G Model

AGG-2269; No. of Pages 6

Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx

Contents lists available at ScienceDirect

Archives of Gerontology and Geriatrics

journal homepage: www.elsevier.com/locate/archger

Can impairment in memory, language and executive functions predict

neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings
from a cross-sectional study
José Marı́a Garcı́a-Alberca a,b,*, José Pablo Lara b, Marcelo Luis Berthier c, Belén Cruz a,
Miguel Ángel Barbancho b, Cristina Green c, Salvador González-Barón b
a
Memory and Alzheimer’s Disease Unit, Instituto Andaluz de Neurociencia y Conducta, Alamos, 17, 29012 Malaga, Spain
b
Cognitive Neurophysiology Unit, Centro de Investigaciones Médico-Sanitarias, University of Málaga. Campus de Teatimos. Malaga. Spain
c
Cognitive Neurology and Aphasia Unit, Centro de Investigaciones Médico-Sanitarias, University of Málaga. Campus de Teatimos. Malaga. Spain

A R T I C L E I N F O A B S T R A C T

Article history: The authors performed a cross-sectional study to examine the relationship between specific cognitive
Received 21 January 2010 domains and behavioral and psychological symptoms in dementia (BPSD) in 125 patients with probable
Received in revised form 2 May 2010 AD. Cognitive deficits were evaluated with the mini mental state examination (MMSE), trail-making test
Accepted 3 May 2010
(TMT), Rey auditory verbal learning test (RAVLT), and semantic fluency test (SFT) and phonemic fluency
test (PhFT), whereas the neuropsychiatric inventory (NPI) was used to rate BPSD. Patients’ performance
Keywords: in cognitive tests significantly correlated with total NPI scores (p < 0.0001). After controlling for
Alzheimer’s disease
demographic and clinical characteristics, cognitive impairments in memory, executive function, and
Neuropsychiatric symptoms
Memory function
language (RAVLT, TMT, PhFT, SFT) importantly estimated total NPI scores (p < 0.001, multivariate
Executive function regression models). These findings suggest that the evaluation of cognitive domains may have a
Language functions predictive value for the occurrence of BPSD.
Cognitive impairment ß 2010 Published by Elsevier Ireland Ltd.

1. Introduction Studies that focus on the relation of cognitive deficits in specific

Patients with AD show abnormalities in cognitive, behavioral
and activities of daily living domains (Mega et al., 1996).
Associations between cognitive functions and BPSD have been
examined in several studies (Cummings et al., 1994; Harwood
et al., 2000; Holtzer et al., 2003; Craig et al., 2005) but it is needed
to refine our understanding on their relationship. The occurrence
of BPSD is variable as they tend to co-occur, fluctuate, recur or even
herald the onset of dementia (Holtzer et al., 2003; Spalletta et al.,
2004; Bakker et al., 2005; Craig et al., 2005; Lam et al., 2006). The
prevalence of BPSD in AD patients seems to increase in parallel
with disease progression and to correlate with the level of
functional and cognitive disability (Chung and Cummings, 2000;
Hart et al., 2003; Craig et al., 2005; Stepaniuk et al., 2008).
However, some studies failed to show this relationship or
presented equivocal findings (Bakker et al., 2005; Lam et al.,
2006; Ito et al., 2007; Starr and Lonie, 2007).
* Corresponding author at: Memory and Alzheimer’s Disease Unit, Instituto
Andaluz de Neurociencia y Conducta, Alamos, 17, 29012 Malaga, Spain.
Tel.: +34 952 137 546; fax: +34 952 212 022.
E-mail address: jmgalberca@ianec.com (J.M. Garcı́a-Alberca).
domains with BPSD are important as they may help to elucidate the
pathophysiological bases for these symptoms among patients with
dementia (Harwood et al., 2000). However, most previous studies in
AD analyzing the relationship between cognitive functions and BPSD
administered the MMSE (Folstein et al., 1975) as the unique index of
cognitive status, thus limiting the extent and specificity of their
results (Holtzer et al., 2003). In a large study including 680 AD
patients (Cooper et al., 1990), five of six abnormal behaviors were
associated with MMSE scores. In other two studies, a significant
correlation between MMSE and NPI scores was reported in 435
patients (Craig et al., 2005) and between MMSE and the behavioral
pathology in AD in another series of 114 patients (Harwood et al.,
2000). Other study focused on the relationship between behavioral
changes (assessed with the NPI) and cognitive impairment
measured with the MMSE in 50 AD patients showed that mean
values for total NPI scores increased among groups characterized by
mean MMSE score (Mega et al., 1996). Finally, an autopsy-confirmed
study in 28 AD patients found a significant correlation between
MMSE and the Blessed dementia scale (BDS, Blessed et al., 1968) and
the Haycox dementia behavior scale (HDBS, Haycox, 1984), thus
further suggesting than cognitive and behavioral impairment
progress simultaneously (Kurita et al., 1993).
There are few studies addressing the relationship of deficits in
specific cognitive domains with specific BPSD. One study carried

