From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease.

Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid-rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.

Perfusion imaging predicts short-term clinical outcome in isolated posterior cerebral artery occlusion stroke.

BACKGROUND AND PURPOSE: Ischemic strokes due to isolated posterior cerebral artery (PCA) occlusions represent 5% of all strokes but have significant impacts on patients' quality of life, primarily due to visual deficits and thalamic involvement. Current guidelines for acute PCA occlusion management are sparse, and the prognostic value of perfusion imaging parameters remains underexplored. METHODS: We conducted a retrospective analysis of 32 patients with isolated PCA occlusions treated at Johns Hopkins Medical Institutions between January 2017 and March 2023. Patients underwent pretreatment perfusion imaging, with perfusion parameters analyzed using RAPID software. The primary outcome was short-term clinical outcome as measured by the National Institutes of Health Stroke Scale (NIHSS) at discharge. RESULTS: The median age of the cohort was 70 years, with 34% female and 66% male. Significant correlations were found between NIHSS at discharge and various perfusion parameters, including time-to-maximum (Tmax) >6 seconds (ρ = .55, p = .004), Tmax >8 seconds (ρ = .59, p = .002), Tmax >10 seconds (ρ = .6, p = .001), mismatch volume (ρ = .51, p = .008), and cerebral blood volume (CBV) < 34% (ρ = .59, p = .002). CONCLUSIONS: Tmax and CBV volumes significantly correlated with discharge NIHSS with marginal superiority of Tmax >10 seconds and CBV <42% volumes. These findings suggest that CT and MR perfusion imaging can play a crucial role in the acute management of PCA strokes, though larger, standardized studies are needed to validate these results and refine imaging thresholds specific to posterior circulation infarcts.

Exploring the therapeutic implications of natural compounds modulating apoptosis in vascular dementia.

Vascular dementia (VaD) is a prevalent form of dementia stemming from cerebrovascular disease, manifesting in memory impairment and executive dysfunction, thereby imposing a substantial societal burden. Unfortunately, no drugs have been approved for the treatment of VaD due to its intricate pathogenesis, and the development of innovative and efficacious medications is urgently needed. Apoptosis, a programmed cell death process crucial for eliminating damaged or unwanted cells within an organism, assumes pivotal roles in embryonic development and tissue homeostasis maintenance. An increasing body of evidence indicates that apoptosis may significantly influence the onset and progression of VaD, and numerous natural compounds have demonstrated significant therapeutic potential. Here, we discuss the molecular mechanisms underlying apoptosis and its correlation with VaD. We also provide a crucial reference for developing innovative pharmaceuticals by systematically reviewing the latest research progress concerning the neuroprotective effects of natural compounds on VaD by regulating apoptosis. Further high-quality clinical studies are imperative to firmly ascertain these natural compounds' clinical efficacy and safety profiles in the treatment of VaD.

Dyke-Davidoff-Masson-like syndrome in an adult cat.

Case summary: A 4-year-old cat was presented with acute onset of lateralised neurological central nervous system (CNS) signs and seizures. Haematological and serum biochemical parameters were within normal limits. Imaging diagnostics revealed severe CT and MRI abnormalities of the right brain, similar to Dyke-Davidoff-Masson syndrome (DDMS) in human medicine. This syndrome includes cerebral hemiatrophy with compensatory calvarial hyperostosis and ventriculomegaly. Such changes have previously been reported only once in a single feline case of approximately the same age. In humans, DDMS is described as an embryonic and perinatal developmental disturbance or an acquired injury in early childhood. Relevance and novel information: This case report shows that without further imaging diagnostics, congenital disorders can be overlooked in some rare cases of adult cats with later onset of their first clinical signs.

[Therapeutic and diagnostic complex in intestinal failure syndrome in patients with closed abdominal trauma]. / Lechebno-diagnosticheskii kompleks pri sindrome kishechnoi nedostatochnosti u patsientov s zakrytoi travmoi zhivota.

