SMART-MR Study Research Articles

Plasma Alzheimer's disease markers and MRI load of vascular pathology and neurodegeneration: the SMART-MR Study

Plasma Alzheimer's disease markers and MRI load of vascular pathology and neurodegeneration: the SMART-MR Study

Bear in mind: the role of personal background in semantic animal fluency - The SMART-MR study.

Semantic fluency is a prominent neuropsychological task, typically administered within the category 'animals'. With the increasing development of novel item-level metrics of semantic fluency, a concern around the validity of item-level analyses could be that personal background factors (e.g., hobbies like birdwatching or fishing) may disproportionally influence performance. We analyzed animal fluency performance at the item level and investigated the prevalence of individuals with abundant knowledge in specific classes of animals (e.g., birds, fish, insects) and the relationship of such knowledge with personal background factors and other cognitive tasks (episodic memory and executive functioning). Participants included 736 Dutch middle-aged to older adults from the SMART-MR cohort (mean age 58 ± 9.4 years, 18% women). Individuals were asked to name as many animals as possible for 2 min. Number of people with abundant animal class knowledge was calculated for the ability to recall a series of minimum ≥5 and up to ≥15 animals within a specific class with at most one interruption by an animal from another class. Subsequent analyses to investigate relationships of abundant class knowledge with sociodemographic characteristics (t-tests and chi-square tests) and cognitive performance (linear regressions) were performed for a cut-off of ≥10 animals within a specific class (90th percentile), with a sensitivity analysis for ≥7 animals (67th percentile). A total of 416 (56.2%) participants recalled a series of ≥5 animals from a specific class, 245 (33.3%) participants recalled ≥7, 78 (10.6%) participants recalled ≥10, and 8 (1.1%) participants recalled ≥15. Those who recalled a series of at least 10 animals within a class were older, more often men, and more often retired than those who did not. Moreover, they had a higher total score on animal fluency, letter fluency (i.e., executive functioning), and episodic memory tasks compared to those who did not. Our results suggest that the benefit of abundant animal class knowledge gained by personal background does not disproportionally influence animal fluency performance as individuals with such knowledge also performed better on other cognitive tasks unrelated to abundant knowledge of animal classes.

What Drives Task Performance in Animal Fluency in Individuals Without Dementia? The SMART-MR Study.

In this study, we aim to understand whether and how performance in animal fluency (i.e., total correct word count) relates to linguistic levels and/or executive functions by looking at sequence information and item-level metrics (i.e., clusters, switches, and word properties). Seven hundred thirty-one Dutch-speaking individuals without dementia from the Second Manifestations of ARTerial disease-Magnetic Resonance study responded to an animal fluency task (120 s). We obtained cluster size and number of switches for the task, and eight different word properties for each correct word produced. We detected variables that determine total word count with random forests, and used conditional inference trees to assess points along the scales of such variables, at which total word count changes significantly. Number of switches, average cluster size, lexical decision response times, word frequency, and concreteness determined total correct word count in animal fluency. People who produced more correct words produced more switches and bigger clusters. People who produced fewer words produced fewer switches and more frequent words. Concurrent with existing literature, individuals without dementia rely on language and executive functioning to produce words in animal fluency. The novelty of our work is that such results were shown based on a data-driven approach using sequence information and item-level metrics. https://doi.org/10.23641/asha.23713269.

Ischemic stroke recurrence and mortality in different imaging phenotypes of ischemic cerebrovascular disease: The SMART-MR Study.

