National Institute of Health and Medical Research (INSERM), Paris, France
Correspondence: Dr Sabrina Paterniti, INSERM U360, Hôpital La Salpêtrière, 75651 Paris Cedex 13, France. Tel: +33 (1) 42162554; fax: +33 (1) 42162541
Declaration of interest The EVA study was supported by the Merck, Sharp and DohmeChibret Laboratories (West Point, PA) and the EISAI Company (France).
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ABSTRACT |
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Aims To test whether depressive symptoms predict cognitive decline in elderly people with normal cognition.
Method The Center for Epidemiologic Study depression scale (CESD) and the Mini-Mental State Examination (MMSE) were used to evaluate depressive symptomatology and cognitive functioning, respectively. A sample of 1003 persons aged 59-71 years and with a MMSE score of 26 or over was selected. Cognitive decline was defined as a drop of at least 3 points on the MMSE at 4-year follow-up.
Results Baseline high levels of depressive symptoms predicted a higher risk of cognitive decline at 4-year follow-up. The MMSE score of participants with depression was more likely to fall below 26 at 2-year follow-up and to remain below at 4-year follow-up than the MMSE score of those without depressive symptoms. Persistent but not episodic depressive episodes were associated with cognitive decline.
Conclusions High levels of depressive symptoms, when persistent, are associated with cognitive decline in a sample of elderly people.
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INTRODUCTION |
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METHOD |
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Interviews and examinations were conducted at the study centre. Data on demographic background, occupation, medical history, drug use and personal habits were obtained using a standardised questionnaire during a face-to-face interview. Mean weekly alcohol intake was estimated from a detailed description of alcoholic beverage consumption during a typical week. Participants were asked whether they had suffered from any of six specified common diseases (myocardial infarction, angina, stroke, hypercholesterolaemia, hypertension, diabetes) or had any other chronic medical condition. All drugs used during the month preceding the examination were noted, and were subsequently coded according to the classification proposed by the French national prescription handbook, the Guide National de Prescription des Médicaments (1991). Psychotropic drugs included anxiolytic, hypnotic, sedative, neuroleptic, antidepressant and normothymic agents.
The group was invited to participate in two follow-up examinations, which were conducted 2 years and 4 years after the baseline evaluation.
Population
Among the initial sample of 1389 persons, 200 (14.4%) had a baseline score
on the Mini-Mental State Examination (MMSE) below 26 and were excluded from
the analysis. Of the 1189 persons considered eligible for the study, 18 died
before the 4-year follow-up assessment, 137 were not followed up at 2 years or
4 years, and 31 had not completed the Center for Epidemiologic Studies
depression scale (CESD) rating at baseline. So, 84% of eligible
participants were analysed (n=1003). A further 31 participants had no
CESD assessment at 2-year or 4-year follow-up.
Cognitive function testing
A trained psychologist administered a battery of tests assessing different
areas of cognitive and psychomotor functioning. Tests were chosen with special
regard for their sensitivity to ageing. For the current analysis we considered
a measure of global cognitive abilities, the MMSE
(Folstein et al,
1975), which yields scores ranging from 0 to 30. The MMSE was
administered to participants at baseline and at 2-year and 4-year
follow-up.
Assessment of depressive symptoms
Depressive symptoms were measured using the CESD
(Radloff, 1977). It consists
of 20 self-report items concerning symptoms and feelings experienced during
the preceding week. Each item is scored from 0 to 3 according to the frequency
of the symptom. Evaluation of the CESD in a French population
(Fuhrer & Rouillon, 1989) showed that men and women scoring more than 16 or 22, respectively, should be
considered at high risk of clinical depression. Using this cut-off point the
authors obtained a sensitivity and specificity which were, respectively, 0.76
and 0.71 in detecting a major depressive episode according to DSMIII
criteria (American Psychiatric Association,
1980). In our study the internal consistency of the CESD
was good (standardised Cronbach's =0.88). Work with the CESD in
community samples has consistently identified four factors that underlie the
measure: depressed affect, positive affect, somatic complaints and
interpersonal relationships.
The CESD was sent to the participants by mail approximately 3 weeks before the examination and completed questionnaires were brought back at the time of the examination. The instrument was administered to the participants at the baseline assessment and at 2-year and 4-year follow-up.
Data analysis
We excluded from the data analysis people with a baseline MMSE score lower
than 26 for two reasons: to exclude those with subthreshold levels of
dementia, and to include only those at risk of cognitive decline.
