ABSTRACT
Cerebral cavernous malformations (CCMs) are vascular disorders that affect up to 0.5% of the total population. About 20% of CCMs are inherited because of familial mutations in CCM genes, including CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10, whereas the etiology of a majority of simplex CCM-affected individuals remains unclear. Here, we report somatic mutations of MAP3K3, PIK3CA, MAP2K7, and CCM genes in CCM lesions. In particular, somatic hotspot mutations of PIK3CA are found in 11 of 38 individuals with CCMs, and a MAP3K3 somatic mutation (c.1323C>G [p.Ile441Met]) is detected in 37.0% (34 of 92) of the simplex CCM-affected individuals. Strikingly, the MAP3K3 c.1323C>G mutation presents in 95.7% (22 of 23) of the popcorn-like lesions but only 2.5% (1 of 40) of the subacute-bleeding or multifocal lesions that are predominantly attributed to mutations in the CCM1/2/3 signaling complex. Leveraging mini-bulk sequencing, we demonstrate the enrichment of MAP3K3 c.1323C>G mutation in CCM endothelium. Mechanistically, beyond the activation of CCM1/2/3-inhibited ERK5 signaling, MEKK3 p.Ile441Met (MAP3K3 encodes MEKK3) also activates ERK1/2, JNK, and p38 pathways because of mutation-induced MEKK3 kinase activity enhancement. Collectively, we identified several somatic activating mutations in CCM endothelium, and the MAP3K3 c.1323C>G mutation defines a primary CCM subtype with distinct characteristics in signaling activation and magnetic resonance imaging appearance.
Subject(s)
Hemangioma, Cavernous, Central Nervous System/genetics , MAP Kinase Kinase Kinase 3/genetics , Mutation , Amino Acid Sequence , Class I Phosphatidylinositol 3-Kinases/genetics , Endothelial Cells/metabolism , Germ-Line Mutation , Hemangioma, Cavernous, Central Nervous System/pathology , Human Umbilical Vein Endothelial Cells , Humans , MAP Kinase Kinase Kinase 3/metabolism , MAP Kinase Signaling System , Models, MolecularABSTRACT
Growing evidence suggests that systemic immune and inflammatory responses may play a critical role in the formation and development of aneurysms. Exploring the differences between single intracranial aneurysm (SIA) and multiple IAs (MIAs) could provide insights for targeted therapies. However, there is a lack of comprehensive and detailed characterization of changes in circulating immune cells in MIAs. Peripheral blood mononuclear cell (PBMC) samples from patients with SIA (n = 16) or MIAs (n = 6) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. A total of 25 cell clusters were identified, revealing that the immune signature of MIAs included cluster changes. Compared to patients with SIA, patients with MIAs exhibited immune dysfunction and regulatory imbalance in T-cell clusters. They also had reduced numbers of CD8+ T cells and their subgroups CD8+ Te and CD8+ Tem cells, as well as reduced numbers of the CD4+ T-cell subgroup CD27-CD4+ Tem cells. Furthermore, compared to SIA, MIAs were associated with enhanced T-cell immune activation, with elevated expression levels of CD3, CD25, CD27, CCR7, GP130, and interleukin 10. This study provides insights into the circulating immune cell profiles in patients with MIAs, highlighting the similarities and differences between patients with SIA and those with MIAs. Furthermore, the study suggests that circulating immune dysfunction may contribute to development of MIAs.
ABSTRACT
BACKGROUND: The fusiform aneurysm is a nonsaccular dilatation affecting the entire vessel wall over a short distance. Although PDGFRB somatic variants have been identified in fusiform intracranial aneurysms, the molecular and cellular mechanisms driving fusiform intracranial aneurysms due to PDGFRB somatic variants remain poorly understood. METHODS: In this study, single-cell sequencing and immunofluorescence were employed to investigate the phenotypic changes in smooth muscle cells within fusiform intracranial aneurysms. Whole-exome sequencing revealed the presence of PDGFRB gene mutations in fusiform intracranial aneurysms. Subsequent immunoprecipitation experiments further explored the functional alterations of these mutated PDGFRB proteins. For the common c.1684 mutation site of PDGFRß, we established mutant smooth muscle cell lines and zebrafish models. These models allowed us to simulate the effects of PDGFRB mutations. We explored the major downstream cellular pathways affected by PDGFRBY562D mutations and evaluated the potential therapeutic effects of Ruxolitinib. RESULTS: Single-cell sequencing of two fusiform intracranial aneurysms sample revealed downregulated smooth muscle cell markers and overexpression of inflammation-related markers in vascular smooth muscle cells, which was validated by immunofluorescence staining, indicating smooth muscle cell phenotype modulation is involved in fusiform aneurysm. Whole-exome sequencing was performed on seven intracranial aneurysms (six fusiform and one saccular) and PDGFRB somatic mutations were detected in four fusiform aneurysms. Laser microdissection and Sanger sequencing results indicated that the PDGFRB mutations were present in smooth muscle layer. For the c.1684 (chr5: 149505131) site mutation reported many times, further cell experiments showed that PDGFRBY562D mutations promoted inflammatory-related vascular smooth muscle cell phenotype and JAK-STAT pathway played a crucial role in the process. Notably, transfection of PDGFRBY562D in zebrafish embryos resulted in cerebral vascular anomalies. Ruxolitinib, the JAK inhibitor, could reversed the smooth muscle cells phenotype modulation in vitro and inhibit the vascular anomalies in zebrafish induced by PDGFRB mutation. CONCLUSION: Our findings suggested that PDGFRB somatic variants played a role in regulating smooth muscle cells phenotype modulation in fusiform aneurysms and offered a potential therapeutic option for fusiform aneurysms.
