Search Results (68)

The focal “hot spot” neuropathologies in COVID-19 infection are revealing footprints of a hidden underlying collapse of a novel ultrafast ultradian Piezo2 signaling system within the nervous system. Paradoxically, the same initiating pathophysiology may underpin the systemic findings in COVID-19 infection, namely the multiorgan SARS-CoV-2 infection-induced vascular pathologies and brain–body-wide systemic pro-inflammatory signaling, depending on the concentration and exposure to infecting SARS-CoV-2 viruses. This common initiating microdamage is suggested to be the primary damage or the acquired channelopathy of the Piezo2 ion channel, leading to a principal gateway to pathophysiology. This Piezo2 channelopathy-induced neural switch could not only explain the initiation of disrupted cell–cell interactions, metabolic failure, microglial dysfunction, mitochondrial injury, glutamatergic synapse loss, inflammation and neurological states with the central involvement of the hippocampus and the medulla, but also the initiating pathophysiology without SARS-CoV-2 viral intracellular entry into neurons as well. Therefore, the impairment of the proposed Piezo2-induced quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling seems to be the principal and critical underlying COVID-19 infection-induced primary damage along the brain axes, depending on the loci of SARS-CoV-2 viral infection and intracellular entry. Moreover, this initiating Piezo2 channelopathy may also explain resultant autonomic dysregulation involving the medulla, hippocampus and heart rate regulation, not to mention sleep disturbance with altered rapid eye movement sleep and cognitive deficit in the short term, and even as a consequence of long COVID. The current opinion piece aims to promote future angles of science and research in order to further elucidate the not entirely known initiating pathophysiology of SARS-CoV-2 infection. Full article

In the treatment of ischemic stroke, an innovative approach is the use of neuroprotective compounds. Natural peptides, including adrenocorticotropic hormone (ACTH), can serve as the basis for such drugs. Previously, a significant effect of non-hormonal ACTH(4-7)PGP (Semax) and ACTH(6-9)PGP peptides on the functions of the nervous system was shown. Also, while using RNA-Seq, we firstly revealed differentially expressed genes (DEGs) that associated with peptides in the penumbra-associated region of the frontal cortex (FC) of rats at 24 h after transient middle cerebral artery occlusion (tMCAO) model. Peptides significantly reduced profile disturbances caused by ischemia for almost two-thousand DEGs in FC related to the neurotransmitter and inflammatory response. Here, we studied how peptides affected the expression of genes in the striatum with an ischemic focus, predominantly. The same animals from which we previously acquired FC were used to collect striatum samples. Peptides generated fewer DEGs in the striatum than in the FC. Both peptides tended to normalize the profile of disturbances caused by ischemia for hundreds of DEGs, whereas 152 genes showed an even more affected profile in the striatum under ACTH(6-9)PGP action. These DEGs were associated with inflammation, predominantly. About hundred genes were overlapped between both peptides in both tissues and were associated with neuroactive ligand-receptor interaction, predominantly. Thus, genes that are associated with the ACTH-like peptide action in rat brain regions with varying levels of ischemia injury were identified. Moreover, differential spatial regulation of the ischemia process in the rat brain at the transcriptome levels was discovered under peptides with different ACTH structures. We suppose that our results may be useful for selecting more effective neuroprotective drug structures in accordance with their specific tissue/damage therapeutic impact. Full article

Hydrocephalus is a complex neurological condition marked by abnormal cerebrospinal fluid (CSF) accumulation, often leading to elevated intracranial pressure and structural brain damage. Despite advances in surgical treatment, diagnostic precision and prognosis remain challenging, especially in idiopathic normal pressure hydrocephalus (iNPH). This narrative review aims to synthesize the current knowledge regarding molecular and neuroimaging biomarkers that hold diagnostic, prognostic, and therapeutic significance in hydrocephalus. A comprehensive literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar. The inclusion criteria encompassed peer-reviewed studies involving congenital or acquired hydrocephalus and reporting on mechanistic, diagnostic, or monitoring biomarkers. Both established and emerging biomarkers were included, and preclinical findings were considered when translational relevance was apparent. The review highlights a broad spectrum of molecular markers including aquaporins, vascular endothelial growth factor, neurofilaments, glial fibrillary acidic protein, matrix metalloproteinases, and neuroinflammatory markers. The genetic markers associated with ciliogenesis also show promise in subtyping disease. Parallel to molecular advances, neuroimaging techniques, ranging from classic markers like Evans’ index to advanced modalities such as diffusion tensor imaging (DTI), arterial spin labeling (ASL), and glymphatic MRI, provide functional perspectives on hydrocephalus diagnosis and management, while artificial intelligence may further enhance diagnostic algorithms. Molecular and imaging markers could not only increase diagnostic confidence, but also provide information on disease causes and progression. As research progresses, merging various methodologies may result in more accurate diagnoses. Full article

