RESEARCH ARTICLE
Do the Cambridge Neuropsychological Test Automated Battery episodic memory measures discriminate amnestic mild cognitive impairment? Onésimo Juncos-Rabadán, Arturo X. Pereiro, David Facal, Alba Reboredo and Cristina Lojo-Seoane Department of Developmental and Educational Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain Correspondence to: O. Juncos-Rabadán, E-mail: [email protected]
Although visual recognition memory and visuospatial paired associates learning has been shown to be impaired in amnestic mild cognitive impairment (aMCI), the sensitivity and specificity of the visual memory tests used to identify aMCI are not well defined. The current study attempted to analyze the sensitivity and specificity of three visual episodic memory tests (Pattern Recognition Memory [PRM], Delayed Matching to Sample [DMS], and Paired Associated Learning [PAL]) from the CANTAB, in differentiating aMCI patients from control healthy participants. Methods: Seventy seven aMCI patients and 85 cognitive normal controls aged over 50 years performed the PRM, DMS, and PAL tests. Univariate and multivariate logistic regression and receiver operating characteristic curve analyses were used to study the relationships between aMCI and visual memory measures. Results: The three Cambridge Neuropsychological Test Automated Battery measures significantly predicted aMCI. The optimal predictive model combined the total percent correct responses for PRM and DMS with the PAL total errors (six shapes adjusted), with a sensitivity of 72%, specificity of 83%, and achieved predictive accuracy of 80%. Conclusion: Visual episodic memory tasks such as those involved in the PRM, DMS, and PAL tests (included in the Cambridge Neuropsychological Test Automated Battery) may sensitively discriminate aMCI patients from normal controls. These tests may be useful for correct diagnosis of aMCI. Copyright # 2013 John Wiley & Sons, Ltd.
Objective:
Key words: visual memory; assessment; cognitive impairment; recognition memory; learning History: Received 2 April 2013; Accepted 2 October 2013; Published online 22 October 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4042
Introduction Although somewhat controversial, the term mild cognitive impairment (MCI) is defined as a diagnostic entity for characterizing individuals who suffer from some cognitive impairment, but of insufficient severity to constitute dementia (Petersen, 2004). There is a 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 or not the memory is impaired (Albert et al., 2011). The general core clinical and cognitive criteria (Albert et al., 2011) for diagnosing MCI are Copyright # 2013 John Wiley & Sons, Ltd.
as follows: (i) evidence of concern about a change in cognition, in comparison with the previous level; (ii) evidence of poorer performance in one or more cognitive domains that is greater than expected for the patient’s age and educational background; (iii) preservation of independence in functional abilities; and (iv) nonfulfillment of diagnostic criteria for dementia. The amnestic MCI (aMCI) type is most likely to progress to Alzheimer’s Disease (AD) and is a useful clinical designation for describing individuals who have a memory deficit characteristic of prodromal AD (i.e., amnestic syndrome of hippocampal type) (Dubois et al., 2007; Dubois et al., 2010). Diagnostic criteria for aMCI are Int J Geriatr Psychiatry 2014; 29: 602–609
Does CANTAB discriminate mild cognitive impairment?
based on the primary feature of memory impairment; single domain aMCI (sda-MCI) requires only the presence of objective episodic memory impairment; whereas the multiple-domain (mda-MCI) subtype requires the presence of additional impairments in other non-amnestic domains. . Among the several possible memory tests thought to be sensitive to early changes occurring in the preclinical phase of AD and in MCI, visual recognition memory and visuospatial paired associated learning tasks have been shown to be impaired in MCI. The Cambridge Neuropsychological Test Automated Battery (CANTAB) includes visual memory tests, such as the Pattern Recognition Memory (PRM), Delayed Matching to Sample (DMS) and Paired Associates Learning (PAL) tests, which have proven particularly sensitive to hippocampal damage and have been validated in cases of AD (Sahakian et al. 1988; Sahgal et al. 1992). Normative data from a large (n ≈ 800) sample of healthy community dwelling elderly volunteers are available for these tests, and acceptable to good test–retest reliability has been confirmed. Impairment of visual recognition memory, based on the delayed matching-to-sample schedule (Barbeau et al., 2004) and on other visuospatial recognition memory tasks (Alescio-Lautier et al. ., 2007), has been reported in MCI. The visuospatial paired associate learning task included in the PAL test has been shown to be impaired at an early stage of AD and to be a good predictor of the probability that an individual with mild memory impairments or aMCI will subsequently be diagnosed with probable AD (Swainson et al., 2001; Blackwell et al., 2004; Ahmed et al., 2008). Recent studies have demonstrated that impaired performance of the PAL test may significantly differentiate aMCI from controls and may be a predictor of decline to AD (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012), with good sensitivity (0.80) and acceptable specificity (0.66) (Mitchell et al., 2009) for two-year outcomes. Other visuospatial associative learning tests, such as the Placing Test, which measures the ability to remember associations between objects and their locations, can detect early deficits suggestive of cognitive impairment or MCI in a population of healthy older adults (de Jager et al., 2003; Anderson et al., 2006; Zamboni et al., 2013). However, the sensitivity and specificity of the visual memory tests for discriminating aMCI patients from controls are not well established. De Jager and colleagues (de Jager et al., 2003) found that the specificity and sensitivity of the Placing Test for discriminating between 29 cases with aMCI and 51 controls were around 70% and 60%, respectively. These authors also Copyright # 2013 John Wiley & Sons, Ltd.
