Search Results for: Scoperta una nuova molecola anti-cancro

Stroke, Volume 56, Issue Suppl_1, Page AWMP37-AWMP37, February 1, 2025. Introduction:Post-stroke fatigue (PSF) is a common and debilitating consequence of cerebrovascular accidents, potentially stemming from central and peripheral mechanisms. Recent studies have linked myasthenia gravis-related antibodies to PSF, though data on their role remains limited. Current treatments for PSF are often ineffective, underscoring the need for more research into its underlying causes and management.Objectives:This study investigates the presence of myasthenia gravis-related antibodies in patients with PSF after motor recovery, focusing on low-density lipoprotein receptor-related protein 4 (LRP4) and AGRIN antibodies. We aim to evaluate their clinical response to targeted therapies, excluding anti-AChR and anti-MuSK antibodies.Methods:We conducted a cross-sectional study involving patients with PSF who had undergone myasthenia antibody testing. The study cohort included individuals with fatigue following good motor recovery, who tested positive for LRP4 and AGRIN antibodies. Clinical, demographic, and imaging data were analyzed, with clinical response assessed using the Modified Rankin Scale (mRS) at follow-up.Results:Among 935 patients at the stroke unit over two years, 50 were tested for myasthenia antibodies due to PSF. Of these, 17 (34%) were positive for either anti-AGRIN (70.58%) or anti-LRP4 (64.71%) antibodies. Fatigue was reported by 82.35% of the antibody-positive patients. This group consisted of 35.29% females with a mean age of 66.7 years. Most had a history of ischemic stroke (88.23%), with 11.76% having experienced hemorrhagic stroke.All 17 patients received cholinergic medications, showing significant improvement in mRS scores. The Wilcoxon signed-rank test revealed a p-value of

Stroke, Volume 56, Issue Suppl_1, Page A160-A160, February 1, 2025. Introduction:Offspring from preeclamptic women are at increased risk of neurologic disorders later in life and have an increased risk of death from stroke. We hypothesized that the unfavorable intrauterine environment during preeclampsia (PE) causes cerebrovascular dysfunction and inflammation in offspring that worsens stroke outcome.Methods:Adult male and female offspring (n=6-8/group) from Sprague Dawley rats that had normal pregnancies (NormP-F1) or experimental PE (ePE-F1) underwent transient MCA occlusion (tMCAO) for 3 hours with 1 hour of reperfusion. Blood gases were kept within normal ranges. Multisite laser Doppler was used to measure changes in pial collateral flow and MCA cerebral blood flow (CBF) simultaneously. Infarct and edema were measured by TTC staining. After tMCAO, plasma was obtained to measure circulating inflammatory factors using Multiplex and ELISA. Data are reported as mean±SEM.Results:Offspring from ePE dams had elevated blood glucose, and sex-specific increases in infarct and edema—only ePE-F1 males had significantly larger infarcts compared to all other groups (48.0±5.7% vs. 9.0±1.3% ePE-F1 female, 10.9±3.9% NormP-F1 male, and 4.9±1.9% NormP-F1 female). The rate of hemorrhagic transformation (HT) was increased in both ePE-F1 males (100%) and females (62.5%) vs. NormP-F1s (male: 37.5%, female: 0%). The increased infarct in ePE-F1 males was associated with poor collateral flow, decreasing -59.8±3.3% which remained low during the ischemic period. In contrast collateral flow decreased -43.9±17.8% in ePE-F1 females that was not sustained and increased to baseline after 40 min of tMCAO. Both female and male NormP-F1’s had robust collateral flow, decreasing only -14.8±25.5% and -17.5±22.1%, respectively. There was an increase in circulating VEGF in ePE-F1 males vs NormP-F1 males (188.8±69.3 vs 39.2±7.5 pg/ml; p

