Abnormal spatial and non-spatial cueing effects in mild. cognitive impairment and Alzheimer s disease

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1 Neurocase (2005) 11, Copyright Taylor & Francis Inc. ISSN: print DOI: / Abnormal spatial and non-spatial cueing effects in mild Neurocase cognitive impairment and Alzheimer s disease ANDREA TALES 1, ROBERT J. SNOWDEN 2, JUDY HAWORTH 1, and GORDON WILCOCK 1 1 Department of Care of the Elderly, University of Bristol, Clinical Research Centre and Memory Disorders Clinic, The BRACE Centre, Blackberry Hill Hospital, Bristol UK and 2 School of Psychology, Cardiff University, Cardiff, Wales, UK Our aim was to further characterize the clinical concept of mild cognitive impairment (MCI). We examined visual attention-related processing in 12 patients with amnestic MCI, 16 healthy older adults and 16 patients with Alzheimer s disease (AD) by measuring performance on computer-based tests of attentional disengagement, alerting ability, and inhibition of return. Unlike the healthy older controls, the patients with AD and the patients with amnestic MCI exhibited a significant detriment in both the ability to disengage attention from an incorrectly cued location and the ability to use a visual cue to produce an alerting effect. The pattern of results displayed by the MCI group indicates that patients who only appear clinically to suffer from a deficit in memory also display a deficit in specific aspects of visual attention-related processing, which closely resemble the magnitude seen in AD. Introduction Older adults who report a detrimental change in their memory are often referred by their GP for further assessment, for example, to a memory disorders clinic. It is frequently observed that, on formal testing, many of these individuals are neither cognitively normal nor demented. Instead they appear to fall into an intermediate state commonly referred to as mild cognitive impairment (MCI) (Petersen, 2003; Knopman et al., 2003; Davis and Rockwood, 2004). Presentation of MCI can take the form of deficits in several areas of cognitive function (multiple domain MCI, i.e., slight impairment in multiple cognitive domains but not of a sufficient magnitude to constitute dementia) or an isolated non-memory deficit (single non-memory domain MCI, i.e., a relatively isolated impairment in a single non-memory domain such as language or executive function). The most frequent profile, however, is that of amnestic MCI (Busse et al., 2003; Knopman et al., 2003; Petersen 2003). In this form of the disorder the individual complains of memory impairment and formal neuropsychological testing indicates abnormal memory function in the Received 4 May, 2004; accepted 31 August, 2004 The authors would like to thank the Bristol Research Into Alzheimer s and Care of the Elderly (BRACE) Charity [Registered Charity Number ] for financial support. The authors would also like to thank all the participants taking part and Mr A. Hughes for statistical support. Address correspondence to Andrea Tales, Department of Care of the Elderly, University of Bristol, Clinical Research Centre and Memory Disorders Clinic, The BRACE Centre, Blackberry Hill Hospital, Manor Rd, Bristol, BS16 2EW, UK. Andrea.Tales@northbristol.swest.nhs.uk presence of otherwise normal cognitive function and preserved activities of daily living (Petersen, 2003). This patient group is clinically important as such individuals have a higher risk of progressing to dementia, particularly AD in those with amnestic MCI, compared to healthy controls of the same age (e.g., Lautenschlager et al., 2001; Petersen, 2003). The advent of drug treatment for AD has resulted in the search for markers capable of more accurately determining which patients with MCI, particularly those with amnestic MCI, will develop AD (Rentz et al., 2004). In order to identify potential disease markers it is necessary to further characterize MCI and its relationship to healthy ageing and the development of AD, and to determine whether, in addition to deficits in cognitive function, particularly memory, deficits also exist in other aspects of brain function in these patients. Increasing evidence suggests that visual attention-related deficits accompany the well- established cognitive decline typical of AD, even at the early stages of the disease (Perry and Hodges, 1999). As a result of apparently limited processing resources, attention often has to be sequentially shifted to and focused upon specific regions of interest in order to select for priority or higher level processing. This shift of attention can be endogenous (at will) and is commonly employed when we perform visual search, that is, when we are looking for a pre-defined object in a cluttered scene, such as looking for a friend in a crowd. This visual search ability has been found to be significantly poorer in AD (e.g., Foster et al., 1999; Tales et al., 2004) and in MCI (Tales et al., 2005, see also Perry and Hodges, 2003). A shift in attention can also be elicited in response to cues within the environment such as a sudden change or movement which automatically (or exogenously) captures attention and directs it to the location of the change, resulting in the rapid

