Virus-Shaped Mesoporous Silica Nanostars to Improve the Transport of Drugs across the Blood-Brain Barrier.

Conditions affecting the brain are the second leading cause of death globally. One of the main challenges for drugs targeting brain diseases is passing the blood-brain barrier (BBB). Here, the effectiveness of mesoporous silica nanostars (MSiNSs) with two different spike lengths to cross an in vitro BBB multicellular model was evaluated and compared to spherical nanoparticles (MSiNP). A modified sol-gel single-micelle epitaxial growth was used to produce MSiNS, which showed no cytotoxicity or immunogenicity at concentrations of up to 1 µg mL-1 in peripheral blood mononuclear and neuronal cells. The nanostar MSiNS effectively penetrated the BBB model after 24 h, and MSiNS-1 with a shorter spike length (9 ± 2 nm) crossed the in vitro BBB model more rapidly than the MSiNS-2 with longer spikes (18 ± 4 nm) or spherical MSiNP at 96 h, which accumulated in the apical and basolateral sides, respectively. Molecular dynamic simulations illustrated an increase in configurational flexibility of the lipid bilayer during contact with the MSiNS, resulting in wrapping, whereas the MSiNP suppressed membrane fluctuations. This work advances an effective brain drug delivery system based on virus-like shaped MSiNS for the treatment of different brain diseases and a mechanism for their interaction with lipid bilayers.

Common Neurologic Diseases in Geriatric Dogs.

The increase in the canine geriatric population means that veterinarians are more often confronted with diseases that are more prevalent in patients in this age group. As in other organ systems, degenerative, neoplastic, and vascular diseases are the most prevalent neurologic disorders in older dogs. A neurological disease in an older dog poses a challenge for the clinician due to the presence of concomitant diseases and age-related changes that make it difficult to interpret the neurological examination. In addition, given the age of the patients, some owners do not allow advanced imaging tests, and it is necessary to establish the most likely presumptive diagnosis to initiate treatment. Although many of these diseases can cause clinical signs that can be very upsetting, some of them can be managed with symptomatic therapy and have a good prognosis, such as idiopathic vestibular syndrome. Moreover, advances in and the greater availability of therapeutic options such as surgery and radiation therapy may increase survival and quality of life in diseases with a more serious prognosis, such as tumours. The aim of this review is to summarize the clinical presentation, diagnosis, and treatment of the more frequent diseases affecting the central nervous systems of geriatric dogs.

Application of novel CRISPR tools in brain therapy.

In recent years, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based genome editing toolkit has been widely used to modify the genome sequence of organisms. As the CRISPR toolbox continues to grow and new CRISPR-associated (Cas) proteins are discovered, its applications have expanded beyond conventional genome editing. This now encompass epigenetic editing, gene expression control, and various other functions. Notably, these advancements are finding practical application in the treatment of brain diseases. Furthermore, the amalgamation of CRISPR and Chimeric Antigen Receptor T-cell (CAR-T) technologies has emerged as a potential approach for disease treatment. With this in mind, this review commences by offering a comprehensive overview of recent advancements in CRISPR gene editing tools. This encompasses an exploration of various Cas proteins, gene expression control, epigenetic editing, base editing and primer editing. Additionally, we present an in-depth examination of the manifold applications of these innovative CRISPR tools in the realms of brain therapeutics, such as neurodegenerative diseases, neurological syndromes and genetic disorders, epileptic disorders, and brain tumors, also explore the pathogenesis of these diseases. This includes their utilization in modeling, gene screening, therapeutic gene editing, as well as their emerging synergy with CAR-T technology. Finally, we discuss the remaining technical challenges that need to be addressed for effective utilization of CRISPR tools in disease treatment.

The impact of ATP-binding cassette transporters in the diseased brain: Context matters.

ATP-binding cassette (ABC) transporters facilitate the movement of diverse molecules across cellular membranes, including those within the CNS. While most extensively studied in microvascular endothelial cells forming the blood-brain barrier (BBB), other CNS cell types also express these transporters. Importantly, disruptions in the CNS microenvironment during disease can alter transporter expression and function. Through this comprehensive review, we explore the modulation of ABC transporters in various brain pathologies and the context-dependent consequences of these changes. For instance, downregulation of ABCB1 may exacerbate amyloid beta plaque deposition in Alzheimer's disease and facilitate neurotoxic compound entry in Parkinson's disease. Upregulation may worsen neuroinflammation by aiding chemokine-mediated CD8 T cell influx into multiple sclerosis lesions. Overall, ABC transporters at the BBB hinder drug entry, presenting challenges for effective pharmacotherapy. Understanding the context-dependent changes in ABC transporter expression and function is crucial for elucidating the etiology and developing treatments for brain diseases.