Currently, severe combined abdominal trauma ranks third among all causes of mortality In Russia, second only to cardiovascular and oncologic diseases. In the period from 2019 to 2020 in our country, a slight decrease in traumatism is noted due to a decrease in the number of traffic accidents as the main cause of combined and multiple trauma. The number of abdominal injuries from the total number of injuries In Russian regions ranges from 1.5 to 36.5% and is accompanied by a high level of disability (25-80% in combined trauma and 5-8% in isolated trauma). Despite modern medical advances, lethality in combined trauma of abdominal organs varies from 10.7 to 69.7%, with closed abdominal trauma accounting for up to 6% of fatal outcomes. OBJECTIVE: Improving treatment outcomes in patients with closed abdominal trauma through comprehensive diagnosis of SCN and optimization of enteral therapy in patients with closed abdominal trauma. MATERIAL AND METHODS: The study included 40 patients (29 (72.5%) men and 11 (27.5%) women), who underwent examination and treatment at the State Budgetary Institution "Research Institute of SP. Im. N.V. Sklifosovsky Research Institute of St. Petersburg State Medical Center with the diagnosis: Closed abdominal trauma. The age of the patients varied from 25 to 81 years (Mean age was 49.6±13.1). To evaluate the effectiveness of intensive therapy, the patients were divided into 2 groups: the comparison group (n=26) included patients who were treated with complex conservative therapy. Patients of the main group (n=14) conservative therapy was supplemented with the use of ER to restore the functional activity of the intestine under the control of ultrasound and assessment of the degree of intra-abdominal hypertension, as well as with Intestamine to stimulate the intestinal trauma. RESULTS: In the course of the study it was found that, as a result of complex enteral therapy in the patients of the main group, starting from the 7th day of stay in the ORIT, positive dynamics was observed, consisting in a statistically significant decrease in the levels of lactate, ALT, AST, LDH, and CRP. By the 14th day there was also a statistically significant decrease in leukocyte and PCT levels. The lethality in the main group amounted to 7.2%, n=1. At the same time, in patients of the comparison group only by the 7th day there was a decrease in concentration of CRP (p=0.065), by the 10th day - ALT (<0.001) and by the 14th day there was a decrease in leukocytes level (p=0.038). Lethality in this group amounted to 23.1%, n=6. CONCLUSION: Timely initiation of pathogenetic enteral therapy contributes to faster normalization of clinical and laboratory parameters, protection of intestinal barrier function, prevention of complications associated with bacterial translocation and bacterial overgrowth syndrome, increase in immunoresistance of the organism.

Cerebral hypoperfusion resulting from improper cannulation positioning during aortic dissection surgery: a case report.

BACKGROUND: Selective antegrade cerebral perfusion (sACP) is a crucial cerebral protection technique employed during aortic dissection surgeries involving cardiopulmonary bypass. However, postoperative neurological complications, particularly those related to cannulation issues and perfusion problems, remain a significant concern. CASE PRESENTATION: This case report details an unusual instance where a 38-year-old male patient with Marfan syndrome experienced cerebral hypoperfusion during emergency surgery for Stanford Type A aortic dissection. Despite following standard protocols, a significant drop in regional cerebral oxygen saturation (rSO2) and abnormal blood pressure fluctuations were observed shortly after initiating sACP via the innominate artery. After initial attempts to optimize perfusion flow proved ineffective, the cannulation position was adjusted, leading to improvements. Nevertheless, the patient subsequently exhibited signs of cerebral hypoperfusion and was found to have suffered a new cerebral infarction. CONCLUSIONS: This case report underscores the importance of precise cannula placement during sACP procedures and the dire consequences that can arise from improper positioning. It emphasizes the need for continuous monitoring and prompt intervention in cases of abnormal cerebral oxygenation and blood pressure, as well as the value of considering cannulation-related issues as potential causes of postoperative neurological complications.

Magnetic nanomagnetic nanoparticles combining with Slit2 gene and bone marrow mononuclear cells to improve cognitive dysfunction in rats with chronic cerebral ischemia.

