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Supplemental Material

Spaan, Raaijmakers, and Jonker, Neuropsychology, Vol…………

Appendix A: More Detailed Methodological Information

Participants

Subjects were selected from the Longitudinal Aging Study Amsterdam

(LASA), a large-scaled population-based study of elderly individuals with the

objective of determining the predictors and consequences of changes in physical,

cognitive, emotional and social functioning in elderly people (Deeg, Beekman,

Kriegsman & Westendorp-De Serière, 1998). In 1992/1993, the first cycle of

interviews and (medical) examinations took place; every three years the participants

were invited to participate in a new cycle. The LASA participants had given informed

consent to volunteer in additional studies coordinated by LASA, such as the study

described in this paper.

At T1, recent LASA data (from the third cycle held in 1998/1999) were used to

select subjects for the current research. All subjects were community dwelling elderly

people. First, the LASA participants were screened for depression by means of the

‘Center for Epidemiologic Studies Depression Scale’ (CES-D; Radloff, 1977).

Participants scoring 16 or above were excluded (Beekman et al., 1997). Secondly, the

participants were screened for Cerebrovascular Accidents (CVA). Participants were

excluded if they ever experienced a CVA.

In addition, in order to create a cognitively heterogeneous sample at T1 (which

should result, at T2, in as many demented subjects as possible), two subgroups were

created according to their global level of cognitive functioning, measured by the Mini-

Mental State Examination (MMSE; Folstein, Folstein & McHugh, 1975): the

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cognitively impaired (CI) group and the normal control (NC) group. The CI group

scored in the 21-25 range of the MMSE. The NC group scored in the 27-30 range of

the MMSE1. A systematic decision procedure was constructed, which included two or

three administrations of the MMSE (obtained from T1, the third LASA cycle and, if

these were discrepant, the second cycle three years before). In this way, each subject

was classified to the most representative subgroup and the most consistent score was

determined (see Appendix B for details). This procedure takes into account the fact

that the MMSE score is not 100% reliable. CI subjects were matched to NC subjects

for age, years of education, and sex.

Additional data derived from recent LASA data showed that the subjects

screened for the CI group performed significantly worse than the NC subjects on three

available different cognitive measures: the 15 Words Test (similar to the Auditory

Verbal Learning Test, delayed recall; p=.010), the Coding Task (similar to WAIS

Digit Symbol, measuring information processing speed; p<.001), and the Raven

Coloured Progressive Matrices (measuring nonverbal abstract reasoning ability;

p<.001). The CI group is supposed to be at risk for developing dementia (within a few

years). The NC group is supposed to be cognitively intact.

The CI subjects might be interpreted as suffering from Mild Cognitive

Impairment (MCI). The corresponding criteria proposed by Petersen et al. (1999) are:

(1) subjective memory impairments, preferably corroborated by an informant, (2)

objective memory impairment, when compared with persons of similar age and

education, (3) ‘normal’ general cognitive function (although processing speed and

cognitive flexibility may be impaired as well (Petersen, 2000)), (4) normal activities

of daily living (ADL), and (5) not demented. The only criterion that we cannot meet

in our study is the first one regarding the subjective memory impairment since we do

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not have systematic information on this criterion. Although subjective memory

complaints were (not surprisingly given the nature of this group) frequently voiced

when subjects were initially tested, no systematic questionnaire was administered that

might have measured the existence of subjective memory complaints in a valid and

reliable way. Thus, strictly speaking, the CI group does not officially meet the MCI

criteria, though there will be a high resemblance (most likely similar to the ‘Multiple

Cognitive Deficits’-type; e.g., Lopez et al., 2003a, 2003b; Busse, Bischkopf, Riedel-

Heller & Angermeyer, 2003). Therefore, we will apply the descriptive term

‘cognitively impaired’ (CI) instead of MCI, which is associated with Petersen’s

criteria.

At T1, all subjects should be non-demented, in order to be able to examine

preclinically demented cases. Because the MMSE is merely a cognitive screening

measure, the at risk group of CI subjects was additionally administered a validated

short version of the Cambridge Examination for Mental Disorders of the Elderly

(CAMDEX; Neri, Rubichi, DeVreese, Roth & Cipolli, 1998). Thus, demented

subjects (n=7) and subjects with other neurological or psychiatric causes of cognitive

dysfunctioning were excluded. This instrument provides for a dementia diagnosis

consistent with the DSM-IV criteria. It consists of an extensive cognitive/memory

section (the CAMCOG) and other questions related to the DSM-IV criteria. In

addition, subjects who were not able or willing to continue the test administration

were excluded (n=4; excluding also non-native Dutch speakers). Ultimately, at T1,

valid and complete data sets were available for 119 clinically non-demented subjects:

51 CI subjects and 68 NC subjects.

These subjects were approached for a second test two years after the initial

administration of the memory test battery (T2). Subjects who had died or had become

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physically (e.g., deaf, blind, suffered from CVA or were otherwise seriously ill) or

mentally (e.g., seriously depressed) incapable to participate in the second

administration (according to recent LASA data) were not approached. Ultimately,

valid and complete data sets were available for 96 subjects at T2 (43 CI ss. and 53 NC

ss.).