Subject(s)
Intracranial Aneurysm , Myocytes, Smooth Muscle , Receptor, Platelet-Derived Growth Factor beta , Animals , Female , Humans , Male , Intracranial Aneurysm/genetics , Intracranial Aneurysm/metabolism , Mutation , Myocytes, Smooth Muscle/metabolism , Phenotype , Receptor, Platelet-Derived Growth Factor beta/genetics , Receptor, Platelet-Derived Growth Factor beta/metabolism , Zebrafish/geneticsABSTRACT
BACKGROUND: Coexistence of intracranial atherosclerotic stenosis (ICAS) and unruptured intracranial aneurysms (UIAs) is increasingly encountered in clinical practice. This study aims to determine the prevalence of ICAS in patients with UIAs and procedural ischemic risk associated with ICAS when treating UIAs. METHODS: Based on the CAIASA study (Coexistence of Atherosclerotic Intracranial Arterial Stenosis With Intracranial Aneurysms), we prospectively included patients undergoing treatment procedures for UIAs from October 2015 to December 2020 at Beijing Tiantan Hospital, China. We used computed tomography angiography or digital subtraction angiography to diagnose ICAS (stenosis≥50%). Multivariable logistic regression and propensity-score matching were performed to evaluate the risk of procedure-related ischemic stroke and unfavorable outcome associated with ICAS. The ICAS score was used to explore the association between different burden of ICAS and procedure-related ischemic risk. RESULTS: Among 3949 patients who underwent endovascular or open surgical procedures for UIAs, 245 (6.2%) had ICAS. After exclusion, 15.7% (32/204) of patients with ICAS experienced procedure-related ischemic stroke compared with 5.0% (141/2825) of patients without ICAS. From the unmatched and matched cohort, ICAS was significantly associated with increased risk of procedure-related ischemic stroke (unmatched: adjusted odds ratio=3.11 [1.89-5.11]; and matched: adjusted odds ratio=2.99 [1.38-6.48]). This association became more evident among patients not receiving antiplatelet therapy (Pinteraction=0.022). For patients undergoing different treatment modalities, similar increased risks were observed (clipping: adjusted odds ratio=3.43 [1.73-6.79]; and coiling: adjusted odds ratio=3.59 [1.94-6.65]). Higher ICAS score was correlated with higher procedural ischemic risk (Ptrend<0.001). CONCLUSIONS: The occurrence of ICAS is not infrequent in patients with UIAs. ICAS confers an ~2-fold increased procedural ischemic risk, irrespective of clipping or coiling. Previous antiplatelet therapy may decrease the risk. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02795078.
