Arterial stiffness and progression of structural brain changes: The SMART-MR study.

OBJECTIVE: To examine the cross-sectional and prospective associations between arterial stiffness and structural brain changes within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with manifest arterial disease. METHODS: Distension measurements of the common carotid arteries and a brain MRI were performed in 526 patients (mean age 59 ± 10 years). After a mean follow-up of 4.1 years (range 3.6-5.8), brain MRI was repeated in 308 patients. Brain segmentation was used to quantify total brain volume, cortical gray matter volume, ventricular volume, and white matter lesion (WML) volume (relative to intracranial volume). Infarcts were rated visually. RESULTS: Cross-sectional multivariable regression analyses showed that 1 SD decrease in carotid distension, indicating increased arterial stiffness, was associated with smaller relative total brain and cortical gray matter volumes (B = -0.24%, 95% confidence interval [CI] -0.44 to -0.04%, and B = -0.47%, 95% CI -0.75 to -0.19%), with larger WML volume (B = 0.09%, 95% CI -0.01 to 0.19%), and with higher risk of having nonlacunar (cortical or large subcortical) brain infarcts (relative risk = 1.44, 95% CI 1.14 to 1.81). However, our prospective findings showed that carotid distension was not significantly associated with progression of brain atrophy, WML volume, or brain infarcts. CONCLUSION: In this population of patients with manifest arterial disease, stiffening of the carotid arteries was cross-sectionally associated with more brain atrophy, WML volume, and nonlacunar infarcts, but did not lead to changes in brain volumes or infarcts after 4 years.

Angiotensin-converting enzyme in cerebrospinal fluid and risk of brain atrophy.

BACKGROUND: Higher angiotensin-converting enzyme (ACE) activity might increase the risk of Alzheimer's disease by increasing blood pressure, and subsequent development of cerebral small vessel disease (CSVD). Yet, it may also decrease this risk, as it functions to degrade amyloid-ß, thereby reducing brain atrophy. OBJECTIVE: To examine the cross-sectional associations of serum and cerebrospinal fluid (CSF) ACE protein levels and activity with brain atrophy and CSVD in a memory clinic cohort. METHODS: In 118 subjects from the memory clinic based Amsterdam Dementia Cohort (mean age 66 ± 8 years), ACE protein levels (ng/ml) and activity in CSF and serum were investigated. Poisson regression analyses were used to associate ACE measurements with rated global cortical atrophy, medial temporal lobe atrophy, lacunar infarcts, white matter hyperintensities, and microbleeds on brain MRI. RESULTS: Higher CSF ACE activity was associated with a reduced risk of global brain atrophy. The relative risk (95% CI) of having global cortical atrophy ≥2 per SD increase in CSF ACE activity was 0.67 (0.49; 0.93). ACE levels were not significantly related to measures of CSVD. CONCLUSIONS: These results show that high ACE might have protective effects on the brain. This could suggest that ACE inhibitors, which may lower CSF ACE levels, are not preferred as antihypertensive treatment in patients at risk for Alzheimer's disease.

The association of angiotensin-converting enzyme with biomarkers for Alzheimer's disease.

INTRODUCTION: Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer's disease (AD) as ACE functions to degrade amyloid-ß (Aß). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aß, total tau (tau) and tau phosphorylated at threonine 181 (ptau). METHODS: We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid ß1-42, tau and ptau (pg/ml) in CSF. RESULTS: Cross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aß, indicating more brain Aß pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 (0.04; 0.15), 0.06 (0.00; 0.12) and 0.05 (0.00; 0.11), respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B's (95% CI) per SD increase were 0.15 (0.06; 0.25) and 0.17 (0.10; 0.25), respectively. CONCLUSIONS: These results strengthen the hypothesis that ACE degrades Aß. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD.

Blood pressure and progression of brain atrophy: the SMART-MR Study.

IMPORTANCE: Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease. OBJECTIVE: To examine the associations of baseline BP and change in BP over time with progression of brain atrophy. DESIGN: The Secondary Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) Study is a prospective cohort study with baseline measurements in 2001-2005 and follow-up measurements in 2006-2009. The mean follow-up time was 3.9 years. SETTING: University Medical Center Utrecht, the Netherlands. PARTICIPANTS: A total of 663 patients (mean [SD] age, 57 [9] years; 81% male) with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysm were included. MAIN OUTCOMES AND MEASURES: Using automated segmentation at baseline and follow-up, change in brain parenchymal fraction, cortical gray matter fraction, and ventricular fraction (%ICV) were quantified as indicators of progression of global, cortical, and subcortical brain atrophy. RESULTS: Multivariable adjusted regression analysis showed that patients with lower baseline diastolic BP (DBP) or mean arterial pressure had more progression of subcortical atrophy. The mean differences in the change in ventricular fraction between low and high DBP was 0.07% (95% CI, 0.01-0.14) and between low and high mean arterial pressure was 0.05% (95% CI, 0.00-0.10). Furthermore, in patients with higher baseline BP (DBP, mean arterial pressure, or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels. CONCLUSIONS AND RELEVANCE: In patients with manifest arterial disease, low baseline DBP was associated with more progression of subcortical atrophy, irrespective of the BP course during follow-up. Furthermore, in patients with higher baseline BP, declining BP levels over time were associated with less progression of subcortical atrophy. This could imply that BP lowering is beneficial in patients with higher BP levels, but caution should be taken with further BP lowering in patients who already have a low DBP.

