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Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

The Stroke Preclinical Assessment Network (SPAN) is a multicenter preclinical trial platform using rodent models of transient focal cerebral ischemia to address translational failure in experimental stroke. In addition to centralized randomization and blinding and large samples, SPAN aimed to introduce heterogeneity to simulate the heterogeneity embodied in clinical trials for robust conclusions. Here, we report the heterogeneity introduced by allowing the 6 SPAN laboratories to vary most of the biological and experimental model variables and the impact of this heterogeneity on middle cerebral artery occlusion (MCAo) performance. We included the modified intention-to-treat population of the control mouse cohort of the first SPAN trial (n=421) and examined the biological and procedural independent variables and their covariance. We then determined their impact on the dependent variables cerebral blood flow drop during MCAo, time to achieve MCAo, and total anesthesia duration using multivariable analyses. We found heterogeneity in biological and procedural independent variables introduced mainly by the site. Consequently, all dependent variables also showed heterogeneity among the sites. Multivariable analyses with the site as a random effect variable revealed filament choice as an independent predictor of cerebral blood flow drop after MCAo. Comorbidity, sex, use of laser Doppler flow to monitor cerebral blood flow, days after trial onset, and maintaining anesthesia throughout the MCAo emerged as independent predictors of time to MCAo. Total anesthesia duration was predicted by most independent variables. We present with high granularity the heterogeneity introduced by the biological and model selections by the testing sites in the first trial of cerebroprotection in rodent transient filament MCAo by SPAN. Rather than trying to homogenize all variables across all sites, we embraced the heterogeneity to better approximate clinical trials. Awareness of the heterogeneity, its sources, and how it impacts the study performance may further improve the study design and statistical modeling for future multicenter preclinical trials.

Background Intracerebral hemorrhage remains the deadliest form of stroke worldwide, inducing neuronal death through a wide variety of pathways. Therapeutic hypothermia is a robust and well-studied neuroprotectant widely used across a variety of specialties. Aims This review summarizes results from preclinical and clinical studies to highlight the overall effectiveness of therapeutic hypothermia to improve long-term intracerebral hemorrhage outcomes while also elucidating optimal protocol regimens to maximize therapeutic effect. Summary of review A systematic review was conducted across three databases to identify trials investigating the use of therapeutic hypothermia to treat intracerebral hemorrhage. A random-effects meta-analysis was conducted on preclinical studies, looking at neurobehavioral outcomes, blood brain barrier breakdown, cerebral edema, hematoma volume, and tissue loss. Several mixed-methods meta-regression models were also performed to adjust for variance and variations in hypothermia induction procedures. Twwenty-one preclinical studies and five human studies were identified. The meta-analysis of preclinical studies demonstrated a significant benefit in behavioral scores (ES = −0.43, p = 0.02), cerebral edema (ES = 1.32, p = 0.0001), and blood brain barrier (ES = 2.73, p ≤ 0.00001). Therapeutic hypothermia was not found to significantly affect hematoma expansion (ES = −0.24, p = 0.12) or tissue loss (ES = 0.06, p = 0.68). Clinical study outcome reporting was heterogeneous; however, there was recurring evidence of therapeutic hypothermia-induced edema reduction. Conclusions The combined preclinical evidence demonstrates that therapeutic hypothermia reduced multiple cell death mechanisms initiated by intracerebral hemorrhage; yet, there is no definitive evidence in clinical studies. The cooling strategies employed in both preclinical and clinical studies were highly diverse, and focused refinement of cooling protocols should be developed in future preclinical studies. The current data for therapeutic hypothermia in intracerebral hemorrhage remains questionable despite the highly promising indications in preclinical studies. Definitive randomized controlled studies are still required to answer this therapeutic question.

Purpose The trend of atherosclerotic plaque feature evolution is unclear in stroke patients with and without recurrence. We aimed to use three-dimensional whole-brain magnetic resonance vessel wall imaging to quantify the morphological changes of causative lesions during medical therapy in patients with symptomatic intracranial atherosclerotic disease. Methods Patients with acute ischemic stroke attributed to intracranial atherosclerotic disease were retrospectively enrolled if they underwent both baseline and follow-up magnetic resonance vessel wall imaging. The morphological features of the causative plaque, including plaque volume, peak normalized wall index, maximum wall thickness, degree of stenosis, pre-contrast plaque-wall contrast ratio, and post-contrast plaque enhancement ratio, were quantified and compared between the non-recurrent and recurrent groups (defined as the recurrence of a vascular event within 18 months of stroke). Results Twenty-nine patients were included in the final analysis. No significant differences were found in plaque features in the baseline scan between the non-recurrent ( n = 22) and recurrent groups ( n = 7). The changes in maximum wall thickness (–13.32% vs. 8.93%, P = 0.026), plaque-wall contrast ratio (–0.82% vs. 3.42%, P = 0.005) and plaque enhancement ratio (–11.03% vs. 9.75%, P = 0.019) were significantly different between the non-recurrent and recurrent groups. Univariable logistic regression showed that the increase in plaque-wall contrast ratio (odds ratio 3.22, 95% confidence interval 1.55–9.98, P = 0.003) was related to stroke recurrence. Conclusion Morphological changes of plaque features on magnetic resonance vessel wall imaging demonstrated distinct trends in symptomatic intracranial atherosclerotic disease patients with and without stroke recurrence.

