Neurotoxicity Research, 2008, VOL. 14(2,3). pp. 263-272
F.P. Graham Publishing Co.
Non-Cognitive Psychopathological Symptoms
Associated with Incident Mild Cognitive Impairment
and Dementia, Alzheimer's Type
ANTONIO LOBOa,b, RAÚL LÓPEZ-ANTÓNb,c, CONCEPCIÓN DE-LA-CÁMARAb,c,
MIGUEL ÁNGEL QUINTANILLAc, ANTONIO CAMPAYOb,c, PEDRO SAZb,d and ZARADEMP WORKGROUP
aDepartment of Psychiatry, University of Zaragoza, Instituto Aragonés de Ciencias de la Salud and Hospital
Clínico Universitario, Zaragoza, Spain; bCentro de Investigacion Biomédica en Red de Salud Mental (CIBERSAM),
Ministry of Health; cInstituto Aragonés de Ciencias de la Salud and Hospital Clínico Universitario, Zaragoza,
Spain; dDepartment of Psychiatry, University of Zaragoza, Spain. alobo@unizar.es
(Submitted 22 October 2007; Revised 18 February 2008; In final form 18 February 2008)
Objective: To test the hypothesis that specific
psychopathological non-cognitive symptoms are
associated with incident mild cognitive impairment (MCI), while different symptoms are associated with incident dementia of Alzheimer's
type (DAT). Methods: A representative community sample of 4,803 individuals aged 55+ years
was interviewed in a two-phase screening, in
Wave I or ZARADEMP I. This is the baseline,
cross-sectional study of the ZARADEMP Project,
a longitudinal study to document incidence and
risk factors of dementia. The main instrument
for assessment of participants was the
ZARADEMP Interview, which includes standardized Spanish versions of instruments such
as the Mini-Mental Status Examination and the
Geriatric Mental State GMS-AGECAT. Two
years later, in Wave II or ZARADEMP II, the
cognitively non-deteriorated elderly were reassessed in a similar, two-phase procedure.
"Incident cases" of both dementia and DAT
(DSM-IV-TR criteria), as well as MCI (operationally defined Petersen's criteria) were diagnosed by a panel of psychiatrists. Statistical,
logistic regression models, adjusted by age, sex
and education were used to test the hypothesized
association. Results: "Irritability", "neurovegetative symptoms", "sleep problems", "concentration difficulties", "loneliness" and "subjective slowing" documented at baseline were associated with incident MCI (odds ratio, OR range
1.71-2.67). A different profile of non-cognitive
symptoms was associated with incident DAT,
specifically "tension" (OR= 2.45), "sleep problems" (OR= 2.81), and "observed slowing"
(OR= 4.35). On the contrary, "subjective restriction of activities" seemed to be negatively associated with DAT (OR= 0.12). Conclusions: To our
knowledge, this is the first report about some
specific psychopathological, non-cognitive symptoms associated with incident MCI and/ or incident DAT, when controlling by each other. The
psychopathological profile associated with MCI
is different from the profile preceding DAT.
Keywords: Dementia; Dementia of Alzheimer's Type;
Community study; Non-Cognitive symptoms;Logistic
regression model
*Corresponding author: Tel.: +34 976 55 11 67; FAX: +34 976 76 17 12; E-mail: alobo@unizar.es
ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2008 FP Graham Publishing Co., www.NeurotoxicityResearch.com
264
A. LOBO et al.
INTRODUCTION
There is an increasing concern for the problem of
dementia in the elderly population. Most current
concepts of dementia follow the so called "cognitive paradigm" (Berrios, 1989). The essential characteristic of dementia in the influential DSM-IV-TR
is "the development of multiple cognitive deficits",
specifically "impaired memory" and "at least one of
the following: aphasia, apraxia, agnosia and disturbance in executive functioning" (American
Psychiatric Association, 2000). While the DSM-IVTR also describes "associated symptoms" (e.g.,
lack of insight and unrealistic assessment of his/her
own abilities; anxiety and depression; delusions
and hallucinations; etc.), they are not included
among the diagnostic criteria. However, the limitations of the "cognitive paradigm" have been underlined (Berrios, 1989). This author has pointed out
that "the major disintegration of psychological
organisation which is characteristic of dementia is
likely to involve other systems such as perception,
motility, personality organisation, emotional experience and volition".