Stroke, Volume 56, Issue Suppl_1, Page AWP368-AWP368, February 1, 2025. Introduction:Oxidative stress plays an important role in both early brain injury and delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Despite the beneficial effects demonstrated in preclinical studies with drugs targeting oxidative stress, their clinical translation has been hindered. There were critical issues in previous preclinical studies underpinning clinical translation, including inadequate demonstration of blood-brain barrier (BBB) penetration and insufficient assessment of drug concentration and biological activity in brain tissue. MnP-05 is a novel manganese porphyrin-based superoxide-dismutase mimic, which penetrates the BBB far better than previous compounds and exhibits superior anti-free radical properties compared to previous free radical scavenger. In this study, we evaluated the effect of MnP-05 on short-term outcomes of SAH in mice.Methods:We used 12-week-old male C57BL/6J mice. We induced SAH by an endovascular perforation of the right internal carotid artery. Mice (n = 31) were started on treatment with either MnP-05 or PBS 60 minutes after the induction of SAH. We set the dosing regimen as 1 mg/kg intravenous bolus followed by 5 mg/kg/day continuous intraperitoneal injection for 72 hours. We compared a composite neurological score, and rotarod performance (%baseline), between the two treatment groups for 7 days. We also compared the mRNA expression of oxidative stress and apoptosis markers in perihematomal brain tissue between the groups.Results:There were no specific side effects found in MnP-05 treatment group. There were no differences in blood pressure or body weight between the two groups. Seven-day neurological outcomes were better in MnP-05 group as evidenced by the significantly better composite neurological scores (22.9 vs. 19.4, P

Stroke, Volume 56, Issue Suppl_1, Page AWP343-AWP343, February 1, 2025. Background:Taurine is a sulfur-containing amino acid present in most mammalian tissues that plays a critical role in regulation of numerous physiological processes. Taurine has been recently identified as a potential neuroprotective agent due to its potent antioxidant and anti-inflammatory properties. However, its effects on stroke recovery are unexplored. Here, we investigated the effects of chronic taurine supplementation on immune cells and recovery in aged stroke mice.Hypothesis:We hypothesized that aged stroke mice treated with taurine will show enhanced recovery compared to vehicle-treated mice. We examined if this beneficial effect was independent of infarct size and was associated with changes in immune cell responses.Methods:Human plasma samples were assessed by mass spectrometry in control and stroke patients. For murine studies, aged (16-18 months) C57BL/6 WT mice were subjected to a reversible 60-MCAO. Three days after stroke, mice were randomly assigned into two groups: one received taurine (n=6M,10F) and the other received water without taurine (n=5M,11F). Behavioral tests were performed at intervals until euthanasia on post-stroke day 42. Flow Cytometry (FACS) was performed to assess for cellular changes in the blood and tissues. Finally, as gut microbiota composition is implied in immune regulation, we determined changes in the microbiota following taurine treatment by performing 16s analysis on fecal samples.Results:First, we compared plasma taurine levels in healthy controls (n=20) and acute stroke patients (n=29) obtained through unbiased metabolomics. Taurine was significantly lower in stroke patients (p

