Current Alzheimer Research, 2010, 7, 517-526 517

Prevalence of Neuropsychiatric Symptoms in Mild Cognitive Impairment

and Alzheimer’s Disease, and its Relationship with Cognitive Impairment

M. Fernández-Martínez*, A. Molano, J. Castro and J.J. Zarranz

Neurological Department, Hospital de Cruces. Plaza de Cruces s/n. Baracaldo, 48903, Vizcaya, Spain

Abstract:Objective The study aimed to describe the prevalence of Neuropsychiatric symptoms (NPS) in Alzheimer’s di-
sease (AD), amnestic mild cognitive impairment (MCI) and controls using the 12-item Neuropsychiatric Inventory (NPI)
and to analyze the relationships between neuropsychiatric symptoms with specific neuropsychological tests.Patients and
methods; We prospectively studied 485 patients from the Memory Unit in Cruces Hospital (Spain), 344 met the criteria of
NINCDS-ADRDA for probable AD (99 were classified as mild and 245 as moderate-severe), 91 for MCI and 50 were
controls. Mini-mental State Examination (MMSE) and CDR (Clinical Dementia Rating) were used to evaluate global
cognitive function and to classify the severity of cognitive impairment. The neuropsychological test battery included
memory test, verbal fluency, visuoespatial skills and daily living scales. The 12-items Neuropsychiatric Inventory (NPI)
version was used to assess neuropsychiatric symptoms. All patients underwent a neuroimaging study (CT scan and/or
MRI). Patients were not treated with antidementia or psychotropic drugs. Results;Apathy and depression were more
prevalent NPS in moderate-severe AD (78.4% and 44.1%, respectively), mild AD (64.6% and 41.4%, respectively) and
MCI (50.5% and 33%, respectively) patients than in controls (6% and 8%, respectively). The prevalence and the mean
scores of all symptoms increased along the severity of the disease, except for sleep and appetite disorders. In patients with
mild AD a relationship was found between the presence of NPS and RDRS-2 scale (p = 0.003); and between NPS and
RDRS-2 (p = 0.029) and SS-IQCODE scales (p = 0.039) in moderate-severe patients.Conclusions; NPS were more preva-
lent in AD and MCI patients than in controls. In AD and MCI patients apathy and depression were the most prevalent
NPS. The prevalence and the mean scores of all symptoms gradually increased along the severity of the disease, except
for sleep and appetite disorders. We have no found a relationship between neuropsycological test and the presence of
NPS, but in patients with mild and moderate-severe AD there is a relationship with daily living scales.
Keywords: Alzheimer´s disease, mild cognitive impairment, dementia, neuropsychiatric inventory, prevalence, neuropsy-
chiatric symptoms, apathy, depression.

INTRODUCTION
Dementia is a syndrome characterized by acquired global
cognitive impairment as well as the presence of neuropsy-
chiatric symptoms (NPS). Assessment of the behavioral as-
pects of cognitive impairment has acquired growing impor-
tance, although it was a field overlooked by clinicians for
years.
Behavioral disorders in many cases have been considered
as secondary to assessment of the cognitive deficit itself.
This is so to the point that the main criteria for Alzheimer's
disease (AD) and mild cognitive impairment (MCI) do not
include references to these behavioral aspects or do so only
slightly [1]. In other types of dementia, however, such as
frontotemporal dementia (FTD) [2] and dementia with Lewy
bodies (DLB) [3], NPS are pathognomonic and are included
in the consensus criteria.
Behavioural symptoms may be the presenting manife-
stations of dementing disorders, appearing before cognitive
MCI is an heterogeneous condition and is currently de-
fined as a syndrome with impairment of memory or another
*Address correspondence to this author at the Neurological Department.
Hospital de Cruces. Plaza de Cruces s/n. Baracaldo, 48903. Vizcaya. Spain;
Tel:+ 34 94 6006363; E-mail: mfernandezm@meditex.es
alterations [4], at some time during the course of the illness
[4, 5] and varying according to dementia severity [6].
cognitive domain that does not interfere substantially with
personal affairs and nor result in inability to live inde-
pendently. MCI can evolve into different types of dementia.
Furthermore amnestic MCI is probably the most empirically
validated type evolves to AD at a higher rate than in the gen-
eral population [7]. Patients with these transitional state be-
tween normal cognitive aging and dementia constitutes a
high-risk group, because most of them develop dementia at a
rate of 10% to 15% per year compared with 1% to 2% per
year in the general population [8].
Many reserchers have utilised a variety of criteria for
defining MCI, but there is a general consensus in that they
refer to non demented persons, with cognitive deficits me-
surable in some form or another and represent a clinical syn-
drome that can be used to classify patients who don´t fulfil a
diagnosis of dementia, but who have a high risk of progress-
ing [9].
Several studies [10, 11] have assessed the presence of
NPS in MCI. The design, the setting and the MCI criteria
varies among the different studies. Some of them are longi-
tudinal [12-20], or cross-sectional [10, 11, 21-26]. The set-
ting includes tertiary centers, clinical trials and population-

