It is widely known that each tissue has unique mechanisms to respond to injury and maintain homeostasis effectively. Although peripheral nerves have limited regeneration capacity, they conduct a complicated regeneration process by orchestrating multiple cell complexes after injury. In addition to drawing attention to anterograde and retrograde transportation, the absence of a cell body in the damaged area also points to the significance of immune and glial cells in the environment. Cellular reorganization following injury in the dorsal root ganglion, which takes place in the cell bodies of sensory peripheral nerve fibers, has attracted much attention. Growing research has been focused on investigating the molecular and cellular interactions occurring in sensory neurons and glial cells within the dorsal root ganglia after injury. It is clearly becoming that the sensory neurons and glial cells in the dorsal root ganglion are derived from the same embryological origins. Therefore, this information attracts attention to the potential of these two cells to differentiate into each other in case of injury. The focus of these studies is to illuminate the genes and pathways responsible for an increase in the plasticity of the neurogenic cell line following nerve injury. This review explores and discusses the underlying mechanisms responsible for maintaining homeostasis in the dorsal root ganglion and regeneration of peripheral nerves and how neuronal plasticity functions in the regeneration of the injury.

Degeneration and dysfunction of neurons in the brain are hallmarks of neurodegenerative diseases. Over the past decades, significant efforts have been devoted to the development and validation of biomarkers for neurodegenerative diseases. The range and diversity of biomarkers for central nervous system (CNS) diseases has continued to expand, encompassing biofluid-based sources such as blood or cerebrospinal fluid (CSF), nucleic acids, tissues, and imaging. While imaging and tissue biopsy-based markers are continually being identified and their applications expanding, they do have limitations compared with RNA and protein biomarkers. This review comprehensively summarizes various biomarkers, including microRNA (miRNA), long noncoding RNA (lncRNA), circulating miRNA (cimiRNA), and proteins, in the context of CNS disorders. In addition, the review emphasizes the existing limitations and challenges associated with the use of biomarkers in both clinical practice and research on neurodegenerative diseases. In conclusion, this review provides an insightful overview of the identified biomarkers for neurodegenerative diseases, underscoring the crucial role of biomarker research in combating these debilitating conditions. The article also highlights future challenges related to the implementation of novel biomarkers in clinical practice and trials, thereby contributing to the ongoing efforts to advance the understanding and management of neurodegenerative diseases.

Behavioural environment and behavioural responses of an individual are known to affect multiple aspects of physiology including neuroendocrine and growth factor signalling, angiogenesis, stem cell dynamics, tissue homeostasis, and maintenance. Despite substantial evidence, the role of behaviour-physiology interface in human health and disease remains underappreciated. The hypothesis proposed here suggests that deficiencies of certain behaviours that have evolved to become essential or “vitactions” can potentially trigger multiple health problems. Altered growth factor expression because of vitaction deficiencies affects angiogenesis and vascular function, neuronal maintenance, transport of glucose and other nutrients to the brain, mitochondrial function, oxidative stress, inflammation, and protein aggregation dynamics all implicated in Alzheimer’s disease (AD). Exercise is already known to be effective in prevention of AD. The hypothesis suggests that it is the behavioural component of exercise over mechanical activity and calorie burning that has crucial effects on brain health through multiple signalling pathways. Similar to vitamin deficiencies, where supplying the deficient vitamin is the only effective solution, for vitaction deficiencies supplying the deficient behavioural stimuli through behaviourally enriched exercise can be the most effective remedy.

Short-chain fatty acids (SCFAs) play a key role regulating immune and metabolic homeostasis. Consequently, dysregulation in SCFA levels is involved in the pathogenesis of autoimmune, inflammatory, metabolic, and neurodegenerative disorders. These metabolites are generated by gut microbiota, and their production is influenced mainly by diet. Here, an overview is provided of how SCFA production is associated with diet and with neurological disorders. The mechanisms by which SCFAs exert beneficial effects are analysed, along with how their production may be boosted by diet and how the use of specific dietary interventions might improve the outcome of neurological diseases.

