Minke Kooistra

Diabetes mellitus and progression of vascular brain lesions and brain atrophy in patients with symptomatic atherosclerotic disease. The SMART-MR study

AIM Diabetes mellitus (DM) is associated with brain atrophy and vascular brain lesions. Cardiovascular disease is a key determinant in this association. We assessed whether DM increased the rate of progression of brain atrophy, vascular brain lesions, and cognitive decline in patients with symptomatic atherosclerotic disease. METHODS In 663 patients (58±10years) from the SMART-MR study (n=89 with DM), 1.5T MRI and neuropsychological examination were performed at baseline and after 3.9±0.4years follow-up. RESULTS Repeated measures ANCOVA (adjusted for age, sex, and vascular risk factors) showed that patients with DM had smaller total brain volume (mean differences as percentage of intracranial volume (ICV) [95% CI]: -1.36% [-1.81; -0.91]), smaller gray matter volume (-1.23% [-1.85; -0.61]), larger ventricular volume (0.32% [0.14; 0.49]), and larger white matter lesion volume (0.31% [0.09; 0.53]) than patients without DM. Patients with DM had accelerated increase in ventricular volume over time compared with patients without DM (mean differences ventricular volume as percentage of ICV: 0.32% [0.25; 0.39] vs. 0.17% [0.15; 0.19]; p-interaction DM×time<0.01). Poisson regression showed that patients with DM had an increased risk for incident brain infarcts (relative risk [95% CI]: 1.62 [1.04; 2.53]). Patients with and without DM had similar performance on cognition. CONCLUSIONS DM on top of existing symptomatic atherosclerotic disease is associated with increased brain atrophy and vascular brain lesion load that proceed at a slightly higher rate than in patients without DM.

Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 tesla MRI: The PREDICT-MR study

INTRODUCTION Smaller hippocampal volumes have been associated with major depressive disorder (MDD). The hippocampus consists of several subfields that may be differentially related to MDD. We investigated the association of occurrence of major depressive episodes (MDEs), assessed five times over seven years, with hippocampal subfield and entorhinal cortex volumes at 7 tesla MRI. METHODS In this prospective study of randomly selected general practice attendees, MDEs according to DSM-IV-R criteria were assessed at baseline and after 6, 12, 39 and 84 months follow-up. At the last follow-up, a T2 (0.7 mm(3)) 7 tesla MRI scan was obtained in 47 participants (60±10 years). The subiculum, cornu ammonis (CA) 1 to 3, dentate gyrus&CA4 and entorhinal cortex volumes were manually segmented according a published protocol. RESULTS Of the 47 participants, 13 had one MDE and 5 had multiple MDEs. ANCOVAs, adjusted for age, sex, education and intracranial volume, revealed no significant differences in hippocampal subfield or entorhinal cortex volumes between participants with and without an MDE in the preceding 84 months. Multiple episodes were associated with smaller subiculum volumes (B=-0.03 mL/episode; 95% CI -0.06; -0.003), but not with the other hippocampal subfield volumes, entorhinal cortex, or total hippocampal volume. LIMITATIONS A limitation of this study is the small sample size which makes replication necessary. CONCLUSIONS In this exploratory study, we found that an increasing number of major depressive episodes was associated with smaller subiculum volumes in middle-aged and older persons, but not with smaller volumes in other hippocampal subfields or the entorhinal cortex.

Vascular brain lesions, brain atrophy, and cognitive decline. The Second Manifestations of ARTerial disease--Magnetic Resonance (SMART-MR) study.

We examined the association between brain atrophy and vascular brain lesions (i.e., white matter lesions [WMLs] or brain infarcts), alone or in combination, with decline in memory and executive functioning over 4 years of follow-up in 448 patients (57 ± 9.5 years) with symptomatic atherosclerotic disease from the Second Manifestations of ARTerial disease--Magnetic Resonance SMART-MR study. Automated brain segmentation was used to quantify volumes of total brain, ventricles, cortical gray matter, and WMLs on 1.5-T magnetic resonance imaging (MRI). Brain infarcts were rated visually. WML volume was associated with significant decline in z score of executive functioning. No independent associations between MRI measures and memory decline were found. Significant declines in z scores of memory performance and of executive functioning were observed in patients with a combination of severe atrophy (upper quartile) and most vascular brain lesions (upper quartile) compared with those with minimal atrophy (lowest quartile) and fewest vascular brain lesions (lowest quartile). Our findings suggest that in patients with symptomatic atherosclerotic disease, the combination of brain atrophy and WMLs or brain infarcts accelerates cognitive decline over 4 years.

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

OBJECTIVE We 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. METHODS Within 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. RESULTS At 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. CONCLUSION These 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.