Deep Learning for Alzheimer's Disease Prediction: A Comprehensive Review.

Alzheimer's disease (AD) is a neurological disorder that significantly impairs cognitive function, leading to memory loss and eventually death. AD progresses through three stages: early stage, mild cognitive impairment (MCI) (middle stage), and dementia. Early diagnosis of Alzheimer's disease is crucial and can improve survival rates among patients. Traditional methods for diagnosing AD through regular checkups and manual examinations are challenging. Advances in computer-aided diagnosis systems (CADs) have led to the development of various artificial intelligence and deep learning-based methods for rapid AD detection. This survey aims to explore the different modalities, feature extraction methods, datasets, machine learning techniques, and validation methods used in AD detection. We reviewed 116 relevant papers from repositories including Elsevier (45), IEEE (25), Springer (19), Wiley (6), PLOS One (5), MDPI (3), World Scientific (3), Frontiers (3), PeerJ (2), Hindawi (2), IO Press (1), and other multiple sources (2). The review is presented in tables for ease of reference, allowing readers to quickly grasp the key findings of each study. Additionally, this review addresses the challenges in the current literature and emphasizes the importance of interpretability and explainability in understanding deep learning model predictions. The primary goal is to assess existing techniques for AD identification and highlight obstacles to guide future research.

Use of neurofilament light chain to identify structural brain diseases in dogs.

BACKGROUND: Neurofilament light chain (NfL) is released into the peripheral circulation by damaged axons. OBJECTIVES: To evaluate the diagnostic value of serum NfL concentration in dogs with intracranial diseases. ANIMALS: Study included 37 healthy dogs, 31 dogs with idiopathic epilepsy (IE), 45 dogs with meningoencephalitis of unknown etiology (MUE), 20 dogs with hydrocephalus, and 19 dogs with brain tumors. METHODS: Cohort study. Serum NfL concentrations were measured in all dogs using single-molecule array technology. RESULTS: Serum NfL concentration in dogs with each structural disease was significantly higher than in healthy dogs and dogs with IE (P = .01). The area under the receiver operating characteristic curve of NfL for differentiating between dogs with structural diseases and IE was 0.868. An optimal cutoff value of the NfL 27.10 pg/mL had a sensitivity of 86.67% and a specificity of 74.19% to differentiate the dogs with IE from those with structural brain diseases. There were significant correlations between NfL concentrations and lesion size: (1) MUE, P = .01, r = 0.429; (2) hydrocephalus, P = .01, r = 0.563. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum NfL could be a useful biomarker for distinguishing IE from structural diseases in dogs and predicting the lesion sizes of MUE and hydrocephalus.

Effective cryopreservation of human brain tissue and neural organoids.

Human brain tissue models and organoids are vital for studying and modeling human neurological disease. However, the high cost of long-term cultured organoids inhibits their wide-ranging application. It is therefore urgent to develop methods for the cryopreservation of brain tissue and organoids. Here, we establish a method using methylcellulose, ethylene glycol, DMSO, and Y27632 (termed MEDY) for the cryopreservation of cortical organoids without disrupting the neural cytoarchitecture or functional activity. MEDY can be applied to multiple brain-region-specific organoids, including the dorsal/ventral forebrain, spinal cord, optic vesicle brain, and epilepsy patient-derived brain organoids. Additionally, MEDY enables the cryopreservation of human brain tissue samples, and pathological features are retained after thawing. Transcriptomic analysis shows that MEDY can protect synaptic function and inhibit the endoplasmic reticulum-mediated apoptosis pathway. MEDY will enable the large-scale and reliable storage of diverse neural organoids and living brain tissue and will facilitate wide-ranging research, medical applications, and drug screening.

Revolutionizing Neurocare: Biomimetic Nanodelivery Via Cell Membranes.