Objective: To describe the impact of COVID-19 on acute cerebrovascular disease care across 9 comprehensive stroke centers throughout Los Angeles County (LAC). Methods: Volume of emergency stroke code activations, patient characteristics, stroke severity, reperfusion rates, treatment times, and outcomes from February 1 to April 30, 2020, were compared against the same time period in 2019. Demographic data were provided by each participating institution. Results: There was a 17.3% decrease in stroke code activations across LAC in 2020 compared to 2019 (1,786 vs. 2,159, respectively, χ2 goodness of fit test p < 0.0001) across 9 participating comprehensive stroke centers. Patients who did not receive any reperfusion therapy decreased by 16.6% in 2020 (1,527) compared to 2019 (1,832). Patients who received only intravenous thrombolytic (IVT) therapy decreased by 31.8% (107 vs. 157). Patients who received only mechanical thrombectomy (MT) increased by 3% (102 vs. 99). Patients who received both IVT and MT decreased by 31.8% (45 vs. 66). Recanalization treatment times in 2020 were comparable to 2019. CSCs serving a higher proportion of Latinx populations in the eastern parts of LAC experienced a higher incidence of MT in 2020 compared to 2019. Mild increase in stroke severity was seen in 2020 compared to 2019 (8.95 vs. 8.23, p = 0.046). A higher percentage of patients were discharged home in 2020 compared to 2019 (59.5 vs. 56.1%, p = 0.034), a lower percentage of patients were discharged to skilled nursing facility (16.1 vs. 20.7%, p = 0.0004), and a higher percentage of patients expired (8.6 vs. 6.3%, p = 0.008). Conclusion: LAC saw a decrease in overall stroke code activations in 2020 compared to 2019. Reperfusion treatment times remained comparable to prepandemic metrics. There has been an increase in severe stroke incidence and higher volume of thrombectomy treatments in Latinx communities within LAC during the pandemic of 2020. More patients were discharged home, less patients discharged to skilled nursing facilities, and more patients expired in 2020, compared to the same time frame in 2019.

Despite a current emphasis on equity in stroke care, one of the most common stroke assessment tools that is used both nationally and internationally, includes an anachronistic image that projects cultural, linguistic, and socioeconomic bias. This image, titled The Cookie Theft picture, is included in the National Institutes of Health Stroke Scale and was originally developed in 1972. Now, 50 years later, it does not reflect our current diverse, linguistically rich, and multicultural patient population.

Background and aims Intracranial atherosclerotic disease (ICAD) is a major etiologic cause for acute ischemic stroke (AIS) and transient ischemic attack (TIA). The study was designed to investigate if differential morphological features exist in symptomatic atherosclerotic lesions between AIS and TIA patients. Methods The culprit plaques from 45 AIS patients and 42 TIA patients were analyzed for the degree of stenosis, vessel wall irregularity, normalized wall index (NWI), remodeling index, plaque-wall contrast ratio (CR), high signal intensity on T1-weighted images, plaque enhancement ratio and enhancement grade. These plaque features along with clinical characteristics were compared between AIS and TIA groups as well as between their stenosis degree-matched subgroups. Results Overall, grade 2 enhancement (OR 3.85, 95%CI 1.42–10.46, p = 0.006) and hyperlipidemia (OR 3.04, 95%CI 1.13–8.22, p = 0.025) were independent indicators for AIS, whereas high NWI (OR 1.47, 95%CI 0.76–2.86, p = 0.004) was associated with TIA. In the comparison between the subgroups with moderate (30%–69%) stenosis, high plaque-wall CR (OR 5.38, 95%CI 1.39–20.75, p = 0.008) was associated with AIS, whereas high NWI (OR 2.50, 95%CI 0.61–10.00, p = 0.006) was associated with TIA. Conclusions Our study reveals differential morphological features in symptomatic ICAD lesions between AIS and TIA patients. Probing these features with MR vessel wall imaging may provide insights into the prognosis of patients with ICAD.

INTRODUCTION We aim to report 3 cases of central nervous system (CNS) vasculitides, in which high-resolution magnetic resonance vessel wall imaging (HR-VWI) findings were instrumental in the diagnosis and management. CASE REPORT Case 1: A 41-year-old obese, smoker female with arterial hypertension presented with recurrent transient ischemic attacks. Computed topography angiography demonstrated bilateral middle cerebral artery (MCA) stenosis. HR-VWI revealed uniform enhancement and thickening of the arterial wall, suggestive of MCA vasculitis. The patient reported chronic calf rash that was biopsied and revealed unspecified connective tissue disease. With immunomodulation, patient remained asymptomatic and 6-month surveillance HR-VWI showed improved MCA stenoses.Case 2: A 56-year-old male with herpes simplex virus 1 encephalitis was treated with antiviral therapy and improved clinically. Two months later, the brain magnetic resonance imaging revealed new temporo-parietal edema and distal MCA hyperintense vessels. HR-VWI showed MCA concentric smooth contrast enhancement, that was attributed to postinfectious vasculitis and had resolved on follow-up HR-VWI.Case 3: A 41-year-old male presented with 1-week of headache and encephalopathy. Brain magnetic resonance imaging revealed punctate multifocal acute ischemic infarcts and no contrast-enhancement. HR-VWI showed multifocal diffuse enhancement of distal cerebral vasculature. Patient subsequently developed branch retinal artery occlusion and hearing loss and was diagnosed with Susac syndrome. No recurrent symptoms were noted after immunotherapy initiation. CONCLUSIONS In these 3 cases, HR-VWI identified distinctive vascular inflammatory changes, which were crucial to guide the etiological workup, positive diagnosis, surveillance neuroimaging, and targeted treatment. HR-VWI is an important diagnostic tool in CNS vasculitides, by providing nuanced information about arterial wall integrity and pathology.