2 86 Tales et al. and efficient processing of subsequent information occurring at that location. A popular method for assessing the efficiency of exogenous attention-related processing is the computer-based exogenous cueing paradigm (Posner, 1980). In a typical task the participant responds to a target that can occur at one of two locations on either side of a fixation mark. Prior to the appearance of the target, a visual cue, designed to automatically attract attention, appears at one of these locations so that attention may be focused at this locus in advance of the target. It is commonly found that at short intervals between the appearance of the cue and that of the target (around 200ms) the response to the target is speeded when the target subsequently appears at the same location as the cue compared to when the target appears on the opposite side to that of the preceding cue. The difference in reaction time (RT) between these respectively invalidly and validly cued target responses is referred to as the validity effect, which although typically small in magnitude (Tales et al., 2002b) represents the extra time needed to disengage and shift attention to the location of the target from its incorrectly cued position. If the interval between the appearance of the cue and the target is increased to around 800ms the effect of the cue is reversed, i.e., invalidly cued targets are responded to more rapidly compared to those which are validly cued. This inhibition of return (IOR) effect represents a strategy to bias attention toward potentially important novel locations and away from a previously (but recently) attended region (Posner and Cohen, 1984; Reuter- Lorenz et al., 1996; Wolfe, 2003). In addition to the facility for signalling the spatial location of an imminent event, e.g. a target, the cue also possesses an intrinsic ability to phasically alert the brain. This alerting effect (e.g., Fernandez-Duque and Posner, 1997) results in an increase in the brain s sensitivity to potentially important events (i.e., the target) and is typically observed as a speeded reaction time in response to the target. The intrinsic phasic alerting capability of visual cues (also apparent at cue to target intervals around 200ms) is measured by comparing the time taken to respond to the target when it is preceded by a cue in each of two possible target locations (i.e., a spatially neutral cue) to the response time when the target is not pre-cued. In a previous study examining exogenous spatial shifts of attention in AD and ageing we have shown that invalidly cueing the location of a subsequent target has no significant effect upon its detection for healthy older adults, but by comparison, results in a significantly slowed response (i.e., a large validity effect) in patients with AD which suggests a detriment in the ability to disengage attention away from an incorrectly cued location in these patients (Tales et al.,2002b, see also Parasuraman et al., 1992). The results of a further study designed to investigate phasic visual alertness in ageing and AD also indicated that whereas both younger and older adults displayed a significant alerting effect, i.e., a speeded reaction time to the target when pre-cued, patients with AD failed to do so (Tales et al., 2002a). Previous research has however tended to find no functional deficit in IOR in AD compared to normal ageing (e.g., Faust and Balota, 1997 [experiment 2]; Danckert et al., 1998; Langley et al., 2001). The present study was designed primarily to investigate the status of attentional disengagement and alerting in amnestic MCI compared to patients with AD and healthy older adult control participants. In addition, the inclusion of longer cue to target intervals enabled the determination of the status of IOR in the MCI and AD patients in relation to the healthy older adults and whether the normal relationship between the attention-related effects and the time interval between the cue and the target is maintained in these patients. Methods Stimuli In this study we presented an exogenous, overt Posner-style cueing paradigm and compared the time taken to detect the target when it was preceded, at three cue to target intervals of 200, 400 and 800ms by 1) valid and invalid cues in order to determine the magnitude of the validity (typically elicited at 200ms) and the IOR effect (typically elicited at 800ms) and 2) a spatially neutral cue (i.e., the cue appeared at both locations) or no cue (no cue at any location) in order to determine the magnitude of the alerting effect (normally evident at 200ms). This design also enabled us to determine whether the normal relationship between the cue-to-target interval and the effects elicited were maintained in MCI and AD. A further advantage of this design is that both spatial cueing effects (i.e., the validity effect and the IOR effect) and the non-spatial effects (the alerting effect) are investigated concurrently using the same paradigm and the same patient and control populations. All stimuli were presented on a MAC Powerbook 180 computer that was viewed from a distance of 57cm. The target stimuli were horizontal or vertical lines of 10mm length and Fig. 1. Stimuli. (a) The valid-cue trial where the target appears (after a time interval of 200, 400 or 800 ms) at the same location as the cue. (b) The invalid-cue trial where the target appears (after a time interval of 200, 400 or 800ms) at the location contralateral to that of the cue.