Stroke, Volume 56, Issue Suppl_1, Page AWP353-AWP353, February 1, 2025. Mesenchymal stem cells (MSCs) have recently received attention as an intervention to reverse or slow neurodegenerative, stroke and injury-related changes in the aging brain as they suppress inflammation and facilitate tissue repair. In support of this idea, we have shown that extracellular vesicles (EVs) derived from bone marrow MSCs enhance recovery of motor function of the hand following cortical injury in aged female rhesus monkeys. Specifically, EV-treated treated monkeys (n=5) exhibited full recovery of fine motor function by 3-5 weeks post-injury while vehicle monkeys (n=5) reached a plateau short of full recovery by 8-12 weeks post-injury. Post-mortem analyses of perilesional brain tissue from the same monkeys, revealed multifaceted cellular effects of EVs including downregulating inflammatory microglial phenotypes, dampening neuronal hyperexcitability, and enhancing neuronal and myelin plasticity. To explore the relationship between these processes and functional recovery, we utilized multi-labeling immunohistochemistry (IHC) and high-resolution confocal microscopy to assess microglia phenotypes, neuronal synaptic marker expression and microglia-neuronal interactions in perilesional cortex. To assess these markers, semi-quantitative stereology in Neurolucida and particle analysis in ImageJ were utilized. Results show that MSC-EV treatment decreased the densities of pro-inflammatory hypertrophic microglia expressing LN3+, a marker for MHC II receptors, upregulated with immune activation. Conversely, MSC-EV treatment and functional recovery was significantly correlated with increased proportion of hypertrophic microglia expressing the key complement pathway protein C1q, a phenotype associated with enhanced debris-clearance and repair after degeneration. Interestingly this EV-associated increase in C1q+ hypertrophic microglia was correlated with decreased putatively damaged synapses tagged with C1q and greater synaptic marker expression in perilesional cortex. These data suggest that MSC-EVs promote a shift from pro- to anti-inflammatory repair microenvironment, via enhancement of debris clearance after injury. These findings demonstrate the efficacy of MSC-EVs as a therapeutic, likely acting to reduce inflammatory cascades, facilitate repair and rebalance neuronal synaptic connections to support recovery after cortical injury.

Stroke, Volume 56, Issue Suppl_1, Page AWP344-AWP344, February 1, 2025. Introduction:Nitro-oleic acid (OA-NO2) is an endogenous peroxisome proliferator-activated receptor-γ (PPARγ) ligand and can activate this receptor under both physiological and pathological conditions. In this study, we explore the role and molecular mechanisms of OA-NO2in maintaining blood-brain barrier (BBB) integrity and enhancing neurovascular function during ischemic stroke, with a particular emphasis on the activation of PPARγ signaling pathways.Methods:EC-selective PPARγ conditional knockout (EC-PPARγ cKO) and wild-type (WT) mice underwent 1-hour middle cerebral artery occlusion (MCAO) with 1 to 7 days of reperfusion. Mice were treated with oleic acid (OA) or OA-NO2(10 mg/kg) via tail vein 2 hours after MCAO. Sensorimotor function was assessed using the rotarod, foot fault, and adhesive tape removal tests. BBB integrity was measured with fluorescein-dextrans, and brain infarct was analyzed with anti-MAP2 immunostaining. Peripheral immune cell infiltration was examined by immunofluorescent methods. Total RNA and proteins were extracted from brain tissue. BBB tight junction mRNAs, proteins, and inflammatory factors were quantified using qPCR and Western blotting.Results:OA-NO2treatment significantly enhanced sensorimotor function in stroke mice compared to the OA group. However, this beneficial effect was lost in the EC-PPARγ cKO mice. Compared to OA controls, intravenous administration of OA-NO2led to reduced BBB leakage in ischemic brains, as indicated by a significant decrease in the extravasation of BBB tracers. This reduction in BBB leakage was also abolished in the EC-PPARγ cKO mice. Furthermore, OA-NO2treatment reduced brain infarction in stroke mice, but this protective effect was completely reversed in the EC-PPARγ cKO mice. Interestingly, OA-NO2treatment promoted a shift towards an anti-inflammatory microglial phenotype (M2) in the peri-infarct regions of EC-PPARγ WT mice, but not in EC-PPARγ cKO mice. Mechanistically, OA-NO2increased levels of major endothelial tight junction mRNAs and proteins, including Claudin 5 and ZO-1, in EC-PPARγ WT mice but not in EC-PPARγ cKO mice following ischemic stroke.Conclusions:Treatment with OA-NO2effectively reduces BBB leakage-triggered peripheral immune cell infiltration, brain infarction, and long-term neurobehavioral deficits in mice following ischemic stroke. The neurovascular protection conferred by OA-NO2primarily operates through PPARγ-dependent signaling pathways.

