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Glioblastoma is the most common malignant primary brain tumor with poor overall survival. Magnetic resonance imaging (MRI) is the main imaging modality for glioblastoma but has inherent shortcomings. The molecular and cellular basis of MR signals is incompletely understood. We established a ground truth-based image analysis platform to coregister MRI and light sheet microscopy (LSM) data to each other and to an anatomic reference atlas for quantification of 20 predefined anatomic subregions. Our pipeline also includes a segmentation and quantification approach for single myeloid cells in entire LSM datasets. This method was applied to three preclinical glioma models in male and female mice (GL261, U87MG, and S24), which exhibit different key features of the human glioma. Multiparametric MR data including T2-weighted sequences, diffusion tensor imaging, T2 and T2* relaxometry were acquired. Following tissue clearing, LSM focused on the analysis of tumor cell density, microvasculature, and innate immune cell infiltration. Correlated analysis revealed differences in quantitative MRI metrics between the tumor-bearing and the contralateral hemisphere. LSM identified tumor subregions that differed in their MRI characteristics, indicating tumor heterogeneity. Interestingly, MRI signatures, defined as unique combinations of different MRI parameters, differed greatly between the models. The direct correlation of MRI and LSM allows an in-depth characterization of preclinical glioma and can be used to decipher the structural, cellular, and, likely, molecular basis of tumoral MRI biomarkers. Our approach may be applied in other preclinical brain tumor or neurologic disease models, and the derived MRI signatures could ultimately inform image interpretation in a clinical setting.SIGNIFICANCE STATEMENT We established a histologic ground truth-based approach for MR image analyses and tested this method in three preclinical glioma models exhibiting different features of glioblastoma. Coregistration of light sheet microscopy to MRI allowed for an evaluation of quantitative MRI data in histologically distinct tumor subregions. Coregistration to a mouse brain atlas enabled a regional comparison of MRI parameters with a histologically informed interpretation of the results. Our approach is transferable to other preclinical models of brain tumors and further neurologic disorders. The method can be used to decipher the structural, cellular, and molecular basis of MRI signal characteristics. Ultimately, information derived from such analyses could strengthen the neuroradiological evaluation of glioblastoma as they enhance the interpretation of MRI data.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Masculino , Feminino , Humanos , Animais , Camundongos , Glioblastoma/diagnóstico por imagem , Imagem de Tensor de Difusão , Microscopia , Glioma/diagnóstico por imagem , Glioma/patologia , Imageamento por Ressonância Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologiaRESUMO
OBJECTIVE: Several studies have proven the benefits of a wide extent of resection (EOR) of contrast-enhancing tumor in terms of progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma (GBM). Thus, gross-total resection (GTR) is the main surgical goal in noneloquently located GBMs. Complete tumor removal can be almost doubled by microscopic fluorescence guidance. Recently, a study has shown that an endoscope with a light source capable of inducing fluorescence allows visualization of remnant fluorescent tumor tissue even after complete microscopic fluorescence-guided (FG) resection, thereby increasing the rate of GTR. Since tumor infiltration spreads beyond the borders of contrast enhancement on MRI, the aim of this study was to determine via volumetric analyses of the EOR whether endoscope-assisted FG resection enables supratotal resection beyond the borders of contrast enhancement. METHODS: The authors conducted a retrospective single-center analysis of a consecutive series of patients with primary GBM presumed to be noneloquently located and routinely operated on at their institution between January 2015 and February 2018 using a combined microscopic and endoscopic FG resection. A 20-mg/kg dose of 5-aminolevulinic acid (5-ALA) was administered 4 hours before surgery. After complete microscopic FG resection, the resection cavity was scanned using the endoscope. Detected residual fluorescent tissue was resected and embedded separately for histopathological examination. Nonenhanced and contrast-enhanced 3D T1-weighted MR images acquired before and within 48 hours after tumor resection were analyzed using 3D Slicer. Bias field-corrected data were used to segment brain parenchyma, contrast-enhancing tumor, and the resection cavity for volume definition. The difference between the pre- and postoperative brain parenchyma volume was considered to be equivalent to the resected nonenhancing but fluorescent tumor tissue. The volume of resected tumor tissue was calculated from the sum of resected contrast-enhancing tumor tissue and resected nonenhancing tumor tissue. RESULTS: Twelve patients with GBM were operated on using endoscopic after complete microscopic FG resection. In all cases, residual fluorescent tissue not visualized with the microscope was detected. Histopathological examination confirmed residual tumor tissue in all specimens. The mean preoperative volume of brain parenchyma without contrast-enhancing tumor was 1213.2 cm3. The mean postoperative volume of brain parenchyma without the resection cavity was 1151.2 cm3, accounting for a mean volume of nonenhancing but fluorescent tumor tissue of 62.0 cm3. The mean relative rate of the overall resected volume compared to the contrast-enhancing tumor volume was 244.7% (p < 0.001). CONCLUSIONS: Combined microscopic and endoscopic FG resection of GBM significantly increases the EOR and allows the surgeon to achieve a supratotal resection beyond the borders of contrast enhancement in noneloquently located GBM.
