Ophthalmic conditions associated with dementia risk: The Cardiovascular Health Study.

INTRODUCTION: Ophthalmic conditions and dementia appear to overlap and may share common pathways, but research has not differentiated dementia subtypes. METHODS: Diagnoses of cataracts, age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma were based on medical histories and International Classification of Diseases, Ninth Revision (ICD-9) codes for 3375 participants from the Cardiovascular Health Study. Dementia, including Alzheimer's disease (AD) and vascular dementia (VaD), was classified using standardized research criteria. RESULTS: Cataracts were associated with AD (hazard ratio [HR] = 1.34; 95% confidence interval [CI] = 1.01-1.80) and VaD/mixed dementia (HR = 1.41; 95% CI = 1.02-1.95). AMD was associated with AD only (HR = 1.87; 95% CI = 1.13-3.09), whereas DR was associated with VaD/mixed dementia only (HR = 2.63; 95% CI = 1.10-6.27). DISCUSSION: Differential associations between specific ophthalmic conditions and dementia subtypes may elucidate pathophysiologic pathways. Lack of association between glaucoma and dementia was most surprising from these analyses.

Revised Framingham Stroke Risk Score, Nontraditional Risk Markers, and Incident Stroke in a Multiethnic Cohort.

BACKGROUND AND PURPOSE: Limited data exist on the performance of the revised Framingham Stroke Risk Score (R-FSRS) and the R-FSRS in conjunction with nontraditional risk markers. We compared the R-FSRS, original FSRS, and the Pooled Cohort Equation for stroke prediction and assessed the improvement in discrimination by nontraditional risk markers. METHODS: Six thousand seven hundred twelve of 6814 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) were included. Cox proportional hazard, area under the curve, net reclassification improvement, and integrated discrimination increment analysis were used to assess and compare each stroke prediction risk score. Stroke was defined as fatal/nonfatal strokes (hemorrhagic or ischemic). RESULTS: After mean follow-up of 10.7 years, 231 of 6712 (3.4%) strokes were adjudicated (2.7% ischemic strokes). Mean stroke risks using the R-FSRS, original FSRS, and Pooled Cohort Equation were 4.7%, 5.9%, and 13.5%. The R-FSRS had the best calibration (Hosmer-Lemeshow goodness-of-fit, χ2=6.55; P=0.59). All risk scores were predictive of incident stroke. C statistics of R-FSRS (0.716) was similar to Pooled Cohort Equation (0.716), but significantly higher than the original FSRS (0.653; P=0.01 for comparison with R-FSRS). Adding nontraditional risk markers individually to the R-FSRS did not improve discrimination of the R-FSRS in the area under the curve analysis, but did improve category-less net reclassification improvement and integrated discrimination increment for incident stroke. The addition of coronary artery calcium to R-FSRS produced the highest category-less net reclassification improvement (0.36) and integrated discrimination increment (0.0027). Similar results were obtained when ischemic strokes were used as the outcome. CONCLUSIONS: The R-FSRS downgraded stroke risk but had better calibration and discriminative ability for incident stroke compared with the original FSRS. Nontraditional risk markers modestly improved the discriminative ability of the R-FSRS, with coronary artery calcium performing the best.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

Associations Between Measures of Disability and Quality of Life at Three Months After Stroke.

Background: The modified Rankin Scale (mRS), which measures degree of disability in daily activities, is the most common outcome measure in stroke research. Quality of life (QoL), however, is impacted by factors other than disability. The goal of this study was to assess the correlation between functional dependence and a more patient-centered QoL measure, the European QoL visual analog scale (EQ VAS). Methods: We reviewed prehospital and hospital records from 11 acute care hospitals in Seattle, Washington (USA) from June 2000 to January 2003 for this cohort study. Patients with a final diagnosis of stroke were contacted three to four months after stroke, and mRS and EQ VAS were assessed. Good QoL was defined as EQ VAS ≥65. Results: Of 760 patients with stroke, 346 were available at three to four months. Most (296, 85.5%) had ischemic stroke. Overall, mRS and QoL were negatively correlated (Spearman's ρ -0.53, p < 0.001). Percentage of good QoL decreased as mRS increased from 0 to 5 (88%, 70%, 52%, 50%, 31%, 20%, respectively, p < 0.001). However, 36% (n = 62) of patients with dependent mRS (3-5, n = 174) reported good QoL, and 30% (n = 52) of patients with independent mRS (0-2, n = 172) reported poor QoL. In multivariable analysis, older age, male gender, and absence of dementia, were associated with good QoL despite dependent mRS; atrial fibrillation was associated with poor QoL despite independent mRS. Conclusions: QoL decreases with increasing mRS, but exceptions exist with good QoL despite high mRS. To provide patient-centered care, clinicians and researchers should avoid equating disability with QoL after stroke.

