RESEARCH ARTICLE
Visual memory profiling with CANTAB in mild cognitive impairment (MCI) subtypes Onésimo Juncos-Rabadán1, David Facal1, Arturo X. Pereiro1 and Cristina Lojo-Seoane1 Department of Developmental and Educational Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain Correspondence to: O. Juncos-Rabadán, E-mail: [email protected]
Objective: Although visual memory has been shown to be impaired in amnestic mild cognitive impairment (aMCI), the differences between MCI subtypes are not well defined. The current study attempted to investigate visual memory profiles in different MCI subtypes. Methods: One hundred and seventy volunteers aged older than 50 years performed several visual memory tests included in the CANTAB battery. Participants were classified into four groups: (1) multiple domain aMCI (mda-MCI) (32 subjects); (2) single domain aMCI (sda-MCI)(57 subjects); (3) multiple domain non amnestic MCI (mdna-MCI) (32 subjects); and (4) controls (54 healthy individuals without cognitive impairment). Parametric and non parametric analyses were performed to compare the groups and to obtain their corresponding memory profiles. Results: The mda-MCI group exhibited impairments in both dimensions of episodic memory (recognition and recollection/recall), and also in learning and working memory, whereas the sda-MCI only showed impairment in recollection-delayed recall and learning. The mdna-MCI group displayed impairment in working memory but good preservation of learning and episodic memory. Conclusion: The CANTAB visual memory profiles may contribute to better cognitive characterization of patients with different MCI subtypes, allowing comparison across several processes involved in visual memory such as attention, recognition, recollection and working memory. Copyright # 2014 John Wiley & Sons, Ltd. Key words: visual memory; assessment; cognitive impairment; recognition memory; learning; working memory History: Received 4 October 2013; Accepted 3 February 2014; Published online 14 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4095
Introduction The term mild cognitive impairment (MCI) is generally used to refer to a clinical construct that may imply development of Alzheimer’s disease (AD) or of another form of dementia in the future, or it may imply stability or improvement of clinical symptoms (Petersen, 2004, 2009). There is general consensus regarding the criteria used to diagnose MCI and the classification of MCI into two main broad types, amnestic and non-amnestic, depending on whether memory is deteriorated or intact. The following general criteria are used in diagnosing MCI: (i) evidence of concern about a change in cognition, preferably corroborated by an informant; (ii) poorer performance in one
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or more cognitive domains that is greater than would be expected for the patient’s age and educational background; (iii) functional activities mainly preserved or minimally impaired; and (iv) non-fulfilment of diagnostic criteria for dementia (Albert et al., 2011). The two main types of MCI can be further differentiated into single and multiple domain MCI depending on whether the impairment affects one or more cognitive domains. Diagnostic criteria for amnestic subtypes of MCI include impairment of episodic memory, whereas those for non-amnestic subtypes include impairment in one or several cognitive domains with well-preserved episodic memory (Gauthier et al., 2006; Petersen, 2009). Studies of visual memory in MCI are scarce, and to our knowledge, no such studies have compared
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different MCI subtypes. In a study of aMCI patients, Barbeau et al. (2004, 2008) reported impairment of visual recognition memory based on the performance of a delayed matching-to-sample task. These authors found that some aMCI patients showed impaired recall and recognition, whereas others showed impaired recall but preserved recognition. Although the authors explained that they excluded patients with impairments in multiple domains other than memory, the neuropyschological description (Barbeau et al., 2008, Table 1, p. 1011) indicates that the aMCI subgroup with impairments in a delayed matching-to-sample test (DMSt) performed less well on the measures of executive functioning (verbal fluency) than the amnestic MCI (aMCI) subgroup without impairments in DMSt. The presence of impairment in executive functioning indicates that the corresponding aMCI subgroup may have included patients with multiple domain aMCI (mda-MCI). Alescio-Lautier et al. (2007) reported visuospatial recognition memory deficits in eight patients with single domain aMCI (sda-MCI). In a recent study, Westerberg et al. (2013) evaluated visual memory in 20 patients with aMCI by using a task involving recognition of silhouette images of common objects. The performance of aMCI patients was significantly worse than that of controls in the yes-no recognition test but not in the forced-choice recognition test. Recent studies have demonstrated that impaired performance of the paired
associates learning (PAL) test included in the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Sahakian et al. 1988) can significantly differentiate aMCI from controls and therefore may be a predictor of decline to AD (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012). Other visuospatial associative learning tests, which measure the ability to remember associations between objects and their locations, can detect early deficits suggestive of MCI (de Jager et al., 2003; Anderson et al., 2006; Zamboni et al., 2013). Saunders and Summers (2010) reported that the aMCI group displayed a significantly shorter span length than the control group in the CANTAB Spatial span (SSP) test. Recently, Juncos-Rabadán et al. (2013) reported that visual episodic memory tests (pattern recognition memory [PRM], delayed matching-to-sample [DMS] and paired associates learning [PAL] included in the CANTAB) can accurately distinguish aMCI patients from normal controls. Taking into account that most previous studies have focused on aMCI without differentiating the subtypes, the aim of the present study was to examine visual memory impairment in both aMCI subtypes (mdaMCI and sda-MCI) and in the non amnestic MCI type by using four CANTAB tests (PRM, DMS, SSP and PAL). Study of visual memory profiles in the aMCI subtypes and in the non-amnestic MCI type (which has generally been excluded from previous studies of
Table 1 Mean values and standard deviations (in parentheses) of the demographic and neuropsychological measures used in the study
Age Years of education Memory complaints (informant) MMSE CVLT (short delay free recall) CVLT(long delay free recall) Language Attention-calculation Praxis Executive function Visual acuity
1 Multiple domain amnestic MCI (mda-MCI) n = 32
2 Single domain amnestic MCI (sda-MCI) n = 57
3 Multiple domain non amnestic MCI (mdna-MCI) n = 32
4 HC n = 54
Fa Fb Fc χ
71.06 (8.36) 10.18 (4.09) 17.16 (4.4.09)
68.96 (8.60) 9.52 (4.08) 16.52 (4.44)
66.78 (8.56) 7.96 (3.77) 17.81 (5.24)
68.16 (8.75) 9.35 (4.62) 13.58 (3.44
Fa = 1.31 Fb = 1.59 Fb = 6.57**
23.40 (1.58) 3.28 (2.08)
27.50 (1.50) 4.10 (1.93)
24.53 (2.35) 9.25 (2.10)
28.01 (1.18) 9.57 (3.05)
χ d = 92.74** Fc = 99.57**
2
1, 3 < 2, 4f 1, 2 < 3, 4e
4.25 (3.35)
5.28 (2.97)
9.78 (2.69)
10.31 (3.03)
Fc = 49.57**
1, 2 < 3, 4e
23.15 (2.32) 5.43 (2.25 9.37 (2.73) 13.84 (3.78) 0.40 (0.16)
24.96 (2.42) 7.40 (1.64) 10.77 (1.74) 16.92 (3.58) 0.43 (0.21)
23.50 (2.06) 4.40 (1.73) 9.93 (2.72) 15.00 (4.19) 0.43 (0.17)
25.35 (2.06) 7.33 (1.56) 10.88 (1.20) 17.61 (4.61) 0.51(0.23)
Fc = 10.41** Fc = 27.90** 2 χ d = 12.37** Fc = 9.74** Fa = 1.35
1, 3 < 2, 4e 1, 3 < 2, 4e 1, 3 < 2, 4f 1, 3 < 2, 4e
2d
Post hoc
1, 2, 3 > 4e
Figures in bold format represent each one of the four groups (1,2,3,4). MCI, mild cognitive impairment; HC, healthy control; MMSE, mini–mental state examination; CVLT, California Verbal Learning Test. a Analysis of variance, dg (3,171); b Analysis of covariance (ANCOVA) with age as covariate, dg (4,170); c ANCOVA with age and years of education as covariates; d Kruskal-Wallis test e Intergroup differences, Bonferroni test f Intergroup differences, Mann-Whitney test **p < 0.01, *p < 0.05
Copyright # 2014 John Wiley & Sons, Ltd.