3 Abnormal cueing effects in MCI and AD 87 that is, that the eyes started off in this position for each trial. Rest periods were given as required. The stimuli were presented in two blocks giving in total 16 valid trials, 16 invalid trials and 12 catch trials (in which no target appeared), 8 double cue trials and 8 no-cue trials, for each cue to target interval of 200, 400 and 800ms. Participants were instructed on the task requirements and asked to respond as quickly and as accurately as possible to target occurrence by pressing a large hand-held button. All participants were asked to explain the task to the experimenter in order to demonstrate their understanding of the task requirements and all participants were asked to perform several practice trials. Fig. 2. Stimuli (a) The double cue (i.e. spatially neutral cue) trial where the target appears after a time interval of 200, 400 or 800 ms at either location. (b) The no-cue trial where the target appears at either location. 1mm width. The target stimuli were presented 60mm either side of a small fixation cross, located at the center of the screen. The visual cues consisted of four small squares that defined a larger square. The small squares had a side of 3mm and defined a larger square of side 26mm; the width of the lines was 0.25mm. The larger square was centred 60mm horizontally from the fixation cross (two 7mm long lines of width 0.5mm). The screen s background luminance level was 37.5 cd/m 2. All stimuli were black (-2.0 cd/m 2 ) and thus had a Weber contrast (δl/l) of Each trial commenced with the presentation of the fixation mark (the central cross) of 1000 ms duration. The cue was then presented and remained on screen for the duration of the trial. The target stimulus was presented 200, 400 or 800 ms after the onset of the cue. The target remained on screen until a response was made. The participant was required to press the button when the target occurred and was instructed to then return the eyes to the center cross in preparation for the next stimulus 1. The experimenter monitored the participant s eyes in order to ensure that they returned to the center cross, 1 In our previous studies examining attentional disengagement and alerting effects (Tales et al., 2002 a,b) covert cueing was employed. This covert paradigm is used specifically to elicit information regarding discrete attention-related processes without contamination by ocular function. However, the associated prerequisite sustained eye immobilization can lead to data loss if fixation cannot be maintained and puts extra demands on patients. As evidence suggests that overt and covert attention mechanisms are anatomically and functionally linked (Posner, 1978; Vandenberghe et al., 2001, Corbetta et al., 1998) the present study therefore employed overt cueing in which eye movements were allowed. This design removed the need for sustained fixation, thus making the task less demanding for the patients and reducing the potential for lost data due to eye movements, but still represented a typical situation in which the alerting, validity and IOR effects are expected to be manifest. The number of trials for each condition was also reduced, thus decreasing the time taken to complete the task and minimizing test fatigue. Participants The diagnosis of MCI and AD was based on neurological, physical and biochemical examination, including the integrity of daily living skills, neuroimaging, family interview and detailed history, psychiatric interview and neuropsychological testing according to DSM IV (American Psychiatric Association, 1994) and NINCDS-ADRDA guidelines (McKhann et al., 1984). The neuropsychological test battery included the Mini-Mental State Examination (Folstein et al., 1975), WAIS-III sub-tests of digit span forwards and backwards, similarities and picture completion (Wechsler, 1998), face recognition (Wilson et al., 1998), Hopkins Verbal Learning Test-Revisited (HVLT-R) (Benedict et al., 1998), the Boston Naming test (Fastenau et al., 1998), S-word fluency and animal fluency (Spreen and Strauss, 1998), Weigl s color-form sorting test (Byrne et al., 1998), the CLOX test (Royall et al., 1998), the Visual form discrimination test (Benton et al., 1994) and digit copying (Kendrick, 1985). The diagnosis of amnestic MCI was given to patients who had made a formal complaint of memory impairment (corroborated by a relative), and who on formal examination, were not demented but exhibited abnormal memory function (as demonstrated by performance of at least 1.5 standard deviations below the age and education norms of the HVLT-R, Benedict et al.,1998) in the presence of otherwise normal cognitive function, and preserved activities of daily living. In addition, all the MCI patients had scored 0.5 on the clinical dementia rating scale (CDR) (Hughes et al., 1982). The patient groups were recruited on a consecutive incident patient basis from the Bristol Memory Disorders. Twelve amnestic MCI patients were recruited, 8 male, 4 female, mean age 72.2 (SD 6.1) years, mean years of education 11.4 (SD 2.3) and a mean MMSE score of 26 (SD 1.7). The AD group consisted of 16 patients, 5 male, 11 female, mean age 76.2 (SD 4.4) years, mean years education, 10.9 (SD 2.2) and a mean MMSE score of 21.3 (SD 2.2). There was no difference in the mean age of the MCI and AD groups [t (26) = 1.9, p > 0.05] or in the mean years of education of these groups [t (26) = 0.8, p> 0.05]. The healthy older adult control group consisted of 16 individuals (8 male, 8 female), mean age 72.3 (SD 3.9) years, mean