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518 Current Alzheimer Research, 2010, Vol. 7, No. 6
based studies; and the studies have used several different sets
of MCI criteria and different tools for neuropsychiatric as-
sessment. The most commonly used instrument was the NPI
[27].
In many cases behavioral disorders are the mode of pres-
entation of cognitive impairment and dementia, and their
assessment can aid in differential diagnosis. Neuropsy-
chiatric symptoms can induce marked disability in patients
with dementia, increase the caregiver stress [28], and have
serious adverse consequences for patients, families and care-
givers, such as greater impairment in daily living activities
[29, 30], faster cognitive decline [31], worse quality of life
[32], and increasing overall financial cost [33]. They are also
one of the most common causes of caregiver burden and
nursing home placement of patients [34].
In recent years, these symptoms have been the subject of
research, and can currently be assessed by standardized in-
struments such as the BEHAVE-AD scale [35] or the Neuro-
psychiatric Inventory (NPI) [27], with good validity and reli-
ability.
The prevalence of NPS in dementias is high, ranging
from 61% to 92% [10, 36-39], depending on the population
studied, type of dementia, and test batteries applied.
OBJECTIVE
The aim of this study was to describe the prevalence of
NPS in patients with Alzheimer’s disease (AD), amnestic
mild cognitive impairment (MCI) and controls, their rela-
tionship to dementia severity; and to analyze the relation-
ships between the neuropsychiatric symptoms with specific
neuropsychological tests.
PATIENTS AND METHODS
Patients
The Memory Unit in Cruces Hospital (Barakaldo, Biz-
kaia, Spain) is integrated in the Neurological Department.
This Unit receives approximately 400 new patients per year
from a referral area of 1 million inhabitants, of which 16%
are older than 65 years. This Unit is staffed by a multidisci-
plinary team, with two neurologists, two neuropsychologists
and a specialist nurse in neurology. Patients are referred by
primary care physicians and neurology and psychiatry spe-
cialists.
Study Design
A cross-sectional, prospective, observational study was
carried out from January 2002 to December 2007 in patients
attending the Memory Unit for the first time were enrolled.
The NINCDS-ADRDA criteria for probable AD, and
Petersen’s criteria [7] for amnestic MCI were used. The
Mini-Mental State Examination (MMSE) [40] and Clinical
Dementia Rating (CDR) [41] were used to evaluate global
cognitive function and to classify patients by severity of
cognitive impairment. NPS were assesed by the validated
spanish version of NPI. All patients with AD and MCI un-
derwent a neuroimaging study (head CT scan and/or MRI).
Fernández-Martínez et al.
The subject sample included patients with AD and MCI
that at the time of the interview were not undergoing antide-
mentia or psychotropic drugs (benzodiazepines, neuro-
leptics and/or antidepressants). The third group consisted of
cognitively normal subjects.
A specific database was designed in Access 2002 and
declared to the Spanish Data Protection Agency. The study
was approved by the Ethics Committee of Cruces Hospital.
All patients signed informed consent to undergo the exami-
nation. The study was conducted in accordance with the
Declaration of Helsinki concerning medical research in hu-
man subjects.
Evaluation
A certified neurologist (MFM) carried out the diagnostic
evaluation including a complete medical history, physical
and neurological examination. The evaluation also included
routine laboratory examinations: hematology, biochemistry,
thyroid stimulating hormone, vitamin B12 and folic acid
levels and syphilis serological testing; and a neuroimaging
study (head CT scan and/or MRI).
The neuropsychological tests used included the New
York University logical memory test (immediate and delayed
paragraph recall) [42], the CERAD word list [43], clock
drawing test, and semantic verbal fluency test.
The evaluation also included the spanish adaptation of
RDRS-2 (Rapid Disability Rating Scale-2) [44]: this scale
evaluates three funtional and cognitive domains: assistance
with activities of daily living, degree of disability and degree
of cognitive impairment, the total score is the sum of three
subscales. We also used [44, 45] the SS-IQCODE (validated
spanish version of IQCODE) [46], this questionnaire was
designed to measure changes in various aspects of cognition,
memory, and activities of daily living. This test is useful,
simple and reliable for testing the function and cognitive
decline of patients over time.
The Clinical Dementia Rating Scale (CDR) [41] was
used to evaluate the severity of cognitive impairment. Global
cognitive status was also assessed by the Minimental State
Examination [40], using a version adapted to the Spanish
population with a validated cut level for dementia at 24 or
less (mild dementia scores were between 21 to 23, moderate
scores were between 11 to 20 and severe dementia scores
were
10).
Data from these evaluations were used to make an initial
diagnosis and to classify study participants into groups based
on the following criteria: patients were classified by the CDR
scale in normal CDR= 0; MCI= CDR 0.5; and mild, mode-
rate and severe AD = CDR 1-2-3 respectively. Participants
were classified into the following groups:
Amnestic Mild Cognitive Impairment (MCI) Group
Subjects who met Petersen’s criteria for amnestic MCI
[7, 9, 47]. Participants have to meet the adaptated operational
criteria for MCI, that includes: subjective memory com-
plaints by patients or informants and evidence of objective
memory defined as having scores below the cut off values of
the New York University logical memory test (delayed para-
graph recall), and/or recall CERAD word list [43] ( 1.5 SD
Prevalence of Neuropsychiatric Symptoms
below age and education adjusted norms) and score in CDR
scale of 0,5.
Dementia Group
Diagnosis based on DSM-IV criteria for dementia and
NINCDS-ADRDA criteria for AD. For the purposes of this
