Boston Criteria v2.0 for Cerebral Amyloid Angiopathy Without Hemorrhage: An MRI-Neuropathologic Validation Study.

BACKGROUND AND OBJECTIVES: Updated criteria for the clinical-MRI diagnosis of cerebral amyloid angiopathy (CAA) have recently been proposed. However, their performance in individuals without symptomatic intracerebral hemorrhage (ICH) presentations is less defined. We aimed to assess the diagnostic performance of the Boston criteria version 2.0 for CAA diagnosis in a cohort of individuals ranging from cognitively normal to dementia in the community and memory clinic settings. METHODS: Fifty-four participants from the Mayo Clinic Study of Aging or Alzheimer's Disease Research Center were included if they had an antemortem MRI with gradient-recall echo sequences and a brain autopsy with CAA evaluation. Performance of the Boston criteria v2.0 was compared with v1.5 using histopathologically verified CAA as the reference standard. RESULTS: The median age at MRI was 75 years (interquartile range 65-80) with 28/54 participants having histopathologically verified CAA (i.e., moderate-to-severe CAA in at least 1 lobar region). The sensitivity and specificity of the Boston criteria v2.0 were 28.6% (95% CI 13.2%-48.7%) and 65.3% (95% CI 44.3%-82.8%) for probable CAA diagnosis (area under the receiver operating characteristic curve [AUC] 0.47) and 75.0% (55.1-89.3) and 38.5% (20.2-59.4) for any CAA diagnosis (possible + probable; AUC 0.57), respectively. The v2.0 Boston criteria were not superior in performance compared with the prior v1.5 criteria for either CAA diagnostic category. DISCUSSION: The Boston criteria v2.0 have low accuracy in patients who are asymptomatic or only have cognitive symptoms. Additional biomarkers need to be explored to optimize CAA diagnosis in this population.

DMT1 ubiquitination by Nedd4 protects against ferroptosis after intracerebral hemorrhage.

OBJECTIVE: Neuronal precursor cells expressed developmentally down-regulated 4 (Nedd4) are believed to play a critical role in promoting the degradation of substrate proteins and are involved in numerous biological processes. However, the role of Nedd4 in intracerebral hemorrhage (ICH) remains unknown. This study aims to investigate the regulatory role of Nedd4 in the ICH model. METHODS: Male C57BL/6J mice were induced with ICH. Subsequently, the levels of glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, as well as the expression of divalent metal transporter 1 (DMT1) and Nedd4 were assessed after ICH. Furthermore, the impact of Nedd4 overexpression was evaluated through analyses of hematoma area, ferroptosis, and neurobehavioral function. The mechanism underlying Nedd4-mediated degradation of DMT1 was elecidated using immunoprecipitation (IP) after ICH. RESULTS: Upon ICH, the level of DMT1 in the brain increased, but decreased when Nedd4 was overexpressed using Lentivirus, suggesting a negative correlation between Nedd4 and DMT1. Additionally, the degradation of DMT1 was inhibited after ICH. Furthermore, it was found that Nedd4 can interact with and ubiquitinate DMT1 at lysine residues 6, 69, and 277, facilitating the degradation of DMT1. Functional analysis indicated that overexpression of Nedd4 can alleviate ferroptosis and promote recovery following ICH. CONCLUSION: The results demonstrated that ferroptosis occurs via the Nedd4/DMT1 pathway during ICH, suggesting it potential as a valuable target to inhibit ferroptosis for the treatment of ICH.

An autopsy case of cerebral hemorrhage in an HIV-infected patient with suspected HIV-associated cerebrovascular disease.

