Treatment Of Brain Diseases Research Articles

The Influence of Size and Chemical Composition of Silver and Gold Nanoparticles on in vivo Toxicity with Potential Applications to Central Nervous System Diseases.

The physicochemical and optical properties of silver nanoparticles (SNPs) and gold nanoparticles (GNPs) have allowed them to be employed for various biomedical applications, including delivery, therapy, imaging, and as theranostic agents. However, since they are foreign body systems, they are usually redistributed and accumulated in some vital organs, which can produce toxic effects; therefore, this a crucial issue that should be considered for potential clinical trials. This review aimed to summarize the reports from the past ten years that have used SNPs and GNPs for in vivo studies on the diagnosis and treatment of brain diseases and those related to the central nervous system, emphasizing their toxicity as a crucial topic address. The article focuses on the effect of the nanoparticle´s size and chemical composition as relevant parameters for in vivo toxicity. At the beginning of this review, the general toxicity and distribution studies are discussed separately for SNPs and GNPs. Subsequently, this manuscript analyzes the principal applications of both kinds of nanoparticles for glioma, neurodegenerative, and other brain diseases, and discusses the advances in clinical trials. Finally, we analyze research prospects towards clinical applications for both types of metallic nanoparticles.

Abstract PO035: Engineered glioblastoma tumor models reveal extracellular matrix signals influence the efficacy of targeted inhibitors

Abstract Biomaterial-based ex vivo models of healthy and diseased brain tissue are among those tools that may help study the complexity of cerebral tissue to better diagnose, prevent, and treat brain diseases. We have established engineered brain tumor biomaterials based on methacrylamide-functionalized gelatin hydrogels and used microfluidic-forming techniques to generate platforms that combine transitions of biophysical and biomolecular properties found in the glioblastoma tumor microenvironment, from the core to the tumor margins (1). Moreover, this biomaterial approach is able to monitor the response of patient-derived xenograft (PDX) cell populations with different molecular signatures; in particular, we have analyzed the amplified and the constitutively activated vIII mutant EGF receptor. We have also characterized PDX response to targeted inhibitors, such as erlotinib, a tyrosine kinase inhibitor that specifically blocks EGFR (2). Patients with glioblastoma (GBM) exhibit poor survival rates, tied both to the significant intra and interpatient heterogeneity of the tumor as well as the complex signaling pathways underlying malignancy. Spatial and temporal gradients regulate cell proliferation, migration, and differentiation during cancer. Therefore, the use of a microfluidic approach to fabricate patterned biomaterials, have the ability to examine transitions between defined environments (e.g., glioma core, periphery and neural tissue). Cells within these structured materials can be fully analyzed by imaging, secretomic and gene expression analyses. Cell morphology evolved to a more spread shape from low to high crosslinking density of gelatin and hypoxic levels depended on cell concentration. Using patient derived GBM tumor samples we are able to generate a miniaturized tumor tissue analog to examine how the heterogeneities within the tumor microenvironment impact glioma malignant phenotype, growth, and therapeutic efficacy. The ability to manipulate tumor extracellular matrix (ECM) can improve therapeutic outcomes and restrict glioma infiltration. Our in vitro tumor model is able to analyze the relationship between HA and the invasive phenotype of GBM tumor cells. We show that cell growth, motility and proteomic responses of GBM cells within our platform were significantly altered by HA molecular weight in response to a tyrosine kinase inhibitor. These results provide additional insights regarding the importance of extracellular microenvironment in the invasive potential of GBM tumors. We have demonstrated that repeated dosing of erlotinib promotes expression of PDGFRb in EGFR vIII mutant cells and that extracellular HA plays a favorable role in the inhibition of EGFR, through STAT3 deactivation (3). (1) Pedron S et al. (2015), Adv. Mater., 27: 1567; (2) Pedron S. et al. (2017), Adv. Healthcare Mater., 6: 1700529; (3) Pedron S, et al. (2019), Biomaterials, 219: 119371. Citation Format: Sara Pedron, Jann N. Sarkaria, Brendan A.C. Harley. Engineered glioblastoma tumor models reveal extracellular matrix signals influence the efficacy of targeted inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO035.

SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models

Astrocytes and microglia are brain‐resident glia that can establish harmful inflammatory environments in disease contexts and thereby contribute to the progression of neuronal loss in neurodegenerative disorders. Correcting the diseased properties of glia is therefore an appealing strategy for treating brain diseases. Previous studies have shown that serum/ glucocorticoid related kinase 1 (SGK1) is upregulated in the brains of patients with various neurodegenerative disorders, suggesting its involvement in the pathogenesis of those diseases. In this study, we show that inhibiting glial SGK1 corrects the pro‐inflammatory properties of glia by suppressing the intracellular NFκB‐, NLRP3‐inflammasome‐, and CGAS‐STING‐mediated inflammatory pathways. Furthermore, SGK1 inhibition potentiated glial activity to scavenge glutamate toxicity and prevented glial cell senescence and mitochondrial damage, which have recently been reported as critical pathologic features of and therapeutic targets in Parkinson disease (PD) and Alzheimer disease (AD). Along with those anti‐inflammatory/neurotrophic functions, silencing and pharmacological inhibition of SGK1 protected midbrain dopamine neurons from degeneration and cured pathologic synuclein alpha (SNCA) aggregation and PD‐associated behavioral deficits in multiple in vitro and in vivo PD models. Collectively, these findings suggest that SGK1 inhibition could be a useful strategy for treating PD and other neurodegenerative disorders that share the common pathology of glia‐mediated neuroinflammation.

Inorganic Nanoparticle-Loaded Exosomes for Biomedical Applications.

Exosomes are intrinsic cell-derived membrane vesicles in the size range of 40–100 nm, serving as great biomimetic nanocarriers for biomedical applications. These nanocarriers are known to bypass biological barriers, such as the blood–brain barrier, with great potential in treating brain diseases. Exosomes are also shown to be closely associated with cancer metastasis, making them great candidates for tumor targeting. However, the clinical translation of exosomes are facing certain critical challenges, such as reproducible production and in vivo tracking of their localization, distribution, and ultimate fate. Recently, inorganic nanoparticle-loaded exosomes have been shown great benefits in addressing these issues. In this review article, we will discuss the preparation methods of inorganic nanoparticle-loaded exosomes, and their applications in bioimaging and therapy. In addition, we will briefly discuss their potentials in exosome purification.

Behavioral and Functional Assessment of Ultrasound Neuromodulation on Caenorhabditis Elegans.

Ultrasound brain stimulation is a promising modality for probing brain function and treating brain diseases. However, its mechanism is as yet unclear, and in vivo effects are not well-understood. Here, we present a top-down strategy for assessing ultrasound bioeffects in vivo, using Caenorhabditis elegans. Behavioral and functional changes of single worms and of large populations upon ultrasound stimulation were studied. Worms were observed to significantly increase their average speed upon ultrasound stimulation, adapting to it upon continued treatment. Worms also generated more reversal turns when ultrasound was ON, and within a minute post-stimulation, they performed significantly more reversal and omega turns than prior to ultrasound. In addition, in vivo calcium imaging showed that the neural activity in the worms' heads and tails was increased significantly by ultrasound stimulation. In all, we conclude that ultrasound can directly activate the neurons of worms in vivo, in both of their major neuronal ganglia, and modify their behavior.