The differences in MMSE scores between baseline and 4-year follow-up examinations were analysed as quantitative variables, and also as binary variables. For the latter analyses, cognitive decline was defined as a decrease of 3 points or more in the MMSE scores. We defined low cognitive functioning at follow-up as MMSE scores of 25 or less at 2-year and 4-year follow-up. Participants were defined as having high baseline levels of depressive symptoms when their baseline CESD score was above the gender-specific cut-off point. In order to evaluate whether the risk of cognitive decline is higher when the participant reports several depressive episodes at follow-up evaluation, we defined three study groups. Participants reporting high levels of depressive symptoms at one or at more than one evaluation were assigned to an episodic or a persistent depressive group, respectively, and were compared with participants who did not have high depressive symptom scores at any of the three assessments.
We tested whether a high depressive symptom score was associated with cognitive decline using multivariate analyses (covariance analysis and logistic regression models). All multivariate analyses were adjusted for gender, age, education (years of schooling), alcohol (mean weekly alcohol intake evaluated in millilitres of pure alcohol) and tobacco use (current smokers, former smokers, or never smokers), psychotropic drug use and the presence of chronic medical diseases, because these variables are known to be significantly associated with cognitive performance and psychopathological characteristics.
In order to examine whether the observed relationship between CESD score and cognitive decline was due to depressed mood rather than to the cumulative number of symptoms, we evaluated whether the CESD sub-score depressive affect was predictive of cognitive decline, using linear and logistic regression models. We calculated the depressive affect subscore, by summing the scores of items measuring the cognitive symptoms of depression (bothered, blues, depressed, fearful, lonely, cried and sad) (Radloff & Teri, 1986). The sub-score ranged from 0 to 21.
Statistical testing was done at the conventional two-tailed -level
of 0.05. Data were analysed using the SAS package, Version 6
(SAS Institute, 1989).
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RESULTS |
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Comparison between participants according to follow-up
A slightly higher percentage of participants who were not followed up had a
high depressive symptom score at baseline; they also had lower MMSE scores
than those followed up. Participants not followed up had fewer years of
schooling and used more psychotropic drugs. No difference was observed for
gender, age or alcohol use.
Depressive symptoms at baseline and the risk of cognitive
decline
Participants with high levels of depressive symptoms showed a greater
decrease in MMSE score between the baseline and 4-year follow-up assessments
(Table 2). High levels of
depressive symptoms were also associated with a higher risk of a 3-point
decrease in MMSE score and with a higher risk of low cognitive functioning at
follow-up.
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Persistent depressive symptoms and cognitive decline
Persistent but not episodic depressive symptoms were
associated with greater cognitive decline and with low cognitive functioning
at follow-up (Table 3). In
order to test whether persistent but not episodic depressive symptoms
predicted cognitive decline in those with depressive symptoms at baseline, we
compared participants depressed at baseline but not at 2-year and 4-year
follow-up (episodic, n=39) and participants depressed
at baseline and at 2-year and/or 4-year follow-up (persistent,
n=77) with participants not depressed at baseline. The
persistent group had twice the risk of cognitive decline (odds
ratio 2.0, 95% CI 1.1-3.5) of participants who were not depressed; episodic
depressive symptoms were not associated with cognitive decline (OR 0.8, 95% CI
0.3-2.2).
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The finding that depressive symptoms predict cognitive decline might be due to depressive symptoms being the consequence of a slight initial cognitive decline. In order to test this possibility, we considered the group of participants without cognitive decline between baseline and 2-year follow-up (Table 4). A high level of depressive symptoms at 2-year follow-up was associated with a greater decrease in MMSE score between the 2-year and 4-year follow-up assessments in this group.
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Depressive affect
Linear and logistic regression models adjusted for baseline cognitive
scores and covariables were used to examine the association between the
sub-score depressive affect and cognitive decline. In a linear
regression model, depressive affect was associated with a greater decrease in
MMSE score between baseline and 4-year follow-up (b=-0.06, s.e.=0.02,
P=0.0003). Logistic regressions showed that depressive affect was
also associated with a higher risk of low cognitive functioning at follow-up
(OR 1.07, 95% CI 1.01-1.13) and a higher risk of a 3-point decrease in MMSE
score (OR 1.06, 95% CI 1.00-1.12).