Ochratoxin A (OTA), a toxic compound generated by Aspergillus and Penicillium fungi, is a common contaminant in different food and animal feed sources, thereby posing possible dangers to human well-being. Although OTA is widely recognized for its kidney-damaging properties, new findings have also indicated its potential to harm the nervous system. Current research trends have increasingly examined the part played by environmental poisons, such as mycotoxins, in the development of diseases. This systematic review gathers and assesses the features of OTA along with the insights acquired from studies on its neurotoxicity. This work presents recent research that demonstrates some mechanisms by which OTA crosses the intestinal and blood–brain barriers, penetrating neural structures. In addition, it discusses the effect of OTA on several types of neural cells and its roles in apoptosis, neuroinflammation, and neurogenesis defects, while also determining the effects of antioxidant systems that neutralize the effects of OTA. This paper identifies crucial gaps in the research and highlights the necessity for further in-depth studies into how OTA affects the processes underlying neurodegeneration. Filling these knowledge gaps could provide valuable insights into the neurotoxic potential of OTA and its relevance to neurological disorders. Full article

Unaccustomed and/or strenuous eccentric contractions are known to cause delayed-onset muscle soreness. In spite of this fact, their exact cause and mechanism have been unknown for more than 120 years. The exploration of the diverse functionality of the Piezo2 ion channel, as the principal proprioceptive component, and its autonomously acquired channelopathy may bring light to this apparently simple but mysterious pain condition. Correspondingly, the neurocentric non-contact acute compression axonopathy theory of delayed-onset muscle soreness suggests two damage phases affecting two muscle compartments, including the intrafusal (within the muscle spindle) and the extrafusal (outside the muscle spindle) ones. The secondary damage phase in the extrafusal muscle space is relatively well explored. However, the suggested primary damage phase within the muscle spindle is far from being entirely known. The current manuscript describes how the proposed autonomously acquired Piezo2 channelopathy-induced primary damage could be the initiating transient neural switch in the unfolding of delayed-onset muscle soreness. This primary damage results in a transient proprioceptive neural switch and in a switch from quantum mechanical free energy-stimulated ultrafast proton-coupled signaling to rapid glutamate-based signaling along the muscle–brain axis. In addition, it induces a transient metabolic switch or, even more importantly, an energy generation switch in Type Ia proprioceptive terminals that eventually leads to a transient glutaminolysis deficit and mitochondrial deficiency, not to mention a force generation switch. In summary, the primary damage or switch is likely an inward unidirectional proton pathway reversal between Piezo2 and its auxiliary ligands, leading to acquired Piezo2 channelopathy. Full article

Early neurological deterioration is associated with poor functional outcomes in stroke patients, but the underlying mechanisms remain unclear. This study aims to understand the progression of stroke-related brain damage using a rhesus monkey model with ischemic occlusion. Multiparameter MRI was used to monitor the progressive evolution of the brain lesion following stroke. Resting-state functional MRI, dynamic susceptibility contrast perfusion MRI, diffusion tensor imaging, and T1- and T2-weighted scans were acquired prior to surgery and at 4–6 h, 48 h, and 96 h following the stroke. The results revealed a sudden increase in infarction volume after the hyper-acute phase but before 48 h on diffusion-weighted imaging (DWI), with a slight extension by 96 h. Lower relative cerebral blood flow (CBF) and time to maximum (Tmax) prior to the stroke, along with a progressive decrease post-stroke, were observed when compared to other stroke monkeys in the same cohort. Functional connectivity (FC) in the ipsilesional secondary somatosensory cortex (S2) and primary motor cortex (M1) exhibited an immediate decline on Day 0 compared to baseline and followed by a slight increase on Day 2 and a further decrease on Day 4. These findings provide valuable insights into infarction progression, emphasizing the critical role of collateral circulation and its impact on early neurological deterioration during acute stroke. Full article