Implantable wirelessly powered optoelectronic device for optogenetics

In vivo optogenetics provide special and powerful capabilities in regulation of neurons, research of neural circuits and even in treatment of brain diseases. However, conventional hardware for such studies tethers the experimental animals to remote light sources, power sources, or other functional modules, which imposes considerable physical constrains on natural behaviors and limits the range of the experiment. To enable flexible and convenient optogenetic manipulation of neural circuit with finite disruption of animal behavior, a wirelessly powered optoelectronic device, composing mainly of a radio frequency (RF) energy harvester and a high-performance GaN-based light-emitting diode (LED), is demonstrated and can be used to construct an implantable optrode for optogenetics. The wireless RF power signal is collected through an antenna and a two-stage voltage doubling rectifier circuit, and finally converted into high-amplitude DC voltage. Provided with 25-dBm RF power with a distance of 0.2 m, the RF energy harvesting and processing circuit can output a stable 2.81 V DC voltage and drive the designed GaN-based LED to work normally. After being successfully lit, the emission peak wavelength of the LED locates 455 nm and the output optical power density reaches 214.9 mW / mm2, which is fully capable of activating light-sensitive ion channel channelrhodopsin-2. The total area of the device is 3 mm × 3.2 mm, which is suitable for subdermal implantation.

How gut microbes could drive brain disorders

Scientists are starting to work out how the gut microbiome can affect brain health. That might lead to better and easier treatments for brain diseases. Scientists are starting to work out how the gut microbiome can affect brain health. That might lead to better and easier treatments for brain diseases.

2D Nanomaterials for Tissue Engineering and Regenerative Nanomedicines: Recent Advances and Future Challenges.

Regenerative medicine has become one of the hottest research topics in medical science that provides a promising way for repairing tissue defects in the human body. Due to their excellent physicochemical properties, the application of 2D nanomaterials in regenerative medicine has gradually developed and has been attracting a wide range of research interests in recent years. In particular, graphene and its derivatives, black phosphorus, and transition metal dichalcogenides are applied in all the aspects of tissue engineering to replace or restore tissues. This review focuses on the latest advances in the application of 2D-nanomaterial-based hydrogels, nanosheets, or scaffolds that are engineered to repair skin, bone, and cartilage tissues. Reviews on other applications, including cardiac muscle regeneration, skeletal muscle repair, nerve regeneration, brain disease treatment, and spinal cord healing are also provided. The challenges and prospects of applications of 2D nanomaterials in regenerative medicine are discussed.

Identifying drug targets for neurological and psychiatric disease via genetics and the brain transcriptome.

Discovering drugs that efficiently treat brain diseases has been challenging. Genetic variants that modulate the expression of potential drug targets can be utilized to assess the efficacy of therapeutic interventions. We therefore employed Mendelian Randomization (MR) on gene expression measured in brain tissue to identify drug targets involved in neurological and psychiatric diseases. We conducted a two-sample MR using cis-acting brain-derived expression quantitative trait loci (eQTLs) from the Accelerating Medicines Partnership for Alzheimer’s Disease consortium (AMP-AD) and the CommonMind Consortium (CMC) meta-analysis study (n = 1,286) as genetic instruments to predict the effects of 7,137 genes on 12 neurological and psychiatric disorders. We conducted Bayesian colocalization analysis on the top MR findings (using P<6x10-7 as evidence threshold, Bonferroni-corrected for 80,557 MR tests) to confirm sharing of the same causal variants between gene expression and trait in each genomic region. We then intersected the colocalized genes with known monogenic disease genes recorded in Online Mendelian Inheritance in Man (OMIM) and with genes annotated as drug targets in the Open Targets platform to identify promising drug targets. 80 eQTLs showed MR evidence of a causal effect, from which we prioritised 47 genes based on colocalization with the trait. We causally linked the expression of 23 genes with schizophrenia and a single gene each with anorexia, bipolar disorder and major depressive disorder within the psychiatric diseases and 9 genes with Alzheimer’s disease, 6 genes with Parkinson’s disease, 4 genes with multiple sclerosis and two genes with amyotrophic lateral sclerosis within the neurological diseases we tested. From these we identified five genes (ACE, GPNMB, KCNQ5, RERE and SUOX) as attractive drug targets that may warrant follow-up in functional studies and clinical trials, demonstrating the value of this study design for discovering drug targets in neuropsychiatric diseases.