Over the last two decades, immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG), previously thought to be a biomarker of multiple sclerosis (MS), have been shown to cause a distinct disease called MOG antibody-associated disease (MOGAD). MOGAD accounts for approximately one-third of all demyelinating syndromes in children and is the second most common central nervous system (CNS) demyelinating disease after MS. The diagnosis is made by detecting anti-MOG IgG antibodies against the natural MOG antigen, in the presence of compatible clinical and neuroradiological features. However, due to controversies in the methodologies for detecting anti-MOG antibodies and their diagnostic cutoff values, as well as the expanding clinical spectrum, accurate diagnosis may be challenging, at least in a subset of patients. Clinical presentations of MOGAD vary by age; the highest rates are seen in acute disseminated encephalomyelitis in younger children and optic neuritis, myelitis, or brainstem symptoms in older children. Although it was previously thought to be a milder demyelinating disorder and to have a monophasic course in the majority of patients, recent studies have shown that relapses occur in about half of the patients and sequelae develop in a significant proportion of them, especially in those with persistently high antibody titers, leukodystrophy-like magnetic resonance imaging (MRI) lesions, and spinal cord involvement. However, due to the monophasic course in about half of the patients, long-term treatment is not recommended after the first clinical episode but is recommended for patients who experience relapse. Accurate and early diagnosis of MOGAD is essential for proper management and better outcome. This review covers the challenges in the diagnosis of MOGAD in children.

Acute ischemic stroke (AIS) is the leading cause of disability worldwide, and recanalization therapy is significant in the hyperacute phase of AIS. However, reperfusion injury and hemorrhagic transformation after recanalization predict poor prognosis of AIS. How to minimize reperfusion injury and hemorrhagic transformation, which greatly improves the prognosis of vascular recanalization, is becoming a hot topic in AIS research and an urgent problem to be solved. A wealth of neuroprotective drug studies is now available, while some of the neuroprotectants have met with failure in human studies. It is discussed in this review about the progress in neuroprotective therapy for AIS based on understanding the pathophysiologic mechanisms of reperfusion injury and hemorrhagic transformation, as well as challenges in exploring new neuroprotectants.

Carbon nanotubes, an emerging class of carbon nanomaterials, possess tremendous potential for application in biotechnology and biomedicine particularly in neurological disorders. Carbon nanotubes owing to their fascinating properties have the potential to revolutionize medicine and technology, particularly in the realm of drug delivery, biosensing, bioimaging, and as therapeutic agents to tackle complex neurological disorders such as Alzheimer’s and Parkinson’s disease. In this review, a summary of the use of carbon nanotubes for neuropathological outcomes such as alleviating oxidative stress and amyloid formation, which are well-studied molecular outcomes associated with Alzheimer’s and Parkinson’s disease. In the end, challenges associated with the clinical testing of carbon nanotubes and possible ways to overcome them are highlighted.

Depression is a known risk factor for dementia. Antidepressants are the most commonly used treatment for this condition, and are effective in at least half to two-thirds of cases. Extensive evidence from in vitro and animal models suggests that antidepressants have anti-inflammatory and neuroprotective properties. These effects have been shown to reduce the oxidative damage, amyloid aggregation, and expression of pro-inflammatory genes associated with animal models of neurodegenerative disorders. However, longitudinal research in humans has shown that antidepressants do not protect against dementia, and may even be associated with a risk of cognitive deterioration over time in older adults. The contrast between two sets of findings represents a paradox of significant clinical and public health significance, particularly when treating depression in late life. This review paper attempts to resolve this paradox by critically reviewing the medium- and long-term effects of antidepressants on peripheral immune-inflammatory responses, infection risk, gut microbiota, and neuroendocrine responses to stress, and how these effects may influence the risk of neurodegeneration. Briefly stated, it is possible that the peripheral actions of antidepressant medications may antagonize their beneficial effects against neuroinflammation. The implications of these findings are then explored with a particular focus on the development and testing of multimodal neuroprotective and anti-inflammatory treatments that could reduce the risk of Alzheimer’s and related dementias in patients suffering from depression.