Purpose: Cognitive dysfunction caused by chronic cerebral hypoperfusion (CCH) is the leading cause of vascular dementia. Therefore, it is necessary to explore the mechanism that causes cerebral injury and find an effective therapy. Methods: Bone marrow mononuclear cells (BMMNCs) were extracted to detect the activity by CCK-8 kit and verify the transfection efficiency using reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR). A CCH rat model was established. Superparamagnetic iron oxide nanoparticles (BMPs)-PEI-Slit2/BMMNCs were injected into the tail vein and intervened with an external magnetic field. Hematoxylin and eosin staining was used to observe the pathological changes in brain tissue. The Slit/Robo pathway-related proteins Slit2 and Robo4 were detected by RT-qPCR and Western blotting. Results: The neurological score of the CCH group significantly increased compared with that of the sham group (P<0.05). The levels of brain injury markers S-100ß and NSE were significantly higher in the CCH group than in the sham group (P<0.05). Neuronal apoptosis in the frontal cortex and hippocampus of CCH rats significantly increased compared with that of the sham group (P<0.05). The expression levels of Slit2 and Robo4 mRNAs and proteins in brain tissue of CCH rats significantly increased (P<0.05). The neurological function scores of CCH rats treated with BMP-PEI-Slit2/BMMNC significantly increased after Robo4 siRNA administration (P<0.05). Conclusion: BMP combination with the CCH-related gene Slit2 can effectively improve the efficiency of BMMNC transplantation in treatment.

Carotid artery vascular stenosis causes the blood-CSF barrier damage and neuroinflammation.

BACKGROUND: The choroid plexus (ChP) helps maintain the homeostasis of the brain by forming the blood-CSF barrier via tight junctions (TJ) at the choroid plexus epithelial cells, and subsequently preventing neuroinflammation by restricting immune cells infiltration into the central nervous system. However, whether chronic cerebral hypoperfusion causes ChP structural damage and blood-CSF barrier impairment remains understudied. METHODS: The bilateral carotid stenosis (BCAS) model in adult male C57BL/6 J mice was used to induce cerebral hypoperfusion, a model for vascular contributions to cognitive impairment and dementia (VCID). BCAS-mediated changes of the blood-CSF barrier TJ proteins, apical secretory Na+-K+-Cl- cotransporter isoform 1 (NKCC1) protein and regulatory serine-threonine kinases SPAK, and brain infiltration of myeloid-derived immune cells were assessed. RESULTS: BCAS triggered dynamic changes of TJ proteins (claudin 1, claudin 5) accompanied with stimulation of SPAK-NKCC1 complex and NF-κB in the ChP epithelial cells. These changes impacted the integrity of the blood-CSF barrier, as evidenced by ChP infiltration of macrophages/microglia, neutrophils and T cells. Importantly, pharmacological blockade of SPAK with its potent inhibitor ZT1a in BCAS mice attenuated brain immune cell infiltration and improved cognitive neurological function. CONCLUSIONS: BCAS causes chronic ChP blood-CSF damage and immune cell infiltration. Our study sheds light on the SPAK-NKCC1 complex as a therapeutic target in neuroinflammation.

Research progress on the pathogenesis of AKI complicated by ECMO.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) stands as a pivotal intervention for patients grappling with cardiopulmonary insufficiency. However, alongside its therapeutic benefits, ECMO carries the risk of complications, with acute kidney injury (AKI) emerging as a significant concern. The precise pathophysiological underpinnings of AKI in the context of ECMO remain incompletely elucidated. METHODS: A comprehensive literature review was conducted to explore the epidemiology and pathophysiological mechanisms underlying the utilization of ECMO in the management of AKI. RESULTS: ECMO initiates a multifaceted cascade of inflammatory reactions, encompassing complement activation, endothelial dysfunction, white blood cell activation, and cytokine release. Furthermore, factors such as renal hypoperfusion, ischemia-reperfusion injury, hemolysis, and fluid overload exacerbate AKI. Specifically, veno-arterial ECMO (VA-ECMO) may directly induce renal hypoperfusion, whereas veno-venous ECMO (VV-ECMO) predominantly impacts pulmonary function, indirectly influencing renal function. CONCLUSION: While ECMO offers significant therapeutic advantages, AKI persists as a potentially fatal complication. A thorough comprehension of the pathogenesis underlying ECMO-associated AKI is imperative for effective prevention and management strategies. Moreover, additional research is warranted to delineate the incidence of AKI secondary to ECMO and to refine clinical approaches accordingly.

Characterization and Automatic Discrimination between Predominant Hypoperfusion and Hyperperfusion Stages of NPDR.

