The fate of the 0.5s: predictors of 2-year outcome in mild cognitive impairment.
ABSTRACT Impairments in executive cognition (EC) may be predictive of incident dementia in patients with mild cognitive impairment (MCI). The present study examined whether specific EC tests could predict which MCI individuals progress from a Clinical Dementia Rating (CDR) score of 0.5 to a score ≥1 over a 2-year period. Eighteen clinical and experimental EC measures were administered at baseline to 104 MCI patients (amnestic and non-amnestic, single- and multiple-domain) recruited from clinical and research settings. Demographic characteristics, screening cognitive measures and measures of everyday functioning at baseline were also considered as potential predictors. Over the 2-year period, 18% of the MCI individuals progressed to CDR ≥ 1, 73.1% remained stable (CDR = 0.5), and 4.5% reverted to normal (CDR = 0). Multiple-domain MCI participants had higher rates of progression to dementia than single-domain, but amnestic and non-amnestic MCIs had similar rates of conversion. Only three EC measures were predictive of subsequent cognitive and functional decline at the univariate level, but they failed to independently predict progression to dementia after adjusting for demographic, other cognitive characteristics, and measures of everyday functioning. Decline over 2 years was best predicted by informant ratings of subtle functional impairments and lower baseline scores on memory, category fluency, and constructional praxis.
- SourceAvailable from: Mauro Copelli[Show abstract] [Hide abstract]
ABSTRACT: Verbal fluency is the ability to produce a satisfying sequence of spoken words during a given time interval. The core of verbal fluency lies in the capacity to manage the executive aspects of language. The standard scores of the semantic verbal fluency test are broadly used in the neuropsychological assessment of the elderly, and different analytical methods are likely to extract even more information from the data generated in this test. Graph theory, a mathematical approach to analyze relations between items, represents a promising tool to understand a variety of neuropsychological states. This study reports a graph analysis of data generated by the semantic verbal fluency test by cognitively healthy elderly (NC), patients with Mild Cognitive Impairment-subtypes amnestic (aMCI) and amnestic multiple domain (a+mdMCI)-and patients with Alzheimer's disease (AD). Sequences of words were represented as a speech graph in which every word corresponded to a node and temporal links between words were represented by directed edges. To characterize the structure of the data we calculated 13 speech graph attributes (SGA). The individuals were compared when divided in three (NC-MCI-AD) and four (NC-aMCI-a+mdMCI-AD) groups. When the three groups were compared, significant differences were found in the standard measure of correct words produced, and three SGA: diameter, average shortest path, and network density. SGA sorted the elderly groups with good specificity and sensitivity. When the four groups were compared, the groups differed significantly in network density, except between the two MCI subtypes and NC and aMCI. The diameter of the network and the average shortest path were significantly different between the NC and AD, and between aMCI and AD. SGA sorted the elderly in their groups with good specificity and sensitivity, performing better than the standard score of the task. These findings provide support for a new methodological frame to assess the strength of semantic memory through the verbal fluency task, with potential to amplify the predictive power of this test. Graph analysis is likely to become clinically relevant in neurology and psychiatry, and may be particularly useful for the differential diagnosis of the elderly.Frontiers in Aging Neuroscience 01/2014; 6:185. · 2.84 Impact Factor
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ABSTRACT: Objective: The Veterans Affairs Saint Louis University Mental Status (SLUMS) examination is a screening tool that has the sensitivity to detect mild neurocognitive impairment and dementia. This study explores patients’ cognitive impairment trajectories based on the SLUMS examination score changes after 7.5 years. Design: Retrospective chart review. Setting: The Geriatric Research, Education, and Clinical Center at the Department of Veterans Affairs Medical Center (VAMC), St Louis, MO. Participants: A review of 533 charts indicated that 357 patients who had participated in the SLUMS examination validation study in 2003 were still alive. Measurement: Charts were screened for indicators of cognitive status in both 2003 and 2010 and interventions after baseline evaluation. Results: The mean age of the 357 individuals in 2003 was 74, all were men, and 73% had a high school education or more. A total of 223 (62%) of the 357 completed the SLUMS examination at baseline and at the 7.5-year follow-up visit; of those, 33 (15%) progressed to mild cognitive deficit, 20 (9%) progressed to severe cognitive deficit, and 53 (24%) improved or reverted back to normal. Further exploration revealed that at least one reversible cause was identified for most (n = 36/53, 68%) of the reversions. The primary interventions that differentiated reversers from nonreversers were correction of visual loss (P = .005) and discontinuation of anticholinergic medications (P = .002). Conclusion: Cognitive improvement (reversion) as indicated by the SLUMS examination after 7.5 years was associated with the correction of some reversible causes. This stresses the importance of early detection and exclusion of reversible causes for persons screened for cognitive dysfunction using the SLUMS examination.Journal of the American Medical Directors Association 05/2014; · 4.78 Impact Factor
Journal of the International Neuropsychological Society (2011), 17, 277–288.
Copyright E INS. Published by Cambridge University Press, 2010.