A male in his late 30s was found dead in his home. He was diagnosed with human immunodeficiency virus (HIV) about six years prior. The HIV infection was well controlled before his death. He was 166 cm in height and 75 kg in weight. Aside from discoloration of the skin on the right lower patellar, there were no obvious injuries. His brain weighed 1456 g. A cut surface of the brain revealed left thalamic hemorrhage. Histologically, infiltration of phagocytic cells was observed in the bleeding site. Thalamic hemorrhage was considered to be his cause of death in this case. Due to the effects of anti-HIV therapy, the mortality rate from HIV infection has decreased and the causes of death of HIV-infected persons have changed. HIV-infected persons have been suggested to be associated with cerebrovascular disease, especially juvenile ischemic stroke. Patients with acquired immunodeficiency syndrome (AIDS) have an increased risk of cerebrovascular disease. Possible mechanisms of cerebrovascular disease in HIV-infected individuals include coagulopathy, secondary effects of embolism and central nervous system infection, and direct vascular disease due to HIV. At the time of autopsy, his post-mortem interval was estimated to be approximately two weeks. Therefore, it was difficult to clarify histologically the cerebrovascular disorder that caused his cerebral hemorrhage. In recent years, anti-HIV therapy has reduced the number of AIDS-related deaths, but deaths in HIV-infected people from cardiovascular disease are increasing. This case is considered to be a valuable forensic autopsy case of an HIV-infected patient who actually died due to cerebral hemorrhage in Japan.

Microglial uptake of hADSCs-Exo mitigates neuroinflammation in ICH.

Intracerebral hemorrhage (ICH) is associated with secondary neuroinflammation, leading to severe central nervous system damage. Exosomes derived from human adipose-derived mesenchymal stem cells (hADSCs-Exo) have shown potential therapeutic effects in regulating inflammatory responses in ICH. This study aims to investigate the role of hADSCs-Exo in ICH and its underlying mechanism involving miRNA-mediated regulation of formyl peptide receptor 1 (FPR1). Flow cytometry was used to identify hADSCs and extract exosomes. Transmission electron microscopy and Western blot were performed to confirm the characteristics of the exosomes. In vitro experiments were conducted to explore the uptake of hADSCs-Exo by microglia cells and their impact on inflammatory responses. In vivo, an ICH mouse model was established, and the therapeutic effects of hADSCs-Exo were evaluated through neurological function scoring, histological staining, and immunofluorescence. Bioinformatics tools and experimental validation were employed to identify miRNAs targeting FPR1. hADSCs-Exo were efficiently taken up by microglia cells and exhibited anti-inflammatory effects by suppressing the release of inflammatory factors and promoting M1 to M2 transition. In the ICH mouse model, hADSCs-Exo significantly improved neurological function, reduced hemorrhage volume, decreased neuronal apoptosis, and regulated microglia polarization. miR-342-3p was identified as a potential regulator of FPR1 involved in the neuroprotective effects of hADSCs-Exo in ICH. hADSCs-Exo alleviate neuroinflammation in ICH through miR-342-3p-dependent targeting of FPR1, providing a new therapeutic strategy for ICH.

Nrdp1-mediated Macrophage Phenotypic Regulation Promotes Functional Recovery in Mice with Mild Neurological Impairment after Intracerebral Hemorrhage.

Neuregulin receptor degradation protein 1 (Nrdp1) is a ring finger E3 ubiquitin ligase involved in some inflammation through ubiquitination, including macrophage polarization following cerebral hemorrhage. However, there is limited understanding regarding the mechanisms through which Nrdp1 modulates macrophage polarization and the potential impact of this modulation on neurological function. Using stereotactic injection and adenoviral transfection techniques, the corresponding animal models were constructed through injecting adenovirus, saline, or blood into the mouse striatum at different periods of time in this research. The alteration in the ratio of various M1/M2 phenotype-associated markers (e.g., CD86, CD206, IL-6, IL-10, etc.) was evaluated through immunohistochemistry, immunofluorescence, western blotting, and elisa assays. Additionally, neurological function scores and behavioral tests were utilized to evaluate changes in neurological function in mice after cerebral hemorrhage. Our results show that overexpression of Nrdp1 promotes the expression of a variety of M2 macrophage-associated markers and enhance transcriptional activity of arginase-1 (Arg1) protein through ubiquitination for early regulation M2 macrophage polarization. Additionally, Nrdp1 promotes hematoma absorption, increases IL-10 expression, inhibits inducible nitric oxide synthase (iNOS), IL-6, and TNF-α production, alleviates neurological impairment and brain edema, and accelerates functional recovery. These findings suggest that modulating macrophage polarization through Nrdp1 could be a therapeutic strategy for neurofunctional impairment in cerebral hemorrhage.

