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Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.

The heterogeneity of Parkinson’s disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut–brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.

The use of therapeutic antibodies for treating diseases in the CNS is hampered by the blood-brain barrier (BBB). In this issue, Edavettal et al.1 report on a novel bioengineered antibody not only capable of passing the BBB but also for intervening in pathological protein deposition and subsequent induction of clearing by microglia.

Osteopontin (OPN) is a multifunctional protein found in all vertebrates. OPN is expressed in many different cell types, and is consequently found in most tissues and physiological secretions. OPN is involved in a multitude of biological processes, such as activation and regulation of the immune system; biomineralization; tissue-transformative processes, including growth and development of the gut and brain; interaction with bacteria; and many more. OPN is found in the highest concentrations in milk, where it is believed to initiate and regulate developmental, immunological and physiological processes in infants who consume milk. Processes for the isolation of bovine OPN for use in infant formula have been developed, and in recent years, many studies have investigated the effects of the intake of milk OPN. The purpose of this article is to review and compare existing knowledge about the structure and function of milk OPN, with a particular focus on the effects of milk OPN on human health and disease.

Glioblastomas are highly malignant brain tumors that derive from brain-tumor-initiating cells (BTICs) and can be subdivided into several molecular subtypes. Metformin is an antidiabetic drug currently under investigation as a potential antineoplastic agent. The effects of metformin on glucose metabolism have been extensively studied, but there are only few data on amino acid metabolism. We investigated the basic amino acid profiles of proneural and mesenchymal BTICs to explore a potential distinct utilization and biosynthesis in these subgroups. We further measured extracellular amino acid concentrations of different BTICs at baseline and after treatment with metformin. Effects of metformin on apoptosis and autophagy were determined using Western Blot, annexin V/7-AAD FACS-analyses and a vector containing the human LC3B gene fused to green fluorescent protein. The effects of metformin on BTICs were challenged in an orthotopic BTIC model. The investigated proneural BTICs showed increased activity of the serine and glycine pathway, whereas mesenchymal BTICs in our study preferably metabolized aspartate and glutamate. Metformin treatment led to increased autophagy and strong inhibition of carbon flux from glucose to amino acids in all subtypes. However, oral treatment with metformin at tolerable doses did not significantly inhibit tumor growth in vivo. In conclusion, we found distinct amino acid profiles of proneural and mesenchymal BTICs, and inhibitory effects of metformin on BTICs in vitro. However, further studies are warranted to better understand potential resistance mechanisms against metformin in vivo.

The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma.

Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised β = −0.375, p = 0.037) and network local efficiency (standardised β = −0.468, p

Background In Alzheimer’s disease (AD), amyloid-β 1–42 (Aβ42) neurotoxicity stems mostly from its soluble oligomeric aggregates. Studies of such aggregates have been hampered by the lack of oligomer-specific research tools and their intrinsic instability and heterogeneity. Here, we developed a monoclonal antibody with a unique oligomer-specific binding profile (ALZ-201) using oligomer-stabilising technology. Subsequently, we assessed the etiological relevance of the Aβ targeted by ALZ-201 on physiologically derived, toxic Aβ using extracts from post-mortem brains of AD patients and controls in primary mouse neuron cultures. Methods Mice were immunised with stable oligomers derived from the Aβ42 peptide with A21C/A30C mutations (AβCC), and ALZ-201 was developed using hybridoma technology. Specificity for the oligomeric form of the Aβ42CC antigen and Aβ42 was confirmed using ELISA, and non-reactivity against plaques by immunohistochemistry (IHC). The antibody’s potential for cross-protective activity against pathological Aβ was evaluated in brain tissue samples from 10 individuals confirmed as AD (n=7) and non-AD (n=3) with IHC staining for Aβ and phosphorylated tau (p-Tau) aggregates. Brain extracts were prepared and immunodepleted using the positive control 4G8 antibody, ALZ-201 or an isotype control to ALZ-201. Fractions were biochemically characterised, and toxicity assays were performed in primary mouse neuronal cultures using automated high-content microscopy. Results AD brain extracts proved to be more toxic than controls as demonstrated by neuronal loss and morphological determinants (e.g. synapse density and measures of neurite complexity). Immunodepletion using 4G8 reduced Aβ levels in both AD and control samples compared to ALZ-201 or the isotype control, which showed no significant difference. Importantly, despite the differential effect on the total Aβ content, the neuroprotective effects of 4G8 and ALZ-201 immunodepletion were similar, whereas the isotype control showed no effect. Conclusions ALZ-201 depletes a toxic species in post-mortem AD brain extracts causing a positive physiological and protective impact on the integrity and morphology of mouse neurons. Its unique specificity indicates that a low-abundant, soluble Aβ42 oligomer may account for much of the neurotoxicity in AD. This critical attribute identifies the potential of ALZ-201 as a novel drug candidate for achieving a true, clinical therapeutic effect in AD.