The Fate of the 0.5s: Predictors of 2-Year Outcome in Mild
Eleni Aretouli,1Ozioma C. Okonkwo,1,2Jaclyn Samek,1AND Jason Brandt1,2,3
1Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland
2Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
3The Copper Ridge Institute, Sykesville, Maryland
(RECEIVED July 15, 2010; FINAL REVISION November 23, 2010; ACCEPTED November 23, 2010)
Impairments in executive cognition (EC) may be predictive of incident dementia in patients with mild cognitive
impairment (MCI). The present study examined whether specific EC tests could predict which MCI individuals progress
from a Clinical Dementia Rating (CDR) score of 0.5 to a score Z1 over a 2-year period. Eighteen clinical and
experimental EC measures were administered at baseline to 104 MCI patients (amnestic and non-amnestic, single- and
multiple-domain) recruited from clinical and research settings. Demographic characteristics, screening cognitive measures
and measures of everyday functioning at baseline were also considered as potential predictors. Over the 2-year period,
18% of the MCI individuals progressed to CDRZ1, 73.1% remained stable (CDR50.5), and 4.5% reverted to normal
(CDR50). Multiple-domain MCI participants had higher rates of progression to dementia than single-domain, but
amnestic and non-amnestic MCIs had similar rates of conversion. Only three EC measures were predictive of subsequent
cognitive and functional decline at the univariate level, but they failed to independently predict progression to dementia
after adjusting for demographic, other cognitive characteristics, and measures of everyday functioning. Decline over
2 years was best predicted by informant ratings of subtle functional impairments and lower baseline scores on memory,
category fluency, and constructional praxis. (JINS, 2011, 17, 277–288)
Keywords: Mild cognitive impairment, Dementia, Predictors of decline, Executive cognition, Clinical Dementia Rating
scale, MCI outcome
Older adults with mild cognitive impairment (MCI) are at
substantially higher risk of dementia than cognitively normal
elderly (5–10% for MCI vs. 1–2% for normal elderly per
year) (Mitchell & Shiri-Feshki, 2009; Petersen et al., 1999).
Distinct clinical subtypes of MCI have been identified, the
most extensively studied of which is amnestic MCI (aMCI).
These are persons with memory complaints and psychometric
evidence of memory decline, but intact overall cognitive
function and generally preserved activities of daily living
no higher than 0.5 on the Clinical Dementia Rating (CDR)
(Hughes,Berg, Danziger, Coben, & Martin, 1982).Ithas been
suggested thataMCI has a lessfavorable prognosis thandothe
non-amnestic subtypes (naMCI) (Fischer et al., 2007; Morris
& Cummings, 2005; Ravaglia et al., 2008). However, this is
not a consistent finding (Mitchell, Arnold, Dawson, Nestor, &
Hodges, 2009; Nordlund et al., 2010; Rozzini et al., 2007). In
fact, many have reported that it is the presence of deficits in
multiple cognitive domains [multiple-domain MCI (mdMCI)]
rather than any specific domain that confers increased risk
for dementia (Alexopoulos, Grimmer, Perneczky, Domes, &
Kurz, 2006b; Baars et al., 2009; Manly et al., 2008; Rasquin,
Lodder, Visser, Lousberg, & Verhey, 2005).
Although research has focused on the progression from
MCI to dementia, reversion from MCI to normal cognition
has also been documented, with rates ranging from 4% to
53% (Fisk, Merry, & Rockwood, 2003; Kryscio, Schmitt,
Salazar, Mendiondo, & Markesbery, 2006; Larrieu et al.,
2002; Ravaglia et al., 2006). Finally, a considerable number
of individuals with MCI (11–21%) remain stable when fol-
lowed for up to 10 years (Fisk & Rockwood, 2005; Ganguli,
Dodge, Shen, & DeKosky, 2004; Mitchell & Shiri-Feshki,
2009; Visser, Kester, Jolles, & Verhey, 2006). Thus, the
outcome of MCI is varied.
Distinguishing the MCI individuals who are on a trajectory
Correspondence and reprint requests to: Jason Brandt, PhD, Department
of Psychiatry and Behavioral Sciences, The Johns Hopkins Hospital, 600 N.
Wolfe Street, Meyer 218, Baltimore, MD 21287-7218. E-mail: jbrandt1@
cognitive difficulties is of increasing importance. There is
some evidencethatpharmacological interventionin MCI could
delay the onset of dementia, or slow its progression (Aisen,
2008;Doodyet al.,2009; Petersen et al.,2005;Yesavageet al.,
2007).An accurate prognosis canhelppatients andtheir family
plan for the care of the patient and make long-term financial
decisions. Finally, identifying the ‘‘preclinical’’ stages of the
disease could enhance our understanding of its early evolution,
enabling us to study the pathological changes that occur before
unambiguous symptoms emerge.
There are multiple approaches to the preclinical detection
ofa neurodegenerative disease, including use of brain imaging
(Jack et al., 2008), blood and cerebrospinal fluid biomarkers
(Mattsson et al., 2009), and genetic risk assessment (Caselli
et al., 2009). The present study considers neurocognitive
characteristics, since they are so easily attainable, widely
available, and usually part of the routine clinical assessment of
people at risk for dementia.
cognition (EC) are particularly predictive of the development
of dementia. First, they are relatively common among indivi-
duals with MCI (Chen et al., 2000; Daly et al., 2000; Griffith
et al., 2003) and present at the early stages of many diseases
that cause dementia, such as Alzheimer’s disease, Parkinson’s
disease, or Huntington’s disease (Jacobs, Marder, et al., 1995;
Mahieux et al., 1998; Woods & Troster, 2003). Second, many
of the cognitive tests that others have reported to have prog-
nostic value for dementia have substantial executive control
requirements (Bondi et al., 1994; Elias et al., 2000; Jacobs,
Sano, et al., 1995; Rapp & Reischies, 2005). Finally, several
longitudinal studies suggest that EC measures are associated
with subsequent decline (Albert, Moss, Tanzi, & Jones, 2001;
Chen et al., 2000; Crowell, Luis, Vanderploeg, Schinka, &
Mullan, 2002; Daly et al., 2000).