Diagnosis of cerebrovascular disease is based on both clinical and radiological findings, however, they do not always correlate. To investigate ischemic stroke recurrence and mortality in patients with different imaging phenotypes of ischemic cerebrovascular disease. Within the SMART-MR study, a prospective patient cohort with arterial disease, cerebrovascular diseases of participants at baseline were classified as no cerebrovascular disease (reference group, n = 828), symptomatic cerebrovascular disease (n = 204), covert vascular lesions (n = 156), or imaging negative ischemia (n = 90) based upon clinical and MRI findings. Ischemic strokes and deaths were collected at 6 month-intervals up to 17 years of follow-up. With Cox regression, relationships between phenotype and ischemic stroke recurrence, cardiovascular mortality, and non-vascular mortality were studied adjusted for age, sex, and cardiovascular risk factors. Compared to reference group risk for recurrent ischemic stroke was increased not only in the symptomatic cerebrovascular disease (HR 3.9, 95% CI 2.3-6.6), but also in the covert vascular lesion (HR 2.5, 95% CI 1.3-4.8) and the imaging negative ischemia groups (HR 2.4, 95% CI 1.1-5.5). Risk for cardiovascular mortality was increased in the symptomatic cerebrovascular disease (HR 2.2, 95% CI 1.5-3.2) and covert vascular lesions groups (HR 2.3, 95% CI 1.5-3.4), while the risk was less strong but also increased in the imaging negative ischemia group (HR 1.7, 95% CI 0.9-3.0). People with all imaging phenotypes of cerebrovascular disease have increased risk of recurrent ischemic stroke and mortality compared to other arterial diseases. Strict preventive measures should be performed even when imaging findings or clinical symptoms are absent. For use of anonymized data, a reasonable request has to be made in writing to the UCC-SMART study group and the third party has to sign a confidentiality agreement.

Carotid Artery Stenosis and Progression of Hemispheric Brain Atrophy: The SMART-MR Study

Introduction: It has been hypothesized that carotid artery stenosis (CAS) may lead to greater atrophy of subserved brain regions; however, prospective studies on the impact of CAS on progression of hemispheric brain atrophy are lacking. We examined the association between CAS and progression of hemispheric brain atrophy. Methods: We included 654 patients (57 ± 9 years) of the SMART-MR study, a prospective cohort study of patients with manifest arterial disease. Patients had baseline CAS duplex measurements and a 1.5T brain MRI at baseline and after 4 years of follow-up. Mean change in hemispheric brain volumes (% of intracranial volume [ICV]) was estimated between baseline and follow-up for left-sided and right-sided CAS across three degrees of stenosis (mild [≤29%], moderate [30–69%], and severe [≥70%]), adjusting for demographics, cerebrovascular risk factors, and brain infarcts. Results: Mean decrease in left and right hemispheric brain volumes was 1.15% ICV and 0.82% ICV, respectively, over 4 years of follow-up. Severe right-sided CAS, compared to mild CAS, was associated with a greater decrease in volume of the left hemisphere (B = −0.49% ICV, 95% CI: −0.86 to −0.13) and more profoundly of the right hemisphere (B = −0.90% ICV, 95% CI: −1.27 to −0.54). This pattern was independent of cerebrovascular risk factors, brain infarcts, and white matter hyperintensities on MRI, and was also observed when accounting for the presence of severe bilateral CAS. Increasing degrees of left-sided CAS, however, was not associated with greater volume loss of the left or right hemisphere. Conclusions: Our data indicate that severe (≥70%) CAS could represent a risk factor for greater ipsilateral brain volume loss, independent of cerebrovascular risk factors, brain infarcts, or white matter hyperintensities on MRI. Further longitudinal studies in other cohorts are warranted to confirm this novel finding.

White matter hyperintensity shape is associated with cognitive functioning – the SMART-MR study

White matter hyperintensity (WMH) shape has been associated with the severity of the underlying brain pathology, suggesting it is a potential neuroimaging marker of WMH impact on brain function.In 563 patients with vascular disease (58 ± 10 years), we examined the relationship between WMH volume, shape, and cognitive functioning. WMH volume and shape were automatically determined on 1.5T brain MRI data. Standardized linear regression analyses estimated the association between WMH volume and shape (concavity index, solidity, convexity, fractal dimension, and eccentricity) and memory and executive functioning, adjusted for age, sex, educational level, and reading ability.Larger WMH volumes were associated with lower executive functioning Z-scores (b (95%-CI): -0.09 (-0.17;-0.01)). Increased shape complexity of periventricular/confluent WMH associated with lower executive functioning (concavity index +1SD: -0.13 (-0.20;-0.06); solidity -1SD: -0.09 (-0.17;-0.02)) and lower memory function (fractal dimension +1SD: -0.10 (-0.18;-0.02)). Of note, the association between concavity index and executive functioning was independent of WMH volume (-0.12 (-0.19;-0.04)).Our results suggest that WMH shape contains additional information about WMH burden, not otherwise captured by WMH volume.

