Pathological Brain Tissue Research Articles

Surface-Enhanced Raman Scattering Nanosensing and Imaging in Neuroscience.

Monitoring neurochemicals and imaging the molecular content of brain tissues in vitro, ex vivo, and in vivo is essential for enhancing our understanding of neurochemistry and the causes of brain disorders. This review explores the potential applications of surface-enhanced Raman scattering (SERS) nanosensors in neurosciences, where their adoption could lead to significant progress in the field. These applications encompass detecting neurotransmitters or brain disorders biomarkers in biofluids with SERS nanosensors, and imaging normal and pathological brain tissues with SERS labeling. Specific studies highlighting in vitro, ex vivo, and in vivo analysis of brain disorders using fit-for-purpose SERS nanosensors will be detailed, with an emphasis on the ability of SERS to detect clinically pertinent levels of neurochemicals. Recent advancements in designing SERS-active nanomaterials, improving experimentation in biofluids, and increasing the usage of machine learning for interpreting SERS spectra will also be discussed. Furthermore, we will address the tagging of tissues presenting pathologies with nanoparticles for SERS imaging, a burgeoning domain of neuroscience that has been demonstrated to be effective in guiding tumor removal during brain surgery. The review also explores future research applications for SERS nanosensors in neuroscience, including monitoring neurochemistry in vivo with greater penetration using surface-enhanced spatially offset Raman scattering (SESORS), near-infrared lasers, and 2-photon techniques. The article concludes by discussing the potential of SERS for investigating the effectiveness of therapies for brain disorders and for integrating conventional neurochemistry techniques with SERS sensing.

Supervised latent factor modeling isolates cell-type-specific transcriptomic modules that underlie Alzheimer’s disease progression

Late onset Alzheimer’s disease (AD) is a progressive neurodegenerative disease, with brain changes beginning years before symptoms surface. AD is characterized by neuronal loss, the classic feature of the disease that underlies brain atrophy. However, GWAS reports and recent single-nucleus RNA sequencing (snRNA-seq) efforts have highlighted that glial cells, particularly microglia, claim a central role in AD pathophysiology. Here, we tailor pattern-learning algorithms to explore distinct gene programs by integrating the entire transcriptome, yielding distributed AD-predictive modules within the brain’s major cell-types. We show that these learned modules are biologically meaningful through the identification of new and relevant enriched signaling cascades. The predictive nature of our modules, especially in microglia, allows us to infer each subject’s progression along a disease pseudo-trajectory, confirmed by post-mortem pathological brain tissue markers. Additionally, we quantify the interplay between pairs of cell-type modules in the AD brain, and localized known AD risk genes to enriched module gene programs. Our collective findings advocate for a transition from cell-type-specificity to gene modules specificity to unlock the potential of unique gene programs, recasting the roles of recently reported genome-wide AD risk loci.

APNmAb005, an anti‐tau antibody targeting synaptic tau oligomers, in Phase 1 for treatment of Alzheimer’s Disease and primary tauopathies

AbstractBackgroundAccumulation of tau oligomers at the synapses in Alzheimer’s disease (AD) disrupts neuronal activities and leads to neurodegeneration. Tau immunotherapy has been actively pursued as a treatment for tauopathies in the past decade. Despite several failed Phase 2 trials of N‐terminus binding antibodies a variety of tau epitopes are being investigated at different stages of clinical trials. APNmAb005 is a humanized monoclonal antibody designed to block synaptic toxicity elicited by tau oligomers.MethodAPNmAb005 was selected as a clinical candidate from APRINOIA’s antibody discovery platform based on its unique binding properties to pathological tau in vitro immunoassays as well in vivo efficacy studies in rTg4510 mice. Humanized APNmAb005 is in IgG4 backbone and the production was scaled up successfully with good stability and solubility to support preclinical and clinical development. GLP safety study was conducted in cynomolgus monkeys. A Phase 1a randomized, double‐blind, placebo‐controlled study of APNmAb005 in healthy subjects is underway.ResultEpitope‐mapping study reveals that APNmAb005 binds to a conformation‐dependent epitope in the mid‐region, which results in a preferable recognition of pathological tau in early Braak stage (III‐IV) AD brains as well as tau aggregates in astrocytes and oligodendrocytes in brains from progressive supranuclear palsy (PSP) patients but not monomeric tau in normal brains. APNmAb005 blocks in vitro tau seeding at nanomolar concentrations and rescues neuronal loss in rTG4510 mice. Four‐week repeat dosing toxicology study shows no observed adverse effects.ConclusionAPNmAb005 is a conformation selective antibody that binds to tau oligomers and aggregates preferentiually in synapses in pathological brain tissues and inhibits tau spreading. The mid‐region conformation dependent epitope is distinct from all other tau antibodies currently in clinical development. APNmAb005 offers a unique tau immunotherapy for neurodegenerative disorders and is currently in Phase 1 to evaluate its safety and tolerability.

