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The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND. [ABSTRACT FROM AUTHOR]

Identifying early and non-invasive biomarkers to detect individuals in the earliest stages of the Alzheimer's disease continuum is crucial. As a result, electrophysiology and plasma biomarkers are emerging as great candidates in this pursuit due to their low invasiveness. This is the first magnetoencephalography study to assess the relationship between minimum spanning tree parameters, an alternative to overcome the comparability and thresholding problem issues characteristic of conventional brain network analyses, and plasma phosphorylated tau231 levels in unimpaired individuals, with different risk levels of Alzheimer's disease. Seventy-six individuals with available magnetoencephalography recordings and phosphorylated tau231 plasma determination were included. The minimum spanning tree for the theta, alpha and beta bands for each subject was obtained, and the leaf fraction, tree hierarchy and diameter were calculated. To study the relationship between these topological parameters and phosphorylated tau231, we performed correlation analyses, for the whole sample and considering the two risk sub-groups separately. Increasing concentrations of phosphorylated tau231 were associated with greater leaf fraction and tree hierarchy values, along with lower diameter values, for the alpha and theta frequency bands. These results emerged for the whole sample and the higher risk group, but not for the lower risk group. Our results indicate that the network topology of cognitively unimpaired individuals with elevated plasma phosphorylated tau231 levels, a marker of Alzheimer's disease pathology and amyloid-β accumulation, is already altered, shifting towards a more integrated network increasing its vulnerability and hub-dependency, mostly in the alpha band. This is indicated by increases in leaf fraction and tree hierarchy, along with reductions in diameter. These results match the initial trajectory proposed by theoretical models of disease progression and network disruption and suggest that changes in brain function and organization begin early on., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: It is known that the immune system is dysregulated in schizophrenia, having a state similar to chronic neuroinflammation. The origin of this process is unknown, but it is known that T and B lymphocytes, which are components of the adaptive immune system, play an important role in the pathogenic mechanisms of schizophrenia., Methods: We analysed the membrane of PBMCs from patients diagnosed with schizophrenia through proteomic analysis (n = 5 schizophrenia and n = 5 control). We found the presence of the Kv1.3 voltage-gated potassium channel and its auxiliary subunit β1 (KCNAB1) and β2 (KCNAB2). From a sample of 90 participants, we carried out a study on lymphocytes with whole-cell patch-clamp experiments (n = 7 schizophrenia and n = 5 control), western blot (n = 40 schizophrenia and n = 40 control) and confocal microscopy to evaluate the presence and function of different channels. Kv in both cells., Results: We demonstrated the overexpression of Kv1.1, Kv1.2, Kv1.3, Kv1.6, Kv4.2, Kv4.3 and Kv7.2 channels in PBMCs from patients with schizophrenia. This study represents a groundbreaking exploration, as it involves an electrophysiological analysis performed on T and B lymphocytes from patients diagnosed of schizophrenia compared to healthy participants. We observed that B lymphocytes exhibited an increase in output current along with greater peak current amplitude and voltage conductance curves among patients with schizophrenia compared with healthy controls., Conclusions: This study showed the importance of the B lymphocyte in schizophrenia. We know that the immune system is altered in schizophrenia, but the physiological mechanisms of this system are not very well known. We suggest that the B lymphocyte may be relevant in the pathophysiology of schizophrenia and that it should be investigated in more depth, opening a new field of knowledge and possibilities for new treatments combining antipsychotics and immunomodulators. The limitation is that all participants received antipsychotic medication, which may have influenced the differences observed between patients and controls. This implies that more studies need to be done where the groups can be separated according to the antipsychotic drug., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity. Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues, including different brain regions. Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection, like the support of cell growth/survival, enhancement promotion of synapse formation, autophagy, and inhibition of the secretion of proinflammatory cytokines, microglial activation, and apoptosis during neural morphogenesis. The glial cells, including astrocytes and microglia, maintain metabolic homeostasis and defense against pathogens in the central nervous system. After brain insult, microglia are the first cells to respond, followed by reactive astrocytosis. These activated cells produce proinflammatory mediators like cytokines or chemokines to react to the insult. Furthermore, under these circumstances, microglia can become chronically inflammatory by losing their homeostatic molecular signature and, consequently, their functions during many diseases. Several processes promote the development of neurological disorders and influence their pathological evolution: like the formation of protein aggregates, the accumulation of abnormally modified cellular constituents, the formation and release by injured neurons or synapses of molecules that can dampen neural function, and, of critical importance, the dysregulation of inflammatory control mechanisms. The glucagon-like peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies, restoring brain cell homeostasis under inflammatory conditions, modulating microglia activity, and decreasing the inflammatory response. This review summarizes recent advances linked to the anti-inflammatory properties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis, Alzheimer's disease, Parkinson's disease, vascular dementia, or chronic migraine., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