Association of Plasma YKL-40 With MRI, CSF, and Cognitive Markers of Brain Health and Dementia.

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. RESULTS: Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (ß = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (ß = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. DISCUSSION: Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF. We implemented a multipronged follow-up, across fluids, platforms, and ancestries (Europeans and East-Asian), including testing associations of direct plasma protein measurements with MRI-cSVD. We highlight 16 proteins robustly associated in both CSF and plasma, with 24/4 proteins identified in CSF/plasma only. cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing). Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects. This first cSVD proteogenomic signature opens new avenues for biomarker and therapeutic developments.

17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status.

BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.

Assessment of Risk Factors and Clinical Importance of Enlarged Perivascular Spaces by Whole-Brain Investigation in the Multi-Ethnic Study of Atherosclerosis.

Importance: Enlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain. Objective: Toperform a whole-brain investigation of ePVSs in a large community-based cohort. Design, Setting, and Participants: This cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included. Main Outcomes and Measures: Enlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models. Results: In the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (ß = 3.59 × 10-3; 95% CI, 2.80 × 10-3 to 4.39 × 10-3), systolic blood pressure (ß = 8.35 × 10-4; 95% CI, 5.19 × 10-4 to 1.15 × 10-3), use of antihypertensives (ß = 3.29 × 10-2; 95% CI, 1.92 × 10-2 to 4.67 × 10-2), and negatively associated with Black race (ß = -3.34 × 10-2; 95% CI, -5.08 × 10-2 to -1.59 × 10-2). Thalamic ePVS volume was positively associated with age (ß = 5.57 × 10-4; 95% CI, 2.19 × 10-4 to 8.95 × 10-4) and use of antihypertensives (ß = 1.19 × 10-2; 95% CI, 6.02 × 10-3 to 1.77 × 10-2). Insular region ePVS volume was positively associated with age (ß = 1.18 × 10-3; 95% CI, 7.98 × 10-4 to 1.55 × 10-3). Brainstem ePVS volume was smaller in Black than in White participants (ß = -5.34 × 10-3; 95% CI, -8.26 × 10-3 to -2.41 × 10-3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (ß = 1.14 × 10-4; 95% CI, 3.38 × 10-5 to 1.95 × 10-4) and negatively associated with age (ß = -3.38 × 10-4; 95% CI, -5.40 × 10-4 to -1.36 × 10-4). Temporal region ePVS volume was negatively associated with age (ß = -1.61 × 10-2; 95% CI, -2.14 × 10-2 to -1.09 × 10-2), as well as Chinese American (ß = -2.35 × 10-1; 95% CI, -3.83 × 10-1 to -8.74 × 10-2) and Hispanic ethnicities (ß = -1.73 × 10-1; 95% CI, -2.96 × 10-1 to -4.99 × 10-2). Conclusions and Relevance: In this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

Hypertension, white matter hyperintensities, and concurrent impairments in mobility, cognition, and mood: the Cardiovascular Health Study.