0167-4943/$ – see front matter ß 2010 Published by Elsevier Ireland Ltd.

doi:10.1016/j.archger.2010.05.004

Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004
G Model
AGG-2269; No. of Pages 6
2 J.M. Garcı´a-Alberca et al. / Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx
out in the early stages of dementia suggested that isolated
executive impairments, measured with MMSE and the Cambridge
cognition examination (CAMCOG, Roth et al., 1986) are predictive
of abnormal behavior at long-term follow-up (Tung Tsoi et al.,
2008). Impaired executive function showed a modest correlation
with agitation, apathy and disinhibition in one study (Senanarong
et al., 2005), whereas poor performance on four tests of executive
functioning was significantly associated with the agitation/
disinhibition factor and total neuropsychiatric score on the
neuro-behavioral rating scale (NRS, Schultzer et al., 1992) in
another study (Chen et al., 1998). Using a comprehensive
neuropsychological test battery, a more severe cognitive im-
pairment was observed in AD patients presenting misidentification
and hallucinations (Perez-Madriñan et al., 2004). Thus, further
studies are necessary to assess if decline in specific cognitive
domains can provide additional information with respect to their
association with BPSD in AD (Levy and Chelune, 2007).
The main goal of this study was to obtain new data regarding the
association of specific cognitive impairments and BPSD in a cross-
sectional study of AD patients. We examined whether this association
is independent of demographic and clinical variables that may
influence the clinical expression of BPSD. A better understanding of
cognitive impairments associated with BPSD may be useful both to
identify potential predictors and to individualize treatment strate-
gies for patients and caregivers. A second aim was to examine
whether or not the severity of specific cognitive impairments
correlated with BPSD and have a predictive value.
2. Patients and methods
2.1. Subjects
This was a cross-sectional study that enrolled 125 consecutive
outpatients presenting for evaluation of dementia at the ‘‘Memory
and Alzheimer’s Disease Unit of the Instituto Andaluz de Neuro-
ciencia y Conducta’’ and the ‘‘Centro de Investigaciones Médico-
Sanitarias of the University of Málaga’’ (Málaga, Spain). Diagnostic
evaluation included complete medical history, physical and
neurological examination, cognitive tests, and blood tests (thyroid
stimulant hormone, T-4 and T-3 thyroid hormones, serological tests
for syphilis, and levels of vitamin B-12, and folic acid), and magnetic
resonance imaging of the brain. All patients satisfied the criteria of
the National Institute of Neurological and Communicative Disorders
and the Alzheimer’s Disease and Related Disorders Association
(NINCDS/ADRDA) for probable AD (McKhann et al., 1984). Patients
were clinically defined in stages 4, 5 and 6 of the global deterioration
scale (GDS) (Reisberg et al., 1982). Patients with MMSE scores over
23/30 were included if all other inclusion criteria were satisfied. A
further inclusion criterion was that the responsible caregiver must
live with the patient, be directly involved in the patient’s care and be
reliable to inform. Exclusion criteria were delirium, active diseases
that could affect cognitive functions either systemic (e.g., diabetes
mellitus, hypothyroidism) or neurological (e.g., cortical o subcortical
stroke, epilepsy, head injury), history of alcohol or substance abuse,
history of psychiatric disease previous to the onset of cognitive
decline (within the preceding 2 years before onset of dementia) or
severe sensorial deficits.
All performed procedures were approved by the Ethical
Committees of the both Instituto Andaluz de Neurociencia y
Conducta and University of Malaga. All patients or their authorized
representatives were required to sign an informed consent.
2.2. Cognitive and neuropsychiatric assessment
The cognitive status was assessed with several cognitive tests.
MMSE was used as a global measurement of cognitive status. The
Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004
RAVLT (Rey, 1958) was used to evaluate working memory and long
term memory through the immediate recall score (the sum of all
correct responses given in the five consecutive trials) and the
delayed recall score (number of correct responses after a 20 min
delay period). The TMT (parts A and B) (Reitan and Wolfson, 1993)
was used to evaluate sustained visual attention, sequence
alternation, cognitive flexibility, processing speed, visual search,
motor performance and executive functioning. The typical cut-off
or discontinuation time for TMT administration (3 min for part A
and 5 min for part B) was assigned to those patients who were not
able to complete the test. Verbal tests of SFT (animal naming)
(Peña-Casanova, 1990) and for words beginning with the letter ‘‘p’’
(PhFT) were used to evaluate phonological and lexical retrieval in
oral modality. BPSD were examined with the NPI (Cummings et al.,
1994) that evaluates 12 neuropsychiatric disturbances common in
dementia. Frequency, severity and composite (frequency  sever-
severity) total scores and score for each behavior were obtained.
2.3. Statistical analysis
Descriptive statistics were obtained for all variables including
demographic and clinical characteristics (age, gender and years of
education, duration of illness, GDS, psychiatric disorders previous
history and use of psychoactive and antidementia drugs),
neuropsychological tests (MMSE, RAVLT, PhFT, SFT, TMT) and
NPI. For the sake of the analysis, age, education level and duration
of dementia were dichotomized, and a median split on the
cognitive variables was obtained. Analysis of the distribution type
was performed using the Kolmogorov–Smirnov’s test. Correlation
studies were performed with the Pearson coefficient in cases of
normal distribution was present or with the Spearman coefficient
when appropriate. Stepwise multivariate regression models were
performed to assess the potential predictive value of cognitive
functions on BPSD including adjusted R2, standard error of estimate
(SEE), standardized (b) and unstandardized (B) coefficients. The
regression analysis was also run after controlling for the potential
confounding effects of age, gender, duration of dementia, history of
psychiatric disorders, use of psychoactive and antidementia drugs.
Regression diagnostics were performed to assess the validity of the
linear model assumptions and fit. All statistical tests were two-
tailed and performed at the p < 0.05 level of significance. Analyses
were performed using SPSS Version 15.0.
3. Results
3.1. Demographic and clinical characteristics of the sample
Demographic and clinical characteristics of the 125 AD patients
and their performances in the cognitive evaluation are shown in
Table 1, including dichotomized variables. The mean age was 76
years with an average level of education of 6 years. Nearly 70% of
patients were women. The estimated duration of dementia was 62
months. A 25% had previous history of psychiatric disorders and
most patients received pharmacological treatments (psychoactive
drugs: 38%, antidementia drugs: 70%). Patients were grouped
according to the GDS as belonging to stages 4 (N = 33), 5 (N = 42)
and 6 (N = 50). The mean GDS score was 5.1. A high correlation was
observed between the GDS and the duration of illness (r = 0.74,
p < 0.01, Spearman’s coefficient). Mean overall cognitive scores
(MMSE = 14.5) suggested moderate to severe dementia.
Most patients (N = 122, 98%) had BPSD (number of BPSD per
patient, mean  S.D.: 5.1  1.87; range: 1–10). Total scores of the NPI
(frequency, severity and composite) and number of patients
presenting each symptom and their score are presented in Table 2.
The most prevalent symptoms in the sample were apathy (74%)
followed by irritability (66%), dysphoria (60%), agitation (55%),
G Model
AGG-2269; No. of Pages 6