Background Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces extra-cranial collaterals to intracranial vessels. We present the results of a phase-II trial of EDAS in intracranial atherosclerotic disease patients. Aims To evaluate the feasibility, safety, and preliminary efficacy of EDAS in intracranial atherosclerotic disease patients. Methods ERSIAS was a prospective objective-performance-criterion trial of EDAS plus intensive medical management (IMM) in intracranial atherosclerotic disease (ICAD) patients failing medical treatment. Primary endpoint was any stroke/death within 30-days post-surgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with an objective-performance-criterion based on a 10% reduction from the 20% rate in the intensive medical management arm of the stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial (SAMMPRIS) in patients with poor collaterals. Event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from SAMMPRIS and the carotid occlusion surgery study (COSS). Results During a median follow-up of 24.5 months, 5 (9.6%) of 52 patients had a primary endpoint event. The primary endpoint rate at one year met the threshold for nonfutility and advancement to phase III (Conclusion ERSIAS phase II provides evidence of safety and strong signals of efficacy of EDAS-plus-intensive medical management, supporting advancement to a seamless phase-IIb/III trial. Clinical Trial Registration URL: https://www.clinicaltrials.gov.NCT01819597 .

Background and Purpose: A recombinant engineered variant of APC (activated protein C), 3K3A-APC, lacks anticoagulant properties ( Methods: Tenecteplase-mediated lysis of thrombin generated plasma clots of human normal pooled plasma was monitored in the presence of varying doses of 3K3A-APC. The effects on fibrinolysis by tenecteplase and alteplase were compared. Results: The presence of 3K3A-APC shortened the time for clot lysis induced by tenecteplase at very low levels but not at higher therapeutic concentrations of tenecteplase. Comparisons of alteplase-mediated clot lysis to tenecteplase clot lysis showed that both thrombolytic agents behaved similarly in the presence of 3K3A-APC. Conclusions: These results indicate that 3K3A-APC does not interfere with tenecteplase’s clot lysis function.

Changes in neurovascular coupling are associated with both Alzheimer's disease and vascular dementia in later life, but this may be confounded by cerebrovascular risk. We hypothesized that hemodynamic latency would be associated with reduced cognitive functioning across the lifespan, holding constant demographic and cerebrovascular risk. In 387 adults aged 18-85 (mean = 48.82), dynamic causal modeling was used to estimate the hemodynamic response function in the left and right V1 and V3-ventral regions of the visual cortex in response to a simple checkerboard block design stimulus with minimal cognitive demands. The hemodynamic latency (transit time) in the visual cortex was used to predict general cognitive ability (Full-Scale IQ), controlling for demographic variables (age, race, education, socioeconomic status) and cerebrovascular risk factors (hypertension, alcohol use, smoking, high cholesterol, BMI, type 2 diabetes, cardiac disorders). Increased hemodynamic latency in the visual cortex predicted reduced cognitive function (p

Background and purpose Mechanical circulatory support (MCS) devices are commonly used in heart failure patients. These devices carry risk for presumably embolic and additionally hemorrhagic stroke. Alterations in blood flow play a key role in stroke pathophysiology, and we aimed to learn more about hemodynamic compromise. In this study, we used transcranial Doppler (TCD) ultrasound to define hemodynamics of commonly used nonpulsatile MCS devices, as well as pulsatile devices, with special attention to the total artificial heart (TAH). Methods From 2/2013 through 12/2016, we prospectively enrolled patients with MCS who underwent TCD imaging. We analyzed TCD parameters, including peak systolic velocity, end-diastolic velocity, pulsatility indices (PIs), and number of high-intensity transient signals. Waveform morphologies were compared between various MCS devices. Results We performed 132 TCD studies in 86 MCS patients. Waveforms in patients supported by venoarterial-extracorporeal membrane oxygenation demonstrated continuous flow without clear systolic peaks with an average (±SD) PI of .43 (±.2). PIs were low in patients with continuous-flow left ventricular assist devices with a mean PI of .32 (±.13). Impella patients had morphologically distinct pulsatile waveforms and a higher mean PI of .65 (±.24). In intra-arterial balloon pump patients, mean PI was 1.01 (±.16) and diastolic upstrokes were pronounced. In TAH patients, mean middle cerebral artery velocity of 79.69 (±32.33) cm/seconds and PI of .74 (±.14) approached normal values. Conclusion TCD can detect characteristic waveforms in patients supported by various MCS devices. These device-specific TCD patterns are recognizable and reproducible.

Introduction Missing outcome data may undermine interpretation of randomised clinical trials by weakening power and limiting apparent effect size. We assessed bias and inefficiency of two imputation methods commonly used in stroke trials evaluating the efficacy of iv thrombolysis. Patients and methods We searched the virtual international stroke trials archive (VISTA)-acute for ischaemic stroke patients with 90-day modified Rankin scale as an outcome, and known thrombolysis status. We excluded any with missing 30-day modified Rankin scale. We planned two analyses; first, we calculated odds ratios for outcome in thrombolysed versus not thrombolysed from imputed-only data, (a) among patients with missing modified Rankin scale 90 and (b) among matched patients with intact data (using propensity score methods and relevant covariates). Imputation approaches were last observation carried forward (LOCF) or multiple imputation. Outcome comparisons used dichotomisation and shift analysis. Thereafter, we calculated whole-population odds ratios using LOCF and multiple imputation (also through dichotomisation and shift analysis); first with the original 1.5% missing outcome data, and then artificially increasing the burden (5%; 10%; 20%; 30%). Results We considered 9657 patients from eight of the studies included in VISTA, 3034 (31%) thrombolysed. Missing data replacement by LOCF with analysis by dichotomisation gave the highest estimate of thrombolysis influence. Imputing while increasing the burden of missing data progressively raised the odds ratios estimates, though thresholds for overestimation were 10% for LOCF; 20% for multiple imputation. Discussion: Replacing missing outcome data tended to overestimate differences of thrombolysed versus non-thrombolysed patients, but had minimal impact below a 10% burden of missing data. Conclusion: In the specific context of acute stroke trials testing iv thrombolytics, replacing missing data by carrying forward the last observation tended to overestimate treatment odds ratios more than multiple imputation.

