Cerebrovascular Disease and Evolution of Depressive Symptoms in the Cardiovascular Health Study
Background and Purpose— Previous studies have reported an association between cerebrovascular disease and depressive symptoms. The Cardiovascular Health Study (CHS) provides an opportunity to examine the relationship between vascular brain pathology seen on neuroimaging and changes in depressive symptoms.
Methods— The sample included 3236 CHS participants who had an MRI brain scan. Demographic variables, medical history, functional status, and apolipoprotein E genotype were obtained at baseline. Annual scores on a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale were obtained initially and up to 7 years subsequently.
Results— After controlling for important covariates, occurrence of depressive symptoms (defined as modified CES-D score of >7) was associated with small lesions in the basal ganglia, large cortical white-matter lesions, and severe subcortical white-matter grade. Neuroimaging variables did not predict incident depression among those who were nondepressive at the time of MRI. Persistence of depressive symptoms across 2 consecutive time points was associated with small basal ganglia lesions and large cerebral cortical white-matter lesions. Worsening of depression (increase in CES-D score of ≥5) was associated with subcortical white-matter lesions.
Conclusions— These findings suggest that cerebrovascular disease at baseline is related to depression symptoms over time. Further studies are needed to investigate the differential effects of subcortical white- versus gray-matter lesions on mood.
The relationship between cerebrovascular disease and depressive symptoms has been well documented. In clinical studies of depressed individuals1–3⇓⇓ and in larger population studies,4,5⇓ vascular changes, particularly subcortical white- and gray-matter lesions visualized on MRI, are associated with worse depressive symptoms. Recognition of these findings has led investigators to propose the term vascular depression to describe a clinical subtype of major depression characterized by apathy, psychomotor changes, and cognitive impairment in the presence of cerebrovascular disease demonstrated on neuroimaging or by focal neurological findings (eg, mild hemiplegia, facial droop).6,7⇓
Other studies have examined longitudinal outcomes of individuals with cerebrovascular disease. Nondepressed older adults experienced a significant increase in cerebral white-matter and basal ganglia hyperintensities over a 5-year period.8 Studies of clinical populations of older depressed patients have shown that the presence of subcortical white- and gray-matter hyperintensities is associated with poor short-term response to antidepressant treatment1,2,9–11⇓⇓⇓⇓ and to electroconvulsive therapy.12 In longer-term studies, depressed patients with subcortical hyperintensities are at greater risk for chronic depression and cognitive decline13 and for later dementia.14 Less clear is the relationship between subcortical hyperintensities and longitudinal changes in depressive symptoms in community populations.
The Cardiovascular Health Study (CHS) is a population-based study of cardiovascular disease in people ≥65 years of age. Using data from the CHS, we sought to examine the association between baseline MRI lesions and depressive symptoms measured longitudinally. In particular, we sought to use this large database to determine whether baseline structural brain disease is associated with persistence of depression symptoms, worsening of depression symptoms, and occurrence of new severe depressive symptoms over several years. We examined these relationships while controlling for demographic, clinical, and functional status variables that may influence the reporting of depressive symptoms.
The original CHS cohort consisted of 5201 subjects ≥65 years of age who were recruited from a random sample of Health Care Financing Administration Medicare eligibility lists between 1989 and 1990 in 4 communities across the country: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh (Allegheny County), Pennsylvania. In 1992 and 1993, an additional 687 black participants were recruited from the centers in Pennsylvania, California, and North Carolina, bringing the total CHS cohort to 5888 subjects. Details regarding the CHS study design and characteristics of the original CHS cohort have been published previously.15,16⇓ All eligible participants had to be ≥65 years of age, able to give informed consent, and able to respond to questions without a proxy respondent. Potential respondents who were wheelchair bound at home, institutionalized, or undergoing cancer treatment at baseline were excluded. Among the eligible participants, 58% agreed to enroll in the study and undergo baseline evaluation. Participants who enrolled in the study were more likely to be younger, were more educated, and were more likely to be married than nonparticipants.15,16⇓ The present analyses included 3236 subjects who agreed to have an MRI brain scan in 1991 to 1994 (see MRI Procedure section).
Depression was assessed with the shortened (10-item) version of the Centers for Epidemiologic Studies Depression (CES-D) scale.17 As with the full CES-D, the shortened version is a self-report measure of depressive symptoms experienced in the past week and as such is not a diagnostic instrument. Its 10 items are coded on a scale of 0 to 3 points for a maximum of 30 points and focus on mood (5 items), level of irritability (1 item), energy level (2 items), concentration (1 item), and sleep (1 item). Higher score indicates greater depressive symptoms. The CES-D was obtained annually through June 30, 1997. The number of individuals with modified CES-D data at each of 8 years of ascertainment beginning in 1989 to 1990 was 5192, 4896, 4652, 5065, 4600, 4390, 4297, and 3884.