study, patients were considered to have mild dementia if they
had a score of 21 or more on the MMSE, and moderate-
severe dementia if the score was 20 or less, and a score in
CDR scale >1.
Control Group
Healthy volunteers with no memory impairment were
recruited in the hospital and neurology outpatient clinics.
The same test were used in this group; control group is de-
fined as having normal scores on values of the New York
University logical memory test (delayed paragraph recall)
and/or recall CERAD word list (age and education adjusted
norms) and a score in CDR scale of 0.
The neuropsychiatric symptoms of patients and controls
included in the study were assessed by a trained blind neuro-
psychologist (A.M.S.), who estimated their prevalence in the
past month. The 12-item version of the Neuropsychiatric
Inventory (NPI) validated for spanish population was used.
This is a semi-structured interview administered by a clini-
cian to the caregiver, rating the severity and frequency of 12
neuropsychiatric symptoms: delusions, hallucinations, de-
pression, anxiety, apathy, irritability, euphoria, agitation,
disinhibition, aberrant motor activity, sleep disturbances and
appetite change. There is a screening question to evaluate
each sub-area; if the answer to this screening question is
“no”, then no further questions are asked. If the answer is
“yes”, then subquestions are asked and a rating of the fre-
quency and severity of each behavior is made based on the
following scale: the frequency of the behavior is scored on a
scale of 1 to 4 points (1= occasionally, 2= often, 3= fre-
quently, 4= very frequently). Severity is scored on a scale of
1 to 3 points (1= mild, 2 = moderate and 3= severe). A maxi-
mum score of 12 (frequency X severity) is possible for each
behavior. An overall score is generated by adding together
the total score of each individual symptom. The overall score
ranges from 0 (no symptoms) to 144 points.
The NPI has been validated in Spanish [48] and has
proven good sensitivity and specificity for assessing NPS
and their response to treatment. For the purpose of this study
the definition used for regarding a symptom as being present
is a score >0.
Statistical Analysis
Statistical analysis was performed using the SPSS®
package, version 15.0. Demographic characteristics of the
different patient groups and controls were compared. Con-
tinuous variables such as MMSE score, age, schooling and
NPI scores were compared using analysis of variance, and a
post hoc analysis (Dunnett’s T3 test) was performed for
groups with different variances.
The prevalence of at least one neuropsychiatric symptom
and the prevalence of each individual symptom was calcu-
lated for AD, MCI and controls. The prevalence of each of
the 12 behavioral disorders was compared between groups
Current Alzheimer Research, 2010, Vol. 7, No. 6 519
using the chi-square (
2) test, with adjustment for type 1 er-
rors from multiple comparisons; i.e, p<0.005 (=0.05/10)
would considered significant. When there were significant
differences in a domain, the comparisons were performed by
Fisher’s exact test. Comparisons were made between con-
trols versus MCI, MCI versus mild AD, and finally between
mild AD versus moderate-severe AD.
Correlations were established between the different NPI
items, total NPI score and MMSE score and based on each
diagnostic group (AD, MCI and controls) by using the
Spearman correlation coefficient. The significance level for
all comparisons was p<0.05. The strength of association of a
correlation coefficient with a value of 0-0.19 was assessed as
very weak, 0.20-0.39 as weak, 0.40-0.59 as moderate, 0.60-
0.79 as strong and 0.80-1 as very strong correlation.
A multinomial logistic regression model was constructed
to determine if the MMSE and CDR scores were related to
the presence of NPS. The presence of at least one of these
symptoms was the dependent variable, while the reference
value was the presence of the behavioral disorder. The inde-
pendent variables were MMSE and CDR scores.
A second multinomial logistic regression model was con-
structed to determine if the neuropsychological test and daily
living scales (independent variables) were related to the
presence of NPS. The presence of at least one of these NPS
was the dependent variable.
RESULTS
A total of 485 subjects, 344 with AD, 91 with MCI and
50 controls were enrolled. Among AD patients, 245 were
classified as moderate-severe and 99 as mild AD. The mean
age in moderate-severe AD patients was 75.42 years, 75.31
years in mild AD patients, 74.19 years in MCI patients and
74.55 years for the control group. Total years of schooling
was approximately 10 years for all groups. No statistically
significant differences were found in age or years of school-
ing. MMSE scores were 12.67, 21.93, 26.43 and 28.56, re-
spectively. There were more women in the moderate-severe
AD, mild AD and control group (73.9%, 56.6% and 66%,
respectively) than in the MCI group (45.1%) (Table 1).
At least one NPS was present in 93.5% of patients with
moderate-severe AD, 85.9% of patients with mild AD,
70.3% of patients with MCI and 42% of controls (Table 2).
Apathy was the most prevalent NPS both in moderate-
severe AD (78.4%), mild AD (64.6%) and MCI (50.5%)
patients. It was followed by depression (44.1%), aberrant
motor activity (38.4%) and agitation (37.1%) in moderate-
severe AD patients; depression (41.4%), agitation (30.3%)
and irritability (28.3%) in mild AD patients; and depression
(33%), irritability (27.5%) and sleep disturbance (23,1%) in
MCI patients. The most prevalent symptoms in the control
group were sleep disturbance (14%), anxiety (12%), depress-
sion (8%); and apathy and appetite change (6%) (Table 2).
Aberrant motor activity, apathy, hallucinations, anxiety,
delusions were significantly more prevalent in patients with
moderate-severe AD than in patients with mild AD. These
differences were also significant for the presence of at least
one NPS.
520 Current Alzheimer Research, 2010, Vol. 7, No. 6 Fernández-Martínez et al.