First-degree relatives of Alzheimer's disease patients constitute a key population in the search for early markers. Our group identified functional connectivity differences between cognitively unimpaired individuals with and without a family history. In this unprecedented follow-up study, we examine whether family history is associated with a longitudinal increase in the functional connectivity of those regions. Moreover, this is the first work to correlate electrophysiological measures with plasma p-tau231 levels, a known pathology marker, to interpret the nature of the change. We evaluated 69 cognitively unimpaired individuals with a family history of Alzheimer's disease and 28 without, at two different time points, approximately 3 years apart, including resting state magnetoencephalography recordings and plasma p-tau231 determinations. Functional connectivity changes in both precunei and left anterior cingulate cortex in the high-alpha band were studied using non-parametric cluster-based permutation tests. Connectivity values were correlated with p-tau231 levels. Three clusters emerged in individuals with family history, exhibiting a longitudinal increase of connectivity. Notably, the clusters for both precunei bore a striking resemblance to those found in previous cross-sectional studies. The connectivity values at follow-up and the change in connectivity in the left precuneus cluster showed significant positive correlations with p-tau231. This study consolidates the use of electrophysiology, in combination with plasma biomarkers, to monitor healthy individuals at risk of Alzheimer's disease and emphasizes the value of combining noninvasive markers to understand the underlying mechanisms and track disease progression. This could facilitate the design of more effective intervention strategies and accurate progression assessment tools., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

The growth and development of the human brain is a long and complex process that requires a precise sequence of genetic and molecular events. This begins in the third week of gestation with the differentiation of neural progenitor cells and extends at least until late adolescence, possibly for life. One of the defects of this development is that we know very little about the signals that modulate this sequence of events. The first 3 years of life, during breastfeeding, is one of the critical periods in brain development. In these first years of life, it is believed that neurodevelopmental problems may be the molecular causes of mental disorders. Therefore, we herein propose a new hypothesis, according to which the chemical signals that could modulate this entire complex sequence of events appear in this early period, and the molecular level study of human breast milk and colostrum of mothers who give birth to children in different gestation periods could give us information on proteins influencing this process. In this work, we collected milk and colostrum samples (term, late preterm and moderate/very preterm) and exosomes were isolated. The samples of exosomes and complete milk from each fraction were analyzed by LC-ESI-MS/MS. In this work, we describe proteins in the different fractions of mature milk and colostrum of mothers with term, late preterm, or very preterm delivery, which could be involved in the regulation of the nervous system by their functions. We describe how they differ in different types of milk, paving the way for the investigation of possible new neuroregulatory pathways as possible candidates to modulate the nervous system.

Human milk is the biological fluid with the highest exosome amount and is rich in microRNAs (miRNAs). These are key regulators of gene expression networks in both normal physiologic and disease contexts, miRNAs can influence many biological processes and have also shown promise as biomarkers for disease. One of the key aspects in the regeneration of the nervous system is that there are practically no molecules that can be used as potential drugs. In the first weeks of lactation, we know that human breast milk must contain the mechanisms to transmit molecular and biological information for brain development. For this reason, our objective is to identify new modulators of the nervous system that can be used to investigate neurodevelopmental functions based on miRNAs. To do this, we collected human breast milk samples according to the time of delivery and milk states: mature milk and colostrum at term; moderate and very preterm mature milk and colostrum; and late preterm mature milk. We extracted exosomes and miRNAs and realized the miRNA functional assays and target prediction. Our results demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function. We found 132 different miRNAs were identified across all samples. Sixty-nine miRNAs had significant differential expression after paired group comparison. These miRNAs are implicated in gene regulation of dopaminergic/glutamatergic synapses and neurotransmitter secretion and are related to the biological process that regulates neuron projection morphogenesis and synaptic vesicle transport. We observed differences according to the delivery time and with less clarity according to the milk type. Our data demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function.

The glucagon-like peptide-1 (GLP-1) is a pleiotropic hormone well known for its incretin effect in the glucose-dependent stimulation of insulin secretion. However, GLP-1 is also produced in the brain and displays a critical role in neuroprotection and inflammation by activating the GLP-1 receptor signaling pathways. Several studies in vivo and in vitro using preclinical models of neurodegenerative diseases show that GLP-1R activation has anti-inflammatory properties. This review explores the molecular mechanistic action of GLP-1 RAS in relation to inflammation in the brain. These findings update our knowledge of the potential benefits of GLP-1RAS actions in reducing the inflammatory response. These molecules emerge as a potential therapeutic tool in treating neurodegenerative diseases and neuroinflammatory pathologies.