Stroke, Volume 56, Issue Suppl_1, Page AWP349-AWP349, February 1, 2025. The first Stroke Preclinical Assessment Network (SPAN 1) tested 6 therapeutic interventions initiated at the time of reperfusion in models of focal ischemic stroke, including models of cardiovascular risk factors. To improve preclinical testing rigor and reproducibility, the testing was conducted as a large, randomized controlled trial across 6 sites with a coordinating center that concealed treatments and blinded neurobehavior video assessments. The trial had an adaptive design with preset levels of efficacy and futility interrogated after each of 4 stages relative to placebo (P). The primary outcome was turning preference on the corner test at 30 days. Secondary outcomes included corner test turns at 7 days, foot-faults on a grid walk test at 7 and 30 days, and MRI lesion volume at 2 and atrophy at 30 days. Based on the primary outcome data pooled from young mice, aging mice, high-fat diet obese mice and spontaneously hypertensive rats (SHRs), the poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (V), was considered futile after the second stage (V=271; P=171). Here, we performed a secondary analysis of the veliparib data on individual subgroup models, secondary outcomes, and effects of sex. Veliparib (10 mg/kg) injected IV at reperfusion failed to show a benefit on the corner test or grid walk test at 7 or 30 days of recovery or a reduction in lesion volume in young mice (V=114; P=56), obese mice (V=38; P=34), or SHRs (V=39; P=41). However, in aging mice (17-18-months-old; V=39; P=40), veliparib significantly improved performance on the corner test (P= 0.009) and grid walk test (P= 0.002) at 7 days; the benefit was independent of sex. However, mortality in the aging mice was greater than in the other subgroup models at all sites, and significance in the corner test was lost at 30 days (P= 0.10) associated with the decreased sample size. Aging mice were especially susceptible to respiratory arrest during anesthesia while conducting MRI scans. Lesion volume at 2 days was small in the veliparib (2-3% of hemisphere) and placebo (4%) groups, suggesting that the benefit of veliparib on neurobehavior might be due to its known anti-inflammatory effects rather than by decreasing infarct volume. Because ischemic stroke predominantly occurs in the aging population, further research into the neurobehavior benefit of PARP inhibitors in aged animal models of stroke is warranted in protocols that omit post-ischemic anesthesia so as to improve survival.

Stroke, Volume 56, Issue Suppl_1, Page AWP397-AWP397, February 1, 2025. Backgrounds:Our prior work demonstrated the upregulation of miR-200 family miRNAs specifically miR-141&miR-200c after stroke in mice models. Moreover, we found a significant upregulation of miR-141 in stroke patient’s blood samples and validated the potential of targeting miR-141 to mitigate ischemic stroke damage. In this study, we aimed to validate the upregulation of miR-200c in stroke patients plasma samples and evaluate the potential of inhibiting miR-200c alone or in combination with miR-141 to mitigate stroke damage in oxygen-glucose deprivation (OGD) in microglial BV2 cells.Methods:Total RNA (including miRNAs) was isolated from plasma samples of stroke patients and healthy controls and miR-200c expression was assessed by qPCR.In vitro, an oxygen-glucose deprivation (OGD) model in BV2 cells was used to assess the potential of inhibition using antagomiRs of miR-200c alone and in combination with miR-141 on cell viability, cytotoxicity, apoptosis and inflammation via MTT, LDH assays, and qPCR for gene expression. TargetScan web portal was used to obtain the potential targets of miR-200c/141 and explored the molecular mechanism behind this neuroprotection.Results:miR-200c was significantly upregulated in stroke patients compared to healthy individuals, confirming the current study’s translational potential. We found a gradual increase in miR-200c expression after 1h, 2h, 3h, and 4h ( >5 folds) OGD followed by 24h reperfusion (R). Inhibition of miR-200c or miR-141/200c cluster after 4h OGD/24h R showed a synergistic effect on cell viability and cytotoxicity. Inhibition of the miR-141/200c increased anti-apoptotic geneBcl2and reduced the pro-apoptotic (Bax) and pro-inflammatory genes (Il-1β, Il-6,andTnf-α) in BV2 cells following OGD/R. According to TargetScan analysis,Smad2is a direct target of miR-200c,Tgfb2is targeted by miR-141, andZeb1is commonly targeted by both miR-200c and miR-141-3p; the expression of these genes significantly decreases following OGD/R. The inhibition of miR-141/200c restored the levels ofTgfβ2, Smad2&Zeb1.Conclusion:Cluster miR-141/200c can act as a biomarker and a prominent therapeutic target for stroke treatment.In vitro, inhibition of miR-200c alone or together with miR-141-3p protects from OGD-induced injury in microglial BV2 cells by reducing neuroinflammation and apoptosis. Overall, the Tgfβ2/Zeb1 pathway is involved in the cluster miR-141/200c mediated neuroprotection.