Table 1. Patient Demographic Characteristics

Moderate-severe AD Mild AD MCI Controls

(n = 245) (n = 99) (n = 91) (n =50) p value

Age 75.42±7.99 75.31±6.88 74.19±5.28 74.55±6.96 0.468

(mean, SD)

Female gender 181 (73.9%) 56 (56.6%) 41 (45.1%) 33 (66%) < .001

(n, percentage)

Years of schooling (mean, SD) 9.69±2.53 10.59±3.63 9.99±4.55 10.06±3.98 0.562

MMSE score (mean, SD) 12.67±5.21 21.93±1.38 26.43±1.77 28.56±1.14 < .001

SD: standard deviation.

Table 2. Prevalence of Neuropsychiatric Symptoms in AD, MCI and Controls

Patients with Patients with Patients with Controls Moderate- Mild AD ver- MCI versus
moderate- mild AD MCI (N = 50) severe AD sus MCI control
severe AD (N = (N = 99) (N = 91) versus mild AD (p value) (p value)
245) (p value)

At least 1 symp- 93.5% 85.9% 70.3% 42% 0.034* 0.023* 0.001**

tom

Delusions 31% 20.2% 8.8% 0% 0.047* 0.039* 0.050*

Hallucinations 11.8% 3% 0% 0% 0.012* 0.247 NS

Agitation 37.1% 30.3% 18.7% 0% 0.262 0.045* 0.001**

Depression 44.1% 41.4% 33% 8% 0.719 0.235 0.001**

Anxiety 33.9% 22.2% 16.5% 12% 0.039* 0.362 0.623

Euphoria 7.3% 4% 2.2% 2% NS NS NS

Apathy 78.4% 64.6% 50.5% 6% 0.010** 0.034* < .001**

Disinhibition 22% 20.2% 14.3% 2% 0.773 0.339 0.019*

Irritability 32.7% 28.3% 27.5% 2% 0.445 0.515 < .001**

AMA 38.4% 21.2% 9.9% 0% 0.002** 0.045* 0.027*

Sleep 23.7% 27.3% 23.1% 14% NS NS NS

Appetite 24.5% 15.2% 19.8% 6% NS NS NS

Total NPI Score 20.64±16.66 15.33±17.04 12.80±12.80 1.06±1.82 0.054 0.071 < .001**
(mean. SD)

AMA: aberrant motor activity.