Optical recording of brain functions based on voltage-sensitive dyes

To better understand the spatial distribution of brain functions, we need to monitor and analyze neuronal activities. Electrophysiological technique has provided an important method for the exploration of some neural circuits. However, this method cannot simultaneously detect the activities of nerve cell groups. Therefore, methods that can monitor the spatial distribution of neuronal population activity are demanded to explore brain functions. Voltage-sensitive dyes (VSDs) shift their absorption or emission optical signals in response to different membrane potentials, allowing assessing the global electrical state of neurons. Optical recording technique coupled with VSDs is a promising method to monitor the brain functions by detecting optical signal changes. This review focuses on the fast and slow responses of VSDs to membrane potential changes and optical recordings utilized in the central nervous system. In this review, we attempt to show how VSDs and optical recordings can be used to obtain brain functional monitoring at high spatial and temporal resolution. Understanding of brain functions will not only greatly improve the cognition of information transmission of complex neural network, but also provide new methods of treating brain diseases such as Parkinson’s and Alzheimer’s diseases.

经鼻腔给药的纳米颗粒及其治疗脑部疾病的进展

经鼻腔给药的纳米颗粒及其治疗脑部疾病的进展

Chapter 28 - Electrical stimulation of the fornix for the treatment of brain diseases

Deep brain stimulation (DBS) has proven to be safe and effective for both hypo- and hyperkinetic movement disorders of basal ganglia origin, while its application to other neural pathways such as the circuit of Papez is under investigation. In particular, the fornix has gained interest as potential DBS target to decrease rates of cognitive decline, enhance memory, aid visuospatial memorization, and improve verbal recollection. While the exact mechanisms of action of fornix DBS are not completely understood, studies found enhanced hippocampal acetylcholine release, synaptic plasticity, and decreased inflammatory responses in cortex and hippocampus. Nevertheless, it is still premature to conclude that fornix DBS can be used in the treatment of cognitive disorders, and the field needs sound, preclinically tested, and disease-specific a posteriori hypotheses.

Neural Stem Cells Therapy to Treat Neurodegenerative Diseases

Neural stem cells have the ability to proliferation, differentiate and renew, which plays an important role in the growth, maturation and senescence of the human brain. But according to researches, neural stem cells in the brain do not remain active throughout an organism's lifetime. Many neural stem cells become dormant when the brain matures, and may be activated when the body is sick to selectively heal the disease. In recent years, there are many studies on neural stem cells. Joshua[1] and Ting Zhang[2] show that neurodegenerative diseases such as ischemic stroke, Alzheimer's disease and Parkinson's disease can be improved by the transplantation of neural stem cells, however the specific mechanism is not clear. This paper investigates three main questions: Why neural stem cell transplantation is chosen as a treatment? Where does NSCs derive from in clinical transplantation? How does neural stem cell transplantation treat brain diseases? And we also figure out the answers to these three questions. Firstly, transplantation of hypothalamic NSCs can delay the process of aging in the host, and Chemokines and EVs which secreted by neural stem cells can delay aging and defend neurodegenerative diseases. Secondly, the sources of NSCs can be divided into three types. The first is to isolate NSCs from primary tissue and cultivate them in vitro. The second is to produce the required cells by inducing pluripotent stem cells and embryonic stem cells. The third way to get NCS is through transdifferentiation of somatic cells. Thirdly, in brain diseases, transplanted NSCs can migrate from the aggregation site to the site of the disease, reducing damage to the blood-brain barrier, repairing learning and memory abilities that depend on the hippocampus and secreting neurotrophic factors.

Gold-based nanomaterials for the treatment of brain cancer.