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Neoplasias Encefálicas , Glioblastoma , Ácido Aminolevulínico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Glioblastoma/diagnóstico por imagem , Glioblastoma/cirurgia , Humanos , Imageamento por Ressonância Magnética , Estudos RetrospectivosRESUMO
BACKGROUND: Delayed cerebral ischemia is one of the leading causes of death and disability in patients with subarachnoid hemorrhage (SAH). Transluminal balloon angioplasty (TBA) is a therapeutic option for vasospasms affecting proximal intracranial arteries. METHODS: Aim of this study was to report our experience using the Scepter C balloon catheter in the treatment of cerebral vasospasms due to SAH and evaluate the postprocedural result with the iFlow tool. We reviewed cases of patients treated at our hospital from 2014 to 2018. Patients were screened with transcranial doppler sonography (TCD) and multimodal computed tomography. In case of significant vasospasms, patients were transferred to the angiography suite and treated. We used the iFlow tool to quantify and evaluate the angiographic results by measuring and comparing peak density values on angiograms before and after the mechanical dilation. RESULTS: The use of the Scepter C balloon catheter was feasible in all cases. Vasospasms of the anterior cerebral artery were treated in ten cases. We didn't observe complications or vasospasm recurrences of the treated arteries. The temporal difference between distal vessels and the proximal reference vessel was significantly reduced from a mean of 53%, prior to dilatation, to 26% after the treatment. The difference between pre-dilatation and post-dilatation values was statistically significant for the anterior circulation at the proximal as well as at the distal vessels. CONCLUSIONS: We successfully treated endovascularly patients suffering from cerebral vasospasms refractory to medical treatment using the Scepter C balloon catheter. We didn't observe any complications. The therapeutic effect could be easily and reliably assessed with the iFlow tool.
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Angioplastia com Balão/instrumentação , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/cirurgia , Adulto , Catéteres , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Glioblastoma (GBM) is the most common primary brain tumor. It is highly malignant and has a correspondingly poor prognosis. Diagnosis and monitoring are mainly accomplished with MRI, but remain challenging in some cases. Therefore, complementary methods for tumor detection and characterization would be beneficial. Using magnetic resonance elastography (MRE), we performed a longitudinal study of the biomechanical properties of intracranially implanted GBM in mice and compared the results to histopathology. The biomechanical parameters of viscoelastic modulus, shear wave speed and phase angle were significantly lower in tumors compared with healthy brain tissue and decreased over time with tumor progression. Moreover, some MRE parameters revealed sub-regions at later tumor stages, which were not easily detectable on anatomical MRI images. Comparison with histopathology showed that softer tumor regions contained necrosis and patches of viable tumor cells. In contrast, areas of densely packed tumor cells and blood vessels identified with histology coincided with higher values of viscoelastic modulus and shear wave speed. Interestingly, the phase angle was independent from these anatomical variations. In summary, MRE depicted longitudinal and morphological changes in GBM and may prove valuable for tumor characterization in patients.