Brain disorders represent a significant challenge in medical science due to the formidable blood-brain barrier (BBB), which severely limits the penetration of conventional therapeutics, hindering effective treatment strategies. This review delves into the innovative realm of biomimetic nanodelivery systems, including stem cell-derived nanoghosts, tumor cell membrane-coated nanoparticles, and erythrocyte membrane-based carriers, highlighting their potential to circumvent the BBB's restrictions. By mimicking native cell properties, these nanocarriers emerge as a promising solution for enhancing drug delivery to the brain, offering a strategic advantage in overcoming the barrier's selective permeability. The unique benefits of leveraging cell membranes from various sources is evaluated and advanced technologies for fabricating cell membrane-encapsulated nanoparticles capable of masquerading as endogenous cells are examined. This enables the targeted delivery of a broad spectrum of therapeutic agents, ranging from small molecule drugs to proteins, thereby providing an innovative approach to neurocare. Further, the review contrasts the capabilities and limitations of these biomimetic nanocarriers with traditional delivery methods, underlining their potential to enable targeted, sustained, and minimally invasive treatment modalities. This review is concluded with a perspective on the clinical translation of these biomimetic systems, underscoring their transformative impact on the therapeutic landscape for intractable brain diseases.

Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children.

Apart from the typical respiratory symptoms, coronavirus disease 2019 (COVID-19) also affects the central nervous system, leading to central disorders such as encephalopathy and encephalitis. However, knowledge of pediatric COVID-19-associated encephalopathy is limited, particularly regarding specific subtypes of encephalopathy. This study aimed to assess the features of COVID-19-associated encephalopathy/encephalitis in children. We retrospectively analyzed a single cohort of 13 hospitalized children with COVID-19-associated encephalopathy. The primary outcome was the descriptive analysis of the clinical characteristics, magnetic resonance imaging and electroencephalography findings, treatment progression, and outcomes. Thirteen children among a total of 275 (5%) children with confirmed COVID-19 developed associated encephalopathy/encephalitis (median age, 35 months; range, 3-138 months). Autoimmune encephalitis was present in six patients, acute necrotizing encephalopathy in three, epilepsy in three, and central nervous system small-vessel vasculitis in one patient. Eight (62%) children presented with seizures. Six (46%) children exhibited elevated blood inflammatory indicators, cerebrospinal fluid inflammatory indicators, or both. Two (15%) critically ill children presented with multi-organ damage. The magnetic resonance imaging findings varied according to the type of encephalopathy/encephalitis. Electroencephalography revealed a slow background rhythm in all 13 children, often accompanied by epileptic discharges. Three (23%) children with acute necrotizing encephalopathy had poor prognoses despite immunotherapy and other treatments. Ten (77%) children demonstrated good functional recovery without relapse. This study highlights COVID-19 as a new trigger of encephalopathy/encephalitis in children. Autoimmune encephalitis is common, while acute necrotizing encephalopathy can induce poor outcomes. These findings provide valuable insights into the impact of COVID-19 on children's brains.

Bibliometric analysis of hot literature on neural circuit research.

Numerous brain diseases have been attributed to abnormalities in the connections of neural circuits. Exploration of neural circuits may give enlightenment in treating some intractable brain diseases. Here, we screened all publications on neural circuits in the Web of Science database from 2007 to 2022 and analyzed the research trends through VOSviewer, CiteSpace, Microsoft Excel 2019, and Origin. The findings revealed a consistent upward trend in research on neural circuits during this period. The United States emerged as the leading contributor, followed by China and Japan. Among the top 10 institutions with the largest number of publications, both the United States and China have a strong presence. Notably, the Chinese Academy of Sciences demonstrated the highest publication output, closely followed by Stanford University. In terms of influential authors, Karl Deisseroth stood out as one of the most prominent investigators. During this period, the majority of publications and citations on neural circuit research were found in highly influential journals including NEURON, NATURE JOURNAL OF NEUROSCIENCE, and so forth. Keyword clustering analysis highlighted the increasing focus on neural circuits and photogenetics in neuroscience research, and the reconstruction of neural circuits has emerged as a crucial research direction in brain science. In conclusion, over the past 15 years, the increasing high-quality publications have facilitated research development of neural circuits, indicating a promising prospect for investigations on neurological and psychiatric diseases.

Neurofilament light chain but not glial fibrillary acidic protein is a potential biomarker of overt hepatic encephalopathy in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Hepatic encephalopathy (HE) is a frequent complication of cirrhosis and may cause cerebral damage. Neurodegenerative diseases can induce the release of neuroproteins like neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in body fluids, including blood plasma. We investigated whether NfL and GFAP could serve as potential diagnostic plasma biomarkers for overt HE (oHE). MATERIALS AND METHODS: We included 85 patients from three prospective cohorts with different stages of liver disease and HE severity. The following patients were included: 1) 34 patients with primary sclerosing cholangitis (PSC) with compensated disease; 2) 17 patients with advanced liver disease without oHE before elective transjugular intrahepatic portosystemic shunt (TIPS) placement; 3) 17 intensive care unit (ICU) patients with oHE and 17 ICU patients without cirrhosis or oHE. Plasma NfL and GFAP were measured using single molecule assays. RESULTS: ICU oHE patients had higher NfL concentrations compared to pre-TIPS patients or ICU controls (p < 0.05, each). Median GFAP concentrations were equal in the ICU oHE and pre-TIPS patients or ICU controls. Plasma NfL and GFAP concentrations correlated with Model for End-Stage Liver Disease (MELD) scores (R = 0.58 and R = 0.40, p < 0.001, each). CONCLUSIONS: Plasma NfL deserves further evaluation as potential diagnostic biomarker for oHE and correlates with the MELD score.

