Background: Cumulative fragility index (FI) analysis enables quantification of the evidential strength of intravenous alteplase’s core indication—treatment of disabling acute ischemic stroke within 3 hours of onset. Methods: Meta-analyses were performed (study level) or identified (individual participant level) for freedom-from-disability (modified Rankin Scale [mRS] score 0–1, primary efficacy), functional independence (mRS score 0–2, secondary efficacy), and mortality outcomes. Individual trial and cumulative FI analyses were serially conducted after each successive randomized controlled trial (RCT). FI scores were classified as follows: not robust (FI 0–4), somewhat robust (FI 5–12), robust (FI 13–33), and highly robust (FI >33). Results: Nine randomized controlled trials were identified from 1995 to 2021 of within-3-hour intravenous alteplase for acute ischemic stroke. In study-level meta-analyses, alteplase increased freedom-from-disability outcome (mRS score 0–1), 31.0% versus 22.3%, relative risk, 1.39 (95% CI, 1.20–1.61); P <0.00001; increased functional independence (mRS score 0–2), 39.7% versus 31.2%, relative risk, 1.29 (95% CI, 1.14–1.45), P <0.000; and did not alter mortality, 24.1% versus 26.1%; P =0.23. Overall FIs for study-level meta-analyses were both highly robust at 42 and 40 for mRS score 0–1 and mRS score 0–2, respectively. Serial FI analyses showed robust evidential strength for intravenous alteplase superiority with publication of the 2 NINDS-tPA trials (National Institute of Neurological Disorders and Stroke–tissue-type plasminogen activator) in 1995, increased to highly robust in 2012, and remains highly robust in 2021. Conclusions: Within-3-hour intravenous alteplase for acute ischemic stroke is one of the most robustly proven therapies in medicine. The initial concurrent trials 25 years ago showed robust evidence for benefit and, after additional studies, advanced to highly robust.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the coronavirus disease 2019 (COVID-19) pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Damage to axons is a core feature of ischemic stroke and cerebrovascular disease. The burden of axonal injury is correlated with the acute clinical deficits, the underlying burden of ischemic brain injury, the prognosis of recovery, and may be a meaningful therapeutic target for brain repair. Neurofilament light chain (NfL) has been identified as a blood-based biomarker that reflects neuroaxonal damage resulting from stroke. However, the utility of NfL as a blood-based biomarker in stroke is confounded by studies examining different temporal windows and patient populations. We conducted a systematic review and meta-analysis to verify the utility of blood NfL as a diagnostic, prognostic, and monitoring stroke biomarker. Nineteen studies reporting serum/plasma NfL values for a total of 4,237 distinct patients with stroke were identified. Using available summary data from the 10 studies that employed a common immunoassay platform, we utilized random effects linear mixed modeling and weighted averages to create a phasic model of serum/plasma NfL values in distinct time periods of acute stroke. Weighted averages show that blood NfL levels vary significantly across three distinct temporal epochs of acute (0–7 days), subacute (9–90 days), and chronic (&gt;90 days) stroke with a steep peak in the early subacute period between 14 and 21 days after stroke. Blood NfL values can function as a diagnostic biomarker in distinguishing acute ischemic stroke from transient ischemic attack as well as amongst other cerebrovascular subtypes. Release of NfL into the bloodstream after stroke follows a distinct temporal dynamic that lags several weeks behind stroke onset and reliably associates with a stroke diagnosis despite some variability based on stroke subtype and severity. Identification of these temporal dynamics and the contribution of co- existent cerebrovascular disease states can improve the value of NfL as a stroke biomarker.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l’AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

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