This article was downloaded by: [RMIT University] On: 16 March 2013, At: 09:50 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Journal of Clinical and Experimental Neuropsychology Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ncen20 Serial position effects in Alzheimer's disease, mild cognitive impairment, and normal aging: Predictive value for conversion to dementia Catarina Cunha a , Manuela Guerreiro b c , Alexandre de Mendonça c , Paulo Eduardo Oliveira d & Isabel Santana a a Department of Neurology, Neuropsychology Laboratory, Coimbra University Hospital, Coimbra, Portugal b Department of Neurology, Language Studies Laboratory, Santa Maria Hospital, Lisbon, Portugal c Molecular Medicine Institute, Lisbon, Portugal d Mathematical Department, CMUC, Coimbra University, Coimbra, Portugal Version of record first published: 25 Jun 2012. To cite this article: Catarina Cunha , Manuela Guerreiro , Alexandre de Mendonça , Paulo Eduardo Oliveira & Isabel Santana (2012): Serial position effects in Alzheimer's disease, mild cognitive impairment, and normal aging: Predictive value for conversion to dementia, Journal of Clinical and Experimental Neuropsychology, 34:8, 841-852 To link to this article: http://dx.doi.org/10.1080/13803395.2012.689814 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
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This article was downloaded by: [RMIT University]On: 16 March 2013, At: 09:50Publisher: RoutledgeInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: MortimerHouse, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Clinical and ExperimentalNeuropsychologyPublication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/ncen20
Serial position effects in Alzheimer's disease,mild cognitive impairment, and normal aging:Predictive value for conversion to dementiaCatarina Cunha a , Manuela Guerreiro b c , Alexandre de Mendonça c , Paulo EduardoOliveira d & Isabel Santana aa Department of Neurology, Neuropsychology Laboratory, Coimbra UniversityHospital, Coimbra, Portugalb Department of Neurology, Language Studies Laboratory, Santa Maria Hospital,Lisbon, Portugalc Molecular Medicine Institute, Lisbon, Portugald Mathematical Department, CMUC, Coimbra University, Coimbra, PortugalVersion of record first published: 25 Jun 2012.
To cite this article: Catarina Cunha , Manuela Guerreiro , Alexandre de Mendonça , Paulo Eduardo Oliveira &Isabel Santana (2012): Serial position effects in Alzheimer's disease, mild cognitive impairment, and normal aging:Predictive value for conversion to dementia, Journal of Clinical and Experimental Neuropsychology, 34:8, 841-852
To link to this article: http://dx.doi.org/10.1080/13803395.2012.689814
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial orsystematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distributionin any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that thecontents will be complete or accurate or up to date. The accuracy of any instructions, formulae, anddrug doses should be independently verified with primary sources. The publisher shall not be liable forany loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever causedarising directly or indirectly in connection with or arising out of the use of this material.
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY2012, 34 (8), 841–852
Serial position effects in Alzheimer’s disease, mildcognitive impairment, and normal aging: Predictive
value for conversion to dementia
Catarina Cunha1, Manuela Guerreiro2,3, Alexandre de Mendonça3,Paulo Eduardo Oliveira4, and Isabel Santana1
1Department of Neurology, Neuropsychology Laboratory, Coimbra University Hospital, Coimbra,Portugal2Department of Neurology, Language Studies Laboratory, Santa Maria Hospital, Lisbon, Portugal3Molecular Medicine Institute, Lisbon, Portugal4Mathematical Department, CMUC, Coimbra University, Coimbra, Portugal
Serial position effects in word list learning have been used to differentiate normal aging and dementia. Prominentrecency and diminished primacy have consistently been observed in Alzheimer’s disease (AD). We examined serialposition effects in patients with mild cognitive impairment (MCI), in patients with AD, and in normal healthycontrols. Additionally, we classified MCI patients into those who progressed to AD (MCI-p) and those who didnot (MCI-np). We compared two serial position measures: regional and standard scores. Regional scores, mainlythe primacy effect, improved discrimination between MCI and controls and between MCI-np and MCI-p, provingto be more sensitive and specific than the recency effect.
The serial position paradigm has been a prominentaspect of human memory theory for over a century(Tulving, 1985) due to its ability to elucidate theprocesses of learning and memory, as reflected inthe primacy and recency effects. It has been charac-terized since the early experiments of Ebbinghaus,(Squire & Kandel, 2002) but have been highlightedin 1953 by McCrary and Hunter who tested thehypothesis about the percentages of errors at serialposition that define an invariate distribution in rolelearning curves.
The primacy effect refers to the finding thatearly-presented items of a word list are typicallybetter recalled than midlist items. Also end-listitems are usually better recalled than midlist items,
This work was supported by the Portuguese Foundation for Science and Technology (FCT) through PIC/IC/83206/2007.Address correspondence to Catarina Cunha, Rua Carlos Seixas, 165, 2◦ Esq, 3030-177 Coimbra, Portugal (E-mail: catarina.
a phenomenon known as the recency effect. Thispattern is called the typical serial position effect.The primacy effect tends to reflect the enhancedrecall of items that have entered into long-termmemory, while recency items are assumed to subsistin the short-term memory/working memory store(Atkinson & Shiffrin, 1968).When recall is plottedaccording to the serial position paradigm, theresulting learning curve is U-shaped (Murdock,1962). Similar profiles are observed in healthyolder and younger adults (Carlesimo, Sabbadini,Fadda, & Caltagirone, 1995; Mitrushina, Satz,Chervinsky, & D’Elia, 1991; Petersen, Smith,Kokmen, & Irving, 1992; Wright, 1982), althoughoverall recall in older adults may be lower. Diverseserial position profiles in tasks of word list recallhave been explored to identify learning profiles of
The initial symptom of AD is a decline inepisodic memory, which is related to the very earlyneuropathological changes observed in the hip-pocampus and entorhinal cortex (Salmon, 2000).However, according to the National Institute ofNeurological and Communicative Disorders andStroke–Alzheimer’s Disease and Related DisordersAssociation (NINCDS-ADRDA; McKhann et al.,1984), individuals with probable AD should presentother cognitive deficits besides memory loss (e.g.,language, executive functions, attention, and visu-ospatial abilities) that may also impact workingmemory tasks. Even with the revised NINCDS-ADRDA (McKhann et al., 2011) clinical criteriafor AD, the memory impairment maintains as themajor criterion together with the corroboration ofthe evidence of biomarkers.