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DISCUSSION |
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Mechanisms of association
Different mechanisms may explain why depressive symptoms predict cognitive
decline. Depression may be a psychological reaction to perceived cognitive
loss. Schmand et al
(1997) found that depressive
symptoms at baseline did not predict future dementia when memory complaints
were accounted for. In our study depressive symptoms preceded cognitive
decline, in the absence of previous loss of cognitive performance; it is
therefore unlikely that in our group depression is only a psychological
reaction to perceived cognitive loss. On the other hand, it is possible that
the MMSE does not permit the evaluation of finer cognitive losses. Cognitive
deficits usually associated with depression may be responsible for an earlier
onset of cognitive decline or dementia. However, in our study depressive
symptoms also predicted cognitive decline in participants with the highest
MMSE scores, so it is not likely that this phenomenon can explain all the
data.
Somatic symptoms such as fatigue or concentration disorders may be early symptoms of dementia; they are also symptoms of depressive disorders and are included as items of depression rating scales. A high depression score may thus reflect early symptoms of dementia. In our study, the observation that the affective dimension of CESD was predictive of cognitive decline shows that the observed association between depressive score and subsequent cognitive decline was not only due to the somatic component of depression.
In our study group of people with initial depressive symptoms, persistent (but not episodic) depression was associated with a higher risk of cognitive decline. This result is in agreement with the observation that people with depressive symptoms often suffer from cognitive impairment, which may be severe (pseudo-dementia) but is generally transitory and resolves on treatment of the depression (Stoudemire et al, 1993). The fact that initially high levels of depressive symptoms predict subsequent persistent low cognitive functioning together with the observation that persistent but not episodic depressive episodes are associated with cognitive decline suggest that a chronic mechanism is responsible for the observed association. Depressive symptoms may be a prodrome of cognitive decline the early manifestation of a neurodegenerative process, causing depression and dementia. Depressive symptoms and cognitive decline are linked to modifications in activity of similar cerebral areas (Baker et al, 1997). Some studies have found that both are associated with the presence of signal hyperintensities on magnetic resonance brain scans (O'Brien et al, 1996). The loss of noradrenergic neurons associated with dementia might also explain depression as a prodrome of dementia (Förstl et al, 1992). Alternatively, depression might represent a causal factor in cognitive decline. Some studies indicate that early-onset depression (Palsson et al, 1999) or depression that has a history of 10 years or more (Speck et al, 1995) are stronger risk factors for dementia. Some authors have proposed that chronic depression causes cognitive decline by the release of adrenocorticotrophic hormone and the consequent secretion of glucocorticoids (O'Brien, 1997). Prolonged secretion of glucocorticoids may have harmful effects and lead to hippocampal atrophy (Sapolsky, 1996).
Practical and clinical implications
Although it is not possible to define causal mechanisms in an
epidemiological study, the fact that depression predicts cognitive decline in
elderly people has practical and clinical implications. The detection of
depressive symptoms in these people is important because early treatment of
depression may improve prognosis. In addition, depressive symptoms, especially
when they are persistent, may be the first sign of the decrease in cognitive
functioning, carrying not only a higher risk of dementia, but also a higher
mortality (Gussekloo et al,
1997; Rozzini et al,
1998). People with cognitive decline may benefit from drugs that
might slow the progression of the disease. Nevertheless, diagnosis of
depression is more difficult in elderly people, in whom symptoms such as
fatigue, loss of libido and sleep disturbances occur more frequently even in
the absence of depression. A possible consequence is that chronic depression
in this age group may be underdiagnosed, because somatic symptoms are
attributed to physical rather than psychiatric causes
(Hasin & Link, 1988). In
our study only 4% of the group with high levels of depressive symptoms were
receiving specific (anti-depressant) treatment. A high proportion of people
with chronic depression use benzodiazepines
(Bonner & Howard, 1995),
which have been associated in the elderly with a higher risk of cognitive
impairment (Gorenstein et al,
1995).
Limitations of the study
In our study no history of depressive symptoms was obtained and no
diagnosis of depressive disorder was made. It cannot therefore be deduced
whether early or late depression is responsible for cognitive decline and
which clinical form of depression is associated with cognitive impairment.
Moreover, study participants who were not followed up had higher levels of
depressive symptoms and lower MMSE scores at baseline than those who were
followed up. The association between depressive symptoms and cognitive decline
may be underestimated. However, few patients were lost to follow-up (13%) and
so major bias is unlikely.
In conclusion, our finding that depressive symptoms predict cognitive decline may have important clinical implications. Depression may be a harbinger of initial cognitive decline.
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication November 26, 2001. Revision received June 25, 2002. Accepted for publication June 27, 2002.
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