Scholarly Activity

INTRODUCTION: Current therapies for acute ischemic stroke (AIS) fail to address microvascular dysfunction. Lamiflo™, a high-molecular-weight drag-reducing polymer (DRP), enhances microvascular flow via hemodynamic modulation. We tested its efficacy when given 1 or 3 hours after transient middle cerebral artery occlusion (tMCAO). METHODS: Wistar rats underwent 3.5-hour monofilament tMCAO. Lamiflo™ (5 ppm) or saline was administered i.v. at 1 or 3 h (n=5/group). At 3.5 h, Laser Speckle Contrast Imaging (LSCI) was used to evaluate cortical microcirculation. On day 1, neurobehavior was evaluated, followed by post-mortem infarct volume (TTC), and blood-brain barrier (BBB) permeability (Evans Blue) determination. RESULTS: tMCAO progressively impaired cortical microcirculation, leading to tissue ischemia and BBB disruption. Lamiflo™ improved cortical microcirculation via collateral flow enhancement, thereby reducing infarct volume, BBB degradation, leading to improved functional outcome (all p< 0.05). DRP efficacy reduced with the time of application from 1 h to 3 hours after tMCAO, but remained significant. CONCLUSIONS: Lamiflo™ preserves cerebral microcirculation via collateral flow enhancement, limits infarct and BBB damage, and improves outcomes up to 3 h post-tMCAO, supporting its use as a microcirculatory adjunct in AIS.

INTRODUCTION: Brainstem seizures are a rare phenomenon of brainstem stroke possibly resulting from injury to the proposed centrencephalic system. We observed hypoxic respiratory arrest resulting from these brainstem seizures involving tonic spasm of the diaphragm, a complication to our knowledge not previously reported in the literature. DESCRIPTION: A 69-year-old female presented with acute onset of altered mental status and left-sided weakness. CT angiography showed basilar artery thrombosis. The patient was taken for a thrombectomy, but recanalization could not be achieved. An MRI of the brain demonstrated acute infarction of the pons and bilateral cerebellum. Several days later, she had a sudden episode of acute hypoxia with oxygen saturation dropping to as low as 30. On evaluation, the patient appeared to have tonic spasms of her respiratory muscles resulting in complete respiratory arrest with loss of tidal volume, refractory hypoxemia, hemodynamic instability, and limited chest wall movement with manual ventilation. She required increased sedation which allowed the team to effectively ventilate her along with improvement in her hemodynamics and oxygen saturation. She developed another tonic spasm which was refractory to additional doses of sedation. Cisatracurium was administered which aborted this phenomenon resulting in a rapid clinical improvement. The patient continued on high doses of sedation and was started on carbamazepine as daily preventative therapy. After this treatment strategy was initiated, the patient was not observed to have any further episodes. DISCUSSION: Brainstem seizures with diaphragmatic tonic spasm represent a rare complication of basilar artery occlusion. This phenomenon is not well described in literature making it difficult to manage, ultimately leading to high-risk clinical scenarios such as hypoxic respiratory arrest. Our case highlights a dual pronged approach to management including abortive therapy, utilizing high doses of sedation and neuromuscular blockade, in conjunction with a preventative strategy with an antiepileptic drug, carbamazepine. Further studies are required to identify the underlying etiology of diaphragmatic tonic spasms and treatment guidelines in order to prevent patient harm.