The role of cognitive and brain reserve in memory decline and atrophy rate in mid and late-life: The SMART-MR study

ObjectiveInvestigate associations of cognitive and brain reserve with trajectories of memory decline in mid-life and late-life, and whether the relationship of memory decline with atrophy differs as a function of reserve. MethodsParticipants were 989 Dutch middle-aged to older adults from the SMART-MR prospective cohort, followed up to 12 years with up to 3 measurements of memory and brain MRI. Education and Dutch National Adult Reading Test (DART) were used as proxies of cognitive reserve, and intracranial volume (ICV) and baseline brain parenchymal fraction (BPF) for brain reserve. Univariate growth curve models analyzed associations of reserve with memory decline, and multiple-group bivariate growth curve models tested the longitudinal brain–memory relationship as a function of reserve. Models were additionally stratified by mid-life and late-life. ResultsHigher DART, education, and BPF were related to a slower rate of memory decline, particularly in late-life, but ICV was not. A positive covariance indicated that an individual who undergoes atrophy also undergoes memory decline—this relationship did not differ across cognitive or brain reserve, but was not present in mid-life. Memory declined slower than brain volume, yet rates were more similar in the low DART, education, and BPF groups. DiscussionHigher cognitive (DART, education) and brain reserve (BPF) work protectively in longitudinal memory change. ICV is an inappropriate proxy of brain reserve, failing to show any association with memory performance at baseline or over time. Deconstructing relationships of reserve capacities with longitudinal cognitive and brain outcomes may identify focus areas with potential for intervention.

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions—a neuroimaging marker of ICAS—and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden—defined as the number of vessel wall lesions—was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12–2.43), lacunes (RR = 1.45; 95% CI: 1.14–1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13–1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02–0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: –0.23 to –0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: –0.29 to –0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (p = 0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (p = 0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.

Intracranial Vessel Wall Lesions on 7T MRI (Magnetic Resonance Imaging).

Background and Purpose- Intracranial vessel wall lesions are a novel imaging marker of intracranial atherosclerosis (ICAS), but data on their occurrence and risk factors are lacking. Our aim was to study the frequency, distribution, and risk factors of intracranial vessel wall lesions on 7T magnetic resonance imaging in patients with a history of vascular disease. Methods- Within the SMART-MR study (Second Manifestations of Arterial Disease-Magnetic Resonance), cross-sectional analyses were performed in 130 patients (68±9 years) with assessable 7T intracranial vessel wall-magnetic resonance imaging data. Associations between vascular risk factors and ICAS burden, defined as the total number of vessel wall lesions, were estimated using linear regression analyses with ICAS burden as the dependent variable, adjusted for age and sex. Results- Ninety-six percent of patients had ≥1 vessel wall lesion. The mean±SD (range) ICAS burden was 8.5±5.7 (0-32) lesions. Significant associations were found between ICAS burden and age ( b=2.0 per +10 years; 95% CI, 0.81- 3.10), systolic blood pressure ( b=0.9 per +10 mm Hg; 95% CI, 0.27-1.42), diabetes mellitus ( b=3.2 for presence of diabetes mellitus; 95% CI, 0.79-5.72), hemoglobin A1c level ( b=1.2 per +1%; 95% CI, 0.19-2.26), apoB (apolipoprotein-B) ( b=4.7 per +1 g/L; 95% CI, 0.07-9.35), and hs-CRP (high-sensitivity C-reactive protein) level ( b=2.7 for hs-CRP >3 mg/L; 95% CI, 0.22-5.11). No significant associations were found with sex, smoking, and other lipid-factors. Conclusions- Vessel wall lesions are a novel and direct magnetic resonance imaging marker of ICAS. In this cohort, 96% of patients had at least 1 lesion on 7T vessel wall-magnetic resonance imaging. More lesions were found with older age, higher systolic blood pressure, diabetes mellitus, and higher levels of hemoglobin A1c, apoB, and hs-CRP.