Fibromyalgia syndrome (FMS) is characterised by the presence of distributed pain in different areas of the body accompanied by the alteration of some functions such as the activity of the neurovegetative system, the sleep quality, or the presence of fatigue. The present narrative review aims to evaluate some key studies regarding the effects of different therapeutic exercise (TE) modalities on clinical variables of interest in patients with FMS, as well as to discuss some of the possible mechanisms of action of TE in improving pain intensity in patients with FMS. All aerobic, strengthening, and body-mind exercises were shown to bring about changes in the improvement of clinical variables of interest in patients with FMS. In addition, with regard to the improvement of pain intensity, there are different arguments that could explain the hypoalgesic effect of TE (structured in physical, neurophysiological, and psychosocial mechanisms). In conclusion, TE is a clinical tool with great potential for patients with FMS as it may produce hypoalgesia through physical, neurophysiological, and psychosocial mechanisms. All these TE modalities have demonstrated in isolation a remarkable effectiveness in the overall improvement of patients with FMS. However, more research is needed in this field especially on the long-term effects and on the combination of the different training modalities.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is associated with selective and progressive loss of motor neurons. As a consequence, the symptoms of ALS are muscle cramps and weakness, and it eventually leads to death. The general markers for early diagnosis can assist ALS patients in receiving early intervention and prolonging their survival. Recently, some novel approaches or previously suggested methods have validated the potential for early diagnosis of ALS. The purpose of this review is to summarize the status of current general markers discovery and development for early diagnosis of ALS, including genes, proteins neuroimaging, neurophysiology, neuroultrasound, and machine learning models. The main genetic markers evaluated are superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), transactivation-responsive DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes. Among proteins, neurofilament light chain is still the most established disease-specific adaptive change in ALS. The expression of chitinases, glial fibrillary acidic protein (GFAP), and inflammatory factors are changed in the early stage of ALS. Besides, more patient-friendly and accessible feature assays are explored by the development of neuroimaging, neurophysiology, and neuroultrasound techniques. The novel disease-specific changes exhibited the promising potential for early diagnosis of ALS. All of these general markers still have limitations in the early diagnosis, therefore there is an urgent need for the validation and development of new disease-specific features for ALS.

The currently available pharmacological anti-dementia treatments provide only temporary and limited benefits. Not surprisingly, patients and professionals increasingly explore non-pharmacological interventions that may alleviate dementia symptoms. Among these interventions is hyperbaric oxygen therapy (HBOT). A brief review is presented on HBOT use in medicine, with its mode of action in dementia, specifically Alzheimer’s disease, as well as a case report of self-initiated HBOT in a 62-year-old man with a clinical diagnosis of probable Alzheimer’s disease. He had over 400 HBOT sessions [2–3 times weekly, with a duration of 30–50 min, in a multi-place hyperbaric chamber at 2 atmospheres absolute (ATA)] over 7 years and use of donepezil (10 mg daily) for the last 3 years when formally diagnosed by the National Health Service (NHS) Memory Service. The patient’s longitudinal neurocognitive and neuroradiological evidence over 7 years of follow-up remained stable (with no major cognitive decline and no behavioral changes) when compared to his initial presentation when diagnosed by the private health provider. His driving remains unimpaired, and he continues to be independent. This highlights the potential HBOT benefits including those on visuospatial ability and activities of daily living in people with Alzheimer’s disease. This case report argues for more extensive research into the clinical effects of HBOT in Alzheimer’s disease. Discussion of HBOT use is along with the latest advances in anti-amyloid immunotherapy for Alzheimer’s disease, as well as HBOT augmentation of current and novel dementia drug delivery via nanotechnology.

Recent investigations have shed light on the potential of seaweed, an abundant source of bioactive compounds, to mitigate and combat neurodegenerative diseases. In this comprehensive review, the accumulating evidence supporting the neuroprotective properties of seaweed-derived compounds is evaluated and their putative mechanisms of action are elucidated. The background of this review encompasses the general understanding of neurodegenerative diseases as debilitating conditions characterized by the progressive loss of nerve cell function and viability in the central nervous system. Furthermore, the global prevalence of these diseases, encompassing Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, and the persistent absence of effective treatments are emphasized. To address this critical issue, an innovative avenue of research is explored by investigating the potential of seaweed and its diverse array of bioactive compounds. By examining the available literature, the evidence supporting the neuroprotective effects of seaweed-derived compounds is consolidated. These bioactive constituents exhibit promising properties in preventing and mitigating neurodegeneration. Mechanistically, their actions involve intricate pathways that contribute to neuronal survival, reduction of oxidative stress, inhibition of neuroinflammation, and modulation of protein aggregation processes. This review provides a comprehensive analysis of the mechanisms underlying the neuroprotective effects of seaweed compounds. In conclusion, this review highlights the potential of seaweed as a valuable source of neuroprotective compounds and underscores the advancements made in this burgeoning field. The identification and elucidation of the mechanisms through which seaweed compounds exert their neuroprotective effects hold promise for the development of novel therapeutic interventions. These findings transcend disciplinary boundaries, offering insight into the potential application of seaweed-derived compounds as a valuable resource for combating neurodegenerative diseases across scientific domains.