Txnrd2 Attenuates Early Brain Injury by Inhibition of Oxidative Stress and Endoplasmic Reticulum Stress via Trx2/Prx3 Pathway after Intracerebral Hemorrhage in Rats.

Thioredoxin-reductase 2 (Txnrd2) belongs to the thioredoxin-reductase family of selenoproteins and is a key antioxidant enzyme in mammalian cells to regulate redox homeostasis. Here, we reported that Txnrd2 exerted a major influence in brain damage caused by Intracerebral hemorrhage (ICH) by suppressing endoplasmic reticulum (ER) stress oxidative stress and via Trx2/Prx3 pathway. Furthermore, we demonstrated that pharmacological selenium (Se) rescued the brain damage after ICH by enhancing Txnrd2 expression. Primarily, expression and localization of Txnrd2, Trx2 and Prx3 were determined in collagenase IV-induced ICH model. Txnrd2 was then knocked down using siRNA interference in rats which were found to develop more severe encephaledema and neurological deficits. Mechanistically, we observed that loss of Txnrd2 leads to increased lipid peroxidation levels and ER stress protein expression in neurons and astrocytes. Additionally, it was revealed that Se effectively restored the expression of Txnrd2 in brain and inhibited both the activity of ER stress protein activity and the generation of reactive oxygen species (ROS) by promoting Trx2/Prx3 kilter when administrating sodium selenite in lateral ventricle. This study shed light on the effect of Txnrd2 in regulating oxidative stress and ER stress via Trx2/Prx3 pathway upon ICH and its promising potential as an ICH therapeutic target.

Cathepsin B as a key regulator of ferroptosis in microglia following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke marked by elevated mortality and disability rates. Recently, mounting evidence suggests a significant role of ferroptosis in the pathogenesis of ICH. Through a combination of bioinformatics analysis and basic experiments, our goal is to identify the primary cell types and key molecules implicated in ferroptosis post-ICH. This aims to propel the advancement of ferroptosis research, offering potential therapeutic targets for ICH treatment. Our study reveals pronounced ferroptosis in microglia and identifies the target gene, cathepsin B (Ctsb), by analyzing differentially expressed genes following ICH. Ctsb, a cysteine protease primarily located in lysosomes, becomes a focal point in our investigation. Utilizing in vitro and in vivo models, we explore the correlation between Ctsb and ferroptosis in microglia post-ICH. Results demonstrate that ICH and hemin-induced ferroptosis in microglia coincide with elevated levels and activity of Ctsb protein. Effective alleviation of ferroptosis in microglia after ICH is achieved through the inhibition of Ctsb protease activity and protein levels using inhibitors and shRNA. Additionally, a notable increase in m6A methylation levels of Ctsb mRNA post-ICH is observed, suggesting a pivotal role of m6A methylation in regulating Ctsb translation. These research insights deepen our comprehension of the molecular pathways involved in ferroptosis after ICH, underscoring the potential of Ctsb as a promising target for mitigating brain damage resulting from ICH.

Geniposide ameliorates brain injury in mice with intracerebral hemorrhage by inhibiting NF-κB signaling.