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Neoplasias Encefálicas/diagnóstico por imagem , Técnicas de Imagem por Elasticidade , Glioblastoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Elasticidade , Glioblastoma/patologia , Camundongos Nus , Bainha de Mielina/metabolismo , Imagens de Fantasmas , Fatores de Tempo , ViscosidadeRESUMO
BACKGROUND: Reports on the relationships between white matter lesion load (WMLL) and fatigue and anxiety in multiple sclerosis (MS) are inconsistent. OBJECTIVE: To investigate the association of total and tract-specific WMLL with fatigue and anxiety. METHODS: Total and regional T2 WMLL was assessed for 19 tracts in 48 MS patients (30 females). ICBM-DTI-81 Atlas-based parcellation was combined with WMLL segmentation of T2-weighted magnetic resonance imaging (MRI). Fatigue, anxiety, and depression were assessed using Fatigue Impact Scale, State Trait Anxiety Inventory, and Beck Depression Inventory, respectively. RESULTS: Fatigue, anxiety, and depression showed significant inter-correlation. We found no association between fatigue and total or regional WMLLs, whereas anxiety was associated with total and regional WMLLs in nine tracts. After adjusting for total WMLL, age, and depression, only the column and body of the fornix (CBF) remained significantly associated with anxiety. Post hoc analyses showed no CBF lesions on T1-weighted MRI and suggested, but could not confirm, that the septum pellucidum might play a role in the pathogenesis of anxiety. CONCLUSION: Our results suggest that anxiety in MS patients may have a neuropathological substrate in the septo-fornical area, which requires further validation using larger sample size and ultra-high-field MRI in targeted prospective studies.
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Ansiedade/etiologia , Encéfalo/patologia , Esclerose Múltipla/patologia , Esclerose Múltipla/psicologia , Adulto , Ansiedade/patologia , Fadiga/etiologia , Fadiga/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Branca/patologiaRESUMO
BACKGROUND AND PURPOSE: Intrahospital time delays significantly affect the neurological outcome of stroke patients with large-vessel occlusion. This study was conducted to determine whether a one-stop management can reduce intrahospital times of patients with acute large-vessel occlusion. METHODS: In this observational study, we report the first 30 consecutive stroke patients imaged and treated in the same room. As part of our protocol, we transported patients with a National Institutes of Health Stroke Scale score of ≥10 directly to the angio suite, bypassing multidetector computed tomography (CT). Preinterventional imaging consisted of noncontrast flat detector CT and flat detector CT angiography, acquired with an angiography system. Patients with large-vessel occlusions remained on the angio table and were treated with mechanical thrombectomy; patients with small artery occlusions were treated with intravenous thrombolysis, whereas patients with an intracranial hemorrhage and stroke mimics were treated as per guidelines. Door-to-groin puncture times were recorded and compared with our past results. RESULTS: Thirty patients were transferred directly to our angio suite from June to December 2016. The time from symptom onset to admission was 105 minutes. Ischemic stroke was diagnosed in 22 of 30 (73%) patients, 4 of 30 (13.5%) had an intracranial hemorrhage, and 4 of 30 (13.5) were diagnosed with a Todd's paresis. Time from admission to groin puncture was 20.5 minutes. Compared with 44 patients imaged with multidetector CT in the first 6 months of 2016, door-to-groin times were significantly reduced (54.5 minutes [95% confidence interval, 47-61] versus 20.5 minutes [95% confidence interval, 17-26]). CONCLUSIONS: In this small series, a one-stop management protocol of selected stroke patients using latest generation flat detector CT led to a significant reduction of intrahospital times.