The association between lacunes and white matter hyperintensity features on MRI: The SMART-MR study

Lacunes and white matter hyperintensities (WMHs) are features of cerebral small vessel disease (CSVD) that are associated with poor functional outcomes. However, how the two are related remains unclear. In this study, we examined the association between lacunes and several WMH features in patients with a history of vascular disease. A total of 999 patients (mean age 59 ± 10 years) with a 1.5 T brain magnetic resonance imaging (MRI) scan were included from the SMART-MR study. Lacunes were scored visually and WMH features (volume, subtype and shape) were automatically determined. Analyses consisted of linear and Poisson regression adjusted for age, sex, and total intracranial volume (ICV). Patients with lacunes (n = 188; 19%) had greater total (B = 1.03, 95% CI: 0.86 to 1.21), periventricular/confluent (B = 1.08, 95% CI: 0.89 to 1.27), and deep (B = 0.71, 95% CI: 0.44 to 0.97) natural log-transformed WMH volumes than patients without lacunes. Patients with lacunes had an increased risk of confluent type WMHs (RR = 2.41, 95% CI: 1.98 to 2.92) and deep WMHs (RR = 1.41, 95% CI: 1.22 to 1.62) and had a more irregular shape of confluent WMHs than patients without lacunes, independent of total WMH volume. In conclusion, we found that lacunes on MRI were associated with WMH features that correspond to more severe small vessel changes, mortality, and poor functional outcomes.

SIDEDNESS OF CAROTID ARTERY STENOSIS AND BRAIN VOLUME LOSS IN THE LEFT AND RIGHT HEMISPHERE: THE SMART-MR STUDY

Previous studies found an association between carotid stenosis degree and progression of brain atrophy, however no study reported on the relationship between sidedness of carotid stenosis and brain volume in the left and right hemispheres. We assessed the association between carotid stenosis side and changes in cerebral hemispheric volumes in patients with vascular disease. Within the SMART-MR study 1.5tesla MRI was performed in 1232 patients at baseline (mean age 58±10 years) and 663 after 4 years of follow-up. Carotid artery stenosis duplex measurements were performed at baseline and stenosis was defined at the cutpoint of 70%. Automated brain segmentation was used to quantify brain volumes and CSF. Volumes of the left and right hemispheres were calculated using the midsagittal surface. Using ANCOVA mean volume at baseline and mean change in volume between baseline and follow-up of the left and right hemisphere was estimated across 4 groups: no stenosis; left-sided stenosis only; right-sided stenosis only; bilateral stenosis adjusting for age and sex. In the total sample, brain volume (BV) of the left hemisphere was smaller than the right hemisphere (mean difference -1.06 %ICV; 95% CI -1.13 to -1.00) but this difference did not increase with age. Cross-sectionally, compared to participants without stenosis, those with left-sided stenosis had significantly smaller volume of the left but not the right hemisphere. However, right-sided stenosis was associated with smaller volumes of both hemispheres (Figure 1A). Similarly, in the longitudinal analysis a significant decrease in volume of both hemispheres was found in participants with right-sided stenosis, but not for left-sided stenosis (Figure 1B). In this population, as opposed to left-sided stenosis, right-sided stenosis results in brain volume reduction in both hemispheres. Studies should investigate whether other factors may explain this association or whether brain hemispheres have differential vulnerability to risk factors with aging. Left and right brain volumes in 4 groups: without carotid stenosis, left-sided stenosis, right-sided stenosis and bilateral stenosis. Bars represent mean (standard error) BV as % ICV. * p < 0.05 for difference in BV compared to corresponding hemisphere of the group without carotid stenosis (mean difference left hemisphere in left-sided stenosis -0.86 %lCV; 95% Cl -1.55 to -0.17, right hemisphere in right-sided stenosis -1.28 %ICV; 95% CI -1.90 to -0.67). Δp = 0.06 for difference in BV compared to the left hemisphere of the group without carotid stenosis (mean difference -0.60 %lCV; 95% Cl -1.22 to 0.03). lCV = intracranial volume. Longitudinal association between carotid stenosis groups and change in BV. Bars represent mean (standard error) change in BV as % ICV after a mean 3.9 years of follow-up. * p < 0.05 for decrease in BV compared to corresponding hemisphere of the group without carotid stenosis (mean difference left hemisphere in right-sided stenosis -0.45 %ICV; 95% CI -0.86 to -0.03, right hemisphere in right-sided stenosis -0.95 %ICV; 95%CI -1.37 to -0.53, left hemisphere in bilateral stenosis -0.81 %ICV; 95% CI -1.36 to -0.29, right hemisphere in bilateral stenosis -0.62 %ICV; 95% CI -1.16 to -0.09). ICV = intracranial volume.