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence. We aimed to investigate the role of circulating exosomal microRNAs (e-miRNAs) in recurrent ischemic events in ICAD. Consecutive patients with severe ICAD undergoing intensive medical management (IMM) were prospectively enrolled. Those with recurrent ischemic events despite IMM during 6-month follow up were algorithmically matched to IMM responders. Baseline blood e-miRNA expression levels of the matched patients were measured using next generation sequencing. A total of 122 e-miRNAs were isolated from blood samples of 10 non-responders and 11 responders. Thirteen e-miRNAs predicted IMM failure with 90% sensitivity and 100% specificity. Ingenuity pathway analysis (IPA) determined 10 of the 13 e-miRNAs were significantly associated with angiogenesis-related biological functions (p

After initial enthusiasm for mild therapeutic hypothermia (TH) treatment after brain injuries, including global cerebral ischemia after cardiac arrest, subsequent trials suggested similar benefit using only targeted temperature management (TTM), with fewer side effects. Globally, effective treatment of brain ischemia with TH has declined. Recent data suggest, however, that TH to 33°C may be superior to TTM. We review the background and rationale underlying TH and TTM. We present previously published data from our own laboratory that confirms TH to 33°C provides superior brain cytoprotection, compared to 35°C or 37°C, over a range of delays to treatment and several durations of TH. We illustrate that the treatment effect size of either or 35 is superior to 37, but the effect size difference between 33 and 35, although significant, is small. We estimate that to demonstrate the superiority of TTM over TH, a clinical trial would need between 3,000 and 9,000 patients depending on the desired treatment effect size. Our review and our own data suggest that TH to 33°C is superior to TTM to 36°C, but an extremely large clinical trial would be needed to demonstrate the difference.

Despite the high mortality and disability associated with traumatic brain injury (TBI), effective pharmacologic treatments are lacking. Of emerging interest, bioactive lipids, including specialized pro-resolving lipid mediators of inflammation (SPMs), act to attenuate inflammation after injury resolution. The SPM lipidome may serve as a biomarker of disease and predictor of clinical outcomes, and the use of exogenous SPM administration represents a novel therapeutic strategy for TBI. This review article provides a comprehensive discussion of the current pre-clinical and clinical literature supporting the importance of bioactive lipids, including SPMs, in TBI recovery. We additionally propose a translational approach to answer important clinical and scientific questions to advance the study of bioactive lipids and SPMs towards clinical research. Given the morbidity and mortality associated with TBI with limited treatment options, novel approaches are needed.

We search for ischemic stroke treatment knowing we have failed—intensely and often—to translate mechanistic knowledge into treatments that alleviate our patients’ functional impairments. Lessons can be derived from our shared failures that may point to new directions and new strategies. First, the principle criticisms of both preclinical and clinical assessments are summarized. Next, previous efforts to develop single-mechanism treatments are reviewed. Finally, new definitions, novel approaches, and different directions are presented. In previous development efforts, the basic science and preclinical assessment of candidate treatments often lacked rigor and sufficiency; the clinical trials may have lacked power, rigor, or rectitude; or most likely both preclinical and clinical investigations were flawed. Single-target agents directed against specific molecular mechanisms proved unsuccessful. The term neuroprotection should be replaced as it has become ambiguous: protection of the entire neurovascular unit may be called cerebral cytoprotection or cerebroprotection. Success in developing cerebroprotection—either as an adjunct to recanalization or as stand-alone treatment—will require new definitions that recognize the importance of differential vulnerability in the neurovascular unit. Recent focus on pleiotropic multi-target agents that act via multiple mechanisms of action to interrupt ischemia at multiple steps may be more fruitful. Examples of pleiotropic treatments include therapeutic hypothermia and 3K3A-APC (activated protein C). Alternatively, the single-target drug NA-1 triggers multiple downstream signaling events. Renewed commitment to scientific rigor is essential, and funding agencies and journals may enforce quality principles of rigor in preclinical science. Appropriate animal models should be selected that are suited to the purpose of the investigation. Before clinical trials, preclinical assessment could include subjects that are aged, of both sexes, and harbor comorbid conditions such as diabetes or hypertension. With these new definitions, novel approaches, and renewed attention to rigor, the prospect for successful cerebroprotective therapy should improve.

