Elsevier

Cortex

Volume 44, Issue 7, July–August 2008, Pages 869-880
Cortex

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An fMRI study of verbal episodic memory encoding in amnestic mild cognitive impairment

https://doi.org/10.1016/j.cortex.2007.04.005Get rights and content

Abstract

Amnestic mild cognitive impairment (aMCI) is a high-risk and often prodromal state for the development of Alzheimer's disease (AD) and is characterised by isolated episodic memory impairment. Functional neuroimaging studies in healthy subjects consistently report left prefrontal cortex (PFC) activation during verbal episodic memory encoding. The PFC activation at encoding is related to semantic processing which enhances memory. The purpose of this study was to ascertain whether impaired verbal episodic memory in aMCI is related to PFC dysfunction. Using functional magnetic resonance imaging (fMRI) we compared 10 aMCI patients with 10 elderly controls during verbal encoding. The encoding task was sensitive to the effects of semantic processing. Subsequent recognition was tested to measure encoding success. Behavioural results revealed impaired recognition and a lower false recognition rate for semantically related distracters (lures) in aMCI, which suggest impaired semantic processing at encoding. Both groups activated left hemispheric PFC, insula, premotor cortex and cerebellum, but group comparisons revealed decreased activation in left ventrolateral PFC in the aMCI group. The magnitude of activation in left ventrolateral PFC during encoding was positively correlated with recognition accuracy in the control group but not in the aMCI group. We propose that verbal episodic memory impairment in aMCI is related to PFC dysfunction which affects semantic processing at encoding.

Introduction

Episodic memory refers to the processes that support the formation of new memory representations for unique events plus the context in which they occurred (encoding processes) and the conscious recollection of these memory representations (Baddeley, 2001). From lesion studies the medial temporal lobes have long been recognised as essential for episodic encoding. More recently an important contribution from frontal lobes has become apparent. Whereas medial temporal lobe lesions may result in dense amnesia for both the event and its context, frontal lobe lesions may lead to amnesia for context (Incisa della Rocchetta and Milner, 1993, Janowsky et al., 1989). Functional neuroimaging has been widely used to investigate memory processes in both normal individuals and those with memory impairment. Verbal episodic encoding consistently activates left hemispheric prefrontal cortex (PFC) and temporal lobe structures [for a review see Cabeza and Nyberg, 2000]. Left PFC activity relates to deep meaning-based (semantic) processing during encoding, which optimises memory and involves the executive processes of generating, maintaining, selecting and organising semantically related information (Fletcher and Henson, 2001, Wagner et al., 1998). Indeed, disruption of left PFC function by transcranial magnetic stimulation results in impaired verbal encoding (Floel et al., 2004), and disruption of semantic elaboration results in decreased left PFC activation and reduced memory performance (Fletcher et al., 1995, Grady et al., 1995). The extent of activation of the left frontal cortex (and hippocampus) during verbal encoding correlates positively with subsequent successful recognition (Morcom et al., 2003, Wagner et al., 1998).

Amnesia is a hallmark of established Alzheimer's disease (AD) and is readily explained on the basis of the burden of Alzheimer pathology in the temporal lobes. Impairment of episodic memory is, however, frequently the earliest feature of the disease, and may precede dementia by as much as 10 years, during which time a diagnosis of amnestic mild cognitive impairment (aMCI) may be applicable (Robbins et al., 1996, Small et al., 2000, Swainson et al., 2001, Tierney et al., 2005). aMCI is a high-risk state for the development of AD and frequently it is a prodromal stage of AD with a 10–15% annual conversion rate (Petersen et al., 2001, Petersen et al., 1999).