The brain extracellular matrix (ECM) is involved in crucial processes of neural support, neuronal and synaptic plasticity, extrasynaptic transmission, and neurotransmission. ECM is a tridimensional fibrillary meshwork composed of macromolecules that determine its bioactivity and give it unique characteristics. The characterization of the brain ECM is critical to understand its dynamic in SZ. Thus, a comparative study was developed with 71 patients with schizophrenia (SZ) and 70 healthy controls. Plasma of participants was analysed by label-free liquid chromatography-tandem mass spectrometry, and the results were validated using the classical western blot method. Lastly, immunostaining of post-mortem human brain tissue was performed to analyse the distribution of the brain ECM proteins by confocal microscopy. The analysis identified four proteins: fibronectin, lumican, nidogen-1, and secreted protein acidic and rich in cysteine (SPARC) as components of the brain ECM. Statistical significance was found for fibronectin (P = 0.0166), SPARC (P = 0.0003), lumican (P = 0.0012), and nidogen-1 (P < 0.0001) that were decreased in the SZ group. Fluorescence imaging of prefrontal cortex (PFC) sections revealed a lower expression of ECM proteins in SZ. Our study proposes a pathophysiological dysregulation of proteins of the brain ECM, whose abnormal composition leads to a progressive neuronal impairment and consequently to neurodegenerative processes due to lack of neurophysiological support and dysregulation of neuronal homeostasis. Moreover, the brain ECM and its components are potential pharmacological targets to develop new therapeutic approaches to treat SZ., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Substance-related disorders (SRD) have been consistently associated with alterations both in cognitive and executive functions, which affect to patients' quality of life. The main objective of this work was to test the beneficial cognitive effects on patients with SRD after the implementation of "Trisquel," an intervention program in board game format. To check the effectiveness of Trisquel program, a group of people diagnosed with SRD was randomly assigned either to the experimental group or to the control group. The experimental group performed Trisquel structured sessions twice a week during 3 months, while the control group performed routinely conventional therapeutic activities with the same frequency and duration. Neuropsychological tests were done to both groups before and after the intervention. After the 3 months of intervention the experimental group showed the following statistically significant improvements for WAIS-III subtests: number key, symbol search, arithmetic, direct digits, inverse digits, total digits, letters-numbers in the processing speed index and in the working memory index. Regarding STROOP tests, statistically significant progress was observed in the phonetic fluency letter P, phonetic fluency letter M, phonetic fluency letter R subtests, word-reading and word-color subtests. The control group only obtained improvements for WAIS-III subtests of arithmetic, letters-numbers and in the working memory index. The results of this study confirm that "Trisquel" is an effective intervention program for people diagnosed with SRD, getting improvements in processing speed (psychomotor and reading), attentional subprocesses (focused and sustained) and executive functions (updating and inhibition)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Piñón-Blanco, Vergara-Moragues, Gutiérrez-Martínez, Fernández-Palleiro, Rodrigues, Rodrigues-Amorím, Lage-López, González-López, Velasquez, Amorim, Lloves-Moratinos, Viéitez-Fernández, Sabio-Fernandez, Graña-Torralba, Vilar-Díaz, Carrera-Machado, Cancelo-Martinez, Ferreira, Cardoso, Rivera-Baltanás, Otero-Lamas, Olivares and Spuch.)

At the beginning of the pandemic, we observed that lithium carbonate had a positive effect on the recovery of severely ill patients with COVID-19. Lithium is able to inhibit the replication of several types of viruses, some of which are similar to the SARS-CoV-2 virus, increase the immune response and reduce inflammation by preventing or reducing the cytokine storm. Previously, we published an article with data from six patients with severe COVID-19 infection, where we proposed that lithium carbonate could be used as a potential treatment for COVID-19. Now, we set out to conduct a randomized clinical trial number EudraCT 2020-002008-37 to evaluate the efficacy and safety of lithium treatment in patients infected with severe SARS-CoV-2. We showed that lithium was able to reduce the number of days of hospital and intensive care unit admission as well as the risk of death, reduces inflammatory cytokine levels by preventing cytokine storms, and also reduced the long COVID syndromes. We propose that lithium carbonate can be used to reduce the severity of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spuch, López-García, Rivera-Baltanás, Cabrera-Alvargonzález, Gadh, Rodrigues-Amorim, Álvarez-Estévez, Mora, Iglesias-Martínez-Almeida, Freiría-Martínez, Pérez-Rodríguez, Pérez-González, López-Domínguez, Longueira-Suarez, Sousa-Domínguez, Araújo-Ameijeiras, Mosquera-Rodríguez, Crespo, Vila-Fernández, Regueiro and Olivares.)