MCI (Petersen et al., 1999; Petersen et al., 2001)is considered to be a transitional state betweennormal functioning and dementia and refers tocognitive impairment greater than expected for agiven age that fails to meet the criteria for dementia(Winblad et al., 2004). The clinical feature of mostof these patients is an isolated impairment in learn-ing and retaining new information (Albert, Blacker,Moss, Tanzi, & McArdle, 2007; Bondi, Salmon,Galasko, Thomas, & Thal, 1999; Petersen et al.,1999). Furthermore, MCI has been identified asan important risk factor for developing AD witha 15% annual conversion rate compared to 1–2%in the healthy elderly population (Petersen et al.,2001). In some patients, MCI already representsa prodromal stage of AD (Dubois et al., 2007;Howieson et al., 2008). MCI remains a challeng-ing entity despite increased interest in identifyingAD early in the course of the disease. Moreover,together with Petersen criteria, it seems importantto develop more specific instruments to determinewhether a patient with MCI has incipient ADor a benign form of MCI without risk of pro-gression. An important question to be addressedrelates to changes that occur in the level of learningand retaining new information in individuals whomeet the criteria for MCI and the course of theirprogression to AD.
Different patterns of learning strategies areobserved in Alzheimer’s patients compared to MCIpatients and normal aging subjects. A prominentrecency effect has been consistently observed inword list learning among AD patients (Delis et al.,1991; Foldi, Brickman, Schaefer, & Knutelska,2003; Gainotti & Marra, 1994), reflecting a highly
passive learning strategy (Delis & Kramer, 2000).Moreover, these patients show an inability to trans-fer new information from short-term to long-termstorage as evidenced by a reduction of the pri-macy effect (Becker, Lopez, & Butters, 1999).As such, probable AD patients characteristicallyperform below healthy controls and MCI patientson memory tests requiring recall or recognitionof recently presented material (Lowndes & Savage,2007). In contrast, the serial position profile in MCIpatients remains contradictory and less explored.Three major studies were conducted to examine theserial position effect in MCI. Bennett and collabo-rators, using the University of Southern California(USC)-Repeatable Episodic Memory Test with a15-item list (Bennett, Golob, Parker, & Starr,2006), found no differences between MCI patientsand normal controls. Another study used the 10-word memory test of the CERAD (Consortiumto Establish a Registry for Alzheimer’s Disease)and found differences between MCI and controlsin the pattern of a word-recalling task (Shankleet al., 2005). Finally, Howieson and collaborators(Howieson et al., 2010) compared different serialposition scoring methods between MCI, AD, andcontrols in the CERAD memory test. They con-cluded that MCI patients exhibited a diminishedprimacy effect compared to controls and that noalternative scoring system was better than stan-dard scoring in distinguishing MCI patients fromcontrols.
The current study investigated the serial posi-tion effect in a large sample of over 500 sub-jects, including normal elderly and MCI and ADpatients. Unlike previous studies, we used the WordRecall Task of the Alzheimer’s Disease AssessmentScale–Cognitive (ADAS-COG; Rosen, Mohs, &Davis, 1984), one of the most widely used instru-ments in clinical practice and in clinical trials.In this large population and using this instrument,we aimed to determine the ability of the serialposition effect to discriminate among the groups(Experiment 1). Taking advantage of an ongo-ing longitudinal study with MCI patients in ourcenter, we intended to study the capacity of theserial position effect to predict conversion fromMCI to dementia during a four-year period, whichis an innovative approach. For this, the baselineprimacy and recency effects of 134 informativesubjects (patients clinically followed in our cen-ter for at least four years) were compared withthose for MCI patients who remained stable or pro-gressed to Alzheimer’s disease, and the predictivevalue of the serial position effect was determined(Experiment 2).
Participants were outpatients with cognitiveimpairment recruited at the Memory Clinic ofthe Neurology Department of University Hospitalof Coimbra. All patients were evaluated usinga comprehensive neurological assessment thatwas performed by a neurologist and includeda detailed history from the patient and a reli-able informant, a neurological examination, acomprehensive neuropsychological assessment, anda functional/psychiatric evaluation. Mainly toexclude other diseases as causes of cognitiveimpairment or relevant medical conditions, patientsreceived a general medical examination, routinelaboratory tests for dementia, single photon emis-sion computed tomography (SPECT) and morpho-logic imaging studies (brain computed tomography,CT, or magnetic resonance imaging, MRI), andeventually cerebrospinal fluid (CSF) analysis. Theseprocedures were submitted to the ethics board ofCoimbra University Hospital, and all participantsgave their informed consent.
Our study sample in Experiment 1 consisted ofpatients diagnosed with probable AD (205 patients)according to NINCDS-ADRDA (McKhann et al.,1984). For inclusion, AD patients should score pos-itive for cognitive impairment in the Mini MentalState Examination (MMSE; Portuguese-adaptedversion by Guerreiro, Fonseca, Barreto & Garcia,2003) and score positive for dementia (1.5 SDsabove the mean) in the ADAS-COG (Portuguese-adapted version by Guerreiro et al., 2003).