Copines, a Family of Calcium Sensor Proteins and Their Role in Brain Function.

The Copines are a family of evolutionary conserved calcium-binding proteins found in most eukaryotic organisms from protists to humans. They share a unique architecture and contain tandem C2 domains and a Von Willebrand factor type A (VWA) domain. C2 domains in Copines bind calcium, phospholipids, and other proteins and mediate the transient association of these proteins with biological membranes at elevated calcium levels. The VWA domain also binds calcium and is involved in protein-protein interactions. Here, we provide a comprehensive review of the sequences, structures, expression, targeting, and function of the entire family of known Copine proteins (Copine 1-9 in mammals) with a particular emphasis on their functional roles in the mammalian brain. Neuronal Copines are implicated in a wide array of processes from cell differentiation to synaptic transmission and plasticity and are also linked to several pathological conditions from cancers to brain diseases. This review provides the most up-to-date insights into the structure and function of Copines, with an emphasis on their role in brain function.

Swimming short fibrous nasal drops achieving intraventricular administration.

Adequate drug delivery across the blood-brain barrier (BBB) is a critical factor in treating central nervous system (CNS) disorders. Inspired by swimming fish and the microstructure of the nasal cavity, this study is the first to develop swimming short fibrous nasal drops that can directly target the nasal mucosa and swim in the nasal cavity, which can effectively deliver drugs to the brain. Briefly, swimming short fibrous nasal drops with charged controlled drug release were fabricated by electrospinning, homogenization, the π-π conjugation between indole group of fibers, the benzene ring of leucine-rich repeat kinase 2 (LRRK2) inhibitor along with charge-dipole interaction between positively charged poly-lysine (PLL) and negatively charged surface of fibers; this enabled these fibers to stick to nasal mucosa, prolonged the residence time on mucosa, and prevented rapid mucociliary clearance. In vitro, swimming short fibrous nasal drops were biocompatible and inhibited microglial activation by releasing an LRRK2 inhibitor. In vivo, luciferase-labelled swimming short fibrous nasal drops delivered an LRRK2 inhibitor to the brain through the nasal mucosa, alleviating cognitive dysfunction caused by sepsis-associated encephalopathy by inhibiting microglial inflammation and improving synaptic plasticity. Thus, swimming short fibrous nasal drops is a promising strategy for the treatment of CNS diseases.

Identification of gene biomarkers for brain diseases via multi-network topological semantics extraction and graph convolutional network.

BACKGROUND: Brain diseases pose a significant threat to human health, and various network-based methods have been proposed for identifying gene biomarkers associated with these diseases. However, the brain is a complex system, and extracting topological semantics from different brain networks is necessary yet challenging to identify pathogenic genes for brain diseases. RESULTS: In this study, we present a multi-network representation learning framework called M-GBBD for the identification of gene biomarker in brain diseases. Specifically, we collected multi-omics data to construct eleven networks from different perspectives. M-GBBD extracts the spatial distributions of features from these networks and iteratively optimizes them using Kullback-Leibler divergence to fuse the networks into a common semantic space that represents the gene network for the brain. Subsequently, a graph consisting of both gene and large-scale disease proximity networks learns representations through graph convolution techniques and predicts whether a gene is associated which brain diseases while providing associated scores. Experimental results demonstrate that M-GBBD outperforms several baseline methods. Furthermore, our analysis supported by bioinformatics revealed CAMP as a significantly associated gene with Alzheimer's disease identified by M-GBBD. CONCLUSION: Collectively, M-GBBD provides valuable insights into identifying gene biomarkers for brain diseases and serves as a promising framework for brain networks representation learning.

Riding waves to improve functioning: a quantitative evaluation of a Surf Week in individuals with chronic phase brain injury with six months follow-up.

