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

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.

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.

Eligibility Criteria:
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