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University of Manchester, Division of Psychiatry, Education and Research Centre, South Manchester University Hospital, Manchester, UK
University of Manchester, Division of Psychiatry, Education and Research Centre, South Manchester University Hospital, Manchester, UK and Department of Psychiatry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Vascular Studies Unit, Academic Surgery Unit, University of Manchester
University of Manchester, Division of Psychiatry, Education and Research Centre, South Manchester University Hospital, Manchester
Vascular Studies Unit, Academic Surgery Unit, University of Manchester
University of Manchester, Division of Psychiatry, Education and Research Centre, South Manchester University Hospital, Manchester, UK
Correspondence: Dr N. Purandare, University of Manchester, Division of Psychiatry, Education and Research Centre, 2nd floor, Wythenshawe Hospital, Manchester M23 9LT, UK. Tel: +44 (0)161 291 5887; fax: +44 (0)161 291 5882; email: nitin.purandare{at}manchester.ac.uk
Funding detailed in Acknowledgements.
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ABSTRACT |
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Aims To evaluate the association between spontaneous cerebral emboli and depressive symptoms in Alzheimer's disease and vascular dementia.
Method In a cohort of 142 patients with dementia (72 with Alzheimer's disease and 70 with vascular dementia), the association between spontaneous cerebral emboli and clinically relevant depressive symptoms was examined using multiple logistic regression analyses.
Results Spontaneous cerebral emboli were significantly more frequent in the patients with clinically relevant depressive symptoms (66 v. 37%, P=0.03). After adjustment for age, gender, Mini-Mental State Examination score, type of dementia and significant cardiovascular risk factors, the relationship remained significant (OR=3.47, 95% CI 1.10-10.97).
Conclusions Spontaneous cerebral emboli are associated with clinically relevant depressive symptoms in dementia, and further research is needed to explore the nature of this relationship.
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INTRODUCTION |
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METHOD |
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Depressive symptoms
Depressive symptoms were assessed at an interview with carers using the
Neuropsychiatric Inventory (NPI; Cummings
et al, 1994), which rates depressive symptoms and 11
other non-cognitive symptoms in the patient over the previous month. If the
screening question is answered positively, the severity is classified into
`mild', `moderate' or `severe' (score 1-3) and the frequency into `less than
once a week', `once a week', `most days, but not every day' and `every day'
(score 1-4). The NPI symptom score is calculated by multiplying the scores for
severity and frequency, which gives a range of 1-12 if a symptom is present
and a score of 0 if a symptom is absent. A score of 4 or more on the
depressive symptom sub-scale (mild symptoms occurring every day, or moderate
to severe symptoms occurring at least once a week) was used to identify
clinically relevant depressive symptoms
(Aalten et al, 2005;
Holthoff et al,
2005).
Cerebral emboli
The presence of spontaneous cerebral emboli was investigated independently
in the Vascular Studies Unit at South Manchester University Hospital by
technologists who did not have access to information about dementia type or
details of the patients' symptoms. The methods, including the key technical
parameters, have been described previously
(Ringelstein et al,
1998; Purandare et
al, 2006). Briefly, continuous transcranial Doppler
insonation of the middle cerebral arteries via the transtemporal windows for 1
h was used to detect the emboli. The output was recorded on digital tape for
subsequent analysis by a vascular technologist, masked to patient identity.
Patients were observed during each session for any movement so that artefacts
could be identified. Emboli were defined using international consensus
criteria, which specify that embolic signals should be transient (lasting less
than 300 ms), at least 3 dB higher than the background blood flow signal,
unidirectional within the Doppler spectrum, and accompanied by an audible
`snap', `chirp' or `moan' (Consensus
Committee of the Ninth International Cerebral Hemodynamic Symposium,
1995). Detection of one or more embolic signals constituted a
positive finding.
Cardiovascular risk factors
The severity of carotid disease was imaged using colour duplex ultrasound
(Ultramark 9; Advanced Technology Laboratories, Inc., Washington, DC, USA).