Executive cognition encompasses a wide range of abilities
and processes (Miyake et al., 2000). An important limitation
of previous studies investigating the ability of EC to predict
incident dementia is that the sampling of EC was limited, typi-
cally to two or three tests (Albert et al., 2001; Amieva et al.,
2004; Chen et al., 2000; Crowell et al., 2002; Daly et al., 2000;
Tierney et al., 1996). Although including multiple EC measures
as potential predictor variables may be statistically problematic,
of specific varieties of EC. In fact, patients with MCI have been
found to be impaired on only specific aspects of EC (Brandt
et al., 2009; Zhang, Han, Verhaeghen, & Nilsson, 2007).
Previous studies had other methodological limitations, as
well. The participants’ outcome status was usually defined
based on the presence or absence of a clinical diagnosis of
dementia. Differences in diagnostic procedures or limiting
the outcome to patients receiving the diagnosis of probable
Alzheimer’s disease (i.e., excluding those with non-AD
dementias) may have contributed to discrepant findings or may
have limited the generalizability of previous findings. We cir-
decline sufficient for a dementia diagnosis, but operationalized
have not sufficiently considered the role of demographic
characteristics, such as age and education. Finally, it is unclear
whether executive functioning predicts development of
dementia above and beyond other factors, such as abilities to
perform daily tasks at baseline or other aspects of cognition.
The purpose of the present study was to determine whether
specific aspects of EC contribute uniquely to the detection of
individuals who progress to dementia (CDR scores Z1) and
whether they do so beyond and above other demographic,
other cognitive and clinical characteristics. We examined the
outcomes of patients with four subtypes of MCI over a 2-year
period and their association with baseline performances on
18 clinical and experimental EC tests. In addition, we exam-
ined whether specific MCI subtypes were associated with
higher rates of cognitive and functional decline. Multiple-
domain MCI patients were predicted to be at higher risk of
decline than the other MCI subtypes.
A total of 141 persons with MCI participated in the study.
Most (70%) were recruited from the Johns Hopkins
Alzheimer’s Disease Research Center (ADRC) and from
other research studies. A smaller number of participants
(30%) were referred from University clinics and physicians
in the community. Ninety percent of the participants were
Caucasian, and 10% were African American.
Participants were diagnosed with MCI according to
Petersen criteria (Petersen, 2004; Winblad et al., 2004).
Inclusion criteria included a Mini-Mental State Exam
(MMSE) score in the normal range (i.e., at or above the
20th percentile for age and education; range526–30 in our
sample) (Bravo & Hebert, 1997) and a global score of 0.5 on
the CDR (Hughes et al., 1982). In addition, participants
were required to perform at or below 1.5 standard deviations
below the mean for age and education (i.e., 6.7th percentile),
according to published norms, on one or more of the
following screening tests: Logical Memory (story A) of the
Wechsler Memory Scale-Revised (WMS-R) (Wechsler,
1987), the 30-item version of the Boston Naming Test
(Brandt et al., 1989; Goodglass & Kaplan, 1983), word list
generation (for the letters FAS [Phonemic Fluency] and
the semantic categories animals and vegetables [Category
Fluency]) (Rascovsky, Salmon, Hansen, Thal, & Galasko,
2007), and clock drawing to request (Rouleau, Salmon,
Butters, Kennedy, & McGuire, 1992). Finally, each partici-
pant was required to have a study partner who could provide
information about his/her functional abilities.
Exclusion criteria were any history of major mental illness,
cancer). Volunteers with past or present depression were not
excluded since depression is very common in MCI and may be
related to outcome (Jorm, 2001; Lyketsos et al., 2002).
E. Aretouli et al.
A total of 141 participants received baseline neuro-
psychological evaluations, fulfilled our criteria for MCI, and
were subsequently assigned to one of four MCI subgroups:
amnestic single domain (AS; n536), amnestic multiple
domain (AM; n545), non-amnestic single domain (NAS;
n526), and non-amnestic multiple domain (NAM; n517).
The criteria for subgroup membership were based on per-
formance on the four cognitive screening tests described
above; see Brandt et al. (2009) for details. Of the 141 parti-
cipants with a baseline assessment, 104 had a follow-up
examination after 2 years. Five MCI participants were
deceased by the second evaluation, 15 refused participation,
and 9 were not reachable (attrition rate per year510.9%).
Eight participants had not yet received follow-up evaluations
at the time of the analysis and were, therefore, excluded. The
final sample included 30 AS, 38 AM, 23 NAS, and 13 NAM
patients. Additional details regarding the study participants
have been published previously (Brandt et al., 2009).
Participant status 2 years after baseline assessment was
assessed with a repeat CDR interview with the study partner.
