Steven M. Greenberg

Vascular Contributions to Cognitive Impairment and Dementia A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Background and Purpose— This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Methods— Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee. Results— The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people. Conclusions— Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.

Guidelines for the Primary Prevention of Stroke A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches to atherosclerotic disease of the cervicocephalic circulation, and antithrombotic treatments for preventing thrombotic and thromboembolic stroke. Further recommendations are provided for genetic and pharmacogenetic testing and for the prevention of stroke in a variety of other specific circumstances, including sickle cell disease and patent foramen ovale.

Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration

Summary Cerebral small vessel disease (SVD) is a common accompaniment of ageing. Features seen on neuroimaging include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. SVD can present as a stroke or cognitive decline, or can have few or no symptoms. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive deficits, physical disabilities, and other symptoms of neurodegeneration. Terminology and definitions for imaging the features of SVD vary widely, which is also true for protocols for image acquisition and image analysis. This lack of consistency hampers progress in identifying the contribution of SVD to the pathophysiology and clinical features of common neurodegenerative diseases. We are an international working group from the Centres of Excellence in Neurodegeneration. We completed a structured process to develop definitions and imaging standards for markers and consequences of SVD. We aimed to achieve the following: first, to provide a common advisory about terms and definitions for features visible on MRI; second, to suggest minimum standards for image acquisition and analysis; third, to agree on standards for scientific reporting of changes related to SVD on neuroimaging; and fourth, to review emerging imaging methods for detection and quantification of preclinical manifestations of SVD. Our findings and recommendations apply to research studies, and can be used in the clinical setting to standardise image interpretation, acquisition, and reporting. This Position Paper summarises the main outcomes of this international effort to provide the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE).

Cerebral microbleeds a guide to detection and interpretation

Cerebral microbleeds (CMBs) are increasingly recognised neuroimaging findings in individuals with cerebrovascular disease and dementia, and in normal ageing. There has been substantial progress in the understanding of CMBs in recent years, particularly in the development of newer MRI methods for the detection of CMBs and the application of these techniques to population-based samples of elderly people. In this Review, we focus on these recent developments and their effects on two main questions: how CMBs are detected, and how CMBs should be interpreted. The number of CMBs detected depends on MRI characteristics, such as pulse sequence, sequence parameters, spatial resolution, magnetic field strength, and image post-processing, emphasising the importance of taking into account MRI technique in the interpretation of study results. Recent investigations with sensitive MRI techniques have indicated a high prevalence of CMBs in community-dwelling elderly people. We propose a procedural guide for identification of CMBs and suggest possible future approaches for elucidating the role of these common lesions as markers for, and contributors to, small-vessel brain disease.

Variants conferring risk of atrial fibrillation on chromosome 4q25.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart.

Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation

Context The appropriate level of warfarin anticoagulation in elderly patients with atrial fibrillation has been debated because of an age-associated increase in intracerebral hemorrhage. Contribution Patients with atrial fibrillation and intracerebral hemorrhage who were receiving anticoagulation were matched with similar patients who did not develop intracerebral hemorrhage. Although intracerebral hemorrhage was associated with increasing age (especially > 85 years) and increasing international normalized ratios (INRs) (especially > 3.5), the incidence of intracerebral hemorrhage was not statistically different in patients with INRs less than 2.0 and those with INRs between 2.0 and 3.0. This was true even among those older than 75 years of age. Implications Risk for intracerebral hemorrhage is not diminished in elderly patients with atrial fibrillation when anticoagulation is maintained below an INR of 2.0. The Editors Intracranial hemorrhage is the most dangerous complication of warfarin anticoagulant therapy because of its high short-term risk for death and severe neurologic deficit (1-5). Warfarin is extremely effective in reducing the risk for ischemic stroke associated with atrial fibrillation (6, 7). However, fear of hemorrhage may prompt some physicians to avoid prescribing anticoagulation (8), especially in elderly patients, who appear to have a higher risk for hemorrhage (8-13). Prominent recent guidelines recommend using lower-intensity anticoagulation for the primary prevention of stroke in patients older than 75 years of age who have atrial fibrillation (14) and suggest a target international normalized ratio (INR) range of 1.6 to 2.5, despite evidence that the risk for ischemic stroke increases sharply at INRs less than 2.0 (15, 16). Previous studies have not thoroughly addressed the relationship of age and anticoagulation intensity to the risk for intracranial hemorrhage among patients with atrial fibrillation (1, 2). A study of 121 patients with warfarin-associated intracranial hemorrhage used the now-outdated prothrombin time ratio as a measure of anticoagulation intensity and did not specifically address risk in patients with atrial fibrillation (1). Earlier studies also included patients receiving anticoagulation for mechanical valves, whose risk-to-benefit ratio is different from that of patients with atrial fibrillation (1, 2, 17). As the number of individuals with atrial fibrillation increases (18-21) and as a greater proportion of older adults receive anticoagulant therapy (22), more precise data are needed about the association of age, INR, and risk for intracranial hemorrhage. Intracranial hemorrhage, although critically important, is an uncommon complication among patients with atrial fibrillation who are receiving anticoagulation. As a result, randomized trials and cohort studies have difficulty accumulating enough hemorrhage events to powerfully assess risk factors. To address these limitations, we performed a large casecontrol study to evaluate the relationship of increasing age and INR to the risk for intracranial hemorrhage among patients with nonvalvular atrial fibrillation. Methods Case-Patients We performed a casecontrol study comparing 2 groups: 1) case-patients with nonvalvular atrial fibrillation who developed intracranial hemorrhage while taking warfarin and 2) controls who were receiving anticoagulation for nonvalvular atrial fibrillation but did not develop intracranial hemorrhage. We found potential case-patients using the Partners HealthCare System Research Patient Data Registry, which can identify patients with specific International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses by searching the Massachusetts General Hospital billing system. We searched for patients 18 years of age or older who had diagnoses of atrial fibrillation (ICD-9-CM code 427.31) and intracranial hemorrhage (ICD-9-CM codes 430, 431, 432.0, 432.1, 432.9) at any time from October 1993 to June 2002. By 1993, nearly all prothrombin time ratios at the hospital were reported as INRs. We reviewed medical records to confirm whether patients were eligible, that is, whether they had intracranial hemorrhage documented by computed tomography or magnetic resonance imaging and documentation of warfarin therapy for atrial fibrillation at the time of the event. We excluded patients who were not taking warfarin at the time of hemorrhage; those who were receiving anticoagulation for rheumatic heart disease, mitral stenosis, or mechanical valve placement; those whose event was an ischemic stroke with hemorrhagic conversion; or those in whom clinical factors may have led to hemorrhage independent of warfarin therapy. These factors included underlying anatomic brain abnormalities (such as tumors or aneurysms), antecedent major head trauma (skull fracture, trauma with loss of consciousness, motor vehicle injury, or neurosurgical procedures), or platelet count less than 50 109 cells/L. Starting in July 1994, consecutive patients with intracerebral hemorrhage have been enrolled through the Massachusetts General Hospital emergency department as part of a longitudinal cohort study (23). To validate our automated search strategy, we compared our case-patient list with the list of patients identified through the cohort study and found that our search strategy missed only 4 patients with intracerebral hemorrhage. We obtained data on patient date of birth, sex, and ethnicity from computerized records. The type of hemorrhage (intracerebral, subdural, subarachnoid, intraventricular, or epidural) was determined through review of radiology reports. Data on presenting symptoms, history of minor head trauma, concomitant aspirin use, and disposition status were obtained from review of the admission medical record and were recorded on a standardized data collection form. We recorded the INR measurement obtained closest to the onset of symptoms. If an INR was not available or fresh frozen plasma or vitamin K was administered before the measurement, we considered INR data missing. We reviewed medical charts for documentation of the following comorbid conditions: history of cerebrovascular disease (defined as previous ischemic stroke or carotid artery disease), hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, and cancer (excluding nonmelanoma skin cancer). Controls Controls were sampled from patients managed by the Massachusetts General Hospital Anticoagulation Management Services clinic, which followed approximately 1000 patients receiving anticoagulation for atrial fibrillation at any given time during the study period. All patients who were followed in the anticoagulation clinic, received anticoagulation for atrial fibrillation, and had an INR measurement obtained in the same month and year as the given case date were assigned a random number. Six controls per case-patient were then randomly selected. We matched case-patients to controls by INR date to account for any technical changes in INR testing that may have occurred over time. Because of this sampling method, an individual patient could potentially serve as a control for more than 1 case-patient (24). Like case-patients, controls were 18 years of age or older; were receiving anticoagulation for atrial fibrillation; and had no documented rheumatic heart disease, mitral stenosis, or valve replacement. We sought data on potential confounders of the association of age, INR, and risk for intracranial hemorrhage, focusing on relevant comorbid conditions and combined use of aspirin with warfarin. We reviewed available computerized discharge summaries, outpatient clinic notes, and medication lists from up to 2 years before the admission date. If combination warfarin and aspirin use was not documented, patients were considered to not be taking aspirin. Statistical Analysis Case-patients were categorized by type of hemorrhage: intracerebral, subdural, and other (subarachnoid, intraventricular, or epidural). Clinical differences between types of hemorrhage were compared by using the KruskalWallis test for continuous variables (age and INR) and chi-square tests for categorical variables. We compared case-patients with controls by using multivariable conditional logistic regression, matching on INR date. Patient age was divided into 5-year intervals that were coded as indicator variables, and the odds of intracranial hemorrhage for each interval were compared with the odds of hemorrhage at a referent age of 70 to 74 years. The INR was divided into a set of ordered intervals that were coded as indicator variables. The relative odds for intracranial hemorrhage at each interval were calculated by using an INR of 2.0 to 3.0 as the referent category. In addition to age, INR, sex, and ethnicity, the following variables were included in the multivariable models to control for potential confounding effects of clinical factors and aspirin use: cerebrovascular disease, hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, cancer, and concomitant aspirin use. If no records were available for review, comorbid conditions and aspirin use were coded as missing. We used multiple imputations for missing data on ethnicity, comorbid conditions, and aspirin use (25). We tested for interactions between age and INR and comorbid conditions using 2-way interactions. None of the interaction terms were included in the model if they were not statistically significant when tested collectively. We tested the models goodness of fit using the HosmerLemeshow method (26). Because the hospitals anticoagulation clinic did not follow some case-patients before the event, and since factors relating to differences in outpatient care and monitoring could have confounded our analyses, we repeated these analyses in the subgroup of case-patients managed by the anticoagulation clinic. These restricted analyses approximated