DISPROPORTIONATE INCREASE IN VENTRICULAR RELATIVE TO SULCAL CEREBROSPINAL FLUID VOLUME AND COGNITIVE FUNCTIONING: THE SMART-MR STUDY

Global cerebral volume loss is associated with neurodegenerative diseases but also with normal aging. To understand their etiology studies aim to pinpoint specific brain tissue regions that are affected early in the disease process or investigate disproportionate volume loss of specific brain tissue regions. Here, we take a different perspective by examining the disproportionate increase in ventricular relative to sulcal cerebrospinal fluid (CSF) and the association with age and cognitive functioning. Within the SMART-MR study a 1.5T MRI was performed in 1232 patients with vascular disease (mean age 58±10 years, 80% male). Automated brain segmentation was used to quantify brain tissue volumes, CSF and lesions. The ventricular-sulcal CSF (VS) ratio was calculated by dividing ventricular volume by sulcal CSF volume. Z-scores for the domains memory and executive functioning were calculated. Multiple linear regression analysis was used to estimate the associations of VS ratio with age and with memory performance and executive functioning. The mean ventricular and sulcal CSF volumes were 31±15ml and 276±43ml, respectively. The VS ratio was 0.11±0.05. Pearson correlation coefficients between the natural log-transformed VS ratio and total brain volume, intracranial volume, brain parenchymal fraction, log-deep WMH, log-periventricular WMH, and age were 0.02 (p=0.52), 0.18, -0.40, 0.21, 0.33, and 0.35, respectively (p-values <0.0001). The VS ratio increased with older age (p<0.0001) independent of sex, total WMH, and ICV. It was also significantly associated with poorer memory performance (b of Z-score=-1.29; 95% CI -2.41 to -0.17) and poorer executive functioning (b of Z-score=-1.72; 95% CI -2.78 to -0.67), adjusted for age, sex, log-WMH, and ICV. In this population, a disproportionate increase in ventricular volume relative to sulcal CSF is associated with older age and with poorer memory and executive functioning. Future studies should investigate to what extent this is a biomarker of accelerated cognitive aging.

Detection and characterization of small infarcts in the caudate nucleus on 7 Tesla MRI: The SMART-MR study

Small infarcts are among the key imaging features of cerebral small vessel disease (CSVD), but remain largely undetected on conventional MRI. We aimed to evaluate (1) imaging criteria for the detection of small infarcts in the caudate nucleus on 7T MRI, (2) intra- and inter-rater agreement, (3) frequency and (4) detection rate on 7T versus 1.5T MRI. In 90 patients (68 ± 8 years) with a history of vascular disease from the SMART-MR study, we defined 7T imaging criteria for cavitated and non-cavitated small infarcts in the caudate nucleus. In a separate set of 23 patients from the SMART study, intra-rater and inter-rater agreement was excellent for presence, number, and individual locations (Kappa’s, ICCs, and Dice similarity coefficients ranged from 0.85 to 1.00). In the 90 patients, 21 infarcts (20 cavitated) in 12 patients were detected on 7T (13%) compared to 7 infarcts in 6 patients on 1.5T (7%). In conclusion, we established reproducible imaging criteria for the detection of small infarcts in the caudate nucleus on 7T MRI and showed that 7T MRI allows for a higher detection rate than conventional 1.5T MRI. These imaging criteria can be used in future studies to provide new insights into the pathophysiology of CSVD.

Cognitive performance and the course of depressive symptoms over 7 years of follow-up: the SMART-MR study.

Depressive symptoms and cognitive impairment often co-occur, but their interactive relationship is complex and the direction of causation is still a topic of research. We examined the influence of cognitive performance on the course of depressive symptoms during 7 years of follow-up in patients with vascular disease. Within the SMART-MR study, 736 patients (mean age 62 ± 10 years) had neuropsychological assessment on four cognitive domains at baseline [memory (MEM), working memory (WMEM), executive functioning (EXEC), and information processing speed (SPEED)]. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) at baseline and every 6 months during 7 years of follow-up. Generalized Estimating Equation (GEE) models were used to assess the association between cognitive performance with depressive symptoms at multiple time points during follow-up. Interaction terms between the respective cognitive domains and time was included to examine if the course of depressive symptoms differed according to baseline cognitive performance. The GEE analyses showed no significant interactions between the respective cognitive domains and time indicating no different course of depressive symptoms according to baseline cognitive performance. Lower MEM, EXEC or SPEED, but not WMEM performance, was significantly associated with more depressive symptoms during follow-up per z score decrease: MEM [B = 0.70, 95% confidence interval (CI) 0.35-1.05]; EXEC (B = 0.88, 95% CI 0.41-1.36), and SPEED (B = 0.57, 95% CI 0.21-0.92). Poorer cognitive performance on the domains MEM, EXEC and SPEED, but not WMEM, was associated with higher levels of depressive symptoms over 7 years of follow-up, but not with a different course of depressive symptoms over time.

