Covert Brain Infarcts Research Articles

HDL (High-Density Lipoprotein) Subspecies, Prevalent Covert Brain Infarcts, and Incident Overt Ischemic Stroke: Cardiovascular Health Study.

Whether HDL (high-density lipoprotein) is associated with risk of vascular brain injury is unclear. HDL is comprised of many apo (apolipoprotein) species, creating distinct subtypes of HDL. We utilized sandwich ELISA to determine HDL subspecies from plasma collected in 1998/1999 from 2001 CHS (Cardiovascular Health Study) participants (mean age, 80 years). In cross-sectional analyses, participants with higher apoA1 in plasma and lower apoE in HDL were less likely to have prevalent covert magnetic resonance imaging-defined infarcts: odds ratio for apoA1 Q4 versus Q1, 0.68 (95% CI, 0.50-0.93), and odds ratio for apoE Q4 versus Q1, 1.36 (95% CI, 1.01-1.84). Similarly, apoA1 in the subspecies of HDL that lacked apoC3, apoJ, or apoE was inversely related to covert infarcts, and apoE in the subspecies of HDL that lacked apoC3 or apoJ was directly related to covert infarcts in prospective analyses. In contrast, the concentrations of apoA1 and apoE in the complementary subspecies of HDL that contained these apos were unrelated to covert infarcts. Patterns of associations between incident overt ischemic stroke and apoA1, apoE, and apoA1 and apoE in subspecies of HDL were similar to those observed for covert infarcts but less pronounced. This study highlights HDL subspecies defined by apo content as relevant biomarkers of covert and overt vascular brain injury.

23 Prevalence of Covert Brain Infarction in Patients Undergoing Computed Tomography in the Emergency Department

Covert brain infarctions (CBI) are focal lesions detected on brain imaging consistent with ischemia, in the absence of a history of overt stroke or neurologic dysfunction. CBIs are associated with increased risk of future stroke and dementia. The frequency of this finding in emergency department (ED) patients is not well known. Stroke prevention interventions may be indicated in these patients, yet it is unclear whether ED patients are routinely alerted to the finding, or whether appropriate treatments are recommended. The goal of this study was to determine the frequency of CBI in patients undergoing computed tomography (CT) in the ED and to determine how often clinicians act on these findings or make patients aware of them. All patients over 50 years of age who underwent a non-contrast enhanced head CT in the ED from January to August 2018 were identified. Patients with a history of stroke, or prior brain imaging with any ischemia, were excluded, as were patients admitted to the hospital. Clinical data, including patient history and presence of CBI, were noted. Medical records were reviewed to determine whether the patients with CBI were informed of the finding, either verbally as documented or in their discharge instructions. Subsequent interventions for CBI patients were noted (neurology consultation or medication adjustment). A total of 832 patients were included in our analysis. The average age was 62 years and 50% were female (Table 1). CBI were present in 11% of patients (n=95). Patients with CBI were older and more likely to have hypertension. Only 9% (n=9) of CBI patients were clearly made aware of the finding. Of the patients with CBI, 27% (n = 26) were already on aspirin and 28% (n=27) on a statin. Of those not on medication, aspirin was added in 2 patients and blood pressure medication was added or adjusted in 2 patients. A statin medication was not started on any patients with CBI. Neurology consult was obtained in 9% (n=9) of patients with CBI, of whom 2 were made aware of the findings. The prevalence of CBI in patients over 50 presenting to the ED who undergo head CT and are subsequently discharged from the ED is 11%. Only 9% of these patients were made aware of the finding, with minimal intervention for stroke prevention at the time of their visit. Interventions targeting this population should be considered.

Phenotypes of Chronic Covert Brain Infarction in Patients With First-Ever Ischemic Stroke: A Cohort Study.