4 88 Tales et al. years education 11.1 (SD 1.8), who were recruited from the healthy volunteer participant panel at the Bristol Memory Disorders Clinic. They scored within the normal range on recent cognitive screening using the modified telephone interview of cognitive status (TICS-m) (Prince et al., 1999) and the MMSE (Folstein et al., 1975). There was no difference in age between the older control and the MCI groups [t (26) = 0.08, p > 0.05, the AD group was however older than the older group [t (30) = 2.6, p < 0.05]. There was no significant difference in mean years of education between the older control and the MCI groups [t (26) = 0.4, p > 0.05] or between the older and the AD groups [t (30) = 0.5, p > 0.05]. Although medication could not be controlled in any of the groups, none of the participants were receiving medication deemed likely to affect cognitive function and none of the patients were receiving therapy of any kind for their cognitive problems. Individuals were excluded from the study if they had a history of stroke, had sustained a head injury, or suffered from any other psychiatric disorder or neurological disease or were taking drugs that might influence performance. None of the participants had a history or clinical evidence of a major medical or neurological abnormality and all had normal or corrected-to-normal vision. To further ensure visual capability appropriate for the task all participants were asked to read aloud the task instructions displayed on the computer screen. All participants were also given practice trials in which they were required to report what they could see on screen, that is, to describe the fixation cross, the cues and the targets. All participants gave written informed consent and the research protocol was approved by the local research ethics committee. Data analysis After initial visual inspection of the RT to the trials on which a target was presented scores < 150 ms were eliminated as anticipatory and scores >1500 as due to lapses of concentration. Trials in which obvious distraction and in which the eyes were not focused on the cross at the beginning of a trial were also excluded from analysis. From the remaining reaction times the median reaction time for each condition for each group was determined and any catch trials recorded. The scores were then transformed by taking the logarithm of the median RT. Analysis of variance (ANOVA) was then performed on these transformed scores. This was done for two reasons. First, the overall responses of both MCI and AD patients are slower than the older controls resulting in differences in the variance of RTs for these groups. This discrepancy violates one of the assumptions of ANOVA, namely homogeneity of variance, rendering the interpretation of results problematic. When log-transformed, the variances are similar. Second, the overall slowing of function could potentially lead to larger search effects without specific dysfunction of the attention system (Tales et al.,2002b; Snowden et al., 2001). If changes in cueing effects are apparent in transformed scores, then the results cannot be accounted for simply in terms of overall slowing of function. The mean % correct responses for all groups were highly similar, rising above 90% for all conditions. The mean number of false responses on catch trials over all conditions for the older control, the MCI and the AD group were 0.25 (SD 0.57), 0.17 (SD 0.4) and 0.5 (SD 0.7) respectively indicating that all groups understood the task instructions. As we specifically wanted to examine the spatial and alerting effects of the cues separately (Jonides and Mack, 1984; Witte et al., 1997 a,b; Frenandez-Duque and Posner, 1997; Tales et al., 2002 a,b) and for reasons of clarity, the results pertaining to the spatial cues (valid versus invalid cues) and non-spatial cues (no cue versus double cues) will be analysed and presented separately. Results The effects of spatial cues: The validity and the inhibition of return effects Figure 3a displays the mean reaction times (RTs) for each group for the valid and invalid trials at the cue to target intervals. Figure 3b illustrates the effect of the cue (i.e., RT invalid RT valid ). Analysis of variance revealed no significant main effect of group [F (2,41) = 2.4, ns], no significant main effect of cue type [F(1,41) = 0.43, ns] and no significant main effect of cue to target interval [F(2,82) = 1.6, ns]. There was a strong cue to target interval by cue type interaction [F (2,82) = 32.5, p<0.0005], a significant interaction between cue type and group [F(1,41) = 3.3, p<0.05] but no significant interaction between cue to target interval and group [F (4,82) = 0.8, ns]. Finally, the 3-way interaction between cue to target interval, cue type and group reached significance [F (4,82) = 2.99, p <0.05]. A-priori planned analysis of the difference between the cues at each cue to target interval, for each group using logtransformed data was conducted using 2-tailed t-tests. Spatial cueing effects for the older adult group At the 200ms cue to target interval the older adults displayed a small and non-significant validity effect, that is, a slight increase in RT to the target when it was preceded by the invalid compared to valid target [t (15) = 0.73, ns]. This absence of a significant validity effect indicates a preserved efficient process of disengaging exogenously cued attention in healthy ageing (see also Tales et al., 2002). Increasing the interval to 400 ms resulted in a slight reduction in RT to the target when it was preceded by the invalid compared to the valid target, (indicative of the pattern expected for IOR) but failed to reach significance [t (15) = -0.95, ns]. However, extending the interval to 800ms resulted in a significant IOR effect, [ t (15) = -4.2, p < 0.001] indicating a preserved ability to prevent the focus of exogenously cued attention from returning to previously attended locations.