AD: Alzheimer´s disease.
MCI: mild cognitive impairment.
NS: adjustement of multiple comparisons in the
2 test (p > 0.005) among the groups.
p value (Fisher´s exact test).
* significant at p<0.05.
** significant at p<0.01.

There were statistically significant differences in the
presence of apathy, delusions, agitation, and aberrant motor
activity between mild AD and MCI. These differences were
also significant for the presence of at least one NPS.
When MCI patients were compared to the control group,
statistically significant differences were found in all NPS and
for the presence of at least one NPS, except in hallucinations,
anxiety, euphoria, and sleep and appetite disturbances. No
significant differences were found in the prevalence of sleep
disorders and appetite change among the groups.
When total NPI scores were compared between patients
with moderate-severe AD, mild AD, MCI and controls by
performing analysis of variance, there were statistically sig-
nificant differences between the 4 groups. In the post hoc
Prevalence of Neuropsychiatric Symptoms Current Alzheimer Research, 2010, Vol. 7, No. 6 521

analysis (Dunnett’s T3 method), there were differences be-
tween moderate-severe AD and mild AD (p=0.054) and be-
tween mild AD versus MCI (p=0.071) that did not reach
statistical significance. Significant differencies were found
between MCI versus controls (p=< .001).
We have no found a significant correlation between
MMSE and NPI scores in controls and patients with mild
AD. In patients with MCI a significant and weak association
was found between aberrant motor activity and MMSE
scores. In patients with moderate-severe AD there was a sig-
nificant correlation between apathy, aberrant motor activity,
hallucinations and total NPI score with MMSE, the strength
of these associations being very weak (Table 3).
In the multinomial logistic regression analysis for the
total sample, there wasn´t a relationship between MMSE
scores and the presence of at least one NPS. However CDR
scores were related to the presence of at least one NPS (Ta-
ble 4).
When we perform an additional analyses into the rela-
tionships between the presence of neuropsychiatric symp-
toms with more specific neuropsychological tests, and func-
tional scales by patients groups (Tables 5 and 6); in controls
and patients with MCI neither the neuropsychological test
nor daily living scales were related to the presence of any
NPS. However in patients with mild AD a relationship was
found between the presence of NPS and RDRS-2 (p =
0.003); and between NPS and RDRS-2 (p = 0.029) and SS-
IQCODE (p = 0.039) in moderate-severe patients.
DISCUSSION
In our study, NPS were common in AD and MCI patients
when compared with control subjects. Already in the early

Table 3. Correlations between MMSE and NPI Scores

Controls Patients with MCI Patients with mild AD Patients with moderate-
severe AD

Spearman coefficient
and (p value)

Delusions NA 0.058 0.036 -0.120

0.586 0.723 0.061

Hallucinations NA NA 0.100 -0.199**

0.324 0.002

Agitation NA 0.051 0.024 -0.166

0.634 0.811 0.009

Depression -0.021 -0.018 0.075 0.004

0.884 0.862 0.463 0.954

Anxiety -0.042 -0.153 0.097 0.063

0.772 0.147 0.341 0.329

Euphoria 0.051 -0.045 0.027 0.015

0.723 0.674 0.790 0.819

Apathy 0.176 -0.154 0.044 -0.289**

0.222 0.145 0.664 < .001

Disinhibition 0.051 -0.044 0.040 < .001

0.723 0.682 0.696 0.996

Irritability 0.200 0.049 0.006 -0.038

0.163 0.647 0.955 0.555

AMA NA -0.214* -0.068 -0.276**

0.042 0.503 < .001

Sleep 0.022 -0.062 0.029 0.011

0.878 0.562 0.779 0.869

Appetite 0.083 -0.103 -0.112 -0.007

0.569 0.333 0.268 0.917

Total NPI Score -0.109 0.072 0.052 -0.214**

0.453 0.496 0.606 0.001

p value: * significant at p<0.05, ** significant at p<0.01

NA: not applicable.
522 Current Alzheimer Research, 2010, Vol. 7, No. 6 Fernández-Martínez et al.