Brain cancer, also known as intracranial cancer, is one of the most invasive and fatal cancers affecting people of all ages. Despite the great advances in medical technology, improvements in transporting drugs into brain tissue have been limited by the challenge of crossing the blood-brain barrier (BBB). Fortunately, recent endeavors using gold-based nanomaterials (GBNs) have indicated the potential of these materials to cross the BBB. Therefore, GBNs might be an attractive therapeutic strategy against brain cancer. Herein, we aim to present a comprehensive summary of current understanding of the critical effects of the physicochemical properties and surface modifications of GBNs on BBB penetration for applications in brain cancer treatment. Furthermore, the most recent GBNs and their impressive performance in precise bioimaging and efficient inhibition of brain tumors are also summarized, with an emphasis on the mechanism of their effective BBB penetration. Finally, the challenges and future outlook in using GBNs for brain cancer treatment are discussed. We hope that this review will spark researchers’ interest in constructing more powerful nanoplatforms for brain disease treatment.

Biophotonic Strategies of Measurement and Stimulation of the Cranial and the Extracranial Lymphatic Drainage Function

In this review, we discuss the crucial role of cranial and the extracranial lymphatics in keeping the central nervous system (CNS) health. We talk about the important lymphatic mechanism of removal of metabolites and toxins from the brain, which orchestrates the regenerative processes in CNS. We debate a novel knowledge about the lymphatic mechanism responsible for maintaining the balance between the exit and the entrance of molecules and cells from and into CNS. Finally, we highlight the pioneering technologies of biophotonic stimulation of lymphatic drainage function that can open a new era for the development of novel bedside, readily applicable and commercially viable technologies for the treatment of brain diseases.

Guest Editorial Introduction to the Special Issue on Recent Advances in Ultrasound Technology for Brain Imaging and Therapy

The emergence of new technologies has dramatically accelerated our understanding of the human brain function. Over the past decade, ultrasound has become a valuable tool in preclinical animal studies and clinical practice in many areas of the brain. This is because it can not only provide information about the structure and function of brain tissues but also constitute a potential treatment tool for brain disease. The recent FDA approval and success of ultrasound ablation techniques for essential tremors is an example of how ultrasound can revolutionize clinical practice. Similarly, recent brain ultrasound advances such as noninvasive blood–brain barrier (BBB) opening, ultrasound neuromodulation, and functional brain imaging have great potential to improve human patient outcomes in neurology and neurosurgery. Ultrasound is thus expected to play an increasingly important role in the diagnosis and treatment of brain disease in the upcoming years.

Ultrasound for the Brain: A Review of Physical and Engineering Principles, and Clinical Applications.

The emergence of new ultrasound technologies has improved our understanding of the brain functions and offered new opportunities for the treatment of brain diseases. Ultrasound has become a valuable tool in preclinical animal and clinical studies as it not only provides information about the structure and function of brain tissues but can also be used as a therapy alternative for brain diseases. High-resolution cerebral flow images with high sensitivity can be acquired using novel functional ultrasound and super-resolution ultrasound imaging techniques. The noninvasive treatment of essential tremors has been clinically approved and it has been demonstrated that the ultrasound technology can revolutionize the currently existing treatment methods. Microbubble-mediated ultrasound can remotely open the blood-brain barrier enabling targeted drug delivery in the brain. More recently, ultrasound neuromodulation received a great amount of attention due to its noninvasive and deep penetration features and potential therapeutic benefits. This review provides a thorough introduction to the current state-of-the-art research on brain ultrasound and also introduces basic knowledge of brain ultrasound including the acoustic properties of the brain/skull and engineering techniques for ultrasound. Ultrasound is expected to play an increasingly important role in the diagnosis and therapy of brain diseases.

Design of a Versatile Angle-Rotatable Skull-Shaped Conformal Transcranial Focused Ultrasound Transducer for Noninvasive Brain Therapy.