Homocysteine, progression of ventricular enlargement, and cognitive decline: the Second Manifestations of ARTerial disease-Magnetic Resonance study.

BACKGROUND: Homocysteine may be a modifiable risk factor for cognitive decline and brain atrophy, particularly in older persons. We examined whether homocysteine increased the risk for cognitive decline and brain atrophy, and evaluated the modifying effect of age. METHODS: Within the Second Manifestations of ARTerial disease-Magnetic Resonance study-a prospective cohort study among patients with atherosclerotic disease-longitudinal analyses were performed in 663 patients (mean age: 57 ± 9 years; follow-up: 3.9 ± 0.4 years). At baseline and follow-up, brain segmentation on magnetic resonance imaging was used to quantify relative (%) cortical, ventricular, and global brain volumes, and z-scores of memory and executive functioning were calculated. Linear regression analysis was used to estimate associations of homocysteine (per standard deviation increase) and hyperhomocysteinemia (HHCY) with brain volumes, memory, and executive functioning at follow-up, adjusted for baseline brain volume, memory, and executive functioning, respectively, and age, sex, and vascular risk factors. Furthermore, interaction terms between homocysteine and age (continuous) were added. RESULTS: Significant interactions were observed between total plasma homocysteine (tHcy) and age with cortical, ventricular, and global brain volume (for all three measures: P < .05), and between HHCY and age with executive functioning (P = .04), and results were stratified by age. In patients aged ≥65 years, increasing tHcy level and HHCY were significantly associated with progression of ventricular enlargement (B = 0.07%, 95% confidence interval [CI]: 0.01% to 0.13% and B = 0.16%, 95% CI: 0.01% to 0.31%, respectively) and with a decline in executive function (B = -0.29, 95% CI: -0.54 to -0.04 and B = -0.84, 95% CI: -1.37 to -0.32, respectively). CONCLUSION: Elevated tHcy was related to progression of ventricular enlargement and increased the risk for a decline in executive functioning in older persons.

Serum angiotensin-converting enzyme and recurrent vascular events. The SMART-MR study.

OBJECTIVE: Chronic exposure to high levels of angiotensin-converting enzyme (ACE) might increase the risk of hypertensive cardiovascular events. However, little data are available on the association of direct measures of ACE activity with vascular risk and disease. We examined whether serum ACE levels were associated with the risk of recurrent vascular events. METHODS: Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, analyses were performed in 950 patients (mean age 58 ± 10 years) without use of ACE-inhibitors or angiotensin II receptor blockers. At baseline, participants underwent a vascular screening and serum ACE levels (U/L) were measured. Patients were followed for recurrent vascular events, including vascular death, ischemic stroke, and ischemic coronary heart disease (CHD). RESULTS: After a mean follow up of 7.2 years (range 0.2-10.1 years), we documented 55 cases of vascular death, 33 cases of ischemic stroke, and 77 cases of ischemic CHD. Multivariable Cox-regression models showed that higher baseline ACE levels were associated with an increased risk of ischemic stroke and CHD; HR's (95%CI) were 1.7 (1.0-2.7) and 1.8 (1.2-2.9). High ACE particularly increased risk of stroke in patients with high blood pressure (defined as >140/90 mmHg) (HR = 4.8; 95%CI 1.0-19.4). This relation was independent of several confounders including use of antihypertensive medication. Serum ACE was not significantly associated with risk of vascular death. CONCLUSION: Our results suggest that in a population with high vascular risk, higher serum ACE levels contribute to an increased risk of ischemic stroke and CHD events.

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.

APOE ε4 differentially influences change in memory performance depending on age. The SMART-MR study.

The apolipoprotein E (APOE) gene may act differently in young and old persons, known as antagonistic pleiotropy. We therefore examined the prospective associations between the APOE ε4 allele and cognitive functioning, and the modifying effect of age, in 375 nondemented adults (mean age 57 ± 10 years; follow-up period 3.8 ± 0.2 years) with available data on APOE genotype and cognitive functioning, within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) cohort study. Neuropsychological tests assessing memory performance and executive functioning were performed at baseline and follow-up, and composite z-scores were calculated. Age significantly modified the association of APOE ε4 with change in memory performance (p interaction = 0.02). In persons ≤ 57 years (median split), an APOE ε4 allele was associated with an increase in immediate recall (B = 0.42; 95% confidence interval [CI], 0.17 to 0.66) and delayed recall (B = 0.37; 95% CI, 0.09 to 0.64), while in persons > 57 years, an APOE ε4 allele was associated with decline in immediate recall (B = -0.25; 95% CI, -0.52 to 0.01). Our findings suggest that the APOE ε4 allele has a differential effect on change in verbal memory performance depending on age, consistent with the hypothesis of antagonistic pleiotropy.