Second Manifestations Of ARTerial disease-Magnetic Resonance Research Articles

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: TheSMART-MR Study.

Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aβ (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Low-grade carotid artery stenosis is associated with progression of brain atrophy and cognitive decline. The SMART-MR study

Asymptomatic low-grade carotid artery stenosis (LGCS) is a common finding in patients with manifest arterial disease, however its relationship with brain MRI changes and cognitive decline is unclear. We included 902 patients (58 ± 10 years; 81% male) enrolled in the Second Manifestations of Arterial Disease – Magnetic Resonance (SMART-MR) study without a history of cerebrovascular disease. LGCS was defined as 1–49% stenosis on baseline carotid ultrasound, whereas no LGCS (reference category) was defined as absence of carotid plaque. Brain and white matter hyperintensity (WMH) volumes and cognitive function were measured at baseline and after 4 (n = 480) and 12 years (n = 222) of follow-up. Using linear mixed-effects models, we investigated associations of LGCS with progression of brain atrophy, WMH, and cognitive decline. LGCS was associated with greater progression of global brain atrophy (estimate −0.03; 95%CI, −0.06 to −0.01; p = 0.002), and a greater decline in executive functioning (estimate −0.02; 95%CI, −0.031 to −0.01; p < 0.001) and memory (estimate −0.012; 95%CI, −0.02 to −0.001; p = 0.032), independent of demographics, cardiovascular risk factors, and incident brain infarcts on MRI. No association was observed between LGCS and progression of WMH. Our results indicate that LGCS may represent an early marker of greater future brain atrophy and cognitive decline.

Microinfarcts in the Deep Gray Matter on 7T MRI: Risk Factors, MRI Correlates, and Relation to Cognitive Functioning-The SMART-MR Study.

The clinical relevance of cortical microinfarcts has recently been established; however, studies on microinfarcts in the deep gray matter are lacking. We examined the risk factors and MR imaging correlates of microinfarcts in the deep gray matter on 7T MR imaging and their relation to cognitive functioning. Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, 213 patients (mean age, 68 [SD, 8] years) had a risk-factor assessment, 7T and 1.5T brain MR imaging, and a cognitive examination. Microinfarcts on 7T MR imaging were defined as lesions of <5 mm. Regression models were used to examine the age-adjusted associations among risk factors, MR imaging markers, and microinfarcts. Cognitive function was summarized as composite and domain-specific z scores. A total of 47 microinfarcts were found in 28 patients (13%), most commonly in the thalamus. Older age, history of stroke, hypertension, and intima-media thickness were associated with microinfarcts. On 1.5T MR imaging, cerebellar infarcts (relative risk = 2.75; 95% CI, 1.4-5.33) and lacunes in the white (relative risk = 3.28; 95% CI, 3.28-6.04) and deep gray matter (relative risk = 3.06; 95% CI, 1.75-5.35) were associated with microinfarcts, and on 7T MR imaging cortical microinfarcts (relative risk = 2.33; 95% CI, 1.32-4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in the global z score between patients with multiple microinfarcts versus none = -0.97; 95% CI, -1.66 to -0.28, P = .006) and across all cognitive domains. Microinfarcts in the deep gray matter on 7T MR imaging were associated with worse cognitive functioning and risk factors and MR imaging markers of small-vessel and large-vessel disease. Our findings suggest that microinfarcts in the deep gray matter may represent a novel imaging marker of vascular brain injury.

Association of Ischemic Imaging Phenotype With Progression of Brain Atrophy and Cerebrovascular Lesions on MRI