J.M. Garcı´a-Alberca et al. / Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx 3

Table 1 Table 2
Demographic and clinical variables of AD patients and mean performances on the Mean total NPI scores and number, percentage and mean composite scores of the 12
cognitive evaluation. NPI behaviors (listed by frequency of occurrence).

Variables Mean  S.D. (range), or N (%) NPI total scores Mean  S.D. (range)

Age, years (N = 125) 76.40  6.10 (57–95) Frequency (/44) 9.86  4.56 (0–21)
<76 51 (41) Severity (/48) 13.46  6.05 (0–26)
76 74 (59) Composite (/136) 27.90  16.22 (0–66)

Gender, male/female 38 (30.4)/87 (69.6) NPI behaviors scores n (%) Mean  S.D.

Education, years 6.34  2.70 (1–13) Apathy 92 (74) 5.30  4.27

<7 80 (64) Irritability 82 (66) 3.18  3.05
7 45 (36) Dysphoria 75 (60) 3.84  3.54
Agitation 69 (55) 2.86  3.21
Duration of dementia, months 62.21  26.16 (18–120) Anxiety 67 (54) 2.70  3.23
<67 69 (55) Aberrant motor behavior 59 (47) 3.71  4.87
67 56 (45) Delusions 47 (38) 1.73  2.97
Sleep disturbances 45 (36) 1.78  2.91
History of psychiatric disorders 31 (24.80)
Disinhibition 37 (30) 0.78  1.65
GDS
Appetite abnormalities 35 (28) 1.30  2.39
4 33 (27)
Hallucinations 25 (20) 0.72  1.95
5 42 (33)
Euphoria 5 (4) 0.14  1.10
6 50 (40)

Psychoactive drugs 48 (38.40)