Each participant had the same study partner for both CDR
interviews, except 9 participants, whose initial informants
were not available for the follow-up interview. For the
purposes of this study, subjects are described as having
progressed to dementia if they had a CDR global score Z1 at
follow-up. If they obtained a CDR global score of 0, they are
described as having reverted to normal. If they obtained a
0.5 at follow-up, they are described as still having MCI.
Executive function measures
Eighteen EC measures representing six conceptually distinct
domains of EC were administered to the participants. Most of
the EC measures are from widely used, standardized tests that
The tests and the specific measure selected from each one are
shown in Table 1. In addition, the following three experimental
tasks were developed specifically for the present study:
Completions & corrections test (Manning & Brandt,
2006). In this task, the examinee is read 12 altered idiomatic
expressions and asked to repeat each one verbatim. Five of the
extensions of the original (‘‘Hip, Hip,. . .’’), while the remain-
ing seven are meant to induce corrections (‘‘The tooth, the
whole tooth, and nothing but the tooth.’’). Number of phrases
Table 1. Summary of tests of executive function (Brandt et al., 2009)
Proposed domainTest Measures Scores range
Alternate Uses Test (Guilford, Christensen, Merryfield, &
Random Number Generation (Brugger, Monsch, Salmon,
& Butters, 1996)
Tinker Toy Test (Koss, Patterson, Mack, Smyth, &
Whitehouse, 1998; Lezak, 1982)
Total raw score 0–36
Sum of written trial RNG and oral
Total raw score
Inhibition of Prepotent
D-KEFS Stroop Test (Delis, Kaplan, & Kramer, 2001)
Hayling Test (Burgess & Shallice, 1997)
Completions & Corrections Test (Manning & Brandt,
Inhibition trial scaled score
Total scaled score
Total correct score
Planning and Sequencing Porteus Maze Test (Porteus, 1965)
D–KEFS Tower Test (Delis et al., 2001)
Tic-Tac-Toe (Brandt et al., 2009; Crowley & Siegler, 1993) Total correct score
Test Age score
Total achievement scaled score
and Set Shifting
D-KEFS Sorting Test (Delis et al., 2001)
Brixton Spatial Anticipation Test (Burgess & Shallice, 1997) Total scaled score
Verbal Concept Attainment Test (Bornstein, 1982)
Confirmed sorts scaled score0–19
0–24Total correct raw score
Stanford Binet Absurdities Test (Thordike, Hagen, &
Iowa Gambling Test (Bechara, Damasio, Tranel, &
Experimental Judgment Test
Total raw score 0–32
Advantageous selections (C1D deck
responses) on block 5 minus block 1
Mean percent deviation
Working Memory and
Trail Making Test (Reitan, 1958)
Brief Test of Attention (Schretlen, Bobholz, & Brandt, 1996) Total correct raw score
TEA; Telephone Search While Counting (Robertson, Ward,
Ridgeway, & Nimmo-Smith, 1994)
Time on Part B minus time on Part A_
_Dual task decrement score
Note. D-KEFS5Delis-Kaplan Executive Function System; TEA5Test of Everyday Attention.
Outcome in mild cognitive impairment
Tic-tac-toe (Brandt et al., 2009; Crowley & Siegler,
A standardized version of this well-known paper-
and-pencil game was developed specifically for the present
study. Sixteen trials were played, with the examiner and
participant alternating who moves first. On half the trials on
which the examiner started, s/he purposely made a sub-
optimal initial move (i.e., one other than a corner), thereby
allowing the patient an advantage. The examinee is credited
every loss; ties result in no change in score.
Experimental judgment test (Brandt et al., 2009).
task requires that the subject estimate three attributes of the
examiner, specifically his/her age, height, and weight. Score
on the test is the mean percent deviation from actual values
on the three items.
Measures of functional status
Three informant-reported ratings of daily functioning were
included in the present study, since even mild restriction in
instrumental activities of daily living (IADL) has been found
to be associated with a much higher risk of progression to
deficit (Peres et al., 2006). The study partners’ responses on
questionnaires assessing functional status were not considered
in the calculation of the CDR scores.
The Activities of Daily Living-Prevention Instrument
developed by the Alzheimer’s Disease Cooperative Study
Committee (ADCS ADL-PI) (Ferris et al., 2006; Galasko
et al., 2006) consists of 15 items assessing performance on
complex activities of daily living rated on a 3-point scale
(05‘‘no difficulty’’ to 25‘‘a lot of difficulty’’). The sum of
ratings on the 15 functional items constitutes the score.
The Informant Questionnaire on Cognitive Decline in the
Elderly (IQCODE) (Jorm & Jacomb, 1989) assesses changes
in an elderly subject’s everyday cognitive abilities as mani-
fested in daily life. Twenty-six cognitive activities of daily
life are described and rated on a 5-point scale compared to 10
years previously (15‘‘much better’’ to 55‘‘much worse’’).
The mean of the 26 ratings was used in our analyses.
The Dysexecutive Questionnaire (DEX) (Wilson, Alder-
man, Burgess, Emslie, & Evans, 1996) measures behavioral
changes evident in daily functioning that result from a dys-
executive syndrome. Twenty statements describing common
problems of everyday life are rated on a 5-point scale accord-
ing to their frequency (05‘‘never’’ to 45‘‘very often’’).
