The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on a global scale. One of the main molecular mechanisms responsible for the development of Neuro-PASC, in individuals of all ages, is the formation and inadequate proteolysis/clearance of phase-separated amyloid crystalline aggregates—a hallmark feature of aging-related neurodegenerative disorders. Amyloidogenesis during viral infection and persistence is a natural, inevitable, protective defense response that is exacerbated by SARS-CoV-2. Acting as chemical catalyst, SARS-CoV-2 accelerates hydrophobic collapse and the heterogeneous nucleation of amorphous amyloids into stable β-sheet aggregates. The clearance of amyloid aggregates is most effective during slow wave sleep, when high levels of adenosine triphosphate (ATP)—a biphasic modulator of biomolecular condensates—and melatonin are available to solubilize amyloid aggregates for removal. The dysregulation of mitochondrial dynamics by SARS-CoV-2, in particular fusion and fission homeostasis, impairs the proper formation of distinct mitochondrial subpopulations that can remedy challenges created by the diversion of substrates away from oxidative phosphorylation towards glycolysis to support viral replication and maintenance. The subsequent reduction of ATP and inhibition of melatonin synthesis during slow wave sleep results in incomplete brain clearance of amyloid aggregates, leading to the development of neurological manifestations commonly associated with age-related neurodegenerative disorders. Exogenous melatonin not only prevents mitochondrial dysfunction but also elevates ATP production, effectively augmenting the solubilizing effect of the adenosine moiety to ensure the timely, optimal disaggregation and clearance of pathogenic amyloid aggregates in the prevention and attenuation of Neuro-PASC.

Purinergic signaling, mediated by ATP and adenosine receptors, plays a crucial role in cellular communication and homeostasis within the central nervous system (CNS), particularly by regulating synaptic activity, glial cell functions, and neuroplasticity. Glial cells, including astrocytes and microglia, contribute to both short-term processes, such as neurotransmission and neuroinflammation, and long-term functions, including synaptic remodeling, tissue repair, and behavioral adaptation. Dysregulation of purinergic signaling in these cells has been implicated in the pathogenesis of various neurodegenerative and neuropsychiatric disorders. This article explores the evolving concept of the synapse, highlighting the active role of glial cells in synaptic modulation and emphasizing the significance of purinergic signaling in synaptic function and responses to conditions such as injury and neurotoxicity. Specifically, it examines the roles of ATP and adenosine receptors—such as P2X4, P2X7, P2Y1, and P2Y12—in mediating key astrocytic and microglial functions, including neuroinflammation, phagocytosis, synaptic plasticity, and neuronal damage. Furthermore, the article discusses the involvement of purinergic receptors in neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, Rett syndrome, and autism spectrum disorder, as well as potential therapeutic strategies targeting these receptors to mitigate inflammation, promote tissue repair, and improve clinical outcomes.

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. It presents a significant challenge in terms of accurate diagnosis, disease progression monitoring, and the development of effective treatments. This article addresses the role of neuroimaging as an advancing tool for diagnosis, monitoring progression, and treatment of AD. A comprehensive review of existing literature on the use of neuroimaging in AD was conducted using various databases. The different imaging techniques, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), were examined in terms of their ability to detect amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), the hallmark pathological features of AD. Neuroimaging enables the visualization of Alzheimer-related biomarkers, such as Aβ plaques, tau protein tangles, neuro-inflammation, and synaptic dysfunction, providing valuable insights into disease pathophysiology and progression. These imaging techniques assist in the early detection of AD, distinguishing it from other conditions and evaluating the effectiveness of treatments. This has the potential to significantly transform the way AD is managed clinically. By providing insights into the molecular changes that occur in the brain during the course of the disease, neuroimaging can facilitate early diagnosis, monitor disease progression, and inform treatment decisions. Furthermore, neuroimaging holds great potential for accelerating drug development by allowing researchers to assess the efficacy of novel therapies in real time. Overall, the integration of neuroimaging into the clinical management of AD has the potential to revolutionize the way we approach diagnosis, treatment, and research in AD.

The use of neurostimulation devices for the treatment of Alzheimer’s disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD.

Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are among the most significant health concerns worldwide, characterized by neuronal dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Epigallocatechin gallate, a green tea polyphenol, has been reported to possess multifaceted neuroprotective properties. It reduces oxidative stress through free radical scavenging, activation of antioxidant enzymes, and stabilization of mitochondrial function. It also inhibits neuroinflammation through modulation of key signaling pathways. It suppresses amyloid-beta aggregation in Alzheimer’s and alpha-synuclein fibrillation in Parkinson’s, thus attenuating toxic protein accumulation. Its activity in the induction of autophagy and promotion of synaptic plasticity supports neuronal survival and function. However, low bioavailability and metabolic instability hinder its translation into the clinic. Strategies including nanoparticle encapsulation, structural modifications, and combination therapies are being explored to overcome these challenges. Future research could establish epigallocatechin gallate as a viable candidate for managing neurodegenerative disorders.