603
studied the memory component of the Cambridge Cognitive Examination (CAMCOG), which includes visual and verbal delayed recall and visual recognition, and they found that the overall accuracy of the test for differentiating positive and negative predementia-AD was around 66% with a sensitivity of 72% and a specificity of 60% (de Jager et al., 2010). Chamberlain and colleagues (Chamberlain et al., 2011) used the PRM, DMS, and PAL memory tests, in combination with other neuropsychological tests, to analyze cognitive deterioration in a two-year longitudinal study of AD patients and subjects with subjective memory impairment (SMI). For SMI subjects, 60% of the variance in cognitive deterioration was accounted for by a model including gender (females, worse outcome), PAL (six-stage errors), spatial recognition memory, and early change scores for ADAS-cog (a scale for assessing cognitive symptoms in AD) (Rosen et al., 1984) and a test of visual attention. The aim of the present study was to analyze the sensitivity and specificity of the following three visual episodic memory tests, which are included in the CANTAB, for differentiating aMCI patients from healthy controls: PRM, DMS, and PAL. A further aim was to assess the influence of age on episodic visual memory, taking into account previous studies that confirmed significant age-related decline in the performance of some CANTAB tests (Robbins et al., 1994; Skolimowskaa et al., 2011). Methods Participants
Seventy-seven patients aged over 50 years with MCI were recruited from participants who took part in the ongoing longitudinal cognitive assessment studies carried out in Primary Care Health Centres in Santiago de Compostela and Vigo, Spain (Juncos-Rabadán et al., 2012). All subjects met the general criteria for MCI outlined by Albert et al. (2011) and the criteria for aMCI proposed by Petersen and colleagues (Petersen, 2004; Dubois et al., 2007). Diagnosis of aMCI was given clinically, and on the basis of the test of verbal memory California Verbal Learning Test and other cognitive domains different from visual memory. Twenty-nine of the aMCI fulfilled criteria for multiple domain aMCI (mda-MCI) and forty-eight subjects fulfilled criteria for single domain aMCI (sda-MCI). All subjects fulfilled the following criteria: (i) informant-corroborated memory complaints assessed by the Questionnaire for subjective memory complaints (Benedet and Seisdedos, Int J Geriatr Psychiatry 2014; 29: 602–609
O. Juncos-Rabadán et al.
604
1996; short version); (ii) performance of less than 1.5 SDs below age norms on the Spanish version of the California Verbal Learning Test, which evaluates short and long delay free recall (Benedet and Alejandre, 1998); (iii) no significant impact on activities of daily living assessed by the Lawton and Brody Index (Lawton and Brody, 1969); and (iv) not demented according the NINCDS-ADRDA and DMS-IV criteria. With respect to general cognitive functioning, the mda-MCI subjects scored more than 1.5 standard deviations below agerelated and education-related norms in the Spanish version of the MMSE, adapted and validated by with normal age and education groups (Lobo et al., 1999), and in at least two cognitive subscales of the CAMCOG-R, which assesses deterioration in specific domains such as language, attention-calculation, praxis, perception, and executive functioning (Huppert et al., 1996; Gallagher et al., 2010). Eighty-five control participants scoring higher than the cut-off on memory, general cognitive functioning, and specific cognitive domain tests were recruited from the same Primary Care Health Centres. The demographic and neuropsychological profile of the participants is summarized in Table 1, together with the differences between groups calculated by the corresponding analysis of covariants (see Statistical analysis). None of the participants has 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, GDS, short version; Yesavage et al., 1983) were not included in the study. All participants had normal or correctedto-normal vision and hearing ability. All subjects 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 1964 Declaration of Helsinki. All participants underwent extensive evaluation, including review of their medical history and neuropsychological assessment. The CANTAB-R measures
Pattern Recognition Memory. This is a test of visual pattern recognition memory in a two-choice forced discrimination paradigm. The subject is presented with two series of 12 visual patterns, each presented individually. In the recognition phase, the subject is Copyright # 2013 John Wiley & Sons, Ltd.