In addition to the repeated administration of the memory test battery, the

CAMDEX was re-administered in order to determine the subjects that had developed

dementia in the intervening period (i.e., CAMDEX diagnosis ‘mild/moderate

dementia’; n=6). Furthermore, the general practitioner (GP) of the subjects that

dropped out at T2 was asked whether the particular subject had become demented in

the past two years according to the official medical records (resulting in three

additional demented cases). All of these 9 subjects that turned out to be demented at

T2 originated from the CI group created at T1 (i.e., CI subjects who had developed

dementia at T2). In this way, three clinical subgroups were obtained, based on the

dementia assessment at T2 and screening of cognitive performance at T1:

(1) Normal Control (NC; n=68): no cognitive dysfunctions, intact ADL functioning,

not demented, not depressed, no CVA history.

(2) Cognitively Impaired (CI; n=42): various cognitive dysfunctions (i.e., MMSE,

delayed recall, processing speed, nonverbal abstract reasoning ability), but intact

ADL functioning and not demented, not depressed, no CVA history. Considered

to be at risk for developing dementia in the (near) future.

(3) (Pre)clinically Demented (PCD; n=9): various cognitive dysfunctions, intact ADL

functioning and not demented at T1, but diagnosed as demented according to

DSM-IV criteria at T2 – preclinically demented (PCD) at T1; clinically demented

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(CD) at T2 (most likely cause: Alzheimer’s Disease considering the absence of

CVA history or depression).

See Table 1 in main manuscript for further characteristics (demographic and

screening variables) of these three clinical subgroups.

In addition, the characteristics of the group of subjects that were re-tested at T2

(n=96) were compared with the characteristics of the subjects that dropped out at T2

(n=23). The only difference between these two groups was that the dropped out

subjects, with a mean age at T1 of 82.00 years (SD 6.58), were significantly older than

the at T2 re-tested subjects (mean age 78.10 (SD 8.45); p=.008).

General Procedure

At T1, an appointment for the memory test administration was made with the

LASA participants that conformed to the inclusion and exclusion criteria after they

had given informed consent. The administration of the memory test battery took place

in the home environment of the subject by means of a laptop computer. The test

administration was conducted by a neuropsychologist (P.E.J.S.), who operated the

computer (i.e., the subject only had to look at the screen on which the stimuli were

presented). The instructions (for each subtest) were presented orally. The subject was

explained beforehand that distracting circumstances had to be avoided in order to

concentrate well (noises of TV, telephone, inexpected visitors, etc.). Since there were

many short breaks between subtests (or between different trials), interruptions hardly

ever occurred during testing. If performance was clearly affected by an occasional

interruption, the particular subtest data were indicated as ‘missing values’. Subsequent

to the memory test administration, the CI subjects were informed that they would be

visited by a physician, who administered the short version of the CAMDEX (Neri et

al., 1998). This visit took place within six weeks of the memory test administration.

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Two years later, the subjects that were still available at T2 were invited for the

second administration phase. The repeated administration took place, on average,

103.47 weeks (SD 3.88) after the first administration of the memory test battery (95-

122 weeks). The procedure of the test administration at T2 was identical to the

procedure at T1, except for the additional administration of the CES-D and questions

regarding CVA in order to control for these variables (as was done at T1).

In addition, the subjects scoring 26 or below on the MMSE, administered at

T2, were visited by the physician who administered the validated short version of the

CAMDEX in order to identify the subjects that had become clinically demented in the

past two years. Subjects who scored 27 of above on the MMSE were considered not

to be demented (i.e., the same procedure was applied at T1). However, subjects who

scored 27 or above and, nevertheless, demonstrated cognitive deficits that caused

doubts about their non-demented status were visited by the physician as well. This

procedure made sure that no demented cases were missed. All subjects that were

administered the CAMDEX were discussed with an experienced neurologist (C.J.),

who was responsible for the final assessment.

