PRecisiOn Medicine In StrokE: Evolution of Plasma Brain-Derived Tau in Acute Stroke

Study Overview
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Brief Summary
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The investigators recently identified Brain-derived tau (BD-tau) as a sensitive blood-based biomarker for brain injury in acute ischemic stroke: in patients with acute ischemic stroke, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome. While informing on the relation of BD-tau with imaging-based metrics of brain injury, this cross-sectional study was restricted to BD-tau assessments upon admission and at day 2 and could not inform on key characteristics of the evolution of plasma BD-tau, including when exactly it starts to rise, how long it continues to rise, and how it is determined by infarct characteristics as well as comorbidities. Here, the investigators aim to assess plasma BD-tau every hour from admission to 48 hours after onset to evaluate the hypothesis that BD-tau rises immediately after onset and plateaus between three and 48 hours after onset.

Detailed Description
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Ischemic stroke remains a leading cause of death and long-term disability worldwide,1 despite major advancements in reperfusion therapies.2,3 While neuroimaging modalities have expanded patient eligibility for reperfusion therapies by estimating ischemic core and salvageable tissue,4-7 their assessments are mostly single-timed. Currently available clinical algorithms lack the capacity to continuously track the dynamic evolution of how the primary core progresses to a final infarct, which, however, is a major determinant of functional outcome.8-10 Monitoring infarct trajectories could support therapeutic decision-making in patients with large-vessel occlusion stroke and unveil determinants of stroke progression, aiding in patient selection for trials evaluating cytoprotection11 and targeting clinically ineffective reperfusion.12 Previously studied blood-based biomarkers such as Neurofilament Light Chain (NfL),13 neuron-specific enolase (NSE),14 glial fibrillary acidic protein (GFAP),15,16 and S 100 calcium-binding protein B (S100B)17 either failed to capture the extent of brain injury within the acute phase of stroke or lack specificity. Plasma levels of brain-derived tau (BD-tau) were recently found to show high value for monitoring brain injury in patients with acute ischemic stroke: In 502 patients with acute IS, plasma BD-tau was associated with imaging-based metrics of brain injury upon admission, increased within the first 24 hours in correlation with infarct progression, and at 24 hours was superior to final infarct volume in predicting 90-day functional outcome.18 While informing on the relation of BD-tau with imaging-based metrics of brain injury, this large cross-sectional study was restricted to BD-tau assessments upon admission (median time from onset: 4.4 hours) and at day 2 (median time from onset: 22.7 hours) and could not inform on key characteristics of the evolution of plasma BD-tau, including when exactly it starts to rise, how long it continues to rise, and how it is determined by infarct characteristics as well as comorbidities. That knowledge would be of great value to determine the responsiveness of plasma BD-tau to brain injury after onset and to evaluate whether BD-tau plateaus at different time points after onset indicating no further infarct progression. Here, the investigators hypothesize that BD-tau rises immediately after onset and plateaus between three and 48 hours after onset. PROMISE-BD-100 will thus assess BD-tau levels every hour from admission to 48 hours from stroke onset in patients that present with the clinical diagnosis of an acute ischemic stroke due to a large- or medium-vessel occlusion within 9 hours from symptom onset.

Official Title
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PRecisiOn Medicine In StrokE Study on the Evolution of Plasma Brain-Derived Tau in 100 Patients With Acute Ischemic Stroke

Conditions
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Stroke, Stroke, Acute, Stroke, Ischemic, Cerebrovascular Disorders, Brain Diseases, Central Nervous System Diseases, Brain Ischemia, Nervous System Diseases

Intervention / Treatment
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* Diagnostic Test: Plasma levels of BD-tau


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: clinical diagnosis of acute ischemic stroke presentation within 9 hours of symptom onset large- or medium-vessel occlusion (i.e. an occlusion of the ICA, MCA [segments M1-M4], ACA [segments A1-A3], basilar artery, or PCA [segments P1 to P3]) confirmed by CT or MRI angiography at least 18 years of age written informed consent Exclusion Criteria: CT or MRI showing intracranial hemorrhage upon admission A history of ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, subdural hematoma, epidural hematoma, CNS tumor, meningitis, or encephalitis within the last three months severe renal dysfunction (eGFR < 30ml/min/1.73m2) dementia pre-stroke disability defined as a premorbid modified Rankin Scale score > 1