INTRODUCTION: Retinal imaging is a non-invasive tool to study retinal vasculature and neurodegeneration. Patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD)-related cognitive disorder exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid beta-protein (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification, holding promise as an early-stage pathological biomarker of AD. In this exploratory study, we sought to determine whether retinal vascular features combined with retinal amyloid burden correlate with the neurocognitive status.METHODS: We used scanning laser ophthalmoscopy to assess quantitative CRFI in a cohort of patients with cognitive impairment that underwent standard neuropsychological testing. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index, vessel inflection index and branching angle was quantified. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole, proximal mid-periphery, and distal mid-periphery. Investigators performing quantifications were blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters and cognitive domain Z-scores.RESULTS: In this pilot study, 34 subjects underwent automated retinal amyloid imaging and 29 subjects (55% female, mean age 64±6 years) had the combined retinal amyloid and peripapillary vascular analysis. Eleven subjects had normal cognition, 15 MCI, 2 probable AD and 1 non-AD dementia. CRFI was increased in individuals with impaired versus normal cognitive function (p 0.0012). Venous VTI was the most significant vascular parameter that differ across levels of CDR. Branching angle correlated with amyloid count in the distal mid-periphery (p=0.03), whereas vessel inflexion index correlated with posterior pole amyloid count (p=0.02). The combined proximal mid-periphery amyloid count – venous tortuosity index was found to exhibit highly significant group differences between cognitively impaired and cognitively normal subjects (0.49 ± 1.1 vs 0.91 ± 1.4, p=0.006). The combined proximal mid-periphery amyloid-venous tortuosity index also correlated with verbal memory (Wechsler Memory Scale-IV; p=0.001) and cognitive-related quality of life (SF-36 mental component score Z-scores; p=0.039).CONCLUSION: Retinal venular tortuosity discriminates across cognitive scores and in combination with proximal mid-periphery amyloid count predicts verbal memory and cognitive-related quality-of-life. Future research is needed to confirm the clinical utility of this integrated retinal imaging-based methodology.

Background Vascular endothelial growth factor-A165 (VEGF-A165) has been identified as a combination of 2 alternative splice variants: proangiogenic VEGF-A165a and antiangiogenic VEGF-A165b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are 2 main types of intracranial arterial steno-occlusive disorders with distinct capacities for collateral formation. Recent studies indicate that VEGF-A165 regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A165 isoforms in ICAD and MMD. Methods Sixty-six ICAD patients, 6 MMD patients, and 5 controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A165a and VEGF-A165b plasma levels were measured at baseline, within 1 week after patients having surgery, and at 1, 3, and 6 months after treatment. Results A significantly higher baseline VEGF-A165a/b ratio was observed in MMD compared to ICAD (P = .016). The VEGF-A165a/b ratio increased significantly and rapidly after surgical treatment in ICAD (P = .026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A165a/b ratio, but at a slower rate, reaching the peak at 3 months after initiation of treatment (baseline versus 3 months VEGF-A165a/b ratio, P = .028). Conclusions Our study shows an increased VEGF-A165a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A165a/b ratio in ICAD patients.

Objective Agonism of protease-activated receptor (PAR) 1 by activated protein C (APC) provides neuro- and vasculoprotection in experimental neuroinjury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurological injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. Methods The NeuroNEXT trial, RHAPSODY, used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360, and 540 μg/kg of 3K3A-APC. After intravenous tissue plasminogen activator, intra-arterial mechanical thrombectomy, or both, patients were randomized to 1 of the 4 doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. Results Between January 2015 and July 2017, we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest-dose 3K3A-APC tested, 540 μg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p = 0.046) and total hemorrhage volume from an average of 2.1 ± 5.8 ml in placebo to 0.8 ± 2.1 ml in the combined treatment arms (p = 0.066). Interpretation RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540 μg/kg for the PAR1 active cytoprotectant, 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. Clinical trial registration Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02222714. ANN NEUROL 2019;85:125-136.

Introduction: Retinal vascular features predict cognitive performance and retinal imaging is a non-invasive tool to study brain health. Patients with Alzheimer’s disease (AD)-related cognitive disorders exhibit both retinal vascular abnormalities and intraretinal accumulation of amyloid-beta (Aβ) plaque. Curcumin-enhanced retinal fluorescence imaging (CRFI) was recently translated as a safe imaging tool for retinal Aβ plaque quantification. In this study, we sought to determine whether and which retinal arterial and venous parameters are predictive of retinal Aβ burden and cognitive Z-scores. Methods: We used scanning laser ophthalmoscopy with RetiaTM (Centervue, Inc) to obtain CRFI in a cohort of patients with cognitive decline. Retinal blood vessels were segmented in a predefined circumpapillary region of interest. For each centerline, vessel tortuosity index (VTI), vessel inflection index (VII), and branching angle (VBA) were quantified, independently for arteries and veins. Additionally, we automatically quantified retinal amyloid count in the supero-temporal quadrant and its subregions: posterior pole (PP), proximal mid-periphery (PMP), and distal mid-periphery (DMP). All quantifications were done blinded to the subjects’ clinical characteristics. Linear regression models were used to assess the correlations between retinal vascular and amyloid parameters. Results: 29 subjects (55% female, mean age 64±6 years) were included in the analysis: 11 had normal cognition, 16 mild cognitive impairment and 2 probable AD. Venous VTI was the only vascular parameter significantly different across levels of Clinical Dementia Rate scores and between cognitively normal and impaired. Venous VBA was a significant predictor of DMP amyloid count (p=0.03). Arterial VII significantly predicted PP amyloid count (p=0.02). VBA predicted Wechsler Adult Intelligence Scale Z-score (p=0.08). The combined VTI-PMP amyloid index significantly predicted Wechsler Memory Scale, California Verbal Learning Test and SF-36 mental component score Z-scores (p Conclusion: Retinal venous tortuosity discriminates across cognitive scores and in combination with PMP amyloid count may predict verbal memory and related quality-of-life scores.