INTRODUCTION: Use of direct oral anticoagulants for atrial fibrillation and venous thromboembolism can cause intracranial bleeding. While guidelines recommend andexanet alfa for reversing factor Xa inhibitors, its high cost and thrombotic risk have led to off-label use of 4F-PCC, despite limited comparative data. This quality improvement study evaluates the effectiveness of andexanet alfa vs. 4F-PCC for bleeding control in clinical practice. METHODS: We conducted a retrospective review (Oct 2020–Oct 2024) of patients who: 1) had a head CT showing intracranial hemorrhage, 2) were on a FXa inhibitor, and 3) received 4F-PCC or andexanet alfa. Demographics, clinical severity (NIH Stroke Scale [NIHSS], Glasgow Coma Scale [GCS]), hemorrhage features, treatment timing, and discharge outcomes were compared. Hemorrhage volumes were measured with Synapse imaging software. Primary outcomes were absolute and percent hemorrhage volume change, significant hemorrhage growth (>6 mL or >33%), and neurological deterioration (≥2-point GCS decrease or ≥4-point NIHSS increase). RESULTS: Of 134 eligible patients, 43 received andexanet alfa and 91 received 4F-PCC. Traumatic bleeds accounted for 64% of cases. Common diagnoses included traumatic subdural hemorrhage (n=31), spontaneous intracerebral hemorrhage (n=30), and traumatic multicompartmental hemorrhage (n=28). Mean age was 78 years, baseline GCS was 13, and mean baseline hemorrhage volume was 43 mL (range: 0.1–284 mL). Age, gender, race, and door-to-needle times were similar between groups. Andexanet alfa patients had higher NIHSS (20 vs. 13, p=0.004) and lower GCS (10 vs. 11, p=0.019) on admission. Mean absolute and percent volume changes were similar; however, more patients on andexanet alfa had significant hemorrhage growth (42% vs. 23%, p=0.029). Neurological deterioration rates were comparable. Ischemic or thromboembolic complications were similarly low for andexanet alfa (2%) and 4F-PCC (4%). CONCLUSIONS: In this real-world analysis, andexanet alfa was linked to a higher risk of significant intracranial hemorrhage growth than 4F-PCC, despite similar rates of neurological deterioration, thromboembolic events, functional disability, and mortality. 4F-PCC may serve as a clinically viable alternative for reversing FXa inhibitor anticoagulation in intracranial hemorrhage.

Introduction: Vascular dementia (VaD) induces white matter (WM) damage, however, the molecular mechanisms underlying WM dysfunction and VaD remain unclear. The present study investigated the role of miR-219 in VaD-induced WM damage. Methods: MiR-219 mediates oligodendrocyte progenitor cell (OPC) function. To investigate the potential role of miR-219 in VaD-induced WM damage, we generated an inducible transgenic mouse line with specific ablation of miR-219 in oligodendrocyte progenitor cells (NG2-CreERT2; miR-219flox; Tau/GFP, miR-219 KO). VaD was induced by intracarotid administration of cholesterol crystals to provoke multiple microinfarcts (MMI) in mice. Cognitive and depression-like behaviors were evaluated by the forced swim, Morris water maze, and passive avoidance tests conducted at 21-30 days post MMI. Results: RT-PCR confirmed a significant down regulation of miR-219 in the WM of miR-219 KO mice compared to WT mice. Immunohistochemistry revealed that wild-type MMI mice (WT+MMI) significantly reduced NG2+ OPCs and diminished myelin basic protein (MBP) in the corpus callosum (CC). However, compared to WT-MMI, miR-219 KO MMI mice had significant reduction of NG2+ OPCs and MBP+ myelin (p<0.01, n=3-5/group). Western blot showed that miR-219 KO+MMI mice significantly reduced marker proteins of mature oligodendrocytes (OLs) including APC (adenomatous polyposis coli) by 67%, CNPase by 47%, and MBP by 43% (p<0.05 vs WT+MMI, n=3/group). RNA-seq data revealed that deregulated genes in miR-219 KO+MMI mice were highly associated with OPC generation and differentiation, myelination, and myelin sheath compared to genes in WT+MMI mice. Downregulation of miR-219 increased its target genes of PDGFRα (Platelet-derived growth factor receptor alpha) and Foxj3 (Forkhead box J3) in the CC and striatum, which are known to regulate OPC function. Additionally, WT+MMI mice exhibited significantly increased escape latency in the passive avoidance test, reduced time spent in the target platform quadrant in the Morris water maze test, and decreased active time in the forced swim test compared to sham controls, indicating cognitive and behavioral deficits. MiR-219 KO+MMI mice exhibited an exacerbated cognitive decline and increased depression-like behavior compared to WT+MMI mice. Conclusions: Ablation of miR-219 in OPCs aggravates MMI- induced WM damage and cognitive and behavioral deficits, suggesting that therapy targeting augmentation of miR-219 can reduce VaD-induced WM damage.