Background and Objective To investigate the association of silent vascular lesions, imaging negative ischemia, and symptomatic cerebrovascular disease with long-term progression of brain atrophy and cerebrovascular lesions in patients with arterial disease. Methods Within the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study, stroke status of participants at baseline was classified as no cerebrovascular disease (reference group, n = 829), symptomatic cerebrovascular disease (n = 206), silent vascular lesion (n = 157), and imaging-negative ischemia (n = 90) according to clinical and MRI findings. With the use of linear mixed models, changes in brain and white matter hyperintensity (WMH) volumes at baseline and during 12 years of follow-up were studied in stroke classifications. Relative risks were estimated for new infarcts during follow-up associated with stroke classifications. Analyses were adjusted for age, sex, cardiovascular risk factors, and medications. Results Symptomatic cerebrovascular disease associated with 0.35 SD (95% confidence interval [CI] 0.24–0.47) smaller brain volume and 0.61 SD (95% CI 0.48–0.74) larger WMH volume at baseline and increased risk for new infarcts during follow-up (risk ratio [RR] 2.89, 95% CI 2.00–4.16). Silent vascular lesions were associated with 0.15 SD (95% CI 0.01–0.88) smaller brain volume, 0.02 SD (95% CI 0.01–0.03) steeper brain atrophy slope, and 0.48 SD (95% CI 0.32–0.64) larger WMH volume at baseline, in addition to increased risk for lacunes (RR 2.08, 95% CI 1.48–2.94). Individuals with imaging-negative ischemia had increased risk for cortical infarcts (RR 2.88, 95% CI 2.17–3.82). Discussion Patients with symptomatic cerebrovascular disease, silent vascular lesions, or imaging-negative ischemia have a different course of brain volume loss and cerebrovascular lesion development. These findings may have implications for future stroke risk and dementia and need further investigation.

Association of White Matter Hyperintensity Markers on MRI and Long-term Risk of Mortality and Ischemic Stroke: The SMART-MR Study.

ObjectiveTo determine whether white matter hyperintensity (WMH) markers on MRI are associated with long-term risk of mortality and ischemic stroke.MethodsWe included consecutive patients with manifest arterial disease enrolled in the Second Manifestations of Arterial Disease–Magnetic Resonance (SMART-MR) study. We obtained WMH markers (volume, type, and shape) from brain MRI scans performed at baseline using an automated algorithm. During follow-up, occurrence of death and ischemic stroke was recorded. Using Cox regression, we investigated associations of WMH markers with risk of mortality and ischemic stroke, adjusting for demographics, cardiovascular risk factors, and cerebrovascular disease.ResultsWe included 999 patients (59 ± 10 years; 79% male) with a median follow-up of 12.5 years (range 0.2–16.0 years). A greater periventricular or confluent WMH volume was independently associated with a greater risk of vascular death (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13–1.47) for a 1-unit increase in natural log-transformed WMH volume and ischemic stroke (HR 1.53, 95% CI 1.26–1.86). A confluent WMH type was independently associated with a greater risk of vascular (HR 1.89, 95% CI 1.15-3.11) and nonvascular death (HR 1.65, 95% CI 1.01–2.73) and ischemic stroke (HR 2.83, 95% CI 1.36-5.87). A more irregular shape of periventricular or confluent WMH, as expressed by an increase in concavity index, was independently associated with a greater risk of vascular (HR 1.20, 95% CI 1.05–1.38 per SD increase) and nonvascular death (HR 1.21, 95% CI 1.03–1.42) and ischemic stroke (HR 1.28, 95% CI 1.05–1.55).ConclusionsWMH volume, type, and shape are associated with long-term risk of mortality and ischemic stroke in patients with manifest arterial disease.

Intracranial atherosclerosis on 7T MRI and cognitive functioning: The SMART-MR study.

To investigate the association between intracranial atherosclerosis (ICAS) and cognitive functioning in patients with a history of vascular disease. Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed in 130 patients (mean ± SD age 68 ± 9 years) with 7T vessel wall MRI data. Vessel wall lesions were rated according to established criteria and summed into a circulatory and artery-specific ICAS burden. Associations between ICAS burden and Z scores of memory, executive functioning, working memory, and processing speed were estimated using linear regression analyses adjusted for age, sex, education, reading ability, and vascular risk factors. A total of 125 patients (96%) had ≥1 vessel wall lesion; the mean ICAS burden was 8.5 ± 5.7. A statistically nonsignificant association was found between total ICAS burden and memory (b = -0.03 per +1 lesion; 95% confidence interval [CI] -0.05 to 0.00). No associations were found for the other domains. A statistically significant association was found for ICAS burden of the posterior cerebral artery (PCA) and memory (b = -0.12 per +1 lesion; 95% CI -0.23 to -0.01) and executive functioning (b = -0.10 per +1 lesion; 95% CI -0.19 to -0.01). Statistically nonsignificant associations were found for the anterior cerebral artery (ACA) burden and memory (b = -0.13 per +1 lesion; 95% CI -0.26 to 0.01) and executive functioning (b = -0.11 per +1 lesion; 95% CI -0.22 to 0.01). Additional adjustments for large infarcts, white matter hyperintensities, lacunes, and ≥50% carotid stenosis produced similar results. Our results suggest an artery-specific vulnerability of memory and executive functioning to ICAS, possibly due to strategic brain regions involved with these cognitive domains, which are located in the arterial territory of the PCA and ACA.