Phagocytosis and innate immunity

Phagocytosis is an evolutionarily conserved process utilized by many cells to ingest microbial pathogens, and apoptotic and necrotic corpses. Recent investigation has revealed a fundamental requirement for two co-ordinated cellular processes--cytoskeletal alterations and membrane trafficking--in the phagocytic event. Some elements of this machinery are co-opted by certain pathogens to gain entry into host cells.

Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage

Background: Warfarin increases mortality of intracerebral hemorrhage (ICH). The authors investigated whether this effect reflects increased baseline ICH volume at presentation or increased ICH expansion. Methods: Subjects were drawn from an ongoing prospective cohort study of ICH outcome. The effect of warfarin on baseline ICH volume was studied in 183 consecutive cases of supratentorial ICH age ≥ 18 years admitted to the emergency department over a 5-year period. Baseline ICH volume was determined using computerized volumetric analysis. The effect of warfarin on ICH expansion (increase in volume ≥ 33% of baseline) was analyzed in 70 consecutive cases in whom ICH volumes were measured on all subsequent CT scans up to 7 days after admission. Multivariable analysis was used to determine warfarin’s influence on baseline ICH, ICH expansion, and whether warfarin’s effect on ICH mortality was dependent on baseline volume or subsequent expansion. Results: There was no effect of warfarin on initial volume. Predictors of larger baseline volume were hyperglycemia (p < 0.0001) and lobar hemorrhage (p < 0.0001). Warfarin patients were at increased risk of death, even when controlling for ICH volume at presentation. Warfarin was the sole predictor of expansion (OR 6.2, 95% CI 1.7 to 22.9) and expansion in warfarin patients was detected later in the hospital course compared with non-warfarin patients (p < 0.001). ICH expansion showed a trend toward increased mortality (OR 3.5, 95% CI 0.7 to 8.9, p = 0.14) and reduced the marginal effect of warfarin on ICH mortality. Conclusions: Warfarin did not increase ICH volume at presentation but did raise the risk of in-hospital hematoma expansion. This expansion appears to mediate part of warfarin’s effect on ICH mortality.