Intracellular amyloid β oligomers (AβOs) have been linked to Alzheimer’s disease (AD) pathogenesis and to the neuronal damage in this neurodegenerative disease. Calmodulin, which binds AβO with very high affinity, plays a pivotal role in Aβ-induced neurotoxicity and has been used as a model template protein for the design of AβO-antagonist peptides. The hydrophobic amino acid residues of the COOH-terminus domain of Aβ play a leading role in its interaction with the intracellular proteins that bind AβO with high affinity. This review focuses on Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ and their endogenous production in the brain, highlighting the role of the proteasome as a major source of this type of peptides. It is emphasized that the level of these hydrophobic endogenous neuropeptides undergoes significant changes in the brain of AD patients relative to age-matched healthy individuals. It is concluded that these neuropeptides may become helpful biomarkers for the evaluation of the risk of the onset of sporadic AD and/or for the prognosis of AD. In addition, Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ seem a priori good candidates for the development of novel AD therapies, which could be used in combination with other drug-based therapies. Future perspectives and limitations for their use in the clinical management of AD are briefly discussed.

Intracranial artery dolichoectasia (IADE) is a vascular anomaly characterized by dilation and/or tortuosity of one or more intracranial arteries. While many cases are incidental findings on imaging, the associated ischemic neurological complications of IADE can be severe and must be promptly recognized. This study aims to increase awareness among general practitioners and neurologists regarding this rare and potentially life-threatening condition. We utilized reputable databases for this scoping review, including PubMed, Scopus, and Google Scholar, from database inception through September 2024, using a combination of terms such as “Dolichoectasia of Basilar Artery”, “Intracranial Dolichoectasia”, and “Ischemic Stroke”. Our scoping review revealed that IADE is a challenging and often underdiagnosed condition, with an estimated prevalence of less than 1% in the general population. Hypertension, atherosclerosis, and advanced age are well-documented risk factors. To minimize the risk of misdiagnosis, we briefly elucidated the pathophysiology of IADE, correlating it with clinical and radiological features. We discuss the diagnostic criteria for IADE based on radiological imaging, addressing the advantages and limitations of different techniques. Finally, we highlight the unmet clinical needs related to IADE management, which may involve pharmacological and surgical therapies tailored to individual cases, with careful consideration of safety and efficacy.

Epilepsy, a complex and widespread neurological disorder, has evolved in its understanding from ancient misconceptions to modern scientific advancements. This special issue highlights pivotal research and reviews on the mechanisms underlying epilepsy, innovative treatment strategies, and the psychosocial dimensions of living with this condition. Together, these contributions reflect the growing interdisciplinarity and depth in epilepsy research.

Depression is characterized by affective symptoms and neuropsychological deficits. After treatment, affective symptoms frequently remit, but cognitive alterations may remain affecting the lives of people and having an impact on health, economy, and societies. The present work describes the methods, procedures, and equipment for a randomized three-arm controlled experiment designed to measure the effects of exergames on executive functions (EFs) under depression. EFs are complex cognitive functions that are essential for organizing information, planning an action, reasoning, decision-making, and problem-solving. Literature shows that EFs are compromised in depression, affecting daily-life activities and other cognitive domains. To conduct the experiment, depressed middle-aged adults will be randomly distributed into three experimental groups: an intervention group training with exergames, an active control group training only with cognitive video games, and a passive control group or wait-list. EFs are evaluated at three different time points: pre-post intervention, and three months follow-up, using the Wisconsin Card Sorting Test (WCST). Researchers will collect cognitive-behavioral and neural information [event-related potentials (ERPs)]. Results will be explored by performing analysis of variance to compare the outcomes of the diverse groups at the three different time points, understanding the benefits of exergames in terms of EFs under depression. The study of simultaneous multidomain interventions in depression holds promise for the development of novel approaches, to implementing psychological and neuropsychological health [this experiment is part of a registered clinical trial entitled “MUDgame” (ClinicalTrials.gov identifier NCT06536530). Registered on August 2024, https://clinicaltrials.gov/study/NCT06536530].