For the diagnosis of MCI (222 patients),we followed Petersen’s criteria for amnestic-MCI(Petersen et al., 1999): (a) Informants were alwaysrequired to confirm memory complaints and preser-vation of normal functioning; (b) objective confir-mation of memory impairment, as well as main-tenance of normal general cognition and absenceof dementia, was based on a Portuguese-adaptedcomprehensive neuropsychological assessment, theLisbon Battery to Evaluate Dementia (Garcia,1984; Guerreiro, 1998). We excluded patients withpositive scores for cognitive decline or dementiaaccording to the MMSE and the ADAS-COG.Normal elderly controls (CTR; n = 104) wererecruited from the Santa Maria Hospital, LanguageStudies Laboratory in Lisbon and the UniversityHospital of Coimbra, Neurology Department.Subjects had no memory complaints, history ofbrain damage, psychiatric illness, chronic drug oralcohol abuse, or any medical illness likely toaffect cognition and performed in the normal range
for the Portuguese population in the MMSE andADAS-COG.
Procedure
The Alzheimer Disease Assessment Scale(ADAS; Guerreiro et al., 2003) is a neuropsycho-logical battery that measures the presence andseverity of the most important symptoms of AD.In this investigation, we compared the total scoreof the word recall task of the ADAS-COG for thethree groups of subjects. In this task, participantsread aloud a 10-item list of frequent and concretewords in a simple immediate recall paradigm inthree consecutive trials. The word presentationorder varied across the three trials according tothe Portuguese version of ADAS-COG, with arandomized order each trial. The words had a pre-sentation rate of 2 seconds/item, and the subjectsrecalled them verbally, immediately after the read-ing. The scoring system did not depend on orderof recall. The recall measures were obtained onTrials 1–3 using the number of words rememberedin each of the three trials. Learning was measuredusing the learning over trials (LOT) formula ofIvnik and collaborators (Ivnik et al., 1990), whichis the total number of words recalled for the threetrials subtracted by (3 × number of words recalledin Trial 1)—that is, (sum of Trials 1–3) – (3 ×Trial 1).
To compute the serial position effects, we dividedthe 10-word list as follows: The first 3 words consti-tuted the initial region, the next 4 words constitutedthe middle region, and the last 3 words made upthe final region. We analyzed the number of wordsrecalled in each region of the list (initial, middle,and final regions) and compared the results usingraw scores. Serial position effects were measuredin two ways: (a) region scores were defined as thepercentage of items recalled from primacy, recency,and the middle and were computed by dividingthe number of items recalled from each region bythe total number of items presented in that regionover the three learning trials; (b) standard scoreswere defined as the percentage of words recalledin a list region divided by the total number ofwords correctly recalled by the participants over thethree learning trials without age adjusting (Delis,Kramer, Kaplan, & Ober, 1987; Foldi et al., 2003).These scores represent learning over the three tri-als and were designated the “global group pro-file.” Because the word presentation order acrossthe three trials varied, we conducted the sameserial position effects analysis for each indepen-dent trial, which was designated the “specific groupprofile.”
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Statistical analysis
The statistical analysis was performed usingthe Statistical Package for Social Sciences (SPSS,Version 17) software. Descriptive statistics werecalculated for demographic data and MMSE andADAS-COG scores. Data were analyzed using one-way analysis of variance (ANOVA) and repeatedmeasures ANOVA in Experiment 1 and a two-sample independent t test in Experiment 2.
We also used R, available through the R Projectfor Statistical Computing (Version 2.11) (Wand &Jones, 1995) to perform some nonparametric esti-mation on the data. The function ksmooth fromthe package KernSmooth was used to computenonparametric approximations for regressions, thusavoiding the shape restrictions that are alwaysimplicit in the usual regression procedures. Finally,we calculated the sensitivity and specificity of themeasures using receiver operating characteristiccurve analyses.
EXPERIMENT 1
Results
Group characteristics: Demographics,MMSE, ADAS-COG, and LOT
Group characteristics concerning demographicvariables and scores on MMSE, ADAS-COG, andLOT are presented in Table 1. For each variable,a separate one-way ANOVA was used to com-pare the three groups. There were no significantdifferences in age among the three groups, F(2,530) = 1.15, MSE = 101.05, p = .17. Relatingto education, F(2, 530) = 8.23, MSE = 17.75,the CTR group was similar to the MCI group,but there were significant differences with the ADgroup (p < .001). According to MMSE, F(2, 528) =276.97, MSE = 15.36, and ADAS-COG, F(2, 529)= 294.77, MSE = 60.82, the CTR group hadthe best performance, followed by the MCI, and,finally, by the AD group (p < .001). The compar-ison of the LOT, F(2, 530) = 25.65, MSE = 7.01,
among the three groups revealed that AD patientsshowed a lower learning rate than MCI and CTR(p < .001), while both of the latter groups had thesame learning pattern over the trials.
As education was not matched between thegroups, we measured the possible influence of thisvariable on the outcomes. The usual parametricregression approaches seemed poorly suited forthis purpose as they always imply a prior knowl-edge of the shape of the curve. Thus, we con-ducted nonparametric regression (Wand & Jones,1995). The graphical representations of the resultsobtained are shown in Figure 1. Regarding edu-cation, the curves obtained are almost horizontal,suggesting that education does not affect the out-come of the serial position effects.
