric testing is to reveal specific changes in underlying brain systems, we sought here to determine the neural correlates of the different measures associated with three common verbal memory measures that are typically part of clinical research batteries in AD. Specifically, we focused on correlates of immediate recall (early versus later trials), delayed recall, and recognition memory. These measures were derived from three standardized psychometric memory instruments. Drawing on the concept in both pathology (Arnold et al., 1991, Braak & Braak, 1991, Brun & Gustafson, 1976) and imaging studies (Baron et al., 2001, Fox et al., 2001, Frisoni et al., 2002, Thompson et al., 2001) that early in its course AD is not a diffuse process but is in fact associated with abnormalities in a relatively stereotyped set of brain regions, we utilized a relatively novel region of interest (ROI) approach in which a set of regions that have been previously demonstrated to be sensitive to mild AD – the “Cortical Signature of AD” (Bakkour et al., 2009, Dickerson et al., 2009) – was defined on the cortical surface. These regions, along with the hippocampus, represent structures most likely to be associated with the pathology of AD and serve as a type of lesion model for understanding the brain–behavior relationships of the memory measures.

We predicted that early immediate memory trials would be most dependent on regions supporting working memory and perhaps other aspects of controlled-strategic processing and semantic elaboration, but that later trials would be more dependent on MTL structures. Delayed recall and recognition, which require the storage of information over time, were expected to be more dependent on MTL structures than the immediate trials. Finally, following the dual process model, we predicted that recognition memory performance, dependent on a combination of recollection and familiarity, would be more strongly associated with extrahippocampal MTL cortical atrophy while free recall, dependent solely on recollection, would be associated with hippocampal volume.

Section snippets

Participants

Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). The ADNI was launched in 2003 by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Food and Drug Administration, private pharmaceutical companies and non-profit organizations, as a $60-million, 5-year public–private partnership. The primary goal of ADNI has been to test whether imaging measures,

Demographic data

A total of 146 patients (74 females; 72 males) with AD [mean age 75.4 ± 7.4 (SD) years; mean education 14.9 ± 3.2 (SD) years] were included in the analyses. The racial and ethnic distribution of this group was consistent with the overall ADNI cohort [93.2% Caucasian; 4.1% African American; 1.4% Asian American; 2.7% Hispanic; (Petersen et al., 2010)]. Consistent with the mild status of these patients (72 with CDR = 0.5; 74 with CDR = 1), the mean Mini Mental State Examination (MMSE) and CDR-sum of boxes

Discussion

Successful episodic memory function involves the coordination of a number of different cognitive processes that likely are subserved by the interaction of several large-scale neural networks. The present results support this contention by revealing dissociable anatomic substrates that differentially support memory performance depending on the stage of processing: encoding upon initial exposure, learning with repeated study, and delayed recall and recognition. Given the substantially disparate

Acknowledgments

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare,

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    Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu\ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at http://www.loni.ucla.edu/ADNI/Collaboration/ADNI_Manuscript_Citations.pdf).

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