Non-cognitive psychopathological symptoms,
which have been called "behavioural and psychological symptoms of dementia" (BPSD) (Finkel et
al., 1997), have lately stirred considerable interest:
they are common both in clinical samples (Ortiz et
al., 2006) and in the general population (Lyketsos
et al., 2002); and they are considered to predict a
poorer outcome (Chan et al., 2003; Shin et al.,
2005). We have recently shown that affective symptoms, and particularly negative-type symptoms are
very frequent in cases of dementia living in the
community, the latter having powerful specificity in
the distinction with non-cases (Saz et al., 2008).
Depression has been associated with subsequent
dementia (Jorm et al., 1991), but other studies
could not confirm the association with depressive
symptoms (Ganguli et al., 2006). Furthermore,
there is not much evidence about other non-cognitive, psychopathological symptoms preceding the
onset of dementia. While non-cognitive symptoms
such as the affective ones might be considered secondary manifestations of a dementing illness or a
psychopathological reaction to the handicaps in the
demented, these symptoms, but particularly negative-type symptoms could also be studied as possi-
ble risk factors and/or early markers or prodromic
manifestations of dementia (Teng et al., 2007).
On the other hand, mild cognitive impairment
(MCI) has emerged in the field of dementia studies,
and has been suggested as a transitional stage
between age related memory decline and dementia
of Alzheimer's type (DAT) (Modrego and Ferrandez,
2004). Conversion rates from MCI to DAT range
from 4% to 23% in community based samples
(Bruscoli and Lovestone, 2004) and 10% to 31% in
clinic-based samples (Luis et al., 2003). This variability may be related to differences in diagnostic
criteria, but also to sample selection. On the basis
of both clinical experience and preliminary analysis
of our previous research, we maintain the general
hypothesis that MCI such as it is described in the
literature is in fact a heterogeneous group of disturbances of mild severity, which includes early cases
of dementia, but also affective disorders.
We are involved in the ZARADEMP Project, a
longitudinal study of dementia and psychiatric morbidity in a large, representative sample of the
elderly population. In this setting, the objective of
this paper was, first, to study the association of
specific non-cognitive, psychopathological symptoms assessed during the baseline study with incident cases of dementia and DAT, but also of MCI.
And second, to test the hypothesis that the profile of
associated symptoms of dementia, and specially
DAT, is different from the profile in MCI, affective
symptoms being more frequent in the latter.
METHOD
Background, Design and Sampling Technique
The ZARADEMP Project is a longitudinal, threewave epidemiological study designed to document
the incidence of dementia, and to complete a casecontrol study of risk factors in incident cases. The
objectives and methods of the project have been
described elsewhere (Lobo et al., 2005). The site of
the study was Zaragoza, the fifth largest city in
Spain (622,371 inhabitants). We report here from
the baseline, cross-sectional study or ZARADEMP-I
(Z-I), and from the first follow-up wave or
ZARADEMP-II (Z-II). A stratified random sample
of individuals aged 55+, with proportional allocation by age and sex, drawn from census lists was
selected in the baseline. The refusal rate was 20.5%,
NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT
and ultimately 4,803 people were interviewed.
After excluding cases and subcases of dementia
for the follow-up (n=742), 4,061 individuals were
approached for Z-II, and eventually 3,244 individuals were interviewed, the refusal rate being
9.9% (n=402). We report here data from the incident cases identified during the follow-up period
in Z-II.
Instruments
The ZARADEMP Interview was used in this project. It incorporates several international instruments, previously standardized in Spain by our
research group. For the purpose of this report, the
following will be described:
Geriatric Mental State (GMS), a semi-structured standardized clinical interview for assessing the mental
state of elderly persons (Copeland et al., 1987; 1992).
It includes neuropsychological items and a computerized diagnostic program, AGECAT, can be applied
(Copeland et al., 1987; Saz et al., 1996).