BACKGROUND: Neuroinflammation and oxidative stress are critical players in intracerebral hemorrhage (ICH). Geniposide is an active component of Gardenia that has anti-inflammatory effects. This study focused on the roles and mechanisms of geniposide in ICH. METHODS: ICH was established by injecting collagenase IV into C57BL/6 mice. To determine the functions of geniposide and NF-κB inhibition in ICH model mice, geniposide (1, 25, or 50 mg/kg) or PDTC (a NF-κB inhibitor) was administered. Neurological functions were assessed with the modified neurological severity score (mNSS) test. Hematoxylin and eosin staining were performed to identify pathological changes. IL-1ß and TNF-α levels were estimated with ELISA kits. NF-κB p65 localization was determined by immunofluorescence staining. Oxidative stress was analyzed by measuring ROS levels. RESULTS: Geniposide alleviated cerebral edema and neurological deficits. Geniposide inhibited neuroinflammation and oxidative stress after ICH, and the inhibitory effects were enhanced by NF-κB inhibition. Additionally, geniposide inhibited NF-κB signaling. CONCLUSION: Geniposide alleviates brain injury by suppressing inflammation and oxidative stress damage in experimental ICH models by inhibiting NF-κB signaling.

A dispensable role of oligodendrocyte-derived laminin-α5 in brain homeostasis and intracerebral hemorrhage.

Laminin, a major component of the basal lamina in the CNS, is also expressed in oligodendrocytes (OLs). However, the function of OL-derived laminin remains largely unknown. Here, we performed loss-of-function studies using two OL-specific laminin-α5 conditional knockout mouse lines. Both mutants were grossly normal and displayed intact blood-brain barrier (BBB) integrity. In a mouse model of intracerebral hemorrhage (ICH), control mice and both mutants exhibited comparable hematoma size and neurological dysfunction. In addition, similar levels of hemoglobin and IgG leakage were detected in the mutant brains compared to the controls, indicating comparable BBB damage. Consistent with this finding, subsequent studies revealed no differences in tight junction protein (TJP) and caveolin-1 expression among control and knockout mice, suggesting that neither paracellular nor transcellular mechanism was affected in the mutants. Furthermore, compared to the controls, both mutant lines showed comparable oligodendrocyte number, oligodendrocyte proliferation rate, MBP/MAG levels, and SMI-32 expression, highlighting a minimal role of OL-derived laminin-α5 in OL biology. Together, these findings highlight a dispensable role of OL-derived laminin-α5 in both brain homeostasis and ICH pathogenesis.

Consistency of mouse models with human intracerebral hemorrhage: core targets and non-coding RNA regulatory axis.

Intracerebral hemorrhage (ICH) has a high mortality and disability rate. Numerous basic studies on pathogenesis and therapeutics have been performed in mice. However, the consistency of the experimental mouse model and the human ICH patient remains unclear. This has slowed progress in translational medicine. Furthermore, effective therapeutic targets and reliable regulatory networks for ICH are needed. Therefore, we determined the differentially expressed (DE) messenger RNAs (mRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) before and after murine ICH and analyzed their regulatory relationships. Subsequently, data on mRNAs from human peripheral blood after ICH were obtained from the Gene Expression Omnibus database. The DE mRNAs after human ICH were compared with those of the mouse. Finally, we obtained seven genes with translational medicine research value and verified them in mice. Then the regulatory network of these genes was analyzed in humans. Similarly, species homologies of these regulatory pathways were identified. In conclusion, we found that the mouse ICH model mimics the human disease mainly in terms of chemokines and inflammatory factors. This has important implications for future research into the mechanisms of ICH injury and repair.

Deubiquitylating Enzyme OTUB1 Facilitates Neuronal Survival After Intracerebral Hemorrhage Via Inhibiting NF-κB-triggered Apoptotic Cascades.

