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Abstract
Objectives Depression and cognitive impairment are highly prevalent in later life and frequently co-occur. Structural changes in critical brain regions may underlie both conditions. The authors examined associations of infarcts, white-matter lesions (WML) and atrophy at different locations with depressive symptoms and cognitive functioning.
Methods Within the Second Manifestations of Arterial Disease-Memory, Depression and Aging (SMART-Medea) study, cross-sectional analyses were performed in 585 non-demented patients aged ≥50 years with symptomatic atherosclerotic disease. Volumetric measures of WML and atrophy were obtained with 1.5 T MRI; infarcts were rated visually. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (score ≥6). z Scores of executive functioning, memory and processing speed were calculated. Analyses were adjusted for age, sex, education, intelligence, vascular disease, physical functioning and co-occurring brain changes.
Results Depressive symptoms were present in 102 (17%) patients and were associated with poorer memory (B=−0.26, 95% CI −0.47 to −0.06). Large subcortical infarcts and lacunar infarcts in deep white-matter tracts were both associated with depressive symptoms (RR=2.66, 95% CI 1.28 to 5.54; RR=2.02, 95% CI 1.14 to 3.59) and poorer executive functioning and memory. Periventricular WML volume was associated with poorer executive functioning; cortical infarcts in the left hemisphere and media flow region, ventricular volume and cortical atrophy were associated with a slower processing speed.
Conclusion In this sample of non-demented older persons, subcortical infarcts contributed to an increased risk of depressive symptoms as well as cognitive impairment. This depended on location in projecting white-matter tracts, and not on infarct size.
- Atherosclerosis
- MRI
- atrophy
- cerebral infarction
- cognition
- cerebrovascular disease
- depression
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Introduction
Depressive disorders and cognitive impairment are common and disabling conditions in older people. Moreover, depressive symptoms are frequently accompanied by impairment in several cognitive domains,1 which often persists after recovery from a depressive episode.2 The mechanisms underlying this association are not fully understood, but structural cerebral changes, including atrophy and cerebrovascular changes, may contribute to depressive symptoms as well as cognitive impairment in later life.
Location of structural changes in brain regions, involved in the regulation of emotions and cognitive functioning, has received increasing interest as an underlying mechanism in depressive symptoms and cognitive impairment. The ‘vascular depression’ hypothesis has proposed that disruption of frontal–subcortical pathways by small-vessel lesions could predispose to increased vulnerability of late-life depression3 and was based on previous studies associating disruption of frontostriatal pathways with impairment in cognitive and behavioural functions.4 Most neuroradiological studies investigating associations of infarcts, small-vessel lesions or atrophy with depressive symptoms or cognitive functioning, however, only assessed lesion severity, and did not examine the influence of lesion location.5–14 Studies that did, often relied upon small sample sizes15 or limited their investigations to infarcts, white-matter lesions (WML) or atrophy alone.16–18 Also, findings are highly diverse, with some studies emphasising the importance of deep WML and lacunar infarcts in basal ganglia on the risk of depressive symptoms,17 18 and of periventricular WML and lacunar infarcts in the thalamus in predicting poorer cognitive functioning.14 16 19 Others reported contradictory findings 20 21 or no significant associations.22 Further, different cognitive domains were often not distinguished.15 Finally, combining different study results is complicated by the heterogeneity in population characteristics and lesion-rating methods. It would therefore be interesting to examine different lesion types and locations, depressive symptoms and cognitive functioning within one study population.
We examined the extent and location of large- and small-vessel infarcts, WML volume and atrophy, depressive symptoms and functioning in different cognitive domains in patients with symptomatic atherosclerotic disease. We expect that as a result of their vascular burden, these patients are more vulnerable to the presence of cerebrovascular and degenerative changes than the general population. We hypothesised that cerebrovascular lesions in frontal–subcortical pathways would be associated with an increased risk of depressive symptoms and poorer executive functioning, whereas cerebrovascular or atrophic changes in the left hemisphere and parietotemporal regions or thalamus would be associated with poorer memory and processing speed.
