Flemming, Kelly D.

Objective: To determine the frequency and characteristics of symptomatic intracerebral hemorrhage in a population-based study Patients and Methods: The population-based Mayo Clinic Study of Aging included 4,994 participants age ≥50 years entered from 11/29/2004 to 3/11/2017. Participants with intracranial hemorrhage were identified using the Rochester Epidemiology Project medical records linkage system. Medical records of these individuals were reviewed. Each hemorrhage was classified as deep, lobar, or cerebellar intracerebral hemorrhage (ICH) or convexity subarachnoid hemorrhage (cSAH). Traumatic, subdural, non-convexal SAH, and epidural hemorrhages were excluded. Patient demographics, presence of hypertension, antithrombotic regimen, APOE genotype, and amyloid PET scan results were collected when available. Individuals with hemorrhages were matched 3:1 on age and gender to controls without symptomatic hemorrhage. Analyses within the cases and between the groups were performed. Results: Symptomatic hemorrhages were identified in 57 individuals for a frequency of 1.14%. Twenty-one were classified as deep, 26 lobar, 5 cerebellar, and 5 cSAH. Mean age at the time of hemorrhage was 80.9 years (SD ±7.9). 54.4% of hemorrhages occurred in men. Hypertension was present in 45.6%. Of those with lobar ICH or cSAH, 87.1% were on an antithrombotic compared to 65.6% of controls (p=0.02) and 32.3% of these were on warfarin compared to 12.9% of controls (p=0.01). APOE genotype was available in 54 of the 57. APOE e2 and/or e4 was found in 46.7% of those with lobar ICH/cSAH compared to 39.1% of controls (p=0.47) and 35.0% of those with deep ICH versus 39.3% of controls (p=0.73). Of the 31 with either lobar ICH or cSAH, 7 underwent amyloid PET scans; of these, 71.4% were abnormal compared to 42.9% of controls with mean SUVR of 1.911 and 1.565, respectively (p=0.08). Conclusions: Symptomatic ICH occurred in approximately 1 in 100 individuals age 50-94 years in this population-based study. In a matched case-control study, antithrombotic use (particularly warfarin) was statistically associated with the development of an ICH. While only a subset underwent amyloid PET, there was a trend towards greater amyloid load in those who developed a lobar or cSAH compared to controls.

Introduction: Accurately balancing risks of interventional treatment and intracranial hemorrhage (ICH) in the untreated course of unruptured brain arteriovenous malformation (uBAVM) patients is critical for optimal management. Observational studies of uBAVM afford an opportunity to address important gaps and previous criticisms of randomized data to help guide treatment decisions and assess long-term risk/benefit ratio. We previously published an individual patient data meta-analysis (IPDMA) in 4 MARS cohorts and identified ICH presentation and increasing age as significant predictors of ICH during follow-up, but was not powered to detect predictors in those with uBAVM. Thus, the goals of this project are to identify risk factors for ICH in uBAVMs, to estimate the risk with precision, and to create personalized, risk-prediction models. Methods: MARS is an international, multi-center study of 11 cohorts with target enrollment of 4,500 uBAVM patients ascertained through population-based or referral-based studies. We are harmonizing both retrospective and prospective data, including clinical, lifestyle, imaging, and angiographic factors. Treatments, complications, and functional outcomes (physician and patient-reported) will be updated annually between 2018-2022. We propose to: 1) identify predictors of outcome in uBAVMs using IPDMA; 2) test whether long-term outcomes differ by treatment using statistical approaches for causal inference and unbiased estimates; 3) compare treatment outcomes in randomized and non-randomized data to address generalizability; and 4) validate models and provide a novel tool for calculating individualized risks. Eligible sites have: a) prior BAVM publications; b) data from a minimum of 100 uBAVM patients; c) agree to random outcome adjudication; and d) agree to MARS data sharing policy. Discussion: The NIH-funded MARS consortium will provide important and comprehensive characterization of the untreated and treated course of uBAVMs, using large observational datasets and sophisticated epidemiological approaches. The data and models generated will be a useful resource for decision-making. We welcome participation from eligible sites with longitudinal data on uBAVM patients