Serial position effects
Raw scores. A repeated measures ANOVA wasconducted to test initial, middle, and final itemsrecalled across the three subject groups. For this3 × 3 analysis, diagnostic group (AD, MCI, andCTR) was a between-subjects factor, and position(initial, middle, and final) was a within-subject fac-tor. Using the position raw scores as the dependentmeasure, a significant main effect of group, F(2,534) = 151.14, MSE = 0.34, p < .001, indicatedthe presence of significant group differences, withthe AD patients scoring significantly worse thanthe CTR and MCI groups (p < .001) and MCIscoring significantly worse than CTR (p < .001).The significant Group × Position interaction, F(2,534) = 236.10, MSE = 0.28, p < .001, indicateda differential pattern of performance in the initial,middle, and final recall of words. As expected, theAD group showed a significant disadvantage in allpositions of the list. CTR showed a relative advan-tage in all regions of the list with the exception ofthe final region where they performed equally toMCI. Figure 2 displays this interaction.
Global group profiles. In Table 2, we present themeans, standard deviations, and univariate tests
TABLE 1Comparisons of demographic characteristics and results on MMSE, ADAS-COG, and LOT in the three groups
Characteristic AD (n = 205) MCI (n = 222) CTR (n = 104) p Post hoc
Figure 1. Nonparametric approximations for regressions using the R Project for Statistical Computing (Wand & Jones, 1995) to test theinfluence of education in primacy, middle, and recency scores.
of within-subject and between-subject effects ofthe serial position effects in regional and standardscores in the clinical and control groups. To com-pare how presented information was recalledfrom each region of the list, regional and stan-dard scores were used as the dependent vari-able. A 3 × 3 repeated measures ANOVA, withGreenhouse–Geisser correction, was conducted toassess whether there were differences among pri-macy, middle, and recency effects across the threesubject groups. Additionally, a Bonferroni correc-tion was conducted in the post hoc comparisons(Table 3).
Region and standard scores. The repeated mea-sures ANOVA was conducted to test the regionalscores (primacy, middle, and recency) across thethree subject groups. For this 3 × 3 analysis, diag-nostic group (AD, MCI, and CTR) was a between-subject factor, and serial position (primacy, middle,and recency) was a within-subjects factor. Usingthe regional scores as the dependent measure, a sig-nificant main effect of group, F(2, 528) = 180.87,MSE = 293.28, p < .001, indicated that there wasa significant difference among the three groups.Using a Bonferroni correction, we conducted posthoc multiple comparisons between regional scores
Figure 2. Number of words recalled in the initial, middle,and final regions of the Word-Recall subtest of ADAS-COG(Alzheimer Disease Assessment Scale–Cognitive) and compar-isons across the three subject groups. AD = Alzheimer’s disease;MCI = mild cognitive impairment; CTR = controls. ∗p < .001.
and the three subject groups (Table 3). The resultssuggest that the AD group performed worse inall measures than MCI and CTR (p < .001),and MCI performed significantly worse than CTR(p < .001). Additionally, the significant DiagnosticGroup × Serial Position Effects interaction, F(2,528) = 204.55, MSE = 284.05, p < .001, indicated adifferential pattern of performance in the primacy,middle, and recency effects across the groups.
The same procedures were applied for the stan-dard scores as the dependent measure, and a sig-nificant main effect of group, F(2, 525) = 155.70,MSE = 252, p < .001, was found, showing thatthe three scores were significantly different. Withthe Bonferroni correction, post hoc multiple com-parisons (Table 3) revealed that these scores weresuitable to discriminate between AD and MCI, withAD exhibiting the worst performance. The two-way
group–serial position interaction was nonsignifi-cant, indicating a similar performance in primacy,middle, and recency across the groups.
Serial position effects across the threetrials: Specific group profiles
A comparative analysis with regional and stan-dard measures of the serial position effects acrossthe three learning trials was conducted.
Concerning region scores (Figure 3), a one-wayANOVA was used to compare primacy, middle, andrecency effects in each of the three learning trials inthe three subject groups. In the first trial, significantdifferences in primacy, F(2, 530) = 58.75, MSE =744.61, middle, F(2, 530) = 15.34, MSE = 473.05,and recency, F(2, 530) = 40.22, MSE = 896.44,were observed in all groups (p < .001), followingthe AD < MCI < CTR profile. In the second trial,the primacy, F(2, 530) = 85.52, MSE = 810.56,effect continued to differ for all the groups (p <
.001) in the same manner as in the previous pro-file (AD < MCI < CTR); the recency effect, F(2,530) = 60.54, MSE = 872.23, p < .001, and middleeffect, F(2, 530) = 14.21, MSE = 736.25, p < .005,performance was according to the AD < (MCI =CTR) profile. In the third trial, the profiles betweenthe groups and the serial position effects were equalto the performance on the second trial.
The analysis of the standard scores by a one-way ANOVA (Figure 4) showed that in the firsttrial, the primacy effect, F(2, 529) = 7.25, MSE= 616.14, behaved as AD < (MCI = CTR) pro-file (p < .005); the recency effect, F(2, 529) = 0.12,MSE = 844.51, was similar in all three groups; andthe middle effect, F(2, 530) = 4.6, MSE = 690.10,profile was the same as that in the primacy effect:AD < (MCI = CTR), p < .050. In the second trial,
TABLE 2Word recall subtest of ADAS-COG means and standard deviations in serial position effect among AD patients,
MCI patients, and CTR
Serial position effect scores
MeasureAD patients(N = 205)
MCI patients(N = 222) CTR (N = 104)
Within-subjects effects(serial position effects) p
Figure 3. Serial position effects among AD patients, MCIpatients, and normal controls across the three trials: regionscores (%). AD = Alzheimer’s disease; MCI = mild cognitiveimpairment; CTR = controls.