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Angiografia Cerebral , Hemorragias Intracranianas , Admissão do Paciente , Acidente Vascular Cerebral , Tomografia Computadorizada por Raios X , Doença Aguda , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/terapia , Masculino , Estudos Prospectivos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Fatores de TempoRESUMO
OBJECTIVES: CTP images analyzed with the Alberta stroke program early CT scale (ASPECTS) have been shown to be optimal predictors of clinical outcome. In this study we compared two biomarkers, the cerebral blood volume (CBV)-ASPECTS and the CTA-ASPECTS as predictors of clinical outcome after thrombectomy. METHODS: Stroke patients with thrombosis of the M1 segment of the middle cerebral artery were included in our study. All patients underwent initial multimodal CT with CTP and CTA on a modern CT scanner. Treatment consisted of full dose intravenous tissue plasminogen activator, when applicable, and mechanical thrombectomy. Three neuroradiologists separately scored CTP and CTA images with the ASPECTS score. RESULTS: Sixty-five patients were included. Median baseline CBV-ASPECTS and CTA-ASPECTS for patients with favourable clinical outcome at follow-up were 8 [interquartile range (IQR) 8-9 and 7-9 respectively]. Patients with poor clinical outcome showed a median baseline CBV-ASPECTS of 6 (IQR 5-8, P < 0.0001) and a median baseline CTA-ASPECTS of 7 (IQR 7-8, P = 0.18). Using CBV-ASPECTS and CTA-ASPECTS raters predicted futile reperfusions in 96 % and 56 % of the cases, respectively. CONCLUSIONS: CBV-ASPECTS is a significant predictor of clinical outcome in patients with acute ischemic stroke treated with mechanical thrombectomy. KEY POINTS: ⢠CBV-ASPECTS is a significant predictor of clinical outcome. ⢠Single phase CTA-ASPECTS has low predictive value. ⢠Using CBV-ASPECTS, raters identified futile reperfusions in 96 % of the cases.
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Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Idoso , Biomarcadores/metabolismo , Volume Sanguíneo/fisiologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/cirurgia , Angiografia Cerebral/métodos , Circulação Cerebrovascular/fisiologia , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/cirurgia , Masculino , Imagem Multimodal/métodos , Variações Dependentes do Observador , Prognóstico , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Ativador de Plasminogênio Tecidual/metabolismo , Resultado do TratamentoRESUMO
The detection of pathological tissue alterations by manual palpation is a simple but essential diagnostic tool, which has been applied by physicians since the beginnings of medicine. Recently, the virtual "palpation" of the brain has become feasible using magnetic resonance elastography, which quantifies biomechanical properties of the brain parenchyma by analyzing the propagation of externally elicited shear waves. However, the precise molecular and cellular patterns underlying changes of viscoelasticity measured by magnetic resonance elastography have not been investigated up to date. We assessed changes of viscoelasticity in a murine model of multiple sclerosis, inducing reversible demyelination by feeding the copper chelator cuprizone, and correlated our results with detailed histological analyses, comprising myelination, extracellular matrix alterations, immune cell infiltration and axonal damage. We show firstly that the magnitude of the complex shear modulus decreases with progressive demyelination and global extracellular matrix degradation, secondly that the loss modulus decreases faster than the dynamic modulus during the destruction of the corpus callosum, and finally that those processes are reversible after remyelination.
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Encéfalo/patologia , Doenças Desmielinizantes/patologia , Técnicas de Imagem por Elasticidade/métodos , Animais , Axônios , Quelantes/administração & dosagem , Quelantes/química , Cobre/química , Cuprizona/administração & dosagem , Cuprizona/química , Feminino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Background: Endovascular thrombectomy (EVT) reduces disability in patients with acute ischemic stroke (AIS); however, its efficacy in patients aged >80 years remains unclear. Objectives: This study aimed to assess the impact of premorbid modified Rankin Scale (pmRS) scores and age on patients with AIS undergoing EVT and the effect of EVT on functional outcome and mortality. Methods: We conducted a retrospective cohort study and screened the Heidelberg Recanalization Registry (HeiReKa) database for patients with AIS between 1999 and 2021. Outcomes were stratified by age (<80, 80-89, and ≥90 years) and pmRS score (0-2 vs. 3-5). Adjusted odds ratios for outcomes and mortality at 3 months after treatment were examined. Results: Finally, 2,591 patients were included [including those aged ≥90 years (n = 158)]. Poor functional outcomes were associated with advanced age, vascular risk factors, stroke severity, and vessel status. Conversely, lower prestroke disability and younger age were associated with better outcomes and reduced mortality. A pmRS of 3-5 was associated with an increased risk of mortality and worse functional outcomes regardless of age. Notably, patients aged ≥90 years with a pmRS of 0-2 had significantly better outcomes than those aged <80 years with a pmRS of 3-5. Conclusion: Both age and pmRS are important in assessing the benefits of EVT. However, prestroke functional status might be more crucial than biological age in determining outcomes following EVT.