The aim of this study was to assess the rate of chronic covert brain infarctions (CBIs) in patients with acute ischemic stroke (AIS) and to describe their phenotypes and diagnostic value. This is a single-center cohort study including 1546 consecutive patients with first-ever AIS on magnetic resonance imaging imaging from January 2015 to December 2017. The main study outcomes were CBI phenotypes, their relative frequencies, location, and association with vascular risk factors. Any CBI was present in 574/1546 (37% [95% CI, 35%-40%]) of patients with a total of 950 CBI lesions. The most frequent locations of CBI were cerebellar in 295/950 (31%), subcortical supratentorial in 292/950 (31%), and cortical in 213/950 (24%). CBI phenotypes included lacunes (49%), combined gray and white matter lesions (30%), gray matter lesions (13%), and large subcortical infarcts (7%). Vascular risk profile and white matter hyperintensities severity (19% if no white matter hyperintensity, 63% in severe white matter hyperintensity, P<0.001) were associated with presence of any CBI. Atrial fibrillation was associated with cortical lesions (adjusted odds ratio, 2.032 [95% CI, 1.041-3.967]). Median National Institutes of Health Stroke Scale scores on admission were higher in patients with an embolic CBI phenotype (median National Institutes of Health Stroke Scale, 5 [2-10], P=0.025). CBIs were present in more than a third of patients with first AIS. Their location and phenotypes as determined by MRI were different from previous studies using computed tomography imaging. Among patients suffering from AIS, those with additional CBI represent a vascular high-risk subgroup and the association of different phenotypes of CBIs with differing risk factor profiles potentially points toward discriminative AIS etiologies.

Correction to: Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

Correction to: Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

Slow-Wave Sleep and MRI Markers of Brain Aging in a Community-Based Sample.

To test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI. We studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), APOE ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression. Less slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], p = 0.015; percentage, 0.16 [0.08], p = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], p = 0.034), and higher white matter hyperintensities volume (absolute duration, -0.12 [0.05], p = 0.010; percentage, -0.10 [0.04], p = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts. Loss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep.

Increased self‐reported sleepiness is associated with larger brain volume and less ischemic brain injury in a community sample

AbstractBackgroundSleepiness has been associated with an increased risk of Alzheimer’s disease (AD) and vascular dementia, but few studies have investigated its association with markers of accelerated brain aging. We evaluated the association between sleepiness and MRI measures; and whether the apolipoprotein E4 (APOE4) allele status moderates this relationship.MethodWe studied 492 participants (58.8 ± 8.8 years, 49.4%M) in the Framingham Heart Study aged &gt;40 years without significant neurological diseases, such as dementia and stroke. We used the Epworth Sleepiness Scale (ESS) to assess sleepiness. Brain MRI metrics were volumes of white matter hyperintensities (WMH), total brain, cortical gray matter (GM) and subcortical GM, all investigated as a percentage of total intracranial volume; we also identified covert brain infarcts (CBI). Linear and logistic regressions were used to assess the association between ESS scores and brain structure. Model 1 adjusted for age, age squared, sex, and time between the ESS and MRI (3.3 ± 1.0 years). Model 2 additionally adjusted for APOE4 allele carrier status, Framingham Stroke Risk Profile scores, sleep medication, body mass index, and depression. We included an interaction term between APOE4 allele status and ESS score, adjusted for model 1 covariates, to evaluate potential effect modification.ResultHigher ESS scores, indicating greater sleepiness, were associated with higher total brain volume (b = 0.33; SE = 0.13; p = 0.02), higher cortical GM volume (b = 0.26; SE = 0.12; p = 0.03), and a lower risk of CBI (OR = 0.57; 95%CI = 0.36‐0.93; p = 0.02) adjusted for both models 1 and 2 covariates. These associations were present when further adjusting for the apnea‐hypopnea index, education and habitual sleep duration. A significant interaction was observed between APOE4 and ESS scores (p = 0.008), where higher ESS was associated with higher cortical GM in non‐carriers (b = 0.43; SE = 0.14; p = 0.002). Conversely, in carriers, higher ESS was associated with lower cortical GM (b = ‐0.36; SE = 0.22; p = 0.09, trend).ConclusionIncreased self‐reported sleepiness was associated with findings of better brain health, including higher cortical GM volume and less CBI. Genetic susceptibility to AD modified this relationship, where increased sleepiness was associated with higher cortical GM volume only in APOE4 non‐carriers. Better brain health may be associated with higher self‐reported sleepiness via better cognition and self‐awareness in those who are not at increased risk of developing AD.

Brain imaging biomarkers of carotid artery disease.

Extracranial carotid artery atherosclerotic disease is a major contributor to ischemic stroke. Carotid atherosclerotic disease can present with a spectrum of findings ranging from mild carotid intima-media thickness to high-risk vulnerable carotid plaque features and carotid stenosis. Before leading to clinically overt stroke or transient ischemic attack, there may be other markers of downstream ischemia secondary to carotid atherosclerotic disease. In this review article, we will review some of the imaging findings that may be seen downstream to carotid artery disease on various imaging modalities, including hemodynamic and perfusional abnormalities which may be seen on CT, MR, or using other advanced imaging techniques, white matter hyperintensities on brain imaging, silent or covert brain infarctions, cerebral microbleeds, and regional and generalized cerebral volume loss. Many of these imaging findings are seen routinely on brain magnetic resonance imaging in patients without overt clinical symptoms. Despite frequently being asymptomatic, many of these imaging findings are also strongly associated with increased risk of future stroke, cognitive impairment, and even mortality. We will review the existing evidence underpinning the associations between these frequently encountered imaging findings and carotid artery atherosclerotic disease. Future validation of these imaging findings could lead to them being powerful biomarkers of cerebrovascular health.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Mid to Late Life Hypertension Trends and Cerebral Small Vessel Disease in the Framingham Heart Study.