The deubiquitylase OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) has been implicated in the pathogenesis of various human diseases. However, the molecular mechanism by which OTUB1 participates in the pathogenesis of intracerebral hemorrhage (ICH) remains elusive. In the present study, we established an autologous whole blood fusion-induced ICH model in C57BL/6 J mice. We showed that the upregulation of OTUB1 contributes to the attenuation of Nuclear factor kappa B (NF-κB) and its downstream apoptotic signaling after ICH. OTUB1 directly associates with NF-κB precursors p105 and p100 after ICH, leading to attenuated polyubiquitylation of p105 and p100. Moreover, we revealed that NF-κB signaling was modestly activated both in ICH tissues and hemin-exposed HT-22 neuronal cells, accompanied with the activation of NF-κB downstream pro-apoptotic signaling. Notably, overexpression of OTUB1 strongly inhibited hemin-induced NF-κB activation, whereas interference of OTUB1 led to the opposite effect. Finally, we revealed that lentiviral transduction of OTUB1 markedly ameliorated hemin-induced apoptotic signaling and HT-22 neuronal death. Collectively, these findings suggest that the upregulation of OTUB1 serves as a neuroprotective mechanism in antagonizing neuroinflammation-induced NF-κB signaling and neuronal death, shed new light on manipulating intracellular deubiquitylating pathways as novel interventive approaches against ICH-induced secondary neuronal damage and death.

[Analysis of the prevalence of anticoagulant therapy in patients with cognitive disorders and cerebral amyloid angiopathy (CAA)]. / Analyse zur Häufigkeit einer gerinnungshemmenden Medikation bei Patientinnen mit kognitiven Störungen und zerebraler Amyloidangiopathie (CAA).

OBJECTIVES: To investigate the prevalence of coincident anticoagulation in patients with cognitive disorders and possible or probable cerebral amyloid angiopathy (CAA) as well as the relationship between the presence of oral anticoagulation and CAA-specific lesion load. MATERIALS AND METHODS: Patients with subjective cognitive decline (SCD), amnestic and non-amnestic mild cognitive impairment (aMCI/naMCI), Alzheimer's disease (AD), mixed dementia (MD) and vascular dementia (VD) who presented to our outpatient dementia clinic between February 2016 and October 2020 were included in this retrospective analysis. Patients underwent cranial magnetic resonance imaging (MRI). MRI data sets were analyzed regarding the presence of CAA-related MRI biomarkers to determine CAA prevalence. Presence of anticoagulant therapy was determined by chart review. RESULTS: Within the study period, 458 patients (209 male, 249 female, mean age 73.2 ± 9.9 years) with SCD (n = 44), naMCI (n = 40), aMCI (n = 182), AD (n = 120), MD (n = 68) and VD (n = 4) were analyzed. A total of 109 patients (23.8%) were diagnosed with possible or probable CAA. CAA prevalence was highest in aMCI (39.4%) and MD (28.4%). Of patients with possible or probable CAA, 30.3% were under platelet aggregation inhibition, 12.8% were treated with novel oral anticoagulants and 3.7% received phenprocoumon treatment. Regarding the whole study cohort, patients under oral anticoagulation showed more cerebral microbleeds (p = 0.047). There was no relationship between oral anticoagulation therapy and the frequency of cortical superficial siderosis (p = 0.634). CONCLUSION: CAA is a frequent phenomenon in older patients with cognitive disorders. Almost half of CAA patients receive anticoagulant therapy. Oral anticoagulation is associated with a higher number of cortical and subcortical microbleeds.