Stroke, Volume 56, Issue Suppl_1, Page ATP6-ATP6, February 1, 2025. Background:Thymosin alpha 1 (Tα1) had been used in kinds of inflammatory and immunodeficiency diseases as an immunomodulator. According to our clinic observation, patients with acute ischemic stroke (AIS) treated with Tα1 to prevent/cure post-stroke infection display favorable stroke outcome. Whether Tα1 exerts direct neuronal protection besides immunomodulation remains elusive.Aim:To explore the effect of Tα1 on neuronal protection after AIS and unveil the underlying mechanisms.Method:In vivo: 8-10 weeks old male Wild type (WT) mice were subjected to 60 minutes middle cerebral artery occlusion (tMCAO) and administrated Tα-1 by intraperitoneal injection.Ex vivo: Primary mouse neuron is subjected to 60 min oxygen and glucose deprivation (OGD), followed by Tα-1 treatment.Results:Compared with untreated group, Tα1 treatment displayed decreased infarct volume, limited neuronal loss, attenuated white matter injury，restricted neuroinflammation and improved neurological functions. Treatment of antibiotics or glucocorticoid failed to substitute the therapeutic effects of Tα1, indicating extra protection of Tα1 treatment besides anti-infection and immunomodulation. As for primary mouse neuron, Tα1 treatment showed fewer neuron death and higher cell viability upon OGD stimulation. Bothin vivoandex vivoexperiments revealed that Tα1 directly inhibited ischemia-induced neuronal death. Mechanistically, Tα1 enhanced mitophagy by down-regulating Drp1, thus promoted mitochondrial renewal and supported neuronal viability.Conclusions:Our results identified that Tα1 possessed direct neuronal protection and improved prognosis of AIS. Given the multi-functions of Tα1 including anti-infection, immunomodulation and neuronal protection, we propose that Tα1 is a promising therapy against AIS.

Stroke, Volume 56, Issue Suppl_1, Page ADP57-ADP57, February 1, 2025. Introduction:Neonatal Hypoxic-Ischemic Encephalopathy (nHIE) is a leading cause of infant mortality and long-term morbidity, with males experiencing higher mortality rates and poorer neurological outcomes than females. The underlying causes of this sex difference remains unclear but may be due to sex-specific inflammatory responses to acute brain injury.Hypothesis:We hypothesized that the neutrophil response to neonatal brain injury is sexually dimorphic and contributes to outcomes after nHIE.Methods:We conducted a retrospective study at a single academic institution, analyzing data from 2011 to 2021 (n=310). Inclusion criteria were gestational age ≥ 36 weeks, mild to severe HIE by Sarnat staging, CBC reported within the 1st day of life, and exclusion of concomitant infection (eligible group n= 201). In neonatal mice, we utilized the Rice-Vannucci Model of nHIE at postnatal day 9 (PND9) in C57BL/6 pups. Hypoxic-ischemic injury was induced via permanent ligation of the right common carotid artery followed by 50 minutes of hypoxia (n=14), with controls receiving sham surgeries (n=14).Results:Infants diagnosed with nHIE had significantly higher neutrophil counts than control infants admitted to the NICU within 24 hours after birth. Female infants with nHIE exhibited significantly higher neutrophil counts than males (15.2 vs.10.8 k/cm^3 ,p < 0.01), while there was no sex-difference in the control group (n=109). In PND9 mice, 72 hours after nHIE, females had a higher overall neutrophil count in blood and brain (p < 0.02). Male neutrophils produced significantly higher levels of pro-inflammatory cytokines, including IL-1β and TNF-α (p < 0.03,p < 0.01). Female neutrophils exhibited enhanced neuronal phagocytosis (increased intracellular NeuN, p < 0.03) and higher levels of anti-inflammatory/tissue recovery markers such as AHR and MMP9 (p < 0.02). Lastly, consistent with the dimorphic clinical outcomes observed in neonates with nHIE, female mice exhibited enhanced locomotion compared to males (reciprocal social test, p