Background: Stroke and cardiac arrest are major contributors to global mortality. The development of cardiac complications such as cardiac arrest, myocardial infarction, and arrhythmias is higher in people who experience stroke, and these complications are more pronounced in individuals with pre-existing heart conditions. The aim of this study is to assess long-term mortality trends in people who have had a stroke and cardiac arrest in the U.S. and to discern populations at highest risk. Methods: Mortality rates were obtained from the CDC WONDER Database among adults aged 45 years and older who had a stroke (ICD-10 code 164) and cardiac arrest (ICD-10 code 146) from 1999 to 2023. Age-adjusted mortality rates (AAMRs) per 100,000 population and annual percent change (APC) were calculated via Joinpoint regression with a 95% confidence interval (CI), analyzing trends by year, race, gender, ethnicity, and region. Results: There were a total of 385,887 stroke and cardiac arrest-related deaths between 1999 and 2023 among adults aged ≥ 45 years. Overall AAMR followed a decreasing trend over the years, from 23.9 in 1999 to 12.9 in 2009 (APC: -6.28; 95% CI: -6.97 to -5.58), then falling to 6.7 in 2023 (APC: -4.17; 95% CI: -4.78 to -3.55). Males had a persistently higher mortality as compared to females, with AAMRs of 7.6 and 6.0 in 2023, respectively. NH Blacks/African Americans had the highest AAMR, followed by Hispanic/Latino, NH White, and NH American Indian/Alaska Native. Geographically, the Western region had the highest AAMR, followed by the Northeast, the South, and the Midwest. Moreover, metropolitan areas had a higher mortality rate (14.5) compared to non-metropolitan areas (14.0). Conclusion: Our study shows a decreasing trend in stroke and cardiac arrest-related mortality among older adults in the United States from 1999 to 2023. We observed significant demographic and geographic disparities, with higher mortality among men, Blacks/African Americans, individuals in the Western region, and those living in metropolitan areas.

Background: Cerebral hyperperfusion syndrome (CHS) after carotid revascularization procedures, such as carotid artery stenting (CAS) and carotid endarterectomy (CEA), is a well-described and serious complication. Predicting which patients are most likely to experience CHS utilizing transcranial doppler (TCD) ultrasonography remains uncertain. We aimed to conduct a systematic review and meta-analysis in order to assess the diagnostic accuracy of TCD-related parameters in predicting CHS after carotid interventions. Methods: We conducted a systematic search of PubMed, EMBASE, and Web of Science from inception to July 12, 2025, and performed a meta-analysis to evaluate the role of TCD-related parameters obtained pre- and post-intervention in predicting CHS. Articles evaluating the diagnostic accuracy of TCD studies in predicting CHS in adult patient population undergoing CEA or CAS were included. We utilized a bivariate random-effects model to assess the diagnostic accuracy of TCD parameters and performed the review according to the Preferred Reported Items for Systematic and Meta-analyses (PRISMA) guidelines. Results: Of the 3571 initially identified studies, 15 studies of 5160 patients met the inclusion criteria. Pooled analysis demonstrated that a two-fold increase in the mean flow velocity (MFV) of the ipsilateral middle cerebral artery (MCA) following carotid intervention was associated with an overall sensitivity of 56% (95% confidence interval [CI], 31%-79%, I2=66.2%) and specificity of 93% (95% CI, 86%-96%, I2=66.2%73.4%) for predicting CHS. Moreover, a two-fold increase of ipsilateral peak systolic velocity (PSV) of the MCA demonstrated sensitivity of 54% (95% CI, 26%-79%, I2=46.8%) and specificity of 97% (95% CI, 90%-99%, I2=72.1%). Across the studies, negative predictive value ranged between 95-100% for the aforementioned metrics. A one-fold increase in MCA MFV demonstrated a sensitivity of 88% (95% CI, 68%-96%) and specificity of 81% (95% CI, 74%-86%). In subgroup analysis restricted to patients undergoing CEA, a two-fold increase in MCA MFV yielded sensitivity of 88% (95% CI, 68%-96%) and specificity of 92% (95% CI, 86%-96%). Conclusions: After carotid revascularization procedure, absence of a two-fold increase in MCA MFV or PSV on TCD strongly indicates that CHS is unlikely to occur. However, the modest sensitivity reduces the usefulness of this technique as an early screening tool.