Phase-controlled focused ultrasound transducers have opened up a new way to noninvasively treat brain diseases. However, due to the geometry and the heterogeneous medium of the human skull, the currently used hemispherical transducers cannot guarantee that the ultrasound emitted by the transducer penetrates the skull normally; consequently, the impact of the shear wave on the treatment area has to be considered. The usual approach is to turn off elements in the transducer with excessively large incident angles, but this approach reduces the efficiency of the transducer. This article presents the design of a novel transducer that can be rotated according to the different geometric shapes of the skull. The incident angles of the elements in the transducer are modified so that the effect of the shear wave on the treatment area can be ignored and the efficiency of the transducer is improved. The results of computed tomography (CT) model simulation of nine skulls verify the versatility and feasibility of the new transducer. We believe that this kind of rotatable transducer has clinical and engineering significance.

Innovative Applications of MR-Guided Focused Ultrasound for Neurological Disorders

Magnetic resonance-guided focused ultrasound (MRgFUS) is a cutting-edge technology that is changing the practice of movement disorders surgery. Given the noninvasive and innovative nature of this technology, there is great interest in expanding the use of MRgFUS to additional diseases and applications. Current approved applications target the motor thalamus to treat tremor, but clinical trials are exploring or plan to study noninvasive lesions with MRgFUS to ablate tumor cells in the brain as well as novel targets for movement disorders and brain regions associated with pain and epilepsy. Although there are additional potential indications for lesioning, the ability to improve function by destroying parts of the brain is still limited. However, MRgFUS can also be applied to a brain target after intravenous delivery of microbubbles to create cavitations and focally open the blood-brain barrier (BBB). This has already proven to be safe and technically feasible in human patients with Alzheimer's disease, and this action alone has potential to clear extracellular pathology associated with this and other neurodegenerative disorders. This also provides a foundation for noninvasive intravenous delivery of therapeutic molecules to precise brain targets after transient disruption of the BBB. Certain chemotherapies for brain tumors, immunotherapies, gene, and cell therapies are all examples of therapeutic or even restorative agents that normally will not enter the brain without direct infusion but which have been shown in preclinical studies to effectively traverse the BBB after transient disruption with MRgFUS. Here we will review these novel applications of MRgFUS to provide an overview of the extraordinary potential of this technology to expand future neurosurgical treatments of brain diseases.

The Mini Linguistic State Examination (MLSE): A standardised tool to classify and monitor primary progressive aphasia

AbstractBackgroundLanguage assessment is critical in the diagnosis of patients with neurodegenerative diseases, in particular those presenting with progressive speech and language impairment such as the primary progressive aphasias (PPA). Current diagnostic criteria identify three main variants of PPA based on clinical and neuroimaging features: semantic variant PPA ‐ characterised by dramatically reduced ability to understand the meaning of words and objects; nonfluent variant PPA – featuring problems with the grammatical and phonetic aspects of language production; and logopenic variant PPA – characterised by a striking inability to repeat spoken sentences. Most currently utilised assessments of the heterogeneous language profiles of PPA are time‐consuming and not readily comparable across languages. Improved tools to screen, diagnose, and monitor these conditions will be essential to progress in the characterisation and treatments for brain diseases underlying PPAs. The aim of the current project is to develop and fully validate English and Italian versions of an abbreviated language assessment instrument, the Mini Linguistic State Examination (MLSE), which will be able to detect the differing patterns of linguistic deficit that characterise the three variants of PPA with complete equivalence between English and Italian versions.MethodsParticipants completed the MLSE test which included tasks of picture naming, word and sentence repetition, word and sentence comprehension, semantic association, reading, writing, and picture description.ResultsData were used to present contrasting characteristics of the MLSE performance in 61 patients with PPA (20 PNFA, 17 SD, and 24 LPA), and a matched control group (40 controls; aged: 45‐75 years).ConclusionsThe MLSE will provide a much‐needed short clinical tool to classify and monitor PPA. Additionally, the MLSE will be a template for further language‐specific versions.