BACKGROUND/OBJECTIVES: Diabetic retinopathy (DR) is a common diabetes complication that can lead to blindness through vision-threatening complications like clinically significant macular edema and proliferative retinopathy. Identifying eyes at risk of progression using non-invasive methods could help develop targeted therapies to halt diabetic retinal disease progression. METHODS: A set of 82 imaging and systemic features was used to characterize the progression of nonproliferative diabetic retinopathy (NPDR). These features include baseline measurements (static features) and those capturing the temporal dynamic behavior of these static features within one year (dynamic features). Interpretable models were trained to distinguish between eyes with Early Treatment Diabetic Retinopathy Study (ETDRS) level 35 and eyes with ETDRS levels 43-47. The data used in this research were collected from 109 diabetic type 2 patients (67.26 ± 2.70 years; diabetes duration 19.6 ± 7.26 years) and acquired over 2 years. RESULTS: The characterization of the data indicates that NPDR progresses from an initial stage of hypoperfusion to a hyperperfusion response. The performance of the classification model using static features achieved an area under the curve (AUC) of the receiver operating characteristics equal to 0.84 ± 0.07, while the model using both static and dynamic features achieved an AUC of 0.91 ± 0.05. CONCLUSION: NPDR progresses through an initial hypoperfusion stage followed by a hyperperfusion response. Characterizing and automatically identifying this disease progression stage is valuable and necessary. The results indicate that achieving this goal is feasible, paving the way for the improved evaluation of progression risk and the development of better-targeted therapies to prevent vision-threatening complications.

Decreased Quantitative Cerebral Blood Volume Is Associated With Poor Outcomes in Large Core Patients.

BACKGROUND: Recent large core trials have highlighted the effectiveness of mechanical thrombectomy (MT) in acute ischemic stroke with large vessel occlusion. Variable perfusion-imaging thresholds and poor Alberta Stroke Program Early Computed Tomography Score reliability underline the need for more standardized, quantitative ischemia measures for MT patient selection. We aimed to identify the computed tomography perfusion parameter most strongly associated with poor outcomes in patients with acute ischemic stroke-large vessel occlusion with significant ischemic cores. METHODS: In this study from 2 comprehensive stroke centers from 2 comprehensive stroke centers within the Johns Hopkins Medical Enterprise (Johns Hopkins Hospita-East Baltimore and Bayview Medical Campus) from July 29, 2019 to January 29, 2023 in a continuously maintained database, we included patients with acute ischemic stroke-large vessel occlusion with ischemic core volumes defined as relative cerebral blood flow <30% and ≥50 mL on computed tomography perfusion or Alberta Stroke Program Early Computed Tomography Score <6. We used receiver operating characteristics to find the optimal cutoff for parameters like cerebral blood volume (CBV) <34%, 38%, 42%, and relative cerebral blood flow >20%, 30%, 34%, 38%, and time-to-maximum >4, 6, 8, and 10 seconds. The primary outcome was unfavorable outcomes (90-day modified Rankin Scale score 4-6). Multivariable models were adjusted for age, sex, diabetes, baseline National Institutes of Health Stroke Scale, intravenous thrombolysis, and MT. RESULTS: We identified 59 patients with large ischemic cores. A receiver operating characteristic curve analysis showed that CBV<42% ≥68 mL is associated with unfavorable outcomes (90-day modified Rankin Scale score 4-6) with an area under the curve of 0.90 (95% CI, 0.82-0.99) in the total and MT-only cohorts. Dichotomizing at this CBV threshold, patients in the ≥68 mL group exhibited significantly higher relative cerebral blood flow, time-to-maximum >8 and 10 seconds volumes, higher CBV volumes, higher HIR, and lower CBV index. The multivariable model incorporating CBV<42% ≥68 mL predicted poor outcomes robustly in both cohorts (area under the curve for MT-only subgroup was 0.87 [95% CI, 0.75-1.00]). CONCLUSIONS: CBV<42% ≥68 mL most effectively forecasts poor outcomes in patients with large-core stroke, confirming its value alongside other parameters like time-to-maximum in managing acute ischemic stroke-large vessel occlusion.

Peripheral blood diagnostic markers of chronic cerebral hypoperfusion.