The Johns Hopkins University Institutional Review Board
fully reviewed and approved the study protocol. Written
informed consent was obtained from all participants and their
Statistical analyseswereperformed using PASW 17. One-way
to compare the four groups on demographic and clinical
characteristics at baseline. The w2was further used to test the
association of participants’ group and subgroup membership
(aMCI vs. naMCI; single domain MCI [sdMCI] vs. multiple
domain MCI [mdMCI]) at baseline with the frequency of
compared the baseline characteristics and performances of
those who progressed to a CDR global score of 1 or more with
the performances of those who remained at 0.5.
The ability of demographic and clinical characteristics,
the cognitive screening tests and the EC measures to predict
progression from CDR50.5 to CDRZ1 was assessed with
univariate logistic regression analyses. Stable MCI was the
reference group in all analyses. Variables significantly predict-
ing the MCI outcome in the univariate regression models were
then entered in a hierarchical logistic regression modeltogether
with demographic characteristics. The hierarchical regression
model was developed to determine whether EC predicts out-
and other cognitive factors. Therefore, in the first block,
demographic variables (age, education, sex) were forced to
enter; in the second block, measures of everyday functioning
follow-up could enter; in the third block, the screening battery
tests that predicted progression to dementia at the univariate
level could enter; finally, in the fourth block, the EF variables
that were significant predictors at the univariate level were
allowed to enter. Variables in each block were entered in a
forward stepwise manner, using the likelihood ratio criterion.
A receiver operating characteristic (ROC) curve was plotted
to illustrate the sensitivity and specificity of the predictive
model that resulted from the hierarchical regression analysis.
An omnibus forward stepwise logistic regression model,
using the likelihood ratio criterion, was computed to test the
predictive ability of the variables that were significant pre-
dictors of progression at the univariate level when entered
simultaneously. The purpose of this omnibus regression
analysis was to test the prognostic value of EC in the context
of all other clinical and cognitive measures.
Due to sample size constraints, all the regression analyses
were performed within the pooled MCI sample, rather than
within the subgroups separately. In the present paper,
although we describe all three possible outcomes of MCI
patients (reversion to normal, stable MCI and progression
to dementia), we modeled only progression to dementia due
to the small number of the MCI individuals who reverted to
normal (i.e., only nine persons scored 0 on the CDR at the
Demographic and Clinical Baseline Characteristics
The demographic and clinical characteristics of the partici-
pants at baseline are summarized in Table 2. The groups did
not differ in age (F(3,104)52.06; p..05) or education
F(3,104)52.03; p..05), but had different sex distributions
(w2510.06; df53; p5.018); women predominated in the
NAM group. The groups had equivalent MMSE scores
E. Aretouli et al.
(F(3,104)5.91; p..05), and self-reported symptoms of
depression (F(3,104)5.90; p..05), but their CDR sum of
boxes (CDR-SB) differed (F(3,104)55.12; p5.002), with
AS patients having lower scores (less impairment) than the
three other groups.
From the 104 MCI patients at baseline, 76 remained stable
(73.1%), 19 progressed to CDRZ1 (18%, or 9% per year),
and 9 reverted to CDR50 (9%, or 4.5% per year) at 2-year
follow-up (see Figure 1). The presence of impairment in
memory (i.e., aMCI vs. naMCI) was not associated with pro-
gression to dementia (w251.97; df52; p..05), whereas the
presence of impairments in multiple domains (i.e., sdMCI vs.
mdMCI), regardless of the specific domains involved, was so
associated (w2518.34; df52; p,.001). More specifically,
of the 51 mdMCI individuals at baseline, 16 (31%) progressed
to dementia over a 2-year period, compared with only 3 of
to normal, whereas 9 (17%) of the sdMCI did.
Detailed information on the baseline and follow-up neuro-
psychological test scores and clinical characteristics of the
participants by MCI subgroup is presented in Table 3.
Baseline Demographic, Clinical and Cognitive
Characteristics of Groups Defined by
To further explore the outcome of the MCI patient groups, we
compared the baseline characteristics and performances on
the screening measures of those who converted to dementia
(n519) with those who remained MCI (n576). The groups
did not differ on age (F(1,92)52.14; p5.147), years of edu-
cation (F(1,92)50.02; p5.890), sex distribution (w250.28;
df51; p5.595), MMSE scores (F(1,92)53.50; p5.065) or
ratings on the CDR-SB (F(1,92)52.83; p5.096). However,
those who developed dementia had lower initial scores on the
Category Fluency Test (F(1,92)58.59; p5.004), the Clock
Drawing Test (F(1,92)54.82; p5.031), and the delayed
recall of Logical Memory of the WMS-R (F(1,92)57.95;
p5.006) than those who remained MCI after 2 years.
Predictors of Progression to Dementia in MCI
Univariate logistic regression models
Univariate logistic regression models were used to examine
the predictive value for dementia of each measure separately.
Demographic characteristics in our sample were not asso-
ciated with the CDR score after 2 years. However, ratings on
specific measures of everyday functioning, in particular the
ADCS ADL-PI and the IQCODE, predicted progression to
CDRZ1 at the follow-up visit. Higher scores on both mea-
sures (indicating worse functioning) were associated with
increase in the likelihood of developing dementia at 2 years.