Structural Brain Injury on Brain Magnetic Resonance Imaging in Acute Respiratory Distress Syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an acute inflammatory respiratory failure condition that may be associated with brain injury. We aimed to describe the types of structural brain injuries detected by brain magnetic resonance imaging (MRI) among patients with ARDS. METHODS: We retrospectively reviewed and collected data on brain injuries as detected by brain MRI during index hospitalization of all patients with ARDS at a single tertiary center in the United States from January 2010 to October 2018 (pre-COVID era). Structural brain injuries were classified as cerebral ischemia (ischemic infarct and hypoxic-ischemic brain injury) or cerebral hemorrhage (intraparenchymal hemorrhage, cerebral microbleeds, subarachnoid hemorrhage, and subdural hematoma). Descriptive statistics were conducted. RESULTS: Of the 678 patients with ARDS, 66 (9.7%) underwent brain MRI during their ARDS illness. The most common indication for brain MRI was encephalopathy (45.4%), and the median time from hospital admission to MRI was 10 days (interquartile range 4-17). Of 66 patients, 29 (44%) had MRI evidence of brain injury, including cerebral ischemia in 33% (22 of 66) and cerebral hemorrhage in 21% (14 of 66). Among those with cerebral ischemia, common findings were bilateral globus pallidus infarcts (n = 7, 32%), multifocal infarcts (n = 5, 23%), and diffuse hypoxic-ischemic brain injury (n = 3, 14%). Of those with cerebral hemorrhage, common findings were cerebral microbleeds (n = 12, 86%) and intraparenchymal hemorrhage (n = 2, 14%). Patients with ARDS with cerebral hemorrhage had significantly greater use of rescue therapies, including prone positioning (28.6% vs. 5.8%, p = 0.03), inhaled vasodilator (35.7% vs. 11.5%, p = 0.046), and recruitment maneuver (14.3% vs. 0%, p = 0.04). CONCLUSIONS: Structural brain injury was not uncommon among selected patients with ARDS who underwent brain MRI. The majority of brain injuries seen were bilateral globus pallidus infarcts and cerebral microbleeds.

Use of MR signal intensity variations to highlight structures at risk along brain biopsy trajectories.

OBJECTIVE: Postoperative intracerebral hemorrhages are significant complications following brain stereotactic biopsy. They can derive from anatomical structure (sulci, vessels) damage that is missed during stereotactic trajectory planning. In this study, the authors investigated the ability to detect contact between structures at risk and stereotactic trajectories using signal analysis from MRI obtained during clinical practice, with the aim to propose a visual tool to highlight areas with anatomical structures at risk of damage along the biopsy trajectory. METHODS: The authors retrospectively analyzed actual stereotactic trajectories using intraoperative imaging (intraoperative 2D radiographs in the exploratory data set and intraoperative 3D scans in the confirmatory data set). The MR signal variation along each biopsy trajectory was matched with the patient's anatomy. RESULTS: In the exploratory data set (n = 154 patients), 32 contacts between the actual biopsy trajectory and an anatomical structure at risk were identified along 28 (18.2%) biopsy trajectories, corresponding to 8 preventable intracerebral hemorrhages. Variations of the mean derivative of the MR signal intensity were significantly different between trajectories with and without contact (the pathological threshold of the mean derivative of the MR signal intensity was defined as ± 0.030 arbitrary units; p < 0.0001), with a sensitivity of 89.3% and specificity of 74.6% to detect a contact. In the confirmatory data set (n = 73 patients), the sensitivity and specificity of the 0.030 threshold to detect a contact between the actual stereotactic trajectory and an anatomical structure at risk were 81.3% and 68.4%, respectively. CONCLUSIONS: Variations of the mean derivative of the MR signal intensity can be converted into a green/red color code along the planned biopsy trajectory to highlight anatomical structures at risk, which can help neurosurgeons during the surgical planning of stereotactic procedures.

Azithromycin reduces hemoglobin-induced innate neuroimmune activation.

Neonatal intraventricular hemorrhage (IVH) releases blood products into the lateral ventricles and brain parenchyma. There are currently no medical treatments for IVH and surgery is used to treat a delayed effect of IVH, post-hemorrhagic hydrocephalus. However, surgery is not a cure for intrinsic brain injury from IVH, and is performed in a subacute time frame. Like many neurological diseases and injuries, innate immune activation is implicated in the pathogenesis of IVH. Innate immune activation is a pharmaceutically targetable mechanism to reduce brain injury and post-hemorrhagic hydrocephalus after IVH. Here, we tested the macrolide antibiotic azithromycin, which has immunomodulatory properties, to reduce innate immune activation in an in vitro model of microglial activation using the blood product hemoglobin (Hgb). We then utilized azithromycin in our in vivo model of IVH, using intraventricular blood injection into the lateral ventricle of post-natal day 5 rat pups. In both models, azithromycin modulated innate immune activation by several outcome measures including mitochondrial bioenergetic analysis, cytokine expression and flow cytometric analysis. This suggests that azithromycin, which is safe for neonates, could hold promise for modulating innate immune activation after IVH.

