BIOSIGNAL - Biomarker signature of stroke aetiology study: The BIOSIGNAL-Study

Background: At least 1 in 6 patients who survives a stroke will suffer another stroke within 5 years. For optimal secondary prevention directed at the underlying mechanism, an aetiological classification of stroke is critical. Even with a thorough evaluation, the aetiology of ischemic stroke remains “undetermined” (i.e. classified as cryptogenic stroke according to the classical TOAST criteria) or not evident but only “possible” or “probable” (according to the SSS TOAST-criteria) and thus in 25-39% of patients a specific secondary prevention cannot be initiated. The highest rates of stroke recurrence and mortality are seen in patients with cardioembolic and cryptogenic stroke. Patients initially diagnosed as cryptogenic stroke can, however, later be found to have a detectable cause of stroke, such as paroxysmal atrial fibrillation (AF) or symptomatic atherosclerotic disease (even if stenosis in initial exam was less than 50%). The use of rapidly measurable serum biomarkers for aetiologic diagnostic assessment on admission may enhance aetiologic classification and thus improve the implementation of optimal secondary prevention, patient outcome and benefit-cost ratio. Several promising candidate blood biomarkers have been described recently to be strongly and independently associated with cardioembolic stroke (CE) or large-artery atherosclerotic stroke (LAA). However no study simultaneously assessed the association of these blood biomarkers with the underlying aetiology and the hard endpoint of stroke recurrence as well as their incremental predictive value over existing prognostic and diagnostic clinical information on admission.Personal Research: In the past 5 years, I conducted patient-centered interdisciplinary (Department of Endocrinology and Neurology) clinical outcome studies focusing on neuroendocrine hormones as prognostic and diagnostic biomarkers in stroke patients. We investigated the prognostic value of neuroendocrine markers (e.g. copeptin, MRproANP, TSH, Cortisol etc.) for optimal risk stratification in acute ischemic stroke patients first in a large single center study (COSMOS n>500). Using this study as derivation set we aimed at validating these data and I performed as one of the primary investigators a multicenter study (the CoRisk Study) in over 1000 patients in collaboration with hospitals in Switzerland and Germany. Moreover I currently investigate promising prognostic inflammatory (e.g. LpPLA2) as well as neuroendocrine markers (e.g. Copeptin, MRproANP) and their association with increased risk of stroke also looking at stroke aetiology in one of the largest cohorts of stroke-free participants focused on stroke outcomes worldwide (n>3000; the Northern Manhattan Study, or NOMAS).Approach: We propose to prospectively evaluate the predictive value of the most promising serum biomarkers to identify treatable stroke etiologies on admission and risk of recurrence in 3000 consecutive incident ischemic stroke patients enrolled by 10 centers in Europe and the US. From these 3000 patients we estimate to include at least 750 individuals with a cryptogenic stroke classified according to the original TOAST classification 2 and 120 individuals when classified by the SSS-TOAST classification3. The clinical endpoints of the study are 1) recurrent stroke within one year, 2) all types of AF detected on admission or by prolonged ambulatory cardiac rhythm monitors, 3) presence of cerebrovascular atherosclerosis detected by ultrasound investigations and 4) new silent ischemic brain lesions and progression of chronic cerebral ischemic lesion volume detected by repeated magnetic resonance imaging (MRI and MRA) and (i.e. on admission and after 12 months). Aim 1: To determine whether the proposed biomarkers independently predict recurrent stroke among all patients. Hypothesis 1: Elevated levels of one or more of the proposed biomarkers will independently predict recurrent strokes during trial follow-up, assessed by structured interviews, as well as chart reviews 1 year after the index stroke.Aim 2: To determine whether CE biomarkers are associated with atrial fibrillation among all patients. Hypothesis 2: Baseline values of one or more of the proposed CE biomarkers will be independently associated with AF, including history of AF, AF detection at baseline, or AF detected during the follow up period by 21-day ambulatory cardiac rhythm monitors and structured interviews as well as chart reviews 1 year after the index stroke.Aim 3: To determine whether LAA biomarkers are associated with a) the presence of cerebrovascular atherosclerosis among all patients. Hypothesis 3: Baseline values of one or more of the proposed LAA biomarkers will be independently associated with the presence of extra and intracranial atherosclerosis among patients with ischemic stroke, assessed by duplex sonsography.Aim 4: To determine whether the proposed biomarkers will predict b) new silent strokes and c) progression of chronic cerebral ischemic lesion (white matter hyper-intensity) volume (WMHV) among cryptogenic stroke patients. Hypothesis 4: Baseline values of one or more of the proposed biomarkers will independently predict a) silent stroke b) progression of WMHV, during study follow-up, assessed by repeated magnetic resonance imaging (MRI) (on admission, and 1 year after the index stroke).Significance: Completion of the proposed study will answer the question of whether patients with higher levels of the selected biomarkers are at increased risk for recurrent events after acute ischemic stroke, and if the selected biomarkers can help to improve identifying patients for established effective secondary prevention treatments, allowing us to potentially reduce overall risk of recurrent stroke and thus improve quality of life.