OBJECTIVE: To investigate the efficacy of ischemia-modified albumin (IMA), lipoprotein-associated phospholipase A2 (Lp-PLA2), brain-derived neurotrophic factor (BDNF), and visinin-like protein-1 (VILIP-1) in diagnosing chronic cerebral hypoperfusion (CCH). METHODS: This retrospective study included 84 patients with suspected chronic cerebral ischemia admitted to Sichuan Provincial People's Hospital between February 2021 and April 2022. Arterial spin labeling (ASL) imaging and biological examinations were performed. According to the ASL perfusion imaging patterns, the patients were divided into a CCH group (n = 55) and a non-CCH group (n = 29). Serum markers of the two groups were compared, and correlation analysis was conducted between ischemic marker levels and cerebral blood flow (CBF) in the ischemic region, as measured by ASL. Receiver operating characteristic (ROC) curve analysis was used to evaluate the efficacy of each marker for diagnosing chronic cerebral ischemia. The Delong test was used to compare AUC size between groups. RESULTS: Compared to the non-CCH group, the CCH group exhibited higher IMA levels and lower BDNF concentrations (P < 0.05). However, VILIP-1 and Lp-PLA2 concentrations were not significantly different between the two groups (P > 0.05). Moreover, IMA and BDNF levels were not correlated with CBF in the hypoperfused area. ROC curve analysis demonstrated that the cut-off values of 24.2915 U/mL and 6.714 ng/L for IMA and BDNF achieved a sensitivity of 83.6% and 41.8% and a specificity of 62.1% and 93.1%, respectively. Lastly, the areas under the curve for IMA and BDNF were 0.738 (95% confidence interval [CI], 0.627-0.848) and 0.631 (95% CI, 0.512-0.751), respectively. CONCLUSION: IMA and BDNF may have clinical value in the diagnosis of CCH.

Right anterior insula ASL hypoperfusion as a diagnostic biomarker of prodromal and mild dementia with Lewy bodies: preliminary evidence using a Bayesian approach.

Identifying and validating a biomarker with high specificity in early-stage dementia with Lewy bodies (DLB) using a feasible method is crucial to enhance the current suboptimal diagnostic procedure. Previous research revealed abnormalities, including hypoperfusion in the right anterior insular cortex at group level, in prodromal DLB. Exploring hypoperfusion of the right anterior insula, at an individual-level and assessing its relevance as a potential imaging biomarker in early DLB, has, to our knowledge, not been investigated. Our preliminary study aims to assess the feasibility of the technique and to provide a methodological framework for further investigation. We assessed the feasibility and accuracy of the hypoperfusion of the right anterior insula per arterial spin labelling magnetic resonance imaging (ASL-MRI) as a diagnostic biomarker in early DLB and provided rough estimates of its sensitivity and specificity. Defining the region of interest based on previous research, we established the biomarker as the hypoperfusion of the right anterior insula. Discriminative and analytical performances were assessed in comparison to a control group of treatment-resistant depression patients. Bayesian diagnostic reasoning was employed to assess the biomarker diagnostic usability in early DLB in two scenarios: healthy elderly controls and mild cognitive impairment. Additionally, we updated probabilities by integrating data from the Mayo-clinic cognitive fluctuations scale and real-time quaking-induced conversion (RT-QuIC) α-synuclein data. Lastly, a whole-brain perfusion analysis of DLB patients was conducted to identify further brain regions with discriminative abilities. We successfully replicated the right anterior insular hypoperfusion (RAI-Hypo) in all DLB patients at the individual level. The overall sensitivity of the biomarker was 96%, and the specificity was 92%. Bayesian testing revealed the biomarker's highest performance in early-stage DLB with cognitive fluctuations, showcasing a diagnostic potential associated with a high precision and moderate accuracy. In a cognitively non-impaired population, the RAI-Hypo showed a limited usability and lacked in selectivity to qualify as a screening tool. The exploratory whole-brain analysis revealed perfect discriminative capacities in the bilateral anterior insulae and the left inferior parietal lobule. Further studies are needed to confirm our preliminary results. If performance is maintained in subsequent studies and is compared to a more suitable control population, the proposed biomarker may be eventually sufficient to discriminate early-stage DLB from non-DLB.

Hypoperfusion Intensity Ratio as an Indirect Imaging Surrogate in Patients With Anterior Circulation Large-Vessel Occlusion and Association of Baseline Characteristics With Poor Collateral Status.