Group 2 innate lymphoid cells suppress neuroinflammation and brain injury following intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) mobilizes circulating leukocytes that contribute to neuroinflammation and neural injury. However, little is known about the endogenous regulatory immune mechanisms to restrict neuroinflammation following ICH. We examined the role of group 2 innate lymphoid cells (ILC2) that are a specialized subset of innate immune modulators in a mouse model of ICH. We found accumulation of ILC2 in the brain following acute ICH and a concomitant increase of ILC2 within the peripheral lymph nodes. Depletion of ILC2 exacerbated neurodeficits and brain edema after ICH in male and female mice. This aggravated ICH injury was accompanied by augmented microglia activity and leukocyte infiltration. In contrast, expansion of ILC2 using IL-33 led to reduced ICH injury, microglia activity and leukocyte infiltration. Notably, elimination of microglia using a colony stimulating factor 1 receptor inhibitor diminished the exacerbation of ICH injury induced by depletion of ILC2. Brain-infiltrating ILC2 had upregulation of IL-13 after ICH. Results from in vitro assays revealed that ILC2 suppressed thrombin-induced inflammatory activity in microglia-like BV2 cells. Thus, our findings demonstrate that ILC2 suppress neuroinflammation and acute ICH injury.

FGF21 alleviates endothelial mitochondrial damage and prevents BBB from disruption after intracranial hemorrhage through a mechanism involving SIRT6.

BACKGROUND: Disruption of the BBB is a harmful event after intracranial hemorrhage (ICH), and this disruption contributes to a series of secondary injuries. We hypothesized that FGF21 may have protective effects after intracranial hemorrhage (ICH) and investigated possible underlying molecular mechanisms. METHODS: Blood samples of ICH patients were collected to determine the relationship between the serum level of FGF21 and the [Formula: see text]GCS%. Wild-type mice, SIRT6flox/flox mice, endothelial-specific SIRT6-homozygous-knockout mice (eSIRT6-/- mice) and cultured human brain microvascular endothelial cells (HCMECs) were used to determine the protective effects of FGF21 on the BBB. RESULTS: We obtained original clinical evidence from patient data identifying a positive correlation between the serum level of FGF21 and [Formula: see text]GCS%. In mice, we found that FGF21 treatment is capable of alleviating BBB damage, mitigating brain edema, reducing lesion volume and improving neurofunction after ICH. In vitro, after oxyhemoglobin injury, we further explored the protective effects of FGF21 on endothelial cells (ECs), which are a significant component of the BBB. Mitochondria play crucial roles during various types of stress reactions. FGF21 significantly improved mitochondrial biology and function in ECs, as evidenced by alleviated mitochondrial morphology damage, reduced ROS accumulation, and restored ATP production. Moreover, we found that the crucial regulatory mitochondrial factor deacylase sirtuin 6 (SIRT6) played an irreplaceable role in the effects of FGF21. Using endothelial-specific SIRT6-knockout mice, we found that SIRT6 deficiency largely diminished these neuroprotective effects of FGF21. Then, we revealed that FGF21 might promote the expression of SIRT6 via the AMPK-Foxo3a pathway. CONCLUSIONS: We provide the first evidence that FGF21 is capable of protecting the BBB after ICH by improving SIRT6-mediated mitochondrial homeostasis.