The Extracellular Matrix in Glioblastomas: A Glance at Its Structural Modifications in Shaping the Tumoral Microenvironment-A Systematic Review.

While many components of the ECM have been isolated and characterized, its modifications in the specific setting of GBMs have only been recently explored in the literature. The aim of this paper is to provide a systematic review on the topic and to assess the ECM's role in shaping tumoral development. An online literature search was launched on PubMed/Medline and Scopus using the research string "((Extracellular matrix OR ECM OR matrix receptor OR matrix proteome) AND (glioblastoma OR GBM) AND (tumor invasion OR tumor infiltration))", and a systematic review was conducted in accordance with the PRISMA-P guidelines. The search of the literature yielded a total of 693 results. The duplicate records were then removed (n = 13), and the records were excluded via a title and abstract screening; 137 studies were found to be relevant to our research question and were assessed for eligibility. Upon a full-text review, 59 articles were finally included and were summarized as follows based on their focus: (1) proteoglycans; (2) fibrillary proteins, which were further subdivided into the three subcategories of collagen, fibronectin, and laminins; (3) glycoproteins; (4) degradative enzymes; (5) physical forces; (6) and glioma cell and microglia migratory and infiltrative patterns. Our systematic review demonstrates that the ECM should not be regarded anymore as a passive scaffold statically contributing to mechanical support in normal and pathological brain tissue but as an active player in tumor-related activity.

The Evolving Need for Neuropsychology in Neurosurgical Settings: Challenges Facing Transformative Care

Clinical neuropsychology has been a valuable asset to neurologic surgery, contributing to lateralization and localization of pathologic brain tissue, identification of eloquent cortex, and evaluation of postoperative neuropsychological functioning. Moreover, neuropsychologists provide empirically driven interventions aimed at supporting preparation and/or recovery of neurosurgery patients. Nonetheless, several challenges may limit the reliability, validity, and generalizability of the assessment data obtained and reduce the usefulness of other neuropsychological services provided. Specifically, linguistic, cultural, educational, and other biases associated with demographic characteristics can lead to a narrowed view of an individual's life experiences, which must be confronted to fulfill the mission of ensuring that all patients have access to care that is appropriate to their needs. Instead of perceiving these challenges as insurmountable barriers, such issues can be viewed as opportunities to catalyze change and foster innovation for the future of neuropsychological care in neurosurgical settings. In addition to reviewing the possible mechanisms of these obstacles, the current article offers tangible solutions at both a macro level (e.g., discipline-wide transformations) and micro level (e.g., individualized patient-centric approaches). Outlined are practical techniques to potentially improve consensus and standardization of methods, advance and globalize research, expand representativeness of measures and practices to serve diverse individuals, and increase treatment adherence through engagement of patients and their families.

The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier.

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression. Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis. Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis, thus inhibiting remyelination. Although many advances have been made in the mechanisms and treatment of multiple sclerosis, it remains very difficult for drugs to reach pathological brain tissues; this is due to the complexity of brain structure and function, especially the existence of the blood-brain barrier. Therefore, herein, we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

Intraoperative cytological diagnosis of brain tumours: Apreliminary study using a deep learning model.