Table 4. Logistic Regression Analysis for the Presence of NSP. Total Sample

Variables Beta p Value OR (95% CI)

MMSE 0.043 0.312 1.044 (0.960-1.135)

CDR -1.585 0.001 .205 (0.080-0.527)

OR: odds ratio

CI: confidence interval

Table 5. Logistic Regression Analysis. Presence of Neuropsychiatric Symptoms and Neuropsycological and Functional Test. Con-
trols and MCI

Controls MCI

Beta p value OR Beta p value OR

MMSE -0.130 0.697 0.878 (0.454 -1.692) -0.222 0.388 0.801 (0.484-1.326)

NYULMT (immediate
-0.256 0.301 0.774 (0.477-1.257) -0.349 0.158 0.706 (0.435-1.145)
recall)

NYULMT(delayed recall) 0.116 0.524 1.123 (0.786-1.603) 0.345 0.111 1.412 (0.924-2.156)

CERAD word list (recall) 0.236 0.298 1.266 (0.812-1.975) -0.301 0.120 0.740 (0.507-1.082)

CDT 0.885 0.139 2.423 (0.750-7.830) -0.032 0.866 0.969 (0.669-1.402)

SS-IQCODE 0.321 0.062 1.379 (0.984-1.931) 0.095 0.102 1.100 (0.981-1.232)

RDRS-2 0.060 0.767 1.062 (0.715-1.577) 0.061 0.533 1.063 (0.981-1.232)

Verbal Fluency Test -0.016 0.871 0.984 ( 0.811-1.194) 0.123 0.344 1.130 ( 0.877-1.457)

NYULMT: New York University logical memory test.

CDT: Clock drawing test.
RDRS-2: Rapid Disability Rating Scale-2.
SS-IQCODE: Informant Questionnaire on Cognitive Decline in the Elderly.
p value: * significant at p<0.05.

Table 6. Logistic Regression Analysis. Presence of Neuropsychiatric Symptoms and Neuropsycological and Functional Test. Pa-
tients with Mild and Moderate-Severe AD

Patients with mild AD Patients with moderate-severe AD

Beta Valor p OR Beta Valor p OR

MMSE 0.000 0.999 1.000 (0.714- 1.402) 0.030 0.773 1.031 (0.840-1.264)

NYULMT
-0.216 0.145 0.806 (0.602-1.078) 0.004 0.993 1.004 (0.433-2.325)
(immediate recall)

NYULMT
-0.083 0.767 0.921 (0.533-1.589) -0.305 0.556 0.737 (0.267-2.034)
(delayed recall)

CERAD word list (recall) -0.24 0.914 0.977 (0.633-1.505) -0.216 0.523 0.806 (0.415-1.563)

CDT -0.216 0.145 0.806 (0.602-1.078) -0.026 0.803 0.975 (0.796-1.194

SS-IQCODE 0.013 0.794 1.013 (0.922-1.112) 0.098 0.029* 1.103 (1.010-1.204)

RDRS-2 0.624 0.003* 1.866 (1.240-2.808) 0.211 0.039* 1.235 (1.011-1.508)

Verbal Fluency Test 0.077 0.119 0.423 (1-0.516) -0.140 0.214 0.869 (0.697-1.084)

NYULMT: New York University logical memory test.