Introduction: Exposure to telestroke in neurology residency is sparse despite its implementation in daily practice. Due to COVID-19, we increased our utilization of telestroke. Given this change in workflow, we investigated how residents utilize telestroke for “Code Brain” (CB) acute stroke evaluations and if expanding the use of telestroke in neurology residency programs is justified. Methods: We retrospectively compared the number of CB evaluations, door to needle (DTN) times, door to decision (DTD) times, and NIHSS from March - June 2019 (in-person evaluations) against those in March - June 2020 (telestroke evaluations). We limited our study to resident-involved cases. Nighttime and weekend CBs are run by a neurology resident and are remotely supervised. Daytime CBs can be run by a resident, fellow, or attending. We assumed that nighttime CBs are resident-run and daytime evaluations are the stroke team’s evaluation. Statistical analysis was performed using R. Results: There were a total of 217 CBs in March - June 2019 and 115 in March - June 2020. In 2019, there were 120 daytime and 97 nighttime CBs; in 2020 there were 62 and 53. The mean DTN for the day for 2019 and 2020 was 45.9 ± 23.2 and 48.4 ± 20.2 (P=0.08). The mean DTN during the night for 2019 and 2020 was 67.3 ± 53.7 and 53.8 ± 25.8 (P=0.64). The mean DTD during the day for 2019 and 2020 was 48.1 ± 41.0 and 44.9 ± 37.6 (P=0.25). The mean DTD during the night for 2019 and 2020 was 60.9 ± 51.1 and 65.8 ± 94.6 (P=0.68). Using a generalized linear model approach to correct for shift (day/night), age, NIHSS, we found no significant differences in DTN or DTD before and after implementing resident-run telestroke. Using Cohen’s approach (1988) we estimated a Type 2 error probability at 7%. Discussion: Our findings show that resident-run telestroke CBs are comparable to CBs run by fellows and attendings as DTN and DTD were not significantly different between the CBs run by residents in-person or via telestroke. These metrics are also comparable for CBs in which a fellow or attending are supervising or running the CB. Implementing resident-run telestroke consultation showed no effect on DTN or DTD after accounting for patient age, NIHSS, or the time of day. These data should reassure programs seeking to grant telestroke privileges to trainees.

Purpose of ReviewMunchausen syndrome by tissue plasminogen activator (tPA) is a phenomenon we describe as patients exhibiting factitious symptoms to assume the role of the sick patient, desiring and received tPA, with no alternative diagnosis or secondary gain to better account for their presentation. To illustrate this phenomenon and its magnitude, we present a series of cases of Munchausen syndrome by tPA, prevalence in our stroke center, and highlight one illustrative case.Recent FindingsOf 335 cases with tPA administration over 29 months, 10 were confirmed as Munchausen syndrome by tPA, reflecting a 3.0% prevalence in our stroke center.SummaryMunchausen syndrome by tPA is an underappreciated phenomenon encountered in evaluating patients with acute stroke symptoms. Administering tPA in Munchausen syndrome poses an ethical dilemma because standard of care favors rapid tPA administration, but administration can cause harm, burdens the healthcare system, and does not treat the patient's Munchausen syndrome.

Objectives: Therapeutic hypothermia is the most potent protective therapy for cerebral ischemia in pre-clinical models, however clinical trials have failed to show a significant benefit in patient outcomes. We sought to reconcile this discrepancy by investigating whether hypothermia impaired glymphatic system mediated waste clearance from brain parenchyma in a rat model. Methods: Sprague -Dawley rats were divided into normothermia and hypothermia groups. Hypothermia was achieved using a perivascular closed-loop cooling circuit implanted one week before the experiments in both the groups. Animals in the normothermia group were kept at 37C while the hypothermia animals were cooled to 33C. Once the targeted temperature was reached, two fluorescent tracers, small molecular weight (Texas Red-Dextran 3KdA) and large molecular weight (FITC -Dextran 2MdA) were injected intracisternally in each animal. Animals in both the groups were monitored for blood pressure and blood gases. Thirty minutes after injection, animals were perfused with 4% paraformaldehyde and 50 micron sections were cut using Leica vibratome. Brain sections were mounted on slides and cover slipped using antifade Fluro gold. Sections were imaged on Carl-Zeiss apotome microscope. For each animal 12 sections were imaged, data was analyzed using NIH Image J software. Results and Discussion: Cerebrospinal fluid tracer efflux in brain was significantly reduced in the hypothermia group compared to the normothermia group. This experiment helps provide insight as to a potential reason clinical trials have failed to show benefit in stroke patients, as hypothermia may have an untoward effect of hindering the brain’s natural clearance system from clearing inflammatory molecules and other waste from brain parenchyma.

Investigators acknowledge the limitations of rodent or non-human primate stroke models, hundreds of putative neuroprotectants have been evaluated in preclinical models, but not one has entered the clinical realm. Initial studies focused on the neuron, but in recent years the focus has widened to also include other neural cells including astrocytes, pericytes and endothelial cells, which together form the neurovascular unit. Some new developments raise renewed hope for neuroprotection: the appearance of new compounds with multiple mechanisms of action, or the promulgation of new standards for a rigorous preclinical testing. At the bedside in the last 5 years, uric acid and nerinetide are the only compounds tested for clinical efficacy in randomised controlled trials (RCTs), where all patients had to receive reperfusion therapies, either intravenous thrombolysis and/or mechanical thrombectomy. In addition, otaplimastat, 3K3A-activated protein C (APC), intra-arterial verapamil and intra-arterial hypothermia were also assessed in combination with reperfusion therapy, but in RCTs that only included feasibility or safety outcomes. Some of these compounds yielded promising results which are discussed in this review. Altogether, a deeper knowledge of the mechanisms involved in the ischaemic death process at the neurovascular unit, an improved preselection and evaluation of drugs at the preclinical stage and the testing of putative neuroprotectants in enriched clinical studies of patients receiving reperfusion therapies, might prove more effective than in the past to reverse a dismal situation that has lasted already too long.