Since it was not possible to conduct a physical examination, the diagnosis

simply said ‘demented’ or ‘not demented’, rather than a specification of the type of

dementia. The CAMDEX did specify the severity of the disease: ‘minimal’, ‘mild’,

‘moderate’ or ‘severe’ dementia. In mild, moderate and severe dementia, all of the

DSM-IV criteria of dementia are satisfied (i.e., the PCD group in the current

research). In minimal dementia, the DSM-IV criteria are not satisfied, because (1) no

additional cognitive deficits are observed (only (‘episodic’) memory impairments are

found), and (2) cognitive deficits do not cause evident impairment in occupational or

social functioning. Therefore, subjects with a ‘minimal dementia’ diagnosis were

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classified as ‘non-demented’ (all originated from the CI group). See Roth et al. (1986)

for more detailed information. It may be argued that the subjects with a ‘minimal

dementia’ classification meet criteria for the MCI ‘amnestic’-type (e.g., Lopez et al.,

2003a, 2003b; Busse et al., 2003; Luis et al., 2004). These subjects are, however, not

presented as a separate group because the category seems rather unstable regarding

conversion to dementia (see Appendix B for details).

Material

Memory Test Battery

The memory tests were administered by means of an Apple PowerBook laptop

computer with an 11.3” active-matrix colour screen (800x600 resolution). Below, the

subtests will be described in the same order as they were presented in the battery.

Ten word list-learning test.

Ten semantically unrelated but concrete imaginable words (nouns) were

consecutively presented on the screen (2 s each; interval 0.5 s), in three trials

presenting the same words but in a different sequence (in order to prevent sequential

effects at free recall). Between presentation and recall phase, a three-digit number was

presented on the screen for 20 seconds, from which the subject had to count

backwards by steps of three. This task was aimed at distracting the subject in order to

prevent recency effects, thus, measuring retrieval from long-term store rather than

from short-term store. The total number of words reproduced over three trials was

used as the main score of this subtest in data analyses (range of scores: [0, 30]).

Digit span task.

After a fixation point (1 s) in the middle of the screen, random digits (varying

from 1 to 9) were consecutively presented on the screen (1 s each; interval 1 s).

Logical sequences of digits were excluded. Immediately after presentation, the subject

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had to orally reproduce the digits in the same order as they were presented on the

screen. The actual task of 10 trials was preceded by two practice trials, both starting

with a four-digit-sequence. Subsequent to a correct response, the next trial presented a

one-digit-more-sequence; subsequent to a wrong response, the next trial presented a

one-digit-less-sequence (ranging between 1- and 10-digit-sequences). The longest

sequence correctly reproduced was not selected as the main ‘digit span’-score,

because this score might not be a representative measure when it occurred only once

or twice in 10 trials. Instead, a span score was computed that was less susceptible to

chance: (1) the longest sequence presented on three or more trials, of which at least

50% of the sequences was correctly reproduced, or (2) the longest sequence presented

on two trials, if both sequences were correctly reproduced.

Word-recognition test (yes/no).

In this subtest, the words from the ‘Ten word list-learning test’ (the ‘targets’)

had to be recognised (by answering ‘yes’ or ‘no’) from a list that also included 10

words not presented previously but semantically related to the targets (the

‘distractors’; matched to the targets for word length). The subject was not alerted to

the semantic relation between the targets and the distractors. Main score: total of

correct decisions (true positive and true negative answers). Range: [0, 20].

Paired-associate learning test.

This subtest was administered according to the same format as the ‘Ten word

list-learning test’, except for the presentation of 10 word pairs (instead of 10

unrelated, separate words). Five pairs were semantically related, the other five were

unrelated (each presented for 3 s; interval 0.5 s); the subject was not alerted to the

semantic relation of the word pairs. Semantic associations between words were

derived from Dutch word association norms (De Groot, 1980; Van Loon-Vervoorn &

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Van Bekkum, 1991). During recall phase, the cues (i.e., the first word of each pair)

were presented in random order. Main score: total of word pairs reproduced over three

trials. Range: [0, 30].

Block span task.

This test is the visuospatial variant on the ‘Digit span task’ (i.e., the same

procedure and the same specific ‘span’-score were applied). Ten square-fields

(‘blocks’) were presented on the screen like the black squares of a chessboard. A

sequence of random blocks flashed consecutively (by turning into black on the white

background; for 1 s each; interval 1 s). Immediately after presentation, the subjects

had to reproduce the sequence by indicating the correct blocks in the correct sequence

at the screen.

Word stem completion task.

Two- or three-letter word stems were consecutively presented on the screen.