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MCI) may contribute to a better understanding of the relationship between the various subtypes of MCI. Methods Participants
One hundred twenty one patients aged older than 50 years with MCI were recruited from participants taking part in an ongoing longitudinal cognitive assessment studies carried out in Primary Care Health Centres in Santiago de Compostela and Vigo, Spain (Juncos-Rabadán et al., 2012, 2013). These patients were recruited by general practitioners from patients who attended primary care centres with complaints of cognitive failure, without prior diagnosis of dementia, psychiatric or neurological disorders, severe illness, deafness or blindness, not receiving quimiotherapy, and not consumers of substances or alcohol. Each participant underwent extensive evaluation, including review of their medical history and neuropsychological assessment. Clinical diagnosis of MCI was made on the basis of the patient’s medical history and neuropsychological assessment. The participants met the general criteria for MCI outlined by Albert et al. (2011) and were classified into three groups according to consensual criteria (Petersen, 2004; Dubois et al., 2007): Group 1 comprised 32 individuals with mda-MCI; Group 2 comprised 57 individuals with sda-MCI; and Group 3 included 32 individuals with multiple domain non amnestic MCI (mdna-MCI). All amnestic MCI patients fulfilled the following criteria: (1) informant-corroborated memory complaints assessed by the Questionnaire for subjective memory complaints (Benedet and Seisdedos, 1996; short version); (2) performance of 1.5 SDs below age norms on the Spanish version of the California Verbal Learning Test (CVLT), which evaluates short and long delay free recall (Benedet and Alejandre, 1998); (3) no significant or minimal impact on activities of daily living assessed by the Lawton and Brody Index (Lawton and Brody, 1969); and (4) not demented, according the NINCDS-ADRDA and DMS-IV criteria. Regarding general cognitive functioning, the mda-MCI patients had scores of 1.5 SDs below age-related and education-related norms in the Spanish version of the Mini-Mental State Examination (MMSE), adapted and validated by with normal age and education groups (Lobo et al., 1999), and in at least two cognitive subscales of the Cambridge Cognitive Examination (CAMCOG-R), which assesses deterioration in specific domains such as Copyright # 2014 John Wiley & Sons, Ltd.
language, attention-calculation, praxis, perception and executive functioning (Huppert et al., 1996; Gallagher et al., 2010). Patients with sda-MCI performed the MMSE and all the subscales of the CAMCOG, except memory, in accordance with age and education norms. Patients with mdnaMCI (who did not fulfil clinical criteria for dementia) scored 1.5 SDs below age-related and education-related norms in the MMSE, with signs of deterioration in the same specific domains as mda-MCI patients, but not in memory. Fifty four control participants who scored higher than the cut-off in memory, general cognitive functioning and specific cognitive tests were recruited from the same Primary Care Health Centres. The demographic and neuropsychological profiles of the participants are summarised in Table 1, together with the between group differences (see Statistical analysis). None of the participants had any history of clinical stroke, traumatic brain injury, motor-sensory defects, alcohol or drug abuse/dependence, and none were diagnosed with any significant medical or psychiatric illnesses. To control for the effects of depression, patients who scored more than 10 in depression screening (Geriatric Depression Scale; Yesavage et al., 1983) were not included in the study. All participants had normal or corrected-to-normal vision and hearing and their visual acuity was controlled. All participants gave their written informed consent prior to participation in the study. The research project was approved by the Galician Clinical Research Ethics Committee (Xunta de Galicia, Spain), and the study was performed in accordance with the ethical standards established in the Declaration of Helsinki as revised in Seoul 2008.
The CANTAB-R measures
Pattern recognition memory assesses visual pattern recognition memory in a two-choice forced discrimination paradigm (Swainson et al., 2001). The participants were presented with two blocks of 12 visual patterns, each presented individually. In the recognition phase, subjects are required to choose between a pattern they have already seen and a novel pattern. The outcome measures were as follows: (a) percentage of correct responses, that is, the total number of correct patterns chosen, expressed as a percentage; (b) percentage of correct responses in each block; and (c) mean correct latency, that is, the time to respond correctly, scored in milliseconds. Int J Geriatr Psychiatry 2014; 29: 1040–1048
Visual memory profiles in MCI
The DMS assesses both simultaneous and shortterm visual memory. It is a four-choice recognition test of abstract patterns that share colour or pattern with distracters (Sahakian et al., 1988; Owen et al., 1993). The outcome variables were as follows: (a) percentage of correct responses (total), which measures the total number (%) of trials in which a correct selection was made in the subject’s first response; (b) percentage of correct responses (simultaneous), which reports the percentage of correct responses in trials in which the target stimulus and the three distracters were presented simultaneously; (c) percentage of correct responses (all delays), which reports the percentage of correct responses when the target and the distracters were presented after the stimulus had been hidden, with delays of 0 ms, 4000 ms and 12 000 ms; (d) percentage of correct responses for 0 ms, 4000 and 12 000 delay; (e) mean correct latency, which reports the average speed of all correct responses; (h) mean correct latency (simultaneous) of response when the target and distracters were presented simultaneously; and (i) mean correct latency (all delays) of response when the target and distracters were presented with a delay. Spatial span is a computerised version of the Corsi Blocks task that assesses visual working memory capacity (Owen et al., 1990). A pattern of white squares is shown on the screen. Some of the squares changes colour, one by one, in a variable sequence. At the end of the presentation of each sequence, a tone indicates that the participant should touch each of the boxes in the same order as they were originally presented. The number of boxes in the sequence is increased from a level of two at the start of the test to a final level of nine, with three sequences at each level. The outcome measures were as follows: (a) span length, that is, the longest sequence successfully recalled by the participant at each level; (b) total errors, that is, the number of times the participant selected an incorrect box; (c) mean time to the last response in span 2, 3 and 4, that is, the mean time to successfully recall the corresponding boxes sequences. Visuospatial Paired Associates Learning (PAL) assesses visuospatial episodic memory and learning (Sahakian et al., 1988). Boxes are displayed on the screen and are opened in a randomised order. One or more boxes contain a pattern. The patterns shown in the boxes are then displayed in the middle of the screen, one at a time, and the subject must touch the box in which the pattern was originally located. If the subject makes an error, the patterns are represented to remind the subject of their locations. The following measures were used: (a) total errors (adjusted), which reports the total number of errors, Copyright # 2014 John Wiley & Sons, Ltd.
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with an adjustment corrected to take into account stages that were failed /not attempted; (b) total errors (adjusted) at different levels of difficulty (1, 2, 3 and 6 patterns or shapes); the six-shape level involves a high level of difficulty and it has been used by several researchers to study MCI and AD (Alladi et al., 2006; Mitchell et al., 2009; Chamberlain et al., 2011); (c) stages completed, that is, the number of stages successfully completed; (d) mean errors to success, which summarises, for all stages, the mean number of errors made before the stage was successfully completed; and (e) mean trials to success, which is obtained by calculating the total number or trials required to locate all the patterns correctly, in all stages attempted, and dividing the result by the number of successfully completed stages. To control the effect of visual acuity on the CANTAB performance, we measured the visual acuity of both eyes by using the Lighthouse near visual acuity test. Statistical analysis
We used analysis of variance to test differences between the MCI and control groups in age and education. We used analysis of covariance (ANCOVA), with age and years of education as covariates controlling for differences in those variables, to analyse neuropsychological group differences. We also used ANCOVA, with age as covariate, to analyse all the CANTAB measures, taking into account that previous studies have demonstrated a significant age-related decline in the performance of some CANTAB tests (Robbins et al., 1994; Skolimowskaa et al., 2011). We used Bonferroni’s tests for post hoc comparisons and Levene’s test to assess the homogeneity of variance. When the variance was not homogeneous, we used the Kruskal-Wallis and Mann-Whitney tests. All statistical analyses were performed with SPSS for Windows, version 18.0. Results Neuropsychological diagnosis
Demographic and neuropsychological data are shown in Table 1. Comparison between groups revealed the following: (1) no significant differences between groups for age and education; (2) significantly fewer memory complaints in the Healthy Control (HC) group than in the three MCI groups; (3) significantly poorer performance of the MMSE by the mda-MCI Int J Geriatr Psychiatry 2014; 29: 1040–1048
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and mdna-MCI patients than by the NC and sda-MCI participants; (4) significantly poorer performance of the CVLT memory measures by the mda-MCI and the sdaMCI groups than by the mdna-MCI and the NC groups; (5) no significant differences between the two amnestic MCI groups in the CVLT measures; (6) significantly poorer performance by both multiple-domain MCI groups than by the sda-MCI and NC groups for language, attention-calculation, praxis and executive functioning; and (7) no significant differences for visual acuity. The results indicate that, as expected, the mda-MCI displayed impairment in general cognitive functioning (MMSE), in memory and in several other specific domains, the sda-MCI displayed only memory impairments, and the mdna-MCI displayed impairment in general cognitive functioning and in several specific domains but not in memory.