The duration and lifetime pattern of hypertension is related to risk of stroke and dementia. In turn, cerebral small vessel disease (CSVD) is the most frequent form of cerebrovascular disease underlying dementia and stroke. Thus, study of the relation of mid to late life hypertension trends with CSVD late in life will help understand hypertension's role and inform preventive efforts of CSVD consequences. We studied 1686 Framingham Heart Study Offspring cohort participants free of stroke and dementia, who were examined in mid and late life, and had available brain magnetic resonance imaging during late life. We related hypertension trends between mid and late life (normotension-normotension N-N, normotension-hypertension N-H, hypertension-hypertension H-H) to cerebral microbleeds and covert brain infarcts (CBI), overall and stratified by brain topography. We used multivariable logistic regression analyses to calculate odds ratio and 95% CIs for CSVD measures. The prevalence of CSVD in late life was 8% for cerebral microbleeds and 13% for covert brain infarcts and increased with longer hypertension exposure across all brain regions. Compared with the trend pattern of N-N, both N-H and H-H trends had higher odds of mixed cerebral microbleeds (2.71 [1.08-6.80], and 3.44 [1.39-8.60], respectively); H-H also had higher odds of any cerebral microbleeds or covert brain infarcts (1.54 [1.12-2.20]), and any covert brain infarcts (1.55 [1.08-2.20]). The burden of CSVD also increased with longer hypertension exposure. Our results highlight hypertension having a major role in subclinical CSVD, across subtypes and brain regions, and call attention to improve recognition and treatment of hypertension early in life.

Covert Brain Infarction: Towards Precision Medicine in Research, Diagnosis, and Therapy for a Silent Pandemic.

Covert Brain Infarction: Towards Precision Medicine in Research, Diagnosis, and Therapy for a Silent Pandemic.

Association between PNPLA3 rs738409 G variant and MRI cerebrovascular disease biomarkers

IntroductionNonalcoholic fatty liver disease (NAFLD) has been associated with greater cerebral white matter hyperintensity (WMH) volume and microbleeds. The adiponutrin (PNPLA3) rs738409 G variant, a robust NAFLD susceptibility variant, has been variably associated with carotid atherosclerosis. We hypothesized that this variant is associated with WMH volume, microbleeds, covert brain infarction (CBI), and small perivascular spaces. MethodsWe performed a cross-sectional analysis of the Northern Manhattan Study-MRI Substudy. The associations between the rs738409 G variant allele and outcomes were assessed using linear regression for WMH volume, logistic regression for microbleeds and CBI, and Poisson regression for small perivascular spaces. Models were adjusted for age, sex, principal components, diabetes, and body mass index. ResultsWe included 1063 Northern Manhattan Study participants who had brain MRI and genotype data available (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%. The prevalence of any microbleeds and CBI were 8% and 18%, respectively. The median WMH volume and small perivascular space count score were 7.7 mL and 6, respectively. GG homozygosity, but not heterozygosity, was associated with WMH volume (β = 0.27; 95% CI, 0.03, 0.51) compared to non-carriers. Having at least one G allele was associated with the presence of microbleeds (Odds ratio, 1.78; 95% CI, 1.02, 3.12); the association was attenuated in other models. No associations were observed for CBI and small perivascular spaces. ConclusionThe PNPLA3 rs738409 G allele was associated with greater WMH volume, and inconsistent associations with microbleeds were seen.

Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD)5: Guidelines for management of vascular cognitive impairment.

IntroductionVascular disease is a common cause of dementia, and often coexists with other brain pathologies such as Alzheimer's disease to cause mixed dementia. Many of the risk factors for vascular disease are treatable. Our objective was to review evidence for diagnosis and treatment of vascular cognitive impairment (VCI) to issue recommendations to clinicians.MethodsA subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed areas of emerging evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assign the quality of the evidence and strength of the recommendations.ResultsUsing standardized diagnostic criteria, managing hypertension to conventional blood pressure targets, and reducing risk for stroke are strongly recommended. Intensive blood pressure lowering in middle‐aged adults with vascular risk factors, using acetylsalicylic acid in persons with VCI and covert brain infarctions but not if only white matter lesions are present, and using cholinesterase inhibitors are weakly recommended.ConclusionsThe CCCDTD has provided evidence‐based recommendations for diagnosis and management of VCI for use nationally in Canada, that may also be of use worldwide.