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The physics of shear waves traveling through matter carries fundamental insights into its structure, for instance, quantifying stiffness for disease characterization. However, the origin of shear wave attenuation in tissue is currently not properly understood. Attenuation is caused by two phenomena: absorption due to energy dissipation and scattering on structures such as vessels fundamentally tied to the material's microstructure. Here, we present a scattering theory in conjunction with magnetic resonance imaging, which enables the unraveling of a material's innate constitutive and scattering characteristics. By overcoming a three-order-of-magnitude scale difference between wavelength and average intervessel distance, we provide noninvasively a macroscopic measure of vascular architecture. The validity of the theory is demonstrated through simulations, phantoms, in vivo mice, and human experiments and compared against histology as gold standard. Our approach expands the field of imaging by using the dispersion properties of shear waves as macroscopic observable proxies for deciphering the underlying ultrastructures.
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Imageamento por Ressonância Magnética , Animais , Camundongos , Humanos , Imageamento por Ressonância Magnética/métodos , Imagens de Fantasmas , Espalhamento de RadiaçãoRESUMO
Glioblastoma is the most common and aggressive primary malignant brain tumor with poor prognosis. Novel immunotherapeutic approaches are currently under investigation. Even though magnetic resonance imaging (MRI) is the most important imaging tool for treatment monitoring, response assessment is often hampered by therapy-related tissue changes. As tumor and therapy-associated tissue reactions differ structurally, we hypothesize that biomechanics could be a pertinent imaging proxy for differentiation. Longitudinal MRI and magnetic resonance elastography (MRE) were performed to monitor response to immunotherapy with a toll-like receptor 7/8 agonist in orthotopic syngeneic experimental glioma. Imaging results were correlated to histology and light sheet microscopy data. Here, we identify MRE as a promising non-invasive imaging method for immunotherapy-monitoring by quantifying changes in response-related tumor mechanics. Specifically, we show that a relative softening of treated compared to untreated tumors is linked to the inflammatory processes following therapy-induced re-education of tumor-associated myeloid cells. Mechanistically, combined effects of myeloid influx and inflammation including extracellular matrix degradation following immunotherapy form the basis of treated tumors being softer than untreated glioma. This is a very early indicator of therapy response outperforming established imaging metrics such as tumor volume. The overall anti-tumor inflammatory processes likely have similar effects on human brain tissue biomechanics, making MRE a promising tool for gauging response to immunotherapy in glioma patients early, thereby strongly impacting patient pathway.
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Neoplasias Encefálicas , Modelos Animais de Doenças , Glioma , Imunoterapia , Imageamento por Ressonância Magnética , Animais , Camundongos , Glioma/diagnóstico por imagem , Glioma/terapia , Glioma/imunologia , Glioma/patologia , Imunoterapia/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética/métodos , Técnicas de Imagem por Elasticidade/métodos , Linhagem Celular Tumoral , Fenômenos Biomecânicos , Humanos , Camundongos Endogâmicos C57BL , Biomarcadores Tumorais/metabolismoRESUMO
Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) including chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cell therapy targeting glioma-associated antigens are an emerging field in glioma immunotherapy. However, imaging techniques for non-invasive monitoring of adoptively transferred T cells homing to the glioma microenvironment are currently lacking. Methods: Ultrasmall iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Here, we develop a protocol for efficient ex vivo labeling of murine and human TCR-transgenic and CAR T cells with iron oxide NPs. We assess labeling efficiency and T cell functionality by flow cytometry and transmission electron microscopy (TEM). NP labeled T cells are visualized by MRI at 9.4 T in vivo after adoptive T cell transfer and correlated with 3D models of cleared brains obtained by light sheet microscopy (LSM). Results: NP are incorporated into T cells in subcellular cytoplasmic vesicles with high labeling efficiency without interfering with T cell viability, proliferation and effector function as assessed by cytokine secretion and antigen-specific killing assays in vitro. We further demonstrate that adoptively transferred T cells can be longitudinally monitored intratumorally by high field MRI at 9.4 Tesla in a murine glioma model with high sensitivity. We find that T cell influx and homogenous spatial distribution of T cells within the TME as assessed by T2* imaging predicts tumor response to ACT whereas incomplete T cell coverage results in treatment resistance. Conclusion: This study showcases a rational for monitoring adoptive T cell therapies non-invasively by iron oxide NP in gliomas to track intratumoral T cell influx and ultimately predict treatment outcome.