Methods
Subjects
The Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study is a prospective cohort study aimed at investigating brain changes on MRI in 1309 independently living patients with symptomatic atherosclerotic disease.23 In brief, between May 2001 and December 2005, all patients newly referred to the University Medical Center Utrecht with manifest coronary artery disease, cerebrovascular disease, peripheral arterial disease or an abdominal aortic aneurysm, and without MR contraindications, were invited to participate. The exclusion criteria were: age ≥80 years at inclusion, diagnosis of a terminal malignancy, not being independent in daily activities (Rankin scale >3), not being sufficiently fluent in Dutch or being referred back to the referring specialist after one visit. During a 1-day visit to our medical centre, physical examination, ultrasonography of the carotid arteries, blood and urine sampling, and MRI of the brain were performed. Risk factors, medical history and functioning were assessed with questionnaires. Neuropsychological testing was introduced in the SMART-MR study in January 2003 and was performed on the same day as the MRI and other investigations.
Between January 2006 and May 2009, all participants still alive were invited for follow-up measurements, including MRI of the brain, neuropsychological testing, physical examination, blood and urine sampling, risk factors, medical history and functioning. In addition, as part of the SMART-Medea (Memory, depression and aging) study, an ancillary study to the SMART-MR study, aimed at investigating brain changes, psychosocial vulnerability and stress factors, depression measurements were added from March 2006. The SMART-MR and SMART-Medea study were approved by the ethics committee of our institution, and written informed consent was obtained from all participants.
In total, 754 of the surviving SMART-MR cohort (61% of n=1238) gave written informed consent and participated at follow-up; 466 persons (38%) refused or did not respond, and 18 persons (1%) were lost to follow-up.
MRI protocol
MR investigations were performed on a 1.5 T whole-body system (Gyroscan ACS-NT, Philips Medical Systems, Best, The Netherlands). The protocol consisted of a transversal T1-weighted gradient-echo sequence (repetition time (TR)/echo time (TE): 235/2 ms), a transversal T2-weighted turbo spin-echo sequence (TR/TE: 2200/11 ms and 2200/100 ms), a transversal T2-weighted fluid-attenuated inversion recovery (FLAIR) sequence (TR/TE/inversion time (TI): 6000/100/2000 ms) and a transversal inversion recovery (IR) sequence (TR/TE/TI: 2900/22/410 ms) (field of view 230×230 mm; matrix size, 180×256; slice thickness, 4.0 mm; slice gap, 0.0 mm; 38 slices).
Brain segmentation
We used the T1-weighted gradient-echo, IR sequence and FLAIR sequence for brain segmentation.24 25 The segmentation program identifies cortical grey matter, white matter, sulcal and ventricular cerebrospinal fluid (CSF), and lesions. Results of the segmentation analysis were visually checked for the presence of infarcts and adapted if necessary to distinguish between WML and infarct volumes. Total brain volume was calculated by summing grey- and white-matter volumes and, if present, WML and infarct volumes. All volumes cranial to the foramen magnum were included. As a result, the total brain volume includes the cerebrum, brainstem and cerebellum. Total intracranial volume (ICV) was calculated by summing total brain volume and sulcal and ventricular CSF volumes.
Infarcts and WML
The whole brain was visually searched for infarcts by a trained investigator and a neuroradiologist. Raters were blinded to patient history and diagnosis. Discrepancies in rating were re-evaluated in a consensus meeting. Infarcts were defined as focal hyperintensities on T2-weighted images of at least 3 mm in diameter. Hyperintensities located in the white matter also had to be hypointense on T1-weighted and FLAIR images in order to distinguish them from WML. Dilated perivascular spaces were distinguished from infarcts based on their location (along perforating or medullary arteries, often symmetrical bilaterally, usually in the lower third of the basal ganglia or centrum semiovale), form (round/oval) and absence of gliosis. Location, flow territory and type were scored for every infarct. Brain infarcts were categorised as cortical infarcts, lacunar infarcts, large subcortical infarcts and infratentorial infarcts. Large subcortical infarcts were >15 mm in size and were not confluent with cortical infarcts. Cortical and large subcortical infarcts were scored in the following locations: left and right hemisphere, and anterior, media and posterior flow regions. We defined lacunar infarcts as infarcts of 3–15 mm in diameter and located in the frontal, parietal, temporal and occipital lobe, corona radiata, internal capsule, semioval center, thalamus or basal ganglia. Infratentorial infarcts were located in the brainstem or cerebellum.