CANTAB results
Pattern recognition memory (Figure 1; Table 2). The percentage of correct responses was significantly lower in the mda-MCI than in all the other groups for all trials and for the first block; for the second block of trials, the percentage of correct responses was significantly lower in the two amnestic groups (mda-MCI and sda-MCI) than in both the control and the mdna-MCI group, but did not differ significantly between the latter two groups. The mean correct latency was only significantly higher in the mda-MCI group than in the control group. Delayed matching-to sample (Figure 2; Table 2). The percentage of correct responses was significantly lower in mda-MCI group than in the healthy controls
for the total trials, for all delays and for 4000 ms delay. For 12 000 ms delay, all three MCI groups (amnestic and non amnestic) performed significantly worse than the control group. No significant differences between MCI groups and healthy control were found for simultaneous and 0 ms delay trials. The mean correct latency was similar in all groups for all conditions. Spatial span (Figure 3; Table 2). No significance between-group differences were found for span length, total errors or mean time to last responses for span lengths of 2, and 3. The mean time to last responses for a span length of 4 was significantly longer in both multiple domain MCI groups than in the sda-MCI and control groups. Taking these results into account, we performed a supplementary bivariate correlation analysis to test the relationships between the latency for a span of 4 and the measures of episodic memory impaired in the two subtypes of amnestic MCI and the measures of executive function impaired in only the two multiple domain MCI subtypes. Latency was significantly correlated with executive function (Spearman’s rho = 0.113, p < 0.05), but not with short and long delay free recall measures (Spearman’s rho = 0.060 and 0.079, respectively). Paired associated learning (Figure 4; Table 2). Both amnestic groups (mda-MCI and sda-MCI) performed significantly worse than the control group on almost all PAL measures: total errors adjusted, errors 6 shapes adjusted, stages completed, mean error to success, and mean trial to success. However, there were no significant differences between the MCI and control groups for the number of errors adjusted in the two easy blocks, with 2 and 3 shapes. Participants with mdna-MCI performed similarly to controls on all the PAL measures. Discussion
Figure 1 Pattern recognition memory profiles. Percentage of correct responses (estimated marginal means) in all (total) trials and in the two trial blocks in the four groups.
Copyright # 2014 John Wiley & Sons, Ltd.
The profiles obtained by PRM measures showed that patients with the mda-MCI subtype displayed impairments in pattern recognition, which were confirmed by the lower number of correct responses in all trials (blocks 1 and 2) and by the longer latencies associated with correct responses. Patients with sda-MCI only displayed recognition impairment in block 2, whereas patients with mdna-MCI did not show any impairment in recognition and performed like the healthy controls. Comparison between multiple and single amnestic MCI subtypes for recognition showed that these subtypes may represent two points along the continuum between normal ageing and AD (Ralph et al., 2003; Brambati et al., 2009). The multiple-domain subtype seems to represent a late phase in which two aspects of episodic Int J Geriatr Psychiatry 2014; 29: 1040–1048
Copyright # 2014 John Wiley & Sons, Ltd.
(total) (simultaneous) (0 delay) (all delays) (4000 delay) (12 000 delay)
89.18 (43.33) 0.06 (0.24) 2.25 (4.77) 7.31 (6.87) 28.93 (14.43) 6.71 (0.99) 7.47 (2.61) 3.31 (0.86)
4.40 (0.83) 11.93 (3.97) 9063.22 (4845.18)
69.09 (13.80) 86.36 (12.45) 66.96 (21.28) 66.33 (16.56) 64.54 (19.37) 58.48 (21.23)
66.79 (11.02 69.01 (18.35) 64.58 (12.57) 4296.07 (1578.97)
56.52 (38.91) 0.03 (0.18) .70 (1.09) 3.87 (4.50) 18.77 (13.62) 7.32 (0.84) 5.66 (2.85) 2.70 (0.81)
4.65 (0.80) 11.60 (3.96) 6698.75 (2526.20)
75.52 (10.73) 88.44 (10.05) 72.06 (15.97) 69.88 (13.42) 74.31 (16.66) 63.27 (18.39)
76.38 (12.75) 81.87 (14.35) 70.90 (15.99) 3680.01 (1479.05)
2 sda-MCI
47.72 (30.04) 0.09 (0.29) 1.03 (1.44) 4.42 (3.89) 15.27 (10.04) 7.63 (0.69) 5.27 (2.74) 2.64 (0.66)
4.45 (0.83) 11.66 (5.25) 7892.75 (2674.63)
74.14 (9.41) 90.31 (11.49) 73.12 (17.49) 68.75 (11.28) 70.62 (15.22) 62.27 (16.46)
80.05 (12.18) 82.32 (14.24) 77.77 (14.68) 3611.22 (1582.10)
3 mdna-MCI
36.89 (27.81) 0.03 (0.18) 0.44 (0.87) 2.33 (2.06) 11.65 (10.04) 7.73 (0.58) 4.25 (2.61) 2.29 (0.64)
4.77 (0.67) 11.68 (3.97) 6429.49 (1666.14)
77.18 (9.54) 91.07 (10.21) 72.67 (15.07) 72.55 (12.00) 75.17 (16.73) 69.82 (15.07)
81.89 (12.13) 84.91 (14.92) 78.87 (14.49) 3176.71 (1106.24)
4 HC
2b
2
χ b = 33.51** Fa = 0.63 2 χ b = 6.69 2 χ b = 18.49** 2 χ b = 33.87** 2 χ b = 29.32** Fa = 9.02** Fa = 12.26**
Fa = 2.36 2 χ b = 4.26 2 χ b = 19.47**
Fa = 3.24* Fa = 1.05 Fa = 0.41 Fa = 2.81* Fa = 2.76* Fa = 2.87*
Fa = 10.30** Fa = 7.22** Fa = 7.02** Fa = 3.92*
Fa χ
0.995 1.000
0.671 0.661 0.679
0.046 0.045 0.047
0.135 0.175
0.737
0.998 0.982 0.979 0.823
Power
0.053
0.150 0.110 0.108 0.063
2
Effect size ŋp
1 > 2, 3 > 4d 1 > 2 > 4d 1, 2 < 4d 1 > 2 > 4c 1 > 2 > 4c
1 > 2 > 3, 4d
1, 3 < 2, 4d
1 < 4c 1 < 4c 1, 2, 3 < 4c
1 < 4c
1 < 2, 3, 4c 1 < 2, 3, 4c 1, 2 < 3, 4c 1 > 4c
Post hoc
MCI, mild cognitive impairment; HC, healthy control; PRM, pattern recognition memory; DMS, delayed matching-to-sample; SSP, spatial span; PAL, paired associates learning. a Analysis of covariance with age as covariate, dg (4,170); b Kruskal-Wallis test; c Intergroup differences, Bonferroni test; d Intergroup differences, Mann-Whitney test; **p < 0.01, *p < 0.05
PAL Total errors (adjusted) Error 1 shapes (adjusted) Error 2 shapes (adjusted) Error 3 shapes (adjusted) Error 6 shapes (adjusted) Stages completed Mean errors to success Mean trials to success
SSP Span length Total errors Time to last response (s.l. 4)
DMS % correct % correct % correct % correct % correct % correct
PRM % correct (total) % correct (Block 1) % correct (Block 2) Correct Latency ms
1 mda-MCI
Table 2 Mean values and standard deviations (in parentheses) of the CANTAB measures
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Figure 2 Delayed matching-to-sample profiles. Percentage of correct responses (estimated marginal means) in all (total) trials and in the simultaneous and delayed trials in the four groups.