Figure 4. Serial position effects among AD patients, MCIpatients, and normal controls across the three trials: standardscores (%). AD = Alzheimer’s disease; MCI = mild cognitiveimpairment; CTR = controls.
there was a significant difference in primacy, F(2,529) = 16.01, MSE = 309.13, in all the groups fol-lowing the AD < MCI < CTR profile (p < .001);the recency effect, F(2, 529) = 2.14, MSE = 532.79,was significantly different in AD < CTR (p = .048);and no differences were found in the middle effect,F(2, 530) = 0.50, MSE = 507.08.
In the third trial, the primacy effect, F(2, 527) =20.04, MSE = 257.21, was different in AD, MCI,and CTR following the AD < (MCI = CTR) pro-file (p < .001). In the recency effect, F(2, 527) =5.99, MSE = 468.89, AD showed differences fol-lowing the AD > (MCI = CTR) profile, p < .005,and, again, there were no differences in the middleeffect, F(2, 530) = 0.56, MSE = 370.30.
Scoring methods comparison
Receiver-operating characteristic (ROC) curveswere generated to measure the ability of these scoresto discriminate between MCI and AD groups. Thearea under the curve (AUC) was compared for eachscoring measure (Table 4).
Results suggest that the regional scores had goodaccuracy in distinguishing AD from MCI (81%primacy, 80% recency) and AD from CTR (91%primacy, 85% recency) and poor accuracy in dis-criminating MCI and CTR (69% primacy, 61%recency). Standard scores revealed lower values ofaccuracy; however, they were significant in differ-entiating AD and MCI (57% primacy), MCI fromCTR (58% primacy, 59% recency), and AD fromCTR (59% primacy, 58% recency).
EXPERIMENT 2
In the second experiment, we present the resultsof the follow-up over the first four years, includ-ing 134 of the initial 222 MCI patients. Eighty-twoof the 134 MCI patients (61%) remained nonpro-gressive (MCI-np), and 52 (39%) progressed to AD(MCI-p). In Table 5, we present the demographiccharacteristics and MMSE and ADAS-COG scoresof the two MCI groups, MCI-p and MCI-np, andresults of comparisons using a two-sample indepen-dent t test.
As we intended to evaluate the capacity of theinitial serial position effects to identify those whowould progress to dementia, we compared the ini-tial primacy and recency scores (Table 5) for bothgroups of patients. The same methods were appliedin this second experiment to compare serial posi-tion effects (standard and regional scores), andcomparisons using a two-sample independent t testwere performed.
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TABLE 4Areas under the ROC curve by scoring measures and p-value comparisons in controls, MCI, and AD
MCI vs. AD MCI vs. CTR AD vs. CTR
Scoring measure AUC p 95% CI AUC p 95% CI AUC p 95% CI
Results suggest that regional scores were effi-cient in differentiating the progressive MCI groupfrom the nonprogressive MCI group. In fact, wefound significant differences in primacy and recencyeffects between the groups, with diminished scoreson both measures in the group that progressed toAD four years later. Considering standard scores,no differences were found in the primacy effectbetween both groups, and only the recency effectwas significantly higher in individuals who pro-gressed to AD.
Again, the ROC curves were calculated to mea-sure the accuracy in the comparisons and the pre-diction of MCI conversion to AD using the regionaland standard scores (Table 6). Considering regionalscores, predictions reached 70% accuracy using theprimacy score and 61% using the recency score.Additionally, the primacy regional score was moresensitive and specific than the recency effect with78% sensitivity and 60% specificity contrasting tothe 70% sensitivity and 47% specificity for therecency score. Concerning standard scores, only therecency effect was able to distinguish the groups
TABLE 6Areas under the ROC curve by scoring measures and
p-value comparisons in progressive and nonprogressiveMCI
various pathologies, including amnesia due tohead trauma and subarachnoidal hemorrhage(Carlesimo, Marfia, Loasses, & Caltagirone,1996), temporal lobe epilepsy (Hermann et al.,1996), Alzheimer’s disease (Carlesimo, Fadda,Sabaddini, & Caltagirone, 1996), and mild cogni-tive impairment (Howieson et al., 2010), amongothers. Different types of neuropsychologicalmemory tests have been used to estimate andcalculate the serial position effects—namely, theCalifornia Verbal Learning Test (CVLT), the ReyAuditory Verbal Learning Test (RAVLT), and theCERAD (Consortium to Establish a Registry forAlzheimer’s Disease). In the current study, weused the ADAS-COG, which is very similar toCERAD and is often used in clinical practice andin clinical trials. As far as we know, these are thefirst results of serial position effects estimated usingthe ADAS-COG–Word-Recall subtest in patientswith AD, MCI, and controls.
In the present study, the AD group exhibited thelowest learning rate compared to controls and MCIpatients. In addition, the AD group serial positioneffect showed a diminished primacy effect in com-parison to recency and a depressed primacy com-pared to the MCI and control groups. These resultsconfirm our prediction that the lack of primacy isa defining feature of word-list learning in patientswith Alzheimer’s disease. They are also consistentwith other studies despite the use of different mem-ory tests, such as Foldi and colleagues (2003) andBayley et al. (2000), studies where the CVLT wasused, and the study by Gainotti and colleagues(Gainotti, Marra, Villa, Parlato, & Chiarotti, 1998)who used the RAVLT. Although the list length islonger and thus more difficult in these instruments,the diminished primacy effect was a common fea-ture across all of these studies.