required to choose between a pattern they have already seen and a novel pattern. The key outcome measure is the percentage of correct patterns chosen. Delayed Matching to Sample. This is a test of simultaneous and delayed matching to sample. It is a 4-choice recognition test of abstract patterns sharing color or pattern with distracters (10 trials at each time delay). The outcome variable is the percentage of correct responses, which measures the total number (%) of trials in which a correct selection was made in the subject’s first response. Visuospatial PAL. This test assesses visuospatial memory and learning. Boxes are displayed on the screen and are opened in a randomized order. One or more boxes contain a pattern. The patterns 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 measure used was the total numbers of errors made at the 6-item level difficulty stage, which is corrected to take into account stages that were failed/not attempted. This stage involves a high level of difficulty and it has been used by several researchers (Alladi et al., 2006; Mitchell et al., 2009; Chamberlain et al., 2011). Statistical analysis
We used ANOVA to test differences between the aMCI and control groups in age and education. We used ANCOVAs, with age and years of education as covariates controlling for differences in those variables, to analyze neuropsychological group differences. We used Bonferroni’s tests for post hoc comparisons and Levene’s test to assess the homogeneity of variance. If the variance was not homogeneous, we used the Kruskal–Wallis test to determine the significance of differences. We used univariate and multivariate logistic regression models (Enter procedure) to explore the value of the CANTAB measures for discriminating between the entire amnestic MCI sample (including mda-MCI and sda-MCI) and controls. We considered the percentage of correct responses in PRM and DMS tests, and the total numbers of errors adjusted made on the 6-level of the PAL as independent variables, and the presence or absence of aMCI as dependent variables. All scores were converted to categorical variables, and a score at least 1.5 SD below that of the control group was considered as a cut-off for determining low and high levels of performance. We have not used the CANTAB norms because at the Int J Geriatr Psychiatry 2014; 29: 602–609
Does CANTAB discriminate mild cognitive impairment?
605
Table 1 Mean values and standard deviations (in parentheses) of the demographic and neuropsychological measures used in the study Control, C
p
Do the Cambridge Neuropsychological Test Automated Battery episodic memory measures discriminate amnestic mild cognitive impairment? Onésimo Juncos-Rabadán, Arturo X. Pereiro, David Facal, Alba Reboredo and Cristina Lojo-Seoane Department of Developmental and Educational Psychology, University of Santiago de Compostela, Santiago de Compostela, Spain Correspondence to: O. Juncos-Rabadán, E-mail: [email protected]
Although visual recognition memory and visuospatial paired associates learning has been shown to be impaired in amnestic mild cognitive impairment (aMCI), the sensitivity and specificity of the visual memory tests used to identify aMCI are not well defined. The current study attempted to analyze the sensitivity and specificity of three visual episodic memory tests (Pattern Recognition Memory [PRM], Delayed Matching to Sample [DMS], and Paired Associated Learning [PAL]) from the CANTAB, in differentiating aMCI patients from control healthy participants. Methods: Seventy seven aMCI patients and 85 cognitive normal controls aged over 50 years performed the PRM, DMS, and PAL tests. Univariate and multivariate logistic regression and receiver operating characteristic curve analyses were used to study the relationships between aMCI and visual memory measures. Results: The three Cambridge Neuropsychological Test Automated Battery measures significantly predicted aMCI. The optimal predictive model combined the total percent correct responses for PRM and DMS with the PAL total errors (six shapes adjusted), with a sensitivity of 72%, specificity of 83%, and achieved predictive accuracy of 80%. Conclusion: Visual episodic memory tasks such as those involved in the PRM, DMS, and PAL tests (included in the Cambridge Neuropsychological Test Automated Battery) may sensitively discriminate aMCI patients from normal controls. These tests may be useful for correct diagnosis of aMCI. Copyright # 2013 John Wiley & Sons, Ltd.