Figure 3 Spatial span profiles. Mean time (estimated marginal means) to the first and last responses for span lengths of 2, 3 and 4 in the four groups
Figure 4 Paired associates learning profiles. Number of errors (adjusted estimated marginal means) for all (total), 1, 2, 3 and 6 shapes in the four groups.
memory, recollection (short and long delay recall) and familiarity (recognition), would be impaired and the single-domain subtype would represent an early phase Copyright # 2014 John Wiley & Sons, Ltd.
O. Juncos-Rabadán et al.
in which recollection is impaired, whereas recognition is quite well preserved. Our findings, which distinguished the amnestic subtypes, may contribute to clarifying the results of previous studies that reported preserved or impaired recognition in patients with aMCI considered as a single group (Wolk et al., 2008; Hudon et al., 2009; Algarabel et al., 2012; Westerberg et al., 2013). Our results for DMS showed an impaired profile, especially in the amnestic multiple-domain MCI subtype. The DMS involves several cognitive processes: perception of colour and abstract shapes (patterns); selective attention, which is evident in the simultaneous trials; recognition memory (familiarity) in the delayed trials; episodic memory (recollection) of different patterns in the short and delayed recall trials; and working memory for simultaneous processing and storage of information (updating) (Miyake et al., 2000) in the four-choice recognition of target patterns from distracters. DMS profiles of performance on the total trials and total delayed trials indicate that the mda-MCI subtype is impaired in episodic memory (recognition) and working memory, whereas perception and selective attention seem to be preserved. This is consistent with the findings of Barbeau et al. (2004, 2008) for a subgroup of aMCI patients who displayed impairments in executive functions. DMS trials with 12 000 ms delay involve greater involvement of episodic memory (delayed recall) and working memory (updating) than trials with 0 or 4000 ms delay. This may explain the different performance of the sda-MCI and mdna-MCI groups in the 12 000 ms delay trials. Impaired performance of these trials by patients with sda-MCI may be caused by impaired recollection (delayed recall), whereas similar impairment in patients with mdna-MCI may be caused by working memory deficits. Considering the PRM and DMS profiles together, we can conclude that recollective processes may be disrupted in the early stages of amnestic MCI (sdaMCI), whereas familiarity (recognition) may remain intact until later stages such as in mda-MCI, as suggested by Westerberg et al. (2013). With respect to non amestic MCI, we conclude that visual recognition is well preserved and suggest that it may be impaired when recognition involves a greater working memory load. Regarding the SSP, the two multiple-domain MCI (amnestic and non amnestic) groups and the control and sda-MCI groups significantly differed in only one measure (the time to the last response for a span of 4). There were no significant differences in memory span length (mean around 4), in contrary to the findings of Saunders and Summers (2010), or in errors. It is possible that subjects with multiple-domain MCI require more processing resources than controls and subjects with sda-MCI to cope with storage and Int J Geriatr Psychiatry 2014; 29: 1040–1048
Visual memory profiles in MCI
simultaneous processing requirements in the most complex SSP sequences. Significant correlations between the SSP latency measure and the working memory measure (CAMCOG) suggest that impairment of working memory, which is common to the multiple domain MCI subtypes, may occur in the SSP profiles. The PAL profiles indicate that the mda-MCI group displayed the highest level of impairment in all the measures. The profile of the sda-MCI group for all the PAL measures represented an intermediate level between the mda-MCI and the control group. Both profiles significantly differentiated aMCI from controls (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012). The performance of the non amnestic MCI group was similar to that of the controls, thus confirming that pair associates learning is well preserved in the mdna-MCI group and that this MCI subtype probably represents a prodomal form of types of dementia in which episodic memory is well preserved (Gauthier et al., 2006; Dubois et al., 2007). In conclusion, the CANTAB visual memory profiles identified by the PRM, DMS, SSP and PAL tests may contribute to better cognitive characterization of patients with different MCI subtypes allowing comparisons across several processes involved in visual memory such as attention, recognition, recollection and working memory. The main limitation of the study is the lack of a single domain non amnestic MCI subtype that impedes to have a complete view of the MCI profiles. Further research on longitudinal changes in these profiles is needed for a better understanding of MCI subtypes and of their possible conversion to different types of dementia. Conflict of interest None declared. Key points
examined visual, episodic and working • We memory and learning in multiple-domain and
• • •
single-domain amnestic and in multiple-domain non amnestic mild cognitive impairment (MCI). The profiles of the mda-MCI patients revealed recognition, recalling, learning and working memory impairments. The profiles of the sda-MCI patients indicated impairment in recall and learning. The profiles of the mdna-MCI patients identified impairment in working memory but not in recognition, recall or learning.
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Acknowledgements This work was financially supported by the Spanish Directorate General for Science and Technology under Projects SEJ2007-67964-CO2-01 and PSI2010-22224C03-01, and by the Galician Government, Consellería de Industria e Innovación/Economía e Industria (PGIDIT07PXIB211018PR; 10PXIB2011070 PR) References Albert M S, DeKosky, StT, Dickson, D, et al. 2011. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7: 270–279. Alescio-Lautier B, Michel BF, Herrera C, et al. 2007. Visual and visuospatial shortterm memory in mild cognitive impairment and Alzheimer disease: Role of attention. Neuropsychologia 45: 1948–1960. Algarabel S, Fuentes M, Escudero J, et al. 2012. Recognition memory deficits in mild cognitive impairment. Aging Neuropsichol C 19: 608–619. Alladi S, Arnold R, Mitchell J, Nestor PJ, Hodges J R. 2006. Mild cognitive impairment: applicability of research criteria in a memory clinic and characterization of cognitive profile. Psychol Med 36: 507–515. Anderson EJ, de Jager CA, Iversen SD. 2006. The Placing Test: preliminary investigations of a quick and simple memory test designed to be sensitive to pre-dementia Alzheimer’s disease but not to normal ageing. J Clin Exp Neuropsyc 28: 843–858. Barbeau EJ , Didic M, Tramoni E, et al. 2004. Evaluation of visual recognition memory in MCI patients. Neurology 62: 1317–1322. Barbeau EJ, Ranjeva JP, Didic M, et al. 2008. Profile of memory impairment and gray matter loss in amnestic mild cognitive impairment. Neuropsychologia 46: 1009–1019. Benedet MJ, Alejandre M A. 1998. TAVEC: test de aprendizaje verbal EspañaComplutense. TEA: Madrid. Benedet MJ, Seisdedos N. 1996. Evaluación clínica de las quejas de la memoria en la vida cotidiana. Editorial Médica Panamericana, S.A: Madrid. Brambati SM, Belleville S, Kergoat MJ, et al. 2009. Single- and multiple-domain amnestic mild cognitive impairment: two sides of the same coin? Dement Geriatr Cogn Disord 28: 541–549. Chamberlain SR, Blackwell AD, Nathan PJ, et al. 2011. Differential cognitive deterioration in dementia: a two year longitudinal study. J Alzheimers D 24: 125–136. Dubois B, Feldman HH, Jacova C, et al. 2007. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 6: 246–248. Gallagher D , Mhaolain AN , Coen R, et al. 2010. Detecting prodromal Alzheimer’s disease in mild cognitive impairment: utility of the CAMCOG and other neuropsychological predictors. Int J Geriatr Psychiatry 25: 1280–1287. Gauthier S, Reisberg B, Zaudig M, et al. 2006. Mild cognitive impairment. Lancet 367: 1262–1270. Hudon C, Belleville S, Gauthier S. 2009. The assessment of recognition memory using the Remember/Know procedure in amnestic mild cognitive impairment and probable Alzheimer’s disease. Brain Cogn 70: 171–179. Huppert F , Jorm AF, Brayne C, et al. 1996. Psychometric properties of the CAMCOG and its efficacy in the diagnosis of dementia. Aging Neuropychol C 3: 1–14. de Jager CA, Hogervorst E, Combrinck M, Budge MM. 2003. Sensitivity and specificity of neuropsychological tests for mild cognitive impairment, vascular cognitive impairment and Alzheimer’s disease. Psychol Med 33: 1039–1050. Juncos-Rabadán O, Pereiro AX, Facal D, et al. 2012. Prevalence and correlates of cognitive impairment in adults with subjective memory complaints in primary care centres. Dement Geriatr Cogn Disord 33: 226–232. Juncos-Rabadán O, Pereiro AX, Facal D, et al. 2013. Do the CANTAB episodic memory measures discriminate amnestic mild cognitive impairment? Int J Geriatr Psychiatry. Lawton MP, Brody EM. 1969. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 3: 179–186. Lobo A, Saz P, Marcos G, et al. 1999. Revalidación y normalización del Mini-Examen Cognoscitivo (primera versión en castellano del Mini-Mental Status Examination) en la población general geríátrica. Med Clin-Barcelona 112: 767–774. Mitchell J, Arnold R, Dawson K, Nestor PJ, Hodges JR. 2009. Outcome in subgroups of mild cognitive impairment (MCI) is highly predictable using a simple algorithm. J Neurol 256: 1500–1509. Miyake A, Friedman NP, Emerson MJ, Witzki H, Howerter A. 2000. The unity and diversity of executive functions and their contributions to complex “frontal lobe” tasks: A latent variable analysis. Cogn Psychol 41: 49–100. Owen AM, Beksinska M, James M, et al. 1993. Visuospatial memory deficits at different stages of Parkinson’s disease. Neuropsychologia 31: 627–644.