For each stem, the subject had to name a word that started with the letters presented

and was the first (Dutch) word that came to mind. This word should add a minimum

of two letters to the presented stem. The test consisted of 10 ‘experimental’ stems –

which could be completed with the words from the ‘Ten word list-learning test’ – and

10 ‘control’ stems, which referred to words that were not presented before. The 20

‘target words’ were selected from a list of word stem completion norms (Phaf &

Wolters, 1991). Words were selected that were not frequently named (twice in 200

completions), in order to reduce the possibility of spontaneous completion. The

experimental and control stems were matched for the number of different words

named for each stem, the number of incorrect words named for each stem and length

of the corresponding target. The subject was not alerted to the relation of this task

with the ‘Ten word list-learning test’. None of the words that were presented in

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previous subtests could complete the stems used in this task. Main score: number of

experimental stems that were completed with a target word minus number of control

stems that were completed with a target word. Range: [-10, 10].

Category fluency test.

The categories ‘animals’ and ‘occupations’ were used. The subject had to

name as many exemplars that belonged to these categories as he could think of within

60 seconds per category. All responses were judged on whether they represented

unique exemplars of the category. Incorrect responses were: repeated responses,

perseverations on previous responses (that represent the same category exemplar, e.g.,

sex-specific and age-specific names of the same animal species), and intrusions (i.e.,

no valid members of the category). Main score: sum of correct animals and correct

occupations that were generated within 60 seconds each.

Mirror-reading task.

Sixty mirror-words were consecutively presented on the screen. The letters

were rotated on the vertical axis. The words had to be read from right to left and were

presented in capital letters2. The subject had to read each word as quickly as possible

without making mistakes. Each stimulus was presented on the screen until the subject

had generated a response. Two practice trials were given in advance. The six blocks

of 10 consecutively presented words (in order to analyse practice effects of mirror-

reading during the task) were matched for word length. Main score: mean reading

time (in seconds) over all correctly read mirror words.

Perceptual identification task.

After a fixation point (1 s) in the middle of the screen, the subject had to

identify words that were briefly presented on the screen, as quickly as possible, by

reading them aloud. Every word was repeatedly presented in ‘tics’ of 16 msec: each

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consecutive presentation of a word lasted one tic longer (it started at two tics and

ended at a maximum of 20 tics). Before and after each presentation of the word, a

mask (XXXXXXXX) was presented for five tics consistently. When the subject

identified the word correctly, the word was clearly presented for 1 s. This was done

because 12 words were presented in another trial as well – in order to be able to

measure the effect of repetition (the perceptual priming effect), the subject must have

had the opportunity to encode the word sufficiently. The subject was not alerted to the

repeated presentation of words in order to prevent explicit remembering. Three

practice trials were given in advance. The test consisted of a total of 48 words, among

which 12 low-frequency (‘LF’) words, 12 middle-frequency (‘MF’) words, 12 high-

frequency (‘HF’) words and 12 repeated presentations of the middle-frequency words

(‘rep-MF’). The word frequencies were derived from the CELEX database (CELEX

Dutch Database Release N31, 1990). The three groups of different words (LF, MF,

HF) were matched for word length. In order to control for practice effects, the

presentation procedure comprised three blocks of 16 words, each block consisting of

four words of each condition (LF, MF, HF, rep-MF). The three blocks were matched

for word frequency, word length and the number of words presented between a MF

word and its repeated presentation. Main ‘semantic memory’ score: mean reaction

time (in tics of 16 ms) over all HF, MF and LF words. Main ‘priming’ score: mean

reaction time (in tics of 16 ms) over the MF words minus mean reaction time over the

rep-MF words.

Two-alternative word-recognition test.

Two words were simultaneously presented on the screen: one was a word from

the ‘Ten word list-learning test’ (a ‘target’) and the other was its semantically related

distractor (the same distractors as in the ‘Word-recognition test’). The subject had to

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recognise the targets (randomly presented on the left or the right of the screen), thus,

measuring delayed recognition. Main score: total of correct decisions (recognised

targets). Range: [0, 10].

Visual Association Test

This test was developed by Lindeboom (Lindeboom, Schmand, Tulner,

Walstra & Jonker, 2002) with the purpose to detect serious (episodic) memory

disorders in elderly persons of 65 years and older, which might be associated with

dementia. This test was additionally administered in the current research in order to

investigate its predictive value with regard to dementia. Six line drawings of common

objects (the ‘cues’; e.g., a chair) were presented. The subject had to name them (aided

by the experimenter if necessary). Subsequently, the same six line drawings were

presented with the addition of a second object (the ‘targets’: e.g., a hedgehog was

sitting on the chair), which the subject also had to name. In the final trial, the original

line drawings (the cues) were presented; the subject had to recall the targets. All

drawings were illogical combinations of (interacting) objects. Main score: total of

target objects that were recalled. Range: [0, 6].

