Wasserman, Bruce A.

Abstract Cardiovascular disease remains a prominent cause of disability and premature death worldwide. Within this spectrum, carotid artery atherosclerosis is a complex and multifaceted condition, and a prominent precursor of acute ischaemic stroke and other cardiovascular events. The intricate interplay among inflammation, oxidative stress, endothelial dysfunction, lipid metabolism, and immune responses participates in the development of lesions, leading to luminal stenosis and potential plaque instability. Even non-stenotic plaques can precipitate a sudden cerebrovascular event, regardless of the degree of luminal encroachment. In this context, carotid imaging modalities have proved their efficacy in providing in vivo characterization of plaque features, contributing substantially to patient risk stratification and clinical management. This review emphasizes the importance of identifying high-risk individuals by use of current imaging modalities, biomarkers, and risk stratification tools. Such approaches inform early intervention and the implementation of personalized therapeutic strategies, ultimately enhancing patient outcomes in the realm of cardiovascular disease management.

AbstractBackground and purposeLower left atrial (LA) function is associated with higher dementia risk and may be mechanistically linked through vascular brain injury, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities study, we assessed the cross‐sectional association between LA function and brain magnetic resonance imaging (MRI) markers of vascular brain injury.MethodsWe included 1488 participants who were free of prevalent dementia, stroke, or atrial fibrillation and who underwent a two‐dimensional echocardiogram and brain MRI in 2011–2013 (mean [± standard deviation] age 76 [± 5] years, 60% female, 27% Black). LA function measures (reservoir, conduit, contractile strain) were assessed in quartiles. Brain MRI measures included cerebral microbleeds, brain infarcts, and white matter hyperintensity (WMH) volume. Logistic regression was used for dichotomous outcomes. Linear regression was used for WMH volume.ResultsOverall, 343 (23%) and 344 participants (23%) had ≥1 cerebral microbleed or brain infarct. After multivariable adjustments, the lowest LA reservoir and conduit strain quartiles (vs. highest quartile) were associated with higher odds of the presence of ≥1 cerebral microbleed (odds ratios [95% confidence intervals] 1.78 [1.42–2.22] and 1.52 [1.22–1.90]). Compared to the highest quartile, participants in the lowest LA conduit strain quartile had 1.51 (95% confidence interval 1.22–1.88) times higher odds of having ≥1 brain infarct. Lower LA contractile strain was associated with lower odds of brain infarcts. No association with WMH volume was noted.ConclusionsWe found that LA reservoir and conduit strain were associated with cerebral microbleeds and brain infarcts. Lower LA function may be linked to dementia risk via vascular brain injury. Prospective studies are needed to confirm these findings.

BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17–2.11), 1.41 (1.02–1.95), and 1.94 (1.32–2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Introduction: Incident intracerebral hemorrhage (ICH) is an uncommon medical event that can lead to devastating outcomes, including death. Small vessel disease (SVD), as measured by cerebral microbleeds (CMBs) and white matter hyperintensities (WMH), has been associated with risk factors and might be a predictor of incident ICH. CMBs result from irregularities in brain vessel structure due to chronic hypertension and cerebral amyloid angiopathy. These microhemorrhages are a possible risk factor for ICH. Methods: A cohort of ARIC (Atherosclerosis Risk in Communities) participants underwent 3T MRI at visit 5 (2011-2013). CMBs were assessed using a T2* gradient echo. CMBs are homogenous hypointense lesions ≤10 mm in diameter. WMH volumes were derived from FLAIR images using an automated program to measure the volumetric burden of leukoaraiosis. During 10 years of follow-up, incident ICH was noted in 7 (0.4%) out of 1,656 participants were dichotomized based on the presence of CMB and the median of WMH volume. Results: ARIC subjects (n=1656, mean age=76±5 years; 40% men; 26% African American race) underwent MRI. CMBs were present in 385 (23.25%) patients out of 1656. ICH occurred in 0.16% and 1.30% of patients without CMBs and with CMBs, respectively. Kaplan Meier (KM) survival analysis between CMBs and ICH was significant (logrank p=0.002). Cox Regression yielded a significant crude hazards ratio (HR 8.7, 95% CI 1.7-44.7, p=0.010). Adjustment for age, gender, race, and hypertension was also significant (HR 9.9, 95% CI 1.9-52.0, p=0.07). KM survival analysis between WMH median (11.68 cm 3 ) and ICH was significant (logrank p=0.006). Figure 1 displays the KM curves of those with and without CMBs and the incidence of ICH as well as those below and above WMH median and incidence of ICH. Conclusion: CMBs and WMH detected by MRI appear to be an important predictor for the occurrence of incident ICH. Further research is needed to observe if MRI could be used to screen subjects at high-risk for elevated risk of incident ICH.