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Glioma , Linfócitos T , Humanos , Animais , Camundongos , Glioma/diagnóstico por imagem , Glioma/terapia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Terapia Baseada em Transplante de Células e Tecidos , Microambiente TumoralRESUMO
Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a ß-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
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Glioma , Nanopartículas , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Humanos , Adjuvantes Imunológicos , Glioma/tratamento farmacológico , Macrófagos , Linfócitos T , Receptor 7 Toll-Like/agonistas , Microambiente Tumoral , Receptor 8 Toll-Like/agonistasRESUMO
BACKGROUND: Mechanical thrombectomy (MT) is the standard of care for patients with a stroke and large vessel occlusion. Clot composition is not routinely assessed in clinical practice as no specific diagnostic value is attributed to it, and MT is performed in a standardized 'non-personalized' approach. Whether different clot compositions are associated with intrinsic likelihoods of recanalization success or treatment outcome is unknown. METHODS: We performed a prospective, non-randomized, single-center study and analyzed the clot composition in 60 consecutive patients with ischemic stroke undergoing MT. Clots were assessed by ex vivo multiparametric MRI at 9.4 T (MR microscopy), cone beam CT, and histopathology. Clot imaging was correlated with preinterventional CT and clinical data. RESULTS: MR microscopy showed red blood cell (RBC)-rich (21.7%), platelet-rich (white,38.3%) or mixed clots (40.0%) as distinct morphological entities, and MR microscopy had high accuracy of 95.4% to differentiate clots. Clot composition could be further stratified on preinterventional non-contrast head CT by quantification of the hyperdense artery sign. During MT, white clots required more passes to achieve final recanalization and were not amenable to contact aspiration compared with mixed and RBC-rich clots (maneuvers: 4.7 vs 3.1 and 1.2 passes, P<0.05 and P<0.001, respectively), whereas RBC-rich clots showed higher probability of first pass recanalization (76.9%) compared with white clots (17.4%). White clots were associated with poorer clinical outcome at discharge and 90 days after MT. CONCLUSION: Our study introduces MR microscopy to show that the hyperdense artery sign or MR relaxometry could guide interventional strategy. This could enable a personalized treatment approach to improve outcome of patients undergoing MT.
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BACKGROUND AND PURPOSE: Biomechanical changes in the brain have not been fully elucidated in Alzheimer's disease (AD). We aimed to investigate the effect of ß-amyloid accumulation on mouse brain viscoelasticity. METHODS: Magnetic resonance elastography was used to calculate magnitude of the viscoelastic modulus (|G*|), elasticity (Gd ), and viscosity (Gl ) in the whole brain parenchyma (WB) and bilateral hippocampi of 9 transgenic J20 (AD) mice (5 males/4 females) and 10 wild-type (WT) C57BL/6 mice (5 males/5 females) at 11 and 14 months of age. RESULTS: Cross-sectional analyses showed no significant difference between AD and WT mice at either timepoints. No sex-specific differences were observed at 11 months of age, but AD females showed significantly higher hippocampal |G*| and Gl and WB |G*|, Gd , and Gl compared to both AD and WT males at 14 months of age. Similar trending differences were found between female AD and female WT animals but did not reach significance. Longitudinal analyses showed significant increases in hippocampal |G*|, Gd , and Gl , and significant decreases in WB |G*|, Gd , and Gl between 11 and 14 months in both AD and WT mice. Each subgroup showed significant increases in all hippocampal and significant decreases in all WB measures, with the exception of AD females, which showed no significant changes in WB |G*|, Gd , or Gl . CONCLUSION: Aging had region-specific effects on cerebral viscoelasticity, namely, WB softening and hippocampal stiffening. Amyloid plaque deposition may have sex-specific effects, which require further scrutiny.