Understanding brain function requires advanced neural probes to monitor electrical and chemical signaling across multiple timescales and brain regions. Microelectrode arrays (MEAs) are widely used to record neurophysiological activity across various depths and brain regions, providing single-unit resolution for extended periods. Recent advancements in flexible MEAs, built on micrometer-thick polymer substrates, have improved integration with brain tissue by mimicking the brain’s soft nature, reducing mechanical trauma and inflammation. These flexible, subcellular-scale MEAs can record stable neural signals for months, making them ideal for long-term studies. In addition to electrical recording, MEAs have been functionalized for electrochemical neurotransmitter detection. Electroactive neurotransmitters, such as dopamine, serotonin, and adenosine, can be directly measured via electrochemical methods, particularly on carbon-based surfaces. For non-electroactive neurotransmitters like acetylcholine, glutamate, and γ-aminobutyric acid, alternative strategies, such as enzyme immobilization and aptamer-based recognition, are employed to generate electrochemical signals. This review highlights recent developments in flexible MEA fabrication and functionalization to achieve both electrochemical and electrophysiological recordings, minimizing sensor fowling and brain damage when implanted long-term. It covers multi-time scale neurotransmitter detection, development of conducting polymer and nanomaterial composite coatings to enhance sensitivity, incorporation of enzyme and aptamer-based recognition methods, and the integration of carbon electrodes on flexible MEAs. Finally, it summarizes strategies to acquire electrochemical and electrophysiological measurements from the same device. Full article

Background/Objectives: Body representations (BRs) are essential for guiding movements, maintaining spatial awareness, and achieving effective interactions with the environment. Several studies suggest that BRs are frequently impaired following unilateral brain damage, emphasising the need for tailored rehabilitation interventions; however, there is a lack of studies evaluating the effectiveness of training specifically designed to improve different kinds of functional BRs after stroke. Therefore, the present study aimed to present and implement a specific rehabilitation training program for BR alterations and evaluate its effectiveness in a sample of adults with unilateral brain damage. Methods: Nine adults with unilateral brain damage and seven age- and education-matched healthy controls were recruited. Both groups underwent a neuropsychological assessment to evaluate BR (action- and nonaction-oriented). Additionally, functional autonomy and motor functioning were assessed in the patient group. Following an initial assessment (T0), the patients participated in a BR-specific rehabilitation intervention. At the end of the rehabilitation program (T1), both groups were re-evaluated with the same tasks used at T0. Results: At T0, the patient group performed worse on BR tasks than the controls. At T1, a significant improvement in the nonaction-oriented BR and functional autonomy was observed in the patient group. Conclusions: This preliminary study suggests the effectiveness of a targeted rehabilitation intervention for BR in promoting enhanced body boundary awareness and greater accuracy in the perception of body part positions, possibly leading to increased functional autonomy. These findings highlight the importance of incorporating BR training in rehabilitation programs for adults with acquired brain damage, alongside motor rehabilitation. Full article

Fucosidosis is a rare lysosomal storage disease caused by α-L-fucosidase deficiency following a mutation in the FUCA1 gene. This enzyme is responsible for breaking down fucose-containing glycoproteins, glycolipids, and oligosaccharides within the lysosome. Mutations in FUCA1 result in either reduced enzyme activity or complete loss of function, leading to the accumulation of fucose-rich substrates in lysosomes. Lysosomes become engorged with undigested substrates, which leads to secondary storage defects affecting other metabolic pathways. The central nervous system is particularly vulnerable, with lysosomal dysfunction causing microglial activation, inflammation, and neuronal loss, leading to the neurodegenerative symptoms of fucosidosis. Neuroinflammation contributes to secondary damage, including neuronal apoptosis, axonal degeneration, and synaptic dysfunction, exacerbating the disease process. Chronic neuroinflammation impairs synaptic plasticity and neuronal survival, leading to progressive intellectual disability, learning difficulties, and loss of previously acquired skills. Inflammatory cytokines and lysosomal burden in motor neurons and associated pathways contribute to ataxia, spasticity, and hypotonia, which are common motor symptoms in fucosidosis. Elevated neuroinflammatory markers can increase neuronal excitability, leading to the frequent occurrence of epilepsy in affected individuals. So, fucosidosis is characterized by rapid mental and motor loss, along with growth retardation, coarse facial features, hepatosplenomegaly, telangiectasis or angiokeratomas, epilepsy, inguinal hernia, and dysostosis multiplex. Patients usually die at an early age. Treatment of fucosidosis is a great challenge, and there is currently no definitive effective treatment. Hematopoietic cell transplantation studies are ongoing in the treatment of fucosidosis. However, early diagnosis of this disease and treatment can be effective. In addition, the body’s immune system decreases due to chemotherapy applied after transplantation, leaving the body vulnerable to microbes and infections, and the risk of death is high with this treatment. In another treatment method, gene therapy, the use of retroviral vectors, is promising due to their easy integration, high cell efficiency, and safety. In another treatment approach, enzyme replacement therapy, preclinical studies are ongoing for fucosidosis, but the blood–brain barrier is a major obstacle in lysosomal storage diseases affecting the central nervous system. Early diagnosis is important in fucosidosis, a rare disease, due to the delay in the diagnosis of patients identified so far and the rapid progression of the disease. In addition, enzyme replacement therapy, which carries fewer risks, is promising. Full article