For the purpose of this study, GMS symptoms
different from those included in the main "cognitive" category in DSM-IV-TR are called "non
cognitive". We selected 23 of these psychopathological symptoms, which are grouped in three
265
categories: "affective", "negative-type" and "other
symptoms" (FIG. 1). They include the nuclear
symptoms for each non-cognitive section of the
GMS, and both affective-type symptoms and
negative-type symptoms receive special emphasis,
because of their special relevance for this study.
Following standard procedures, "0" was the score
when the symptom was absent. However, scores
"1" (symptom present, but mild or not frequent)
and "2" (symptom frequent and/or severe) were
collapsed for the calculation processes.
History and Aetiology Schedule (HAS)
(Copeland et al., 1987; Dewey et al., 1992); a
standardized method of collecting history data
from a caregiver, or directly from the respondent
when he is judged to be reliable. It is crucial to
complete the GMS and facilitate a diagnostic
process using the DSM system.
Mini-Mental Status Examination (MMSE;
Folstein et al., 1975; Lobo et al, 1999), frequently
used internationally to detect cognitive decline.
Lawton & Brody Scale (Lawton and Brody,
1969; Tarraga, 1995) and Katz' Index (Katz et al.,
1963; Alvarez et al., 1992) were used to assess
instrumental and basic activities of daily living,
respectively, and to assess disability (total score
and number of items).
266
A. LOBO et al.
Procedure
A two-phase epidemiological screening design was
used in the baseline study (Z-I) and a similar method was used in the follow-up wave (Z-II). In Phase
I trained senior medical students administered the
ZARADEMP Interview to participants at home.
Outside caregivers were interviewed when the participant was considered to be unreliable. Medical
reports, which are frequently available at participants' homes, were used in the diagnostic process.
Participants were nominated as "probable cases" on
the basis of GMS threshold "global" score and/or
Mini-Mental standard cut-off points. In Phase II of
Z-I the supervising, trained research psychiatrists
reassessed, using the same instruments, in the participant's home, those cases of dementia considered
to be doubtful according to predetermined criteria.
The data on the remaining participants were thoroughly reviewed by the psychiatrists supervising
individually the lay interviewers. However, in Z-II
all probable cases of dementia were reassessed by
research psychiatrists. Our previous studies have
supported the validity of this diagnostic process
done by research psychiatrists in the community
(Lobo et al., 1995). Patients diagnosed of dementia
by the research psychiatrist, but also the elderly
considered to be subcases of cognitive deficit on
the basis of scores below the standardized threshold
point in GMS and/or MMSE were removed from
the follow-up sample. The cohort of the nondemented, non-cognitively deteriorated elderly
composes the sample followed up in consecutive
phases of the Project, starting by Z-II.
In the follow-up wave, or Z-II, the diagnosis of
"incident case" of dementia was confirmed, when
appropriate, by a panel of research psychiatrists.
For the diagnostic process, variables in the
ZARADEMP Project Interview were operationalized to conform with DSM-IV-TR criteria. For the
diagnosis of dementia the following DSM-IV-TR
criteria were required: A1. Impaired memory in the
short and long term. A2. At least one of the following cognitive disturbances: a) Aphasia b) Apraxia c)
Agnosia d) Disturbance in executive functioning.
B. The cognitive deficits in criteria A1 and A2 each
cause significant impairment in social or occupational functioning and represent a significant decline
from a previous level of functioning. C. The deficits
do not appear exclusively during the course of a
delirium. D. The disturbance in not better accounted for by another Axis I disorder (e.g., Major
Depressive Episode, Schizophrenia). For the diagnosis of DAT, DSM-IV-TR criteria were also
required: A. All criteria for dementia described in
the previous paragraph B. The course is characterized by gradual onset and continuing cognitive
decline. C. The deficits of the criteria A1 and A2
for dementia are not due to: C1 Other central nervous system conditions that cause progressive
deficits in memory and cognition. C2 Systemic
conditions that are known to cause dementia. C3
Substances-induced conditions. For the diagnosis
of MCI, we have operationalized Petersen et al.'s,
(1999) criteria, using information from the
ZARADEMP Interview, as follows. Subjects fulfilling DSM-IV-TR criteria of dementia or scoring
below the MMSE standard threshold point were
excluded. Inclusion criteria were: an abnormal
score in the memory items of both the MMSE and
the GMS ("subjective memory loss" and "observed
memory loss"); and scores in the normal range on
both, Lawton & Brody and Katz's Index of ADL's.