Subject(s)
Intracranial Aneurysm , Intracranial Arteriosclerosis , Ischemic Stroke , Humans , Constriction, Pathologic/diagnostic imaging , Constriction, Pathologic/epidemiology , Constriction, Pathologic/complications , Intracranial Aneurysm/diagnostic imaging , Intracranial Aneurysm/epidemiology , Intracranial Aneurysm/surgery , Intracranial Arteriosclerosis/diagnostic imaging , Intracranial Arteriosclerosis/epidemiology , Intracranial Arteriosclerosis/complications , Ischemic Stroke/complications , Platelet Aggregation Inhibitors/therapeutic use , Prevalence , Risk FactorsABSTRACT
Cerebral cavernous malformations (CCMs) refer to a common vascular abnormality that affects up to 0.5% of the population. A somatic gain-of-function mutation in MAP3K3 (p.I441M) was recently reported in sporadic CCMs, frequently accompanied by somatic activating PIK3CA mutations in diseased endothelium. However, the molecular mechanisms of these driver genes remain elusive. In this study, we performed whole-exome sequencing and droplet digital polymerase chain reaction to analyze CCM lesions and the matched blood from sporadic patients. 44 of 94 cases harbored mutations in KRIT1/CCM2 or MAP3K3, of which 75% were accompanied by PIK3CA mutations (P = 0.006). AAV-BR1-mediated brain endothelial-specific MAP3K3I441M overexpression induced CCM-like lesions throughout the brain and spinal cord in adolescent mice. Interestingly, over half of lesions disappeared at adulthood. Single-cell RNA sequencing found significant enrichment of the apoptosis pathway in a subset of brain endothelial cells in MAP3K3I441M mice compared to controls. We then demonstrated that MAP3K3I441M overexpression activated p38 signaling that is associated with the apoptosis of endothelial cells in vitro and in vivo. In contrast, the mice simultaneously overexpressing PIK3CA and MAP3K3 mutations had an increased number of CCM-like lesions and maintained these lesions for a longer time compared to those with only MAP3K3I441M. Further in vitro and in vivo experiments showed that activating PI3K signaling increased proliferation and alleviated apoptosis of endothelial cells. By using AAV-BR1, we found that MAP3K3I441M mutation can provoke CCM-like lesions in mice and the activation of PI3K signaling significantly enhances and maintains these lesions, providing a preclinical model for the further mechanistic and therapeutic study of CCMs.
Subject(s)
Class I Phosphatidylinositol 3-Kinases , Hemangioma, Cavernous, Central Nervous System , MAP Kinase Kinase Kinase 3 , Animals , Mice , Endothelial Cells/metabolism , Endothelium/metabolism , Hemangioma, Cavernous, Central Nervous System/genetics , Hemangioma, Cavernous, Central Nervous System/pathology , Mutation/genetics , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins/genetics , MAP Kinase Kinase Kinase 3/genetics , MAP Kinase Kinase Kinase 3/metabolism , Class I Phosphatidylinositol 3-Kinases/genetics , Class I Phosphatidylinositol 3-Kinases/metabolismABSTRACT
Brain arteriovenous malformations (AVMs) may involve language areas but usually do not lead to aphasia. This study evaluated resting-state functional alterations and investigated the language reorganization mechanism in AVM patients. Thirty-nine patients with AVMs involving language areas and 32 age- and sex-matched healthy controls were prospectively enrolled. The AVM patients were categorized into three subgroups according to lesion location: the frontal (15 patients), temporal (14 patients), and parietal subgroups (10 patients). All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI), and the amplitude of low-frequency fluctuation (ALFF) approach was applied to analyze rs-fMRI data. Language abilities were normal in all participants based on the Western Aphasia Battery. Compared with those of healthy subjects, ALFF values significantly increased (FDR corrected p < .01) in the anterior part of the right putamen in the frontal AVM subgroup, in the posterior part of the right inferior and middle temporal gyrus in the temporal AVM subgroup, and in the inferior lateral part of the left cerebellar hemisphere (lobule VIII) and the right inferior parietal lobule in the parietal AVM subgroup. Functional annotation using Neurosynth indicated that the ALFF t-map was only significantly positively associated with the language-related domain (FDR corrected p < .01). In patients with AVMs involving the language cortex, language network reorganization occurs to maintain normal language abilities. The brain areas recruited into the reorganized language network were located in the right cerebral and left cerebellar hemispheres, both of which are nondominant hemispheres. Differences in lesion location led to distinct reorganization patterns.
Subject(s)
Aphasia , Arteriovenous Malformations , Humans , Brain , Cerebral Cortex , Arteriovenous Malformations/pathology , LanguageABSTRACT
As a prime mover in Alzheimer's disease (AD), microglial activation requires membrane translocation, integration, and activation of the metamorphic protein chloride intracellular channel 1 (CLIC1), which is primarily cytoplasmic under physiological conditions. However, the formation and activation mechanisms of functional CLIC1 are unknown. Here, we found that the human antimicrobial peptide (AMP) LL-37 promoted CLIC1 membrane translocation and integration. It also activates CLIC1 to cause microglial hyperactivation, neuroinflammation, and excitotoxicity. In mouse and monkey models, LL-37 caused significant pathological phenotypes linked to AD, including elevated amyloid-ß, increased neurofibrillary tangles, enhanced neuronal death and brain atrophy, enlargement of lateral ventricles, and impairment of synaptic plasticity and cognition, while Clic1 knockout and blockade of LL-37-CLIC1 interactions inhibited these phenotypes. Given AD's association with infection and that overloading AMP may exacerbate AD, this study suggests that LL-37, which is up-regulated upon infection, may be a driving force behind AD by acting as an endogenous agonist of CLIC1.