Metabolic syndrome, prediabetes, and brain abnormalities on mri in patients with manifest arterial disease: the SMART-MR study.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors leading to atherosclerosis and diabetes. Diabetes is associated with both structural and functional abnormalities of the brain. MetS, even before diabetes is diagnosed, may also predispose to cerebral changes, probably through shared mechanisms. We examined the association of MetS with cerebral changes in patients with manifest arterial disease. Cross-sectional data on MetS and brain MRI were available in 1,232 participants with manifest arterial disease (age 58.6 ± 10.1 years; 37% MetS). Volumes of brain tissue, ventricles, and white matter hyperintensities (WMH) were obtained by automated segmentation and expressed relative to intracranial volume. Infarcts were distinguished into lacunar and nonlacunar infarcts. The presence of MetS (n = 451) was associated with smaller brain tissue volume (B -0.72% [95% CI -0.97, -0.47]), even in the subgroup of patients without diabetes (B -0.42% [95% CI -0.71, -0.13]). MetS was not associated with an increased occurrence of WMH or cerebral infarcts. Impaired glucose metabolism, abdominal obesity, and elevated triglycerides were individual components associated with smaller brain volume. Obesity and hypertriglyceridemia remained associated with smaller brain volume when patients with diabetes were excluded. Hypertension was associated with an increased occurrence of WMH and infarcts. In patients with manifest arterial disease, presence of MetS is associated with smaller brain volume, even in patients without diabetes. Screening for MetS and treatment of its individual components, in particular, hyperglycemia, hypertriglyceridemia, and obesity, may prevent progression of cognitive aging in patients with MetS, even in a prediabetic stage.

COGNITIVE PERFORMANCE AND THE TEMPORAL COURSE OF DEPRESSIVE SYMPTOMS OVER SEVEN YEARS' FOLLOW-UP: THE SMART-MR STUDY

Depressive symptoms frequently occur in patients with cognitive decline and Alzheimer's dementia, but their interactive relationship is complex and the direction of causation is still a topic of research. We examined the temporal course between cognitive performance at baseline and biannually assessed depressive symptoms over seven years of follow-up in non-demented patients with symptomatic atherosclerotic disease. We used data of 736 patients (mean age 62±10 years; 82% male) of the SMART-MR study with neuropsychological assessment on four cognitive domains at baseline and at least one measurement of depressive symptoms. Depressive symptoms were assessed with the Patient Health Questionnaire-9 at baseline and biannually during seven years of follow-up. The PHQ-9 assesses presence of the nine DSM-IV symptoms for major depressive disorder in the past 2 weeks. GEE models, adjusted for age, sex, educational level and DART-score, were used to assess the association between baseline cognitive performance (on the domains memory (MEM), working memory (WMEM), executive functioning (EXEC), and information processing speed (SPEED)) with depressive symptoms at multiple time points during follow-up. An interaction term between the respective cognitive domains and time as dummy variable for each time point was included to examine the temporal relationship. Median (10th-90th percentile) score on the PHQ-9 was 2 (0-8) at baseline and the overall response on the repeated PHQ-9 assessments varied between 86% and 97%. Because GEE analyses showed no significant interactions between the respective cognitive domains and time (interaction p-value MEM=0.79; WMEM=0.89; EXEC=0.52; SPEED=0.65) we repeated the analyses without the interaction terms. These analyses showed that a z-score decrease in MEM, EXEC or SPEED, but not WMEM, was significantly associated with more depressive symptoms averaged across all time points (B (95%CI): 0.70 (0.35; 1.05) for MEM, 0.88 (0.41; 1.36) for EXEC, and 0.57 (0.21; 0.92) for SPEED).

