BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T _max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Given the high risk of recurrent atherosclerotic vascular events in patients with stroke due to intracranial atherosclerotic disease (ICAD), we estimated the potential benefit of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in this population. In this secondary analysis of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, we estimated the association between 30-day low-density lipoprotein (LDL) reduction and recurrent stroke or myocardial infarction (MI) beyond 30 days (primary outcome). Estimates were assessed using adjusted Cox proportional hazards regression. We applied relative LDL reduction estimates from PCSK9i trials to project adjusted incidence rate differences of the primary outcome with an equivalent LDL reduction. Of the 451 patients from SAMMPRIS, 378 met inclusion criteria. In adjusted Cox regression, every 10 mg/dL LDL improvement was associated with a 9% lower rate of the primary outcome (adjusted hazard ratio 0.91, 95% CI 0.83-0.997). Assuming an average projected effect of PCSK9i, estimating if half of SAMMPRIS patients were treated, PCSK9i use could reduce the annualized risk of the primary outcome by 33.2% in this trial population. Every 10 mg/dL reduction in LDL for patients with stroke due to ICAD is associated with lower rates of recurrent stroke or MI, and this theoretical framework suggests that PCSK9i can help achieve this goal. Secondary analysis of NCT00576693 prospectively registered interventional clinical trial. First registered December 7, 2007. Actual study start date: October 2008. https://clinicaltrials.gov/show/NCT00576693. This study provides Class IV evidence that a higher absolute reduction in LDL was associated with a lower risk of recurrent cerebral infarction or MI in patients with recent stroke due to intracranial stenosis.

Hemorrhagic neurovascular diseases, with high mortality and poor outcomes, urge novel biomarker discovery and therapeutic targets. Micro-ribonucleic acids (miRNAs) are potent post-transcriptional regulators of gene expression. They have been studied in association with disease states and implicated in mechanistic gene interactions in various pathologies. Their presence and stability in circulating fluids also suggest a role as biomarkers. This review summarizes the current state of knowledge about miRNAs in the context of cerebral cavernous malformations (CCMs), a disease involving cerebrovascular dysmorphism and hemorrhage, with known genetic underpinnings. We also review common and distinct miRNAs of CCM compared to other diseases with brain vascular dysmorphism and hemorrhage. A systematic search, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, queried all peer-reviewed articles published in English as of January 2025 and reported miRNAs associated with four hemorrhagic neurovascular diseases: CCM, arteriovenous malformations, moyamoya disease, and intracerebral hemorrhage. The PubMed systematic search retrieved 154 articles that met the inclusion criteria, reporting a total of 267 unique miRNAs identified in the literature on these four hemorrhagic neurovascular diseases. Of these 267 miRNAs, 164 were identified in preclinical studies, while 159 were identified in human subjects. Seventeen miRNAs were common to CCM and other hemorrhagic diseases. Common and unique disease-associated miRNAs in this systematic review motivate novel mechanistic hypotheses and have potential applications in diagnostic, predictive, prognostic, and therapeutic contexts of use. Much of current research can be considered hypothesis-generating, reflecting association rather than causation. Future areas of mechanistic investigation are proposed alongside approaches to analytic and clinical validations of contexts of use for biomarkers.

Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is recognized as a diagnostic and prognostic blood biomarker for traumatic brain injury (TBI). This study aimed to evaluate whether UCH-L1 concentrations measured in patients' urine post-injury could serve as a diagnostic or prognostic biomarker for outcomes in various types of acute brain injuries (ABI). This pilot study included 46 ABI patients: aneurysmal subarachnoid hemorrhage (n = 22), ischemic stroke (n = 16), and traumatic brain injury (n = 8), along with three healthy controls. Urine samples were collected at early (1.50 ± 0.70 days) and late (9.17 ± 3.40 days) periods post-admission. UCH-L1 and creatinine levels were quantified using ELISA. UCH-L1 concentrations were compared to functional outcomes (modified Rankin Scale, mRS) and dichotomized into favorable (mRS 0–3) and unfavorable (mRS 4–6) groups. Non-parametric statistical tests and ROC analysis was performed. UCH-L1 concentrations in healthy controls were significantly lower compared to both early and late samples after ABI (p ≤ 0.001). The diagnostic performance of urine UCH-L1 at early timepoint showed excellent discriminatory ability, with AUC of 97.6% (95% CI: 93.0–100, p = 0.006 (sensitivity 98%, specificity 100%). Urine UCH-L1 concentrations, both with and without creatinine normalization, did not distinguish between favorable and unfavorable outcomes in either early (p = 0.88 and p = 0.36) or late samples (p = 0.98 and p = 0.30) in any types of ABI. Although UCH-L1 concentrations in urine did not differentiate between favorable and unfavorable outcomes, a significant difference was observed between healthy subjects and ABI patients. This finding underscores the significant diagnostic utility of urine UCH-L1 concentrations, regardless of the type of acute brain injury.

Background: A type II proatlantal artery is a rare congenital vascular anomaly comprised of a persistent embryologic connection between the carotid and vertebrobasilar circulations. Although generally asymptomatic and detected incidentally, its identification is of clinical importance in neurovascular assessments and interventions. Case Description: A 70-year-old male presented with acute-onset left lower extremity weakness and numbness, out of the window for thrombolytics; computed tomography angiography of the head and neck incidentally identifying a persistent left type II proatlantal artery originating from the external carotid artery and supplying the vertebrobasilar circulation. Magnetic resonance imaging of the brain the following day was unremarkable for acute infarction or other cerebrovascular pathology. Conclusion: This case underscores the significance of recognizing congenital vascular anomalies such as the type II proatlantal artery, particularly in the context of cerebrovascular assessment. Although these variants are often incidental and not associated with increased stroke risk, their presence has implications for neuroendovascular procedures and stroke evaluations. Understanding the anatomic and embryologic origins of these vascular anomalies facilitates accurate interpretation of cerebrovascular imaging and enhances clinical decision-making in patients with these anomalies.

Familial cerebral cavernous malformations (FCCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia (HHT) are driven by genetic mutations causing varying vascular dysmorphism and risk of brain bleeding. Cerebral microbleeds (CMBs) are associated with the aging process with less characterized genetic drivers. This study hypothesizes that common and distinct circulating microRNAs (miRNAs) can reflect mechanisms of vascular dysmorphism and bleeding, which can serve as potential biomarkers in clinical contexts. Differentially expressed (DE) plasma miRNAs (p < 0.05, FDR corrected, absolute fold change [|FC|]>1.5]) were identified between patients with FCCM, SWS, HHT, and CMB, compared to age and sex matched healthy patients. Ingenuity Pathway Analysis as well as transcriptome integration analyses were performed to identify gene targets of the DE miRNAs and their associated pathways. Preselected miRNAs were validated using ddPCR. Eleven circulating DE miRNAs were identified in FCCM, 40 in SWS, 41 in HHT, and 26 in CMB (p < 0.05, FDR-corrected, [|FC|]>1.5]). Further analyses showed that 18 DE miRNAs were commonly dysregulated in any two of the studied neurovascular disorders. The PI3K-Akt and ROBO SLIT signaling pathways were identified across all four disorders. The plasma levels of four miRNAs were further validated (p < 0.05) using ddPCR. The common dysregulated miRNAs across neurovascular disorders reflect shared mechanistic pathways underlying vascular dysmorphism and bleeding. These findings pave the way for further mechanistic exploration of these miRNAs, and their potential clinical application for disease monitoring and therapeutic intervention.