Cholesterol Variability and Cranial Magnetic Resonance Imaging Findings in Older Adults: The Cardiovascular Health Study.

Background and Purpose- Serum cholesterol variability, independent of mean, has been associated with stroke, white matter hyperintensities on cranial magnetic resonance imaging (MRI), and other cardiovascular events. We sought to assess the relationship between total serum cholesterol (TC) variability and cranial MRI findings of subclinical or covert vascular brain injury in a longitudinal, population-based cohort study of older adults. Methods- In the Cardiovascular Health Study, we assessed associations between intraindividual TC mean, trend, and variability over ≈5 years with covert brain infarction (CBI) and white matter grade (WMG) on cranial MRI. Mean TC was calculated for each study participant from 4 annual TC measurements between 2 MRI scans. TC trend was calculated as the slope of the linear regression of the TC measurements, and TC variability was calculated as the SD of the residuals from the linear regression. We evaluated the association of intraindividual TC variability with incident CBI and worsening WMG between 2 MRI scans in primary analyses and with prevalent CBI number and WMG on the follow-up MRI scan in secondary analyses. Results- Among participants who were eligible for the study and free of clinical stroke before the follow-up MRI, 17.9% of 1098 had incident CBI, and 27.8% of 1351 had worsening WMG on the follow-up MRI. Mean, trend, and variability of TC were not associated with these outcomes. TC variability, independent of mean and trend, was significantly associated with the number of CBI (β=0.009 [95% CI, 0.003-0.016] P=0.004; N=1604) and was associated with WMG (β, 0.009 [95% CI, -0.0002 to 0.019] P=0.055; N=1602) on the follow-up MRI. Conclusions- Among older adults, TC variability was not associated with incident CBI or worsening WMG but was associated with the number of prevalent CBI on cranial MRI. More work is needed to validate and to clarify the mechanisms underlying such associations.

Classification of Covert Brain Infarct Subtype and Risk of Death and Vascular Events.

Background and Purpose- To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods- We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results- At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8-0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1-0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3-3.7]) and vascular death (hazard ratio, 2.24 [1.29-3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions- CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Abstract WMP60: Adiponutrin Gene Polymorphism is Associated With Unexplained Embolic Covert Brain Infarction in the Northern Manhattan Study

Introduction: Adiponutrin, encoded by the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ), is involved in lipid metabolism. The PNPLA3 gene rs738409 C&gt;G single nucleotide polymorphism (SNP), particularly when homozygous, is strongly associated with non-alcoholic fatty liver disease, which has been associated with vascular disease. We hypothesized that this PNPLA3 SNP is associated with covert brain infarction (CBI). Methods: We performed a cross-sectional analysis of individuals with rs738409 genotype data in the Northern Manhattan Study MRI sub-study. The exposure was rs738409 allele frequency; noncarriers (CC genotype) served as the reference. The primary outcome was the presence of any CBI. Secondary outcomes were independently adjudicated CBI mechanism categories based on available baseline and follow-up history and imaging data: large artery atherosclerosis, cardioembolism, small vessel disease, and embolism of unknown source (EUS). Multivariable logistic regression was used to assess the relationship between SNP frequency and CBI. Principle component analysis was used to account for population-specific variations in SNP distributions. Models were adjusted for principal components, demographics, vascular risk factors, and alcohol, statin, and antiplatelet use. Results: The sample included 1,063 Northern Manhattan Study participants (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%, with 381 GC heterozygotes and 67 GG homozygotes. The prevalence of CBI was 18% (N=185): 10% (N=19) large artery atherosclerosis, 12% (N=22) cardioembolism, 16% (N=30) small vessel disease, and 62% (N=114) EUS. Individuals heterozygous for the G allele were not at greater odds of any CBI (OR 0.8; 95% CI 0.6-1.2) or any individual type of CBI, compared to CC homozygotes. The odds of any CBI were also not increased among GG homozygotes (OR 1.6; 95% CI 0.8-3.2). However, GG homozygotes were at higher odds of EUS (OR 2.3; 95% CI 1.1-4.8), but not CBI due to other mechanisms. Conclusion: Homozygosity for the PNPLA3 rs738409[G] SNP was associated with greater odds of EUS and may account for some unexplained strokes. Further study is warranted to understand the contribution of PNPLA3 variants to cerebrovascular disease.