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ischemic Stroke<br>100 patients admitted to a specialized stroke service because of an acute ischemic stroke due to large- or medium-vessel occlusion within 9 hours of stroke onset. BD-tau levels and other suggested markers of brain injury (e.g.. NfL) will be assessed every hour from admission to 48 hours after onset. Routinely collected clinical data including from neuroimaging will be collected throughout hospitalization. Clinical follow-up will be performed at 3 months. | Diagnostic Test: Plasma levels of BD-tau<br>* Plasma levels of BD-tau will be assessed using a single-molecule array assay.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome are plasma BD-tau levels in acute ischemic stroke. | The evolution of BD-tau levels will be characterized by: the time point when plasma BD-tau levels start to rise after onset (defined as the earliest time point [in relation to onset] that showed higher BD-tau levels compared with the previous assessment and lower levels compared with the next assessment), the type of rise (e.g. linear, exponential, or logarithmic), and until when plasma BD-tau levels continue to rise (defined as the time point [in relation to onset] compared to which BD-tau levels do not increase by ≥ 5 % compared to 1h, 2h, and 3h afterwards). 5 % were chosen without prior knowledge and in an attempt to account for assay-dependent variations of BD-tau quantifications (coefficient of variation 8-9 %)18 while keeping a biologically and clinically plausible value (rather than e.g. 10 %). | Every hour from admission to 48 hours after onset. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ASPECTS on non-contrast CT |  | Upon admission | 
| Ischemic core volume on CT perfusion |  | Upon admission | 
| Regional leptomeningeal collateral score on CT angiography |  | Upon admission | 
| Final infarct volume | Final infarct volume will be assessed on delayed neuroimaging (CT or MRI), at least 48 after symptom onset. | Between 48 hours after symptom onset and discharge (latest 10 days after onset) | 
| Infarct progression | Infarct progression is defined as the difference between ischemic core volume quantified on admission CT perfusion scans and infarct volume quantified on delayed neuroimaging. | Between admission and discharge (latest 10 days after onset) | 
| 90-day functional outcome | Functional outcome at 90 days (± 14 days) will be assessed using the modified Rankin Scale (mRS). The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death. | 90 days (± 14 days) after onset | 
| 7-day functional outcome | Functional outcome at 7 days (or discharge if earlier) will be assessed using the modified Rankin Scale (mRS). The mRS is a valid and reliable clinician-reported measure of global disability that has been widely applied for evaluating recovery from stroke. It is a scale used to measure functional recovery (the degree of disability or dependence in daily activities) of people who have suffered a stroke. mRS scores range from 0 (best outcome) to 6 (worst outcome), with 0 indicating no residual symptoms; 5 indicating bedbound, requiring constant care; and 6 indicating death. | 7 days after onset | 
| Early recurrent ischemic stroke | The diagnosis of an early recurrent ischemic stroke will be based on i) sudden onset of a new focal neurological deficit within the first seven days after the index stroke that can not be explained by other non-ischemic causes such as seizure, metabolic derangement, or other systemic conditions, and ii) the presence of a new DWI-positive lesion on MRI or a new ischemic lesion on a delayed CT scan that is distinct from the index stroke lesion and that is consistent with the new clinical symptoms. | Between admission and discharge (latest 10 days after onset) | 
| Secondary intracerebral hemorrhage | Secondary intracerebral hemorrhage is defined as a new intracerebral hemorrhage independent of the primary ischemic lesion that is observed between the initial hemorrhage-free neuroimaging scan and discharge | Between admission and discharge (latest 10 days after onset) | 
| Hemorrhagic transformation | The occurrence of hemorrhagic transformation will be evaluated based on the morphological ECASS criteria.20 | Between admission and discharge (latest 10 days after onset) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pathophysiology, Stroke, Brain injury, Biomarker