Using induced pluripotent stem cells derived neurons to model brain diseases

The ability to use induced pluripotent stem cells（i PSC）to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders.Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology.iPSC derived neurons,or other neural cell types,provide the ability to access pathology in cells derived directly from a patient＇s blood sample or skin biopsy where availability of brain tissue is limiting.Thus,utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future.Many brain diseases across the spectrum of neurodevelopment,neurodegenerative and neuropsychiatric are being approached by iPSC models.The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells.In this mini-review,the importance of iPSC cell models validated for pluripotency,germline competency and function assessments is discussed.Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.

Blood-derived factors to brain communication in brain diseases

Brain diseases,mainly including acute brain injuries,neurodegenerative diseases,and mental disorders,have posed a significant threat to human health worldwide.Due to the limited regenerative capability and the existence of the blood–brain barrier,the brain was previously thought to be separated from the rest of the body.Currently,various cross-talks between the central nervous system and peripheral organs have been widely described,including the brain-gut axis,the brain-liver axis,the brain-skeletal muscle axis,and the brain-bone axis.Moreover,several lines of evidence indicate that leveraging systemic biology intervention approaches,including but not limited to lifestyle interventions,exercise,diet,blood administration,and peripheral immune responses,have demonstrated a significant influence on the progress and prognosis of brain diseases.The advancement of innovative proteomic and transcriptomic technologies has enriched our understanding of the nuanced interplay between peripheral organs and brain diseases.An array of novel or previously underappreciated blood-derived factors have been identified to play pivotal roles in mediating these communications.In this review,we provide a comprehensive summary of blood-to-brain communication following brain diseases.Special attention is given to the instrumental role of blood-derived signals,positing them as significant contributors to the complex process of brain diseases.The insights presented here aim to bridge the current knowledge gaps and inspire novel therapeutic strategies for brain diseases.

Feature Enhanced Stacked Auto Encoder for Diseases Detection in Brain MRI

The detection of brain disease is an essential issue in medical and research areas.Deep learning techniques have shown promising results in detecting and diagnosing brain diseases using magnetic resonance imaging(MRI)images.These techniques involve training neural networks on large datasets of MRI images,allowing the networks to learn patterns and features indicative of different brain diseases.However,several challenges and limitations still need to be addressed further to improve the accuracy and effectiveness of these techniques.This paper implements a Feature Enhanced Stacked Auto Encoder(FESAE)model to detect brain diseases.The standard stack auto encoder’s results are trivial and not robust enough to boost the system’s accuracy.Therefore,the standard Stack Auto Encoder(SAE)is replaced with a Stacked Feature Enhanced Auto Encoder with a feature enhancement function to efficiently and effectively get non-trivial features with less activation energy froman image.The proposed model consists of four stages.First,pre-processing is performed to remove noise,and the greyscale image is converted to Red,Green,and Blue(RGB)to enhance feature details for discriminative feature extraction.Second,feature Extraction is performed to extract significant features for classification using DiscreteWavelet Transform(DWT)and Channelization.Third,classification is performed to classify MRI images into four major classes:Normal,Tumor,Brain Stroke,and Alzheimer’s.Finally,the FESAE model outperforms the state-of-theart,machine learning,and deep learning methods such as Artificial Neural Network(ANN),SAE,Random Forest(RF),and Logistic Regression(LR)by achieving a high accuracy of 98.61% on a dataset of 2000 MRI images.The proposed model has significant potential for assisting radiologists in diagnosing brain diseases more accurately and improving patient outcomes.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

Nano-imaging agents for brain diseases: Environmentally responsive imaging and therapy

Precise imaging is essential for the accurate diagnosis and surgical guidance of brain diseases but it is challenging due to the difficulties in crossing the blood-brain barrier(BBB),the difficulties in disease lesion targeting,and the limited contrast in the brain environment.Nano-imaging agents were characterized by functionalized modifications,high contrast,small size,and high biocompatibility,thus providing advantages in BBB crossing,brain targeting,imaging resolution,and real-time monitoring,holding great potential in brain disease imaging.Specific characteristics in brain environment and brain diseases(e.g.,marker proteins on the BBB,the pathogenic proteins in the neurodegenerative diseases or brain tumors,and the tumor and inflammatory microenvironment)provide opportunities for the functionalized nano-imaging agents to improve BBB crossing and disease targeting.Moreover,the versatile nano-imaging agents are endowed with therapeutic agents to facilitate the theranostics of brain diseases.Here,we summarized the common materials and imaging techniques of nano-imaging agents and their imaging treatment applications.We discussed their BBB penetration,environmental response for disease targeting,and therapeutic effects.We also provided insights on the advantages,challenges,and application of nano-imaging agents in detecting and treating brain diseases such as neurodegenerative diseases,brain tumors,stroke,and traumatic brain injury.These discussions will help develop nano-imaging agents-based theranostic platforms for the precise diagnosis and treatment of brain diseases.