Intraoperative pathological diagnosis of central nervous system (CNS) tumours is essential to planning patient management in neuro-oncology. Frozen section slides and cytological preparations provide architectural and cellular information that is analysed by pathologists to reach an intraoperative diagnosis. Progress in the fields of artificial intelligence and machine learning means that AI systems have significant potential for the provision of highly accurate real-time diagnosis in cytopathology. To investigate the efficiency of machine-learning models in the intraoperative cytological diagnosis of CNS tumours. We trained a deep neural network to classify biopsy material for intraoperative tissue diagnosis of four major brain lesions. Overall, 205 medical images were obtained from squash smear slides of histologically correlated cases, with 18 high-grade and 11 low-grade gliomas, 17 metastatic carcinomas, and 9 non-neoplastic pathological brain tissue samples. The neural network model was trained and evaluated using 5-fold cross-validation. The model achieved 95% and 97% diagnostic accuracy in the patch-level classification and patient-level classification tasks, respectively. We conclude that deep learning-based classification of cytological preparations may be a promising complementary method for the rapid and accurate intraoperative diagnosis of CNS tumours.

A polynomial regression-based approach to estimate relaxation rate maps suitable for multiparametric segmentation of clinical brain MRI studies in multiple sclerosis

Background and ObjectiveRelaxation parameter maps (RPMs) calculated from spin-echo data have provided a basis for the segmentation of normal brain tissues and white matter lesions in multiple sclerosis (MS) MRI studies. However, Conventional Spin-Echo (CSE) sequences, once the core of clinical MRI studies, have been largely replaced by faster ones, which do not allow the calculation a-posteriori of RPMs from clinical studies. Aim of the study was to develop and validate a method to estimate RPMs (pseudo-RPMs) from routine clinical MRI protocols (including 3D-Gradient Echo T1w, FLAIR and fast-T2w sequences), suitable for fully automatic multiparametric segmentation of normal-appearing and pathological brain tissues in MS. MethodsThe proposed method processes spatially normalized clinical MRI studies through a multistep pipeline, to collect a set of data points of matched signal intensities (from MRI studies) and relaxation parameters (from a CSE-derived digital template and an MS lesion database), which are then fitted by a multiple and multivariate 4-th degree polynomial regression, providing pseudo-RPMs. The method was applied to a dataset of 59 clinical MRI studies providing pseudo-RPMs that were segmented through a method originally developed for the CSE-derived RPMs. Results of the segmentation in 12 studies were used to iteratively optimize method parameters. Accuracy of segmentation of normal-appearing brain tissues from the pseudo-RPMs was assessed by comparing their age-related changes, as measured in 47 clinical studies, against those measured acquired using CSE sequences in a comparable dataset of 47 patients. Lesion segmentation was validated against manual segmentation carried out by three neuroradiologists. ResultsAge-related changes of normal-appearing brain tissue volumes measured using the pseudo-RPMs substantially overlapped those measured using the RPMs obtained from CSE sequences, and segmentation of MS lesions showed a moderate-high spatial overlap with manual segmentation, comparable to that achieved by the widely used Lesion Segmentation Tool on FLAIR images, with a greater volumetric agreement. ConclusionsThe proposed approach allows calculation from clinical studies of pseudo-RPMs, which are equivalent to those obtainable from CSE sequences, avoiding the need for the acquisition of additional, dedicated sequences for segmentation purposes.

0147 Electrophysiologic Localization of Pathological Brain Tissue Is Accomplished with Intracranial Sleep Staging

0147 Electrophysiologic Localization of Pathological Brain Tissue Is Accomplished with Intracranial Sleep Staging

Lipid Profiles of Human Brain Tumors Obtained by High-Resolution Negative Mode Ambient Mass Spectrometry

Alterations in cell metabolism, including changes in lipid composition occurring during malignancy, are well characterized for various tumor types. However, a significant part of studies that deal with brain tumors have been performed using cell cultures and animal models. Here, we present a dataset of 124 high-resolution negative ionization mode lipid profiles of human brain tumors resected during neurosurgery. The dataset is supplemented with 38 non-tumor pathological brain tissue samples resected during elective surgery. The change in lipid composition alterations of brain tumors enables the possibility of discriminating between malignant and healthy tissues with the implementation of ambient mass spectrometry. On the other hand, the collection of clinical samples allows the comparison of the metabolism alteration patterns in animal models or in vitro models with natural tumor samples ex vivo. The presented dataset is intended to be a data sample for bioinformaticians to test various data analysis techniques with ambient mass spectrometry profiles, or to be a source of clinically relevant data for lipidomic research in oncology.

