N-Acetylaspartate Is an Important Brain Osmolyte

Most of the human diseases related to various proteopathies are confined to the brain, which leads to the development of various forms of neurological disorders. The human brain consists of several osmolytic compounds, such as N-Acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), glutamine (Gln), creatine (Cr), and choline-containing compounds (Cho). Among these osmolytes, the level of NAA drastically decreases under neurological conditions, and, hence, NAA is considered to be one of the most widely accepted neuronal biomarkers in several human brain disorders. To date, no data are available regarding the effect of NAA on protein stability, and, therefore, the possible effect of NAA under proteopathic conditions has not been fully uncovered. To gain an insight into the effect of NAA on protein stability, thermal denaturation and structural measurements were carried out using two model proteins at different pH values. The results indicate that NAA increases the protein stability with an enhancement of structure formation. We also observed that the stabilizing ability of NAA decreases in a pH-dependent manner. Our study indicates that NAA is an efficient protein stabilizer at a physiological pH.

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Brain/MINDS Beyond Human Brain MRI Project: A Protocol for Multi-Site Harmonization across Brain Disorders Throughout the Lifespan

10.1101/2020.05.05.076273 ◽

2020 ◽

Author(s):

Shinsuke Koike ◽

Saori C Tanaka ◽

Tomohisa Okada ◽

Toshihiko Aso ◽

Michiko Asano ◽

...

Keyword(s):

Human Brain ◽

Neurological Disorders ◽

Mixed Model ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Clinical Information ◽

Imaging Biomarkers ◽

Brain Disorders ◽

Human Connectome Project ◽

The Brain

AbstractPsychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (FY2018 ∼ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. The Harmonization protocol (HARP) was established for five high-quality 3T scanners to obtain multimodal brain images including T1 and T2-weighted, resting state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, providing high reproducibility and sensitivity to subject-specific connectome. A total of 75 TS, as well as patients with various psychiatric and neurological disorders, are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a rigorous, prospective harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

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The gut-microbiota-brain axis in autism: what Drosophila models can offer?

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09378-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Safa Salim ◽

Ayesha Banu ◽

Amira Alwa ◽

Swetha B. M. Gowda ◽

Farhan Mohammad

Keyword(s):

Gut Microbiota ◽

Gut Microbiome ◽

Neurological Disorders ◽

Autism Spectrum ◽

Brain Disorders ◽

Mediated Communication ◽

The Impact ◽

Insight Into ◽

Drosophila Models

AbstractThe idea that alterations in gut-microbiome-brain axis (GUMBA)-mediated communication play a crucial role in human brain disorders like autism remains a topic of intensive research in various labs. Gastrointestinal issues are a common comorbidity in patients with autism spectrum disorder (ASD). Although gut microbiome and microbial metabolites have been implicated in the etiology of ASD, the underlying molecular mechanism remains largely unknown. In this review, we have summarized recent findings in human and animal models highlighting the role of the gut-brain axis in ASD. We have discussed genetic and neurobehavioral characteristics of Drosophila as an animal model to study the role of GUMBA in ASD. The utility of Drosophila fruit flies as an amenable genetic tool, combined with axenic and gnotobiotic approaches, and availability of transgenic flies may reveal mechanistic insight into gut-microbiota-brain interactions and the impact of its alteration on behaviors relevant to neurological disorders like ASD.

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Cost of Brain Disorders in Italy – A Review

European Neurological Review ◽

10.17925/enr.2009.04.02.120 ◽

2009 ◽

Vol 4 (2) ◽

pp. 120

Author(s):

Maura Pugliatti ◽

Paola Cossu ◽

Patrik Sobocki ◽

Ettore Beghi ◽

◽

...