5 Abnormal cueing effects in MCI and AD 89 effect [t (11) = -4.6, p<0.001] suggesting that the ability to prevent the focus of exogenously cued attention from returning to a previously attended location is preserved in this group of people. Spatial cueing effects for the AD group At the 200 ms cue to target interval the AD group displayed a highly significant validity effect [t (15) = 3.5, p<0.01] indicating the presence of a significant detriment in the ability to disengage exogenously cued attention away from where it was invalidly cued to in this group. At 400 ms, a validity effect was still present, but failed to reach significance [t (15) = 1.6, ns], and increasing the cue to target interval to 800ms still failed to elicit a significant IOR from the AD group [t (15) = -1.9, ns]. Fig. 3. (a) Reaction times (ms) are plotted against the time interval between cue and target (ms) for the valid cue (open symbols) and invalid cue (solid symbols) trials. The groups are presented by symbol shapes (old circles, MCI squares, AD diamonds). Error bars (±1 standard error of the mean) have been plotted only on the valid cue trials at the interval of 800 ms for illustrative purposes (these were typical of the data for each of the groups in the other conditions). (b) The effect of the cue (RTinvalid RT valid) is plotted against the time interval between cue and target. The groups are presented by symbols shapes (old circles, MCI squares, AD diamonds). Spatial cueing effects for the MCI group The MCI group displayed a significant validity effect [t (11) = 3.3, p<0.01] at the 200 ms cue to target interval, which suggests the presence of a significant abnormality in the efficiency of the process of disengaging exogenously cued attention from an invalidly cued location in this group of people. Increasing the interval to 400 ms resulted in a reduction in RT to the invalidly compared to the validly cued target, an effect indicative of the IOR effect, but failing to reach significance [t (11) = -1.4, ns]. At 800 ms, the MCI group displayed a highly significant IOR The effects of non spatial cues: The alerting effect Figure 4a displays the mean reaction times (RTs) for each group for the double and no-cue trials at the cue to target intervals. Figure 4b illustrates the effect of the cue (i.e. RT no cue RT double ). A three-way analysis of variance on logtransformed data revealed no significant main effect of group [F (2,41) = 2.1, ns], a significant main effect of cue type [F (1,41) = 6.3, p <0.02], but no significant main effect of cue to target interval [F(2, 82) = 0.54, ns]. There was no significant interaction between cue to target interval and group [F (4,82) = 0.79, ns], cue type and group [F (2,41) = 0.59, ns] or cue to target interval and cue type [F(2,82) = 0.07, ns] and finally, no significant 3-way interaction between cue to target interval, cue type and group, [F(4,82) = 1.1, ns]. A-priori planned analysis of the difference between the cues at each cue to target interval, for each group using logtransformed data, was conducted using 2-tailed t-tests. Alerting effects and the older adult control group At the 200 ms cue to target interval the older adult control group displayed a significant alerting effect, (i.e., a significantly speeded RT to the cued compared to the non-cued target) [t (15) = 3.5, p<0.01]. A significant alerting effect, although smaller in magnitude, was also exhibited in this group at a cue to target interval of 400 ms [t (15) = 2.3, p<0.05]. At 800 ms, however, as expected, no significant alerting effect was exhibited [t (15) = 0.35, ns]. The alerting effect and the MCI group The MCI group did not display a significant alerting effect at any cue to target intervals (200- [t (11) = 0.036, ns], 400- [t (11) = 0.067, ns] 800-[t (11) = 1.2, ns]).