Subject(s)
Alzheimer Disease , Cathelicidins , Chloride Channels , Animals , Humans , Mice , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Cathelicidins/metabolism , Cathelicidins/pharmacology , Chloride Channels/metabolism , Microglia/metabolismABSTRACT
[Figure: see text].
Subject(s)
Arteriovenous Malformations/genetics , Epithelial-Mesenchymal Transition , Germ-Line Mutation , Adaptor Proteins, Signal Transducing/genetics , Animals , Arteriovenous Malformations/metabolism , Arteriovenous Malformations/pathology , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Movement , Cells, Cultured , Endoglin/genetics , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Neovascularization, Physiologic , Proto-Oncogene Proteins p21(ras)/genetics , ZebrafishABSTRACT
BACKGROUND AND PURPOSE: The prognostic nutrition index (PNI) has been associated with the prognosis of various medical disorders. This study aimed to explore the correlation between PNI and the long-term outcomes of adult patients afflicted with moyamoya disease (MMD). METHODS: This prospective study initially employed 138 adult patients diagnosed with MMD. After excluding 15 patients who did not meet the criteria, a total of 123 patients were included. Participants were divided into three groups based on the tertile of change in the PNI score. Statistical analysis compared clinical information and lab tests among the groups. The study was conducted between July 1 and December 31, 2019. RESULTS: After adjusting for multiple variables, patients in the upper two tertiles (tertiles 2-3) exhibited a significantly lower risk of adverse long-term outcomes compared to those in the lowest tertile (tertile 1) (OR, 0.089; 95% CI, 0.009-0.895; P = 0.040). Furthermore, adding PNI tertile to traditional risk factors substantially improved predicting adverse long-term outcomes (net reclassification improvement: 98.03%, P = 0.000; integrated discrimination improvement: 4.65%, P = 0.030). However, there was no statistically significant difference between the first PNI tertile (tertile 1) and the upper two tertiles (tertiles 2-3) in the Kaplan-Meier curve of stroke incidence (log-rank test, P = 0.244). CONCLUSIONS: A higher PNI level was significantly associated with a reduced risk of unfavorable long-term outcomes. Nevertheless, the PNI score did not predict stroke recurrence during extended follow-up. This study provides insights into a potential predictor of adverse long-term outcomes after revascularization in MMD patients. REGISTRATION NUMBER: ChiCTR2000031412.
Subject(s)
Moyamoya Disease , Stroke , Adult , Humans , Nutrition Assessment , Prognosis , Moyamoya Disease/surgery , Prospective Studies , Retrospective StudiesABSTRACT
BACKGROUND: Language dysfunction is rarely seen in patients with unruptured brain arteriovenous malformation (AVM) albeit the AVM nidus involving language areas, which provides a unique disease model to study language reorganization. The objective of this study was to investigate the impairment and reorganization patterns and characteristics of language-related white matter in AVMs located at different brain areas. METHODS: Thirty-three patients with AVMs involving language areas were prospectively enrolled. Patients were categorized into 3 groups according to the lesion locations: the frontal (14 patients), temporal (15 patients), and parietal groups (4 patients). Thirty age- and sex-matched healthy controls were enrolled as comparison. All participants underwent diffusion tensor imaging scans, and automated fiber quantification method was applied to quantitatively study the difference of segmented language-related white matter connectivity between 3 AVM groups and control group. RESULTS: Language functions were normal in all subjects according to Western Aphasia Battery test. In the frontal group, fractional anisotropy (FA) value decreased in the left arcuate fascicle and increased in left superior longitudinal fasciculus and uncinate fascicle; in the temporal group, FA values decreased in left inferior fronto-occipital fascicle and inferior longitudinal fascicle and increased in right anterior thalamic radiation and uncinate fascicle; in the parietal group, FA values decreased in left arcuate fascicle and inferior longitudinal fascicle and increased in bilateral anterior thalamic radiations and uncinate fascicles and right inferior fronto-occipital fascicle. In fascicles with decreased FA values, the increase of radial diffusivity was common, and fascicles with increased FA values usually presented along with increased axial diffusivity values. CONCLUSIONS: Remodeling of language-related white matter occurs when traditional language areas are involved by AVM nidus, and its reorganization patterns vary with locations of AVM nidus. Fascicle impairment is mainly caused by the myelin deficits, and its plasticity may be dominated by the axon remodeling procedure.