Keyword(s):

Neurological Disorders ◽

Disease Burden ◽

Psychotic Disorders ◽

Ad Hoc ◽

Cost Model ◽

Adult Mortality ◽

Brain Disorders ◽

European Brain ◽

Socioeconomic Burden ◽

The Brain

Brain disorders represent 35% of the total disease burden in Europe and 37% of the total disease burden in European regions with very low child mortality and low adult mortality; the latter group includes Italy. The negative socioeconomic impact of this burden is reflected in two fundamental issues: consumption of resources and state of health. In recent years, the European Brain Council (EBC), a co-ordinating council formed by European organisations and patient associations in neurological disorders, has encouraged and supported projects aimed at analysing the socioeconomic burden of brain disorders in Europe. Within the EBC, the pan-European study on Cost of Disorders of the Brain in Europe (CDBE) aimed at reporting the best possible estimates of the societal cost of 12 brain disorders (addiction, affective disorders, anxiety disorders, tumours, dementia, epilepsy, migraine and other headaches, multiple sclerosis, Parkinson's disease, psychotic disorders, stroke and trauma) based on the existing literature, using an ad hoc cost model. The aggregated results for Italy from the CDBE study are reviewed in this paper.

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Regional selection of the brain size regulating gene CASC5 provides new insight into human brain evolution

Human Genetics ◽

10.1007/s00439-016-1748-5 ◽

2016 ◽

Vol 136 (2) ◽

pp. 193-204 ◽

Cited By ~ 6

Author(s):

Lei Shi ◽

Enzhi Hu ◽

Zhenbo Wang ◽

Jiewei Liu ◽

Jin Li ◽

...

Keyword(s):

Human Brain ◽

Brain Size ◽

Brain Evolution ◽

Human Brain Evolution ◽

The Brain ◽

Insight Into ◽

Selection Of

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Analysis of shared heritability in common disorders of the brain

Science ◽

10.1126/science.aap8757 ◽

2018 ◽

Vol 360 (6395) ◽

pp. eaap8757 ◽

Cited By ~ 362

Author(s):

◽

Verneri Anttila ◽

Brendan Bulik-Sullivan ◽

Hilary K. Finucane ◽

Raymond K. Walters ◽

...

Keyword(s):

Psychiatric Disorders ◽

Neurological Disorders ◽

Statistical Power ◽

Association Studies ◽

Genetic Correlations ◽

Genome Wide Association Studies ◽

Brain Disorders ◽

Cognitive Measures ◽

Genome Wide ◽

The Brain

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

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IL-6 stimulates a concentration-dependent increase in MCP-1 in immortalised human brain endothelial cells

F1000Research ◽

10.12688/f1000research.8153.2 ◽

2016 ◽

Vol 5 ◽

pp. 270 ◽

Cited By ~ 3

Author(s):

Jai Min Choi ◽

Odunayo O. Rotimi ◽

Simon J. O'Carroll ◽

Louise F.B. Nicholson

Keyword(s):

Endothelial Cells ◽

Human Brain ◽

Systemic Inflammation ◽

Systemic Circulation ◽

Dependent Manner ◽

Brain Endothelial Cells ◽

Concentration Dependent Manner ◽

Inflammatory Conditions ◽

Increased Risk ◽

The Brain

Systemic inflammation is associated with neurodegeneration, with elevated interleukin-6 (IL-6) in particular being correlated with an increased risk of dementia. The brain endothelial cells of the blood brain barrier (BBB) serve as the interface between the systemic circulation and the brain microenvironment and are therefore likely to be a key player in the development of neuropathology associated with systemic inflammation. Endothelial cells are known to require soluble IL-6 receptor (sIL-6R) in order to respond to IL-6, but studies in rat models have shown that this is not the case for brain endothelial cells and studies conducted in human cells are limited. Here we report for the first time that the human cerebral microvascular cell line, hCMVEC, uses the classical mIL-6R signalling pathway in response to IL-6 in a concentration-dependent manner as measured by the production of monocyte chemotactic protein (MCP-1). This novel finding highlights a unique characteristic of human brain endothelial cells and that further investigation into the phenotype of this cell type is needed to elucidate the mechanisms of BBB pathology in inflammatory conditions.

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Not Just a Bystander: The Emerging Role of Astrocytes and Research Tools in Studying Cognitive Dysfunctions in Schizophrenia

International Journal of Molecular Sciences ◽

10.3390/ijms22105343 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5343

Author(s):

Chia-Yuan Chang ◽

Da-Zhong Luo ◽

Ju-Chun Pei ◽

Ming-Che Kuo ◽

Yi-Chen Hsieh ◽

...