References

CELEX Dutch Database Release N31. Computer Software, Nijmegen: Centre

Lexical Information, 1990.

Groot, de, A. M. B. (1980). Mondelinge woordassociatienormen: 100

woordassociaties op 460 Nederlandse zelfstandige naamwoorden [Oral word

association norms: 100 word associations to 460 Dutch nouns]. Lisse: Swets &

Zeitlinger.

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Loon-Vervoorn, van, W. A., & Van Bekkum, I. J. (1991). Woordassociatie

lexicon: Gebaseerd op 1299 woorden en 100 proefpersonen [Word association

lexicon: Based on 1299 words and 100 subjects]. Amsterdam/Lisse: Swets &

Zeitlinger.

Molster, F., & Koekkoek, M. (1997). Meting van het geheugen bij ouderen:

Afname en evaluatie van een verbeterde en aangepaste versie van een

geautomatiseerde geheugentestbatterij [Measurement of memory in elderly:

Administration and evaluation of an improved and adapted version of a computerised

memory test battery]. Unpublished master’s thesis, University of Amsterdam,

Amsterdam.

Phaf, R. H., & Wolters, G. (1991). Spontane aanvulfrequenties voor 168 twee-

en drieletterige woordstammen [Spontaneous completion frequencies for 168 two-

and three-letter word stems]. Internal report, University of Leiden, Leiden.

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Appendix B: Flow Sheet of the Sampling and Testing Protocol

7 prevalent demented

(CAMDEX)

65 CI (based on 2 or 3 MMSE scores*)

82 NC(based on 2 or 3 MMSE scores*)

excluded

4 unwilling or unable to complete test administration

Second screening phase: after CAMDEX and MMSE* administration at T1:

excluded

51 CI 68 NC

Third screening phase: for selecting ss. for analyses presented in current paper: excluding ss. with missing values on 1 subtests and ss. that ever experienced a CVA;& Additional analyses: LASA 3rd cycle data: CI < NC on 3 cognitive measures: 15 Words Test (delayed recall; p=.010), Coding Task (p<.001), Raven CPM (p<.001): CI MCI-‘multiple cognitive deficits’-type;

43 CI 53 NC

Available ss. at second test, 2 years later (T2):

6 converted to dementia (CAMDEX)

3 converted to dementia (GP)

9 Preclinically Demented (PCD)

at T1

42 CI (at T1; at T2 (still) non-

demented)68 NC

* according to systematic decision procedure: if MMSE from LASA 3rd cycle and MMSE from T1 are discrepant (e.g., LASA3: 27, T1: 24), then MMSE from LASA 2nd cycle (‘95/’96) determines the final group classification (NC or CI). Final MMSE score that is applied for analysis in the current paper is equal to the T1 MMSE score if T1 MMSE score and LASA 3rd cycle score are not discrepant (i.e., are both within same range of 21-25 or 27-30 respectively); or equal to average of T1 MMSE score and LASA 3rd cycle score if these scores are discrepant.

15 NC dropped out

Available for analyses (using T1 data):

First screening phase: according to LASA 3rd cycle data (1998/1999; n=1872), for selecting ss. for T1

baseline administration of Memory Test Battery (in 1999/2000): CES-D < 16 (exclusion of depression) + no CVA residual symptoms + MMSE [21,25] (CI ss.) or MMSE [27,30] (matched NC ss.) that agreed to participate:

158 LASA ss. administered at T1: Memory Test Battery and additional MMSE

8 CI dropped out

Dementia assessment, 2 years later (T2): CAMDEX, GP medical records or MMSE > 26 (NC):

Nr. of ss. classified to CAMDEX ‘minimal dementia’ category:

6 min.dem. (T1) 10 min.dem. (T1);T2 ‘non-demented’

5 min.dem. (T2);T1 ‘non-demented’

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Footnotes

1 Tombaugh and McIntyre (1992) reported that the most frequently used cut-off value

for cognitive impairment is 23/24, but their review (Table 2) showed that cognitively

intact elderly subjects generally score higher than 24 – on average 28. Thus, LASA

participants with MMSE>26 are most likely not demented or in cognitive decline,

especially regarding their low average level of education. In addition, when the CI

range would be extended from 21-25 to 18-25, this might result in too many demented

subjects (or ‘mild cognitively impaired subjects’; Tombaugh & McIntyre).

2 A pilot study with elderly subjects (Molster & Koekkoek, 1997) showed that mirror-

reading words in lower-case letters was too difficult, because several lower-case

letters that are rotated on the vertical axis, produce other normal letters (e.g., “b” and

“d”). Using upper-case letters avoids this problem.

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