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1048 Owen AM, Downes JD, Sahakian, BJ, Polkey, CE, Robbins, TW. 1990. Planing and spatial working memory following frontal lesions in man. Neuropsychologia 28: 1021–1034. Petersen RC. 2004. Mild cognitive impairment as a diagnostic entity. J Intern Med 256: 183–194. Petersen RC. 2009. Mild cognitive impairment. Ten years later. Arch Neurol, 66: 1447–1455. Ralph MAL, Patterson K, Graham N, Dawson K, Hodges JR. 2003. Homogeneity and heterogeneity in mild cognitive impairment and Alzheimer’s disease: a crosssectional and longitudinal study of 55 cases. Brain 126: 2350–2362. Robbins TW, James M, Owen, A, et al. 1994. Cambridge neuropsychological test automated battery (CANTAB): a factor analytic study of a large sample of normal elderly volunteers. Dementia 5: 266–281. de Rover, M, Pironti VA, McCabe JA, et al. 2011. Hippocampal dysfunction in patients with mild cognitive impairment: a functional neuroimaging study of a visuospatial paired associates learning task. Neuropsychologia 49: 2060–2070. Sahakian BJ, Morris RG, Evenden JL, et al. 1988. A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson’s disease. Brain 111: 695–718.
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O. Juncos-Rabadán et al. Saunders NLJ, Summers MJ, 2010. Attention and working memory deficits in mild cognitive impairment. J Clin Exp Neuropycho 32: 350–357. Skolimowskaa J, Wesierskaa M, Lewandowskaa M, Szymaszeka A, Szelaga E. 2011. Divergent effects of age on performance in spatial associative learning and real idiothetic memory in humans. Behav Brain Res 218: 87–93. Summers MJ Saunders, NLJ. 2012. Neuropsychological measures predict decline to Alzheimer’s dementia from mild cognitive impairment. Neuropsychology 26: 498–509. Swainson R, Hodges JR, Galton, CJ, et al. 2001. Early detection and differential diagnosis of Alzheimer’s disease and depression with neuropsychological tasks. Dement Geriatr Cogn Disord 12: 265–280. Westerberg C, Mayes A, Florczak S, et al. 2013. Distinct medial temporal contributions to different forms of recognition in amnestic mild cognitive impairment and Alzheimer’s disease. Neuropsychologia 51: 2450–2461. Wolk DA, Signoff ED, Dekosky ST. 2008. Recollection and familiarity in amnestic mild cognitive impairment: a global decline in recognition memory. Neuropsychologia 46: 1965–1978. Yesavage JA, Brink TL, Rose TL, et al. 1983. Development and validation of a geriatric depression rating scale: a preliminary report. J Psychiatr Res 17: 37–49. Zamboni G, de Jager C A, Drazich, E, et al. 2013. Structural and functional bases of visuospatial associative memory in older adults. Neurobiol Aging 34: 961–972.
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Visual memory profiling with CANTAB in mild cognitive impairment (MCI) subtypes Onésimo Juncos-Rabadán1, David Facal1, Arturo X. Pereiro1 and Cristina Lojo-Seoane1 Department of Developmental and Educational Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain Correspondence to: O. Juncos-Rabadán, E-mail: [email protected]
Objective: Although visual memory has been shown to be impaired in amnestic mild cognitive impairment (aMCI), the differences between MCI subtypes are not well defined. The current study attempted to investigate visual memory profiles in different MCI subtypes. Methods: One hundred and seventy volunteers aged older than 50 years performed several visual memory tests included in the CANTAB battery. Participants were classified into four groups: (1) multiple domain aMCI (mda-MCI) (32 subjects); (2) single domain aMCI (sda-MCI)(57 subjects); (3) multiple domain non amnestic MCI (mdna-MCI) (32 subjects); and (4) controls (54 healthy individuals without cognitive impairment). Parametric and non parametric analyses were performed to compare the groups and to obtain their corresponding memory profiles. Results: The mda-MCI group exhibited impairments in both dimensions of episodic memory (recognition and recollection/recall), and also in learning and working memory, whereas the sda-MCI only showed impairment in recollection-delayed recall and learning. The mdna-MCI group displayed impairment in working memory but good preservation of learning and episodic memory. Conclusion: The CANTAB visual memory profiles may contribute to better cognitive characterization of patients with different MCI subtypes, allowing comparison across several processes involved in visual memory such as attention, recognition, recollection and working memory. Copyright # 2014 John Wiley & Sons, Ltd. Key words: visual memory; assessment; cognitive impairment; recognition memory; learning; working memory History: Received 4 October 2013; Accepted 3 February 2014; Published online 14 March 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4095
Introduction The term mild cognitive impairment (MCI) is generally used to refer to a clinical construct that may imply development of Alzheimer’s disease (AD) or of another form of dementia in the future, or it may imply stability or improvement of clinical symptoms (Petersen, 2004, 2009). There is general consensus regarding the criteria used to diagnose MCI and the classification of MCI into two main broad types, amnestic and non-amnestic, depending on whether memory is deteriorated or intact. The following general criteria are used in diagnosing MCI: (i) evidence of concern about a change in cognition, preferably corroborated by an informant; (ii) poorer performance in one
Copyright # 2014 John Wiley & Sons, Ltd.