Mild cognitive impairment is considered a tran-sitional stage between normal aging and dementia,and serial position results have not been consistentacross studies of MCI. We observed a diminishedprimacy effect compared to controls, results inaccordance with those of Howieson and colleagues(2010) with the CERAD Word List. They investi-gated the serial position effects using several scoringsystems to describe their learning strategies and toidentify the best measure to detect MCI. In theirtwo experiments, the MCI groups showed a reducedprimacy effect compared to controls. Additionally,Shankle et al. (2005) found a difference in thepattern of word recall on the CERAD word list,suggesting that serial position effects can be use-ful in identifying MCI patients from normal elderlyindividuals. However, our findings appear to differfrom those of Bennett et al. (2006), who found no
difference between MCI and controls in a learn-ing task in which a 15-word list was presentedin a different order in each of the three trials.The discrepancies in results across studies might beexplained by a number of factors that influence theshape of the serial position curves. It has been estab-lished that the same word order presentation fromtrial to trial enhances consolidation and results ina stronger primacy effect. Moreover, as mentionedabove, the length of the list may affect primacyas well as word frequency and presentation order(Capitani, Della Sala, Logie, & Spinnler, 1992).In our study, the word list length and the random-ized presentation are equivalent to CERAD, andthe results obtained were also similar. Additionally,in Bennett et al. (2006), besides the randomizedpresentation across the three trials, the list waslonger, increasing the difficulty of the task. Thismay eventually explain the discrepancy with otherstudies.
To enhance the effects of primacy and recency,different methods for scoring serial positionhave been developed. We calculated two differentscoring systems (standard and regional scores),adopting the same procedures as those of Foldiand colleagues (2003). They examined the serialposition effects in patients with geriatric depres-sion, patients with AD, and elderly controls usingthe CVLT. They observed that standard scoreswere efficient in differentiating both clinical groups,but only the regional scores were able to discrim-inate between normal controls and depressedpatients. Our results revealed that both scoringmethods were efficient in distinguishing amongAD patients, MCI subjects, and controls, but onlythe regional scores could differentiate MCI fromcontrols for the primacy effect. The standard scoreswere relevant to highlight the increment of therecency effect in AD. In addition, several scoringsystems have been described, such as Shankle’scorrespondence analysis (CA), that requirecomputer-based weighting applications with lim-itations in clinical practice as well as Buschkeretention weighted scoring (RWS; Buschke et al.,2006), which is simpler and faster but was notsuperior to standard scoring for differentiatingMCI from controls (Howieson et al., 2010).
Since the research of the La Rue group (LaRue et al., 2008), it has been asked whether serialposition curves might be useful in identifying pro-dromal AD. In their study, asymptomatic personsat risk for AD (positive family history for dementia)showed a reduced primacy effect compared to sub-jects without familial risk. As patients with MCIhave a high risk of developing AD in longitu-dinal evaluations, the identification of predictors
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for conversion is an important research objective.In the second experiment of our study, we com-pared the baseline regional and standard scores ofMCI patients that progressed to AD in a four-year period with the scores of those subjects whoremained stable. Similar to the La Rue group, weverified that converters presented a reduced pri-macy effect, which is a feature of AD. Furthermore,in a ROC curve analysis, the primacy regional scoreexhibited greater accuracy in predicting progres-sion to AD, identifying 78% of MCI patients thatprogressed to AD (sensitivity) and 60% of the non-converters (specificity). Despite the accuracy rate(70%) being at a medium level, our results sup-port the clinical usefulness of the primacy scoreto improve the diagnosis and prognosis of MCIpatients. It should be highlighted that regionalscores were more efficient than standard scoresin discriminating progressive and nonprogressiveMCI.
One of the earliest features of cognitive decline inMCI is impairment in learning and retaining newinformation (Albert et al., 2007; Bondi et al., 1999;Petersen et al., 1999). The present results show thatMCI patients exhibit changes in the serial positioneffect, with reduced recall of items in the primacyregion compared to CTR, reflecting a diminishedcapacity to transfer new information from short-term to long-term storage (Becker et al., 1999).Serial position effects reflects a pattern of learningnew information, and, according to Atkinson andShiffrin (1968), there is a dissociation between pri-macy (long-term memory) and recency (short-termmemory). However, and besides the observationthat MCI patients exhibited no differences in therecency effect compared to CTR, recent studies sug-gest that changes in MCI tend to occur during theencoding phase, probably more related to short-term memory mechanisms (Clément, Belleville, &Mellah, 2012). Another study suggests that learningand retention measures provide good predictivevalues for conversion to AD, highlighting theimportance of including learning measures in addi-tion to consolidation measures when consideringa diagnosis of MCI and predicting clinical out-come (Chang et al., 2010). Also, our results confirma profile of diminished primacy in MCI patientswho converted to AD four years later, contributingto the prediction of conversion. As such, we cansuggest that during the progression of MCI toAD, recency effect (short-term memory) declinesmuch less than primacy effect (long-term memory).In AD, both working and long-term memory areimpaired; in other words, these patients exhibit apassive learning style (Delis & Kramer, 2000) byincreasing working memory strategies.
There is now great interest in the early diagno-sis of AD and in the identification of biomark-ers as surrogates of the neurodegenerative process.All clinical criteria, including those proposed byBruno Dubois’s group (Dubois et al., 2007) andthe revised NINCDS-ADRDA criteria (McKhannet al., 2011), include memory impairment as themajor criteria, corroborated eventually by the evi-dence of biomarkers. The consideration of multi-ple cognitive markers might improve diagnosis andthe serial position effects associated with conven-tional verbal memory tests and will contribute toan earlier detection and enhanced characterizationof MCI patients.
Original manuscript received 5 December 2011Revised manuscript accepted 11 April 2012
First published online 25 June 2012
REFERENCES
Albert, M., Blacker, D., Moss, M. B., Tanzi, R.,& McArdle, J. J. (2007). Longitudinal change incognitive performance among individuals withmild-cognitive impairment. Neuropsychology, 21,158–169.