6 90 Tales et al. to produce a significant inhibition of return effect, this function was preserved in the MCI group. Discussion Fig. 4. (a) Reaction times (ms) are plotted against the time interval between cue and target (ms) for the double cued (open symbols) and no-cue (solid symbols) trials. The groups are presented by symbols shapes (old circles, MCI squares, AD diamonds). Error bars (±1 standard error of the mean) have been plotted only on the double cue trials at the interval of 800 ms for illustrative purposes (these were typical of the data for each of the groups in the other conditions). (b) The effect of the cue (Rt no cue RT double cue) is plotted against the time interval between cue and target. The groups are presented by symbols shapes (old circles, MCI squares, AD diamonds). The alerting effect and the AD group The AD group did not display a significant alerting effect at any test interval (200- [t (15) = 0.7, ns], [t (15) = 0.6, ns], [t (15) = 0.9, ns]. In summary, unlike the healthy older controls, the patients with Alzheimer s disease and the patients with amnestic mild cognitive impairment exhibited a significant detriment in both the ability to disengage attention from an incorrectly cued location and the ability to use a visual cue to produce an alerting effect. However, although the AD group were unable The aim of this study was to determine further the nature of attention-related processing in amnestic MCI in relation to normal ageing and AD. Using a computer-based Posner-type exogenous cueing technique we found that in comparison to the healthy older adult group, the MCI patients exhibited a significant generalized overall slowing of processing and a significant deficit in the ability to disengage the focus of attention from an incorrectly (invalidly) cued location and an inability to utilise the alerting benefit of visual cues. These MCI-related functional deficits in disengaging attention and alerting closely resemble those found for the AD group in the present study and in our previous studies (Tales et al., 2002 a,b). The ability to prevent the focus of attention from returning to locations that have already been examined recently (the IOR effect) was, however, preserved in the MCI group at a magnitude that was similar to that displayed by the older adult control group. The AD patients, however, failed to produce a significant IOR effect. It should be noted that there is indeed a trend in the data towards an IOR effect. The pattern of attentional disengagement and alerting effects for both the older adults and the AD patients for this study in which overt cueing was employed closely resembles that seen in our previous studies using a covert paradigm (Tales et al., 2002a,b; see also Parasuraman et al., 1992). It is likely therefore that eye movement (after initial fixation on the central cross at the beginning of each trial) has little effect upon the comparative performance of both the older adult and the AD groups and indicates that such AD and MCI-related functional deficits can be elicited by using a simplified methodological approach. For the older control group a significant IOR was elicited in response to overt cueing in the present study that closely resembles the effect seen in older adults in previous studies using covert studies (e.g. Langley et al., 2001; Danckert et al., 1998). These latter studies also measured IOR in patients with AD and found that it was preserved (see also Faust and Balota, 1997). Our own data showed only a trend towards an IOR in the AD patients. There are however numerous differences in the methodology used in the present study and in those of previous studies, noticeably the issue of eye movements, which may differentially affect the process in AD. Further research is therefore required in order to determine the nature of the IOR effect in AD and its relationship to the methodology used to elicit the effect. In summary, the pattern of results displayed by the MCI group indicates that patients who clinically appear to suffer only from a deficit in memory also display deficits in some specific aspects of visual attention-related processing similar to those seen in AD. As the functional integrity of the visual attention-related system is a prerequisite for much of the

7 Abnormal cueing effects in MCI and AD 91 brain s mnemonic, cognitive, perceptual and sensory processing it is likely that inefficiencies in these aspects of processing may affect environmental interaction and, ultimately, behaviour. Individuals with MCI may therefore have deficits that are undetected by conventional neuropsychological and clinical evaluation, with a subsequent underestimation of the true impact of the disease (see Mapstone et al., 2003; Perry and Hodges, 2003). With additional development, measures of attentionrelated function may be of clinical use in further determining the relationship between MCI and AD. Larger studies are therefore in progress to (1) further characterize the attentionrelated functional deficits associated with amnestic and other forms of MCI, (2) address their utility as markers for identifying those individuals who are most likely to develop AD and (3) study the effects in relation to the degree of cognitive impairment and diagnostic criteria. 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