A novel triple-level combinational framework for brain anomaly segmentation to augment clinical diagnosis

ABSTRACT Medical image segmentation techniques have become a very imperative prerequisite for accuracy and easiness of diagnosis in image analysis processes. An effective and novel segmentation technique is still needed for the hour, as it is very challenging for medical practitioners to differentiate the normal and pathological brain tissues in unaided sight. To combat the above limitation, the researchers proposed a robust algorithm for the segmentation of MR brain image based on a novel combination of FCM for segmentation, GLCM for feature extraction and Jaya Algorithm (JA) for optimisation. The combination of GLCM and FCM improves the accuracy of the operation by incorporating the neighbourhood spatial characteristics. Then, the study uses the JA to find the optimal threshold value. At last, the segmented images are subjected to threshold operation using the optimal value. The ground truth images validate the effectiveness of the proposed algorithm, and it also uses the domain-specific parameters such as Peak Signal to Noise Ratio (PSNR) index, Dice Coefficient (DCI) index, Mean Squared Error (MSE) index, Jaccard-Tanimoto Coefficient (JTC) index and Hausdorff Distance (HD). The proposed algorithm delivers JTC and DCI values of 69.3% and 81.9%, respectively, the highest among the other traditional algorithms specified in this work.

Glutamine's protection against brain damage in septic rats via increased protein oxygen-N-acetylglucosamine modification.

This study aimed to observe the effect of glutamine (Gln) on brain damage in septic rats and explore its possible mechanism. Ninety-three Sprague-Dawley rats were randomly divided into five groups: sham operation group, sepsis group, Gln-treated group, quercetin/Gln-treated group, and alloxan/Gln-treated group. The rats in each group were continuously monitored for mean arterial pressure (MAP) and heart rate changes for 16 h. Neuroreflex scores were measured 24 h after surgery. The water content of the brain tissue was measured. Plasma neuron enolase and cysteine protease-3 were measured using the ELISA. The expression levels of heat shock protein 70 (HSP70) and oxygen-N-acetylglucosamine (O-GlcNAc) were determined by western blot analysis. Finally, the brain tissue was observed via hematoxylin and eosin staining. The brain tissue water content, plasma neuron enolase content, brain tissue cysteine protease-3 content, and nerve reflex score were significantly lower in the Gln-treated group than in the sepsis group (P < 0.05). At the same time, the pathological brain tissue damage in the Gln-treated group was also significantly reduced. It is worth noting that the expression of HSP70 and the protein O-GlcNAc modification levels in the Gln-treated group were significantly elevated than the levels in the sepsis group (P < 0.05), and reversed by pretreatment with the HSP and O-GlcNAc inhibitors quercetion and alloxan. Gln can attenuate brain damage in rats with sepsis, which may be associated with increased protein O-GlcNAc modification.

Terahertz dielectric spectroscopy of human brain gliomas and intact tissues ex vivo: double-Debye and double-overdamped-oscillator models of dielectric response.

Terahertz (THz) technology offers novel opportunities in the intraoperative neurodiagnosis. Recently, the significant progress was achieved in the study of brain gliomas and intact tissues, highlighting a potential for THz technology in the intraoperative delineation of tumor margins. However, a lack of physical models describing the THz dielectric permittivity of healthy and pathological brain tissues restrains the further progress in this field. In the present work, the ex vivo THz dielectric response of human brain tissues was analyzed using relaxation models of complex dielectric permittivity. Dielectric response of tissues was parametrized by a pair of the Debye relaxators and a pair of the overdamped-oscillators - namely, the double-Debye (DD) and double-overdamped-oscillator (DO) models. Both models accurately reproduce the experimental curves for the intact tissues and the WHO Grades I-IV gliomas. While the DD model is more common for THz biophotonics, the DO model is more physically rigorous, since it satisfies the sum rule. In this way, the DO model and the sum rule were, then, applied to estimate the content of water in intact tissues and gliomas ex vivo. The observed results agreed well with the earlier-reported data, justifying water as a main endogenous label of brain tumors in the THz range. The developed models can be used to describe completely the THz-wave - human brain tissues interactions in the frameworks of classical electrodynamics, being quite important for further research and developments in THz neurodiagnosis of tumors.