Subject(s)
Arteriovenous Malformations , White Matter , Arteriovenous Malformations/pathology , Brain/diagnostic imaging , Brain/pathology , Diffusion Tensor Imaging/methods , Humans , Language , White Matter/diagnostic imagingABSTRACT
BACKGROUND: The pathogenic mechanisms of periventricular anastomosis (PA) in moyamoya disease remain unknown. Here, we aimed to describe the angiographic profiles of PA and their relationships with really interesting new gene (RING) finger protein 213 (RNF213) genotypes. METHODS: We conducted a retrospective cohort study of moyamoya disease patients consecutively recruited between June 2019 and January 2021 in Beijing Tiantan Hospital, Capital Medical University, China. C-terminal region of RNF213 was sequenced. Angiographic characteristics of PA vessels (lenticulostriate artery, thalamotuberal artery, thalamoperforating artery, anterior choroidal artery, and posterior choroidal artery) were compared between different groups of RNF213 genotypes. The dilatation and extension of PA vessels were measured by using PA score (positive, score 1-5; negative, score 0). Multivariate regression analysis was conducted to assess variables associated with PA score. In addition, gene expression of RNF213 in human brain regions was evaluated from the Allen Human Brain Atlas. RESULTS: Among 260 patients (484 hemispheres), 71.2% carried no RNF213 rare and novel variants, 20.0% carried p.R4810K heterozygotes, and 8.8% carried other rare and novel variants. PA scores in patients with p.R4810K and other rare and novel variants were significantly higher than in wild-type patients (P<0.001). Age (odds ratio [OR], 0.958 [95% CI, 0.942-0.974]; P<0.001), platelet count (OR, 0.996 [95% CI, 0.992-0.999]; P=0.027), p.R4810K variant (OR, 2.653 [95% CI, 1.514-4.649]; P=0.001), other rare and novel variants (OR, 3.197 [95% CI, 1.012-10.094]; P=0.048), Suzuki stage ≥4 (OR, 1.941 [95% CI, 1.138-3.309]; P=0.015), and posterior cerebral artery involvement (OR, 1.827 [95% CI, 1.020-3.271]; P=0.043) were significantly correlated with PA score. High expression of RNF213 was detected in the periventricular area. CONCLUSIONS: RNF213 variants were confirmed to be associated with PA in moyamoya disease. Individuals with RNF213 p.R4810K heterozygotes and other C-terminal region rare variants exhibited different angiographic phenotypes, compared with wild-type patients.
Subject(s)
Adenosine Triphosphatases/genetics , Moyamoya Disease , Ubiquitin-Protein Ligases/genetics , Anastomosis, Surgical , Genetic Predisposition to Disease , Humans , Moyamoya Disease/diagnostic imaging , Moyamoya Disease/genetics , Moyamoya Disease/surgery , Retrospective Studies , Transcription FactorsABSTRACT
OBJECTIVE: Glioma was the most common type of intracranial malignant tumor. Even after standard treatment, the recurrence and malignant progression of lower-grade gliomas (LGGs) were almost inevitable. The overall survival (OS) of patients with LGG varied widely, making it critical for prognostic prediction. Small G Protein Signaling Modulator 1 (SGSM1) has hardly been studied in gliomas. Therefore, we aimed to investigate the prognostic role of SGSM1 and its relationship with immune infiltration in LGGs. METHODS: We obtained RNA sequencing data from The Cancer Genome Atlas (TCGA) to analyze SGSM1 expression. Functional enrichment analyses, immune infiltration analyses, immune checkpoint analyses, and clinicopathology analyses were performed. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. And nomogram model has been developed. Kaplan-Meier survival analysis and log-rank test were used to estimate the relationship between OS and SGSM1 expression. The survival analyses and Cox regression were validated in datasets from the Chinese Glioma Genome Atlas (CGGA). RESULTS: SGSM1 was significantly down-regulated in LGGs. Functional enrichment analyses revealed SGSM1 was correlated with immune response. Most immune cells and immune checkpoints were negatively correlated with SGSM1 expression. The Kaplan-Meier analyses showed that low SGSM1 expression was associated with a poor outcome in LGG and its subtypes. The Cox regression showed SGSM1 was an independent prognostic factor in patients with LGG (HR = 0.494, 95%CI = 0.311-0.784, P = 0.003). CONCLUSION: SGSM1 was considered to be a new prognostic biomarker for patients with LGG. And our study provided a potential therapeutic target for LGG treatment.