Stroke, Volume 56, Issue Suppl_1, Page ADP55-ADP55, February 1, 2025. Background:Left ventricular (LV) injury is a cardioembolic etiology of ischemic stroke. We aimed to 1) evaluate recurrent stroke risk among patients with cryptogenic stroke and LV injury, and 2) determine if there is a treatment effect with anticoagulation in this population.Methods:We analyzed the multicenter, retrospective Cardiac Abnormalities in Stroke Prevention and Recurrence cohort of patients with cryptogenic ischemic stroke. The exposure was LV injury defined by 1) LV ejection fraction (EF) 20-40% and/or 2) LV wall motion abnormality (hypokinesis or akinesis). The primary composite outcome included recurrent stroke, major bleeding, or death. Cox proportional hazard models were built and sequentially adjusted for 1) age and sex (Model 1), and 2) age, sex, race, ethnicity, anti-thrombotic use, and vascular risk factors (Model 2). We then assessed if there was heterogeneity in treatment effect by LV injury status with an interaction term of LV injury and oral anticoagulation use in Model 2.Results:Of 2,641 patients in CASPR, the analytic cohort included 2,191 patients with complete exposure and outcome data (median age 65 years, 49.8% female, median follow-up 1.55 years). There were 113 (5.2%) patients with LV injury (median LVEF 30%, interquartile range 25-34%). There were 559 incident events (321 recurrent strokes [288 ischemic], 71 major hemorrhages, 250 deaths). Among patients with LV injury, 15.9% were prescribed an anticoagulant within 7 days of index stroke (vs 9.6% without LV injury, p=0.03). The unadjusted risk of the primary outcome was non-significantly higher among patients with LV injury vs without (HR 1.40; 95% confidence interval [CI], 0.98-2.00), but became significant in Model 1 (HR 1.50; 95% CI, 1.21-1.85) and in Model 2 (HR 1.35, 95% CI, 1.11-1.64). In the LV injury subgroup, anticoagulation vs antiplatelet therapy was associated with a significant reduction in the primary outcome (HR 0.63, 95% CI, 0.43-0.94). In patients without LV injury, anticoagulation was associated with a higher risk of the composite outcome (HR 4.35, 95% CI, 1.69-11.16, p[interaction]=0.002).Conclusion:In this observational study, there was an increased risk of the primary outcome which included recurrent stroke among patients with cryptogenic stroke and LV injury. Anticoagulation use in LV injury is associated with a significant reduction in the risk of the primary outcome. These findings warrant confirmation in a dedicated randomized controlled trial.

Stroke, Volume 56, Issue Suppl_1, Page ADP50-ADP50, February 1, 2025. Background:Local angiotensin activity is thought to play a critical role in arterial wall homeostasis and remodeling, which contributes to the pathogenesis of subarachnoid hemorrhage (SAH). Here we aimed to assess the association between pharmacologic inhibition of angiotensin-converting enzyme and subsequent non-traumatic SAHMethods:In a retrospective cohort study based on Optum’s Clinformatics® Datamart de-identified Database records (2000-2021), patients with hypertension were included. We collected medication history and assessed the risk of non-traumatic subarachnoid hemorrhage (SAH) associated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB). Cox proportional hazard regression models were used to compare the time to SAH by type of antihypertensive treatment. Analyses were adjusted for baseline demographic and clinical characteristicsResults:7.5 million patients with hypertension were assessed. Patients on ACEI/ARBs with or without other antihypertensives (n=4.8 million,follow-up:6.3 years, average age 61.9, 50.4% female) had lower rates of SAH compared to those on alternative antihypertensive regimens (n=1.3 million, follow-up:5.7 years,average age 61.9, 60.3%female) [HR:0.94(0.91-0.97), p