Capability of physically reasonable OCT-based differentiation between intact brain tissues, human brain gliomas of different WHO grades, and glioma model 101.8 from rats.

Optical coherence tomography (OCT) of the ex vivo rat and human brain tissue samples is performed. The set of samples comprises intact white and gray matter, as well as human brain gliomas of the World Health Organization (WHO) Grades I-IV and glioma model 101.8 from rats. Analysis of OCT signals is aimed at comparing the physically reasonable properties of tissues, and determining the attenuation coefficient, parameter related to effective refractive index, and their standard deviations. Data analysis is based on the linear discriminant analysis and estimation of their dispersion in a four-dimensional principal component space. The results demonstrate the distinct contrast between intact tissues and low-grade gliomas and moderate contrast between intact tissues and high-grade gliomas. Particularly, the mean values of attenuation coefficient are 7.56±0.91, 3.96±0.98, and 5.71±1.49 mm-1 for human white matter, glioma Grade I, and glioblastoma, respectively. The significant variability of optical properties of high Grades and essential differences between rat and human brain tissues are observed. The dispersion of properties enlarges with increase of the glioma WHO Grade, which can be attributed to the growing heterogeneity of pathological brain tissues. The results of this study reveal the advantages and drawbacks of OCT for the intraoperative diagnosis of brain gliomas and compare its abilities separately for different grades of malignancy. The perspective of OCT to differentiate low-grade gliomas is highlighted by the low performance of the existing intraoperational methods and instruments.

Ontario Neurodegenerative Disease Research Initiative (ONDRI): Structural MRI Methods and Outcome Measures

The Ontario Neurodegenerative Research Initiative (ONDRI) is a 3 years multi-site prospective cohort study that has acquired comprehensive multiple assessment platform data, including 3T structural MRI, from neurodegenerative patients with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and cerebrovascular disease. This heterogeneous cross-section of patients with complex neurodegenerative and neurovascular pathologies pose significant challenges for standard neuroimaging tools. To effectively quantify regional measures of normal and pathological brain tissue volumes, the ONDRI neuroimaging platform implemented a semi-automated MRI processing pipeline that was able to address many of the challenges resulting from this heterogeneity. The purpose of this paper is to serve as a reference and conceptual overview of the comprehensive neuroimaging pipeline used to generate regional brain tissue volumes and neurovascular marker data that will be made publicly available online.

Motion Correction in Multimodal Intraoperative Imaging.

Thermographic imaging accompanied with time-resolved analysis is a promising technique for intraoperative imaging in neurosurgery. However, motion due to breathing and pulse of the patient introduces large inaccuracies to the demarcation of normal and pathological brain tissue. Since movements and physiological processes are both manifested as temperature variations, we employ co-registered visual-light images to unambiguously detect motion. In this article, we propose a feature-based approach which is selected from four best-known methods after thorough performance comparison. Complementing our previous work, we evaluate the performance of our methods by applying a frequency analysis and similarity measurements. Our approach enables an accurate motion correction without affecting physiological temperature shifts. Furthermore, real-time performance of the implementation is enabled by serial acceleration and parallelization methods.

Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer's disease

MR-guided focused ultrasound (MRgFUS) can temporarily permeabilize the blood-brain barrier (BBB), noninvasively, to allow therapeutics access to the central nervous system. However, its secondary and potential neuromodulation effects are not well understood. We aimed to characterize the functional impact of MRgFUS BBB opening in human subjects, based on the phase I trial in patients with Alzheimer's disease. We analyzed for changes in bilateral frontoparietal networks in resting state functional MRI from five subjects after BBB opening in the right frontal lobe. We found a transient functional connectivity decrease within only the ipsilateral frontoparietal network that was recovered by the next day. Additionally, baseline to month three comparisons did not reveal any significant differences from matched-controls from the Alzheimer's Disease Neuroimaging Initiative. Overall, MRgFUS may transiently affect neurologic function, but the functional organization is restored at one day and remains unchanged at three months. This first in human data has implications for the development of MRgFUS as a drug delivery platform to pathologic brain tissue and potential use for non-invasive neuromodulation.