MRI phenotypes of the brain are related to future stroke and mortality in patients with manifest arterial disease: The SMART-MR study

Neurodegenerative and neurovascular diseases lead to heterogeneous brain abnormalities. A combined analysis of these abnormalities by phenotypes of the brain might give a more accurate representation of the underlying aetiology. We aimed to identify different MRI phenotypes of the brain and assessed the risk of future stroke and mortality within these subgroups. In 1003 patients (59 ± 10 years) from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, different quantitative 1.5T brain MRI markers were used in a hierarchical clustering analysis to identify 11 distinct subgroups with a different distribution in brain MRI markers and cardiovascular risk factors, and a different risk of stroke (Cox regression: from no increased risk compared to the reference group with relatively few brain abnormalities to HR = 10.34; 95% CI 3.80↔28.12 for the multi-burden subgroup) and mortality (from no increased risk compared to the reference group to HR = 4.00; 95% CI 2.50↔6.40 for the multi-burden subgroup). In conclusion, within a group of patients with manifest arterial disease, we showed that different MRI phenotypes of the brain can be identified and that these were associated with different risks of future stroke and mortality. These MRI phenotypes can possibly classify individual patients and assess their risk of future stroke and mortality.

Hypertensive Target Organ Damage and Longitudinal Changes in Brain Structure and Function: The Second Manifestations of Arterial Disease-Magnetic Resonance Study.

Hypertension has been related to structural and functional brain changes. In high-risk populations, hypertensive target organ damage might better represent exposure to high blood pressure than the blood pressure measurement itself. We examined the association of hypertensive target organ damage with longitudinal changes in brain structure and function within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study. Renal function, albuminuria, and left ventricular hypertrophy on electrocardiography were measured in 663 patients with manifest arterial disease (mean age, 57±9 years; 81% men). Automated brain segmentation was used to quantify progression of global brain atrophy (change in brain parenchymal fraction) and progression of cerebral small vessel disease on 1.5T magnetic resonance imaging, and memory and executive functioning were assessed at baseline and after on average 3.9 years of follow-up. Regression analyses showed that an increasing number of signs of target organ damage was associated with more progression of global brain atrophy and more rapid decline in memory performance. Compared with no target organ damage, mean differences in change in brain parenchymal fraction (95% confidence interval) for 1 and ≥2 signs of organ damage were -0.12 (-0.30; 0.06) and -0.41 (-0.77; -0.05) % intracranial volume, and mean (95% confidence interval) differences in change in memory performance (z score) were -0.15 (-0.29; -0.00) and -0.27 (-0.54; -0.01). Results were independent of blood pressure, antihypertensive treatment, and other confounders. Hypertension target organ damage was not associated with progression of cerebral small vessel disease or change in executive functioning. Routinely assessed signs of hypertensive target organ damage, and in particular impaired renal function, could be used to identify patients at the highest risk of cognitive decline.

Longitudinal Relationship Between Cerebral Small-Vessel Disease and Cerebral Blood Flow