E3 ligase Nedd4L promotes macrophage M1 polarization and exacerbates brain damage by TRAF3/TBK1 signaling pathway after ICH in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a serious medical problem, and promising strategy is limited. Macrophage initiated brain inflammatory injury following ICH, but the molecular mechanism had not been well identified. E3 ligase Nedd4L is implicated in the pathogenesis of the inflammatory immune response. METHODS: In the present study, we detected the levels of Nedd4L in macrophages following ICH. Furthermore, Macrophage M1 polarization, pro-inflammatory cytokine production, BBB disruption, brain water content and neurological function were examined in ICH mice. RESULTS: Here, we demonstrated that E3 ligase Nedd4L levels of macrophage increased following ICH, promoted M1 polarization inflammation by TRAF3. Nedd4L promoted BBB disruption, as well as neurological deficits. Inhibition of Nedd4L significantly attenuated M1 polarization in vivo. Inhibition of Nedd4L decreased TRAF3 and TBK1 levels, and subsequent phosphorylation of p38 and NF-κB p65 subunit following ICH. CONCLUSIONS: Our data demonstrated that Nedd4L was involved in the pathogenesis of ICH, which promoted inflammatory responses and exacerbated brain damage by TRAF3 following ICH.

Cerebral Microbleeds Are Associated with Widespread Blood-Brain Barrier Leakage.

INTRODUCTION: The pathogenesis of cerebral microbleeds (CMBs) is incompletely understood, but blood-brain barrier (BBB) leakage may play a key role. This study aimed to investigate the relationship between compromised BBB integrity and CMBs as well as cognitive function. METHODS: Ninety-seven participants were enrolled in this cross-sectional study, involving 24 CMB patients. Dynamic contrast-enhanced-magnetic resonance imaging was used to measure BBB permeability, and cognitive function was assessed by Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). RESULTS: Compared with participants without CMBs, CMB patients had higher volume transfer constant (Ktrans, all p < 0.01) and area under the concentration curve (AUC, all p < 0.05) in normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter (DGM). Multivariable linear regression analyses revealed that CMB patients had significantly higher Ktrans in NAWM and AUC in NAWM, WMH, and CGM after adjustment for age, sex, vascular risk factors, and cognitive scores. MMSE and MoCA scores decreased with increasing Ktrans in WMH and DGM as well as AUC in WMH after adjustment for age, sex, CMB group, and education length. CONCLUSION: This study demonstrated that widespread BBB leakage was prevalent in CMB patients, suggesting that compromised BBB integrity may play a key role in the pathogenesis of CMBs and could lead to cognitive impairment.

Detection rate of brain MR and MR angiography for neuroimaging abnormality in patients with newly diagnosed left-sided infective endocarditis.

We aimed to investigate the detection rate of brain MR and MR angiography for neuroimaging abnormality in newly diagnosed left-sided infective endocarditis patients with/without neurological symptoms. This retrospective study included consecutive patients with definite or possible left-sided infective endocarditis according to the modified Duke criteria who underwent brain MRI and MR angiography between March 2015 and October 2020. The detection rate for neuroimaging abnormality on MRI was defined as the number of patients with positive brain MRI findings divided by the number of patients with left-sided infective endocarditis. Positive imaging findings included acute ischemic lesions, cerebral microbleeds, hemorrhagic lesions, and infectious aneurysms. In addition, aneurysm rupture rate and median period to aneurysm rupture were evaluated on follow-up studies. A total 115 patients (mean age: 55 years ± 19; 65 men) were included. The detection rate for neuroimaging abnormality was 77% (89/115). The detection rate in patients without neurological symptoms was 70% (56/80). Acute ischemic lesions, cerebral microbleeds, and hemorrhagic lesions including superficial siderosis and intracranial hemorrhage were detected on MRI in 56% (64/115), 57% (66/115), and 20% (23/115) of patients, respectively. In particular, infectious aneurysms were detected on MR angiography in 3% of patients (4/115), but MR angiography in 5 patients (4.3%) was insignificant for infectious aneurysm, which were detected using CT angiography (n = 3) and digital subtraction angiography (n = 2) during follow-up. Among the 9 infectious aneurysm patients, aneurysm rupture occurred in 4 (44%), with a median period of aneurysm rupture of 5 days. The detection rate of brain MRI for neuroimaging abnormality in newly diagnosed left-sided infective endocarditis patients was high (77%), even without neurological symptoms (70%).