Background: Germline mutations in BRCA1 and BRCA2 are well-established hereditary risk factors for breast and ovarian cancers, with lesser-known implications in prostate and pancreatic cancers. These associations reflect impaired DNA damage repair that compromises genomic stability. In animal models, BRCA1 inactivation has also been linked to apoptotic pathways during neurodevelopment, resulting in hypoplasia of key brain regions. We aimed to investigate whether such mechanisms translate to structural brain differences in human BRCA mutation carriers. Methods: We retrospectively analyzed MR brain scans of 12 individuals (6 with BRCA1 mutations and 6 with BRCA2 mutations), along with 12 age-matched breast cancer controls with wildtype BRCA. Patients with a history of prior intracranial lesions were excluded. Automated tissue segmentation and brain parcellation were performed using web-based Vol2Brain and AssemblyNet neuroimaging pipelines, with volumetric measures normalized to a healthy reference population. The small cohort warranted a descriptive analytical approach. Chi-Square and independent samples t-tests were conducted for univariable group comparisons. Results: The mean age was 58.3 years (IQR 48.24-67.0), and 92% (n = 22) were female; 83% (n = 10) of the BRCA group had a breast cancer diagnosis at the time of MRI. Chemotherapy regimens and treatment duration were comparable between groups (p = 0.18 and p = 0.38, respectively). BRCA mutation carriers showed higher white matter (WM) volumes (46.55 ± 11.07 % vs. 38.99 ± 3.53 %, p = 0.034) and lower gray matter (GM) volumes (39.16 ± 9.66% vs. 45.70 ± 3.74%, p = 0.04), with similar intracranial cavity volumes (ICV) and cerebrospinal fluid (CSF). Reduced lobar volumes were observed in the BRCA cohort, with significant findings in the parietal (p = 0.043) and temporal lobes (p = 0.047). Conclusions: Our study builds on growing evidence that carriage of BRCA mutations may exert independent effects on brain structure and morphology. Based on relationships between white matter integrity and cerebral small vessel disease, these findings underscore the need for further research into the role of BRCA mutations in stroke susceptibility and brain aging.

Background: Stroke is a leading cause of death and disability, with diabetes mellitus (DM) increasing the risk. However, trends in stroke mortality not classified as ischemic or hemorrhagic among individuals with DM are poorly understood. Methods: We analyzed CDC WONDER data (1999–2020) for adults aged ≥25 years with non-specified stroke (ICD-10: I64) and DM (E10–E14). Age-adjusted mortality rates (AAMRs) per 100,000 were calculated using the 2000 U.S. standard population. Joinpoint regression assessed trends via Annual Percent Change (APC) and Average Annual Percent Change (AAPC), stratified by demographics and geography. Results: Between 1999 and 2020, there were 407570 deaths due to stroke (not-specified as hemorrhage or infarction) with diabetes mellitus, highest in medical facilities (41.89%). AAMR declined from 12.97 to 7.36, with a drop from 1999–2018 (APC: –4.4), followed by a rise from 2018–2020 (APC: 11.5) and a total AAMR of 8.58. Males (9.31), and NH Black individuals (17.61) had the highest total AAMRs; females (8.00), and NH Whites (7.42) the lowest. The South (9.35), Mississippi (16.2), and Noncore rural areas (9.36) had the highest AAMRs; the Northeast (6.69), Nevada (4.26), and Large Fringe Metro areas (10.75) the lowest. Conclusion: After years of decline, non-specified stroke mortality among adults with DM is rising again, with a disproportionate impact on NH Black males in Noncore Southern regions.