Subject(s)
Brain Neoplasms , Glioma , Biomarkers , Brain Neoplasms/pathology , Glioma/pathology , Humans , Intracellular Signaling Peptides and Proteins , Kaplan-Meier Estimate , PrognosisABSTRACT
Optimal microcatheter shaping is essential for successful endovascular coiling procedures which is sometimes challenging. Our aim was not only to introduce a new shaping method using three-dimensional (3D) printed vessel models but also to prove its feasibility, efficiency and superiority. This was a retrospective cohort study. From September 2019 to March 2021, 32 paraclinoid aneurysms managed with endovascular coiling were retrospectively included and identified. Sixteen aneurysms were coiled using 3D microcatheter shaping method (3D shaping group), and traditional manual shaping method using shaping mandrels was adopted for another 16 patients (control group). The cost and angiographical and clinical outcomes between the two groups were compared, and the feasibility and effectiveness of the new 3D shaping method were evaluated and described in detail. With technical success achieved in 93.75%, most of the 16 shaped microcatheters using new shaping method could be automatically navigated into the target aneurysms without the assistance of microguidewires and could be assessed with favorable accessibility, positioning and stability. Twenty-seven out of 32 aneurysms (84.38%) were completely occluded with the rate of perioperative complications being 12.50%. Although there was no significant difference between the occlusion rates and complication rates of the two groups, the new shaping method could dramatically decrease the number of coils deployed and reduce the overall procedure time. Patient specific shaping of microcatheters using 3D printing may facilitate easier and safer procedures in coil embolization of intracranial aneurysms with shorter surgery time and less coils deployed.
Subject(s)
Embolization, Therapeutic , Endovascular Procedures , Intracranial Aneurysm , Embolization, Therapeutic/methods , Endovascular Procedures/methods , Humans , Intracranial Aneurysm/surgery , Printing, Three-Dimensional , Retrospective Studies , Treatment OutcomeABSTRACT
Brain arteriovenous malformation (AVM), a presumed congenital lesion, may involve traditional language areas but usually does not lead to language dysfunction unless it ruptures. The objective of this research was to study right-hemispheric language reorganization patterns in patients with brain AVMs using functional magnetic resonance imaging (fMRI). We prospectively enrolled 30 AVM patients with lesions involving language areas and 32 age- and sex-matched healthy controls. Each subject underwent fMRI during three language tasks: visual synonym judgment, oral word reading, and auditory sentence comprehension. The activation differences between the AVM and control groups were investigated by voxelwise analysis. Lateralization indices (LIs) for the frontal lobe, temporal lobe, and cerebellum were compared between the two groups, respectively. Results suggested that the language functions of AVM patients and controls were all normal. Voxelwise analysis showed no significantly different activations between the two groups in visual synonym judgment and oral word reading tasks. In auditory sentence comprehension task, AVM patients had significantly more activations in the right precentral gyrus (BA 6) and right cerebellar lobule VI (AAL 9042). According to the LI results, the frontal lobe in oral word reading task and the temporal lobe in auditory sentence comprehension task were significantly more right-lateralized in the AVM group. These findings suggest that for patients with AVMs involving language cortex, different language reorganization patterns may develop for different language functions. The recruitment of brain areas in the right cerebral and cerebellar hemispheres may play a compensatory role in the reorganized language network of AVM patients.
Subject(s)
Brain Mapping , Cerebellum/physiopathology , Cerebral Cortex/physiopathology , Functional Laterality/physiology , Intracranial Arteriovenous Malformations/pathology , Psycholinguistics , Reading , Speech Perception/physiology , Adolescent , Adult , Cerebellum/diagnostic imaging , Cerebral Cortex/diagnostic imaging , Comprehension/physiology , Female , Humans , Intracranial Arteriovenous Malformations/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Ischemic events are the most common postoperative complication in bypass surgery for moyamoya disease (MMD), but the risk factors for pediatric MMD remain unclear. The goal of the study was to investigate the risk factors for postoperative ischemic complications in pediatric MMD patients. METHODS: We retrospectively reviewed a consecutive series of pediatric MMD cases at Beijing Tiantan Hospital, Capital Medical University from June 2010 through June 2019. Preoperative clinical variables and radiographic findings were recorded, and logistic regression analysis was carried out to identify the risk factors for postoperative ischemic events. RESULTS: A total of 533 operations in 336 patients were included in this study. Postoperative complications occurred after 51 operations (9.6%), including 40/447 indirect bypass procedures, 9/70 direct bypass procedures, and 2/16 combined bypass procedures. Postoperative ischemic events were the most common complication and occurred in 30 patients after 31 procedures (8.9% per patient; 5.8% per operation), including 26/447 indirect bypass procedures, 4/70 direct bypass procedures, and 1/16 combined bypass procedures, and the incidence of these events did not differ significantly between indirect and non-indirect bypass (5.8% vs 5.8%; p = 0.999). Multivariate logistic regression analyses revealed that older age at operation (OR 1.129, 95% CI 1.011-1.260, p = 0.032) and posterior cerebral artery involvement (OR 2.587, 95% CI 1.030-6.496, p = 0.043) were significantly associated with postoperative ischemic events. CONCLUSION: We speculate that older age at operation and posterior cerebral artery involvement are risk factors for postoperative ischemic events in pediatric MMD patients.