The CES-D score obtained closest to the MRI scan was chosen as the baseline score for each individual. This version has been shown to capture depression well in older adults enrolled in a health maintenance organization18 and in clinical populations of patients with mood disorders.19 These studies used cutoffs of 10 and 4, respectively, for clinically significant depression. Its use in longitudinal studies has been more limited, with 1 study demonstrating a strong correlation between depressive symptoms at baseline and at 12-month follow-up.18 For the present study, we used a cutoff score of >7 as our proxy for depression. This score was chosen on the basis of cutoff scores used in these previous studies and because this score represented the top quartile of depression symptoms, a strategy used in our previous CHS depression study.4 We defined an increase of ≥5 from baseline CES-D as representing meaningful worsening of depression symptoms, a choice based largely on clinical grounds given the lack of longitudinal data with this instrument.
Functional and Cognitive Assessment
Functional impairment was assessed by subjects’ self-report of ability to perform tasks included in activities of daily living (ADL) and instrumental ADL (IADL). A modified version of the Health Interview Survey Supplement on Aging questionnaire was used to assess both ADL and IADL.20 The ADL section assessed ability to bathe, dress, feed, and toilet oneself, as well as locomotion and continence.21 The IADL section assessed the ability to use a telephone, shop, prepare food, perform light household work, perform heavy household work, and handle finances.22 The Modified Mini-Mental State Examination (3 MS)23 was used to measure cognitive status. The 3 MS expands on the original Folstein et al24 Modified Mini-Mental State Examination and evaluates a broader array of cognitive functions and a wider range of difficulty levels on an objective scale of 0 to 100. The 3 MS includes tests of orientation, registration, attention, calculation, recall, language, and visual-spatial skills.
Other Clinical Variables
Presence of hypertension was determined by taking seated resting blood pressure measurements at the clinic visit following a standardized protocol and by ascertaining history of hypertension and antihypertensive medication use. Subjects were classified as hypertensive if systolic blood pressure was ≥160 mm Hg or diastolic was ≥95 mm Hg or if they reported a history of hypertension and were on antihypertensive medication. Subjects were classified as borderline hypertensive if systolic blood pressure ranged between 140 and 159 mm Hg or diastolic blood pressure ranged between 90 and 94 mm Hg. Subjects were classified as normotensive if systolic blood pressure was <140 mm Hg, diastolic blood pressure was <90 mm Hg, and there was no reported history of hypertension. Subjects were asked whether they had coronary heart disease or had ever had a myocardial infarction. Medical records were obtained, and the information was evaluated by a physician panel using standard criteria to detect cardiovascular disease events.25,26⇓ Coronary heart disease was included as present if there was reported and confirmed myocardial infarction, reported and confirmed angina, and/or prior coronary revascularization procedures.27 Age at the time of the MRI was also provided. Educational achievement was recorded at study entry. Any current use of tricyclic or nontricyclic antidepressants medications was documented.
Apolipoprotein E Genotype
Informed consent was obtained for preparation of DNA for genetic testing. Of the 3236 individuals in the present analysis, 164 did not consent to testing for genes “such as apolipoprotein E (apoE)” relevant to cardiovascular-related outcomes. These individuals were included in the present analyses, but their apoE genotypes were considered unknown. With the use of a standardized method previously described,28 a usable apoE genotype was obtained in 2942 individuals for the present analyses.
As part of the extended CHS follow-up protocol, all members of the cohort were invited to have cranial MRI scans during year 4, 5, or 6 of the study, and of the 80% who agreed to do so, 95% successfully completed the examinations.27,29⇓ Study participants without contraindication to MRI scanning (ie, metallic or electrical implants) who were able to tolerate the procedure underwent the standardized imaging protocol. MRI scans were performed with 1.5-T scanners at 3 field centers and a 0.35-T instrument at the fourth field center using acquisition sequences previously reported.27 The MRI scans were reviewed by trained readers blinded to clinical data. For lesions >3 mm, the κ statistics were 0.71 and 0.78 for the intrareader and interreader reliability, respectively.29
A white-matter lesion severity score was determined by grading the extent of increased white-matter signal intensity on the spin density images in the periventricular and subcortical white-matter area. The grading was on a 10-point scale from 0 to 9, with a higher score indicating more severe white-matter grade.30,31⇓
Lesions in cortical areas and basal ganglia were also examined. They were included if they were focal, nonmass lesions having a vascular pattern and were hyperintense to gray matter on both SD- and T2-weighted images.30 Previous CHS publications have called these lesions infarctlike lesions.30,32⇓ Cortical lesions were included if they were located in frontal, parietal, temporal, or occipital cortical areas. Basal ganglia lesions were included in the caudate nucleus, lentiform nucleus, internal capsule, and thalamus.