Background: Lower (worse) left atrial (LA) function is associated with higher dementia risk. It is unclear whether lower LA function is associated with vascular brain injury on brain MRI, an established correlate for higher dementia risk. Using data from the Atherosclerosis Risk in Communities (ARIC) study, we assessed the cross-sectional association between LA function measures and brain MRI markers of vascular brain injury (cerebral microbleeds, brain infarcts). Hypothesis: Participants with lower LA function will be more likely to have presence of > 1 cerebral microbleed or brain infarct. Methods: ARIC participants who had both an echocardiogram and brain MRI at visit 5 (2011-13) were included. We excluded those with prevalent dementia, stroke, or atrial fibrillation. LA function measures were obtained from 2D-echocardiograms and assessed in quartiles (highest quartile was the reference). Brain MRI measures were assessed as the presence or absence of > 1 cerebral microbleed or brain infarct. Logistic regression was used. Results: Of the 1502 participants (mean [SD] age 76 [5], 60% female, 27% Black) in this analysis, 345 (23%) and 351 (23%) had > 1 cerebral microbleed or brain infarct present. Compared to the highest quartile, lower LA reservoir and conduit strain quartiles were associated with higher odds of cerebral microbleeds. LA contractile strain was not associated with cerebral microbleeds. Compared to the highest quartile, the lowest LA conduit strain quartile, but not reservoir strain, was associated with higher odds of brain infarcts. LA contractile strain was inversely associated with brain infarcts. Conclusion: In this community-based cohort, lower LA function was cross-sectionally associated with cerebral microbleeds and brain infarcts. The inverse relationship with LA contractile strain may be due to contractile function compensating for a decrease in early diastolic filling. Prospective studies are needed to confirm these findings.

Abstract In children with arterial ischemic stroke (AIS), the definitive diagnosis of stroke subtype and confirmation of stroke etiology is necessary to mitigate stroke morbidity and prevent recurrent stroke. The common causes of AIS in children are sharply differentiated from the common causes of adult AIS. A comprehensive, structured diagnostic approach will identify the etiology of stroke in most children. Adequate diagnostic evaluation relies on advanced brain imaging and vascular imaging studies. A variety of medical and surgical secondary stroke prevention strategies directed at the underlying cause of stroke are available. This review aims to outline strategies for definitive diagnosis and secondary stroke prevention in children with AIS, emphasizing the critical role of neuroimaging.

Abstract Numerous factors make the initial diagnostic evaluation of children with suspected arterial ischemic stroke (AIS) a relatively unsettling challenge, even for the experienced stroke specialist. The low frequency of pediatric AIS, diversity of unique age-oriented stroke phenotypes, and unconventional approaches required for diagnosis and treatment all contribute difficulty to the process. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with diagnostic decision making in the initial phase of care.

Abstract Modern hyperacute reperfusion therapies including intravenous thrombolysis and mechanical thrombectomy have transformed the management of arterial ischemic stroke (AIS) in adults. Multiple randomized clinical trials have demonstrated that these therapies enable remarkable improvements in clinical outcome for properly selected patients with AIS. Because pediatric patients were excluded from predicate clinical trials, there is a conspicuous lack of data to guide selection of therapies and inform age-adjusted and pathology-oriented treatment modifications for children. Specifically, technical guidance concerning treatment eligibility, drug dosing, and device implementation is lacking. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with therapeutic decision making.

Introduction: Stiffening of the aorta is associated with increased pulse pressure and transmission of pulsatile energy into the cerebral circulation. An association between increased aortic stiffening with intracranial atherosclerotic disease (ICAD) has not been widely studied. We tested the hypothesis that loss of aortic elasticity (i.e. higher aortic stiffness) is associated with a higher presence of ICAD. Methods: ARIC-NCS participants (n=1412; mean age: 76 years; 42% male; 30% Black) with measures of aortic stiffness and vascular brain magnetic resonance imaging (MRI) at the visit 5 (2011-2013) examination were included. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV) using the VP-1000 Plus device (Omron Co., Japan). cfPWV was discretized into high vs. low aortic stiffness based on the upper 25 th percentile, 13.4 m/s. Brain MRI was performed on 3.0 Tesla scanners using a standardized protocol that included an MR angiography (MRA) and high isotropic resolution vessel MRI. Presence of ICAD was defined as eccentric wall thickening with or without luminal stenosis on MRA. We first examined the functional form relationship between continuous measures of cfPWV and ICAD. Comparing those with high vs. low aortic stiffening, we estimated the prevalence odds of ICAD using logistic regression. Models were adjusted for age, sex, race-center, education, smoking, heart rate, blood-pressure lowering medication, diabetes, LDL-cholesterol, and minutes/week of physical activity. Sampling weights were used for generalizability to the full ARIC cohort at visit 5. We tested for effect modification by race, sex, diabetes, central systolic blood pressure, and use of blood pressure-lowering medication. Results: The mean cfPWV was higher among participants with ICAD (12.6 ± 3.2 m/s) compared to those without ICAD (11.2 ± 2.9 m/s). cfPWV was associated with ICAD in a monotonic, linear fashion (p<0.05). The presence of ICAD was 50.6% among participants with high aortic stiffness (cfPWV above the upper 25th percentile; n=354) compared to 30.2% among participants with low aortic stiffness (n=1058). Compared to participants with low aortic stiffness, those with high aortic stiffness had two-fold higher odds of ICAD (odds ratio (OR): 1.97, 95% confidence interval (CI): 1.68, 2.33). No statistically significant modification of this association was observed. Results were robust to exclusions for prevalent stroke (n=43) and prevalent cardiovascular disease (n=153). Conclusions: Aortic stiffness, a highly prevalent trait among older men and women, is associated with ICAD presence quantified by magnetic resonance angiography. Aortic stiffness, its risk factors and the factors associated with the preservation of aortic elasticity, may play a role in modifying the risk of intracranial atherosclerosis.