Cerebral small-vessel disease and cerebral blood flow (CBF) are interrelated. However, the direction of the relationship is unknown, and longitudinal studies are scarce. We investigated the longitudinal relationship between CBF and white matter hyperintensities (WMHs) and lacunes, as representatives of cerebral small-vessel disease, in patients with manifest arterial disease. Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, 1.5T brain magnetic resonance imaging, including an MR angiography, was obtained at baseline and after on ≈3.9 years of follow-up in 575 patients with manifest arterial disease (mean age, 57±10 years). Longitudinal associations of WMHs and lacunes with parenchymal CBF (pCBF; per 100-mL brain volume) were estimated using regression analyses, adjusted for age, sex, follow-up time, and baseline brain measures. Baseline pCBF was not associated with progression of WMHs and lacunes over time. However, periventricular and deep WMHs at baseline were associated with decline in pCBF; mean (95% confidence interval) decline in pCBF per % intracranial volume increase in periventricular and deep WMH volume was -0.70 (-1.40 to -0.00) and -1.01 (-1.64 to -0.38) mL/min per 100-mL brain volume, respectively. These associations were partly explained by cardiovascular risk factors but remained significant for deep WMHs (mean decline [95% confidence interval] in pCBF per % intracranial volume increase in deep WMH volume was -0.92 [-1.56 to -0.28] mL/min per 100-mL brain volume). Lacunes were not associated with change in pCBF. In patients with manifest arterial disease, baseline periventricular and deep WMH volumes were associated with decline in pCBF over time, but baseline pCBF was not associated with progression of WMHs and lacunes over time.

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

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. 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. 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. 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.

Homocysteine and progression of generalized small-vessel disease

Assuming the involvement of homocysteine in a generalized small-vessel disease, we investigated the association of homocysteine levels with progression of white matter lesions, lacunar infarcts, and kidney disease. Within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) Study, a prospective cohort study on brain aging in patients with symptomatic atherosclerotic disease, 663 patients (aged 57 ± 9 years) had vascular screening and 1.5-tesla MRI at baseline and after a mean follow-up of 3.9 years. Multiple regression analysis was used to estimate the longitudinal association between total homocysteine level, defined as a continuous variable and as hyperhomocysteinemia (the highest quintile of homocysteine), and progression of white matter lesion volume, lacunar infarcts, and estimated glomerular filtration rate. After adjusting for age, sex, follow-up time, and vascular risk factors, hyperhomocysteinemia was significantly associated with increased risk of white matter lesion progression (odds ratio 2.4, 95% confidence interval [CI] 1.5-4.1) and lower estimated glomerular filtration rate at follow-up (B = -3.4 mL/min, 95% CI -5.9 to -0.9) and borderline significantly associated with new lacunar infarcts (odds ratio 1.8, 95% CI 0.9-3.4). Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected.

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.

Association between Subcortical Vascular Lesion Location and Cognition: A Voxel-Based and Tract-Based Lesion-Symptom Mapping Study. The SMART-MR Study

IntroductionLacunar lesions (LLs) and white matter lesions (WMLs) affect cognition. We assessed whether lesions located in specific white matter tracts were associated with cognitive performance taking into account total lesion burden.MethodsWithin the Second Manifestations of ARTerial disease Magnetic Resonance (SMART-MR) study, cross-sectional analyses were performed on 516 patients with manifest arterial disease. We applied an assumption-free voxel-based lesion-symptom mapping approach to investigate the relation between LL and WML locations on 1.5 Tesla brain MRI and compound scores of executive functioning, memory and processing speed. Secondly, a multivariable linear regression model was used to relate the regional volume of LLs and WMLs within specific white matter tracts to cognitive functioning.ResultsVoxel-based lesion-symptom mapping identified several clusters of voxels with a significant correlation between WMLs and executive functioning, mostly located within the superior longitudinal fasciculus and anterior thalamic radiation. In the multivariable linear regression model, a statistically significant association was found between regional LL volume within the superior longitudinal fasciculus and anterior thalamic radiation and executive functioning after adjustment for total LL and WML burden.ConclusionThese findings identify the superior longitudinal fasciculus and anterior thalamic radiation as key anatomical structures in executive functioning and emphasize the role of strategically located vascular lesions in vascular cognitive impairment.

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.

Cerebral Small Vessel Disease and Risk of Death, Ischemic Stroke, and Cardiac Complications in Patients With Atherosclerotic Disease