The peak systolic velocity in the internal carotid arteries was used to
calculate the degree of stenosis, using established criteria
(Sidhu & Allen, 1997).
Blood pressure was measured manually after a 5 min rest. Pulse pressure,
calculated as the difference between the systolic and diastolic blood
pressures, is related to arterial stiffness and as such was used as a measure
of atherosclerosis (Van Popele et
al, 2001). A blood sample was taken to assess lipid profile
and apolipo-protein E genotype. Data on the following cardiovascular risk
factors were collected at interview with patients and their care-givers, and
by reviewing case notes: smoking status (current/former/non); alcohol
consumption per week over 14 units (women) or 21 units (men); drug history;
and history of myocardial infarction, angina, stroke, transient ischaemic
attacks, hypertension, hypercholesterolaemia or diabetes.
Statistical analyses
We used chi-squared statistics or Fisher's exact test to determine the
univariate relationship between the NPI depression scores (
4) and the
presence of spontaneous cerebral emboli. To control for potential confounders
we performed multiple logistic regression analyses entering the dichotomised
NPI depression scores as the dependent variable and the presence or absence of
emboli as the independent variable. The analysis was repeated initially
without controlling for the effect of potential confounding variables, and
secondarily by using age, gender, type of dementia and level of cognitive
functioning (MMSE score) as independent variables. Thereafter, we also
adjusted for all cardiovascular risk factors that were univariately associated
with depressive symptoms in our sample at the 15% level. The level of
significance in the final model was set at P<0.05
(two-tailed).
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RESULTS |
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Depressive symptoms and cerebral emboli
Spontaneous cerebral emboli were detected in 29 (40%) patients with
Alzheimer's disease and 28 (40%) patients with vascular dementia (Pearson
2, P=0.97). The depression screening question
suggested the possibility of depressive symptoms in 62 patients (44% of the
sample), of whom 15 (11%) patients scored 4 or higher on the depression
sub-scale of the NPI: 9 (13%) of the 72 patients with Alzheimer's disease and
6 (9%) of the 70 patients with vascular dementia (Pearson
2,
P=0.45). The prevalence of this clinically relevant depression was
significantly higher among patients with emboli
(Table 1; Pearson
2, P=0.027).
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Multivariate analyses
The groups with Alzheimer's disease and vascular dementia were combined in
the multivariate analyses, as neither the prevalence of emboli nor depressive
symptoms differed significantly between the two types of dementia. Logistic
regression analysis adjusted for age, gender, diagnosis and cognitive
functioning (MMSE score) revealed a significant association between the
presence of emboli and clinically relevant depressive symptoms: odds
ratio=3.47 (95% CI 1.10-10.97), P=0.034. Of the cardiovascular risk
factors, only a history of a myocardial infarction and/or angina was
univariately associated with depressive symptoms at the 15% level (Pearson
2, P=0.147). Including this variable in the model did
not change the significance, giving a final odds ratio of 3.47 (95% CI
1.09-11.07), P=0.035. None of the included variables had a
significant interaction with type of dementia, showing that diagnosis was not
a major factor in explaining the association.
Semi-quantitative sensitivity analyses were performed by entering into our final model each non-significant cardiovascular risk factor and its interaction with type of dementia to check for differential effects in Alzheimer's disease and vascular dementia. None of these variables nor their interaction with type of dementia approached significance or substantially confounded the relationship between clinically relevant depressive symptoms and spontaneous cerebral emboli. Furthermore, correction for cardiovascular risk factors that were previously associated with spontaneous cerebral emboli in healthy people (history of stroke or transient ischaemic attack, anti-platelet drugs and body mass index; see Purandare et al, 2006) did not change the results significantly (OR=4.19, 95% CI 1.18-14.90, P=0.027).