Antidementia drugs 88 (70.04) immediate recall, and PhFT; those without normal distribution
Cognitive evaluation Mean  S.D. (median; range), or N (%) were years of education, RAVLT delayed recall, TMT (A and B), SFT
MMSE 14.46  4.81 (14; 5–25)
and scores on the 12 NPI behaviors.
<14 59 (47)
14 66 (53) 3.2. Association between cognitive functions and BPSD
RAVLT immediate recall, total words 11.75  6.17 (13; 0–23)
<13 65 (52) The results of the unadjusted relationship between cognitive
13 60 (48) functions and BPSD are presented in Table 3. Total NPI scores
RAVLT delayed recall, total words 0.35  0.81 (0; 0–4)
significantly correlated with the cognitive tests (p < 0.0001, in all
<1 100 (80) cases). High correlation coefficients were obtained between total
1 25 (20) NPI composite score and MMSE (r = 0.75), RAVLT immediate
TMT-A, s 176  13.77 (180; 110–180) recall (r = 0.75), RAVLT delayed recall (r = 0.56), TMT-A
<180 16 (13) (r = 0.42), TMT-B (r = 0.55), SFT (r = 0.68) and PhFT (r = 0.64).
180 109 (87) Multivariate regression models showed that the NPI frequency
TMT-B, s 269  52.58 (300; 180–300) total score was significantly estimated by RAVLT immediate recall,
<300 32 (26) TMT-B, PhFT and SFT (adjusted R2 = 0.60, F = 24.73, df = 7,117,
300 93 (74) p < 0.001, SEE = 3.96). Equally, the NPI severity total score was
SFT, total words 4.82  2.56 (5; 0–11) significantly estimated by RAVLT immediate recall, TMT-B, PhFT,
<5 68 (54) and SFT (adjusted R2 = 0.64, F = 30.34, df = 7,117, p < 0.001,
5 57 (46) SEE = 2.80). Finally, the NPI composite total score was significantly
PhFT, total words 6.01  4.18 (7; 0–21) estimated by RAVLT immediate recall, TMT-B, PhFT, and SFT
<7 67 (54) (adjusted R2 = 0.65, F = 31.12, df = 7,117, p < 0.001, SEE = 9.87).
7 58 (46) The results of the association between cognitive function and
BPSD after adjustment for patient characteristics (age, gender,
anxiety (54%) and aberrant motor behavior (47%). The less prevalent duration of dementia, history of psychiatric disorders, use of
symptoms were hallucinations (20%) and euphoria (4%). psychoactive and antidementia drugs) are shown in Table 4.
Variables with normal distribution were age, duration of illness, Multivariate regression models showed that the NPI frequency
NPI total scores (frequency, severity and composite), MMSE, RAVLT total score was significantly estimated by RAVLT immediate recall,

Table 3
Unadjusted association between scores of the cognitive tests and NPI total scores. Correlation and multivariate regression models of total NPI scores for cognitive test
performances.

Cognitive tests NPI frequency NPI severity NPI composite

r B b r B b r B b
MMSEA 0.72a 0.31 0.25 0.74a 0.14 0.15 0.75a 0.68 0.20
RAVLT immediate recallA 0.69a 0.31 0.32b 0.70a 0.23 0.31c 0.75a 0.18 0.45a
RAVLT delayed recallB 0.57a 0.04 0.01 0.56a 0.04 0.01 0.56a 0.74 0.03
TMT-AB 0.42a 0.04 0.09 0.43a 0.03 0.09 0.42a 0.09 0.08
TMT-BB 0.56a 0.04 0.35b 0.55a 0.04 0.41a 0.55a 0.08 0.24d
SFTA 0.63a 0.56 0.24d 0.66a 0.37 0.21d 0.68a 1.40 0.22d
PhFTA 0.59a 0.34 0.24d 0.64a 0.35 0.32c 0.64a 1.18 0.31d
A
Pearson’s correlation coefficients.
B
Spearman’s correlation coefficients.
a
p < 0.0001.
b
p < 0.001.
c
p < 0.01.
d
p < 0.05.

Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004
G Model
AGG-2269; No. of Pages 6

4 J.M. Garcı´a-Alberca et al. / Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx

Table 4
Multivariate regression models of total NPI scores for cognitive tests performance adjusting for sociodemographics and clinical characteristics of the patients.

Characteristics NPI frequency NPI severity NPI composite

B b p B b p B b p

Gender 0.84 0.06 0.20 0.24 0.02 0.67 1.98 0.06 0.29
Age 1.56 0.13 <0.05 1.12 0.12 <0.05 5.13 0.16 <0.01
Education 0.50 0.04 0.52 0.29 0.03 0.59 0.69 0.02 0.71
Duration of dementia 2.17 0.18 <0.05 0.61 0.07 0.35 3.77 0.12 <0.05
Psychiatric disorders 0.07 0.01 0.93 0.53 0.05 0.37 3.98 0.11 <0.05
Antidementia drugs 1.29 0.09 0.10 0.86 0.08 0.12 3.47 0.09 <0.05
Psychoactive drugs 0.69 0.05 0.34 0.72 0.07 0.16 2.29 0.07 0.19
TMT-B 0.04 0.34 <0.001 0.03 0.37 <0.001 0.06 0.20 <0.05
RAVLT/immediate recall 0.44 0.45 <0.001 0.29 0.39 <0.001 1.44 0.55 <0.001
SFT 0.61 0.26 <0.05 0.33 0.19 0.16 1.29 0.20 <0.05
PhFT 0.28 0.19 0.05 0.31 0.28 <0.001 1.01 0.26 <0.01