Cerebral small vessel disease may be related to vascular and nonvascular pathology. We assessed whether lacunar infarcts and white matter lesions on MRI increased the risk of vascular and nonvascular death and future vascular events in patients with atherosclerotic disease. Brain MRI was performed in 1309 patients with atherosclerotic disease from the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study. Infarcts were scored visually and volumetric assessment of white matter lesion was performed. Patients were followed for a median of 4.5 years (range, 0.2 to 7.1 years) for death, ischemic stroke, and ischemic cardiac complications. Cox regression models showed that presence of lacunar infarcts (n=229) increased the risk of vascular (hazard ratio, 2.6; 95% CI, 1.4 to 4.9) and nonvascular death (hazard ratio, 2.7; 95% CI, 1.3 to 5.3), adjusted for age, sex, vascular risk factors, nonlacunar infarcts, and white matter lesion. These risks were similar for patients with silent lacunar infarcts. White matter lesion volume (relative to total intracranial volume) increased the risk of vascular death (hazard ratio per milliliter increase, 1.03; 95% CI, 1.01 to 1.05) and white matter lesions in the upper quintile compared with lower quintiles increased risk of ischemic stroke (hazard ratio, 2.6; 95% CI, 1.3 to 4.9). Cerebral small vessel disease, with or without a history of cerebrovascular disease, is associated with increased risk of death and ischemic stroke in patients with atherosclerotic disease.

Carotid atherosclerosis and progression of brain atrophy: The SMART‐MR Study

Atherosclerosis has been implicated in the development of brain atrophy. However, support for this association comes from cross-sectional studies. Within the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with symptomatic atherosclerotic disease (mean age ± standard deviation, 58 ± 10 years; 80% men), magnetic resonance imaging of the brain was performed in 1,232 patients at baseline (2001-2005) and in 663 patients at follow-up (2006-2009). Brain segmentation was used to quantify total brain volume, cortical gray matter volume, and ventricular volume as indicators of global, cortical, and subcortical atrophy. At baseline, measurements of carotid intima-media thickness (CIMT) and carotid stenosis were performed. Carotid stenosis was classified into groups 0 of 50%, 50 of 70% (moderate), and >70% (severe) and into unilateral or bilateral stenosis. Cross-sectional regression analyses showed that both increased CIMT and carotid stenosis were associated with decreased relative total brain and cortical gray matter volume. Our prospective findings showed that after a mean follow-up of 3.9 years (range, 3.0-5.8 years), CIMT and moderate stenosis were not related to progression of brain atrophy. Only severe or bilateral carotid stenosis was related to progression of global atrophy (β [95% confidence interval (CI)], -0.52% [-0.84 to -0.20%], -0.94% [-1.45 to -0.43%]), cortical atrophy (β [95% CI], -0.75% [-1.37 to -0.13%], -1.34% [-2.32 to -0.35%]), and subcortical atrophy (β [95% CI], 0.06% [-0.02 to 0.16%], 0.13% [0.01 to 0.28%]). In a study of patients with atherosclerotic disease with 4 years of follow-up, only severe or bilateral carotid stenosis, and not moderate carotid stenosis and increased CIMT, were associated with progression of brain atrophy.

Progression of White Matter Lesion Volume and Health-Related Quality of Life in Patients with Symptomatic Atherosclerotic Disease: The SMART-MR Study

Objectives. Mechanisms influencing the course of physical and mental functioning after an atherosclerotic event are unclear. We examined effects of white matter lesion (WML) activity on changes in functioning in patients with symptomatic atherosclerotic disease. Methods. In 486 patients (58 ± 9 years) of the Second Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) study, volumetric WML measurements on 1.5T MRI were performed at baseline and 3.9 ± 0.4 years followup. Functioning was assessed with the modified Short-Form 12 (SF-12) questionnaire. Associations of WML progression with changes in functioning were adjusted for age, sex, and vascular risk factors. Results. Physical functioning (baseline: 44, 10th–90th percentile 29–55) improved, whereas mental functioning (baseline: 51, 10th–90th percentile 32–60) declined during followup. WML progression (highest quartile versus rest) contributed to a stronger decline in mental functioning (B = −1.76, 95% CI −3.11 to −0.42), but did not influence changes in physical functioning. Conclusions. Progression of WML volume contributes to a decline in mental functioning in patients with symptomatic atherosclerotic disease.