Intraoperative Molecular Imaging with Second Window Indocyanine Green Facilitates Confirmation of Contrast-Enhancing Tissue During Intracranial Stereotactic Needle Biopsy: A Case Series

Stereotactic needle biopsy provides a minimally invasive option for the diagnosis of intracranial lesions but is limited by inconclusive diagnoses on frozen pathology. For rapid pathology, 5-aminovelunic acid and sodium fluorescein have previously demonstrated potential as diagnostic adjuvants. Stereotactic biopsy with near-infrared (NIR) fluorophores has not been reported. We identified 5 representative cases using NIR fluorescent dye indocyanine green (ICG) administered in a high dose, delayed manner. Five patients underwent second window indocyanine green (SWIG)-guided stereotactic biopsy for diagnosis of suspected glioma or tumor recurrence. Up to 5 mg/kg ICG was administered approximately 24 hours prior to surgery. Biopsies were conducted in the standard fashion, targeting regions of suspected tumor using intraoperative frameless navigation. Samples were examined intraoperatively under standard visible light and for fluorescence using conventional NIR imaging platforms. Findings were correlated with frozen and final tumor pathology for all cases. A total of 10 biopsy specimens were obtained. Three did not fluoresce and did not demonstrate tumor on preliminary or final pathology, including a non-gadolinium-enhancing sample taken proximal to the final target. The remaining 7 fluoresced, of which 6 contained tumor and 1 contained necrosis. Fluorescence was also noted in a patient with radiation treatment effect. Overall fluorescence characteristics were highly concordant with preliminary and final diagnoses. SWIG provides rapid intraoperative confirmation of pathologic brain tissue by permeating neoplastic or inflammatory brain tissue via a mechanism similar to that of gadolinium enhancement. SWIG-guided stereotactic biopsy can improve surgical efficiency by enhancing confidence in acquisition of target tissue.

Evaluation of brain energy metabolism and intracellular pH level using phosphorus (31P) MR spectroscopy

Evaluation of brain tumor metabolism is an important issue in brain tumor studies. Phosphorus magnetic resonance spectroscopy (31P-MRS) allows noninvasive examination of metabolic changes occurring in pathologic brain tissue by measuring intracellular pH level based on obtained spectra of phosphorus-containing metabolites involved in cell membrane phospholipids turnover. The purpose of this study was pHmetry of brain tumors using 31P MRS.The mean pH level of the control group of healthy volunteers (N=23) was 6.963 ± 0.044. Measured PME/PDE=1.17 ± 0.20.31P MRS demonstrates highly reproducible results opening prospective for comparative studies with the diseased groups (mainly gliomas) and further translation to the clinical practice.

Phosphorus (P) magnetic resonance spectroscopy for evaluation of brain tissue metabolism and measuring non-invasive pH. A study involving 23 volunteers. Part I

Evaluation of brain metabolism is an important part in examination of brain lesions. Phosphorus magnetic resonance spectroscopy opens up great opportunities for studying the energy metabolism and allows noninvasive examination of metabolic processes occurring both in healthy and in pathologic brain tissue by obtaining a spectrum of phosphorus-containing metabolites involved in the turnover of cell membrane phospholipids. The technique presented in this paper was used to conduct 31P MR spectroscopy and to estimate the ratio between the peaks of the main metabolites and intracellular pH of the healthy brain tissue of 23 volunteers in the age group under 30 years old in clinical settings. Based on the recorded stable phosphorus spectra of metabolites of the healthy brain tissue, the value of intracellular pH (6.963±0.044) and the ratio of the main PME/PDE peaks (1.17±0.20) were calculated. The database was created to subsequently analyze the metabolic changes in brain tissue spectra in norm and in pathology, as well as the intracellular pH variations that have diagnostic and prognostic value.