BACKGROUND: Collateral status (CS) plays a crucial role in infarct growth rate, risk of postthrombectomy hemorrhage, and overall clinical outcomes in patients with acute ischemic stroke (AIS) secondary to anterior circulation large-vessel occlusions (LVOs). Hypoperfusion intensity ratio has been previously validated as an indirect noninvasive pretreatment imaging biomarker of CS. In addition to imaging, derangements in admission laboratory findings can also influence outcomes in patients with AIS-LVO. Therefore, our study aims to assess the relationship between admission laboratory findings, baseline characteristics, and CS, as assessed by hypoperfusion intensity ratio in patients with AIS-LVO. METHODS AND RESULTS: In this retrospective study, consecutive patients presenting with AIS secondary to anterior circulation LVO who underwent pretreatment computed tomography perfusion were included. The computed tomography perfusion data processed by RAPID (Ischema View, Menlo Park, CA) generated the hypoperfusion intensity ratio. Binary logistic regression models were used to assess the relationship between patients' baseline characteristics, admission laboratory findings, and poor CS. A total of 221 consecutive patients with AIS-LVO between January 2017 and September 2022 were included in our study (mean±SD age, 67.0±15.8 years; 119 men [53.8%]). Multivariable logistic regression showed that patients with AIS caused by cardioembolic and cryptogenic causes (adjusted odds ratio [OR], 2.67; 95% CI, 1.20-5.97; P=0.016), those who presented with admission National Institutes of Health Stroke Scale score ≥12 (adjusted OR, 3.12; 95% CI, 1.61-6.04; P=0.001), and male patients (adjusted OR, 2.06; 95% CI, 1.13-3.77; P=0.018) were associated with poor CS. CONCLUSIONS: Stroke caused by cardioembolic or cryptogenic causes, admission National Institutes of Health Stroke Scale score of ≥12, and male sex were associated with poor CS, as defined by hypoperfusion intensity ratio in the patients with AIS-LVO.

Indocyanine green angiography reveals choroidal hypoperfusion in subacute sclerosing panencephalitis (SSPE).

We report the choroidal findings on indocyanine green angiography (ICGA) in two cases of subacute sclerosing panencephalitis (SSPE). The two immunocompetent patients (31-year-old and 30-year-old Asian Indian males) presented with acute-onset rapidly progressing vision loss with findings of necrotizing retinitis involving the central macula. Both patients tested negative for serological evidence of herpes or varicella, and toxoplasma antibodies. The patients demonstrated high serum and cerebrospinal fluid titers of anti-measles antibody (and abnormal electroencephalogram in one patient) leading to the diagnosis of SSPE. ICGA of both patients revealed distinct "dark dots" which showed hypofluorescence in the early and late phases suggestive of choroidal involvement/hypoperfusion. Choroidal involvement in SSPE has not been evaluated before and must be considered in the pathological manifestations of the disease.

The benefit of optimizing recanalization during mechanical thrombectomy in patients with acute ischemic stroke depends on preprocedural tissue-level collateralization.

PURPOSE: Thrombolysis in Cerebral Infarction (TICI) 3 represents the optimal angiographic outcome following mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Although it is known to yield better outcomes than TICI 2b, the influence of preprocedural cerebral hemodynamics on the clinical advantage of TICI 3 over TICI 2b remains unexplored. METHODS: This single-center retrospective analysis involved patients with anterior circulation AIS who underwent successful recanalization during MT at the Comprehensive Stroke Center, University Hospital, Krakow between January 2019 and July 2023. We assessed the benefit of achieving TICI 2c/3 over TICI 2b on the basis of preprocedural computed perfusion imaging results, primarily focusing on early infarct volume (EIV) and tissue-level collaterals indicated by hypoperfusion intensity ratio (HIR). Good functional outcome (GFO) was defined as a modified Rankin Score < 3 on day 90. RESULTS: The study comprised 612 patients, of whom 467 (76.3%) achieved TICI 2c/3. GFO was more frequent in the TICI 2c/3 group (54.5% vs 69.4%, p < 0.001). There was interaction between the recanalization status and both HIR (Pi = 0.042) and EIV (Pi = 0.012) in predicting GFO, with disproportionately higher impact of HIR and EIV in TICI 2b group. The benefit from TICI 2c/3 over TICI 2b was insignificant among patients with good collaterals, defined by HIR < 0.3 (odds ratio:1.36 [0.58-3.18], p = 0.483). CONCLUSION: TICI 2c/3 improves patient functional outcomes compared to TICI 2b regardless of EIV. However, such angiographic improvement may be clinically futile in patients with good tissue-level collateralization. Our findings suggest that preprocedural HIR should be considered when optimization of recanalization is considered during MT.