or more cognitive domains that is greater than would be expected for the patient’s age and educational background; (iii) functional activities mainly preserved or minimally impaired; and (iv) non-fulfilment of diagnostic criteria for dementia (Albert et al., 2011). The two main types of MCI can be further differentiated into single and multiple domain MCI depending on whether the impairment affects one or more cognitive domains. Diagnostic criteria for amnestic subtypes of MCI include impairment of episodic memory, whereas those for non-amnestic subtypes include impairment in one or several cognitive domains with well-preserved episodic memory (Gauthier et al., 2006; Petersen, 2009). Studies of visual memory in MCI are scarce, and to our knowledge, no such studies have compared
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different MCI subtypes. In a study of aMCI patients, Barbeau et al. (2004, 2008) reported impairment of visual recognition memory based on the performance of a delayed matching-to-sample task. These authors found that some aMCI patients showed impaired recall and recognition, whereas others showed impaired recall but preserved recognition. Although the authors explained that they excluded patients with impairments in multiple domains other than memory, the neuropyschological description (Barbeau et al., 2008, Table 1, p. 1011) indicates that the aMCI subgroup with impairments in a delayed matching-to-sample test (DMSt) performed less well on the measures of executive functioning (verbal fluency) than the amnestic MCI (aMCI) subgroup without impairments in DMSt. The presence of impairment in executive functioning indicates that the corresponding aMCI subgroup may have included patients with multiple domain aMCI (mda-MCI). Alescio-Lautier et al. (2007) reported visuospatial recognition memory deficits in eight patients with single domain aMCI (sda-MCI). In a recent study, Westerberg et al. (2013) evaluated visual memory in 20 patients with aMCI by using a task involving recognition of silhouette images of common objects. The performance of aMCI patients was significantly worse than that of controls in the yes-no recognition test but not in the forced-choice recognition test. Recent studies have demonstrated that impaired performance of the paired
associates learning (PAL) test included in the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Sahakian et al. 1988) can significantly differentiate aMCI from controls and therefore may be a predictor of decline to AD (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012). Other visuospatial associative learning tests, which measure the ability to remember associations between objects and their locations, can detect early deficits suggestive of MCI (de Jager et al., 2003; Anderson et al., 2006; Zamboni et al., 2013). Saunders and Summers (2010) reported that the aMCI group displayed a significantly shorter span length than the control group in the CANTAB Spatial span (SSP) test. Recently, Juncos-Rabadán et al. (2013) reported that visual episodic memory tests (pattern recognition memory [PRM], delayed matching-to-sample [DMS] and paired associates learning [PAL] included in the CANTAB) can accurately distinguish aMCI patients from normal controls. Taking into account that most previous studies have focused on aMCI without differentiating the subtypes, the aim of the present study was to examine visual memory impairment in both aMCI subtypes (mdaMCI and sda-MCI) and in the non amnestic MCI type by using four CANTAB tests (PRM, DMS, SSP and PAL). Study of visual memory profiles in the aMCI subtypes and in the non-amnestic MCI type (which has generally been excluded from previous studies of
Table 1 Mean values and standard deviations (in parentheses) of the demographic and neuropsychological measures used in the study
Age Years of education Memory complaints (informant) MMSE CVLT (short delay free recall) CVLT(long delay free recall) Language Attention-calculation Praxis Executive function Visual acuity
1 Multiple domain amnestic MCI (mda-MCI) n = 32
2 Single domain amnestic MCI (sda-MCI) n = 57
3 Multiple domain non amnestic MCI (mdna-MCI) n = 32
4 HC n = 54
Fa Fb Fc χ
71.06 (8.36) 10.18 (4.09) 17.16 (4.4.09)
68.96 (8.60) 9.52 (4.08) 16.52 (4.44)
66.78 (8.56) 7.96 (3.77) 17.81 (5.24)
68.16 (8.75) 9.35 (4.62) 13.58 (3.44
Fa = 1.31 Fb = 1.59 Fb = 6.57**
23.40 (1.58) 3.28 (2.08)
27.50 (1.50) 4.10 (1.93)
24.53 (2.35) 9.25 (2.10)
28.01 (1.18) 9.57 (3.05)
χ d = 92.74** Fc = 99.57**
2
1, 3 < 2, 4f 1, 2 < 3, 4e
4.25 (3.35)
5.28 (2.97)
9.78 (2.69)
10.31 (3.03)
Fc = 49.57**
1, 2 < 3, 4e
23.15 (2.32) 5.43 (2.25 9.37 (2.73) 13.84 (3.78) 0.40 (0.16)
24.96 (2.42) 7.40 (1.64) 10.77 (1.74) 16.92 (3.58) 0.43 (0.21)
23.50 (2.06) 4.40 (1.73) 9.93 (2.72) 15.00 (4.19) 0.43 (0.17)
25.35 (2.06) 7.33 (1.56) 10.88 (1.20) 17.61 (4.61) 0.51(0.23)
Fc = 10.41** Fc = 27.90** 2 χ d = 12.37** Fc = 9.74** Fa = 1.35
1, 3 < 2, 4e 1, 3 < 2, 4e 1, 3 < 2, 4f 1, 3 < 2, 4e
2d
Post hoc
1, 2, 3 > 4e
Figures in bold format represent each one of the four groups (1,2,3,4). MCI, mild cognitive impairment; HC, healthy control; MMSE, mini–mental state examination; CVLT, California Verbal Learning Test. a Analysis of variance, dg (3,171); b Analysis of covariance (ANCOVA) with age as covariate, dg (4,170); c ANCOVA with age and years of education as covariates; d Kruskal-Wallis test e Intergroup differences, Bonferroni test f Intergroup differences, Mann-Whitney test **p < 0.01, *p < 0.05
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MCI) may contribute to a better understanding of the relationship between the various subtypes of MCI. Methods Participants
One hundred twenty one patients aged older than 50 years with MCI were recruited from participants taking part in an ongoing longitudinal cognitive assessment studies carried out in Primary Care Health Centres in Santiago de Compostela and Vigo, Spain (Juncos-Rabadán et al., 2012, 2013). These patients were recruited by general practitioners from patients who attended primary care centres with complaints of cognitive failure, without prior diagnosis of dementia, psychiatric or neurological disorders, severe illness, deafness or blindness, not receiving quimiotherapy, and not consumers of substances or alcohol. Each participant underwent extensive evaluation, including review of their medical history and neuropsychological assessment. Clinical diagnosis of MCI was made on the basis of the patient’s medical history and neuropsychological assessment. The participants met the general criteria for MCI outlined by Albert et al. (2011) and were classified into three groups according to consensual criteria (Petersen, 2004; Dubois et al., 2007): Group 1 comprised 32 individuals with mda-MCI; Group 2 comprised 57 individuals with sda-MCI; and Group 3 included 32 individuals with multiple domain non amnestic MCI (mdna-MCI). All amnestic MCI patients fulfilled the following criteria: (1) informant-corroborated memory complaints assessed by the Questionnaire for subjective memory complaints (Benedet and Seisdedos, 1996; short version); (2) performance of 1.5 SDs below age norms on the Spanish version of the California Verbal Learning Test (CVLT), which evaluates short and long delay free recall (Benedet and Alejandre, 1998); (3) no significant or minimal impact on activities of daily living assessed by the Lawton and Brody Index (Lawton and Brody, 1969); and (4) not demented, according the NINCDS-ADRDA and DMS-IV criteria. Regarding general cognitive functioning, the mda-MCI patients had scores of 1.5 SDs below age-related and education-related norms in the Spanish version of the Mini-Mental State Examination (MMSE), adapted and validated by with normal age and education groups (Lobo et al., 1999), and in at least two cognitive subscales of the Cambridge Cognitive Examination (CAMCOG-R), which assesses deterioration in specific domains such as Copyright # 2014 John Wiley & Sons, Ltd.
language, attention-calculation, praxis, perception and executive functioning (Huppert et al., 1996; Gallagher et al., 2010). Patients with sda-MCI performed the MMSE and all the subscales of the CAMCOG, except memory, in accordance with age and education norms. Patients with mdnaMCI (who did not fulfil clinical criteria for dementia) scored 1.5 SDs below age-related and education-related norms in the MMSE, with signs of deterioration in the same specific domains as mda-MCI patients, but not in memory. Fifty four control participants who scored higher than the cut-off in memory, general cognitive functioning and specific cognitive tests were recruited from the same Primary Care Health Centres. The demographic and neuropsychological profiles of the participants are summarised in Table 1, together with the between group differences (see Statistical analysis). None of the participants had any history of clinical stroke, traumatic brain injury, motor-sensory defects, alcohol or drug abuse/dependence, and none were diagnosed with any significant medical or psychiatric illnesses. To control for the effects of depression, patients who scored more than 10 in depression screening (Geriatric Depression Scale; Yesavage et al., 1983) were not included in the study. All participants had normal or corrected-to-normal vision and hearing and their visual acuity was controlled. All participants gave their written informed consent prior to participation in the study. The research project was approved by the Galician Clinical Research Ethics Committee (Xunta de Galicia, Spain), and the study was performed in accordance with the ethical standards established in the Declaration of Helsinki as revised in Seoul 2008.