The analytic measures of interest were the relative risks of depressive symptoms associated with the presence of basal ganglia lesions, cerebral cortical or subcortical white-matter lesions, and white-matter grade determined by MRI. Logistic regression was used to estimate these relative risks by calculating odds ratios (ORs) and 95% confidence intervals (95% CIs) while adjusting for potential confounding variables. Depressive symptoms were modeled as the outcome variable in several ways: (1) “ever” depression, defined as any occurrence of CES-D score >7 (selected for reasons cited above); (2) “incident” depression, defined as any new occurrence of CES-D score >7 among individuals who had CES-D score ≤7 at baseline; (3) persistence, defined as at least 2 consecutive CES-D scores >7; and (4) increase in depressive symptoms, defined as at least a 5-point increase in CES-D score during follow-up (again, based largely on clinical assumptions). The primary predictor variables in separate models were basal ganglia lesions, subcortical white-matter lesions, cerebral cortical white-matter lesions “each coded by size (small, <3 mm; large, ≥3 mm) and number of lesions”, and white-matter grade (ordinal variable on a scale of 0 to 9).
The following covariates were included in the logistic regression models to control for potential confounding and to evaluate their independent effects on depressive symptoms: age in years at time of MRI (65 to 70, 70 to 74, 75 to 79, 80 to 94 years), sex, race (white, nonwhite), education (did not complete high school, completed high school but did not attend college, attended college, unknown), 3 MS score (linear variable, 0 to 100), ADL score (0, 1, 2, 3 to 6, unknown), IADL score (0, 1, 2, 3 to 6, unknown), coronary heart disease (yes, no), hypertension (none, probable, definite), any current use of antidepressant medication (yes, no), and apoE genotype (ε4 homozygous, ε4 heterozygous, no ε4 allele, genotype unknown).
CES-D scores across 5 waves of ascertainment are presented in the Figure. The depression scores over time are grouped according to 3 levels of white-matter grade obtained at baseline. As can be seen, depression scores are associated slightly with white-matter grade and more strongly with time (ie, age) for each stratum of baseline white-matter grade.
Table 1 demonstrates that compared with those whose scores were never >7 (“never depression”), subjects who had CES-D scores >7 at any time during follow-up (“ever depression”) were more likely to be older (P<0.0001), female (P<0.0001), and black (P=0.0001); to use antidepressant medication (P<0.0001); and to have less education (P<0.0001), a lower 3 MS score (P<0.0001), and impairments in basic ADL (P=0.09) and IADL (P=0.17). Those with ever depression had more coronary heart disease (P=0.03) and hypertension (P=0.03) than individuals with never depression. The distribution of apoE genotype was similar between the 2 groups (P=0.19).
When MRI variables were examined (see Table 2), those with ever depression had more lesions in the cerebral cortical white matter (P=0.03) and more severe white-matter grade (P<0.0001) compared with those with never depression.
A series of logistic regression models suggested a 1.3- to 1.8-fold increased risk of ever depression associated with the presence of any large cerebral cortical white-matter lesion, ≥3 small basal ganglia lesions, or greater severity of white-matter grade (ie, ≥6) (Table 3).
Further results for basal ganglia lesions (large, small, or any lesions) are presented in Table 4. Using this table, we can examine the relationship between the adjustment variables and ever depression (CES-D score >7). For example, with or without adjustment for the other variables listed, men were only half as likely as women ever to have depression (OR, 0.51; 95% CI, 0.44 to 0.59). In each model, older age, female sex, less education, and lower 3 MS score were significantly associated with ever depression, whereas race, hypertension, and history of coronary heart disease were not. The presence of any small basal ganglia lesions was associated with a 24% increased risk of ever depression, but there was no evidence of association between large basal ganglia lesions and depression. The association with small basal ganglia lesions was nearly significant even after adjustment for clinical variables, apoE genotype, and ADL and IADL scores. The results for any large or small basal ganglia lesion were very similar to the results for large lesions alone.