In addition, lower scores on specific cognitive screening tests
at baseline—the Clock Drawing Test, the delayed recall of
the WMS-R Logical Memory, and the Category Fluency—
were associated with higher likelihood of having dementia at
2 years. From the 18 executive function measures, only three
on the Hayling Test, the Alternate Uses Test, and the Verbal
Table 2. Demographic and baseline clinical characteristics of the participants who had 2-year follow-ups
Amnestic MCI Non-amnestic MCI
Single domain Multiple domainSingle domain Multiple domain
Education, highest grade completed
Mini-Mental State Exam, score
Clinical Dementia Rating, sum of boxes
Geriatric Depression Scale, score
74.97 (SD55.82) 78.32 (SD57.25) 74.04 (SD58.18) 76.62 (SD57.34)
16.17 (SD52.17) 16.53 (SD52.42) 15.22 (SD52.91) 15.08 (SD52.25)
28.24 (0.21)28.29 (0.18)
0.86 (0.14)1.51 (0.12)
2.31 (0.42)2.79 (0.37)
Note. All participants had Clinical Depression Rating (CDR) scale global scores of 0.5 at first visit. Means6standard errors, unless otherwise noted. For
continuously distributed variables, effect sizes are h2and p values are based on one-way analysis of variance (ANOVA). For frequency counts (sex), effect
size is Cramer’s V and p value is based on Pearson’s chi-squared test. MCI5mild cognitive impairment.
Fig. 1. Clinical status at 2-year follow-up as a function of group at
entry. F/U5follow-up; CDR5Clinical Dementia Rating scale.
Outcome in mild cognitive impairment
Table 3. Baseline and follow-up scores and clinical characteristics of study participants by subgroup over the 2-year interval
Baseline scoresFollow-up scores
Amnestic MCI Non-amnestic MCIAmnestic MCI Non-amnestic MCI
Single Domain Multiple DomainSingle Domain Multiple Domain Single Domain Multiple DomainSingle DomainMultiple Domain
Logical Memory WMS-R
Boston Naming Test
Clock Drawing Test
Alternate Uses Test
Random Number Generation
Tinker Toy Test
D-KEFS Stroop Test
Completions & Corrections Test
Porteus Maze Test
D-KEFS Tower Test
D-KEFS Sorting Test
Brixton Spatial Anticipation Test
Verbal Concept Attainment Test
Stanford Binet Absurdities Test
Iowa Gambling Test
Experimental Judgment Test
Trail Making Test
Brief Test of Attention
TEA Telephone Search While Counting
Geriatric Depression Scale
Note. Means (6SE). MCI5mild cognitive impairment; WMS-R5Wechsler Memory Scale-Revised; D-KEFS5Delis-Kaplan Executive Function System; TEA5Test of Everyday Attention; ADCS
ADL-PI5Activities of Daily Living-Prevention Instrument developed by the Alzheimer’s Disease Cooperative Study Committee; IQCODE5Informant Questionnaire on Cognitive Decline in the Elderly;
E. Aretouli et al.
Concept Attainment Test were associated with higher like-
lihood of having a CDR score Z1. Table4 presents the results
of the univariate logistic regression analyses for the variables
that significantly predicted CDR score at the follow-up visit.
Hierarchical logistic regression model
Demographic characteristics (Block 1) were forced to enter
into the model first. Among the measures of everyday func-
tioning (Block 2), only ADCS ADL-PI score entered,
accounting for 12.3% of the variance in the outcome. From
the screening battery (Block 3), WMS-R Logical Memory
(delayed recall) entered at step 1, Category Fluency at step 2
and Clock Drawing Test at step 3, explaining an additional
24.9% of variance. Beyond this, none of the EC measures
contributed independently to the prediction of progression
from MCI to dementia. Together, the four test variables in the
model and the demographic characteristics accounted for
41.3% of the variance in the outcome. Overall classification
accuracy of the model was 84.7% (see Table 5).
Omnibus logistic regression model
The logistic regression analysis with entry of all variables
that were significant in the univariate analysis together in a
stepwise manner resulted in findings similar to those of
the hierarchical regression model. Specifically, the ADCS
ADL-PI entered the model first [accounting for 12.8% of
the variance of the outcome; odds ratio (OR)51.179; 95%
confidenceinterval (CI): 1.043–1.333; p5.009], followed by
the WMS-R Logical Memory (11.6% variance explained;
OR5.820; 95% CI: 0.697–.963; p5.016), then the Cate-
gory Fluency (12.2% variance explained; OR5.880; 95%
CI: 0.790–0.981; p5.021), and the Clock Drawing Test
(6.7% variance explained; OR5.623; 95% CI: 0.399–0.972;
p5.037). No demographic characteristic and no EC measure
entered the model. These predictors explained a total of
40.3% of the variance of the outcome.
Sensitivity and specificity of the prediction models
ROC analysis of the ‘‘probability of progression to CDR
Z1’’ score that results from the combined predictors of the
hierarchical regression model indicated high discriminative
accuracy (see Figure 2; AUC5.847; CIs5.742–.953).
Using a probability for dementia cutoff value of 0.146, the
model yielded a sensitivity of 0.94 and a specificity of 0.71.
Thus, 94% of the MCI patients who progressed to dementia
had a probability score higher than 0.146, whereas 71% of
stable MCI patients had a probability score of less than 0.146.