Circulating cortisol and cognitive and structural brain measures: The Framingham Heart Study.

To assess the association of early morning serum cortisol with cognitive performance and brain structural integrity in community-dwelling young and middle-aged adults without dementia. We evaluated dementia-free Framingham Heart Study (generation 3) participants (mean age 48.5 years, 46.8% men) who underwent cognitive testing for memory, abstract reasoning, visual perception, attention, and executive function (n = 2,231) and brain MRI (n = 2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear and logistic regression to assess the relations of cortisol (categorized in tertiles, with the middle tertile as referent) to measures of cognition, MRI volumes, presence of covert brain infarcts and cerebral microbleeds, and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE, and vascular risk factors. Higher cortisol (highest tertile vs middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain and occipital and frontal lobar gray matter volumes. Higher cortisol was associated with multiple areas of microstructural changes (decreased regional FA), especially in the splenium of corpus callosum and the posterior corona radiata. The association of cortisol with total cerebral brain volume varied by sex (p for interaction = 0.048); higher cortisol was inversely associated with cerebral brain volume in women (p = 0.001) but not in men (p = 0.717). There was no effect modification by the APOE4 genotype of the relations of cortisol and cognition or imaging traits. Higher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic younger to middle-aged adults, with the association being evident particularly in women.

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

Blood Pressure and Heart Rate Measures Associated With Increased Risk of Covert Brain Infarction and Worsening Leukoaraiosis in Older Adults.

In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings. In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15% and worsening white matter grade in 27%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95% confidence interval, 1.12-1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95% confidence interval, 1.24-1.69). These findings persisted in secondary and sensitivity analyses. Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.

Abstract TP164: Blood Pressure and Heart Rate Measures and Risk of Covert Brain Infarction and Worsening White Matter in Older Adults

Introduction: Covert brain infarction (CBI) and worsening white matter grade (WMG) on serial MRI are associated with increased risk for ischemic stroke and dementia. Hypothesis: We sought to evaluate the association of various measures of blood pressure and heart rate with these MRI findings. Methods: In the Cardiovascular Health Study, a longitudinal cohort study of cardiovascular disease in older adults, we used relative risk regression to assess the risk of incident CBI and worsening WMG associated with mean, variability, and trend in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) measured at four or more annual clinic visits between two brain MRIs. We included participants who underwent both brain MRIs and had no change in antihypertensive medication status, no CBI on the initial MRI, and no stroke before the follow-up MRI. Results: Among 897 eligible participants, incident CBI occurred in 15% and worsening WMG in 27%. Mean SBP mean was strongly associated with increased risk for incident CBI (RR per 10 mmHg 1.29; 95% CI, 1.13-1.47), and DBP mean was strongly associated with increased risk for worsening WMG (RR per 10 mmHg 1.43; 95% CI, 1.23-1.67). DBP variability may be associated with incident CBI (RR per 10 mmHg 1.71; 95% CI, 1.10-2.65), The HR measures were not associated with these MRI findings. Conclusions: Elevated mean levels of blood pressure contribute to covert cerebrovascular diseases. Control of mean blood pressure levels, even in older adults, remains a high priority for prevention of vascular brain injury.

Long-Term Clinical Impact of Vascular Brain Lesions on Magnetic Resonance Imaging in Older Adults in the Population.

White matter hyperintensity (WMH) volume and covert brain infarcts are highly prevalent in older adults and are often asymptomatic. We compared the impact of WMH volume and brain infarcts on risk of clinical stroke and dementia in older adults in the population. Participants were 1677 individuals aged ≥65 years from the 3-City Dijon study, who were free of stroke and dementia at baseline, followed-up for ≤12 years. Both lesion types were comparably associated with an increased risk of stroke (adjusted hazard ratio, 1.72; 95% confidence interval, 1.24-2.40 for WMH volume and hazard ratio, 2.15; 95% confidence interval, 1.18-3.93 for brain infarcts), but only WMH volume was associated with an increased risk of dementia (hazard ratio, 1.41; 95% confidence interval, 1.09-1.83). The differential impact of WMH and brain infarcts on clinical stroke and dementia suggests relatively different prognostic value of the 2 lesions. WMHs may represent a particularly pertinent magnetic resonance imaging intermediate marker that can be utilized in optimizing prevention strategies for both stroke and dementia in primary care and in trials.