BACKGROUND: Our objective was to investigate the association between hypertension and concurrent impairments in mobility, cognition, and mood; the role of brain white matter hyperintensities in mediating this association; and the impact of these impairments on disability and mortality in elderly hypertensive individuals. METHODS AND RESULTS: -Blood pressure, gait speed, digit symbol substitution test, and the Center for Epidemiological Studies Depression Scale were measured yearly (1992-1999) on 4700 participants in the Cardiovascular Health Study (age: 74.7, 58% women, 17% blacks, 68% hypertension, 3600 had brain magnetic resonance imaging in 1992-1993, survival data 1992-2005). Using latent profile analysis at baseline, we found that 498 (11%) subjects had concurrent impairments and 3086 (66%) were intact on all 3 measures. Between 1992 and 1999, 651 (21%) became impaired in all 3 domains. Hypertensive individuals were more likely to be impaired at baseline (odds ratio 1.23, 95% confidence interval 1.04 to 1.42, P=0.01) and become impaired during the follow-up (hazard ratio=1.3, 95% confidence interval 1.02 to 1.66, P=0.037). A greater degree of white matter hyperintensities was associated with impairments in the 3 domains (P=0.007) and mediated the association with hypertension (P=0.19 for hypertension after adjusting for white matter hyperintensities in the model, 21% hazard ratio change). Impairments in the 3 domains increased subsequent disability with hypertension (P<0.0001). Hypertension mortality also was increased in those impaired (compared with unimpaired hypertensive individuals: HR=1.10, 95% confidence interval 1.04 to 1.17, P=0.004). CONCLUSIONS: Hypertension increases the risk of concurrent impairments in mobility, cognition, and mood, which increases disability and mortality. This association is mediated in part by microvascular brain injury.

Cardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study.

Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.

Rationale and design of the Home Automatic External Defibrillator Trial (HAT).

Most cardiac arrests occur in the home, where emergency medical services (EMS) systems are challenged to provide timely care. Because a large proportion of sudden cardiac arrests (SCAs) are due to ventricular tachycardia or ventricular fibrillation, home use of an automated external defibrillator (AED) might offer an opportunity to decrease mortality in those at risk. Predicting who will have a cardiac arrest in the general population is difficult. Individuals at high risk are usually easily identified and may become candidates for implantable cardioverter defibrillators. It is within the population at lower risk where home AEDs may be most useful. The purpose of the Home Automatic External Defibrillator Trial (HAT) is to test whether providing home access to an AED can improve survival in patients at modest risk of SCA, such as those surviving an anterior myocardial infarction but in whom implantable cardioverter defibrillator therapy is not deemed necessary. Between January 23, 2003, and October 20, 2005, 7001 patients were enrolled, with completion of follow-up scheduled for September 30, 2007. Randomization was conducted in a 1:1 fashion between control therapy, comprising the standard lay response to SCA (calling the EMS and performing cardiopulmonary resuscitation), and the use of an AED first, followed by calling the EMS and performing cardiopulmonary resuscitation. The primary end point is all-cause mortality. Secondary outcomes include survival from SCA (witnessed and unwitnessed, in home and out of home), incremental cost-effectiveness, and quality of life measures for both the patient and the spouse/companion. The results of the trial should be available in mid 2008.

Methodological design for economic evaluation in Public Access Defibrillation (PAD) trial.

OBJECTIVE: Our objective is to describe the rationale and methods for the economic analysis of the PAD trial. The objective of this analysis is to assess whether automated external defibrillators (AEDs) use by lay responders is good value for money. METHODS: Design. This economic evaluation is being conducted concurrently with a randomized trial of (a) control--training to recognize arrest, access 911, and administer cardiopulmonary resuscitation (CPR) while awaiting arrival of emergency medical services providers versus (b) intervention--training to recognize arrest, access 911, administer CPR, and use an AED while awaiting emergency medical services providers. Lay responders in either group were trained to deliver the study intervention. Population. Participating sites identified distinct units with a population of at least 250 people aged > or = 50 years. Outcome. The primary economic outcome is the incremental cost-effectiveness ratio of intervention versus control. RESULTS: Nine hundred ninety-three units including 1260 public and residential locations were randomized. There were 30 survivors in the intervention group and 15 in the control group (P = .03). Sampling will identify program and health care costs. A societal perspective will be adopted. Incremental cost effectiveness will be estimated by using bootstrapping and decision analytic modeling. CONCLUSION: The study will demonstrate whether defibrillation by lay responders improves outcomes at reasonable cost. If so, then the thousands of lives will be improved annually. If not, then limited resources can be invested in other interventions. Our methods also provide a framework for economic evaluations of other interventions for acute cardiovascular events.

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.

OBJECTIVES: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. METHODS: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). RESULTS: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. CONCLUSIONS: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.