Table 4. Univariate associations between baseline demographic, clinical and neuropsychological characteristics and progression to dementia
(CDRZ1) over a 2-year follow-up period
Odds ratio (95% CI)
Everyday functioning measures ADCS-Activities of Daily Living—Prevention Instrument
Screening battery Logical Memory WMS-R (delayed recall)
Word list generation-Category Fluency
Clock Drawing Test
Executive cognition measuresAlternate Uses Test
Verbal Concept Attainment Test
Note: CI5Confidence interval; CDR5Clinical Depression Rating scale; ADCS5Alzheimer’s Disease Cooperative Study; IQCODE5Informant
Questionnaire on Cognitive Decline in the Elderly; WMS-R5Wechsler Memory Scale-Revised.
Table 5. Hierarchical logistic regression predicting functional/cognitive status (MCI or dementia) at 2 year follow-up as a function of
demographic characteristics, and baseline clinical and cognitive factors
Odds ratio (95% CI)
Logical Memory WMS-R (delayed recall)
Word List Generation (semantic categories)
Clock Drawing Test
Note. MCI5mild cognitive impairment; CI5confidence interval; DR25Nagelkerke R Square change; ADCS ADL-PI5Activities of Daily Living-
Prevention Instrument developed by the Alzheimer’s Disease Cooperative Study Committee; WMS-R5Wechsler Memory Scale-Revised.
Outcome in mild cognitive impairment
The present study is, to our knowledge, the first systematic and
comprehensive study of the predictive value of EC for the
outcome of MCI patients. During a 2-year period, 18% of the
MCI individuals progressed to dementia, corresponding to an
annual rate of 9%. The majority of the patients remained stable
over time, whereas 9% returned to normal cognitive status. We
found that MCI individuals with impairments in multiple
domains at baseline were at higher risk of decline over the
2-year period than those with impairment in a single domain
(Alexopoulos et al., 2006b; Loewenstein et al., 2009; Manly
et al., 2008; Mitchell et al., 2009; Nordlund et al., 2010).
One plausible explanation is that mdMCI might represent a
more advanced stage of the disease process than sdMCI
1999) or they did so temporarily in response to one or more
sdMCI reverted to normal, it appears that an isolated cognitive
impairment in an elderly person may be relatively benign.
Whether the presence of memory impairments increases
the risk for subsequent dementia among persons with MCI is
controversial. As in several previous studies, we found that
memory impairment was not specifically associated with an
increased rate of progression to dementia (Mitchell et al.,
2009; Nordlund et al., 2010). However, others concluded that
MCI individuals with isolated memory impairment were
more likely to progress to dementia than those with a single
non-memory impairment or even those with impairments
in multiple domains (Ravaglia et al., 2006; Yaffe, Petersen,
Lindquist, Kramer, & Miller, 2006). Manly et al. (2008)
found that MCI individuals with memory impairments are at
highest risk, especially when other cognitive deficits are
present. Of note, a large community-based study concluded
and heterogeneous; significant proportions remain stable or
improve on long-term follow-ups (Ganguli et al., 2004).
A major finding of the present study is the limited pre-
dictive power of EC measures for the development of
dementia. Only 3 of 18 EC measures—the Alternate Uses
Test, the Hayling Test, and the Verbal Concept Attainment
Test—were significantly associated with incidentdementia at
the univariate level. These tests assess spontaneous flexibility
and generativity, inhibition of prepotent responses and con-
cept rule learning, respectively. However, all three tests also
rely on semantic memory. Both Hayling and Alternate Uses
Test require the participant to inhibit a semantically con-
strained response and the Verbal Concept Attainment Test is
very highly correlated with verbal tests such as the Wechsler
Adult Intelligence Scale (WAIS) Vocabulary (Belleville,
Rouleau, & Van der Linden, 2006; Bornstein, 1982). Thus,
their dependence on semantic memory might also contribute
to their sensitivity to predict cognitive decline and dementia.
Although these three tests were found to be predictive at the
a model that first considered demographic characteristics,
cognitive screening tests, and everyday functioning. Our
in contrast to the reported findings of several longitudinal
studies. Specifically, measures of set-shifting and sequencing
2004; Tierney et al., 1996), and abstract reasoning (Elias et al.,
2000) have been identified as predictors of incident dementia
in MCI patients. However, in none of these studies was the
prognostic value of EC examined after controlling for other
factors (i.e., demographic characteristics, non-executive cog-
likely to have underlying AD neuropathology and progress to
dementia than those with an isolated memory or isolated lan-
guage impairment. Similarly, Farias, Mungas, Reed, Harvey,
and DeCarli (2009) indicated that executive dysfunction
was not associated with an increased risk of progression to
dementia over other factors such as age, education, clinic
recruitment source, and functional status.
There are many confounding factors when one is trying to
assess the predictive value of neurocognitive measures at
baseline for incident dementia. One of the parameters that has
not been adequately emphasized is that the predictive value
of a measure is conditional on the other measures in the
model. Differences in the variables included in the predictive
has been found to be the strongest predictor in several studies
(Albert et al., 2001; Chen et al., 2000; Crowell et al., 2002;
Daly et al., 2000), but not in others (Grober et al., 2008;
Mitchell et al., 2009). Our results suggest that the predictive
utility of EC over other cognitive measures might have been
predictors of the hierarchical model for discrimination of stable mild
cognitive impairment patients and those who progressed to dementia.