CDT: Clock drawing test.
RDRS-2: Rapid Disability Rating Scale-2.
SS-IQCODE: Informant Questionnaire on Cognitive Decline in the Elderly.
p value: * significant at p<0.05.
Prevalence of Neuropsychiatric Symptoms
stages of cognitive impairment, as in the case of MCI pa-
tients, they show a higher prevalence of nearly all behavioral
disorders than the control group. All NPS were more signifi-
cant in the group of subjects with MCI when compared to
controls, except for those that were less common in both
groups (hallucinations, anxiety, euphoria). There were also
differences in terms of the presence of at least one symptom.
Total NPI scores were significantly higher in the group of
subjects with MCI when compared to controls.
There were statistically significant differences in the
presence of apathy, delusions, aberrant motor activity, agita-
tion, when MCI and mild AD patients were compared, and in
terms of the presence of at least one symptom. Total NPI
scores were also higher in the group of subjects with mild
AD when compared to MCI, but didn´t reach statistically
significant differencies (p= 0.071).
This prevalence was also significantly increased in pa-
tients with moderate-severe AD versus mild AD in 5 of the
12 NPS (delusions, hallucinations, anxiety, apathy, aberrant
motor activity), and in the presence of at least one symptom.
In general, the prevalence of all behavioral disorders
gradually increased as cognitive impairment increased, ex-
cept for sleep and appetite disorders.
For the group of patients with cognitive impairment, the
most prevalent symptoms were apathy and depression, fol-
lowed by irritability in MCI, agitation in mild AD, and aber-
rant motor activity in moderate-severe AD.
When subjects were studied in the community setting
[10, 36], the prevalence of NPS was lower. The most com-
mon symptoms in patients with AD were apathy (27-36%),
followed by depression (24-31%), and agitation/aggression
(33-24%). Seventy-four point nine percent of patients with
AD exhibited at least one behavioral disorder in the past
month [10].
The prevalence of NPS in patients with MCI in our study
was lower than in CIND (cognitively impaired not de-
mented) study [49]. In this latter study at least one NPS was
reported in 60% of subjects with NCI (not cognitively im-
paired), 74% with CIND, and 89% with dementia. The most
frequently reported NPS in the CIND group were depression
(42%), irritability (39%) and apathy (37%). In this study,
unlike in our patient sample, there were no significant differ-
ences between subjects with NCI and CIND for any NPI
item, probably because the group of subjects with CIND is
very heterogeneous.
Our study showed a significant difference between pa-
tients with MCI and mild AD in 4 of behavioral disorders of
the NPI (delusions, agitation, apathy, and aberrant motor
activity) but not in the total scores. The only difference
found with a similar study [11] is in the percentage of pa-
tients with delusions, but not in the rest of items or in total
scores. This can be explained by the different size of the pa-
tient sample and because in this latter study patients with
mild AD were probably less impaired than in our study.
However, as in our study, the most common behavioral dis-
orders in patients with MCI were apathy and depression in
39% and irritability in 29%. Similarly, and also as in our
study, the most common behavioral disorders in patients
Current Alzheimer Research, 2010, Vol. 7, No. 6 523
with mild AD were apathy and depression in 51% and 50%,
respectively. Compared to the control group, patients with
MCI were more likely to have depression, apathy, irritability,
anxiety, agitation, and aberrant motor activity. Another study
[26] showed that total NPI scores were different between
controls, patients with MCI and patients with AD. The per-
centage of individuals with MCI and the presence of NPS
was 35%. In one study [50], at least one behavioral disorder
was detected in 84% of patients with mild AD and 92.5%
with moderate AD.
The limitations of some of these studies are that some of
them are being done in the context of a clinical trial [25], the
MCI criteria are only based on clinical evaluation [17, 23,
26, 51], the behavioral instrument is a semistructured inter-
view [13], and some test focus on partial aspects of behavior
[14].
In general, when studies conducted in the hospital or
outpatient clinic setting are compared with epidemiological
studies [39], there is a lower prevalence of behavioral disor-
ders in the latter ones. These observed differences are proba-
bly due in part to the fact that the caregivers of patients with
more serious behavioral disorders request a clinical assess-
ment earlier. On the other hand the differencies in the preva-
lence of NPS in MCI may be due to to the different enroll-
ment criteria for this type of cohort.
The studies conducted in patients with MCI and AD
show a high prevalence of behavioral disorders, mainly apa-
thy, depression, anxiety, irritability and agitation. This preva-
lence increases in parallel to the increase of cognitive im-
pairment.
Most studies agree on apathy and depression as being the
most prevalent symptoms not only in MCI but also in AD
[52-54]. The subsyndrome apathy is probably the most
common [55], and its occurrence in patients with MCI may
be related to the development of dementia [19]. Apathy is
already prominent in patients with MCI, and progresses as
cognitive impairment increases. The cingulate gyrus is af-
fected in early stages of the disease[56-58], and this impair-
ment is probably related to the symptoms of apathy not only
in AD but also in other dementias. In the study of Coopeland
et al. [13], it was observed that passivity was a predictor of
conversion from MCI to dementia.
Depression is also common in patients with AD and
MCI. The relationship between cognitive impairment and
depression is controversial, but the latter could be an inde-
