Majersik, Jennifer Juhl

Background: Migraine is associated with neuroimaging differences in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, it is unknown if migraine-related disability (MRD) or if calcitonin gene-related peptide (CGRP), a vasoactive peptide important in migraine pathology, have radiographic implications. The aims of this study were to identify whether MRD or interictal serum CGRP levels impacted neuroimaging findings for those with CADASIL. Materials and Methods: A cross-sectional analysis was performed. The primary outcomes were neuroimaging differences associated with MRD among those with migraine or interictal serum CGRP levels of those with and without migraine. MRD was defined by 2 migraine disability scales (Migraine Disability Assessment, Headache Impact Test-6). Retrospective brain magnetic resonance imaging was reviewed (average 1.7 ± 2.0 y before enrollment). Rank-sum and χ2 tests were used. Results: Those with migraine (n=25, vs. n=14 without) were younger [median 49 (25 to 82) y vs. 60 (31 to 82) y, P<0.007], had fewer cerebral microbleeds (0 to 31 vs. 0 to 50, P=0.02) and less frequently had anterior temporal lobe T2 hyperintensities [68% (17/25) vs 100% (14/14), P=0.02]. MRD scale outcomes had no significant radiographic associations. Interictal serum CGRP did not differ (migraine: n=18, 27.0±9.6 pg/mL vs. no migraine: n=10, 26.8±15.7 pg/mL, P=0.965). Conclusions: Migraine may forestall microangiopathy in CADASIL, though possibly independent of severity as measured by MRD. Interictal serum CGRP did not differ in our cohort suggesting CGRP may not be vital to migraine pathophysiology in CADASIL. Larger studies are needed to account for age differences.

Introduction: Participation by American Indian and Alaska Natives (AI/AN) in clinical research may improve AI/AN health outcomes and generalizability of the research. Hypothesis: Cultural beliefs have a strong impact on willingness of AI/AN to participate in research. Methods: We developed a survey to identify if cultural beliefs impact perception of clinical research and the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) protocol. Stroke neurologists and CREST-2 investigators participated in the design of the survey. Participants were stratified based on AI/AN self-identification and level of education. Likert-scale responses were tested with the Mann Whitney-U test and dichotomous responses with the Chi-Square test. Results: There were 102 participants: 61% female, mean age 39, and 37% AI/AN. Eight questions evaluated understanding of research concepts within CREST-2; 89% of these responses were correct, with no significant difference in responses between AI/AN and non-AI/AN or between low (n=42) and high (n=60) education. Compared to other ethnic groups, AI/AN identify more with their culture (p=0.002) and consider cultural beliefs when making health care decisions (p=0.005), including participating in a research study (p=0.002). Using the same questions, we found no difference between respondents with low or high education.(Figure 1) Conclusion: These data support our hypothesis that cultural beliefs have a strong impact on AI/AN willingness to participate in research. It is important for researchers to consider cultural beliefs when designing recruitment strategies for AI/AN populations. Future work will address how cultural beliefs affect AI/ANs’ understanding of and willingness to participate in clinical research.

Background: Considerable disagreement exists among experts regarding the appropriate extent of diagnostic testing after ischemic stroke (IS). Evidence-based data guiding stroke evaluation for individual patients according to the underlying phenotype are unknown. We sought to determine the yield of cardiac and arterial evaluations for identifying an alternative major stroke etiology in patients with a given phenotype in the NINDS Stroke Genetics Network (SiGN). Methods: SiGN is a consortium of IS studies at 22 US and European sites aiming to identify stroke susceptibility genes. Adjudicators certified in Causative Classification of Stroke (CCS) system determined major etiologic stroke phenotypes based on chart review. All diagnostic data entered into the CCS software were stored in a confidential database. We determined the probability of identifying an alternative major abnormality based on cardiac (history, EKG, echocardiography) and arterial [intracranial (IC), extracranial (EC)] evaluations in 3 stroke phenotypes: lacunar infarct (LI), large artery atherosclerosis (LAA), and cardiac embolism (CE). Proportions of alternative major etiologies were calculated in patients with complete evaluations in each phenotype. Results: The analyses included 15720 patients. Among these, 2299 had phenotypic subtype of LI (1660 with cardiac and 1691 with arterial evaluations); 4228 had CE (2451 with arterial evaluation); and 2613 had LAA (2047 with cardiac evaluation). Cardiac evaluation revealed a major cardiac source of embolism in 12.3% of patients with LI and 20.3% with LAA. Echocardiography demonstrated an additional major structural cardiac source not seen by history/examination/EKG in 1.9% and 1.6% in LI and LAA respectively. Arterial evaluation led to the identification of ≥50%ipsilateral stenosis in 13.5% (IC: 8.9%, EC: 5.8%) of patients with LI and 17% (IC: 8.1%, EC: 11.3%) of those with CE. In LI patients with complete cardiac and vascular evaluations, 24.1% had an alternative major stroke etiology. Conclusions: A considerable proportion of IS patients with LI, LAA, and CE harbor an alternative major etiology. In the future, these results can be used to generate evidence-based and cost-effective evaluation and management strategies.

Background: Patients with cerebral cavernous angiomas with symptomatic hemorrhage (CASH) have high risk of disability from recurrent bleeding. Candidate medications to prevent rebleeding in CASH lesions will require multisite clinical trials with standardized data collection. Objective: To report the prevalence and baseline cohort features in CASH patients and establish a research network infrastructure for trials. Methods: This prospective observational cohort study includes adults with radiologically verified CASH lesion within 1-year of consent. Exclusions include prior or planned surgical intervention, spinal location, or prior brain irradiation. Six sites enrolled patients into the screening and clinical assessment portion of the study starting July 2018. Patients also had the option to participate in the follow up biomarker validation at 4 sites. Baseline demographics, clinical and imaging information, and outcomes (mRS, PROMIS-29, NIHSS, and EuroQol-5D) were collected. Biomarker imaging included dynamic contrast enhanced quantitative perfusion (DCEQP) and quantitative susceptibility mapping (QSM) that correlated with symptomatic bleeding. Descriptive statistics were performed and one-sample t-test was used to compare whether mean T-scores for PROMIS-29 domains differed significantly from a reference population. Results: As of May 2020, 849 CASH patients were screened of whom 110 (13%) were eligible and enrolled; 73 also enrolled into the biomarker validation study. Average age at enrollment was 46±16 years at a mean of 4.4 months after symptom onset; 53% were female, 41% were familial, and 43% of CASH lesions were brainstem location. At enrollment, 90% of the cohort had independent functional outcome (mRS ≤ 2 and NIHSS <5). Perceived health problems affecting QoL were reported in >30% (EuroQol-5D). CASH cases had significantly worse anxiety but better depression and social satisfaction scores compared to a general population (all P<0.01). Baseline DCEQP and QSM measures did not differ significantly across sites. Conclusion: We demonstrate feasibility of multisite recruitment of CASH patients and report prevalence of baseline features that will aid in design of clinical trials and inclusion of appropriate outcome measures.

Abstract BACKGROUND Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.