The CANTAB-R measures
Pattern recognition memory assesses visual pattern recognition memory in a two-choice forced discrimination paradigm (Swainson et al., 2001). The participants were presented with two blocks of 12 visual patterns, each presented individually. In the recognition phase, subjects are required to choose between a pattern they have already seen and a novel pattern. The outcome measures were as follows: (a) percentage of correct responses, that is, the total number of correct patterns chosen, expressed as a percentage; (b) percentage of correct responses in each block; and (c) mean correct latency, that is, the time to respond correctly, scored in milliseconds. Int J Geriatr Psychiatry 2014; 29: 1040–1048
Visual memory profiles in MCI
The DMS assesses both simultaneous and shortterm visual memory. It is a four-choice recognition test of abstract patterns that share colour or pattern with distracters (Sahakian et al., 1988; Owen et al., 1993). The outcome variables were as follows: (a) percentage of correct responses (total), which measures the total number (%) of trials in which a correct selection was made in the subject’s first response; (b) percentage of correct responses (simultaneous), which reports the percentage of correct responses in trials in which the target stimulus and the three distracters were presented simultaneously; (c) percentage of correct responses (all delays), which reports the percentage of correct responses when the target and the distracters were presented after the stimulus had been hidden, with delays of 0 ms, 4000 ms and 12 000 ms; (d) percentage of correct responses for 0 ms, 4000 and 12 000 delay; (e) mean correct latency, which reports the average speed of all correct responses; (h) mean correct latency (simultaneous) of response when the target and distracters were presented simultaneously; and (i) mean correct latency (all delays) of response when the target and distracters were presented with a delay. Spatial span is a computerised version of the Corsi Blocks task that assesses visual working memory capacity (Owen et al., 1990). A pattern of white squares is shown on the screen. Some of the squares changes colour, one by one, in a variable sequence. At the end of the presentation of each sequence, a tone indicates that the participant should touch each of the boxes in the same order as they were originally presented. The number of boxes in the sequence is increased from a level of two at the start of the test to a final level of nine, with three sequences at each level. The outcome measures were as follows: (a) span length, that is, the longest sequence successfully recalled by the participant at each level; (b) total errors, that is, the number of times the participant selected an incorrect box; (c) mean time to the last response in span 2, 3 and 4, that is, the mean time to successfully recall the corresponding boxes sequences. Visuospatial Paired Associates Learning (PAL) assesses visuospatial episodic memory and learning (Sahakian et al., 1988). Boxes are displayed on the screen and are opened in a randomised order. One or more boxes contain a pattern. The patterns shown in the boxes are then displayed in the middle of the screen, one at a time, and the subject must touch the box in which the pattern was originally located. If the subject makes an error, the patterns are represented to remind the subject of their locations. The following measures were used: (a) total errors (adjusted), which reports the total number of errors, Copyright # 2014 John Wiley & Sons, Ltd.
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with an adjustment corrected to take into account stages that were failed /not attempted; (b) total errors (adjusted) at different levels of difficulty (1, 2, 3 and 6 patterns or shapes); the six-shape level involves a high level of difficulty and it has been used by several researchers to study MCI and AD (Alladi et al., 2006; Mitchell et al., 2009; Chamberlain et al., 2011); (c) stages completed, that is, the number of stages successfully completed; (d) mean errors to success, which summarises, for all stages, the mean number of errors made before the stage was successfully completed; and (e) mean trials to success, which is obtained by calculating the total number or trials required to locate all the patterns correctly, in all stages attempted, and dividing the result by the number of successfully completed stages. To control the effect of visual acuity on the CANTAB performance, we measured the visual acuity of both eyes by using the Lighthouse near visual acuity test. Statistical analysis
We used analysis of variance to test differences between the MCI and control groups in age and education. We used analysis of covariance (ANCOVA), with age and years of education as covariates controlling for differences in those variables, to analyse neuropsychological group differences. We also used ANCOVA, with age as covariate, to analyse all the CANTAB measures, taking into account that previous studies have demonstrated a significant age-related decline in the performance of some CANTAB tests (Robbins et al., 1994; Skolimowskaa et al., 2011). We used Bonferroni’s tests for post hoc comparisons and Levene’s test to assess the homogeneity of variance. When the variance was not homogeneous, we used the Kruskal-Wallis and Mann-Whitney tests. All statistical analyses were performed with SPSS for Windows, version 18.0. Results Neuropsychological diagnosis
Demographic and neuropsychological data are shown in Table 1. Comparison between groups revealed the following: (1) no significant differences between groups for age and education; (2) significantly fewer memory complaints in the Healthy Control (HC) group than in the three MCI groups; (3) significantly poorer performance of the MMSE by the mda-MCI Int J Geriatr Psychiatry 2014; 29: 1040–1048
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and mdna-MCI patients than by the NC and sda-MCI participants; (4) significantly poorer performance of the CVLT memory measures by the mda-MCI and the sdaMCI groups than by the mdna-MCI and the NC groups; (5) no significant differences between the two amnestic MCI groups in the CVLT measures; (6) significantly poorer performance by both multiple-domain MCI groups than by the sda-MCI and NC groups for language, attention-calculation, praxis and executive functioning; and (7) no significant differences for visual acuity. The results indicate that, as expected, the mda-MCI displayed impairment in general cognitive functioning (MMSE), in memory and in several other specific domains, the sda-MCI displayed only memory impairments, and the mdna-MCI displayed impairment in general cognitive functioning and in several specific domains but not in memory.
CANTAB results
Pattern recognition memory (Figure 1; Table 2). The percentage of correct responses was significantly lower in the mda-MCI than in all the other groups for all trials and for the first block; for the second block of trials, the percentage of correct responses was significantly lower in the two amnestic groups (mda-MCI and sda-MCI) than in both the control and the mdna-MCI group, but did not differ significantly between the latter two groups. The mean correct latency was only significantly higher in the mda-MCI group than in the control group. Delayed matching-to sample (Figure 2; Table 2). The percentage of correct responses was significantly lower in mda-MCI group than in the healthy controls
for the total trials, for all delays and for 4000 ms delay. For 12 000 ms delay, all three MCI groups (amnestic and non amnestic) performed significantly worse than the control group. No significant differences between MCI groups and healthy control were found for simultaneous and 0 ms delay trials. The mean correct latency was similar in all groups for all conditions. Spatial span (Figure 3; Table 2). No significance between-group differences were found for span length, total errors or mean time to last responses for span lengths of 2, and 3. The mean time to last responses for a span length of 4 was significantly longer in both multiple domain MCI groups than in the sda-MCI and control groups. Taking these results into account, we performed a supplementary bivariate correlation analysis to test the relationships between the latency for a span of 4 and the measures of episodic memory impaired in the two subtypes of amnestic MCI and the measures of executive function impaired in only the two multiple domain MCI subtypes. Latency was significantly correlated with executive function (Spearman’s rho = 0.113, p < 0.05), but not with short and long delay free recall measures (Spearman’s rho = 0.060 and 0.079, respectively). Paired associated learning (Figure 4; Table 2). Both amnestic groups (mda-MCI and sda-MCI) performed significantly worse than the control group on almost all PAL measures: total errors adjusted, errors 6 shapes adjusted, stages completed, mean error to success, and mean trial to success. However, there were no significant differences between the MCI and control groups for the number of errors adjusted in the two easy blocks, with 2 and 3 shapes. Participants with mdna-MCI performed similarly to controls on all the PAL measures. Discussion
Figure 1 Pattern recognition memory profiles. Percentage of correct responses (estimated marginal means) in all (total) trials and in the two trial blocks in the four groups.
Copyright # 2014 John Wiley & Sons, Ltd.
The profiles obtained by PRM measures showed that patients with the mda-MCI subtype displayed impairments in pattern recognition, which were confirmed by the lower number of correct responses in all trials (blocks 1 and 2) and by the longer latencies associated with correct responses. Patients with sda-MCI only displayed recognition impairment in block 2, whereas patients with mdna-MCI did not show any impairment in recognition and performed like the healthy controls. Comparison between multiple and single amnestic MCI subtypes for recognition showed that these subtypes may represent two points along the continuum between normal ageing and AD (Ralph et al., 2003; Brambati et al., 2009). The multiple-domain subtype seems to represent a late phase in which two aspects of episodic Int J Geriatr Psychiatry 2014; 29: 1040–1048
Copyright # 2014 John Wiley & Sons, Ltd.