Melatonin is widely available as a dietary supplement and/or medicine for sleep. It is an endogenous hormone produced in the pineal gland of the brain, with metabolites providing additional beneficial mechanisms such as supporting long-term memory. Melatonin is well known as a hormone that plays a role in the circadian rhythm (sleep cycle), but additional mechanisms such as antioxidant, and anti-inflammatory activity are elucidated from animal research models. This article discusses melatonin supplementation and the current understanding of how it may provide benefits beyond the use as a sleep aid including a review of the evidence in how it may aid in mitigating components of cognitive decline.

Glioblastoma multiforme (GBM) is characterized by its infiltrative growth pattern and high recurrence rate despite treatment. While local progression within the central nervous system (CNS) is the rule, manifestations outside the CNS, particularly skin and subcutaneous metastases, are very infrequent and seldom reported in the literature. The authors reviewed the current understanding of this rare condition, with the main purpose of giving visibility to its clinical presentation and prognostic implications, thus improving clinical management and encouraging research in this area. A PubMed, Cochrane Library, and EMBASE search from database inception through March 2024 was conducted. In this way, we compiled a total of thirty-five cases in our review. As far as we know, our work gathers the largest number of patients with this condition. Remarkably, we observed that the typical presentation of soft-tissue high-grade glioma metastases is the finding of subcutaneous erythematous nodules in patients previously operated on for a primary CNS tumor, within the craniotomy site and nearby, mostly in the first year after the initial surgery. It was also noted that there is a trend of developing a concomitant CNS recurrence and/or other metastases in different locations, either simultaneously or subsequently. From here, we propose some possible mechanisms that explain the extracranial spread of GBM. We concluded that a poor outcome is expected from the diagnosis of skin and subcutaneous metastases: the mean overall survival was 4.38 months. Yet, assessing individual characteristics is always mandatory; a palliative approach seems to be the best option for the majority of cases.

Glioblastoma multiforme (GBM) is the most common malignant primary central nervous system (CNS) tumor. It presents an aggressive pattern, with a tendency for intracranial progression despite optimal treatment. On the other hand, metastases and manifestations outside the CNS are exceptional, and very few cases have been described. The authors submitted a case of a 48-year-old male diagnosed with a left parietooccipital GBM isocitrate dehydrogenase (IDH) wild-type, non-methylated O⁶-methylguanine-DNA methyltransferase (MGMT). Six months after surgical treatment, followed by a chemotherapy (CT) and radiotherapy scheme, he developed a few subcutaneous erythematous nodules within the surgical scar. A punch biopsy confirmed the histopathology of GBM. The CT scan showed concomitant intracranial progression. We ruled out systemic metastases. As the performance status was good [Karnofsky Performance Status 90 (KPS 90)] and the subcutaneous implants were growing rapidly, limiting the quality of life, we decided to perform palliative surgery to remove the implants. The result was good. Unfortunately, the patient worsened during the following week, after ruling out medical complications, we attributed the worsening to cerebral tumor swelling, revealed in the CT scan, as unresponsive to steroids. He passed away a few days later. Based on the analysis of our case, we intend to provide useful information for the approach to this peculiar manifestation of GBM.

Epilepsy, a neurological disorder characterized by recurrent seizures, presents a complex interplay of cellular and molecular mechanisms. The symptoms manifest themselves at various scales, from ion channels to brain regions to behavior in humans. Various screening, treatment, and preventive measures use this knowledge to tackle the disorder effectively. This article aims to summarize the current state of the art in epileptic markers from ion channels, astrocytes, and synaptic imbalance to whole brain Network Dynamics. Recent research has shed light on the critical involvement of astrocytes, the multifunctional glial cells, in the pathogenesis and modulation of epileptic seizures in humans. Astrocytes, once considered as mere supportive cells, are now recognized as active participants in the regulation of neuronal excitability, synaptic transmission, and brain homeostasis. Ion channel imbalance is one of the widely studied areas in the context of epilepsy and is partially addressed in the abstract. Recent advances in computational neuroscience have led to the development of whole brain network models, providing valuable tools for studying the complex dynamics of epileptic seizures. These models integrate diverse biological factors, including neuronal connectivity, synaptic dynamics, and cellular properties, to simulate the spatiotemporal patterns of epileptic activity across brain regions. Through computational simulations and analysis, whole brain network models offer insights into seizure initiation, propagation, and termination mechanisms, shedding light on the dynamic interactions between epileptic foci and distributed brain networks. Moreover, these models facilitate the exploration of network-based biomarkers for seizure prediction and intervention optimization. Challenges and limitations, such as model complexity and validation against experimental data, are also discussed. Despite these challenges, whole brain network models represent a promising approach for advancing our understanding of epilepsy and identifying novel therapeutic strategies. Future research efforts should focus on refining model fidelity, incorporating multimodal data, and translating computational findings into clinically relevant applications, ultimately improving the management and treatment of epilepsy patients.