We used as a comparison group the non-cases in
Z-II, by eliminating from the sample all GMS
cases of dementia, as well as other GMS cases, in
particular cases of depression and anxiety.
Quality Control and Ethics
Systematic checks on the reliability of the assessments were implemented to prevent the "reliability-drift". Standard ethical principles were maintained throughout the study. Participants were
given a standard information sheet, written consent was obtained, and privacy, confidentiality and
security were maintained, according to Spanish
Law 5/1992.
Statistical Procedures
Statistical analyses were performed using SPSS
14.5 for Windows. Z test was used to calculate differences in frequencies, by groups, with P <0.05 as
the level of significance. We calculated Student's t
to test differences by sex, age and education for
quantitative variables. Confidence intervals (95%)
and standard deviations were also calculated.
To investigate the association of incident cases of
dementia, DAT and MCI with psychopathological
symptoms at baseline, stepwise logistic regression
NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT
models were used. The 23 identified non-cognitive
symptoms were introduced as explanatory variables, keeping sex, age and education as fixed
covariables. We chose a stepwise backwards conditional selection method, that allows for identification of variables that significantly contribute to the
predictive capacity of the model, optimizing the R2
coefficient. For each variable, the criterion for leaving the model was a significance of P >0.005. A
small amount of GMS data was missing (< 5%).
RESULTS
Demographic characteristic of both samples are
summarized in Table I. In both, women and the
elderly with limited educational background predominate. As expected, mean age in Z-II tends to
be older, although differences with Z-I were not
statistically significant. Mean scores in the MiniMental are higher in Z-II, (t=5.99; p < 0.001) but
this might also be expected, since cases of dementia and cognitively deficient elderly had been
removed from the baseline sample for the followup assessment in Z-II. Eighty two cases of dementia, 47 cases of DAT and 208 cases of MCI were
267
identified in Z-II, and 1,645 elderly were considered to be non-cases.
Table II shows results of step-wise logistic regression analysis to test the association of non-cognitive
psychopathological symptoms assessed in the baseline with incident cases of MCI. In the fitted final
model, most symptoms assessed in the affective
section of the GMS ("irritability", "neurovegetative
symptoms", "sleep problems", "loneliness" and
"concentration difficulties") remained associated
with MCI, although "dysphoric mood" or "anxiety"
were not. Similarly, the association with "subjective
slowing" was also documented.
Table III shows the results in relation to incident
cases of dementia. Sleep difficulties documented at
baseline were also associated to the incident cases,
but not the remaining affective symptoms.
"Observed slowing" was very significantly associated to incident dementia (OR = 6.70; 95% C.I.
[3.04-14.78]). On the contrary, "subjective restriction of activities" seemed to be inversely associated
with dementia.
"Sleep problems", but also "tension", a relevant
affective symptom, documented at baseline was
associated with incident cases of DAT (Table IV).
268
A. LOBO et al.
Again, "observed slowing" was very significantly
associated with the outcome of DAT at follow-up
(OR = 4.35; 95% C.I. [1.48-12.80]) and "subjective restriction of activities" seemed to be negatively associated with dementia (OR = 0.12; 95%
C.I. [0.02-0.63]).
DISCUSSION
This is the first study trying to document the association of non-cognitive, psychopathological symptoms assessed at baseline and incident cases of
dementia and DAT, but also of MCI simultaneously.
NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT
Some previous studies documented the association
of depression and dementia (Devanand et al., 1996;
Geerlings et al., 2000; Green et al., 2003). However,
reports are discrepant, since other studies could not
confirm these findings (Dufouil et al., 1996; Vinkers
et al., 2004; Ganguli et al., 2006). We have attempted a different approach, since we studied individual
affective, but also non-affective symptoms, controlling by each other rather than disorders. We show
that "tension" but also "sleep problems" at baseline
are followed by incident DAT, after controlling by
other affective and non affective phenomena.