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Doença de Alzheimer , Técnicas de Imagem por Elasticidade , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Animais , Estudos Transversais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/patologiaRESUMO
CAN-2409 is a replication-deficient adenovirus encoding herpes simplex virus (HSV) thymidine kinase (tk) currently in clinical trials for treatment of glioblastoma. The expression of tk in transduced cancer cells results in conversion of the pro-drug ganciclovir into a toxic metabolite causing DNA damage, inducing immunogenic cell death and immune activation. We hypothesize that CAN-2409 combined with DNA-damage-response inhibitors could amplify tumor cell death, resulting in an improved response. We investigated the effects of ATR inhibitor AZD6738 in combination with CAN-2409 in vitro using cytotoxicity, cytokine, and fluorescence-activated cell sorting (FACS) assays in glioma cell lines and in vivo with an orthotopic syngeneic murine glioma model. Tumor immune infiltrates were analyzed by cytometry by time of flight (CyTOF). In vitro, we observed a significant increase in the DNA-damage marker γH2AX and decreased expression of PD-L1, pro-tumorigenic cytokines (interleukin-1ß [IL-1ß], IL-4), and ligand NKG2D after combination treatment compared with monotherapy or control. In vivo, long-term survival was increased after combination treatment (66.7%) compared with CAN-2409 (50%) and control. In a tumor re-challenge, long-term immunity after combination treatment was not improved. Our results suggest that ATR inhibition could amplify CAN-2409's efficacy in glioblastoma through increased DNA damage while having complex immunological ramifications, warranting further studies to determine the ideal conditions for maximized therapeutic benefit.
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In order to reduce intrahospital times for stroke patients, we have implemented various strategies throughout the last 4 years. Swift restoration of cerebral perfusion is essential for the outcomes of patients with acute ischemic stroke. Endovascular treatment (EVT) has become the standard of care to accomplish this in patients with acute stroke due to large vessel occlusion (LVO). To achieve reperfusion of ischemic brain regions as fast as possible, all in-hospital time delays have to be avoided. Therefore management of patients with acute ischemic stroke was optimized with an interdisciplinary standard operating procedure (SOP). Stroke neurologists, diagnostic as well as interventional neuroradiologists, and anesthesiologists streamlined all necessary processes from patient admission and diagnosis to EVT of eligible patients. In a second step we established a one-stop management of stroke patients, meaning that imaging was acquired with the same angiography suite use for treatment of patients with LVO. In the last section of this chapter we discuss the latest trials on stroke therapy and their implications for our current triage systems and imaging patterns.
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Isquemia Encefálica , Procedimentos Endovasculares , Acidente Vascular Cerebral , Encéfalo , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/terapia , Alemanha/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/terapiaRESUMO
Background: Magnetic resonance imaging is essential for monitoring people with multiple sclerosis, but the diagnostic value of gadolinium contrast administration in spine magnetic resonance imaging is unclear. Objective: To assess the diagnostic value of gadolinium contrast administration in spine magnetic resonance imaging follow-up examinations and identify imaging markers correlating with lesion enhancement. Methods: A total of 65 multiple sclerosis patients with at least 2 spinal magnetic resonance imaging follow-up examinations were included. Spine magnetic resonance imaging was performed at 3 Tesla with a standardized protocol (sagittal and axial T2-weighted turbo spin echo and T1-weighted post-contrast sequences). T2 lesion load and enhancing lesions were assessed by two independent neuroradiologists for lesion size, localization, and T2 signal ratio (T2 signallesion/T2 signalnormal appearing spinal cord). Results: A total of 68 new spinal T2 lesions and 20 new contrast-enhancing lesions developed during follow-up. All enhancing lesions had a discernable correlate as a new T2 lesion. Lesion enhancement correlated with a higher T2 signal ratio compared to non-enhancing lesions (T2 signal ratio: 2.0 ± 0.4 vs. 1.4 ± 0.2, ****p < 0.001). Receiver operating characteristics analysis showed an optimal cutoff value of signal ratio 1.78 to predict lesion enhancement (82% sensitivity and 97% specificity). Conclusion: Gadolinium contrast administration is dispensable in follow-up spine magnetic resonance imaging if no new T2 lesions are present. Probability of enhancement correlates with the T2 signal ratio.