Objective:
Key words: visual memory; assessment; cognitive impairment; recognition memory; learning History: Received 2 April 2013; Accepted 2 October 2013; Published online 22 October 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4042
Introduction Although somewhat controversial, the term mild cognitive impairment (MCI) is defined as a diagnostic entity for characterizing individuals who suffer from some cognitive impairment, but of insufficient severity to constitute dementia (Petersen, 2004). There is a 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 or not the memory is impaired (Albert et al., 2011). The general core clinical and cognitive criteria (Albert et al., 2011) for diagnosing MCI are Copyright # 2013 John Wiley & Sons, Ltd.
as follows: (i) evidence of concern about a change in cognition, in comparison with the previous level; (ii) evidence of poorer performance in one or more cognitive domains that is greater than expected for the patient’s age and educational background; (iii) preservation of independence in functional abilities; and (iv) nonfulfillment of diagnostic criteria for dementia. The amnestic MCI (aMCI) type is most likely to progress to Alzheimer’s Disease (AD) and is a useful clinical designation for describing individuals who have a memory deficit characteristic of prodromal AD (i.e., amnestic syndrome of hippocampal type) (Dubois et al., 2007; Dubois et al., 2010). Diagnostic criteria for aMCI are Int J Geriatr Psychiatry 2014; 29: 602–609
Does CANTAB discriminate mild cognitive impairment?
based on the primary feature of memory impairment; single domain aMCI (sda-MCI) requires only the presence of objective episodic memory impairment; whereas the multiple-domain (mda-MCI) subtype requires the presence of additional impairments in other non-amnestic domains. . Among the several possible memory tests thought to be sensitive to early changes occurring in the preclinical phase of AD and in MCI, visual recognition memory and visuospatial paired associated learning tasks have been shown to be impaired in MCI. The Cambridge Neuropsychological Test Automated Battery (CANTAB) includes visual memory tests, such as the Pattern Recognition Memory (PRM), Delayed Matching to Sample (DMS) and Paired Associates Learning (PAL) tests, which have proven particularly sensitive to hippocampal damage and have been validated in cases of AD (Sahakian et al. 1988; Sahgal et al. 1992). Normative data from a large (n ≈ 800) sample of healthy community dwelling elderly volunteers are available for these tests, and acceptable to good test–retest reliability has been confirmed. Impairment of visual recognition memory, based on the delayed matching-to-sample schedule (Barbeau et al., 2004) and on other visuospatial recognition memory tasks (Alescio-Lautier et al. ., 2007), has been reported in MCI. The visuospatial paired associate learning task included in the PAL test has been shown to be impaired at an early stage of AD and to be a good predictor of the probability that an individual with mild memory impairments or aMCI will subsequently be diagnosed with probable AD (Swainson et al., 2001; Blackwell et al., 2004; Ahmed et al., 2008). Recent studies have demonstrated that impaired performance of the PAL test may significantly differentiate aMCI from controls and may be a predictor of decline to AD (Alladi et al., 2006; de Rover et al., 2011; Summers and Saunders, 2012), with good sensitivity (0.80) and acceptable specificity (0.66) (Mitchell et al., 2009) for two-year outcomes. Other visuospatial associative learning tests, such as the Placing Test, which measures the ability to remember associations between objects and their locations, can detect early deficits suggestive of cognitive impairment or MCI in a population of healthy older adults (de Jager et al., 2003; Anderson et al., 2006; Zamboni et al., 2013). However, the sensitivity and specificity of the visual memory tests for discriminating aMCI patients from controls are not well established. De Jager and colleagues (de Jager et al., 2003) found that the specificity and sensitivity of the Placing Test for discriminating between 29 cases with aMCI and 51 controls were around 70% and 60%, respectively. These authors also Copyright # 2013 John Wiley & Sons, Ltd.
603
studied the memory component of the Cambridge Cognitive Examination (CAMCOG), which includes visual and verbal delayed recall and visual recognition, and they found that the overall accuracy of the test for differentiating positive and negative predementia-AD was around 66% with a sensitivity of 72% and a specificity of 60% (de Jager et al., 2010). Chamberlain and colleagues (Chamberlain et al., 2011) used the PRM, DMS, and PAL memory tests, in combination with other neuropsychological tests, to analyze cognitive deterioration in a two-year longitudinal study of AD patients and subjects with subjective memory impairment (SMI). For SMI subjects, 60% of the variance in cognitive deterioration was accounted for by a model including gender (females, worse outcome), PAL (six-stage errors), spatial recognition memory, and early change scores for ADAS-cog (a scale for assessing cognitive symptoms in AD) (Rosen et al., 1984) and a test of visual attention. The aim of the present study was to analyze the sensitivity and specificity of the following three visual episodic memory tests, which are included in the CANTAB, for differentiating aMCI patients from healthy controls: PRM, DMS, and PAL. A further aim was to assess the influence of age on episodic visual memory, taking into account previous studies that confirmed significant age-related decline in the performance of some CANTAB tests (Robbins et al., 1994; Skolimowskaa et al., 2011). Methods Participants
Seventy-seven patients aged over 50 years with MCI were recruited from participants who took part in the ongoing longitudinal cognitive assessment studies carried out in Primary Care Health Centres in Santiago de Compostela and Vigo, Spain (Juncos-Rabadán et al., 2012). All subjects met the general criteria for MCI outlined by Albert et al. (2011) and the criteria for aMCI proposed by Petersen and colleagues (Petersen, 2004; Dubois et al., 2007). Diagnosis of aMCI was given clinically, and on the basis of the test of verbal memory California Verbal Learning Test and other cognitive domains different from visual memory. Twenty-nine of the aMCI fulfilled criteria for multiple domain aMCI (mda-MCI) and forty-eight subjects fulfilled criteria for single domain aMCI (sda-MCI). All subjects fulfilled the following criteria: (i) informant-corroborated memory complaints assessed by the Questionnaire for subjective memory complaints (Benedet and Seisdedos, Int J Geriatr Psychiatry 2014; 29: 602–609