Astrocytes not only support neuronal function with essential roles in synaptic neurotransmission, action potential propagation, metabolic support, or neuroplastic and developmental adaptations. They also respond to damage or dysfunction in surrounding neurons and oligodendrocytes by releasing neurotrophic factors and other molecules that increase the survival of the supported cells or contribute to mechanisms of structural and molecular restoration. The neuroprotective responsiveness of astrocytes is based on their ability to sense signals of degeneration, metabolic jeopardy, and structural damage, and on their aptitude to locally deliver specific molecules to remedy threats to the molecular and structural features of their cellular partners. To the extent that neuronal and other glial cell disturbances are known to occur in affective disorders, astrocyte responsiveness to those disturbances may help to better understand the roles astrocytes play in affective disorders. The astrocytic sensing apparatus supporting those responses involves receptors for neurotransmitters, purines, cell adhesion molecules, and growth factors. Astrocytes also share with the immune system the capacity to respond to cytokines released upon neuronal damage. In addition, in response to specific signals, astrocytes release unique factors such as clusterin or humanin that have been shown to exert potent neuroprotective effects. Astrocytes integrate the signals above to further deliver structural lipids, remove toxic metabolites, stabilize the osmotic environment, normalize neurotransmitters, provide antioxidant protection, facilitate synaptogenesis, and act as barriers to contain varied deleterious signals, some of which have been described in brain regions relevant to affective disorders and related animal models. Since various injurious signals that activate astrocytes have been implicated in different aspects of the etiopathology of affective disorders, particularly in relation to the diagnosis of depression, potentiating the corresponding astrocyte neuroprotective responses may provide additional opportunities to improve or complement available pharmacological and behavioral therapies for affective disorders.

Self-neuronal regeneration is often limited or nonexistent after neuronal cell damage, making new technologies necessary for treating neurological damage. Although the brain can partially compensate by increasing its plasticity, these compensatory mechanisms can never fully restore the pre-damage state. Analysis of the literature regarding stem cell therapy in case of neurological disorders. Stem cells have shown promise for treating various neurological disorders and disabilities due to their regenerative capacity. Transplanting or administration of different types of stem cells has yielded promising results in animal models and early clinical trials. However, concerns remain regarding their implementation. The type of stem cell used, the optimal method and route of administration, the number of stem cells administered, preconditioning, and the injection schedule all need to be determined. Additionally, the long-term safety of stem cell treatment and the recipient’s age requires further investigation. Despite these concerns, stem cell therapy holds tremendous promise for treating neurological disorders, and continued research and well-designed studies will be crucial for unlocking its full potential.

Vagus nerve stimulation (VNS) has gained prominence in the treatment of various clinical disorders such as migraine, depression, and tinnitus. Based on increased scientific knowledge of the VNS and insights into the vagus nerve (VN) function and anatomy/conduction, robust treatment approaches have been developed. There are both noninvasive and invasive VNS (iVNS) techniques. Currently, only iVNS techniques are approved by the US Food and Drug Administration (FDA). In contrast, transcutaneous VNS (tVNS) is a new treatment option that is receiving increasing attention. The tVNS application uses the cutaneous distribution of afferent VN fibers in the auricle, the auricular branch of the VN (ABVN), or in the neck, the cervical branch of the VN (CBVN). However, the tVNS technique has not yet been sufficiently researched in its application and mode of action to be used clinically on a large scale. Moreover, the stimulation parameters of the VN vary widely in different studies. Despite the growing number of research papers on this topic, more coherence in neurostimulation research and neuroanatomical basis is needed. The aim of this review is to highlight new clinical treatment options based on existing clinically applied treatment options. In this article, current clinical applications of tVNS are analyzed and important stimulation parameters are highlighted. Based on this data, useful new tVNS therapies are recommended. The focus will be placed on the study of inflammatory processes associated with cancer and on applications to cardiovascular events such as heart failure.

Post-translational modifications (PTMs) of alpha-synuclein (α-syn) can alter protein aggregation propensity to affect α-syn oligomer and fibril formation. The inflammatory response in Parkinson’s disease (PD) is mediated by microglia, astrocytes, T cells, B cells, macrophages, and neutrophils, which respond to α-syn aggregates in an attempt to clear synucleinopathy and restore brain homeostasis. This review focuses on the effects of PTMs on α-syn aggregation and cell-specific immune responses to α-syn aggregates in the context of PD.