E. Aretouli et al.
overestimated. An alternative interpretation is that most
cognitive measures, especially those of any complexity, have
substantial executive requirements (Salthouse, Atkinson, &
Berish, 2003), and they consequently restrict the unique var-
iance that ‘‘pure’’ EC measures can account for. Indeed, both
the Clock Drawing Test and the Category Fluency Test rely
on executive skills such as planning, search strategies, self-
& Miller, 2007; Lowery et al., 2003). Finally, other factors,
such as the interval between the baseline and the follow-up
assessment, might affect the sensitivity of a test to detect
decline, since it can be related to the stage of the potential
preclinical course of the MCI patient (Grober et al., 2008).
Among all thecognitive measures, the delayed recall ofthe
Logical Memory, the Category Fluency and the Clock
Drawing Test were the most sensitive predictors of MCI
outcome. Impairment in episodic memory and semantic flu-
ency have been shown to be among the earliest cognitive
changes that are consistent over very long follow-ups in con-
at early stages but tend to be unstable over time (Hodges,
Erzinclioglu, & Patterson, 2006). The Category Fluency Test
and the Clock Drawing Test implicate executive processes but
are also dependent on intact semantic memory (Henry &
Crawford, 2004; Hodges, Salmon,& Butters,1992; Loweryet
al., 2003). There is also considerable evidence that verbal
generativity and ‘‘idea density’’ is significantly compromised
several years before dementia is diagnosed (Oulhaj, Wilcock,
Smith, & de Jager, 2009; Riley, Snowdon, Desrosiers, &
Markesbery, 2005; Snowdon et al., 1996). In addition,
semantic fluency appears dependent on the integrity of the
temporal neocortex, a brain region proportionately affected
very early in the Alzheimer’s disease (Arnold, Hyman, Flory,
Damasio, & Van Hoesen, 1991; Baldo, Schwartz, Wilkins, &
Dronkers, 2006; Henry & Crawford, 2004).
Changes in daily functioning measured with the ADCS
ADL-PI, and the IQCODE at baseline were also found to
have significant prognostic value for the MCI outcome. ADCS
ADL-PI measures minor changes in functional status that occur
in the transition from cognitively normal to MCI or early
dementia and IQCODE is considered ‘‘a measure of the
disablement caused by cognitive decline’’ (Jorm et al., 1996,
are measures of change or deterioration. Thus, these findings
may simply indicate that prior change predicts future change. Of
note, both measures had only weak correlations with the EC
measures (ranging from r52.009 to r52.232) and their
exclusion from the regression model did not change the con-
tribution of EC measures for the prediction of MCI outcome.
Several other studies have documented that worse ratings on
Hyman, Albert, & Blacker, 2007; Morris & Cummings, 2005;
of dementia in clinic- versus population-based studies appears
to be explained by the greater baseline functional impairment
in the MCI patients recruited from clinics (Farias et al., 2009).
Our results underline further the necessity to carefully assess
everyday functioning in persons at risk for dementia.
The present study has certain limitations. First, although
ourMCIsampleisrelativelylarge, itisprobably notadequate
for the number of predictors we tested. We recognize that
our analyses are rather exploratory, but the consistency of
our findings using different regression models supports the
robustness of our conclusions. Second, our criteria for defining
applied both clinical criteria (interview with an informant,
yielding a CDR score of 0.5), as well as psychometric criteria
(based on well-recognized neuropsychological procedures).
Similar methodology has been implemented in several other
studies (Alexopoulos et al., 2006b; Dickerson et al., 2007;
Grundman et al., 2004; Storandt, Grant, Miller, & Morris,
2006) and conforms to the current standard for the diagnosis of
MCI (Petersen, 2004). Third, we operationalized the develop-
Participants were not formally evaluated by a clinician in this
study (although many were so-evaluated and diagnosed in
other research studies or clinics) and we cannot exclude the
possibility that a participant could be assigned a global CDR
score Z1 for other reasons (i.e., caregiver distress). However,
CDR has been used in numerous studies to identify both MCI
and dementia cases (Daly et al., 2000; DeCarli et al., 2004;
Storandt et al., 2006) and neuropathological findings have
(Berg, McKeel, Miller, Baty, & Morris, 1993; Morris, 1997).
In summary, our 2-year follow-up of MCI individuals
confirmed previous findings that persons with multiple cog-
nitive impairments are at higher risk for functional decline
than those with isolated deficits. EC has limited incremental
validity as a predictor of which MCI individuals progress
from CDR50.5 to CDRZ1. However, other cognitive
measures (Logical Memory of the WMS-R, Category Fluency
and the Clock Drawing Test) and measures of everyday
functioning (ADCS ADL-PI) can predict the fate of the 0.5s
withreasonablyhighaccuracy. It stillremains unclear whether
EC can predict which MCI individuals revert to normal
cognitive status, when followed over time.
Albert, Ph.D., and the staff and participants of the Johns Hopkins
Alzheimer’s Disease Research Center. Eleanor Neijstrom, M.S.,
Jaclyn Samek, B.S., and Kevin Manning, M.S., collected the data.
This study was supported by the National Institute on Aging (J.B.,
grant AG-005146). No conflicts of interest exist.
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