O. Juncos-Rabadán et al.
604
1996; short version); (ii) performance of less than 1.5 SDs below age norms on the Spanish version of the California Verbal Learning Test, which evaluates short and long delay free recall (Benedet and Alejandre, 1998); (iii) no significant impact on activities of daily living assessed by the Lawton and Brody Index (Lawton and Brody, 1969); and (iv) not demented according the NINCDS-ADRDA and DMS-IV criteria. With respect to general cognitive functioning, the mda-MCI subjects scored more than 1.5 standard deviations below agerelated and education-related norms in the Spanish version of the MMSE, adapted and validated by with normal age and education groups (Lobo et al., 1999), and in at least two cognitive subscales of the CAMCOG-R, which assesses deterioration in specific domains such as language, attention-calculation, praxis, perception, and executive functioning (Huppert et al., 1996; Gallagher et al., 2010). Eighty-five control participants scoring higher than the cut-off on memory, general cognitive functioning, and specific cognitive domain tests were recruited from the same Primary Care Health Centres. The demographic and neuropsychological profile of the participants is summarized in Table 1, together with the differences between groups calculated by the corresponding analysis of covariants (see Statistical analysis). None of the participants has 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, GDS, short version; Yesavage et al., 1983) were not included in the study. All participants had normal or correctedto-normal vision and hearing ability. All subjects 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 1964 Declaration of Helsinki. All participants underwent extensive evaluation, including review of their medical history and neuropsychological assessment. The CANTAB-R measures
Pattern Recognition Memory. This is a test of visual pattern recognition memory in a two-choice forced discrimination paradigm. The subject is presented with two series of 12 visual patterns, each presented individually. In the recognition phase, the subject is Copyright # 2013 John Wiley & Sons, Ltd.
required to choose between a pattern they have already seen and a novel pattern. The key outcome measure is the percentage of correct patterns chosen. Delayed Matching to Sample. This is a test of simultaneous and delayed matching to sample. It is a 4-choice recognition test of abstract patterns sharing color or pattern with distracters (10 trials at each time delay). The outcome variable is the percentage of correct responses, which measures the total number (%) of trials in which a correct selection was made in the subject’s first response. Visuospatial PAL. This test assesses visuospatial memory and learning. Boxes are displayed on the screen and are opened in a randomized order. One or more boxes contain a pattern. The patterns 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 measure used was the total numbers of errors made at the 6-item level difficulty stage, which is corrected to take into account stages that were failed/not attempted. This stage involves a high level of difficulty and it has been used by several researchers (Alladi et al., 2006; Mitchell et al., 2009; Chamberlain et al., 2011). Statistical analysis
We used ANOVA to test differences between the aMCI and control groups in age and education. We used ANCOVAs, with age and years of education as covariates controlling for differences in those variables, to analyze neuropsychological group differences. We used Bonferroni’s tests for post hoc comparisons and Levene’s test to assess the homogeneity of variance. If the variance was not homogeneous, we used the Kruskal–Wallis test to determine the significance of differences. We used univariate and multivariate logistic regression models (Enter procedure) to explore the value of the CANTAB measures for discriminating between the entire amnestic MCI sample (including mda-MCI and sda-MCI) and controls. We considered the percentage of correct responses in PRM and DMS tests, and the total numbers of errors adjusted made on the 6-level of the PAL as independent variables, and the presence or absence of aMCI as dependent variables. All scores were converted to categorical variables, and a score at least 1.5 SD below that of the control group was considered as a cut-off for determining low and high levels of performance. We have not used the CANTAB norms because at the Int J Geriatr Psychiatry 2014; 29: 602–609
Does CANTAB discriminate mild cognitive impairment?
605
Table 1 Mean values and standard deviations (in parentheses) of the demographic and neuropsychological measures used in the study Control, C
p