Stroke, Volume 56, Issue Suppl_1, Page AWP297-AWP297, February 1, 2025. Background:Existing data indicate recent increases in the prevalence of stroke and relevant risk factors as well as predicted continued increases in coming years. Our objective was to evaluate population-based data on the prevalence of stroke risk factors and related medication use by sex through 2021.Methods:Data on the prevalence of stroke risk factors and medication use were taken from our general population random-digit dial survey conducted during 6 time periods: 1995, 2000, 2005, 2011, 2016, and 2021. Due to survey sampling design, survey participants’ characteristics (sex, race, age) are representative of the Greater Cincinnati Northern Kentucky Stroke Study (GCNKSS) ischemic stroke study population. We examined the proportion of females vs. males who reported having hypertension (HTN), hyperlipidemia (HL), diabetes (DM), and current smoking and who reported using antihypertensive medications, lipid-lowering agents, aspirin, and anticoagulants (AC).Results:Over 6 study periods, a total of 12,336 participants completed the survey; 59% were female, and 25% were Black. Mean age of participants (in years) went up over time in both females (64 [SD 16.3] in 1995 to 69 [SD 16.4] in 2021) and males (61 [SD 15.7] in 1995 to 67 [SD 16.8] in 2021), ptrend

Stroke, Volume 56, Issue Suppl_1, Page ATP214-ATP214, February 1, 2025. Background:Amyloid-related Imaging Abnormalities (ARIA) are adverse effects that occur during amyloid beta monoclonal antibody treatment for Alzheimer’s disease, including edema-type ARIA and hemorrhage-type ARIA. Few retrospective analysis have compared ARIA-H incidence among individual monoclonal antibodies, and a comprehensive comparison is currently lacking. After the approval of these antibodies, research has mainly focused on dosing frequency and drug dosage, leaving it unclear whether ARIA-H is associated with the specific characteristics of different monoclonal antibodies.Methods:1. For monoclonal antibodies targeting Aβ clearance, we selected seven: Aducanumab, Bapineuzumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, and Solanezumab. Our data is derived from systematic reviews and meta-analyses of Phase III clinical trials for these seven monoclonal antibodies. Data from Jeremic D et al. include six monoclonal antibodies (mAbs), while data from Qiao Y et al. include four mAbs. 2. For the evaluation variables, we selected the following factors: the form of monoclonal antibody binding to Aβ protein, binding affinity, binding epitope, Fc subtype of the monoclonal antibody, and the Aβ clearance rate. ARIA-H occurrence was used as a categorical variable for differential analysis. The odds ratio (OR) was utilized for data assessment, with an OR not equal to 1 and a 95% confidence interval excluding 1 used as the criterion for statistical significance. 3. We standardized the data for the seven monoclonal antibodies (mAbs). We compared the ARIA-H occurrence rates for the mAbs, taking into account other dimensional variables.Results:The risk of ARIA-H, from highest to lowest, is as follows: Donanemab, Aducanumab, Bapineuzumab, Lecanemab, Gantenerumab, Crenezumab, Solanezumab. Besides, ARIA-H is associated with the characteristics of mAb. (1)More mature Aβ clearance is associated with a higher risk of ARIA-H.(2)Lower clearance of Aβ oligomers is associated with a higher risk of ARIA-H.(3)Aβ clearance closer to the N-terminus is associated with a higher risk of ARIA-H.(4)mAb with an IgG4 structure are more likely to cause ARIA-H than those with an IgG1 structure.(5)Faster achievement of Aβ clearance thresholds is associated with a higher risk of ARIA-H.Conclusion:This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer’s disease patients.