Ischemic stroke is the most widespread cause of disability and a leading cause of death in developed countries. To date, the most potent approved treatment for acute stroke is recanalization therapy with thrombolytic drugs such as tissue plasminogen activator (rt-PA or tPA) or endovascular mechanical thrombectomy. Although tPA and thrombectomy are widely available in the United States, it is currently estimated that only 10–20% of stroke patients get tPA treatment, in part due to restrictive selection criteria. Recently, however, tPA and thrombectomy selection criteria have loosened, potentially allowing more patients to qualify. The relatively low rate of treatment may also reflect the perceived risk of brain hemorrhage following treatment with tPA. In translational research and a single patient study, protease activated receptor 1 (PAR-1) targeted therapies given along with thrombolysis and thrombectomy appear to reduce hemorrhagic transformation after recanalization. Such adjuncts may likely enhance the availability of recanalization and encourage more physicians to use the recently expanded selection criteria for applying recanalization therapies. This narrative review discusses stroke therapies, the role of hemorrhagic transformation in producing poor outcomes, and presents the data suggesting that PAR-1 acting agents show promise for decreasing hemorrhagic transformation and improving outcomes.

Highlights • Whereas Covid-19 infection has increasing incidence of venous and arterial thrombotic complications, best practices to guide therapeutic anticoagulation don't exist • Acute ophthalmic artery occlusion is a carotid circulation stroke syndrome and must be considered in patients with hypercoagulable states that develop sudden, painless and severe visual loss • The role of D-Dimer in monitoring the hypercoagulable state and response to therapeutic anticoagulation is unelucidated, We report a case of ophthalmic artery occlusion (OAO) in a young patient with Covid-19 infection that was on therapeutic anticoagulation with apixaban for deep venous thrombosis (DVT). A 48-year-old man with obesity was hospitalized with a severe form of Covid-19 infection, complicated with acute respiratory failure, septic shock, dilated cardiomyopathy and fungemia. Despite treatment with prophylactic enoxaparin (initial D-Dimer 1.14 µg/ml FEU (normal < 0.05 µg/ml FEU), D-Dimer increased to above 20 µg/ml FEU and patient continued to spike high fevers. This prompted further investigations and upper and lower extremities DVTs were confirmed and managed with enoxaparin 1mg/kg twice daily. D-dimer level decreased to 4.98 µg/ml FEU while on therapeutic anticoagulation. Three weeks later pending hospital discharge, the anticoagulation was switched to oral apixaban 10 mg twice daily. Patient developed acute severe right eye visual loss of no light perception and was diagnosed with incomplete OAO. D-Dimer was elevated at 2.13 µg/ml FEU. Stroke etiological work-up found no embolic sources, resolution of the dilated cardiomyopathy and negative antiphospholipid antibodies. Treatment was changed to enoxaparin and no thrombotic events were encountered to date. Ocular vascular complications have not yet been reported in Covid-19. Controversy exists on the best management algorithm for the hypercoagulable state associated to Covid-19. Either direct oral anticoagulants or low-molecular-weight-heparin are considered appropriate at discharge for patients with venous thromboembolism. The optimum regimen for ischemic stroke prevention and the significance of D-Dimer for anticoagulation monitoring in Covid-19 remain unclear..

Introduction Despite advances in imaging retinal amyloidosis, a quantitative and topographical investigation of retinal amyloid beta burden in patients with cognitive decline has never been reported. Methods We used the specific amyloid‐binding fluorophore curcumin and laser ophthalmoscopy to assess retinal amyloid imaging (RAI) in 34 patients with cognitive decline. We automatically quantified retinal amyloid count (RAC) and area in the superotemporal retinal sub‐regions and performed correlation analyses with cognitive and brain volumetric parameters. Results RAC significantly and inversely correlated with hippocampal volume (HV; r = ‐0.39, P = .04). The proximal mid‐periphery (PMP) RAC and RA areas were significantly greater in patients with Montreal Cognitive Assessment (MOCA) score < 26 (P = .01; Cohen d = 0.83 and 0.81, respectively). PMP showed significantly more RAC and area in subjects with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to cognitively normal (P = .04; Cohen d = 0.83). Conclusion Quantitative RAI is a feasible technique and PMP RAC may predict HV. Future larger studies should determine RAI's potential as a biomarker of early AD.

Seriously ill patients with coronavirus disease 2019 (COVID‐19) at risk for death exhibit elevated cytokine and chemokine levels and D‐dimer, and they often have comorbidities related to vascular dysfunctions. In preclinical studies, activated protein C (APC) provides negative feedback downregulation of excessive inflammation and thrombin generation, attenuates damage caused by ischemia‐reperfusion in many organs including lungs, and reduces death caused by bacterial pneumonia. APC exerts both anticoagulant activities and direct cell‐signaling activities. Preclinical studies show that its direct cell‐signaling actions mediate anti‐inflammatory and anti‐apoptotic actions, mortality reduction for pneumonia, and beneficial actions for ischemia‐reperfusion injury. The APC mutant 3K3A‐APC, which was engineered to have diminished anticoagulant activity while retaining cell‐signaling actions, was safe in phase 1 and phase 2 human trials. Because of its broad spectrum of homeostatic effects in preclinical studies, we speculate that 3K3A‐APC merits consideration for clinical trial studies in appropriately chosen, seriously ill patients with COVID‐19.