Background: This review focuses on the prognostic role of resting-state functional magnetic resonance imaging (fMRI) in disorders of consciousness (DOCs). Several studies were conducted to determine the diagnostic accuracy in DOC patients to identify prognostic markers and to understand the neural correlates of consciousness. A correct diagnosis of consciousness in unresponsive or minimally responsive patients is important for prognostic and therapeutic management. Functional connectivity is considered as an important tool for the formulation of cerebral networks; it takes into account the primary sensorimotor, language, visual and central executive areas, where fMRI studies show damage in brain connectivity in the areas of frontoparietal networks in DOC patients. Methods: The integration of neuroimaging or neurophysiological methods could improve our knowledge of the neural correlates of clinical response after an acquired brain injury. The use of MRI is widely reported in the literature in different neurological diseases. In particular, fMRI is the most widely used brain-imaging technique to investigate the neural mechanisms underlying cognition and motor function. We carried out a detailed literature search following the relevant guidelines (PRISMA), where we collected data and results on patients with disorders of consciousness from the studies performed. Results: In this review, 12 studies were selected, which showed the importance of the prognostic role of fMRI for DOCs. Conclusions: Currently there are still few studies on this topic. Future studies using fMRI are to be considered an added value for the prognosis and management of DOCs. Full article

Traumatic brain injury (TBI) results from external biomechanical forces that cause structural and physiological disturbances in the brain, leading to neuronal, axonal, and vascular damage. TBIs are predominantly mild (65%), with moderate (10%) and severe (25%) cases also prevalent. TBI significantly impacts health, increasing the risk of neurodegenerative diseases such as dementia, post injury. The initial phase of TBI involves acute disruption of the blood–brain barrier (BBB) due to vascular shear stress, leading to ischemic damage and amyloid-beta accumulation. Among the acute cerebrovascular changes after trauma are early progressive hemorrhage, micro bleeding, coagulopathy, neurovascular unit (NVU) uncoupling, changes in the BBB, changes in cerebral blood flow (CBF), and cerebral edema. The secondary phase is characterized by metabolic dysregulation and inflammation, mediated by oxidative stress and reactive oxygen species (ROS), which contribute to further neurodegeneration. The cerebrovascular changes and neuroinflammation include excitotoxicity from elevated extracellular glutamate levels, coagulopathy, NVU, immune responses, and chronic vascular changes after TBI result in neurodegeneration. Severe TBI often leads to dysfunction in organs outside the brain, which can significantly impact patient care and outcomes. The vascular component of systemic inflammation after TBI includes immune dysregulation, hemodynamic dysfunction, coagulopathy, respiratory failure, and acute kidney injury. There are differences in how men and women acquire traumatic brain injuries, how their brains respond to these injuries at the cellular and molecular levels, and in their brain repair and recovery processes. Also, the patterns of cerebrovascular dysfunction and stroke vulnerability after TBI are different in males and females based on animal studies. Full article