Hemorrhage Burden Predicts Recurrent Intracerebral Hemorrhage After Lobar Hemorrhage

Background and Purpose— Small asymptomatic cerebral hemorrhages detectable by gradient-echo MRI are common in patients with intracerebral hemorrhage (ICH), particularly lobar ICH related to cerebral amyloid angiopathy (CAA). We sought to determine whether hemorrhages detected at the time of lobar ICH predict the major clinical complications of CAA: recurrent ICH or decline in cognition and function. Methods— Ninety-four consecutive survivors of primary lobar ICH (age ≥55) with gradient-echo MRI at presentation were followed in a prospective cohort study for 32.9±24.0 months. A subset of 34 subjects underwent a second MRI after a stroke-free interval of 15.8±6.5 months. Study endpoints were recurrent symptomatic ICH or clinical decline, defined as onset of cognitive impairment, loss of independent functioning, or death. Results— The total number of hemorrhages at baseline predicted risk of future symptomatic ICH (3-year cumulative risks 14%, 17%, 38%, and 51% for subjects with 1, 2, 3 to 5, or ≥6 baseline hemorrhages, P = 0.003). Higher numbers of hemorrhages at baseline also predicted increased risk for subsequent cognitive impairment, loss of independence, or death (P = 0.002) among subjects not previously demented or dependent. For subjects followed after a second MRI, new microhemorrhages appeared in 17 of 34 and predicted increased risk of subsequent symptomatic ICH (3-year cumulative risks 19%, 42%, and 67% for subjects with 0, 1 to 3, or ≥4 new microhemorrhages, P = 0.02), but not subsequent clinical decline. Conclusions— Hemorrhages identified by MRI predict clinically important events in survivors of lobar ICH. Detection of microhemorrhages may be useful for assessing risk in ICH patients and as a surrogate marker for clinical studies.

Apolipoprotein E Genotype and the Risk of Recurrent Lobar Intracerebral Hemorrhage

BACKGROUND Recurrent lobar intracerebral hemorrhage is the hallmark of cerebral amyloid angiopathy. The factors that predispose patients to early recurrence of lobar hemorrhage are unknown. One candidate is the apolipoprotein E gene, since both the epsilon2 and the epsilon4 alleles of apolipoprotein E appear to be associated with the severity of amyloid angiopathy. METHODS We performed a prospective, longitudinal study of consecutive elderly patients who survived a lobar intracerebral hemorrhage. The patients were followed for recurrent hemorrhagic stroke by interviews at six-month intervals and reviews of medical records and computed tomographic scans. RESULTS Nineteen of 71 enrolled patients had recurrent hemorrhages during a mean follow-up period of 23.9+/-14.8 months, yielding a 2-year cumulative rate of recurrence of 21 percent. The apolipoprotein E genotype was significantly associated with the risk of recurrence. Carriers of the epsilon2 or epsilon4 allele had a two-year rate of recurrence of 28 percent, as compared with only 10 percent for patients with the common apolipoprotein E epsilon3/epsilon3 genotype (risk ratio, 3.8; 95 percent confidence interval, 1.2 to 11.6; P=0.01). Early recurrence occurred in eight patients, four of whom had the uncommon epsilon2/epsilon4 genotype. Also at increased risk for recurrence were patients with a history of hemorrhagic stroke before entry into the study (two-year recurrence, 61 percent; risk ratio, 6.4; 95 percent confidence interval, 2.2 to 18.5; P<0.001). CONCLUSIONS The apolipoprotein E genotype can identify patients with lobar intracerebral hemorrhage who are at highest risk for early recurrence. This finding makes possible both the provision of prognostic information to patients with lobar hemorrhage and a method of targeting and assessing potential strategies for prevention.