pendent risk factor for AD [15]. Both depression and demen-
tia share common symptoms and their coexistence in clinical
practice may complicate differential diagnosis in the early
stages of cognitive impairment. Depressive symptoms are
common in patients with AD in the absence of major depres-
sion [59].
There are a variety of sleep and appetite disorders in pa-
tients with AD [28, 60-65]. The etiology is not clear, but it
appears to be related to a set of changes in hypothalamic and
neuroendocrine functions as well as to environmental chan-
ges. In our study, sleep and appetite disorders did not show a
gradual increase in their prevalence as cognitive impairment
progressed, probably because these NPS involve structures
that are affected early: brainstem, pineal gland and hypo-
524 Current Alzheimer Research, 2010, Vol. 7, No. 6
thalamus, and which do not undergo many neuropath-
ological o neurochemical changes over the course of the dis-
ease.
In our study the analysis of correlation by patients group,
between some of the scores on the NPI and MMSE only
showed a very week association between aberrant motor
activity and MMSE scores in MCI; and in patients with
moderate-severe AD a significant correlation between apa-
thy, aberrant motor activity, hallucinations and total NPI
score, but in both cases the strength of this association being
very week. However other similar studies [66], have found a
significant correlation between some of the scores on the
NPI and MMSE.
When we analysed the correlation bettween MMSE and
CDR scale with the presence of NPS; CDR score was related
to the presence of at least one NPS, finding a relationship
with disease severity. Probabily this would indicate the in-
crease in cognitive impairment generally runs parallel to
NPS, at least by using CDR scale, that covers a broad aspects
of general cognition and functional status.
For all the sample of patients and controls we have no
found a relationship between the neuropsycological test used
in our study (memory, lenguage and visuoespatial task) and
the presence of NPS. Not allowing us to establish a link be-
tween NPS and specific cognitive profiles.
However by using scales designed to measure changes in
various aspects of functionality, daily living activities, and
degree of disability we have found a relationship with NPS,
in the group of patients with mild and moderate-severe AD.
This fact probably means that worsening in behavior could
be related with a worsening in funcional abilities and quality
of life.
The results of our study suggest that there is a progres-
sion in NPS from normality to the early stages of MCI and
AD. In general, as cognitive impairment increases, so does
the prevalence of most behavioral disorders. This finding
supports the concept that MCI is an intermediate situation
between normality and AD, not only from a cognitive but
also from a behavioral point of view. Although NPS are not
represented in the diagnostic criteria for MCI and their pres-
ence is not required for diagnosis, their clinical significance
in the early stages of cognitive impairment is increasingly
recognized. MCI is probably a zone of overlap between AD
and normality.
With our data, we can conclude that the presence of some
NPS is a clinical marker of MCI, since when compared with
controls there were differences in all NPS except in 4 of
them. Not all patients with MCI progress to AD. The pres-
ence of behavioral disorders in patients with MCI probably
results in an increased risk for this progression. In this re-
gard. more longitudinal studies are needed to explore this
hypothesis.
Our study has not found a relationship between neuro-
psycological test and the presence of NPS, but if with daily
living scales and functional abilities in the group of patients
with more advanced cognitive impairment. Further research
studies are probably needed to elucidated this issue.
Fernández-Martínez et al.
One of the strengths of this study is that the patients were not
treated with antidementia or psychotropic drugs that could
interfere with behavioral assessment, and that we have tried
to establish a relationship between behavioral, daily living
functioning, and cognition.
However, there are some limitations in this study that
should be taken into consideration. As this was a cross-
sectional study, it did not take into account the fluctuations
in the behavioral symptoms of individual patients, whereas a
longitudinal study would allow the changes occurring in the
course of the disease to be assessed, as well as the possible
role of NPS in progression from MCI to AD. The sample of
controls was small, and finally this study was conducted in
the setting of outpatient neurology clinics, which may not be
representative of a sample of patients from the community.
CONCLUSIONS
NPS were more prevalent in AD and MCI patients than
in controls. In AD and MCI patients apathy and depression
were the most prevalent NPS.
The prevalence and the mean scores of all symptoms
gradually increased along the severity of the disease, except
for sleep and appetite disorders. We have no found a rela-
tionship between neuropsycological test and the presence of
NPS, but in patients with mild and moderate-severe AD,
there is a relationship with daily living scales.
ACKNOWLEDGEMENTS
J. Castro was supported by FBBVA- CAROLINA
Foundation for Neurology Research Clinical Fellowship.
ABBREVIATIONS
AD = Alzheimer´s disease
CDR = Clinical Dementia Rating
DLB = Dementia with Lewy Bodies
DSM-IV = Diagnostic and Statistical Manual of
Mental Disorders-fourth edition
FTD = Frontotemporal dementia
MCI = Mild cognitive impairment
MMSE = Mini-Mental State Examination
NPS = Neuropsychiatric symptoms
NINCDS-ADRDA = Nacional Institute of Neurological
and Communicative Disorders and
Stroke/the Alzheimer´s disease and
Related Disorders Association
NPI = Neuropsychiatric Inventory
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