GBA1-associated Parkinson’s disease (GBA1-PD) is increasingly recognized as a distinct entity within the spectrum of parkinsonian disorders. This review explores the unique pathophysiological features, clinical progression, and genetic underpinnings that differentiate GBA1-PD from idiopathic Parkinson’s disease (iPD). GBA1-PD typically presents with earlier onset and more rapid progression, with a poor response to standard PD medications. It is marked by pronounced cognitive impairment and a higher burden of non-motor symptoms compared to iPD. Additionally, patients with GBA1-PD often exhibit a broader distribution of Lewy bodies within the brain, accentuating neurodegenerative processes. The pathogenesis of GBA1-PD is closely associated with mutations in the GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase). In this review, we discuss two mechanisms by which GBA1 mutations contribute to disease development: ‘haploinsufficiency,’ where a single functional gene copy fails to produce a sufficient amount of GCase, and ‘gain of function,’ where the mutated GCase acquires harmful properties that directly impact cellular mechanisms for alpha-synuclein degradation, leading to alpha-synuclein aggregation and neuronal cell damage. Continued research is advancing our understanding of how these mechanisms contribute to the development and progression of GBA1-PD, with the ‘gain of function’ mechanism appearing to be the most plausible. This review also explores the implications of GBA1 mutations for therapeutic strategies, highlighting the need for early diagnosis and targeted interventions. Currently, small molecular chaperones have shown the most promising clinical results compared to other agents. This synthesis of clinical, pathological, and molecular aspects underscores the assertion that GBA1-PD is a distinct clinical and pathobiological PD phenotype, necessitating specific management and research approaches to better understand and treat this debilitating condition. Full article

The present study aims to highlight the cell protective effect of Tropea red onion (TRO) hydroalcoholic extract and some of its components against “non-essential” heavy metals. For this purpose, the cytoprotective roles of cyanidin, cyanidin-3-O-glucoside and quercetin against Cd, Hg and Pb and of TRO extract against Hg and Pb have been investigated, and data are reported here. To the best of our knowledge, this is the first detailed evaluation of the protective effect against cell damage induced by “non-essential” heavy metals through the simultaneous administration of cyanidin, cyanidin-3-O-glucoside and quercetin with CdCl₂, HgCl₂ or PbCl₂ and the TRO extract against HgCl₂ and PbCl₂. Present data are also compared with our previous results from the TRO extract against Cd. The antioxidant capacity of the extract was also determined by the ferric reducing antioxidant power (FRAP) and the bovine brain peroxidation assay. Both of the assays indicated a good antioxidant capacity of the extract. Cell viability and the impact on necrotic cell death were examined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test and lactate dehydrogenase (LDH) release assay. After 24 h of exposure, Caco-2 cell viability decreased by approximately 50% at 0.25 μM for Cd, Hg and Pb and, after 72 h, the ranking order of “non-essential” heavy metal toxicity on cell viability was PbCl₂ > CdCl₂ > HgCl₂. Cell viability was assessed by treating the cells with the biomolecules at doses of 25, 50 and 100 µg/mL for 24 and 72 h. The same analysis was carried out on Caco-2 cells treated with combinations of TRO extract, cyanidin, cyanidin-3-O-glucoside, or quercetin and “non-essential” heavy metals. Treatments with the bioactive metabolites did not significantly improve cell viability. The identical treatment of Caco-2 cells produced instead LDH release, suggesting a decrease in cell viability. Consistently with the finding that TRO extract showed a good antioxidant activity, we suggest that its higher cytotoxicity, compared to that of the individual assayed phytochemicals, may be derived by the combined antioxidant and chelating properties of all the molecules present in the extract. Therefore, from all the acquired experimental evidence, it appears that the TRO extract may be a better promising protective agent against the toxic effect of Cd, Hg and Pb compared to its bioactive metabolites. Full article

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation’s impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios. Full article

The aim of this study is to explain the higher incidence of subdural haematomas in elderly people compared to young adult. This research addresses the phenomenon by developing two distinct numerical models of the human head, simulating individuals people aged 77 and 28, respectively. These models are methodically constructed based on medical imaging data acquired through collaboration with hospitals and subsequently verified through empirical experimentation. Studies have shown that the main factor that influences the vulnerability to bridging vein rupture in older adults is the degenerative processes of nervous tissue. The most visible structural damage was observed in the outflow cuff segment. This phenomenon can be primarily attributed to specific geometric parameters associated with this anatomical region. The presented research emphasises the importance of computational models in understanding the pathomechanics of brain structures. As a result of the analyses, it was proven that the neurodegenerative processes of the brain that occur with age are crucial in understanding the higher incidence of subdural haematomas in elderly people. Full article