Physical activity, structural brain changes and cognitive decline. The SMART-MR study

ObjectiveWe aimed to examine the cross-sectional and prospective relationship between leisure time physical activity, brain MRI abnormalities and cognitive performance in patients with vascular disease. MethodsWithin the SMART-MR study, 1.5 T MRI of the brain and neuropsychological examinations were performed at baseline (n = 1232) and after 3.9 ± 0.4 years follow-up (n = 663). Automatic brain segmentation was used to quantify intracranial (ICV), total brain, ventricular, and white matter lesion (WML) volumes. Brain infarcts were rated visually. Level of physical activity was expressed in metabolic equivalents (MET) hours p/week. With linear regression analysis we examined associations of level of physical activity with brain MRI measures and with cognitive performance, adjusted for potential confounders. For the association with brain infarcts relative risks (RR) were calculated with Poisson regression. ResultsAt baseline, an increase in physical activity of one SD (39.7 METh/w) was significantly associated with larger total brain volume (B = 0.20% of ICV; 95% CI 0.06; 0.33%). A trend was found for the association of physical activity with smaller ventricular volume (B = −0.04% of ICV; 95% CI −0.09; 0.02%) and with a decreased risk for brain infarcts (RR = 0.91, 95% CI: 0.82–1.02). No association was found with smaller WML volume (B = −0.02% of ICV; 95% CI −0.07; 0.04%). No associations with change in brain structures over time were observed. Also, no associations between physical activity and cognitive performance or cognitive decline were found. ConclusionThese data suggest that leisure time physical activity does not have a significant contribution in preventing or slowing down brain abnormalities and cognitive decline in this cohort of middle-aged individuals already burdened with vascular disease.

Brain volumes and risk of cardiovascular events and mortality. The SMART-MR study

Brain atrophy is a strong predictor for cognitive decline and dementia, and these are, in turn, associated with increased mortality in the general population. Patients with cardiovascular disease have more brain atrophy and a higher morbidity and mortality. We investigated if brain volumes on magnetic resonance imaging were associated with the risk of cardiovascular events and mortality in patients with manifest arterial disease (n = 1215; mean age 58 years). Automated brain segmentation was used to quantify intracranial volume, and volumes of total brain, sulcal cerebrospinal fluid, and ventricles. After a median follow-up of 8.3 years, 184 patients died, 49 patients had an ischemic stroke, and 100 patients had an ischemic cardiac complication. Smaller relative brain volumes increased the risk of all-cause death (hazard ratio [HR] per standard deviation decrease in total brain volume: 1.58, 95% confidence interval [95% CI]: 1.33–1.88), vascular death (HR 1.69, 95% CI: 1.35–2.13), and ischemic stroke (HR 1.96, 95% CI: 1.43–2.69), independent of cardiovascular risk factors. These results suggest that brain volumes are an important determinant of poor outcome in patients with high cardiovascular risk.

Automatic Extraction of the Midsagittal Surface from Brain MR Images using the Kullback–Leibler Measure

The midsagittal surface separates the two hemispheres of the cerebrum. This surface is often typified as a geometrical plane: the midsagittal plane. However, in subjects with a considerable amount of naturally occurring brain torque, the midsagittal surface deviates to a large extent from a plane. In the present study, an automated method to extract the midsagittal surface is proposed, evaluated on a large dataset, and compared to a conventional midsagittal plane representation. The midsagittal plane was extracted from MR images with a technique based on the Kullback-Leibler measure. This plane was used to initialize a surface, that was deformed to represent the midsagittal surface. One hundred subjects were selected from the SMART-MR study: fifty subjects with brain torque and fifty random subjects. Manual delineations of the midsagittal surface were used for evaluation. The extracted midsagittal planes and surfaces were compared to the manual delineations by assessing the absolute volume of misclassified cerebrum tissue. The midsagittal surface resulted in significantly better separations of the hemispheres. In the randomly selected subjects, the error reduced from 2.71 ± 1.05 ml to 2.20 ± 0.66 ml and in subjects with brain torque from 4.85±2.79 ml to 2.23±0.77 ml, with improvements up to 16.6 ml in individual subjects with marked brain torque.