Anne M. Grool

Cerebral small-vessel disease and progression of brain atrophy The SMART-MR study

ABSTRACT Objectives: To investigate whether severity and progression of periventricular and deep white matter lesions (WML) and lacunar infarcts were associated with progression of brain atrophy. Methods: Within the SMART-MR study, a prospective cohort on MRI changes in patients with symptomatic atherosclerotic disease, 565 patients (57 ± 9 years) without large infarcts had vascular screening and 1.5 T MRI at baseline and after a mean follow-up of 3.9 years. With automated brain segmentation, total brain, cortical gray matter, ventricular, and WML volumes were estimated and expressed relative to intracranial volume (%). Lacunar infarcts were rated manually. Results: Using linear regression analyses adjusted for demographics and vascular risk factors, periventricular WML volume at baseline was associated with greater decrease in cortical gray matter volume (B = −1.73%, 95% confidence interval [CI] −3.15% to −0.30%, per 1% WML volume increase) and greater increase in ventricular volume (B = 0.12%, 95% CI 0.04% to 0.20%). Progression of periventricular WML volume corresponded with a greater decrease in cortical gray matter volume (B = −0.45%, 95% CI −0.9% to 0%) and greater increase in ventricular volume (B = 0.15%, 95% CI 0.1% to 0.2%). Presence of lacunar infarcts was associated with greater decline in total brain volume (B = −0.25%, 95% CI −0.49% to −0.01%) and progression of lacunar infarcts with a greater decrease of total brain (B = −0.30%, 95% CI −0.59% to 0.01%) and cortical gray matter volume (B = −0.81%, 95% CI −1.43% to −0.20%). Conclusions: In patients with symptomatic atherosclerotic disease, presence and progression of periventricular WML and lacunar infarcts is associated with greater progression of brain atrophy independent of vascular risk factors.

Location of cerebrovascular and degenerative changes, depressive symptoms and cognitive functioning in later life: the SMART-Medea study

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.

Lacunar Infarcts in Deep White Matter Are Associated with Higher and More Fluctuating Depressive Symptoms During Three Years Follow-up

BACKGROUND Disruption of frontal-subcortical circuits by cerebral small-vessel disease is thought to predispose to depression characterized by motivational symptoms. We examined the influence of lacunar infarcts and white matter lesions (WML) on severity and course of depressive symptoms during 3 years follow-up. METHODS Within the SMART-Medea study, analyses were performed in 650 patients with symptomatic atherosclerotic disease (62±9 years). Volumetric WML measures (deep and periventricular) were obtained with 1.5T magnetic resonance imaging at baseline; infarcts were rated visually. Depressive symptoms were assessed with Patient Health Questionnaire-9 at baseline and during five follow-up times and categorized into motivational and mood scores. RESULTS Using generalized estimating equation models, a relation between lacunar infarcts in deep white matter and an increased severity (mean difference=1.47, 95% confidence interval .33-2.60) and more fluctuating course (p value interaction infarcts * time=.04) of depressive symptoms during follow-up was found, adjusted for age, sex, education, vascular risk, and cognition. This relation was primarily driven by motivational symptoms. Lacunar infarcts were not associated with severity or course of depressive symptoms. Deep WML were associated with a more fluctuating but not more severe course of depressive symptoms. Excluding patients with major depressive disorder did not change the results. CONCLUSIONS In patients with symptomatic atherosclerotic disease and relatively mild depressive symptoms, depressive symptoms, characteristic of motivational problems, remained higher during 3 years follow-up in patients with lacunar infarcts in deep white matter and that symptom severity fluctuated over time.

Structural MRI correlates of apathy symptoms in older persons without dementia: AGES-Reykjavik Study.

Objective: We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons. Methods: Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility–Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status. Results: Compared to those with <2 apathy symptoms, participants with ≥2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference −3.6 mL, 95% confidence interval [CI] −6.2 to −1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference −1.9 mL, 95% CI −3.6 to −0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9–1.3). Excluding participants with a depression diagnosis did not change the associations. Conclusions: In this older population without dementia, apathy symptoms are associated with a more diffuse loss of both gray and white matter volumes, independent of depression.

Self-rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study

Abstract.  Grool AM, van der Graaf Y, Visseren FLJ, de Borst GJ, Algra A, Geerlings MI, on behalf of the SMART Study Group (University Medical Center Utrecht, Utrecht, The Netherlands). Self‐rated health status as a risk factor for future vascular events and mortality in patients with symptomatic and asymptomatic atherosclerotic disease: the SMART study. J Intern Med 2012; 272: 277–286.