Periventricular lesions were defined as WML adjacent to or within 1 cm of the lateral ventricles. Deep lesions were located in deep white-matter tracts with or without adjoining periventricular lesions. Volumes of periventricular and deep WML were summed to obtain the total WML volume. Volumes of WML were normalised for ICV and expressed as a percentage of ICV.
Brain volumes
All brain volumes (total brain volume, ventricular volume and cortical grey-matter volume) were expressed relative to ICV. Brain parenchymal fraction was used as an indicator for global brain atrophy, and cortical grey matter fraction for cortical brain atrophy.
Depressive symptoms
Depressive symptoms in the past 2 weeks were measured with the Patient Health Questionnaire-9 (PHQ-9),26 which assesses the presence of the nine DSM-IV criteria for major depressive disorder on a four-point scale (total score range 0–27). We used a cut-off score of ≥6 to define the presence of depressive symptoms because two recent studies, one of which was performed in patients with coronary heart disease, showed good performance using this cut-off score (sensitivity 82–83%, specificity 79–82%) in screening for a depressive episode.27 28
History of depressive episodes was based on affirmative answers to one of the two DSM-IV core symptoms of the lifetime depression section in the questionnaire (ever having experienced a depressed mood or loss of interest for at least 14 consecutive days) and the age at which the first depressive episode occurred was assessed. Participants who experienced their first episode at 50 years or older were classified as having a first depressive episode in later life. This cut-off was chosen because of the relatively young age of our sample and because this cut-off was proven to be appropriate in detecting differences between age-of-onset groups in a previous study.29
Neuropsychological assessment
We assessed memory, executive functioning, and processing speed and attention. For each of these three cognitive domains, composite z-scores were computed by averaging the z-scores of all subtests per domain.
Verbal memory was assessed with five consecutive trials of the 15-word learning test (a modification of the Rey Auditory Verbal Learning test).30 Immediate and delayed recall were assessed. Non-verbal memory was assessed with the delayed recall of the Rey–Osterrieth Complex Figure test.31
Executive functioning was assessed using three tests. The visual elevator test (subtest of the Test of Everyday Attention32) is a timed test of 10 trials that measures mental flexibility and shifting of attention. The Brixton Spatial Anticipation test33 was used to assess the capacity to discover logical rules and mental inhibition and flexibility. The total number of errors made was scored. The Verbal Fluency test (letter A, 1 min time frame) was used to assess mental flexibility and employment of strategies. Before calculating the z-scores, the scores of the Visual Elevator test and Brixton Spatial Anticipation test were multiplied by −1, so that lower scores represented poorer performance.
Attention was measured with the Digit Span Forward and Digit Span Backward. In total, there were 16 trials, and the maximum of correct trials was scored. The Symbol substitution test (subtest from the Wechsler Adult Intelligence Scale) was administered to measure processing speed, and the number of correct responses during a 2 min time frame was scored.
Global cognitive functioning was measured with the Mini-Mental State Examination (MMSE).34 Participants with an MMSE score of <27 were examined by a physician who conducted an additional in-house standardised dementia interview and physical examination. The results of these investigations together with the outcome of the neuropsychological testing were discussed in a consensus meeting with a geriatrician to diagnose dementia.
Educational level was divided into eight categories, graded from primary school to academic degree, according to the Dutch educational system. Intelligence was assessed using the validated Dutch Adult Reading Test (DART).35
Other variables
During the visit to the medical centre, an overnight fasting venous blood sample was taken to determine glucose levels. Systolic and diastolic blood pressures (mm Hg) were measured two times with a sphygmomanometer and averaged. Hypertension was defined as a mean systolic blood pressure ≥160 mm Hg, mean diastolic blood pressure ≥95 mm Hg or self-reported antihypertensive drug use. Diabetes mellitus was defined as history of diabetes mellitus, glucose ≥7.0 mmol/l or self-reported use of oral antidiabetic drugs or insulin. Physical functioning was assessed with the Physical Component Summary scale of the Short Form-12 (SF-12),36 a shortened version of the Short Form-36 (SF-36) Medical Outcomes Study Health Survey.37
Study sample
Of the 754 patients initially included in the follow-up study, we selected all patients aged 50 years or older (n=680). Of these, four had dementia and were excluded. Of the remaining patients, data on MRI variables were missing in 56 patients (no MRI: 40; motion or artefacts: 16). Of these, data on the PHQ-9 questionnaire were missing in six patients, and cognition data were missing in 29 patients (no cognition tests owing to logistical problems: 10; incomplete test data owing to severe cognitive or behavioural impairment; or extreme visual or hearing handicaps: 19). This resulted in an analytical sample of 585 patients.