Atkinson, R. C., & Shiffrin, R. M. (1968). Human mem-ory: A proposed system and its control processes. InK. W. Spence & J. T. Spence (Eds.), The psychologyof learning and motivation (Vol. 2, pp. 89–105). NewYork, NY: Academic Press.
Bayley, P. J., Salmon, D. P., Bondi, M. W., Bui, B. K.,Olichney, J., Delis, D. C., et al. (2000). Comparisonof the serial position effect in very mild Alzheimer’sdisease, mild Alzheimer’s disease, and amnesiaassociated with electroconvulsive therapy. Journalof the International Neuropsychological Society, 6,290–298.
Becker, J. T., Lopez, O. L., & Butters, M. A.(1999). Episodic memory: Differential patterns ofbreakdown. In R. Morris (Ed.), The cognitiveneuropsychology of Alzheimer-type dementia (pp.71–88). New York, NY: Oxford University Press.
Bennett, I. J., Golob, E. J., Parker, E. S., & Starr,A. (2006). Memory evaluation in mild cognitiveimpairment using recall and recognition tests. Journalof Clinical and Experimental Neuropsychology, 28,1408–1422.
Bondi, M. W., Salmon, D. P., Galasko, D., Thomas,R. G., & Thal, L. J. (1999). Neuropsychologicalfunction and apolipoprotein E genotype inthe preclinical detection of Alzheimer’s disease.Psychology and Aging, 14, 295–303.
Buschke, H., Sliwinski, M. J., Kuslansky, G., Katz,M., Verghesse, J., & Lipton, R. B. (2006).Retention weighted recall improves discrimination ofAlzheimer’s disease. Journal of International Neuro-psychology Society, 12, 436–440.
Capitani, E., Della Sala, S., Logie, R. H., & Spinnler, H.(1992). Recency, primacy, and memory: Reappraisingand standardising the serial position curve. Cortex,28, 315–342.
Carlesimo, G. A., Fadda, L., Sabbadini, M., &Caltagirone, C. (1996). Recency effect in Alzheimer’sdisease: A reappraisal. Quarterly Journal ofExperimental Psychology, 49A, 315–325.
Carlesimo, G. A., Marfia, G. A., Loasses, A., &Caltagirone, C. (1996). Recency effect in anterogradeamnesia: Evidence for distinct memory stores underly-ing enhanced retrieval of terminal items in immediateand delayed recall paradigms. Neuropsychologia, 34,177–184.
Carlesimo, G. A., Sabbadini, M., Fadda, L., &Caltagirone, C. (1995). Different components inword-list forgetting of pure amnesics, degenera-tive demented, and healthy subjects. Cortex, 31,735–745.
Chang, Y., Bondi, L. M., Fennema-Notestine, C.,McEvoy, L., Hagler, D., Jr., Jacobson, M., et al.(2010). Brain substrates of learning and retentionin mild cognitive impairment diagnosis and progres-sion to Alzheimer’s disease. Neuropsychologia, 48,1237–1247.
Clément, F., Belleville, S., & Mellah, S. (2010).Functional neuroanatomy of the encoding andretrieval processes of verbal episodic memory in MCI.Cortex, 46, 1005–1015.
Delis, D., & Kramer, J. (2000). Advances in theneuropsychological assessment of memory disorders.In C. S. Cermak (Ed.), Handbook of neuropsychology(2nd ed., Volume 2, pp. 25–47). Amsterdam, TheNetherlands: Elsevier Science.
Delis, D. C., Kramer, J. H., Kaplan, E., & Ober, B. A.(1987). California Verbal Learning Test: Adult Version.New York, NY: The Psychological Corporation.
Delis, D. C., Massman, P. J., Butters, N., Salmon, D. P.,Cermak, L. S., & Kramer, J. H. (1991). Profiles ofdemented and amnesic patients on the CaliforniaVerbal Learning Test: Implications for the assessmentof memory disorders. Psychological Assessment, 3,16–19.
Dubois, B., Feldman, H. H., Jacova, C., Dekosky, S. T.,Barberger-Gateau, P., Cummings, J., et al. (2007).Research criteria for the diagnosis of Alzheimer’sdisease: Revising the NINCDS-ADRDA criteria.Lancet Neurology, 6, 734–746.
Foldi, N. S., Brickman, A. M., Schaefer, L. A., &Knutelska, M. (2003). Distinct serial position profilesand neuropsychological measures differentiate late lifedepression from normal aging and Alzheimer’s dis-ease. Psychiatry Research, 120, 71–84.
Gainotti, G., & Marra, C. (1994). Some aspects ofmemory disorders clearly distinguish dementia of theAlzheimer’s type from depressive pseudo-dementia.Journal of Clinical and Experimental Neuropsychology,16, 65–78.
Gainotti, G., Marra, C., Villa, G., Parlato, V., &Chiarotti, F. (1998). Sensitivity and specificity of someneuropsychological markers of Alzheimer dementia.Alzheimer Disease and Associated Disorders, 12,152–162.
Garcia, C. (1984). A doença de Alzheimer: Problemas dediagnóstico clínico [Alzheimer disease: Clinical diag-nostic problems] (Unpublished doctoral dissertation).Faculty of Medicine of Lisbon, Lisbon, Portugal.
Guerreiro, M. (1998). Contributo da neuropsicologiapara o estudo das demências [The contributionof neuropsychology to the study of dementia]
(Unpublished doctoral dissertation). Faculty ofMedicine of Lisbon, Lisbon, Portugal.
Guerreiro, M., Fonseca, S., Barreto, J., & Garcia, C.(2003). Escala de Avaliação da Doença de Alzheimer–EADA/Alzheimer Disease Assessment Scale–ADAS.In A. de Mendonça, C. Garcia & M. Guerreiro(Eds.), Escalas e testes na demência. Grupo deEstudos de Envelhecimento Cerebral e Demência(pp. 33–58). Lisbon: UCB Pharma.