Background: Treatment and prevention of acute stroke during the past two decades probably rearranged mortality patterns, while Alzheimer's disease, with no disease-modifying therapy to characterize it, continues to accumulate increasingly onerous burdens for caregivers and health systems. Side-by-side comparison of long-term mortality patterns of these diseases can show emerging disparities and inform strategic resource allocation. Methods: We conducted a population-based, retrospective study of national death certificate data 1999–2023 utilizing the CDC WONDER Multiple Cause-of-Death database. Stroke and Alzheimer's disease were identified with accepted ICD-10 codes (I60–I69 for stroke; G30 for Alzheimer's disease). Age-adjusted mortality rates (AAMRs) were calculated per 100,000 population for comparison to the 2000 U.S. standard population. Temporal trends were analysed using Joinpoint Regression Software, Version 5.4.0 (April 2025) to compute APC and AAPC with 95% CIs. Differences were tested by sex, age groups, race/ethnicity, urbanization, U.S. census regions, and place of death. Results: Mortality from stroke declined significantly (average annual percent change [AAPC] –4.54%, 95% CI –5.52 to –3.55), with short-term bulges in 2018–2021. Mortality from Alzheimer's was stable overall (AAPC 0.56%, 95% CI –1.23 to 2.39) but increasing in women and the oldest-old. Blacks had the highest stroke and Alzheimer's mortality among non-Hispanic Whites. Non-metropolitan counties had higher mortality for both conditions across the board. Alzheimer's death (1,336 per 100,000) was higher than stroke (1,011 per 100,000) death among adults ≥85 years. Hospital death was more common among stroke; Alzheimer's death was more likely in nursing homes and at home. Conclusion: Over 25 years of decline, Mortality from stroke fell in populations due to increased prevention and acute care, while death from Alzheimer's continues uncontrolled in female, older, White, and rural populations. The divergent trends imply additional Alzheimer's disease interventions and cautious chronic care efforts.

Introduction: Intracerebral hemorrhage (IH) and cerebral infarction (CI) are leading causes of stroke mortality in older adults, with hypertension as a principal modifiable risk factor. Although stroke mortality has declined overall, long-term comparisons between these subtypes in hypertensive elderly populations remain insufficient. Methods: CDC WONDER mortality data (1999–2020) were analyzed for decedents aged ≥65 years with hypertension (I10) as the underlying cause of death and IH (I61) or CI (I63) as contributing causes. Age-adjusted mortality rates (AAMRs) per 100,000 were standardized to the 2000 U.S. population. Trends were assessed using Joinpoint regression, reporting annual percent change (APC) with 95% confidence intervals, stratified by sex, race/ethnicity, census region, and urbanization. Results: We identified 101,452 IH-related and 48,670 CI-related deaths. IH mortality declined steadily (AAMR 11.08; APC –2.10%, p<0.001) across all demographics. CI mortality followed a biphasic trajectory—decreasing from 1999–2013 (APC –6.13%, p<0.01) then rising sharply from 2013–2020 (APC 19.01%, p<0.001). IH rates were higher in men overall (11.25) but converged with women by 2020; CI rose more steeply in men post-2013. By race/ethnicity, IH declined in White (APC –2.28%) and Black groups (–2.04%), while CI increased among Hispanic (AAMR 9.04 in 2020) and Asian/Pacific Islander populations. Regionally, IH was highest in the West (10.92) and lowest in the Northeast (7.59) in 2020, whereas CI increases were consistent across regions, with the West and Northeast peaking at 10.94. Declines in IH occurred in both metropolitan (APC –2.28%) and rural (–1.49%) areas, but CI mortality rose in both after 2013 (19.65% vs 16.36%). IH deaths were mainly inpatient, while CI occurred more frequently at home or hospice, reflecting distinct clinical trajectories. Conclusion: IH mortality has declined among hypertensive older adults, reflecting advances in blood pressure control, imaging, and acute care. In contrast, the resurgence in CI mortality after 2013 signals systemic drivers, including rising vascular risk burden, inequities in advanced therapies, and treatment delays. These findings underscore the need for intensified risk factor control, equitable access to acute stroke interventions, and strategies tailored to vulnerable subgroups.