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting aged population around the world. PD is characterized by neuronal Lewy bodies present in the substantia nigra of the midbrain and the loss of dopaminergic neurons with various motor and non-motor symptoms associated with the disease. The protein α-synuclein has been extensively studied for its contribution to PD pathology, as α-synuclein aggregates form the major component of Lewy bodies, a hallmark of PD. In this narrative review, the authors first focus on a brief explanation of α-synuclein aggregation and circumstances under which aggregation can occur, then present a hypothesis for PD pathogenesis in the peripheral nervous system (PNS) and how PD can spread to the central nervous system from the PNS via the transport of α-synuclein aggregates. This article presents arguments both for and against this hypothesis. It also presents various non-pharmacological rehabilitation approaches and management techniques for both motor and non-motor symptoms of PD and the related pathology. This review seeks to examine a possible hypothesis of PD pathogenesis and points to a new research direction focus on rehabilitation therapy for patients with PD. As various non-motor symptoms of PD appear to occur earlier than motor symptoms, more focus on the treatment of non-motor symptoms as well as a better understanding of the biochemical mechanisms behind those non-motor symptoms may lead to better long-term outcomes for patients with PD.

Parkinson’s disease (PD) is a prevalent neurodegenerative disease (NDD) affecting millions of individuals. The pathogenesis of PD centers around α-synuclein (α-Syn), a pivotal protein whose aggregation significantly impacts disease progression. Although existing treatments mainly focus on managing motor symptoms by targeting the dopaminergic system, they frequently overlook other non-motor symptoms. The intricate nature of PD pathogenesis contributes to challenges in disease analysis and has hindered the development of effective PD treatments. In recent years, various novel therapies utilizing immunotherapy methods have exhibited promise in preclinical animal models. In NDDs, immunotherapy aims to counteract the detrimental effects of protein accumulation by neutralizing toxic species and aiding their elimination. Numerous active therapy (AI) and passive immunotherapy (PI) strategies have been devised for PD and related synucleinopathies, many of which are currently undergoing clinical trials. Despite demonstrating remarkable success in animal models, immunotherapies encountered substantial setbacks during the late stages of clinical trials, with the exception of lecanemab, which targets amyloid-β (Aβ) in Alzheimer’s disease (AD) and has recently received approval from the Food and Drug Administration (FDA). The lack of translation from experimental investigations to successful clinical outcomes, particularly in terms of cognitive and functional evaluations, highlights the limitations of relying solely on animal studies to comprehend the effects of immunotherapeutic approaches. This comprehensive review focuses on α-Syn-based immunotherapies and delves into their underlying mechanisms of action. Furthermore, Furthermore, the article discusses recent advancements and future prospects concerning the potential of immunotherapeutic strategies for PD. The focus is on highlighting the latest research in this domain to illuminate the challenges and opportunities related to the development of efficacious immunotherapies for individuals with PD.

Amyotrophic lateral sclerosis (ALS) is the most prevalent type of motor neuron disease (MND) and is diagnosed with a delay from the first appearance of symptoms. Surrogate markers that may be used to detect pathological changes before a significant neuronal loss occurs and allow for early intervention with disease-modifying therapy techniques are desperately needed. Using water molecules that diffuse within the tissue and experience displacement on the micron scale, diffusion magnetic resonance imaging (MRI) is a promising technique that can be used to infer microstructural characteristics of the brain, such as microstructural integrity and complexity, axonal density, order, and myelination. Diffusion tensor imaging (DTI) is the primary diffusion MRI technique used to evaluate the pathogenesis of ALS. Neurite orientation dispersion and density imaging (NODDI), diffusion kurtosis imaging (DKI), and free water elimination DTI (FWE-DTI) are only a few of the approaches that have been developed to overcome the shortcomings of the diffusion tensor technique. This article provides a summary of these methods and their potential as surrogate markers for detecting the onset of ALS at an early stage.

The management of symptomatic chronic subdural hematoma (CSDH) is surgical evacuation and prognosis in most cases is good. Tension pneumocephalus is the presence of air under pressure in the intracranial cavity. A case of tension pneumocephalus developing as a complication of burr hole evacuation of CSDH is illustrated. In this case, tension pneumocephalus was managed by reopening the wound and saline irrigation with a subdural drain placement. Considering this case report and after a careful review of the literature, the physiopathology, diagnosis, and treatment of this complication are highlighted in the article.