Obviously, it might be argued that "sleep problems"
are not necessarily affective symptoms. Sleep difficulties have been found to be common in cases of
dementia (Vitiello and Borson, 2001; Onen and
Onen, 2003), and the possibility exits that they are
symptoms directly due to brain disease. However,
the relevant finding here, which has not been
reported previously, is that the sleep problems precede the onset of the dementing condition. New
studies could clarify to what extent these symptoms
must be considered risk factors or, on the contrary,
early manifestations of the dementing illness.
In fact, a similar argument might be put forward
in relation to the affective symptoms preceding a
diagnosis of dementia at follow-up. A muti-facetted
relationship between depression and dementia has
been previously discussed (Mahendra, 1985; Lobo
et al., 1995). Affective symptoms might be risk factors for dementia (Chen et al., 1999) but also an
early manifestation of brain disease (Wilson et al.,
2002; Green et al., 2003). Careful psychopathological analysis may be useful in future studies to
clarify this dilemma, since symptoms of brain conditions may be phenocopies (Bulbena and Berrios,
1993), with qualitative differences from symptoms
in primarily psychiatric illness. In relation to this,
we believe the use of the GMS, a psychiatric instrument is one asset in this study.
We have also studied non-cognitive symptoms,
mainly negative-type symptoms related to apathy,
assessed at baseline. An association of "observed
slowing", which is also a psychomotor symptom,
with incident DAT is documented here. Previous
authors have reported an association of apathy with
dementia (Lyketsos et al., 2002). However, we
show that it is specifically "observed slowing" the
symptom strongly associated with incident global
269
dementia (OR = 6.70) and specifically incident
DAT (OR = 4.35). No association was found with
other apathy related symptoms, such as "anhedonia" or "anergia", when controlling for the remaining affective and non-affective symptoms. From the
clinical point of view, it may have special interest
to document "observed slowing" in the non-demented elderly, particularly when accompanied by "tension" since both were associated with future DAT.
We may also speculate about the theoretical interest of these findings, in particular in DAT, since
"global dementia" refers, by definition, to a group
of disorders with a common syndrome of cognitive
deterioration. Present day, psychiatric research is
searching for endophenotypes that might be markers for genetic conditions such as DAT. Apathy
might be one such an endophenotype (Borroni et
al., 2006), but this study suggests that more specific symptoms, such as "observed slowing" might
be studied as potential, early markers. The finding
that "subjective restriction of activities" has a
negative association with dementia and DAT was
unexpected. It might be related to the insight
healthy elderly people have about deficits in a normal ageing process. In any case, the results in this
study suggest that special clinical interest, and
even theoretical interest, should be paid to patients
with "objective slowing", but not "subjective
restriction of activities", since they might be at
special risk for DAT.
We believe that the results of this study tend to
support our conjecture that so called MCI is a heterogeneous group of psychopathological, minor
disorders, and not necessarily an early manifestation of a dementing condition. There is considerable evidence that the conversion rate of MCI into
dementia is quite important (Luis et al., 2003;
Bruscoli and Lovestone, 2004; Lopez et al., 2007).
However, the specific rate varies between studies.
We suspect that cases of MCI in some reports
included cases or subcases of affective disorder. In
support of this conjecture, first, the profile of symptoms associated to both incident global dementia
and incident DAT is different from the profile of
incident MCI; and second, contrary to cases of incident dementia, several affective symptoms are
associated with incident MCI. Future studies could
test more specifically the association of affective
disease, and affective symptoms with MCI.