Self-assembled short peptide-based gels are highly promising drug delivery systems. However, implementing a stimulus often requires screening different structures to obtain gels with suitable properties, and drugs might not be well encapsulated and/or cause undesirable effects on the gel's properties. To overcome this challenge, a new design approach is presented to modulate the release of doxorubicin as a model chemotherapeutic drug through the interplay of (di)phenylalanine-coated magnetic nanoparticles, PEGylated liposomes and doxorubicin co-assembly in dehydropeptide-based gels. The composites enable an enhancement of the gelation kinetics in a concentration-dependent manner, mainly through the use of PEGylated liposomes. The effect of the co-assembly of phenylalanine-coated nanoparticles with the hydrogel displays a concentration and size dependence. Finally, the integration of liposomes as doxorubicin storage units and of nanoparticles as composites that co-assemble with the gel matrix enables the tuneability of both passive and active doxorubicin release through a thermal, and a low-frequency alternating magnetic field-based trigger. In addition to the modulation of the gel properties, the functionalization with (di)phenylalanine improves the cytocompatibility of the nanoparticles. Hereby, this work paves a way for the development of peptide-based supramolecular systems for on-demand and controlled release of drugs.

Introduction: Emotion recognition of voices may play an important role in interpersonal communication and patients with schizophrenia present alterations in this regard. Several on-line rehabilitation tools have been developed for treatment in this area. Voices is an on-line prosodic recognition program consisting of identifying different emotional tones in neutral phrases, in different sessions of gradually increasing difficulty. This training tool has previously reported benefits, and a new version has been created called Voices 2 . The main aim of this study is to test the capacity of the Voices 2 program to improve emotion recognition through prosody for adults with schizophrenia. Secondly, it seeks to observe durability effects 1 month after intervention. Method: A randomized, single-blind, multicenter clinical trial was conducted with 44 outpatients diagnosed with schizophrenia or schizoaffective disorder. The intervention group (also called Voices ) was treated with Voices 2 , whereas the control group was treated with auditory training that was not related to emotions. Sociodemographic and clinical data, clinical state (PANSS), Intelligence Quotient and prosodic recognition (RMV-SV) were measured at baseline. After intervention, RMV-SV and PANSS were assessed. One month later, the RMV-SV measure was repeated. Results: The control group ( n = 19) and the Voices group ( n = 22) did not differ on χ 2 , t or U tests in sociodemographic, clinical and psychometric variables at baseline or post-intervention (all p -values > 0.05). In the Voices group, statistically significant differences were observed in the RMV-SV scale applied post-intervention vs. that applied pre-intervention ( Z = 2.47, p = 0.013). Similar results were observed in the 1-month follow-up RMV-SV vs. the pre-intervention RMV-SV ( Z = 1.97, p = 0.049). PANSS scale was also assessed with no significant differences between pre vs. post measures in both groups. Lastly, Voices 2 was rated relatively higher, based on its ease of understanding, entertainment value, usefulness and the appropriateness of use of its emotional glossary. Discussion: Improvements were observed in prosodic recognition following intervention with Voices 2 in the Voices group. Although these results are similar to other clinical trial rehabilitation programs, specific research on the matter remains scarce. Certain aspects, such as the durability of effects or adherence should be thoroughly studied and clarified. Clinical Trial Registration: [https://doi.org/10.17605/OSF.IO/G95C4]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lado-Codesido, Rey Varela, Larios Quiñones, Martínez Agulleiro, Ossa Basanes, Martínez Querol, Mateos, Spuch and García-Caballero.)

This review article provides an update of the empirical research on cognitive fragility conducted in the last four years. The studies retrieved were classified in four different categories. The first category includes articles relating cognitive frailty to cognitive reserve and which continue to highlight the importance of educational level. The second category includes recent research on cognitive fragility biomarkers, involving neuroimaging, metabolism and, in a novel way, microbiota. The third category includes research on how cognitive frailty is related to motor development and physical functioning, exploring e.g. the use of technology to study motor markers of cognitive frailty. Finally, in the fourth category, research clarifying the difference between reversible frailty and potentially reversible cognitive frailty has led to new interventions aimed at reducing cognitive frailty and preventing negative health outcomes. Interventions based on physical activity and multicomponent interventions are particularly emphasized. In addition, recent research explores the long-term effects of dual interventions in older adults living in nursing homes. In summary, research on cognitive frailty has increased in recent years, and applied aspects have gained importance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Facal, Burgo, Spuch, Gaspar and Campos-Magdaleno.)