Keyword(s):

Cognitive Deficits ◽

Negative Symptoms ◽

Brain Disorders ◽

Serotoninergic Neurons ◽

Schizophrenic Patients ◽

Core Symptoms ◽

Behavioral Methods ◽

The Brain ◽

Insight Into

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood–brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.

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Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis

Frontiers in Nutrition ◽

10.3389/fnut.2021.783659 ◽

2021 ◽

Vol 8 ◽

Author(s):

Angela M. Poff ◽

Sara Moss ◽

Maricel Soliven ◽

Dominic P. D'Agostino

Keyword(s):

Neurological Disorders ◽

Motor Performance ◽

Therapeutic Strategy ◽

Preliminary Evidence ◽

Energy Crisis ◽

Seizure Disorders ◽

Neurological Conditions ◽

The Brain ◽

Brain Energy ◽

Glucose Hypometabolism

Diverse neurological disorders are associated with a deficit in brain energy metabolism, often characterized by acute or chronic glucose hypometabolism. Ketones serve as the brain's only significant alternative fuel and can even become the primary fuel in conditions of limited glucose availability. Thus, dietary supplementation with exogenous ketones represents a promising novel therapeutic strategy to help meet the energetic needs of the brain in an energy crisis. Preliminary evidence suggests ketosis induced by exogenous ketones may attenuate damage or improve cognitive and motor performance in neurological conditions such as seizure disorders, mild cognitive impairment, Alzheimer's disease, and neurotrauma.

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Integration of Multimodal Data for Deciphering Brain Disorders

Annual Review of Biomedical Data Science ◽

10.1146/annurev-biodatasci-092820-020354 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Jingqi Chen ◽

Guiying Dong ◽

Liting Song ◽

Xingzhong Zhao ◽

Jixin Cao ◽

...

Keyword(s):

Human Brain ◽

Data Science ◽

Annual Review ◽

Publication Date ◽

Biomedical Data ◽

Brain Disorders ◽

Multimodal Data ◽

Future Data ◽

The Brain ◽

Shed Light

The accumulation of vast amounts of multimodal data for the human brain, in both normal and disease conditions, has provided unprecedented opportunities for understanding why and how brain disorders arise. Compared with traditional analyses of single datasets, the integration of multimodal datasets covering different types of data (i.e., genomics, transcriptomics, imaging, etc.) has shed light on the mechanisms underlying brain disorders in greater detail across both the microscopic and macroscopic levels. In this review, we first briefly introduce the popular large datasets for the brain. Then, we discuss in detail how integration of multimodal human brain datasets can reveal the genetic predispositions and the abnormal molecular pathways of brain disorders. Finally, we present an outlook on how future data integration efforts may advance the diagnosis and treatment of brain disorders. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 4 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14−/− Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22136773 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6773

Author(s):

Yuze Wu ◽

Guojun Wei ◽

Ningning Zhao

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Small Intestine ◽

Neurological Disorders ◽

The Body ◽

Future Studies ◽

The Central Nervous System ◽

Manganese Transport ◽

The Brain ◽

Insight Into

As a newly identified manganese transport protein, ZIP14 is highly expressed in the small intestine and liver, which are the two principal organs involved in regulating systemic manganese homeostasis. Loss of ZIP14 function leads to manganese overload in both humans and mice. Excess manganese in the body primarily affects the central nervous system, resulting in irreversible neurological disorders. Therefore, to prevent the onset of brain manganese accumulation becomes critical. In this study, we used Zip14−/− mice as a model for ZIP14 deficiency and discovered that these mice were born without manganese loading in the brain, but started to hyper-accumulate manganese within 3 weeks after birth. We demonstrated that decreasing manganese intake in Zip14−/− mice was effective in preventing manganese overload that typically occurs in these animals. Our results provide important insight into future studies that are targeted to reduce the onset of manganese accumulation associated with ZIP14 dysfunction in humans.

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