RESUMO
Experimental autoimmune encephalomyelitis (EAE) is a model of multiple sclerosis (MS). EAE reflects important histopathological hallmarks, dissemination, and diversity of the disease, but has only moderate reproducibility of clinical and histopathological features. Focal lesions are less frequently observed in EAE than in MS, and can neither be constrained to specific locations nor timed to occur at a pre-specified moment. This renders difficult any experimental assessment of the pathogenesis of lesion evolution, including its inflammatory, degenerative (demyelination and axonal degeneration), and reparatory (remyelination, axonal sprouting, gliosis) component processes. We sought to develop a controlled model of inflammatory, focal brain lesions in EAE using focused ultrasound (FUS). We hypothesized that FUS induced focal blood brain barrier disruption (BBBD) will increase the likelihood of transmigration of effector cells and subsequent lesion occurrence at the sonicated location. Lesion development was monitored with conventional magnetic resonance imaging (MRI) as well as with magnetic resonance elastography (MRE) and further analyzed by histopathological means. EAE was induced in 12 6-8 weeks old female C57BL/6 mice using myelin oligodendrocyte glycoprotein (MOG) peptide. FUS-induced BBBD was performed 6, 7, and 9 days after immunization in subgroups of four animals and in an additional control group. MRI and MRE were performed on a 7T horizontal bore small animal MRI scanner. Imaging was conducted longitudinally 2 and 3 weeks after disease induction and 1 week after sonication in control animals, respectively. The scan protocol comprised contrast-enhanced T1-weighted and T2-weighted sequences as well as MRE with a vibration frequency of 1 kHz. Animals were sacrificed for histopathology after the last imaging time point. The overall clinical course of EAE was mild. A total of seven EAE animals presented with focal T2w hyperintense signal alterations in the sonicated hemisphere. These were most frequent in the group of animals sonicated 9 days after immunization. Histopathology revealed foci of activated microglia/macrophages in the sonicated right hemisphere of seven EAE animals. Larger cellular infiltrates or apparent demyelination were not seen. Control animals showed no abnormalities on MRI and did not have clusters of activated microglia/macrophages at the sites targeted with FUS. None of the animals had hemorrhages or gross tissue damage as potential side effects of FUS. EAE-animals tended to have lower values of viscoelasticity and elasticity in the sonicated compared to the contralateral parenchyma. This trend was significant when comparing the right sonicated to the left normal hemisphere and specifically the right sonicated compared to the left normal cortex in animals that underwent FUS-BBBD 9 days after immunization (right vs. left hemisphere: mean viscoelasticity 6.1 vs. 7.2 kPa; p = 0.003 and mean elasticity 4.9 vs. 5.7 kPa, p = 0.024; right vs. left cortex: mean viscoelasticity 5.8 vs. 7.5 kPa; p = 0.004 and mean elasticity 5 vs. 6.5 kPa; p = 0.008). A direct comparison of the biomechanical properties of focal T2w hyperintensities with normal appearing brain tissue did not yield significant results. Control animals showed no differences in viscoelasticity between sonicated and contralateral brain parenchyma. We here provide first evidence for a controlled lesion induction model in EAE using FUS-induced BBBD. The observed lesions in EAE are consistent with foci of activated microglia that may be interpreted as targeted initial inflammatory activity and which have been described as pre-active lesions in MS. Such foci can be identified and monitored with MRI. Moreover, the increased inflammatory activity in the sonicated brain parenchyma seems to have an effect on overall tissue matrix structure as reflected by changes of biomechanical parameters.