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Bloode-brain barrier(BBB)strictly controls matter exchange between blood and brain,and severely limits brain penetration of systemically administered drugs,resulting in ineffective drug therapy of brain diseases.However,during the onset and progression of brain diseases,BBB alterations evolve inevitably.In this review,we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer’s disease,Parkinson’s disease,epilepsy,stroke,traumatic brain injury and brain tumor.The advances on optimization of small molecules for BBB crossing and non-systemic administration routes(e.g.,intranasal treatment)for BBB bypassing are not included in this review.

Urinary Biomarkers of Brain Diseases

Biomarkers are the measurable changes associated with a physiological or pathophysio- logical process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clin- ical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

Nanotechnologies meeting natural sources:Engineered lipoproteins for precise brain disease theranostics

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity,from preventive and diagnostic to therapeutic fields.Lipoproteins,because of their inherent blood-brain barrier permeability and lesion-homing capability,have been identified as promising strategies for high-performance theranostics of brain diseases.However,the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes,which can be critical for individual therapeutics and clinical translation.To address these issues,lipoprotein-inspired nano drug-delivery systems(nano-DDSs),which have been learned from nature,have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions.In this review,the barriers in brain disease treatment,advantages of state-of-the-art lipoprotein-inspired nano-DDSs,and bio-interactions of such nano-DDSs are highlighted.Furthermore,the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized.Specifically,the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed.Finally,the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles,such as exosomes,cell membranes,and bacteria,are discussed.

Eating Less Seems To Fend Off Brain Diseases

民间有种说法:饭胀傻瓜,酒醉智汉。当然,这更多地是酒桌上酒友们互相鼓劲的一种说法。不过,威斯康星-麦迪逊大学最近的一项研究表明,这种说法还颇富科学意蕴。该研究认为老年人节食可能对健脑有益,尤其是可减少患某些神经系统疾病(如帕金森和早老性痴呆症)的风险。当然节食应该是适当的。至于对小孩来说节食是不是可以利脑现在没有明证。因而那些因小孩厌食而成心病的父母也不应因此而有太多放松。

Staining neurons with Golgi techniques in degenerative diseases ofthe brain

A detailed morphological study of neurons in healthy and pathological conditions requires reasonably a number of special techniques, which may visualize the majority of neu- rons in a thick three-dimensional arrangement. A detailed visualization of neurons must include the cell body, most of the dendritic arbor, the dendritic spines, the axon, the axonal collaterals and the synapses. An ideal morphological technique for the study of degeneration and regeneration processes of the central nervous system must also visualize clearly the long and short neuronal circuits, as well as the dendritic and axonal bands and tracks.

Dopaminergic mediation in the brain aging and neurodegenerative diseases:a role of senescent cells

Aging is well known to be the main risk factor for the neurodegenerative pathologies,in particular,Parkinson’s disease（PD）and Alzheimer’s disease（AD）.In aging and in the diseases,similar changes in various hallmarks of neurodegeneration（lipofuscin accumulation,autophagia weakening,and disturbances in functions of mitochondriaand lysosomes） were shown （Tan et al., 2014）. Furthermore, dopami- nergic system （DAS） involvement in mechanisms of aging, PD, and AD were revealed （Martorana and Koch, 2014）.

Clearing the corpses： regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead ceils must be quickly removed to avoid the further toxic effects they exert in the pa- renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser- vation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic ceils, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro- logical disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

Advances in electrical impedance tomography-based brain imaging

Novel advances in the field of brain imaging have enabled the unprecedented clinical application of various imaging modalities to facilitate disease diagnosis and treatment. Electrical impedance tomography(EIT) is a functional imaging technique that measures the transfer impedances between electrodes on the body surface to estimate the spatial distribution of electrical properties of tissues. EIT offers many advantages over other neuroimaging technologies,which has led to its potential clinical use. This qualitative review provides an overview of the basic principles,algorithms, and system composition of EIT. Recent advances in the field of EIT are discussed in the context of epilepsy,stroke, brain injuries and edema, and other brain diseases. Further, we summarize factors limiting the development of brain EIT and highlight prospects for the field. In epilepsy imaging, there have been advances in EIT imaging depth,from cortical to subcortical regions. In stroke research, a bedside EIT stroke monitoring system has been developed for clinical practice, and data support the role of EIT in multi-modal imaging for diagnosing stroke. Additionally, EIT has been applied to monitor the changes in brain water content associated with cerebral edema, enabling the early identification of brain edema and the evaluation of mannitol dehydration. However, anatomically realistic geometry,inhomogeneity, cranium completeness, anisotropy and skull type, etc., must be considered to improve the accuracy of EIT modeling. Thus, the further establishment of EIT as a mature and routine diagnostic technique will necessitate the accumulation of more supporting evidence.