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DISCUSSION |
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The lack of association between cardiovascular risk factors and clinically relevant depressive symptoms in our study may be explained by the low prevalence of both in our sample. On the other hand, a substantial number of studies have found that traditional vascular risk factors such as hypertension and diabetes are not an important cause of depression at a population level (Baldwin, 2005). Cervilla et al (2004), for example, followed up 2584 people with moderate hypertension over 54 months and did not find an association between incident depressive symptoms and cardiovascular risk factors. Both general atherosclerotic disease and atrial fibrillation can generate arterial emboli, and both have been associated with depressive symptoms (Lyness et al, 1998; Tiemeier et al, 2004). In our sample, however, the two measures indicative of atherosclerosis (carotid artery disease and pulse pressure) were related neither to depressive symptoms nor to cerebral emboli (data not shown). Although we did not specifically investigate atrial fibrillation, it is unlikely to be a significant confounder because of the exclusion of patients taking anticoagulant medication.
The assessment of clinically relevant depressive symptoms was based on the Neuropsychiatric Inventory, which is a well-validated and highly reliable questionnaire. Forty-four per cent of our population scored positive on the NPI screening question for depression, which is in line with published findings of 25-55% of dementia patients scoring positive for depressive symptoms on the NPI (Lyketsos et al, 2000; Mirakhur et al, 2004). The significance of these symptoms, however, can be questioned (Lyketsos et al, 2000; Cummings, 2003; Holthoff et al, 2005), and an NPI cut-off score of 3/4 has been recommended to indicate clinically relevant depressive symptoms for clinical trials in Alzheimer's disease (Schneider et al, 2001). Based on the cut-off point of 3/4, the proportion of dementia patients with depressive symptoms decreases markedly and falls in the same range (11-25%) as studies in which depression of clinical significance is assessed according to DSM-IV (American Psychiatric Association, 1994) criteria (Burns et al, 1990; Cummings et al, 1995; Weiner et al, 2002). The fact that our prevalence rate of 11% is at the lower end suggests that patients with depression might have more often declined participation. This might also explain the relatively low proportion of women in our study. Our observation of the univariate association between cerebral emboli and depressive symptoms becomes too low for reliable multivariate analyses. Depressive symptoms in dementia fluctuate over time and are persistent in only a minority of patients (Ballard et al, 1996; Eustace et al, 2002). Starkstein et al (1997) found that in patients with Alzheimer's disease, minor depressive symptoms were transient, whereas more severe symptoms suggestive of major depression persisted for over a year. Our criteria for clinically relevant depressive symptoms are more suggestive of major depression, and our hypothesis about the underlying mechanism - disruption of frontostriatal circuits owing to vascular damage by spontaneous cerebral emboli - may explain their persistence.
Some limitations of our study must be addressed. The cross-sectional assessment of depressive symptoms and emboli hinders causative interpretation. Second, the population studied was a convenience sample from specialist secondary care, limiting generalisation. For example, vascular dementia is a heterogeneous disorder, and we recruited relatively few patients with post-stroke dementia, who are thought to be at particular risk of developing depression. Finally, the assessment of depressive symptoms in our study was rather limited. We did not use a separate scale, such as (for example) the Cornell Scale for Depression in Dementia (Alexopolous et al, 1988), to assess depressive symptoms in more depth, and made no attempt to diagnose clinical depression using established diagnostic criteria such as those of DSM-IV or ICD-10 (World Health Organization, 1992).
Although the vascular depression hypothesis is now established, the pathways between vascular risk and depression remain unknown. To our knowledge, depression in dementia has never been linked with spontaneous cerebral emboli. Our results provide preliminary support for the hypothesis that asymptomatic microembolic events might be involved in causation of clinically relevant depressive symptoms in dementia. Further research is required: first, to confirm our findings in a longitudinal design using standardised diagnostic criteria for depression; and second, to examine whether the relationship is unique to depressive symptoms in dementia or can be generalised to late-onset depression in general.
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ACKNOWLEDGMENTS |
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Received for publication August 11, 2005. Revision received March 3, 2006. Accepted for publication May 2, 2006.
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