Subject(s)
Brain Ischemia/etiology , Cerebral Revascularization/adverse effects , Moyamoya Disease/surgery , Adolescent , Age Factors , Brain Ischemia/diagnosis , Brain Ischemia/epidemiology , Child , Child, Preschool , Female , Humans , Incidence , Logistic Models , Magnetic Resonance Angiography , Male , Posterior Cerebral Artery/surgery , Postoperative Complications , Retrospective Studies , Risk FactorsABSTRACT
To investigate the m6a-related long non-coding RNAs (lncRNAs) that may be exploited as potential biomarkers in primary glioblastoma (pGBM), a cohort of 268 glioma samples from GSE16011 dataset was included for discovery. The Chinese Glioma Genome Atlas (CGGA) microarray and RNA sequencing databases were used for validation. Bioinformatic analyses were performed using the R software. The m6a-lncRNA co-expression networks were constructed, and four m6a-related lncRNAs (MIR9-3HG, LINC00900, MIR155HG, and LINC00515) were identified in pGBM patients on the univariate Cox regression analysis. Patients in the low-risk group had longer overall survival (OS) and progression-free survival (PFS) than those in the high-risk group (P = 0.0025, P = 0.0070). Moreover, the high-risk group displayed older age, isocitrate dehydrogenase (IDH) wild-type, classical and mesenchymal TCGA subtype, and G3 CGGA subtype. Distinct m6a status was identified according to histologic grade and two groups (low-risk and high-risk). Functional annotation showed that differentially expressed genes between the two groups were enriched in immune response, apoptosis, cell adhesion, negative regulation of transcription, negative regulation of RNA metabolic process, and regulation of RNA metabolic process. We profiled the m6a status in glioma and identified four m6a-related prognostic lncRNAs for pGBMs.
Subject(s)
Adenosine/analogs & derivatives , Brain Neoplasms/genetics , Glioblastoma/genetics , RNA, Long Noncoding/genetics , Adenosine/genetics , China , Cohort Studies , Computational Biology , Databases, Genetic , Gene Expression Regulation, Neoplastic/genetics , Humans , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , Microarray Analysis , Prognosis , Progression-Free Survival , Survival AnalysisABSTRACT
Comparison in pediatric hemorrhagic arteriovenous malformations (AVMs) to clarify the long-term neurological outcomes and prognostic predictors after surgical intervention was relatively rare, especially in the selection of surgical timing. The objective of this study was to elucidate these points. The authors retrospectively reviewed the pediatric hemorrhagic AVMs resected in their neurosurgical department between March 2010 and June 2017. The natural history was represented by rupture risk. Neurological outcome was assessed with the modified Rankin Scale (mRS) for children. Multivariate logistic regression analyses were used to assess the risk factors for disability (mRS > 2). The hemorrhagic early phase was defined as less than 30 days after bleeding. The corresponding prognosis of different surgical timing (early intervention or delayed intervention) was compared after propensity-score matching (PSM). A total of 111 pediatric hemorrhagic AVM patients were evaluated. The average patient age was 11.1 ± 4.0 years, with a mean follow-up of 4.3 ± 2.1 years. The annualized rupture risk was 9.3% for the pediatric hemorrhagic AVMs, and the annualized re-rupture risk was 9.8%. 7.2% of the patients had disabilities (mRS > 2) and 82.0% achieved neurological deficit-free (mRS < 2) at the last follow-up. Pre-treatment mRS (P = 0.042) and flow-related aneurysms (P = 0.039) were independent factors for long-term disability. In terms of short-term outcomes, early intervention was better than delayed intervention (P = 0.033), but the long-term outcomes were similar between the two groups (P = 0.367). Surgical intervention for pediatric hemorrhagic AVMs is recommended, most of the patients can achieve good neurological outcomes. Moreover, early surgical intervention is preferred after the initial hemorrhage.