Age-related changes in hypothalamic–pituitary–adrenal axis activity in patients with manifest arterial disease

Reports on age-related changes of hypothalamic-pituitary-adrenal (HPA) axis activity are equivocal. In addition, subtle changes in HPA axis activity are associated with cardiovascular risk factors. This study evaluates the effect of age in a large sample of patients with arterial disease on several parts of the circadian rhythm of the HPA axis. Within the Second Manifestations of Arterial Disease-Magnetic Resonance (SMART-MR) study, a prospective cohort study among patients with manifest arterial disease, cross-sectional analyses were performed in 419 patients (age 63 ± 9 years). Circadian cortisol rhythm was assessed with six saliva samples, collected at awakening and 30, 45, and 60 min thereafter and at 10 and 11 pm. Furthermore, a low dose of dexamethasone (0.5 mg) was administered at 11 pm, and saliva was sampled the next morning to test the cortisol suppression. Linear regression analyses adjusted for sex, awakening time, workday, smoking, blood pressure, BMI, diabetes mellitus, and dyslipidemia showed that older age was associated with a blunted cortisol awakening response. Per year increase, the rise (β = -0.15 nmol/l; 95%CI -0.25 to -0.05) and diurnal pattern (β = -0.14 nmol/l; 95%CI -0.25 to -0.02) decreased. Furthermore, older age was associated with higher evening levels (β log transformed = 0.01; 95%CI 0.01-0.02) and higher mean cortisol after dexamethasone (β log transformed = 0.01; 95%CI 0.002-0.02). In patients with arterial disease, HPA axis activity showed reduced variability with older age, independent of cardiovascular risk factors.

Brain volumes and cerebrovascular lesions on MRI in patients with atherosclerotic disease. The SMART-MR study

ObjectiveTo estimate brain volumes, white matter lesion (WML) volume and asymptomatic infarcts on MRI in a large cohort of patients with atherosclerotic disease. MethodsWithin the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) study, a prospective cohort study on determinants and course of brain changes on MRI, cross-sectional analyses were performed in 1044 patients (mean age 58±10 years, 80% male) with coronary artery disease, cerebrovascular disease, peripheral arterial disease, or abdominal aortic aneurysm. Brain segmentation was used to quantify volumes of cortical gray matter, white matter, sulcal and ventricular cerebrospinal fluid, and WML. All volumes were expressed relative to intracranial volume. Brain infarcts were rated visually and distinctions were made between cortical infarcts, large subcortical infarcts, lacunar infarcts, and infarcts in the cerebellum and brainstem. ResultsWith older age a nonlinear (quadratic) decrease in total brain volume was observed and a nonlinear increase in ventricular volume and WML. Cortical gray matter volume showed a linear decrease with age and was stronger in men than in women. WML volumes also increased more strongly in men than in women, while ventricular volume decrease showed no sex difference. Silent brain infarcts were present in 14% of men and women, and increased to 24% of subjects aged 65 years or older. ConclusionIn a population with atherosclerotic diseases, decrease in brain volumes with increasing age is comparable with findings from the general population. However, vascular pathology on MRI, as indicated by white matter lesions and silent brain infarcts may be more common.

Total Cerebral Blood Flow and Hippocampal Volume in Patients with Arterial Disease. the SMART-MR Study

It has been suggested that compared with other brain tissues, the hippocampus in particular is vulnerable to chronic hypoperfusion. We investigated whether total parenchymal cerebral blood flow (pCBF) was associated with hippocampal atrophy, and also whether this relationship was modified by white matter lesions (WMLs). In a cross-sectional analysis within the SMART-MR (Second Manifestations of ARTerial disease-magnetic resonance) study, which is a cohort study among patients with arterial disease, total CBF (tCBF) and hippocampal volume were assessed in 392 patients (mean age: 62+/-9 years, 84% men). Total CBF was expressed in per 100 mL brain volume for obtaining pCBF. Manual volumetric measurements of the hippocampus were carried out on a three-dimensional fast field-echo T1-weighted magnetic resonance imaging scan with isotropic voxels. Automated brain segmentation was used to quantify volumes of the WML and the total brain. A linear regression analysis showed that reduced pCBF was not associated with smaller hippocampal volume after adjustments were made for age and sex. The association attenuated further after additional adjustments were made for vascular risk factors, lacunar infarcts, and WMLs (beta=0.01 mL per s.d. decrease in pCBF; 95% confidence interval: -0.06 to 0.08). The association was not modified by WML (P-value for interaction term pCBF*WML=0.84). We found no evidence of the fact that lower parenchymal blood flow contributes to the neurodegeneration of the hippocampus in a population of patients with arterial disease.