Evidence from patients with Parkinson's disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Here, we identified that the DYT6 gene product THAP1 (THAP domain-containing apoptosis-associated protein 1) and its interaction partner CTCF (CCCTC-binding factor) act as transcription regulators of SNCA. THAP1 controls SNCA intronic enhancers' activities, while CTCF regulates its enhancer-promoter loop formation. The SNCA intronic enhancers present neurodevelopment-dependent activities and form enhancer clusters similar to "super-enhancers" in the brain, in which the PD-associated single-nucleotide polymorphisms are enriched. Deletion of the SNCA intronic enhancer clusters prevents the release of paused RNA polymerase II from its promoter and subsequently reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.

Sandhoff disease (SD) is a fatal neurodegenerative disorder belonging to the family of diseases called GM2 Gangliosidosis. There is no curative treatment of SD. The molecular pathogenesis of SD is still unclear though it is clear that the pathology initiates with the build-up of ganglioside followed by microglial activation, inflammation, demyelination and apoptosis, leading to massive neuronal loss. In this article, we explored the expression profile of selected immune and myelination associated transcripts (Wfdc17, Ccl3, Lyz2, Fa2h, Mog and Ugt8a) at 5-, 10- and 16-weeks, representing young, pre-symptomatic and late stages of the SD mice. We found that immune system related genes (Wfdc17, Ccl3, Lyz2) are significantly upregulated by several fold at all ages in Hexb-KO mice relative to Hexb-het mice, while the difference in the expression levels of myelination related genes is not statistically significant. There is an age-dependent significant increase in expression of microglial/pro-inflammatory genes, from 5-weeks to the near humane end-point, i.e., 16-week time point; while the expression of those genes involved in myelination decreases slightly or remains unchanged. Future studies warrant use of new high-throughput gene expression modalities (such as 10X genomics) to delineate the underlying pathogenesis in SD by detecting gene expression changes in specific neuronal cell types and thus, paving the way for rational and precise therapeutic modalities.

Background Alzheimer’s disease (AD) is foremost characterized by β-amyloid (Aβ)-extracellular plaques, tau-intraneuronal fibrillary tangles (NFT), and neuroinflammation, but over the last years it has become evident that peripheral inflammation might also contribute to the disease. AD patients often demonstrate increased levels of circulating proinflammatory mediators and altered antibody levels in the blood. In our study, we investigated the plasma Immunoglobulin A (IgA) levels in association with apolipoprotein E (APOE) ε4 status and Aβ pathology. Methods IgA levels in antemortem-collected (cohort I) and postmortem-collected (cohort II) plasma samples from AD patients (n = 30 in cohort I and n = 16 in cohort II) and non-demented age-matched controls (NC) (n = 42 in cohort I and n = 7 in cohort II) were measured using ELISA. Hippocampal sections from cohort II were immunostained against IgA, and the IgA area fraction as well as the number of IgA positive (IgA+) cells in the cornu ammonis region were analysed using ImageJ. The relationship between plasma IgA levels and cognition, C-reactive protein (CRP), and cerebrospinal fluid (CSF) AD biomarkers in cohort I as well as neuropathology, IgA+ cell number, and IgA area fraction in cohort II was analysed before and after grouping the cohorts into APOEε4 carriers and APOEε4 non-carriers. Results Plasma IgA levels were higher in AD patients compared to NC in both cohorts. Also, AD patients demonstrated higher IgA area fraction and IgA+ cell number compared to NC. When APOEε4 status was considered, higher plasma IgA levels in AD patients were only seen in APOEε4 non-carriers. Finally, plasma IgA levels, exclusively in APOEε4 non-carriers, were associated with cognition, CRP, and CSF Aβ levels in cohort I as well as with IgA area fraction, IgA+ cell number, and Aβ, Lewy body, and NFT neuropathology in cohort II. Conclusions Our study suggests that AD pathology and cognitive decline are associated with increased plasma IgA levels in an APOE allele-dependent manner, where the associations are lost in APOEε4 carriers.

Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function.

Understanding the vesicular trafficking of receptors and receptor ligands in the brain capillary endothelium is essential for the development of the next generations of biologics targeting neurodegenerative diseases. Such complex biological questions are often approached by in vitro models in combination with various techniques. Here, we present the development of a stem cell-based human in vitro blood-brain barrier model composed of induced brain microvascular endothelial cells (iBMECs) on the modular µSiM (a microdevice featuring a silicon nitride membrane) platform. The µSiM was equipped with a 100 nm thick nanoporous silicon nitride membrane with glass-like imaging quality that allowed the use of high-resolution in situ imaging to study the intracellular trafficking. As a proof-of-concept experiment, we investigated the trafficking of two monoclonal antibodies (mAb): an anti-human transferrin receptor mAb (15G11) and an anti-basigin mAb (#52) using the µSiM-iBMEC-human astrocyte model. Our results demonstrated effective endothelial uptake of the selected antibodies; however, no significant transcytosis was observed when the barrier was tight. In contrast, when the iBMECs did not form a confluent barrier on the µSiM, the antibodies accumulated inside both the iBMECs and astrocytes, demonstrating that the cells have an active endocytic and subcellular sorting machinery and that the µSiM itself does not hinder antibody transport. In conclusion, our µSiM-iBMEC-human astrocyte model provides a tight barrier with endothelial-like cells, which can be used for high-resolution in situ imaging and for studying receptor-mediated transport and transcytosis in a physiological barrier.

The purpose of this current opinion paper is to describe the journey of ingested carbohydrate from ‘mouth to mitochondria’ culminating in energy production in skeletal muscles during exercise. This journey is conveniently described as primary, secondary, and tertiary events. The primary stage is detection of ingested carbohydrate by receptors in the oral cavity and on the tongue that activate reward and other centers in the brain leading to insulin secretion. After digestion, the secondary stage is the transport of monosaccharides from the small intestine into the systemic circulation. The passage of these monosaccharides is facilitated by the presence of various transport proteins. The intestinal mucosa has carbohydrate sensors that stimulate the release of two ‘incretin’ hormones (GIP and GLP-1) whose actions range from the secretion of insulin to appetite regulation. Most of the ingested carbohydrate is taken up by the liver resulting in a transient inhibition of hepatic glucose release in a dose-dependent manner. Nonetheless, the subsequent increased hepatic glucose (and lactate) output can increase exogenous carbohydrate oxidation rates by 40–50%. The recognition and successful distribution of carbohydrate to the brain and skeletal muscles to maintain carbohydrate oxidation as well as prevent hypoglycaemia underpins the mechanisms to improve exercise performance.