TMT-B, PhFT, and SFT (adjusted R2 = 0.63, F = 17.38, df = 11,113,
p < 0.001, SEE = 3.86). Equally, the NPI severity total score was
significantly estimated by RAVLT immediate recall, TMT-B and
PhFT (adjusted R2 = 0.67, F = 21.37, df = 11,113, p < 0.001,
SEE = 2.72). Finally, the NPI composite total score was significantly
estimated by TMT-B, RAVLT immediate recall, PhFT, and SFT
(adjusted R2 = 0.71, F = 24.81, df = 11,113, p < 0.001, SEE = 9.19).
The validity of the linear models was evaluated for both
unadjusted and adjusted multivariate regression analyses. The
predictors were found to be generally linearly associated with
the outcome and model residuals to be normally distributed.
There were significant leverage points but with small influence;
largest Cook’s distances were 0.008 or 0.009 (total frequency
model), 0.009 or 0.01 (total severity model) and 0.007 or 0.01
(total composite model) for unadjusted and adjusted models,
respectively. These results indicate that none of the outlier
values were materially affecting the estimated regression
coefficients.
4. Discussion
Our results provide evidence of strong associations between
cognitive deficits in memory (episodic and semantic), language
and executive functions and BPSD that were unrelated to
demographic and clinical characteristics of the patients. Multivar-
iate regression models showed that the magnitude of the cognitive
effect was robust accounting for 71% of the variance in total NPI
composite score.
Longitudinal studies provide the most reliable characterization
of the temporal progression of BPSD in individual AD patients
(Mega et al., 1996) and true predictors are best identified with a
longitudinal design. Although the design of our study was cross-
sectional design, we controlled several factors that were not
consistently controlled in previous studies. Patients included were
free of medical diseases and neurological conditions (other than
AD) that could influence the profiles of cognitive and neuropsy-
chiatric deficits and only a small proportion of the sample had a
previous history of psychiatric disorders. The proportion of
patients classified as having mild, moderate and severe dementia
according to GSD was similar. All AD patients had reliable
caregivers and those with no reliable caregivers and living alone
or in nursing home facilities were excluded. In addition to the
MMSE, the cognitive status was examined with other tests
sensitive to detect deficits in executive, memory, attention and
language domains (Zakzanis et al., 1999). Although our test battery
did not examine visual and visuoconstructional and visuospatial
abilities, it was more comprehensive than others used in previous
studies assessing BPSD with the NPI, where the MMSE constituted
the unique cognitive assessment instrument (Holtzer et al., 2003;
Bakker et al., 2005; Craig et al., 2005).
We found that nearly all patients (98%) had BPSD. The spectrum
of BPSD was comparable to that described in other clinical samples
and population-based studies with similar age at the onset of
dementia and MMSE scores (Lyketsos et al., 2000, 2002). However,
the estimated prevalence of BPSD were higher in other studies
where samples were of similar mean age but major duration of
illness and functional assessment staging score (FAST, Reisberg,
1988) and minor mean MMSE score, supporting the view that
disease progression in AD is characterized by an increase in BPSD
(Hart et al., 2003; Craig et al., 2005).
Our results show highly significant correlations between all
performed cognitive tests and total NPI scores (frequency, severity
and composite). The relationship between total NPI scores and
MMSE was significant which is in accordance with most (Cooper
et al., 1990; Kurita et al., 1993; Mega et al., 1996; Harwood et al.,
2000; Wilson et al., 2000; Craig et al., 2005; Senanarong et al.,
2005; Starr and Lonie, 2007), but not all studies (Chen et al., 1998;
Senanarong et al., 2005). The results of our study suggest that the
likelihood of detecting this association would increase when
cognitive functioning is comprehensively assessed with specific
cognitive tests and not only with global cognitive screening tests
such as the MMSE. Although memory deficits constitute the
hallmark symptom in AD, its relation with BPSD has received little
attention (Lam et al., 2006). We found a significant correlation
between the RAVLT (both immediate and delayed recall scores)
and NPI total scores. Word fluency tests which assess semantic
memory, verbal skills and executive functions significantly
correlated with NPI total. Finally, the TMT (parts A and B) which
assesses visual attention/concentration, executive functions, and
motor performance, significantly correlated with total NPI scores.
However, in a previous study, only modest correlations using the
NPI were described between the clock drawing test (Agrell and
Dehlin, 1998) and agitation, apathy and disinhibition and between
verbal fluency with agitation (Senanarong et al., 2005).
We have completed correlation studies with multivariate
regression models considering NPI scores as dependent variables
of the cognitive status. The unadjusted proposed models evidenced
that cognitive performances can importantly estimate NPI scores.
The weight of the estimated effect can be emphasized: it accounted
for a 67% of the variance in NPI total composite score (RAVLT
immediate recall, TMT-B, PhFT and SFT). Interestingly, the MMSE
was excluded from the multivariate regression model indicating
the superior importance of more specific cognitive tests in the
proposed models. In few studies, regression analyses were also
performed considering cognition as predictor variables of BPSD
with different findings (Chen et al., 1998; Silveri et al., 2004;
Bakker et al., 2005; Tung Tsoi et al., 2008). In consonance with our
results, executive deficits appearing relatively early in the course of
dementia resulted predictive of abnormal behavior at long-term
follow-up, whereas the MMSE score was not predictive (Tung Tsoi

Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004
G Model
AGG-2269; No. of Pages 6
J.M. Garcı´a-Alberca et al. / Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx
et al., 2008). In other study, scores on executive tests accounted for
34% to 46% of the variance of the NRS total scores, although MMSE
did not correlate with BPSD (Chen et al., 1998). On the other hand,
some studies failed to demonstrate a predictive value of cognitive
performances on NPI scores (Silveri et al., 2004; Bakker et al., 2005;
Starr and Lonie, 2007). Behavioral disorders were not predicted by
neuropsychological models in AD (Silveri et al., 2004); MMSE
explained a small proportion of the variance (2%) of NPI score,
suggesting the independent role of BPSD and cognitive status in
patients suffering from cognitive dysfunction (Bakker et al., 2005).
Multivariate regression analysis identified premorbid intelligence
as the only significant predictor of NPI scores although significant
correlation with other cognitive tests scores was described (Starr
and Lonie, 2007).
It is interesting to note that in most previous studies the
relationship between cognitive deficits and abnormal behavior in
AD was examined weighting the influence of BPSD as predictor
variables on cognitive abilities (Teri et al., 1990; Miller et al., 1993;
Harwood et al., 2000; Scarmeas et al., 2005; Lam et al., 2006;
Stepaniuk et al., 2008). Several abnormal behaviors were consid-
ered to have a predictive value for cognitive decline in AD but again
using only the MMSE (Teri et al., 1990; Miller et al., 1993; Harwood
et al., 2000; Scarmeas et al., 2005). Delusions and hallucinations
(psychosis) were confirmed as predictors of rapid progression
(Lopez et al., 1999; Harwood et al., 2000; Scarmeas et al., 2005) and
patients with agitation or wandering showed a rapid cognitive
decline (Teri et al., 1990; Miller et al., 1993; Ropacki and Jeste,
2005). However, in a study with Chinese subjects associations
between memory and executive functions and BPSD were no
significant suggesting neuropsychiatric syndromes and cognitive
function as relatively independent dimensions of dementia (Lam
et al., 2006).
Our findings highlight the value of identifying specific cognitive
impairments with predictive value of BPSD rather than to detect
the global cognitive impairment; in fact, the MMSE had no
predictive value when analyzing its possible influence on BPSD. A
knowledge of the cognitive profile that is strongly associated with
BPSD may help clinicians to early identify those patients with
higher risk to suffer from BPSD and therefore, to prevent them and
to treat adequately both patients and caregivers (Coin et al., 2009).
The finding that memory, language and executive impairments
may predict BPSD can be useful for designing treatment strategies.
Future studies would reveal if cognitive rehabilitation of these
abnormal functions may help to reduce BPSD and to improve the
quality of life among patients with AD and their caregivers. In
summary, we have provided evidence that the severity of specific
cognitive impairments correlated with the severity of BPSD,
independently of demographic and clinical variables. We have also
identified potential cognitive predictors of BPSD that must be
confirmed with longitudinal studies.
Conflict of interest statement
None.
References
Agrell, A., Dehlin, O., 1998. The clock-drawing test. Age Ageing 27, 399–403.
Bakker, T.J., Duivenvoorden, H.J., van der Lee, J., Trijsburg, R.W., 2005. Prevalence of
psychiatric function disorders in psychogeriatrics patients at referral to nursing
home care—the relation to cognition, activities of daily living and general
details. Dement. Geriatr. Cogn. Disord. 20, 215–224.
Blessed, G., Tomlinson, B.E., Roth, M., 1968. The association between quantitative
measures of dementia and senile change in the cerebral grey matter of elderly
subjects. Br. J. Psychiatry 114, 797–811.
Chen, S.T., Sultzer, D.L., Hinkin, D.H., Mahler, M.E., Cummings, J.L., 1998. Executive
dysfunction in Alzheimer’s disease: association with neuropsychiatric symp-
toms and functional impairment. J. Neuropsychiatry Clin. Neurosci. 10, 426–
432.
Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004
5
Chung, H.A., Cummings, J.L., 2000. Neurobehavioral and neuropsychiatric symp-
toms in Alzheimer’s disease. Neurol. Clin. 18, 829–846.
Coin, A., Najjar, M., Catanzaro, S., Orru, G., Sampietro, S., Sergi, G., Manzato, E.,
Perissinotto, E., Rinaldi, G., Sarti, S., Imoscopi, A., Ruggiero, E., Girardi, A., 2009. A
retrospective pilot study on the development of cognitive, behavioral and
functional disorders in a sample of patients with early dementia of Alzheimer
type. Arch. Gerontol. Geriatr. 49 (Suppl. 1), 35–38.
Cooper, J.K., Mungas, D., Weiler, P.G., 1990. Relation of cognitive status and abnor-
mal behaviors in Alzheimer’s disease. J. Am. Geriatr. Soc. 38, 867–870.
Craig, D., Mirakhur, A., Hart, D.J., McIlroy, S.P., Passmore, A.P., 2005. A cross-
sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer’s
disease. Am. J. Geriatr. Psychiatry 13, 460–468.
Cummings, J.L., Mega, M., Gray, K., Rosenberg Thompson, S., Carusi, D.A., Gornbein,
J., 1994. The Neuropsychiatric Inventory: comprehensive assessment of psy-
chopathology in dementia. Neurology 44, 2308–2314.
Folstein, M.F., Folstein, S.E., McHugh, P.R., 1975. Mini Mental State: a clinical
method for grading the cognitive state of patients for the clinicians. J. Psychiatr.
Res. 12, 189–198.
Hart, D.J., Craig, D., Compton, S.A., Critchlow, S., Kerrigan, B.M., McIrroy, S.P.,
Passmore, A.P., 2003. A retrospective study of the behavioural and psychological
symptoms of mid and late phase Alzheimer’s disease. Int. J. Geriatr. Psychiatry
18, 1037–1042.
Harwood, D.G., Barker, W.W., Ownby, R.L., Mullan, M.J., Duara, R., 2000. Relationship
of behavioral and psychological symptoms to cognitive impairment and func-
tional status in Alzheimer’s disease. Int. J. Geriatr. Psychiatry 15, 393–400.
Haycox, J.A., 1984. A simple, reliable clinical behavioral scale for assessing dement-
ed patients. J. Clin. Psychiatry 45, 23–24.
Holtzer, R., Tang, M., Devanand, D.P., Albert, S.M., Wegesin, D.J., Marder, K., Bell, K.,
Albert, M., Brandt, J., Stern, Y., 2003. Psychopathological features in Alzheimer’s
disease: course and relationship with cognitive status. J. Am. Geriatr. Soc. 51,
953–960.
Ito, T., Meguro, K., Akanuma, K., Meguro, M., Lee, E., Kasuya, M., Ishii, H., Mori, E.,
2007. Behavioral and psychological symptoms assessed with the BEHAVE-AD-
FW are differentially associated with cognitive dysfunction in Alzheimer’s
disease. J. Clin. Neurosci. 14, 850–855.
Kurita, A., Blass, J.P., Nolan, K.A., Black, R.S., Thaler, H.T., 1993. Relationship between
cognitive status and behavioral symptoms in Alzheimer’s disease and mixed
dementia. J. Am. Geriatr. Soc. 41, 732–826.
Lam, L.C., Leung, T., Lui, V.W., Leung, V.P., Chiu, H.F., 2006. Association between
cognitive function, behavioral syndromes and two-year clinical outcome in
Chinese subjects with late-onset Alzheimer’s disease. Int. Psychogeriatr. 18,
517–526.
Levy, J.A., Chelune, G.J., 2007. Cognitive-behavioral profiles of neurodegenerative
dementias: beyond Alzheimer’s disease. J. Geriatr. Psychiatr. Neurol. 20, 227–
238.
Lopez, O.L., Wisniewski, S.R., Becker, J.T., Boller, F., DeKoski, S.T., 1999. Psychiatric
medication and abnormal behavior as predictors of progression in probable
Alzheimer disease. Arch. Neurol. 56, 1266–1272.
Lyketsos, C.G., Steinberg, M., Tschanz, J.T., Norton, M.C., Steffens, D.C., Breitner, J.,
2000. Mental and behavioral disturbances in dementia: findings from the Cache
County Study on memory in aging. Am. J. Psychiatry 157, 708–714.
Lyketsos, C.G., López, O., Jones, B., Fitzpatrick, A.I., Breitner, J., DeKoski, S.T., 2002.
Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment. Results from cardiovascular health study. J. Am. Med. Assoc.
288, 1475–1483.
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., Stadlan, E.M., 1984.
Clinical diagnosis of Alzheimer’s disease: report of the NINCDS–ADRDA Work
Group. Neurology 34, 939–944.
Mega, M.S., Cummings, J.L., Fiorello, T., Gornbein, J., 1996. The spectrum of behav-
ioral changes in Alzheimer’s disease. Neurology 46, 130–135.
Miller, T.P., Tinklenberg, J.R., Brooks, J.O., Fenn, H.H., Yesavage, J.A., 1993. Selected
psychiatric symptoms associated with rate of cognitive decline in patients with
Alzheimer’s disease. J. Geriatr. Psychiatry Neurol. 6, 235–238.
Peña-Casanova, J., 1990. Programa Integrado de Exploración Neuropsicológica. Test
Barcelona (Manual) Masson, Barcelona (in Spanish).
Perez-Madriñan, G., Cook, S.E., Saxton, J.A., Miyahara, S., Lopez, O.L., Jeong, H.J.,
Akaike, T., Cho, C.S., 2004. Alzheimer disease with psychosis: excess cognitive
impairment is restricted to the misidentification subtype. Am. J. Geriatr. Psy-
chiatry 12, 449–456.
Reisberg, B., 1988. Functional assessment staging (FAST). Psychopharmacol. Bull.
24, 653–659.
Reisberg, B., Ferris, S.H., De Leon, M.D., Crook, T., 1982. The global deterioration scale
for assessment of primary degenerative dementia. Am. J. Psychiatry 139, 1136–
1339.
Reitan, R.M., Wolfson, D., 1993. The Halstead-Reitan Neuropsychological Test
Battery: Theory and Clinical Interpretation, 2nd ed. Neuropsychology Press,
Tucson.
Rey, A., 1958. L’Examen Clinique in Psychologie. Presses Universitaires de France,
Paris (in French).
Ropacki, S.A., Jeste, D.V., 2005. Epidemiology of and risk factors for psychosis of
Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am. J.
Psychiatry 162, 2022–2030.
Roth, M., Tym, E., Mountjoy, C.Q., Huppert, F.A., Hendrie, H., Verma, S., Goddard, R.,
1986. CAMDEX. A standardised instrument for the diagnosis of mental disorder
in the elderly with special reference to the early detection of dementia. Br. J.
Psychiatr. 149, 698–709.
G Model
AGG-2269; No. of Pages 6