Data analysis
Depressive symptoms
Log-binomial and Poisson regression models with robust standard errors were used to investigate cross-sectional relationships between presence and location of infarcts, WML volume and atrophy as independent variables, and presence of depressive symptoms as a dependent variable. We estimated relative risks and accompanying CIs38 rather than ORs which overestimate the RR, particularly for outcomes that are common (>10%).39 WML volume (percentage of ICV) and atrophy were entered per SD increase. In model I, associations were adjusted for age, sex and education. We additionally adjusted for hypertension, diabetes mellitus and physical functioning in model II. Because of a possible intercorrelation of MRI variables, we additionally adjusted for co-occurring infarcts and WML in model III. Because brain changes are thought particularly to increase the risk of first onset of depressive symptoms in later life, we repeated all analyses excluding patients with history of a depressive episode before the age of 50.
Cognitive functioning
Linear regression analysis was used to estimate cross-sectional associations of depressive symptoms (PHQ-9 score ≥6) with z-scores of executive functioning, memory and processing speed, because z-scores were continuous outcomes, and assumptions for linear regression were not violated. Associations were adjusted for age, sex, DART score and education in model I. We additionally adjusted for hypertension, diabetes mellitus and physical functioning in model II.
Next, we estimated cross-sectional associations of presence and location of infarcts, WML volume and atrophy with z-scores of executive functioning, memory and processing speed in a similar way. We additionally adjusted for co-occurring infarcts and WML in model III. We chose not to correct for multiple comparisons.40
Results
Of the 585 patients included, 102 (17%) had a PHQ-9 score of ≥6 (table 1). In total, 117 patients (20%) were included in the SMART-MR study at baseline with cerebrovascular disease.
Characteristics of patients 50 years or older with and without depressive symptoms (n=585)
Depressive symptoms
Before distinguishing location, only large subcortical infarcts increased the risk of depressive symptoms (table 2). All subcortical infarcts were located medially, of which five were located in the right and two in the left hemisphere.
Relative risks (RR) of depressive symptoms associated with indicators of cerebral small-vessel and large-vessel disease and global brain atrophy
Lacunar infarcts located in the corona radiata and internal capsule, and cortical infarcts in the anterior flow region were associated with an increased risk of depressive symptoms (figure 1). Associations were attenuated after adjustment for all covariates (RR=2.02, 95% CI 1.14 to 3.59; RR=2.25, 95% CI 0.98 to 5.20), particularly for cortical infarcts (RR=1.89, 95% CI 0.94 to 3.83). Associations with locations of WML and atrophy were not significant (figure 1).
Relative risks of late-life depression, for different locations of lacunar- and cortical infarcts (present vs absent), white-matter lesion (WML) volume and global brain atrophy (per SD increase; adjusted for age, sex and education. Error bars indicate 95% CIs.
Excluding patients with first depressive episode before age 50 (n=169) did not change associations with large subcortical infarcts in models I–III (fully adjusted, RR=4.37, 95% CI 2.30 to 8.29). Lacunar infarcts located in the corona radiata and internal capsule were associated with a similarly increased risk of depressive symptoms in models I–III (fully adjusted, RR=2.04, 95% CI 0.86 to 4.81; RR=4.49, 95% CI 1.65 to 12.21), although the first was no longer statistically significant. Associations with cortical infarcts in the anterior flow region were not significant in models I–III (fully adjusted, RR=1.55, 95% CI 0.61 to 3.94).
Cognitive functioning
The presence of depressive symptoms was significantly associated with poorer memory in models I–II (model II, B=−0.26, 95% CI −0.47 to −0.06), but not with executive functioning (B=−0.09, 95% CI −0.30 to 0.12) or processing speed (B=−0.11, 95% CI −0.30 to 0.08).