Table 5 presents the relationship between MRI findings and incidence of, persistence of, and increase in depression symptoms. For individuals whose CES-D scores were ≤7 at baseline, the incidence of depression (defined as new occurrence of CES-D score >7) was not related to any of the MRI variables after adjustment for age, sex, race, education, antidepressant medication use, 3 MS score, hypertension, and history of coronary heart disease. In other words, individuals with lesions at baseline who were not depressed did not tend to become depressed later. Persistence of depression (defined as CES-D >7 at 2 consecutive time points) was significantly associated with the presence of ≥3 small basal ganglia lesions or any large cerebral cortical white-matter lesion. Large basal ganglia lesions, subcortical white-matter lesion, and white-matter grade were not associated with persistence. There was no significant trend for estimated risk of persistent depression by number of small basal ganglia lesions. Clinically significant worsening in depressive symptoms was defined by an increase in CES-D score of ≥5. Subcortical white-matter lesions were associated with worsening of depressive symptoms, but basal ganglia lesions and cerebral cortical white-matter lesions were not. There was a small, nonsignificant association with white-matter grade.
This study reports several important findings that extend results from previous CHS studies that focused on cross-sectional data.4,33⇓ First, there appeared to be an increase in depression over time that was related to severity of white-matter lesions. Large cortical white-matter lesions, severe subcortical white-matter grade, and small lesions in the basal ganglia are each associated with an occurrence of depressive symptoms (modified CES-D >7) over the course of the study. For ≥3 small basal ganglia lesions, the association remained significant after controlling for age, sex, race, education, antidepressant medication use, 3 MS score, hypertension, coronary heart disease, apoE genotype, and ADL and IADL scores. Baseline neuroimaging variables did not predict the incidence of higher depression scores among those who were nondepressive at baseline. Persistence of higher depression scores across 2 consecutive time points was associated with the presence of ≥3 small basal ganglia lesions or any large cerebral cortical white-matter lesion. Worsening of depression (increase in modified CES-D of ≥5) was associated with subcortical white-matter lesions. Because of the number of statistical tests performed, the significance of the observed associations should be interpreted with caution and confirmed in other study populations.
These results are consistent with previous studies in this population. For example, they confirm our report noting an association between depressive symptoms and small basal ganglia lesions.4 The attenuation of the association between white-matter disease and depression symptoms when adjusting for functional impairment is consistent with previous findings of Sato et al.33 As this group observed, functional consequences of cerebrovascular disease may be the causal pathway by which vascular brain lesions are associated with depressive symptomatology.
Left unclear is the basic question of whether vascular brain lesions cause depression in this population. This notion is supported by the independent association of subcortical white-matter grade and small basal ganglia lesions with the occurrence of higher depression symptoms. Yet the lack of association between lesion variables and occurrence of new depression is interesting and suggests that vascular changes observed at the time of baseline MRI have exerted their effect on mood by the time of initial assessment. Clearly, longitudinal neuroimaging studies are needed to examine the relationship between incident vascular change and depression so that the time course of lesions and emergence of mood symptoms can be examined more precisely. In addition, our observation that individuals with lesions at baseline who were not depressed did not tend to become depressed later raises the question as to whether such individuals may have other, protective factors (biological, psychological, or social) that insulate them from depression. Future studies should address this possibility. Finally, the lack of depression instruments shown to track change in symptoms in this study limits our ability to fully answer questions about incident depression.
Persistence of depressive symptoms, on the other hand, does appear to be related to baseline cerebrovascular disease. Here, the areas of interest are the basal ganglia (small lesions) and cerebral white matter (large lesions). There is well-established literature on cortical stroke and depression,34,35⇓ with particular focus on laterality of findings.36 In addition, there have been reports of depressive symptoms occurring in association with basal ganglia stroke,37 especially in the caudate.38 In studies of patients treated with antidepressant medication or electroconvulsive therapy, persistence of depressive symptoms has been associated with the presence of basal ganglia lesions.12,39⇓ Thus, our finding that the persistence of higher CES-D scores was associated with having ≥3 small basal ganglia lesions or, to a nearly significant degree (OR, 1.20; 95% CI, 0.95 to 1.53), having any small basal ganglia lesion is supported in the literature on both stroke and “silent” vascular change.
Another interesting finding in the study is the association between subcortical white-matter disease and worsening depression, defined as an increase in CES-D score of ≥5. This was seen in subcortical white matter for any lesion, any large lesion, and to a nearly significant degree (OR, 1.57; 95% CI, 0.86 to 2.88), white-matter grade dichotomized as 0 to 5 versus 6 to 9. This effect is demonstrated in the Figure. Certainly, clinical studies of treatment response indicate that subcortical white-matter lesions are associated with worse outcome,10,11,39⇓⇓ but this is the first report of actual worsening of symptoms associated with such changes and may provide the best evidence that cerebrovascular disease independently causes depression symptoms.