Background: Cerebral cavernous malformation is a genetic neurovascular disorder causing aberrant angiogenesis and lesion development within capillary beds. Lesions exhibit impaired endothelial barrier function, causing blood-brain barrier leakage and hemorrhage. Quantitative MRI biomarkers (dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM)) have been shown to correlate with CCM disease progression as measures of barrier leakage and hemorrhagic iron deposition, and there is interest in utilizing these biomarkers as endpoints in clinical trials. However, their consistencies across multiple platforms and institutions has not yet been rigorously verified. Materials and Methods: Instruments used were a 3T Philips Ingenia at University of Chicago and a 3T Siemens Prisma at Northwestern University. QSM was assessed by five balloons filled with varying concentrations of MultiHance, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8, surrounded by an agarose gel. Permeability was assessed by the injection of a bolus of MultiHance through a coiled hose inside a water-filled shell, and the consistency of the peak-to-peak ratio of the curves at the input and output was measured. Each biomarker was assessed by accuracy (to expected values, Pearson correlation), precision (between repeated measurements, paired t-test), and reproducibility (between instruments, paired t-test). Results: QSM measured with an accuracy of r 2 = 0.997 on the Philips Achieva and r 2 = 0.999 on the Siemens Prisma. Each scanner had adequate precision between measurements, showing no significant difference by a paired t-test (p = 0.66 Achieva, p = 0.45 Prisma), and the reproducibility between scanners also showed no significant difference (p = 0.89). The peak-to-peak ratio on DCEQP scans was accurate (r 2 = 0.998), precise between measurements (p = 0.54), and repeatable between instruments (p = 0.49). Conclusion: Quantitative imaging biomarkers DCEQP and QSM are accurate, consistent across multiple measurements, and between platforms and will be useful for future clinical trials in CCM.

Abstract BACKGROUND More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Background: There are concerns about use of certain medications in patients with cavernous malformations (CM) being deleterious such as antithrombotics. In addition, there are select medications such as statins, vitamin D, and NSAIDs which theoretically may have a positive effect on endothelial leakiness. We aimed to determine whether certain medications taken prior to the diagnosis of CM influenced the presentation to medical attention. Methods: We established a prospective cohort of patients with clinically diagnosed CM in 2015. Patients are interviewed at inception and clinical records reviewed. Specifically, several medications are recorded including the use of: antithrombotics, NSAIDs, estrogen, Vitamin E, Vitamin D, SSRI, statin, and multivitamin. Patients are followed prospectively. Data continues to be collected annually on outcome events (bleeding) and ongoing medication use. Results: These results are on the first 103 patients entered into the database. Sixty-four (62.1%) patients are male and the average age at diagnosis is 39.1 years. Sixty-three (61.1%) presented with symptoms and 40 (38.9%) were incidental findings at first diagnosis. Patients taking NSAIDs (p=0.0468), Vitamin D (p=0.035), and statins (p=0.0163) were more likely to present with an incidental CM compared to those who presented symptomatically (hemorrhage, seizure or focal neurologic deficit). There was no significant difference in symptomatic vs. asymptomatic presentation in patients taking estrogens, warfarin, clopidogrel, SSRI, or vitamin E prior to presentation. Conclusion: This data supports the theoretic role of vitamin D, NSAIDS, and statin use in stabilization of endothelial permeability. Ongoing data collection and prospective follow up will allow us to determine if ongoing use of these medications plays a role in reducing risk of future hemorrhage.

Background: Non-traumatic convexal subarachnoid hemorrhages (cSAH) in the elderly can be a manifestation of cerebral amyloid angiopathy (CAA) and predict future intracerebral hemorrhage risk. The frequency of cSAH in the elderly population is unknown. Our objective was to determine the frequency of convexal subarachnoid hemorrhage in a population-based study among individuals who underwent amyloid PET imaging. Methods: Between 11/29/2004 and 3/11/2017 there were 1,687 participants ages 50-years and older in the population-based Mayo Clinic Study of Aging (MCSA) with Pittsburgh compound B (PiB) PET imaging. All intracerebral hemorrhages among participants were identified utilizing the Rochester Epidemiology Project’s records linkage system, and records and images were reviewed to identify those with both symptomatic and asymptomatic convexal subarachnoid hemorrhage. Neuroimaging characteristics, demographics, medications, and ApoE genotype were recorded. Results: Four (0.23%) cSAHs were identified among the individuals who underwent PiB PET imaging. Three were women and median age was 73 (range: 67-84). cSAH occurred in the following locations: right frontal (3), and right parieto-occipital (1). Two went on to develop a lobar intracerebral hemorrhage at a median of 4.75 years after cSAH. Coexisting cerebral microbleeds were identified in one case. The APOE allele combinations of the four participants were: 3/3, 3/3, 2/2, and 2/3. On PiB PET imaging, the median SUVR was 1.81 (range: 1.38-2.34). Conclusion: cSAH is a relatively rare manifestation of CAA occurring in less than 1% of the general population, but may represent a subset with a high risk of future intracerebral hemorrhage. Half of the participants with cSAH had an APOE e2 allele.