The presence of lacunar infarcts and atrophy was significantly associated with worse performance in all domains in models I–II. Associations were attenuated after adjustment for infarcts and WML (model III) and were no longer statistically significant, except for processing speed (table 3). A greater WML volume was significantly associated with poorer executive functioning; presence of large subcortical infarcts with poorer executive functioning and memory; and cortical infarcts with a slower processing speed in models I–III (table 3).
Results of linear regression models with indicators of cerebral small-vessel and large-vessel disease and global brain atrophy as determinants, and z-scores of cognitive domains as outcome variables
When the location was identified, lacunar infarcts in the left hemisphere, corona radiata, semioval center and thalamus were significantly associated with poorer executive functioning and memory in model I (figure 2A,B), and lacunar infarcts located in both hemispheres, frontal lobe, corona radiata and semioval center with a slower processing speed (figure 2C). Adjustment for vascular risk factors and physical functioning did not change these results. Associations attenuated in model III; associations of lacunar infarcts located in the semioval center with poorer executive functioning (B=−0.44, 95% CI −0.73 to −0.15) and processing speed (B=−0.28, 95% CI −0.55 to −0.01), and lacunar infarcts located in the left hemisphere and corona radiata with poorer memory (B=−0.25, 95% CI −0.47 to −0.03; B=−0.35, 95% CI −0.68 to −0.02) remained statistically significant. A greater periventricular WML volume was significantly associated with poorer functioning in all domains and deep WML volume with executive functioning in model I. Only the association of periventricular WML with executive functioning remained significant in model III (B=−0.17, 95% CI −0.25 to −0.09). Cortical infarcts in the anterior flow region were associated with poorer executive functioning; cortical infarcts in the left hemisphere and media flow region, and cortical atrophy with a slower processing speed and a greater ventricular volume with poorer performance in all cognitive domains in model I (figure 2A–C). Only associations of left-sided and media cortical infarcts, ventricular volume and cortical atrophy with a slower processing speed remained significant after adjustment for other infarcts and WML (data not shown).
(A) z Scores of executive functioning for different locations of lacunar and cortical infarcts (present vs absent), white-matter lesion (WML) volume and brain atrophy (per SD increase), adjusted for age, sex, Dutch Adult Reading Test (DART) score and education. Error bars indicate standard errors. *Statistically significant associations. (B). z Scores of memory for different locations of lacunar and cortical infarcts (present vs absent), white-matter lesion (WML) volume and brain atrophy (per SD increase), adjusted for age, sex, DART score and education. Error bars indicate standard errors. *Statistically significant associations. (C). z Scores of processing speed for different locations of lacunar and cortical infarcts (present vs absent), white-matter lesion (WML) volume and brain atrophy (per SD increase), adjusted for age, sex, DART score and education. Error bars indicate standard errors. *Statistically significant associations.
Discussion
In a cohort of non-demented older people with symptomatic atherosclerotic disease, we observed that memory functions were significantly lower in patients with depressive symptoms. As hypothesised, small and large-vessel subcortical infarcts located in projecting deep white-matter tracts were associated with an increased risk of depressive symptoms as well as poorer executive functioning and memory. Periventricular WML volume was associated with poorer executive functioning, but not with depressive symptoms. The finding that cortical infarcts in the left hemisphere and media flow region, and atrophy were associated with a slower processing speed was in line with our second hypothesis.
The main strengths of our study include the extensive information on different types and locations of brain changes on MRI, and the elaborate cognitive test battery, assessing different domains of cognitive functioning. In addition, volumetric MRI measurements enabled more accurate WML and atrophy estimations, and are less influenced by observer bias than visual rating methods.41 Also, associations were adjusted for a variety of potentially important confounders.
Previously, a large community-based study found that lacunar infarcts in the basal ganglia and severe WML were associated with an increased risk of depressive symptoms in later life.17 Another study reported somewhat contradictory findings, suggesting that deep WML, but not lacunar infarcts, were associated with depressive symptoms.18 20 Others could not demonstrate any effect of WML severity or location on depressive symptoms.8 22 Differences in findings between our study and other studies may be explained by differences in the classification of the location of lacunar infarcts. In addition, previous studies often relied upon visual assessment of brain lesions, complicating the comparison of estimates obtained with volumetric methods. Furthermore, most cohort studies included population-based samples, whereas our study sample consisted of patients with symptomatic atherosclerotic disease. The influence of small-vessel changes on depressive symptoms might be attenuated in patients at high vascular risk or with existing atherosclerotic disease. This hypothesis is supported by our finding that adjustment for vascular risk factors attenuated associations of MRI variables with depressive symptoms.