(total) (simultaneous) (0 delay) (all delays) (4000 delay) (12 000 delay)
89.18 (43.33) 0.06 (0.24) 2.25 (4.77) 7.31 (6.87) 28.93 (14.43) 6.71 (0.99) 7.47 (2.61) 3.31 (0.86)
4.40 (0.83) 11.93 (3.97) 9063.22 (4845.18)
69.09 (13.80) 86.36 (12.45) 66.96 (21.28) 66.33 (16.56) 64.54 (19.37) 58.48 (21.23)
66.79 (11.02 69.01 (18.35) 64.58 (12.57) 4296.07 (1578.97)
56.52 (38.91) 0.03 (0.18) .70 (1.09) 3.87 (4.50) 18.77 (13.62) 7.32 (0.84) 5.66 (2.85) 2.70 (0.81)
4.65 (0.80) 11.60 (3.96) 6698.75 (2526.20)
75.52 (10.73) 88.44 (10.05) 72.06 (15.97) 69.88 (13.42) 74.31 (16.66) 63.27 (18.39)
76.38 (12.75) 81.87 (14.35) 70.90 (15.99) 3680.01 (1479.05)
2 sda-MCI
47.72 (30.04) 0.09 (0.29) 1.03 (1.44) 4.42 (3.89) 15.27 (10.04) 7.63 (0.69) 5.27 (2.74) 2.64 (0.66)
4.45 (0.83) 11.66 (5.25) 7892.75 (2674.63)
74.14 (9.41) 90.31 (11.49) 73.12 (17.49) 68.75 (11.28) 70.62 (15.22) 62.27 (16.46)
80.05 (12.18) 82.32 (14.24) 77.77 (14.68) 3611.22 (1582.10)
3 mdna-MCI
36.89 (27.81) 0.03 (0.18) 0.44 (0.87) 2.33 (2.06) 11.65 (10.04) 7.73 (0.58) 4.25 (2.61) 2.29 (0.64)
4.77 (0.67) 11.68 (3.97) 6429.49 (1666.14)
77.18 (9.54) 91.07 (10.21) 72.67 (15.07) 72.55 (12.00) 75.17 (16.73) 69.82 (15.07)
81.89 (12.13) 84.91 (14.92) 78.87 (14.49) 3176.71 (1106.24)
4 HC
2b
2
χ b = 33.51** Fa = 0.63 2 χ b = 6.69 2 χ b = 18.49** 2 χ b = 33.87** 2 χ b = 29.32** Fa = 9.02** Fa = 12.26**
Fa = 2.36 2 χ b = 4.26 2 χ b = 19.47**
Fa = 3.24* Fa = 1.05 Fa = 0.41 Fa = 2.81* Fa = 2.76* Fa = 2.87*
Fa = 10.30** Fa = 7.22** Fa = 7.02** Fa = 3.92*
Fa χ
0.995 1.000
0.671 0.661 0.679
0.046 0.045 0.047
0.135 0.175
0.737
0.998 0.982 0.979 0.823
Power
0.053
0.150 0.110 0.108 0.063
2
Effect size ŋp
1 > 2, 3 > 4d 1 > 2 > 4d 1, 2 < 4d 1 > 2 > 4c 1 > 2 > 4c
1 > 2 > 3, 4d
1, 3 < 2, 4d
1 < 4c 1 < 4c 1, 2, 3 < 4c
1 < 4c
1 < 2, 3, 4c 1 < 2, 3, 4c 1, 2 < 3, 4c 1 > 4c
Post hoc
MCI, mild cognitive impairment; HC, healthy control; PRM, pattern recognition memory; DMS, delayed matching-to-sample; SSP, spatial span; PAL, paired associates learning. a Analysis of covariance with age as covariate, dg (4,170); b Kruskal-Wallis test; c Intergroup differences, Bonferroni test; d Intergroup differences, Mann-Whitney test; **p < 0.01, *p < 0.05
PAL Total errors (adjusted) Error 1 shapes (adjusted) Error 2 shapes (adjusted) Error 3 shapes (adjusted) Error 6 shapes (adjusted) Stages completed Mean errors to success Mean trials to success
SSP Span length Total errors Time to last response (s.l. 4)
DMS % correct % correct % correct % correct % correct % correct
PRM % correct (total) % correct (Block 1) % correct (Block 2) Correct Latency ms
1 mda-MCI
Table 2 Mean values and standard deviations (in parentheses) of the CANTAB measures
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Figure 2 Delayed matching-to-sample profiles. Percentage of correct responses (estimated marginal means) in all (total) trials and in the simultaneous and delayed trials in the four groups.
Figure 3 Spatial span profiles. Mean time (estimated marginal means) to the first and last responses for span lengths of 2, 3 and 4 in the four groups
Figure 4 Paired associates learning profiles. Number of errors (adjusted estimated marginal means) for all (total), 1, 2, 3 and 6 shapes in the four groups.
memory, recollection (short and long delay recall) and familiarity (recognition), would be impaired and the single-domain subtype would represent an early phase Copyright # 2014 John Wiley & Sons, Ltd.
O. Juncos-Rabadán et al.
in which recollection is impaired, whereas recognition is quite well preserved. Our findings, which distinguished the amnestic subtypes, may contribute to clarifying the results of previous studies that reported preserved or impaired recognition in patients with aMCI considered as a single group (Wolk et al., 2008; Hudon et al., 2009; Algarabel et al., 2012; Westerberg et al., 2013). Our results for DMS showed an impaired profile, especially in the amnestic multiple-domain MCI subtype. The DMS involves several cognitive processes: perception of colour and abstract shapes (patterns); selective attention, which is evident in the simultaneous trials; recognition memory (familiarity) in the delayed trials; episodic memory (recollection) of different patterns in the short and delayed recall trials; and working memory for simultaneous processing and storage of information (updating) (Miyake et al., 2000) in the four-choice recognition of target patterns from distracters. DMS profiles of performance on the total trials and total delayed trials indicate that the mda-MCI subtype is impaired in episodic memory (recognition) and working memory, whereas perception and selective attention seem to be preserved. This is consistent with the findings of Barbeau et al. (2004, 2008) for a subgroup of aMCI patients who displayed impairments in executive functions. DMS trials with 12 000 ms delay involve greater involvement of episodic memory (delayed recall) and working memory (updating) than trials with 0 or 4000 ms delay. This may explain the different performance of the sda-MCI and mdna-MCI groups in the 12 000 ms delay trials. Impaired performance of these trials by patients with sda-MCI may be caused by impaired recollection (delayed recall), whereas similar impairment in patients with mdna-MCI may be caused by working memory deficits. Considering the PRM and DMS profiles together, we can conclude that recollective processes may be disrupted in the early stages of amnestic MCI (sdaMCI), whereas familiarity (recognition) may remain intact until later stages such as in mda-MCI, as suggested by Westerberg et al. (2013). With respect to non amestic MCI, we conclude that visual recognition is well preserved and suggest that it may be impaired when recognition involves a greater working memory load. Regarding the SSP, the two multiple-domain MCI (amnestic and non amnestic) groups and the control and sda-MCI groups significantly differed in only one measure (the time to the last response for a span of 4). There were no significant differences in memory span length (mean around 4), in contrary to the findings of Saunders and Summers (2010), or in errors. It is possible that subjects with multiple-domain MCI require more processing resources than controls and subjects with sda-MCI to cope with storage and Int J Geriatr Psychiatry 2014; 29: 1040–1048
Visual memory profiles in MCI
simultaneous processing requirements in the most complex SSP sequences. Significant correlations between the SSP latency measure and the working memory measure (CAMCOG) suggest that impairment of working memory, which is common to the multiple domain MCI subtypes, may occur in the SSP profiles. The PAL profiles indicate that the mda-MCI group displayed the highest level of impairment in all the measures. The profile of the sda-MCI group for all the PAL measures represented an intermediate level between the mda-MCI and the control group. Both profiles significantly differentiated aMCI from controls (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012). The performance of the non amnestic MCI group was similar to that of the controls, thus confirming that pair associates learning is well preserved in the mdna-MCI group and that this MCI subtype probably represents a prodomal form of types of dementia in which episodic memory is well preserved (Gauthier et al., 2006; Dubois et al., 2007). In conclusion, the CANTAB visual memory profiles identified by the PRM, DMS, SSP and PAL tests may contribute to better cognitive characterization of patients with different MCI subtypes allowing comparisons across several processes involved in visual memory such as attention, recognition, recollection and working memory. The main limitation of the study is the lack of a single domain non amnestic MCI subtype that impedes to have a complete view of the MCI profiles. Further research on longitudinal changes in these profiles is needed for a better understanding of MCI subtypes and of their possible conversion to different types of dementia. Conflict of interest None declared. Key points
examined visual, episodic and working • We memory and learning in multiple-domain and
• • •
single-domain amnestic and in multiple-domain non amnestic mild cognitive impairment (MCI). The profiles of the mda-MCI patients revealed recognition, recalling, learning and working memory impairments. The profiles of the sda-MCI patients indicated impairment in recall and learning. The profiles of the mdna-MCI patients identified impairment in working memory but not in recognition, recall or learning.
Copyright # 2014 John Wiley & Sons, Ltd.
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