Subject(s)
Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/surgery , Intracranial Arteriovenous Malformations/diagnosis , Intracranial Arteriovenous Malformations/surgery , Microsurgery/trends , Adolescent , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Infant , Male , Microsurgery/methods , Prognosis , Retrospective Studies , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
We aimed to study the clinical and radiological characteristics of intracranial tumors and explore the possible predictive value of these characteristics in relation to perioperative outcomes in elderly patients. We retrospectively identified 1535 elderly patients (aged 65 years and older) with intracranial tumors who underwent surgical resection between 2014 and 2018 in Beijing Tiantan Hospital. Factors associated with an increased risk of unfavorable perioperative performance and complications were investigated. Meningiomas were the most common tumors in the cohort (43.26%). The overall risk of perioperative death was 0.59%, and 42.80% of patients were discharged with unfavorable performance (Karnofsky Performance Scale [KPS] score ≤ 70). Of all patients, 39.22% had one or more complications after surgical resection. Aggressive surgery significantly lowered the rate of unfavorable perioperative outcomes (P = 0.000) with no increase in postoperative complications (P = 0.153), but it failed to be an independent predictor for perioperative outcomes in the multivariate analysis. Low performance status at admission (KPS ≤ 70) was independently associated with both unfavorable perioperative performance (P = 0.000) and complications (P = 0.000). In addition to the histopathological patterns of tumors, low performance status at admission is an independent predictor for both unfavorable perioperative performance and the occurrence of complications in elderly patients with intracranial tumors who have undergone surgical resections. However, age is not associated with perioperative outcomes in elderly patients.
Subject(s)
Brain Neoplasms/surgery , Neurosurgical Procedures/methods , Aged , Aged, 80 and over , Beijing/epidemiology , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cohort Studies , Female , Humans , Intraoperative Complications/epidemiology , Intraoperative Complications/mortality , Karnofsky Performance Status , Magnetic Resonance Imaging , Male , Meningioma/epidemiology , Meningioma/surgery , Middle Aged , Neurosurgical Procedures/adverse effects , Neurosurgical Procedures/mortality , Postoperative Complications/epidemiology , Predictive Value of Tests , Risk Factors , Sex Factors , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Growing evidence has suggested that hyperhomocysteinemia (HHcy) is a risk factor for cerebral infarction. However, the effect of HHcy on postoperative cerebral ischemia is still unclear. We aim to investigate the relationship between HHcy and postoperative ischemia of adult patients with moyamoya disease (MMD). A total of 138 adult patients with MMD were prospectively recruited from July 1 to December 31, 2019. After excluding 14 patients accepting conservative therapy, all 124 patients who underwent surgical treatment were enrolled. Patients were grouped according to postoperative ischemia and HHcy presentation, respectively. Clinical data and laboratory examinations were compared by statistical analyses. Potential risk factors were evaluated by univariate and multivariate logistic regression analysis. Comparing to the normal, patients with postoperative ischemia were higher in serum homocysteine (Hcy) level (P = 0.039) and HHcy ratio (P = 0.035). Furthermore, HHcy was more common in males (P = 0.007) than females. Logistic analysis results showed that HHcy (OR 5.234, 95% CI 1.127-24.315; P = 0.035) was an independent risk factor. HHcy was significantly associated with postoperative ischemia in MMD patients. Our study found that HHcy was correlated to the risk of postoperative ischemia. HHcy can be used as an indicator and a potential therapeutic target for postoperative ischemia in adult patients with MMD. URL: http://www.chictr.org . Unique identifier: ChiCTR2000031412.
Subject(s)
Brain Ischemia , Hyperhomocysteinemia , Moyamoya Disease , Adult , Brain Ischemia/epidemiology , Brain Ischemia/etiology , Cerebral Infarction , Female , Humans , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/epidemiology , Male , Moyamoya Disease/complications , Moyamoya Disease/epidemiology , Moyamoya Disease/surgery , Risk FactorsABSTRACT
Facing considerable challenges associated with aging and dementia, China urgently needs an evidence-based health-care system for prevention and management of dementia. The Beijing Aging Brain Rejuvenation Initiative (BABRI) is a community-based cohort study initiated in 2008 that focuses on asymptomatic stages of dementia, aims to develop community-based prevention strategies for cognitive impairment, and provides a platform for scientific research and clinical trials. Thus far, BABRI has recruited 10,255 participants (aged 50 and over, 60.3% female), 2021 of whom have been followed up at least once at a 2- or 3-year interval. This article presents aims and study design of BABRI; summarizes preliminary behavioral and neuroimaging findings on mild cognitive impairment (MCI) and results of clinical trials on MCI; and discusses issues concerning early prevention in community, MCI diagnosis methods, and applications of database of aging and dementia. BABRI is proposed to build a systematic framework on brain health in old age.