Previously, the strategic location of lacunar infarcts in the basal ganglia and thalamus has been associated with poorer executive functioning and memory in the LADIS study.16 Furthermore, a study in non-disabled older people reported that greater periventricular WML severity was associated with a slower processing speed.19 In contrast, a study in subjects with mild cognitive impairment suggested that only deep WML were associated with poorer executive functioning and processing speed.21 These data suggest that lesion types are differentially associated with poorer performance in specific cognitive domains, and that these associations strongly depend on lesion location. As hypothesised, subcortical infarcts in projecting white-matter tracts were most strongly associated with poorer executive functioning and memory, whereas WML volume was associated with poorer executive functioning only. Cortical infarcts affecting the frontal lobe were also associated with poorer executive functioning, although not statistically significant. Consistent with our hypothesis, cortical infarcts in the parietotemporal flow region were associated with a slower processing speed. Differences in patient characteristics and overall cognitive performance between our study and previous studies could have explained the different findings. Few subjects (1.4%) in our sample scored below the normal range of global cognitive function (MMSE <24).34 Also, the crude scores for immediate and delayed recall, mental flexibility, attention, processing speed and intelligence of our study population were comparable with age- and education-adjusted scores in another study that included independently living men of similar age.42 In this respect, our population had, on average, a normal age-adjusted cognitive performance. Furthermore, most authors din adjust their analysis for co-occurring infarcts or WML. Our data illustrate that some of the findings were explained by other infarcts or WML, emphasising the importance of statistical adjustment for other structural changes. Finally, associations of infarcts with cognitive function could be mediated by the time since lesion onset.14
A limitation of this study is the cross-sectional design, and we therefore do not know whether brain changes contributed directly to depressive symptoms and poorer cognitive functioning. Furthermore, to assess depressive symptoms, a cut-off value of ≥6 on the Patient Health Questionnaire-9 was used, and although this cut-off has been recommended for patients at high vascular risk,27 it could have created a relatively wide range of severity of depressive symptoms in patients classified as having depressive symptoms, resulting in a decreased contrast between patients with and without depressive symptoms. Also, the largest effect of ischaemic infarcts on depressed mood and cognitive function would be expected in patients suffering the most severe strokes. Because these patients are less likely to participate in our study, this could have contributed to a relative underestimation of the effects. In addition, despite the large sample size, the number of infarcts in distinct anatomical locations was limited, thus contributing to relatively wide CIs and possibly to non-significant associations.
In summary, we found that subcortical infarcts contributed to an increased risk of depressive symptoms as well as poorer executive functioning and memory. This depended on the location in deep white-matter tracts, and not on infarct size. Cortical infarcts in parietotemporal regions, WML and atrophy were associated with worse cognitive functioning, but not with depressive symptoms. Longitudinal studies are needed to assess whether cerebral changes contribute directly to the development of depressive symptoms and impaired cognitive functioning.
Acknowledgments
We gratefully acknowledge the members of the SMART Study Group of University Medical Center Utrecht: A Algra, MD PhD, Julius Center for Health Sciences and Primary Care and Rudolf Magnus Institute for Neurosciences, Department of Neurology; PA Doevendans, MD PhD, Department of Cardiology; DE Grobbee, MD PhD and GEHM Rutten, MD PhD, Julius Center for Health Sciences and Primary Care; LJ Kappelle, MD PhD, Department of Neurology; FL Moll, MD PhD, Department of Vascular Surgery; FLJ Visseren, MD PhD, Department of Vascular Medicine. Furthermore, the authors would like to acknowledge Theo Witkamp and Anneloes Vlek for their work on the visual assessment of the MRI scans.
References
Footnotes
Funding This study was supported by a programme grant from The Netherlands Heart Foundation (NHF: project no 2007B027).
Competing interests None.
Ethics approval Ethics approval was provided by the Medical Ethics Committee University Medical Center Utrecht, The Netherlands.
Provenance and peer review Not commissioned; externally peer reviewed.