Myelin endocytosis by brain endothelial cells causes endothelial iron overload and oligodendroglial iron hunger in hypoperfusion-induced white matter injury.

AIMS: Hypoperfusion induces significant white matter injury in cerebral vascular disorders, including arteriosclerotic cerebral small vessel disease (aCSVD), which is prevalent among the elderly. Iron transport by blood vessel endothelial cells (BVECs) from the periphery supports oligodendrocyte maturation and white matter repair. This study aims to elucidate the association between iron homeostasis changes and white matter injury severity, and explore the crosstalk between BVECs and oligodendroglial lineage cells. METHODS: In vivo: C57BL/6 mice were subjected to unilateral common carotid artery occlusion (UCCAO). In vitro: BVECs with myelin pretreatment were co-cultured with oligodendrocyte progenitor cells (OPCs) or organotypic cerebellar slices subjected to oxygen and glucose deprivation. RESULTS: Circulatory iron tends to be stored in aCSVD patients with white matter injury. Myelin debris endocytosis by BVECs impairs iron transport, trapping iron in the blood and away from the brain, worsening oligodendrocyte iron deficiency in hypoperfusion-induced white matter injury. Iron accumulation in BVECs triggers ferroptosis, suppressing iron transport and hindering white matter regeneration. Intranasal holo-transferrin (hTF) administration bypassing the BBB alleviates oligodendrocyte iron deficiency and promotes myelin regeneration in hypoperfusion-induced white matter injury. CONCLUSION: The iron imbalance between BVECs and oligodendroglial lineage cells is a potential therapeutic target in hypoperfusion-induced white matter injury.

Arterial hypoperfusion as a negative predictive marker for primary hepatic malignancies treated with Y-90 glass microsphere transarterial radioembolization.

Background: Radioembolization with yttrium-90 (Y-90) is utilized to treat primary liver malignancies. The efficacy of this intra-arterial therapy in arterially hypoperfused tumors is not known. Methods: We reviewed data of patients with primary liver tumors treated with Y-90 prescription doses of at least 150 Gy. Baseline patient characteristics, treatment history, imaging-based tumor response assessments, and clinical outcome metrics were recorded. Tumors were classified as arterially hyperperfused versus hypoperfused on post-TARE Y-90 SPECT/CTs or pre-TARE hepatic perfusion SPECT/CTs. Perfusion status was correlated with tumor response assessments and clinical outcomes. Cox proportional hazards models were utilized to compare survival and progression-free survival. Inverse probability weighting was utilized to account for clinical factors and adjusted multivariable proportional hazards analyses to examine the relationship of quantitative perfusion and cancer outcomes. Results: Of 400 Y-90 treatments, 88 patients received a prescribed dose of at least 150 Gy and had pre- or post-treatment SPECT/CT images. 11 and 77 patients had arterially hypoperfused and hyperperfused lesions, respectively. On dedicated liver MRI or CT at 3 months after Y-90, the complete response rates were 5.6% and 16.5% in the hypoperfused and hyperperfused cohort, respectively (P = 0.60). When controlling for various clinical features, including tumor histology, patients with arterially hypoperfused tumors had significantly shorter progression-free survival (HR 1.87, 95% CI - 1.03 - 3.37, P = 0.039) and greater elsewhere liver (HR 3.36, 95% CI = 1.23 - 9.20, P = 0.019) and distant failure (HR 7.64 (2.71 - 21.54, P < 0.001). In inverse probability weighted analysis, patients with arterially hypoperfused tumors had worse overall survival (P = 0.032). In the quantitative analysis, lower levels of lesion perfusion were also associated with worse clinical outcomes, again controlling for tumor histology. Conclusion: Compared to arterially hyperperfused tumors, hypoperfused primary liver tumors treated with Y-90 may have worse clinical outcomes.

Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.