Background Recent work, both clinical and experimental, suggests that the hypothalamic hormone oxytocin (OT) and its receptor (OTR) may be involved in migraine pathophysiology. In order to better understand possible central actions of OT in migraine/headache pathogenesis, we mapped the distribution of OT and OTR in nerve cells and fibers in rat brain with a focus on areas related to migraine attacks and/or shown previously to contain calcitonin gene related peptide (CGRP), another neuropeptide involved in migraine. Methods Distribution of OT and OTR in the adult, rat brain was qualitatively examined with immunohistochemistry using a series of well characterized specific antibodies. Results As expected, OT was extensively localized in the cell somas of two hypothalamic nuclei, the supraoptic (SO or SON) and paraventricular nuclei (Pa or PVN). OT also was found in many other regions of the brain where it was localized mainly in nerve fibers. In contrast, OTR staining in the brain was mainly observed in cell somas with very little expression in fibers. The most distinct OTR expression was found in the hippocampus, the pons and the substantia nigra. In some regions of the brain (e.g. the amygdala and the hypothalamus), both OT and OTR were expressed (match). Mismatch between the peptide and its receptor was primarily observed in the cerebral and cerebellar cortex (OT expression) and hippocampus (OTR expression). Conclusions We compared OT/OTR distribution in the CNS with that of CGRP and identified regions related to migraine. In particular, regions suggested as “migraine generators”, showed correspondence among the three mappings. These findings suggest central OT pathways may contribute to the role of the hypothalamus in migraine attacks.

Creatine deficiency syndromes (CDS) are inherited metabolic disorders caused by mutations in GATM, GAMT and SLC6A8 and mainly affect central nervous system (CNS). AGAT- and GAMT-deficient patients lack the functional brain endogenous creatine (Cr) synthesis pathway but express the Cr transporter SLC6A8 at blood-brain barrier (BBB), and can thus be treated by oral supplementation of high doses of Cr. For Cr transporter deficiency (SLC6A8 deficiency or CTD), current treatment strategies benefit one-third of patients. However, as their phenotype is not completely reversed, and for the other two-thirds of CTD patients, the development of novel more effective therapies is needed. This article aims to review the current knowledge on Cr metabolism and CDS clinical aspects, highlighting their current treatment possibilities and the most recent research perspectives on CDS potential therapeutics designed, in particular, to bring new options for the treatment of CTD.

Background Dysregulation of brain fluid homeostasis associates with brain pathologies in which fluid accumulation leads to elevated intracranial pressure. Surgical intervention remains standard care, since specific and efficient pharmacological treatment options are limited for pathologies with disturbed brain fluid homeostasis. Such lack of therapeutic targets originates, in part, from the incomplete map of the molecular mechanisms underlying cerebrospinal fluid (CSF) secretion by the choroid plexus. Methods The transcriptomic profile of rat choroid plexus was generated by RNA Sequencing (RNAseq) of whole tissue and epithelial cells captured by fluorescence-activated cell sorting (FACS), and compared to proximal tubules. The bioinformatic analysis comprised mapping to reference genome followed by filtering for type, location, and association with alias and protein function. The transporters and associated regulatory modules were arranged in discovery tables according to their transcriptional abundance and tied together in association network analysis. Results The transcriptomic profile of choroid plexus displays high similarity between sex and species (human, rat, and mouse) and lesser similarity to another high-capacity fluid-transporting epithelium, the proximal tubules. The discovery tables provide lists of transport mechanisms that could participate in CSF secretion and suggest regulatory candidates. Conclusions With quantification of the transport protein transcript abundance in choroid plexus and their potentially linked regulatory modules, we envision a molecular tool to devise rational hypotheses regarding future delineation of choroidal transport proteins involved in CSF secretion and their regulation. Our vision is to obtain future pharmaceutical targets towards modulation of CSF production in pathologies involving disturbed brain water dynamics.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Type C hepatic encephalopathy (HE) is a complex neuropsychiatric disorder occurring as a consequence of chronic liver disease. Alterations in energy metabolism have been suggested in type C HE, but $\textit{in vivo}$ studies on this matter remain sparse and have reported conflicting results. Here, we propose a novel preclinical $^{18}$F-FDG PET methodology to compute quantitative 3D maps of the regional cerebral metabolic rate of glucose (CMR$_{glc}$) from a labelling steady-state PET image of the brain and an image-derived input function. This quantitative approach shows its strength when comparing groups of animals with divergent physiology, such as HE animals. PET CMR$_{glc}$ maps were registered to an atlas and the mean CMR$_{glc}$ from the hippocampus and the cerebellum were associated to the corresponding localized $^{1}$H MR spectroscopy acquisitions. This study provides for the first time local and quantitative information on both brain glucose uptake and neurometabolic profile alterations in a rat model of type C HE. A 2-fold lower brain glucose uptake, concomitant with an increase in brain glutamine and a decrease in the main osmolytes was observed in the hippocampus and in the cerebellum. These novel findings are an important step towards new insights into energy metabolism in the pathophysiology of HE., 30 pages, 6 figures