PURPOSE: Environmental enrichment seems to enable people in the chronic phase of acquired brain injury (ABI) to experience new functional abilities and motor/coping strategies and consequently to become more adaptable which might prevent/reverse functional decline. This study describes the influence of a five-days Surf Week program on participants on physical function, self-efficacy, functional balance performance and self-perceived recovery. MATERIALS AND METHODS: A multiple-baseline single-case design was used. Adults participating in the Surf Week in chronic phase of ABI were eligible to participate. Participants completed a battery of tests monitoring physical function, self-efficacy, functional balance performance and self-perceived recovery. This battery was repeated 5 times over a 1-year period, two times pre-Surf Week, three times post-Surf Week. Visual data inspection with two non-overlap methods were used to determine if patients showed sustained improvement in outcomes post-intervention. RESULTS: A moderate to strong indication for improvements on physical function, functional balance performance and self-perceived recovery exists till six months follow-up. No indication was observed on self-efficacy till six months follow-up. CONCLUSIONS: A five-days Surf Week is a physically, cognitively and socially intensive stimulating activity that can positively challenge individuals after ABI and seems to improve physical functioning, functional balance performance and self-perceived recovery.

Surf therapy, if appropriate measures are taken, is a safe yet physically, cognitively and socially intensive stimulating intervention that capitalizes on enriched environment principles, and might address the holistic needs in this population.Surf therapy might positively influence physical function, balance and self-perceived recovery in adults with acquired brain injury in the chronic phase.Rehabilitation professionals should experience/explore with their patients with acquired brain injury challenging (group) outdoors activities such as these, aiming to meet patients' needs, interests, or values in the chronic phase of recovery, and so create successfully participation in activities that capitalizes on enriched environment principles.

41-Year-Old Male with Sub-Acute Encephalopathy, Seizures, and End Stage Renal Disease: A Unifying Diagnosis and Response to Therapy.

We describe a case of a 41-year-old male with a history of end-stage renal disease, hypertension, epilepsy, ischemic stroke, and traumatic brain injury transferred to our tertiary care center for subacute, progressive cognitive impairment. He was found to have disproportionate brain atrophy, focal seizures, and refractory hypertension. Given suspicion for an underlying genetic etiology, a genetic panel for progressive renal disease was sent, revealing two known pathogenic variants in a gene for a cobalamin metabolism disorder, Cobalamin C deficiency. He was started on targeted metabolic supplementation with subsequent improvement in his cognition. Our case highlights the crucial need to expand diagnostic workup to include genetic and metabolic causes in patients with neurologic disease, atypical features, relevant family history and multi-organ dysfunction.

Phototherapy for age-related brain diseases: Challenges, successes and future.

Brain diseases present a significant obstacle to both global health and economic progress, owing to their elusive pathogenesis and the limited effectiveness of pharmaceutical interventions. Phototherapy has emerged as a promising non-invasive therapeutic modality for addressing age-related brain disorders, including stroke, Alzheimer's disease (AD), and Parkinson's disease (PD), among others. This review examines the recent progressions in phototherapeutic interventions. Firstly, the article elucidates the various wavelengths of visible light that possess the capability to penetrate the skin and skull, as well as the pathways of light stimulation, encompassing the eyes, skin, veins, and skull. Secondly, it deliberates on the molecular mechanisms of visible light on photosensitive proteins, within the context of brain disorders and other molecular pathways of light modulation. Lastly, the practical application of phototherapy in diverse clinical neurological disorders is indicated. Additionally, this review presents novel approaches that combine phototherapy and pharmacological interventions. Moreover, it outlines the limitations of phototherapeutics and proposes innovative strategies to improve the treatment of cerebral disorders.

Cation-independent mannose 6-phosphate receptor: From roles and functions to targeted therapies.

The cation-independent mannose 6-phosphate receptor (CI-M6PR) is a ubiquitous transmembrane receptor whose main intracellular role is to direct enzymes carrying mannose 6-phosphate moieties to lysosomal compartments. Recently, the small membrane-bound portion of this receptor has appeared to be implicated in numerous pathophysiological processes. This review presents an overview of the main ligand partners and the roles of CI-M6PR in lysosomal storage diseases, neurology, immunology and cancer fields. Moreover, this membrane receptor has already been noted for its strong potential in therapeutic applications thanks to its cellular internalization activity and its ability to address pathogenic factors to lysosomes for degradation. A number of therapeutic delivery approaches using CI-M6PR, in particular with enzymes, antibodies or nanoparticles, are currently being proposed.

Familial Alzheimer's disease associated with heterozygous NPC1 mutation.

INTRODUCTION: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation. METHODS: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. RESULTS: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1, shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3ß,5α,6ß-triol. DISCUSSION: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.