An explanatory model for how vascular lesions and depression symptoms are linked is not fully developed. Hypotheses include disruption of cortico-striato-pallido-thalamo-cortical40 pathways thought to be important for maintenance of normal mood and appetitive states. Disrupted neural connections between the prefrontal cortex and striatum may be especially salient for development of depression.41
Potential limitations of the study deserve acknowledgment. Because the CHS primarily assessed cardiovascular disease in older adults, neither extensive psychiatric history nor interviews were obtained. The primary outcome variable is reported depressive symptoms, but there is no information to place them in a clinical context. Thus, we do not know if these results necessarily can be generalized to clinical populations of depressed patients. This study is further limited by a lack of a detailed neurological examination that might facilitate clinical correlation between MRI variables, functional status, and focal neurological deficit. Another limitation relates to MRI. For this study and our previous report,4 small basal ganglia lesions were found to be especially salient. In the CHS, interreader reliability has been shown to be less for smaller lesions than for larger lesions (κ=0.32 versus 0.78).29
In our previous article, we noted potential limitations of the modified CES-D instrument.4 Briefly, concerns about this CES-D version regarding its sensitivity and specificity for detecting clinically meaningful depression were articulated. Validation of the instrument is still needed, especially in subjects with cognitive impairment. In this study, it is conceivable that a number of subjects would have experienced cognitive decline over the several waves of assessment. As such, lack of validation of the instrument in cognitively impaired individuals may be another potential limitation of the study. Finally, in our study, we used a cutoff score of >7, representing the upper quartile of CES-D scores in this population. Further study is needed to determine the clinical relevance of this cutoff for this 10-item version. Our definition of worsening of depression as an increase in CES-D score of ≥5 is based on clinical impression rather than on established data. Studies are warranted that will examine clinical correlation with specific cutoff scores for worsening, particularly in aging and increasingly medically sick populations such as the CHS. Lack of an established, clinically meaningful CES-D cutoff for the present cohort is a limitation of the study.
Overall, the major strength of this article is its large number of elderly individuals who have undergone complete clinical, cognitive, and imaging assessment. The ability to control for the many variables that affect CES-D score is a clear advantage. These results point to cortical white-matter and subcortical white- and gray-matter vascular changes as being important in the occurrence and course of depressive symptoms over time. They also raise questions about the differential effects of lesion location that future clinical, imaging, and neuropathological studies should address. As a practical matter of clinical importance, these results further solidify the link between cerebrovascular disease and depression in the elderly. Future efforts should focus on the impact of depression screening by primary care and specialty physicians caring for individuals with risk factors for cerebrovascular disease.
Participating institutions and principal staff of the Cardiovascular Health Study were as follows: Forsyth County, North Carolina: Bowman Gray School of Medicine of Wake Forest University: Gregory L. Burke, Sharon Jackson, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, John Chen, Beverly Tucker; Bowman Gray School of Medicine, EKG Reading Center: Farida Rautaharju, Pentti Rautaharju; Sacrament County, California: University of California, Davis: William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Lawrence Laslett, Marshall Lee, John Robbins, Richard White; Washington County, Maryland: The Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Adrian Dobs, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman; MRI Reading Center, The Johns Hopkins University: R. Nick Bryan, Norman Beauchamp, Carolyn C. Meltzer, Naiyer Iman, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Cynthia Quinn, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue; Allegheny County, Pennsylvania: University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson; Echocardiography Reading Center (baseline), University of California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosake, Nathan Wong; Echocardiography Reading Center (follow-up), Georgetown Medical Center: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb; Ultrasound Reading Center, Geisinger Medical Center: Daniel H. O’Leary, Joseph F. Polak, Laurie Funk; Central Blood Analysis Laboratory, University of Vermont: Edwin Bovill, Elaine Cornell, Mary Cushman, Russell P. Tracy; Respiratory Sciences, University of Arizona, Tucson: Paul Enright; Coordinating Center, University of Washington, Seattle: Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Lynn Shemanski, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Maryann McBurnie, Chuck Spiekerman, Scott Emerson, Cathy Tangen, Priscilla Velentgas; NHLBI Project Office: Robin Boineau, Teri A. Manolio, Peter J. Savage, Patricia Smith.
We acknowledge support from NIMH grants P50 MH60451 and K07 MH01367. The research reported here was supported by contracts N01-HC-85079 through N01-HC-85086 from the National Heart, Lung, and Blood Institute (NHLBI).
- Received December 14, 2001.
- Revision received February 8, 2002.
- Accepted March 7, 2002.
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