Neural stem cell therapy for brain disease

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovasculardiseases, and traumatic brain injuries, are among the major disordersinfluencing human health, currently with no effective therapy. Due to the lowregeneration capacity of neurons, insufficient secretion of neurotrophic factors,and the aggravation of ischemia and hypoxia after nerve injury, irreversible lossof functional neurons and nerve tissue damage occurs. This damage is difficult torepair and regenerate the central nervous system after injury. Neural stem cells(NSCs) are pluripotent stem cells that only exist in the central nervous system.They have good self-renewal potential and ability to differentiate into neurons,astrocytes, and oligodendrocytes and improve the cellular microenvironment.NSC transplantation approaches have been made for various neurodegenerativedisorders based on their regenerative potential. This review summarizes anddiscusses the characteristics of NSCs, and the advantages and effects of NSCs inthe treatment of brain diseases and limitations of NSC transplantation that need tobe addressed for the treatment of brain diseases in the future.

An abnormal resting-state functional brain network indicates progression towards Alzheimer's disease

Brain structure and cognitive function change in the temporal lobe, hippocampus, and prefrontal cortex of patients with mild cognitive impairment and Alzheimer＇s disease, and brain network-connection strength, network efficiency, and nodal attributes are abnormal. However, existing research has only analyzed the differences between these patients and normal controls. In this study, we constructed brain networks using resting-state functional MRI data that was extracted from four populations （nor- mal controls, patients with early mild cognitive impairment, patients with late mild cognitive impairment, and patients with Alzheimer＇s disease） using the Alzheimer＇s Disease Neuroimaging Initiative data set. The aim was to analyze the characteristics of resting-state functional neural networks, and to observe mild cognitive impairment at different stages before the transformation to Alzheimer＇s disease. Results showed that as cognitive deficits increased across the four groups, the shortest path in the rest- ing-state functional network gradually increased, while clustering coefficients gradually decreased. This evidence indicates that dementia is associated with a decline of brain network efficiency. In addi- tion, the changes in functional networks revealed the progressive deterioration of network function across brain regions from healthy elderly adults to those with mild cognitive impairment and AIz- heimer＇s disease. The alterations of node attributes in brain regions may reflect the cognitive functions in brain regions, and we speculate that early impairments in memory, hearing, and language function can eventually lead to diffuse brain injury and other cognitive impairments.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats

Administration of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)is believed to be an effective method for treating neurodevelopmental disorde rs.In this study,we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism.We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy.Rat offspring were intranasally administe red hUC-MSCs on postnatal day 14.We found that polypyrimidine tract-binding protein-1(PTBP-1)participated in the regulation of lipopolysaccharide-induced maternal immune activation,which led to neonatal hypoxic/ischemic brain injury.Intranasal delive ry of hUC-MSCs inhibited PTBP-1 expression,alleviated neonatal brain injury-related inflammation,and regulated the number and function of glial fibrillary acidic protein-positive astrocytes,there by promoting plastic regeneration of neurons and im p roving brain function.These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

The brain as a source and a target of prolactin in mammals

Prolactin is a polypeptide hormone associated with an extensive variety of biological functions.Among the roles of prolactin in vertebrates,some were preserved throughout evolution.This is the case of its function in the brain,where prolactin receptors,are expressed in different structures of the central nervous system.In the brain,prolactin actions are principally associated with reproduction and parental behavior,and involves the modulation of adult neurogenesis,neuroprotection,and neuroplasticity,especially during pregnancy,thereby preparing the brain to parenthood.Prolactin is mainly produced by specialized cells in the anterior pituitary gland.However,during vertebrate evolution many other extrapituitary tissues do also produce prolactin,like the immune system,endothelial cells,reproductive structures and in several regions of the brain.This review summarizes the relevance of prolactin for brain function,the sources of prolactin in the central nervous system,as well as its local production and secretion.A highlight on the impact of prolactin in human neurological diseases is also provided.

Functional magnetic resonance imaging and the brain: A brief review

Functional magnetic resonance imaging(fMRI) is em-ployed in many behavior analysis studies, with blood oxygen level dependent-(BOLD-) contrast imaging being the main method used to generate images. The use of BOLD-contrast imaging in f MRI has been refined over the years, for example, the inclusion of a spin echo pulse and increased magnetic strength were shown to produce better recorded images. Taking careful precautions to control variables during measurement, comparisons between different specimen groups can be illustrated by f MRI imaging using both quantitative and qualitative methods. Differences have been observed in comparisons of active and resting, developing and aging, and defective and damaged brains in various studies. However, cognitive studies using f MRI still face a number of challenges in interpretation that can only be overcome by imaging large numbers of samples. Furthermore, f MRI studies of brain cancer, lesions and other brain pathologies of both humans and animals are still to be explored.

Not only a bad guy:potential proneurogenic role of the RAGE/NF-κB axis in Alzheimer's disease brain

The receptor for advanced glycation endproducts（RAGE）is a receptor of the immunoglobulin superfamily of cell surface molecules which plays important contributions under both physiological and pathological conditions.Over the years extensive research work supported the detrimental role of RAGE in Alzheimer’s disease（AD）pathophysiology,ranging from its involvement in beta amyloid（Aβ）brain influx and clearance,