PURPOSE: The prototypical TSPO radiotracer (R)-[11C]PK11195 has been used in humans for more than thirty years to visualize neuroinflammation in several pathologies. Alternative radiotracers have been developed to improve signal-to-noise ratio and started to be tested clinically in 2008. Here we examined the scientific value of these "(R)-[11C]PK11195 challengers" in clinical research to determine if they could supersede (R)-[11C]PK11195.METHODS: A systematic MEDLINE (PubMed) search was performed (up to end of year 2020) to extract publications reporting TSPO PET in patients with identified pathologies, excluding studies in healthy subjects and methodological studies.RESULTS: Of the 288 publications selected, 152 used 13 challengers, and 142 used (R)-[11C]PK11195. Over the last 20 years, the number of (R)-[11C]PK11195 studies remained stable (6 ± 3 per year), but was surpassed by the total number of challenger studies for the last 6 years. In total, 3914 patients underwent a TSPO PET scan, and 47% (1851 patients) received (R)-[11C]PK11195. The 2 main challengers were [11C]PBR28 (24%-938 patients) and [18F]FEPPA (11%-429 patients). Only one-in-ten patients (11%-447) underwent 2 TSPO scans, among whom 40 (1%) were scanned with 2 different TSPO radiotracers.CONCLUSIONS: Generally, challengers confirmed disease-specific initial (R)-[11C]PK11195 findings. However, while their better signal-to-noise ratio seems particularly useful in diseases with moderate and widespread neuroinflammation, most challengers present an allelic-dependent (Ala147Thr polymorphism) TSPO binding and genetic stratification is hindering their clinical implementation. As new challengers, insensitive to TSPO human polymorphism, are about to enter clinical evaluation, we propose this systematic review to be regularly updated (living review).

Tauopathies are neurodegenerative diseases characterized by tau inclusions in brain cells. Seed-competent tau species have been suggested to spread from cell to cell in a stereotypical manner, indicating that this may involve a prion-like mechanism. Although the intercellular mechanisms of transfer are unclear, extracellular vesicles (EVs) could be potential shuttles. We assessed this in humans by preparing vesicles from fluids (brain-derived enriched EVs [BD-EVs]). These latter were isolated from different brain regions in various tauopathies, and their seeding potential was assessed in vitro and in vivo. We observed considerable heterogeneity among tauopathies and brain regions. The most striking evidence was coming mainly from Alzheimer's disease where the BD-EVs clearly contain pathological species that can induce tau lesions in vivo. The results support the hypothesis that BD-EVs participate in the prion-like propagation of tau pathology among tauopathies, and there may be implications for diagnostic and therapeutic strategies.

Characterising associations between the epigenome, proteome and phenome may provide insight into molecular regulation of biological pathways governing health. However, epigenetic signatures for many neurologically-associated plasma protein markers remain uncharacterised. Here, we report an epigenome and phenome-wide association study of the circulating proteome in relation to brain health. We perform epigenome-wide studies of 4,235 plasma proteins (n=778), identifying 2,895 CpG-protein associations (protein quantitative trait methylation loci; pQTMs) after stringent correction for multiple testing. These were independent of known genetic protein quantitative trait loci (pQTL) and common lifestyle effects, extending current knowledge by analysing a further 3,286 protein measurements with 2,854 novel pQTMs. We then perform a phenome-wide study of each protein in relation to neurological traits in 1,065 individuals, identifying 644 proteins related to cognitive, brain imaging phenotypes or APOE status. By integrating our pQTM dataset with our phenome association study, we uncovered 88 epigenetic associations for protein markers of neurological traits, 83 of which were previously unreported. These data are pertinent to understanding heterogeneity in brain health.

Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.

After ischemic stroke, in the lesion core as well as in the ischemic penumbra, evolution of tissue damage and repair is strongly affected by neuroinflammatory events that involve activation of local specialized glial cells, release of inflammatory mediators, recruiting of systemic cells and vascular remodelling. To take advantage of this intricate response in the quest to devise new protective therapeutic strategies we need a better understanding of the territorial and temporal interplay between stroke-triggered inflammatory and cell death-inducing processes in both parenchymal and vascular brain cells. Our goal is to describe structural rearrangements and functional modifications occurring in glial and vascular cells early after an acute ischemic stroke. Low and high scale mapping of the glial activation on brain sections of mice subjected to 30 minutes middle cerebral artery occlusion (MCAO) was correlated with that of the neuronal cell death, with markers for microvascular changes and with markers for pro-inflammatory (IL-1β) and reparative (TGFβ1) cytokines. Our results illustrate a time-course of the neuroinflammatory response starting at early time-points (1 h) and up to one week after MCAO injury in mice, with an accurate spatial distribution of the observed phenomena.

Variance in IQ is associated with a wide range of health outcomes, and 1% of the population are affected by intellectual disability. Despite a century of research, the fundamental neural underpinnings of intelligence remain unclear. We integrate results from genome-wide association studies (GWAS) of intelligence with brain tissue and single cell gene expression data to identify tissues and cell types associated with intelligence. GWAS data for IQ (N = 78,308) were meta-analyzed with a study comparing 1247 individuals with mean IQ ~170 to 8185 controls. Genes associated with intelligence implicate pyramidal neurons of the somatosensory cortex and CA1 region of the hippocampus, and midbrain embryonic GABAergic neurons. Tissue-specific analyses find the most significant enrichment for frontal cortex brain expressed genes. These results suggest specific neuronal cell types and genes may be involved in intelligence and provide new hypotheses for neuroscience experiments using model systems.

Background Current postresuscitative care after cardiac arrest (CA) does not address the cause of CA. We previously reported that asphyxial CA (ACA) and ventricular fibrillation CA (VFCA) elicit unique injury signatures. We hypothesized that the early cytokine profiles of the serum, heart, and brain differ in response to ACA versus VFCA. Methods and Results Adult male rats were subjected to 10 minutes of either ACA or VFCA. Naives and shams (anesthesia and surgery without CA) served as controls (n=12/group). Asphyxiation produced an ≈4‐minute period of progressive hypoxemia followed by a no‐flow duration of ≈6±1 minute. Ventricular fibrillation immediately induced no flow. Return of spontaneous circulation was achieved earlier after ACA compared with VFCA (42±18 versus 105±22 seconds; P Conclusions Both models of CA resulted in marked systemic, heart, and brain cytokine responses, with similar degrees of change across the 2 CA insults. Changes in cytokine levels after CA were most pronounced in the striatum compared with other brain regions. These collective observations suggest that the amplitude of the changes in cytokine levels after ACA versus VFCA may not mediate the differences in secondary injuries between these 2 CA phenotypes.

Contains fulltext : 227505.pdf (Publisher’s version ) (Open Access) Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement. 4 p.

In order to combat overweight and obesity as a global public health issue and prevent its impact on other debilitating cardiovascular, metabolic and renal diseases, a better understanding of the processes regulating energy metabolism are essential [...]

