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Until 1995, treatment of ischemic stroke consisted exclusively of efforts to prevent recurrence. Since that time, the introduction of recombinant tissue plasminogen activator (rtPA) treatment has significantly improved morbidity and mortality of ischemic stroke [1]. Ischemic stroke is treatable but time is critical. The term “time is brain” has been coined for acute stroke intervention, even before the rtPA trials, to emphasize that the human brain is rapidly and irreversibly lost as stroke progresses and that therapeutic interventions should be emergently pursued [2,3,4,5]. Two decades after the approval of intravenous rtPA for the treatment of ischemic stroke, interventions to reopen an occluded artery through thrombolysis and mechanical thrombectomy remain the only and first priority in ischemic stroke treatment. Accordingly, dramatic effort has been investing to reduce the time from stroke onset to treatment and arrival-to-puncture time for ischemic stroke patients. It is anticipated that an interdisciplinary and rapid response to the emergence of stroke intervention can result in dramatic impact of thrombolysis on this public health problem. Unfortunately, the number of ischemic stroke patients who are treated with thrombolytic therapy is still disappointingly low.
Time is not absolute but relative in term of stroke treatment. Therapeutic time window for ischemic stroke has been continually evolving in the last two decades. The original recommended therapeutic window of intravenous rtPA for ischemic stroke was 3 h of stroke onset [1]. At present, intravenous thrombolysis is for patients with acute onset stroke within 4.5 h, provided that hemorrhage or other contraindications are excluded [6, 7]. Mechanic thrombectomy, in addition to intravenous thrombolysis within 4.5 h, when eligible, is recommended to treat acute stroke patients with larger artery occlusion in the anterior circulation up to 6 h after symptom onset [7]. There is increasing experimental and clinical evidence supporting a variable therapeutic window that may exceed 6 to 8 h. Case study has demonstrated that symptoms can be resolved through endovascular recanalization at the chronic stage up to 80 days after stroke symptom onset [8]. On the other hand, reperfusion after ischemic stroke within the therapeutic window does not necessary lead to improvement of clinical outcome. There is often a mismatch in the clinical trials with higher reperfusion rates but lesser rates of functional recovery, potentially due to futile recanalization. The futile recanalization occurs when successful recanalization fails to improve the functional outcome and accounts for 30–50% revascularization cases in various endovascular trials [9, 10]. Taken together, therapeutic window is not equal to the time window. There are many factors that may impact the therapeutic window of reperfusion therapy for ischemic stroke. For example, time to treatment has been found to be a predictor of outcome only when collaterals were excluded from the model, indicating the important role of collaterals for the time window of ischemic stroke intervention [11]. Furthermore, it has been found that the association between endovascular reperfusion and improved functional and radiologic outcomes is not time dependent in patients with a perfusion-diffusion mismatch [12].
The permanent brain damage is related to both the duration and severity of ischemia. Without measurement of ischemic severity, time is the only and primary factor defining the therapeutic window for ischemic stroke intervention [13]. Precision medicine was initiated with a primary focus on cancer and is rapidly expanding to the whole range of health and disease, including stroke [14]. The highly heterogeneous stroke population and imprecise therapeutic time window lead to a large number of patients in the current stroke trials while a minority of participants drove the cohort effect. The precision medicine calls for novel strategies to define a therapeutic window that take individual variability into account for ischemic stroke treatment beyond the time. Advances in neuroimaging technologies provide diagnostic tools to evaluate the physiological status of intracranial vessels, cerebral hemodynamics, and possible degree of reversibility of ischemic brain damage [15, 16]. “Physiology is brain” has been created to advocate the use of physiological neuroimaging to guide stroke therapy [17]. Physiological neuroimaging has been extensively evaluated in therapeutic time windows where the margin of benefit of reperfusion therapy is much smaller. The perfusion-diffusion mismatch has been believed to be a practical and approximate measure of the tissue at risk, thus, a physiological guidance for thrombolytic intervention. However, recent studies have convicted that mismatch does not optimally define the ischemic penumbra [18]. Hitherto, the intensive research and extensive use of the current neuroimaging modalities have led to mixed results and there is lack of evidence supporting the use of physiological neuroimaging to expanding the therapeutic time window for reperfusion therapy [16, 19,20,21,22]. Novel precision neuroimaging technology remains to be developed to define the precise therapeutic window for the treatment of individual stroke patient [23].
The human brain is by far the most expensive organ in term of energy expenditure in the whole body. The human brain constitutes only 2% of the body weight, but receives 15% of cardiac output, accounts for almost 20% of the total oxygen consumption, and consumes approximately 25% of total body glucose utilization. In addition, the brain has very limited energy storage and relays on coincidental regulation of cerebral blood flow to match the local brain activity and renders it highly vulnerable to ischemic attack. Ischemic stroke is a cerebrovascular event, initiated by occlusion of a cerebral artery and result in cellular energy metabolism crisis and ultimate brain damage. While the pathophysiology during ischemic stroke is highly complex, reduction or absent metabolic activity of brain cells represents the initiative and end point of ischemic stroke. Metabolism dictates the brain function and the degree of reversibility brain tissue after ischemic stroke. Ultimately, metabolism is brain. The current clinical neuroimaging technology does not provide direct measurement for brain metabolism. Precision neuroimaging on brain metabolism may provide more effective tool in the selection of stroke patients for reperfusion intervention [24]. Emerging neuroimaging research on proton MR spectroscopy (MRS), sodium imaging, and oxygen imaging may provide metabolic imaging technique to precisely identify salvageable ischemic lesion in individual patient independent of time [25, 26]. There is no doubt that time is still brain in term of acute stroke intervention. Metabolic neuroimaging with the current imaging modalities and novel technologies may realize the promise of precision medicine to provide precision stroke diagnostic tool for personalized intervention.
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Funding
This work was partly supported by the National Institutes of Health grants 1R21NS087209-01A1 (SY) and R01NS088596 (SY), and American Heart Association SDG16960084 (RL).
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Yang, SH., Lou, M., Luo, B. et al. Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain. Transl. Stroke Res. 9, 93–95 (2018). https://doi.org/10.1007/s12975-017-0566-y
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DOI: https://doi.org/10.1007/s12975-017-0566-y