It is appropriate to consider what underlies the impairment of episodic memory in aMCI, both in structural and in functional terms. The study described here addresses the functional abnormalities of verbal episodic memory encoding. The episodic memory impairment in aMCI may be related to pathology in medial temporal structures and/or frontal cortex. Only a few neuropathological studies have been conducted in MCI, the more heterogenous group which includes the amnestic type. Neuropathological changes of AD have been found in medial temporal lobe structures and in frontal neocortex in MCI (Guillozet et al., 2003, Kordower et al., 2001, Markesbery et al., 2006, Riley et al., 2002). The importance of pathology in the frontal cortex in aMCI may have been overshadowed by focussing on the medial temporal lobes. In vivo positron emission tomographic (PET) studies of amyloid deposition in very mild AD (Mini-Mental State Examination, MMSE  25) demonstrated greater load in frontal cortex compared to parietal and medial temporal lobes (Klunk et al., 2004). The strong inverse correlation between dementia severity and synapse density in frontal cortex reported in AD may indicate, by extrapolating backwards, that in aMCI there is lesser but nevertheless significant reduction in frontal synapse density (Samuel et al., 1994). These findings raise the possibility that cognitive impairment in aMCI and early AD may be a consequence of frontal pathology, and functional imaging studies in MCI and aMCI provide some support for that notion. PFC has been studied in MCI during tasks designed to test the control of attention, and altered PFC activity has been associated with impaired performance. On a sustained attention task, MCI patients showed increased PFC activation when matching the performance of controls (Rosano et al., 2005). Increased task load resulted in greater activation in posterior parietal cortex and decreased speed and accuracy in MCI patients, whereas controls revealed increased PFC activation and decreased speed but maintained accuracy. We previously demonstrated decreased left PFC activation associated with slower reaction times during a divided attention task in the same aMCI group we report on here (Dannhauser et al., 2005). In a study of elderly individuals deemed to be at risk of AD, subjects were impaired in a novel face-name encoding task and this was associated with impaired activation of PFC on functional magnetic resonance imaging (fMRI; Elgh et al., 2003). Asymptomatic cognitively normal adults at increased genetic risk of AD have also been studied and increased activation in left prefrontal, parietal and hippocampal cortex was found when they matched the performance of controls during verbal memory tasks (Bookheimer et al., 2000). The increased activation was interpreted as representing increased effort required to maintain cognition. Although in aMCI altered PFC activity has been associated with impaired attentional processing, it remains to be established whether PFC function is altered during verbal encoding and whether any identified PFC dysfunction is associated with failed executive processing during encoding.

In order to study functional activation related to verbal encoding and the possible contributions of executive failure to impaired encoding in aMCI, we employed fMRI and a verbal memory encoding task similar to the Deese–Roediger–McDermott memory paradigm (Deese, 1959, Roediger and Mcdermott, 1995). In this paradigm, false recognition (incorrect recognition of a novel item as a studied item) can be manipulated by including recognition probes that are either unrelated (novel) or semantically related (lures) to studied items. It is therefore sensitive to the effects of spontaneously adopted, unsupported, encoding strategies which reflect everyday memory function and reflect semantic processing. In healthy subjects semantic elaboration at encoding predictably increases the misidentification of semantically related items (called lures) as studied items (targets). False recognition of lures can be quantified. AD patients show reduced false recognition of lures due to failure to generate and encode semantically related information (Balota et al., 1999, Budson et al., 2000, Budson et al., 2002, Budson et al., 2003). This paradigm can therefore be used to study the possible contribution of executive failure during attempted encoding in individuals with aMCI.

In summary functional studies have established the role of left PFC in executive processing during verbal encoding and altered PFC activity has been associated with impaired attentional processing in aMCI. Our hypothesis was that impaired verbal encoding in aMCI would be associated with impaired semantic processing and altered PFC activity.

Section snippets

Subjects

Ten patients (5 women, 5 men; mean age 72 years, SD 13.5, range 57–81 years) were recruited from our memory clinic and 10 healthy controls (6 women, 4 men; mean age 68 years, SD 7.7, range 50–84 years) of comparable age (aMCI mean 72 years, SD 7.7; controls mean 68 years, SD 13.5; F = .67, p < .4) and years of education (aMCI mean 10.3, SD 1.8, range 9–15; controls mean 10.1, SD 1.4, range 9–12; F = .64, p < .8) were recruited from spouses, relatives and staff. All subjects were right handed and

Neurocognitive and behavioural measures

Results are summarised in Table 1 and Fig. 1.

aMCI patients had significantly lower scores on the CAMCOG subcategories of memory, attention, orientation and language and consequently had lower CAMCOG total scores and MMSE scores compared to controls. They were impaired on the new learning score indicating impaired delayed recall. All aMCI subjects had a CDR score of .5. Behavioural measures revealed impairment of corrected recognition rate in the aMCI group and the difference was predominantly

Discussion

To our knowledge, this is the first functional neuroimaging study of intentional overt verbal encoding in patients with aMCI. We found that impaired recognition in the aMCI group was predominantly due to a higher false alarm rate. In controls, the magnitude of activation in left PFC during encoding was positively correlated with recognition success. aMCI subjects had impaired recognition and reduced activation in left PFC.

Conclusions

Failed semantic elaboration appears to play a significant role in impairing intentional verbal memory encoding in aMCI and the positive correlation found in controls between memory performance and activation in left ventrolateral PFC, an area strongly associated with semantic processing, is absent in aMCI. PFC dysfunction associated with executive failure has been demonstrated in aMCI and in MCI the PFC appears to be affected by AD neuropathology. In addition to the results reported here, we

Acknowledgements

We are grateful to the patients and volunteers who participated in the study. We would like to thank Clair Sweetman, Chris Andrews, Fernando Zelaya, Prof. Mick Brammer, Vincent Giampetro and the MRI unit staff at the Maudsley Hospital, London, for their assistance.

Supported by the Wellcome Trust (No. 066810/z/02/z) and an unrestricted grant from Novartis Pharmaceuticals UK Ltd (GR1A).

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