Outcome prognostication after cardiac arrest (CA) is challenging. Current multimodal prediction approaches would benefit from new biomarkers. MicroRNAs constitute a novel class of disease markers and circulating levels of brain-enriched ones have been associated with outcome after CA. To determine whether these levels reflect the extent of brain damage in CA patients, we assessed their correlation with neuron-specific enolase (NSE), a marker of brain damage. Blood samples taken 48 h after return of spontaneous circulation from two groups of patients from the Targeted Temperature Management trial were used. Patients were grouped depending on their neurological outcome at six months. Circulating levels of microRNAs were assessed by sequencing. NSE was measured at the same time-point. Among the 673 microRNAs detected, brain-enriched miR9-3p, miR124-3p and miR129-5p positively correlated with NSE levels (all p &lt, 0.001). Interestingly, these correlations were absent when only the good outcome group was analyzed (p &gt, 0.5). Moreover, these correlations were unaffected by demographic and clinical characteristics. All three microRNAs predicted neurological outcome at 6 months. Circulating levels of brain-enriched microRNAs are correlated with NSE levels and hence can reflect the extent of brain injury in patients after CA. This observation strengthens the potential of brain-enriched microRNAs to aid in outcome prognostication after CA.

The older-adult population is constantly increasing, hence aging and mechanisms leading to aging are a topic raising increasing interest. Hypovitaminosis D is common amongst old patients and has been proposed as causative of several chronic diseases. Here we review the role of hypovitaminosis D and vitamin D supplementation in sarcopenia and dementia, from bench to bedside.

Speciation is associated with substantial rewiring of the regulatory circuitry underlying the expression of genes. Determining which changes are relevant and underlie the emergence of the human brain or its unique susceptibility to neural disease has been challenging. Here we annotate changes to gene regulatory elements (GREs) at cell type resolution in the brains of multiple primate species spanning most of primate evolution. We identify a unique set of regulatory elements that emerged in hominins prior to the separation of humans and chimpanzees. We demonstrate that these hominin gains perferentially affect oligodendrocyte function postnatally and are preferentially affected in the brains of autism patients. This preference is also observed for human-specific GREs suggesting this system is under continued selective pressure. Our data provide a roadmap of regulatory rewiring across primate evolution providing insight into the genomic changes that underlie the emergence of the brain and its susceptibility to neural disease., The understanding of the changes regulating gene expression relevant for the emergence of the human brain and its susceptibility to disease is limited. Here, the authors identified a set of regulatory elements that evolved in hominins affecting oligodendrocyte function, and link these to autism.

International audience; Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/b-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

BACKGROUND: Abnormal insulin signaling in the brain has been linked to Alzheimer's disease (AD).OBJECTIVE: To evaluate whether cerebrospinal fluid (CSF) insulin levels are associated with cognitive performance and CSF amyloid-β and Tau. Additionally, we explore whether any such association differs by sex or APOE ɛ4 genotype.METHODS: From 258 individuals participating in the Parelsnoer Institute Neurodegenerative Diseases, a nationwide multicenter memory clinic population, we selected 138 individuals (mean age 66±9 years, 65.2% male) diagnosed with subjective cognitive impairment (n = 45), amnestic mild cognitive impairment (n = 44), or AD (n = 49), who completed a neuropsychological assessment, including tests of global cognition and memory performance, and who underwent lumbar puncture. We measured CSF levels of insulin, amyloid-β1-42, total (t-)Tau, and phosphorylated (p-)Tau.RESULTS: CSF insulin levels did not differ between the diagnostic groups (p = 0.136). Across the whole study population, CSF insulin was unrelated to cognitive performance and CSF biomarkers of AD, after adjustment for age, sex, body mass index, diabetes status, and clinic site (all p≥0.131). Importantly, however, we observed effect modification by sex and APOE ɛ4 genotype. Specifically, among women, higher insulin levels in the CSF were associated with worse global cognition (standardized regression coefficient -0.483; p = 0.008) and higher p-Tau levels (0.353; p = 0.040). Among non-carriers of the APOE ɛ4 allele, higher CSF insulin was associated with higher t-Tau (0.287; p = 0.008) and p-Tau (0.246; p = 0.029).CONCLUSION: Our findings provide further evidence for a relationship between brain insulin signaling and AD pathology. It also highlights the need to consider sex and APOE ɛ4 genotype when assessing the role of insulin.