BACKGROUND AND PURPOSE: The first of the 2 NINDS Stroke Study trials did not show a significant increase in early neurological improvement (ENI), defined as NIHSS improvement by ≥ 4, with alteplase treatment. We hypothesized that ENI defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. METHODS: We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as [(admission NIHSS score–24-hour NIHSS score)x100/admission NIHSS score] and delta NIHSS as (admission NIHSS score–24-hour NIHSS score). We compared ENI using these definitions between alteplase vs. placebo patients. We also used receiver operating characteristic (ROC) curve to determine the predictive association of ENI with excellent 3-month functional outcomes [Barthel Index (BI) score 95 – 100 and modified Rankin scale (mRS) 0–1], good 3-month functional outcome (mRS 0–2) and 3-month infarct volume. RESULTS: There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared to the placebo group (28% vs. 15%, p = 0.045) but not median delta NIHSS (3 vs. 2, p = 0.471). ROC curve comparison showed that percent change NIHSS (ROC(percent)) was better than delta NIHSS (ROC(delta)) and admission NIHSS (ROC(admission)) with regards to excellent 3-month BI (ROC(percent) 0.83, ROC(delta) 0.76, ROC(admission) 0.75), excellent 3-month mRS (ROC(percent) 0.83, ROC(delta) 0.74, ROC(admission) 0.78), and good 3-month mRS (ROC(percent) 0.83, ROC(delta) 0.76, ROC(admission) 0.78). CONCLUSION: In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.

Objective: Retinal microvasculature analysis is suitable to study cognitive disorders given retinal and brain vessels share similar properties. Using novel automated technologies, we aimed to investigate whether automatically-quantified retinal vascular changes from retinal fundus photographs predict brain imaging abnormalities in patients with cognitive impairment; and what specific retinal vascular parameters are more predictive of dementia. Methods: In this cross-sectional study, 34 subjects with cognitive complaints underwent neuropsychometric cognitive testing, retinal fundus photography and brain MRI. Retinal vessel tortuosity index (VTI), inflection index (VII) and length (VL) were automatically computed. The number and volume of cerebral microbleeds (CMB) and white matter hyperintensities (WMHI) were measured using SPIN Software (SpinTech, Bingham Farms, MI). The diagnostic groups were compared for demographic, cognitive, retinal and brain imaging parameters using analysis of variance. The association between brain (intracranial volume (ICV), hippocampal volume (HV), lateral ventricle volume (LVV), WMHI and CMB (volume, number), Fazekas scores) and retinal vascular parameters were assessed by using multiple linear regression models. Results: Nine subjects were cognitively normal (CN) and 25 cognitively impaired (CI) (22 with mild cognitive impairment and 3 with dementia). VTI was the only retinal parameter and HV and LVV were the brain parameters that were significantly different between CN and CI subjects (p=0.02). VTI correlated with VL (p=0.02, r=0.33) and branching angle (p=0.004, r=-0.45). The cognitive domains predicted by VTI were abstraction and orientation. VTI correlated with total intracranial volume (p=0.04, r=-0.12). A significant association was demonstrated for VII and WMHI volume (p=0.03, r=0.007), but not Fazekas score. VII and VTI significantly correlated with CMB volume (p=0.04 and 0.03, respectively). Conclusion: Automatically-detected retinal vessel tortuosity indexes predict neuroimaging markers of microvascular disease and total intracranial volume in cognitively impaired individuals. Retinal imaging may be used to screen patients with cognitive disorders.

Introduction: Intracranial atherosclerotic disease (ICAD) is a common cause of ischemic stroke worldwide and carries a high rate of recurrence. Follow-up of symptomatic ICAD routinely relies on assessment of lumen stenosis. Magnetic resonance vessel wall imaging (MR-VWI) has recently demonstrated the potential to reliably quantify plaque features. This work presents our experience in using serial MR-VWI to quantify the morphological changes of culprit lesions in response to medical therapy in patients with symptomatic ICAD. Methods: Twenty-four patients (4 females; age 46.75±14.05 years) with acute ischemic stroke secondary to ICAD underwent baseline (1-44 days after onset) and follow-up (3-15 months after baseline) 3D whole-brain MR-VWI, which was used to acquire pre- and post-contrast images. Quantitative plaque features, including plaque volume, peak normalized wall index (pNWI), maximum wall thickness, stenosis degree, pre-contrast plaque-wall contrast ratio (CR), and post-contrast plaque enhancement ratio (ER), were derived from both baseline and follow-up MR-VWI scans. Patients with 18-month clinical follow-up were divided into progression and non-progression groups depending on whether major vascular events (stroke, TIA, death) occurred. Results: Seventeen patients were categorized into the non-progression group and 4 into the progression group. Maximum wall thickness (P=0.047), CR (P=0.020) and ER (P=0.012) showed significant decreases in the non-progression group. In the progression group, all 4 patients showed an increase in pNWI, stenosis degree and CR; plaque volume, maximum wall thickness and ER increased in three patients. Typical cases are shown in Figure. Conclusions: Quantitative assessment of lesion-specific responses to medical therapy is clinically feasible with serial MR-VWI. The changes of plaque over time may be useful for ischemic stroke risk stratification with implications for ICAD medical management.