270
A. LOBO et al.
Among the strengths of the paper, we should
underline the fact that a sample of incident cases of
dementia and MCI, coming from a large population
sample was studied. Furthermore, we are confident
that this study fulfils present day requirements in
psychiatric epidemiology (Kaelber and Regier,
1995). First, a representative community sample
was investigated including both, institutionalized
and non-institutionalized elderly. Secondly, screening and case ascertainment instruments specifically
developed for the elderly were used; they are widely accepted in the international literature, and were
previously standardized in our specific culture. The
sensitivity coefficients of the instruments used
[GMS "0rganic" = 93.2%; Mini-Mental = 89.8%
(Lobo et al., 1995)] are considered adequate and
comparable to coefficients reported in several studies in this field (Hofman et al., 1991). Thirdly,
although "probable non-cases" among the elderly
were not re-assessed in this study, the high negative
predictive value of the screening instruments used
(Mini-Mental = 97.8%; GMS "organic"= 98.3%)
(Lobo et al., 1995) prevents the likelihood of a substantial reduction in the number of dementia cases
identified. Finally, the standardized, DSM-IV-TR
diagnostic criteria used are considered to be aging
appropriate criteria (Jeste et al., 2005).
Other limitations of the study should be addressed.
The categorization of "non-cognitive" symptoms
such as, "lack of concentration" or "difficulties in
thinking" in this study may be debatable. However,
first, both are subjective symptoms in the GMS
glossary; second, they are considered to be part of
depressive episodes in the DSM-IV-TR system; and
third, they are not included among the cognitive
symptoms of dementia in this diagnostic system.
Similarly, neither "subjective restriction of activities" (psychomotor section in the GMS), nor "disturbances of perception" (psychotic phenomena
section in the GMS) are included among the cognitive symptoms in the DSM-IV-TR. While our previous studies have supported the validity of the
diagnosis of dementia performed by research psychiatrists in the elderly community (Saz et al.,
1996), we anticipated some difficulties, particularly
in the cases not directly assessed by the psychiatrists. Therefore, we have followed previously
determined requirements for the diagnostic process.
Firstly, case definitions and standardized levels of
illness were used (Copeland et al., 1987), and were
applied consistently to minimize the impact on
rates of dementia (Riedel-Heller et al., 2001).
Secondly, we operationalized each one of the items
in the DSM-IV-TR manual with information coming from the standardized assessment instruments
used, to minimize the risk of applying diagnostic
criteria of dementia differently from other researchers (Hofman et al., 1991). Thirdly, all the available
data were thoroughly reviewed by the psychiatrists
supervising individually the lay interviewers before
recording a diagnosis of "dementia". Fourthly, the
doubtful cases were re-examined by the research
psychiatrists. Finally, a panel of research psychiatrists reviewed all cases before making a definitive
diagnosis. Furthermore, we have pilot studied again
in this project the diagnostic agreement between the
psychiatrists supervising the lay interviewers and/
or doing the clinical interview in the elderly homes
and the panel of psychiatrists reviewing the data:
the agreement is considered to be reasonable, as it
occurred in 91.4% of individual "cases" and "subcases" presented. Important uncertainties in epidemiological studies relate to sample attrition, but a
special effort was made to minimize the risk of nonresponse (Lobo et al., 1995; 2005), and the refusal
rate in both waves of the study was comparable to
a number of previous reports (Copeland et al.,
1987; 1998).
In conclusion, this study suggests for the first time
that some specific, non-cognitive psychopathological symptoms assessed at baseline are associated at
follow up with incident MCI and/or incident DAT,
when controlling by each other. On the contrary,
"subjective restriction of activities" was negatively
associated with incident DAT. Furthermore, we
have found support for the hypothesis that the psychopathological profile associated with incident
MCI is different from the profile preceding DAT.
Acknowledgements
Supported by Grants from Fondo de Investigación
Sanitaria, and the Spanish Ministry of Health,
Instituto de Salud Carlos III (grants #94/1562,
97/1321E, 98/0103, 01/0255, 03/0815, 06/0617,
G03/128, Red de Enfermedades Mentales, REMTAP Network #RD06/0011/0010), Madrid, Spain;
Spanish Ministry of Health, Instituto de Salud Carlos
NON-COGNITIVE SYMPTOMS & INCIDENT MCI AND DAT
III, CIBERSAM #CB07/09/0016, Madrid, Spain.
The authors acknowledge the contribution of
medical students and the following researchers, who
participated in the study: G. Marcos, T. Ventura, J.L.
Día, M. Zapata, B. Quetglas, A. Martín, J.A.
Montañés, S. Aznar and A. Lobo-Escolar.
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