The natural course of elevated levels of depressive symptoms in patients with vascular disease over eight years of follow-up. the SMART-Medea study

BACKGROUND Patients with cardiovascular disease have an increased risk for depression, and depression predicts poor prognosis in these patients, but the long-term course of depression is not known. We studied the natural course of elevated levels of depressive symptoms in patients with cardiovascular disease over eight years follow-up. METHODS Within the Second Manifestations of ARTerial disease - Memory, depression and aging (SMART-Medea) study, depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) in 690 patients (62±10 years) at baseline and bi-annually during 8 years follow-up. Natural course was described for symptom severity and course type (never, single episode, intermittent, and chronic) based on the cut-off point of ≥6 on the PHQ-9. Using multinomial regression analysis (reference: never depressed) we estimated age- and sex-adjusted odds ratios (OR) for the associations of demographic factors and vascular disease categories with course type. RESULTS Of the 690 patients, 60% was never depressed, 10% had a single episode, 19% had an intermittent and 11% a chronic course of depression. Increased risk for chronic course was observed for women (OR=3.42; 95% CI=1.98-5.90), those with younger age (OR=3.20; 95% CI=1.73-5.94), and for patients with cerebrovascular disease when compared to patients with coronary artery disease (OR=2.50; 95% CI=1.31-4.78). LIMITATIONS No information was available on clinical diagnosed major depressive disorder and/or clinical events during follow-up. CONCLUSIONS In patients with cardiovascular disease, an intermittent or chronic course of elevated levels of depressive symptoms is very common. Patients with cardiovascular disease may require more careful clinical monitoring and management of depressive symptoms.

Undiagnosed cognitive impairment, health status and depressive symptoms in patients with type 2 diabetes.

AIMS Type 2 diabetes (T2DM) is associated with cognitive impairment. We examined whether undiagnosed cognitive impairment in T2DM-patients is associated with a reduced health status and depressive symptoms. METHODS In an observational study, 225 T2DM-patients aged ≥70years were examined at their homes and (some of them) at a memory clinic for undiagnosed cognitive impairment (dementia or mild cognitive impairment [MCI], defined according to internationally accepted criteria). Questionnaires assessing health status (SF-36, EQ-5D, EQ-VAS) and depressive symptoms (CES-D) were filled out. Health status and depressive symptoms were compared between patients with and without cognitive impairment. RESULTS Patients with cognitive impairment (n=57) showed significantly lower scores on the physical and mental summary scores of the SF-36 than patients with normal cognition (difference: 3.5 (95%-CI 0.7-6.3, p=0.02, effect size 0.41) and 2.9 (95%-CI 0.3-5.6; p=0.03, effect size 0.37). EQ-5D index and EQ-VAS scores were significantly lower in patients with cognitive impairment. Depression (CES-D≥16) occurred almost twice as often in patients with cognitive impairment (RR 1.8; 95%-CI: 1.1-3.0). CONCLUSIONS Undiagnosed cognitive impairment in T2DM-patients is associated with a reduced health status and more depressive symptoms. Detection of cognitive impairment in T2DM-patients identifies a vulnerable patient group that could benefit from tailored treatment and care.

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

BACKGROUND 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. METHOD 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. RESULTS 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). CONCLUSIONS 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.

Physical Activity and Vascular Events and Mortality in Patients with Vascular Disease

INTRODUCTION In patients with CAD, moderate levels of leisure time physical activity are associated with lower risk of mortality. However, less is known about the effects in patients with vascular disease other than CAD. In this study, we examined the association between physical activity and risk of future vascular events and all-cause mortality in patients with vascular disease or risk factors and investigated whether these associations were similar across the different manifestations of vascular disease. METHODS A total of 9942 consecutive patients with various manifestations of vascular disease or risk factors enroled in the Second Manifestations of ARTerial disease study were included. The amount of physical activity was assessed at baseline in MET-hours per week. RESULTS The study population (mean age, 56.7 yr; male, 67%) had a median level of physical activity of 17.4 MET·h·wk(-1). During a median follow-up of 6.7 yr, 1224 vascular events and 1353 cases of all-cause mortality were recorded. Cox regression analyses adjusted for age, sex, smoking, and current alcohol consumption showed that higher levels of physical activity were associated with reduced risk of vascular events (quartile 4 vs quartile 1; hazard ratio, 0.68 (95% confidence interval, 0.58-0.79)) and all-cause mortality (hazard ratio, 0.61 (95% confidence interval, 0.53-0.71)). This reduced risk was observed both in patients with vascular disease and in patients with risk factors. The associations were similar across the different manifestations of vascular disease. CONCLUSIONS Higher levels of leisure time physical activity were associated with reduced risk of vascular events and all-cause mortality in patients with CAD and other manifestations of vascular disease, suggesting that physical exercise programs should also be investigated in these other manifestations.

Hippocampal volume and the course of depressive symptoms over eight years of follow-up.

To estimate the association between hippocampal and total brain volume and the course of depressive symptoms over eight years of follow‐up in patients with a history of vascular disease.

MAJOR DEPRESSIVE EPISODES OVER THE COURSE OF 7 YEARS AND HIPPOCAMPAL VOLUMES AT 1.5 AND 7 TESLA MRI: THE PREDICT-MR STUDY

P1-271 MAJOR DEPRESSIVE EPISODES OVER THE COURSE OF 7 YEARS AND HIPPOCAMPAL VOLUMES AT 1.5 AND 7 TESLA MRI: THE PREDICT-MR STUDY Laura Wisse, Geert Jan Biessels, Minke Kooistra, Yolanda van der Graaf, Mirjam I. Geerlings, UMC Utrecht, Department of Neurology, Utrecht, Netherlands; UMC Utrecht, Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands. Contact e-mail: l.e.m. wisse@umcutrecht.nl