Stroke, Volume 56, Issue Suppl_1, Page ATP228-ATP228, February 1, 2025. Introduction:Cerebrovascular and cardiovascular diseases are major causes of global mortality, with significant impact in India. Clopidogrel, an antiplatelet prodrug, requires activation by CYP enzymes to inhibit platelet activation. Clopidogrel resistance, affecting 4-30% of patients, is often due to CYP2C19 gene variations, among other factors. This study explores genetic variants associated with clopidogrel resistance to improve personalized therapy for thrombotic conditions.Objective:To evaluate the relationship between CYP2C19 polymorphisms and recurrent thrombotic events in patients treated with clopidogrel for coronary artery disease and stroke.Methods:An ambispective observational study at a tertiary hospital over six months included 114 adults on clopidogrel for various ischemic conditions. Exclusion criteria were pregnancy, lactation, intracerebral hemorrhage, atrial fibrillation, left ventricular clot, and cardioembolic stroke. Data were collected from medical records. CYP2C192 and CYP2C193 polymorphisms were analyzed using PCR and gel electrophoresis. Statistical analysis was conducted with chi-square tests in IBM SPSS version 20.0 (p

Stroke, Volume 56, Issue Suppl_1, Page ATP238-ATP238, February 1, 2025. Introduction:Cerebral blood flow (CBF) is a major determinant of when and where within the brain stroke occurs. The brain’s demand for oxygen and nutrients makes it sensitive to pulsatility propagating from the heart. The contribution of cardiac flow to CBF is poorly understood. We present a pilot study using 4D flow MRI to sequentially measure both aortic blood flow and CBF in the same individual and our initial findings comparing blood pressure (BP), cardiac flow, and CBF in healthy volunteers.Methods:We acquired both 4D flow brain MRI and 4D flow cardiac MRI in a single session using a Siemens 3T Magnetom Vida scanner in 5 volunteers (4 male, 1 female) 31.2 ± 10.4 years old. Using a compressed sensing protocol (R=7.7) each 4D flow scan was acquired in under 15 minutes. Brain and cardiac MRI respectively used a 1.4 mm3and 2.1 mm3voxel size; velocity was encoded in 3D at 120 cm/s and 200 cm/s, with 15-25 cardiac phases. 4D flow brain coverage included the ICA, BA, MCA, ACA, and PCA (Fig 1). 4D flow cardiac coverage included the ascending and descending thoracic aorta (Fig 2). 4D flow data were reconstructed using Tempus Pixel (Tempus, IL) and regions of interest were defined to measure volumetric flow rate (Q). Blood flow pulsatility over the cardiac cycle was quantified using pulsatility index (PI). Pearson’s correlation coefficient (r) was calculated for statistical analysis.Results:Aorta Q correlated strongly with cerebral Q, in the ICA and BA (r=0.90), in the MCA, ACA, and PCA (r=0.70). Aorta Q correlated with PI in both the ICA and BA (r=0.81), but not within the MCA, ACA, and PCA (r=0.12). Aorta PI was moderately anticorrelated with PI throughout the cerebral arteries (r=-0.52). Brachial systolic and diastolic BP both correlated with cerebral PI (r=0.68, 0.99, respectively), while moderately anticorrelated with aorta PI (-0.66, -0.52). Pulse pressure correlated strongly with cerebral Q (r=0.85), and less with aorta Q (r=0.59). Heart rate was strongly anti-correlated with aorta PI (r=-0.82) and moderately correlated with cerebral PI (r=0.61).Conclusion:These initial findings demonstrate that flow characteristics Q and PI are similar between the aorta and major arteries feeding the brain (ICA, BA), but the effects of BP and heart rate appear to invert at more distal vessels (MCA, ACA, PCA). We plan to expand this technique to investigate the connection between cardiac and cerebral flow in patients with neurovascular disease.