6 J.M. Garcı´a-Alberca et al. / Archives of Gerontology and Geriatrics xxx (2010) xxx–xxx

Scarmeas, N., Brandt, J., Albert, M., Hadjigeorgiu, G., Papadimitriou, A., Dubois, B.,
Sarazin, M., Devanand, D., Honig, L., Marder, K., Bell, K., Wegesin, D., Blacker, D.,
Stern, Y., 2005. Delusions and hallucinations are associated with worse outcome
in Alzheimer disease. Arch. Neurol. 62, 1601–1608.
Schultzer, D.L., Levin, H.S., Mahler, M.E., 1992. Assessment of cognitive, psychiatric,
and behavioral disturbances in patients with dementia: the Neurobehavior
Rating Scale. J. Am. Geriatr. Soc. 40, 549–555.
Senanarong, V., Poungvarin, N., Jamjumras, P., Sriboonroung, A., Danchaivijit, C.,
Udomphanthuruk, S., Cummings, J.L., 2005. Neuropsychiatric symptoms, func-
tional impairment and executive ability in Thai patients with Alzheimer’s
disease. Int. Psychogeriatr. 17, 81–90.
Silveri, M.C., Salvigni, B.L., Jenner, C., Colamonico, P., 2004. Behavior in degenerative
dementias: mood disorders, psychotic symptoms and predictive value of
neuropsychological deficits. Arch. Gerontol. Geriatr. 38 (Suppl. 1), 365–378.
Spalletta, G., Baldinetti, F., Buccione, I., Fadda, L., Perri, R., Scalmana, S., Serra, L.,
Caltagirone, C., 2004. Cognition and behaviour are independent and heteroge-
neous dimensions in Alzheimer’s disease. J. Neurol. 251, 688–695.
Starr, J.M., Lonie, J., 2007. Relationship between behavioural and psychological
symptoms of dementia and cognition in Alzheimer’s disease. Dement. Geriatr.
Cogn. Disord. 24, 343–347.
Stepaniuk, J., Ritchie, L.J., Tuokko, H., 2008. Neuropsychiatric impairments as
predictors of mild cognitive impairment, dementia, and Alzheimer’s disease.
Am. J. Alzheimers Dis. Other Demen. 23, 326–333.
Teri, L., Hughes, J.P., Larson, E.B., 1990. Cognitive deterioration in Alzheimer’s
disease: behavioral and health factors. J. Gerontol. 45, 58–63.
Tung Tsoi, M.B., Sara Baillon, M.P., James Lindesay, D.M., 2008. Early frontal
executive impairment as a predictor of subsequent behavior disturbance in
dementia. Am. J. Geriatr. Psychiatry 16, 102–108.
Wilson, R.S., Gilley, D.W., Bennet, D.A., 2000. Hallucinations, delusions, and cogni-
tive decline in Alzheimeŕs disease. J. Neurol. Neurosurg. Psychiatry 69, 172–
177.
Zakzanis, K.K., Larry, L., Kaplan, E., 1999. Dementia of Alzheimer’s type. In: Zakzanis,
K.K., Larry, L., Kaplan, E. (Eds.), Neuropsychological Differential Diagnosis. Swets
and Zeitlinger Publisher, Lisse.

Please cite this article in press as: Garcı́a-Alberca, J.M., et al., Can impairment in memory, language and executive functions predict
neuropsychiatric symptoms in Alzheimer’s disease (AD)? Findings from a cross-sectional study. Arch. Gerontol. Geriatr. (2010),
doi:10.1016/j.archger.2010.05.004