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta- A nalysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.

Background Neurological injuries remain the leading cause of death in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). Adequate blood pressure is of paramount importance to optimize cerebral perfusion and to minimize secondary brain injury. Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic variations after successful resuscitation are needed to assist a more individualized post-resuscitation care. Currently, no technique is available for bedside evaluation of global cerebral energy state, and until now blood pressure targets have been based on limited clinical evidence. Recent experimental and clinical studies indicate that it might be possible to evaluate cerebral oxidative metabolism from measuring the lactate-to-pyruvate (LP) ratio of the draining venous blood. In this study, jugular bulb microdialysis and immediate bedside biochemical analysis are introduced as new diagnostic tools to evaluate the effect of higher mean arterial blood pressure on global cerebral metabolism and the degree of cellular damage after OHCA. Methods/design This is a single-center, randomized, double-blinded, superiority trial. Sixty unconscious patients with sustained return of spontaneous circulation after OHCA will be randomly assigned in a one-to-one fashion to low (63 mm Hg) or high (77 mm Hg) mean arterial blood pressure target. The primary end-point will be a difference in mean LP ratio within 48 h between blood pressure groups. Secondary end-points are (1) association between LP ratio and all-cause intensive care unit (ICU) mortality and (2) association between LP ratio and survival to hospital discharge with poor neurological function. Discussion Markers measuring cerebral ischemia caused by cardiac arrest and consecutive resuscitation and reflecting the metabolic changes after successful resuscitation are urgently needed to enable a more personalized post-resuscitation care and prognostication. Jugular bulb microdialysis may provide a reliable global estimate of cerebral metabolic state and can be implemented as an entirely new and less invasive diagnostic tool for ICU patients after OHCA and has implications for early prognosis and treatment. Trial registration ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT03095742). Registered March 30, 2017. Electronic supplementary material The online version of this article (10.1186/s13063-019-3397-1) contains supplementary material, which is available to authorized users.

Oxidative stress (OS) occurs in brains of patients with epilepsy and coincides with brain inflammation, and both phenomena contribute to seizure generation in animal models. We investigated whether expression of OS and brain inflammation markers co-occurred also in resected brain tissue of patients with epileptogenic cortical malformations: hemimegalencephaly (HME), focal cortical dysplasia (FCD) and cortical tubers in tuberous sclerosis complex (TSC). Moreover, we studied molecular mechanisms linking OS and inflammation in an in vitro model of neuronal function. Untangling interdependency and underlying molecular mechanisms might pose new therapeutic strategies for treating patients with drug-resistant epilepsy of different etiologies. Immunohistochemistry was performed for specific OS markers xCT and iNOS and brain inflammation markers TLR4, COX-2 and NF-κB in cortical tissue derived from patients with HME, FCD IIa, IIb and TSC. Additionally, we studied gene expression of these markers using the human neuronal cell line SH-SY5Y in which OS was induced using H2O2 . OS markers were higher in dysmorphic neurons and balloon/giant cells in cortex of patients with FCD IIb or TSC. Expression of OS markers was positively correlated to expression of brain inflammation markers. In vitro, 100 µM, but not 50 µM, of H2O2 increased expression of TLR4, IL-1β and COX-2. We found that NF-κB signaling was activated only upon stimulation with 100 µM H2O2 leading to upregulation of TLR4 signaling and IL-1β. The NF-κB inhibitor TPCA-1 completely reversed this effect. Our results show that OS positively correlates with neuroinflammation and is particularly evident in brain tissue of patients with FCD IIb and TSC. In vitro, NF-κB is involved in the switch to an inflammatory state after OS. We propose that the extent of OS can predict the neuroinflammatory state of the brain. Additionally, antioxidant treatments may prevent the switch to inflammation in neurons thus targeting multiple epileptogenic processes at once.