Cerebellar infarct patterns: The SMART-Medea study

Objective Previous studies on cerebellar infarcts have been largely restricted to acute infarcts in patients with clinical symptoms, and cerebellar infarcts have been evaluated with the almost exclusive use of transversal MR images. We aimed to document the occurrence and 3D-imaging patterns of cerebellar infarcts presenting as an incidental finding on MRI. Methods We analysed the 1.5 Tesla MRI, including 3D T1-weighted datasets, of 636 patients (mean age 62 ± 9 years, 81% male) from the SMART-Medea study. Cerebellar infarct analyses included an assessment of size, cavitation and gliosis, of grey and white matter involvement, and of infarct topography. Results One or more cerebellar infarcts (mean 1.97; range 1–11) were detected in 70 out of 636 patients (11%), with a total amount of 138 infarcts identified, 135 of which showed evidence of cavitation. The average mean axial diameter was 7 mm (range 2–54 mm), and 131 infarcts (95%) were smaller than 20 mm. Hundred-thirty-four infarcts (97%) involved the cortex, of which 12 in combination with subcortical white matter. No infarcts were restricted to subcortical branches of white matter. Small cortical infarcts involved the apex of a deep (pattern 1) or shallow fissure (pattern 2), or occurred alongside one (pattern 3) or opposite sides (pattern 4) of a fissure. Most (87%) cerebellar infarcts were situated in the posterior lobe. Conclusions Small cerebellar infarcts proved to be much more common than larger infarcts, and preferentially involved the cortex. Small cortical infarcts predominantly involved the posterior lobes, showed sparing of subcortical white matter and occurred in characteristic topographic patterns.

Low blood pressure and antihypertensive treatment are independently associated with physical and mental health status in patients with arterial disease: the SMART study

To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease.

Angiotensin-converting enzyme and progression of white matter lesions and brain atrophy--the SMART-MR study.

High levels of angiotensin-converting-enzyme (ACE) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease. However, high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy. Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average (range) 3.9 (3.0-5.8) years of follow-up in 682 persons (mean age 58 ± 10 years). Brain segmentation was used to quantify total, deep, and periventricular white matter lesion (WML) volume, and total brain, cortical gray matter and ventricular volume (%ICV). Lacunar infarcts were rated visually. Regression analyses were used to examine the prospective associations between serum ACE and brain measures. Patients with the highest serum ACE levels (>43.3 U/L) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels (<21.8 U/L); mean difference (95% CI) in change was 0.20 (-0.02; 0.43) %ICV. On the contrary, patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels; mean difference (95% CI) in change was 0.78 (0.21; 1.36) %ICV. Serum ACE was not associated with subcortical atrophy, periventricular WML, or lacunar infarcts. Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume, but with less progression of cortical brain atrophy. This suggests both detrimental and beneficial effects of high ACE levels on the brain.

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.

Mood problems increase the risk of mortality in patients with lacunar infarcts: the SMART-MR study.

Objective A relationship between depression and mortality has been well established, but underlying mechanisms remain unclear. We investigated the influence of cerebral small vessel disease (CSVD), characterized by white matter lesions (WMLs) and lacunar infarcts, on the relationship between mood mortality during 6 years follow-up. Methods Mood problems were assessed with the mental component summary of the 36-item Short-Form Medical Outcomes Study in 1110 patients with symptomatic atherosclerotic disease (mean age 59 years). Volumetric WML estimates were obtained with 1.5-T magnetic resonance imaging; lacunar infarcts were scored visually. Cox regression models were adjusted for age, sex, vascular risk, physical functioning, antidepressants and infarcts. We adjusted for CSVD to examine whether it may be an intermediate or confounding factor. Second, we added interaction terms to investigate whether associations differed between patients with CSVD (absent/present). Results Patients in the lowest quartile of mental functioning, representing most severe mood problems, were at higher, although not significant, risk of death (hazard ratio [HR] = 1.47, 95% confidence interval [CI] = 0.94–2.30) compared with patients in higher quartiles. Adjustment for CSVD did not change this association. Lacunar infarcts, not WML, modified the association of mood problems with mortality (p value for interaction = .01); mood problems strongly increased the risk of mortality in patients with lacunar infarcts (HR = 2.75, 95% CI = 1.41–5.38) but not in those without it (HR = 0.78, 95% CI = 0.39–1.57). Conclusions Patients with lacunar infarcts may be especially vulnerable for the effect of mood problems on mortality. Abbreviations CSVD = cerebral small vessel disease; MRI = magnetic resonance imaging; WML = white matter lesion; SMART-MR = Second Manifestations of Arterial Disease–Magnetic Resonance; SF-36 = 36-item Short-Form Medical Outcomes Study Health Survey; MCS = mental component summary; FLAIR = fluid-attenuating inverse recovery; ICV = intracranial volume; HR = hazard ratio; SD = standard deviation