Guerreiro, M., Silva, A. P., Botelho, M. A., Leitão, O.,Caldas, A. C., & Garcia, C. (2003). Avaliação Brevedo Estado Mental [Mini mental state examination].In A. de Mendonça, C. Garcia & M. Guerreiro(Eds.), Escalas e testes na demência. Grupo de Estudosde Envelhecimento Cerebral e Demência (pp. 27–32).Lisboa. UCB Pharma.
Hermann, B. P., Seidenberg, M., Wyler, A., Davies, K.,Christeson, J., Moran, M., et al. (1996). The effects ofhuman hippocampal resection on the serial positioncurve. Cortex, 32, 323–334.
Howieson, D. B., Carlson, N., Moore, M., Wasserman,D., Abendroth, C., Payne-Murphy, J., et al. (2008).Trajectory of mild cognitive impairment onset.Journal of the International NeuropsychologicalSociety, 14, 192–198.
Howieson, D. B., Mattek, N., Seeyle, A. M., Hiroko,D., Wasserman, D., Zitzelberger, T., et al. (2010).Serial position effects in mild cognitive impair-ment. Journal of Clinical and ExperimentalNeuropsychology. Advance online publication.doi. 10.1080/13803395.2010.516742
Ivnik, R. J., Malec, J. F., Tangalos, E. G., Petersen, R. C.,Kokmen, E., & Kurland, L. T. (1990). The Auditory–Verbal Learning Test (AVLT): Norms for ages 55 yearsand older. Psychological Assessment: A Journal ofConsulting and Clinical Psychology, 3, 304–312.
La Rue, A., Hermann, B., Jones, J. E., Johnson, S.,Asthana, S., & Sager, M. A. (2008). Effect ofparental family history of Alzheimer’s disease onserial position profiles. Alzheimer’s & Dementia, 4,285–290.
Lowndes, G. J., & Savage, G. R. (2007). Early detec-tion of memory impairment in early Alzheimer’sdisease: A neurocognitive perspective on assessment.Neuropsychological Review, 17, 193–202.
McCrary, J., & Hunter, W. S. (1953). Serial posi-tion curves in verbal learning. Science, 117,131–134.
McKhann, G., Drachman, D., Folstein, M., Katzman,R., Price, D., & Stadlan, E. M. (1984). Clinicaldiagnosis of Alzheimer’s disease: Report of theNINCDS-ADRDA Work Group under the aus-pices of Department of Health and Human ServicesTask Force on Alzheimer’s Disease. Neurology, 34,939–944.
McKhann, G., Knopman, D., Chertkow, H., Hyman,B., Jack, C., Kawas, C., et al. (2011). The diag-nosis of dementia due to Alzheimer’s disease:Recommendations from the National Institute onAging and the Alzheimer’s Association workgroup.Alzheimer’s & Dementia. Advance online publication.doi: 10.1016/j.jalz.2011.03.005
Mitrushina, M., Satz, P., Chervinsky, A., & D’Elia, L.(1991). Performance of four age groups of normalelderly on the Rey Auditory–Verbal Learning Test.Journal of Clinical Psychology, 47, 351–357.
Dow
nloa
ded
by [
RM
IT U
nive
rsity
] at
09:
50 1
6 M
arch
201
3
852 CUNHA ET AL.
Murdock, B. B. (1962). The serial position effect offree recall. Journal of Experimental Psychology, 64,482–488.
Petersen, R. C., Smith, G., Kokmen, E., & Irving,R. J. (1992). Memory functioning in normal aging.Neurology, 42, 396–401.
Petersen, R. C., Stevens, J. C., Ganguli, M., Tangalos,E. G., Cummings, J. L., & DeKosky, S. T. (2001).Practice parameter: Early detection of dementia: Mildcognitive impairment (an evidence–based review).Neurology, 56, 1133–1142.
Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J.,Tangalos, E. G., & Kokmen, E. (1999). Mild cognitiveimpairment: Clinical characterization and outcome.Archives of Neurology, 56, 303–308.
Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A newrating scale for Alzheimer’s disease. American Journalof Psychiatry, 141, 1356–1364.
Salmon, D. P. (2000). Disorders of memory inAlzheimer’s disease. In L. S. Cermak (Ed.),Handbook of neuropsychology (2nd ed., volume 2,pp. 155–185). Amsterdam, The Netherlands: ElsevierScience.
Shankle, W. R., Mangrola, T., Chan, T., & Hara, J.(2009). Development and validation of the MemoryPerformance Index: Reducing measurement error inrecall tests. Alzheimer’s & Dementia, 5, 295–306.
Squire, L., & Kandel, E. (2002). From mind to molecules.In L. R. Squire & E. R. Kandel (Eds.), Memory: Frommind to molecules (pp. 10–29). Porto: Porto Editora.
Tulving, E. (1985). Ebbinghaus’s memory: What didhe learn and remember? Journal of ExperimentalPsychology: Learning, Memory & Cognition, 11,485–490.
Wand, M. P., & Jones, M. C. (1995). Kernel smooth-ing: Monographs on statistics and applied probabilitiesNo. 60. London, UK: Chapman & Hall.
Winblad, B., Palmer, K., Kivipelto, M., Jelic, V.,Fratiglioni, L., Wahlund, O., et al. (2004). Mild cog-nitive impairment—Beyond controversies, towardsa consensus: Report of the International WorkingGroup on Mild Cognitive Impairment. Journal ofInternal Medicine, 256, 240–246.
Wright, R. E. (1982). Adult age similarities in free recalloutput order and strategies. Journal of Gerontology,37, 76–79.