Currently, the predominant targets for the treatment of Alzheimer’s disease (AD) are the main components of the two pathological structures: senile plaques (composed of amyloid beta peptide aggregates) or neurofibrillary tangles (constructed of tau protein polymers). However, the existence of adequate disease modifiers based on such targets is discussed. In this special issue, it has been suggested to search for new possible targets for AD therapy. This contribution tries to analyze non-neuronal tissues (periphery) to identify potential factors (target) involved in the development of AD.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder affecting motor neurons. The complex etiopathogenetic mechanism of ALS can lead to extensive alterations, including cortical changes, neuroinflammation, and changes in muscular structure. These ALS-derived alterations may contribute to fatigue, a symptom severely impacting patients’ quality of life that is commonly associated with muscular exercise. Intriguingly, muscular exercise can be at once a promoter of motor neuron degeneration in predisposed patients as well as an effective non-pharmacological treatment of ALS. To fully disclose its therapeutic potential, muscular exercise must be tailored to patients’ phenotypes, balancing potential benefits and risks that are unique to each ALS case. Biomarkers of muscular fatigue, with their potential for insight into inflammation and oxidation, can be used to ensure that the intensity of physical activity remains below the threshold level beyond which exercise might become harmful. In this review, the authors explore the concept of fatigue in ALS patients, focusing on fatigue generation, definition, detection, quantification, and treatment. The study discusses the most important fatigue biomarkers, putting them in relation to the mechanism of fatigue generation and with monitoring of muscular exercise as a possible treatment of fatigue.

Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD) and its risk increases exponentially with aging. The incidence of LOAD is reported to increase from 1 in every 1,000 people aged 37 to 65 in every 100 people aged 80 years and older. LOAD is extensively associated with aging and cognition decline. Several risk factors, including lifestyle choices, environmental factors, and medical ailments, affect cellular stress. The cellular stress can bring upon epigenetic alterations that affect cellular aging making the individual more susceptible to LOAD development. In due course the cellular stress resulting into epigenetic deregulation, oxidative burden, and genomic mutations leads to increased disease risk. Role of epigenetic and non-epigenetic mechanisms in accelerated cellular aging that are reported to increase the risk of LOAD development are summarized in this review. The underlying biological mechanism of cellular aging and the risk factors that could predispose cellular aging and LOAD development are also discussed in the upcoming sections.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by thunderclap headache and intracranial segmental vasoconstriction with or without signs of neurological deficit with a variable course that requires extensive study to prevent complications. The evidence shows RCVS is characterized by being multi-etiological; both the cause and the specific symptoms must be treated to reduce the chance of complications and recurrence. The timely identification of the RCVS and its etiology is the cornerstone of success in managing the disease. New data must be generated to have more efficient resources for the approach to this disease.

Alzheimer’s disease (AD), which affects around twenty-seven million people globally, is an aging-related neurodegenerative condition characterized by the extracellular deposition of misfolded amyloid-β (Aβ) peptides and the intracellular production of neurofibrillary tangles (NFTs) AD results from the death of certain groups of neurons in the brain while appearing to have no impact on neighboring neurons. It is progressive and incurable. Therefore, the pathophysiology of afflicted populations and the development of intervention measures to stop neuronal cell death have been the main areas of attention for delineating therapeutic options. Proinflammatory cytokines are responsible for the stimulation of inflammatory responses and are mostly generated by activated macrophages in the brain. This review discusses how glial cells and innate and adaptive immune responses have a critical role in AD. It also provides information about microglial activation through the cluster of differentiation 40 (CD40) ligation and CD40L. CD40L ligation of microglial CD40 results in a large increase in tumor necrosis factor-α (TNF-α) production. Cultured cortical neuronal injury is caused when microglia are activated by CD40 ligation in the presence of interferon-γ (IFN-γ). This injury is significantly reduced by blocking the CD40 pathway or neutralising TNF-α. The management of AD would require integrating all available information about the innate and adaptive immune response affecting AD-related neuronal death.

The enteric nervous system (ENS) is considered by some authors as the second human brain, given its fundamental role in the regulation process of the central nervous system (CNS). Recent data from scientific literature have shown the existence of close bidirectional communication between the gut microbiota and the CNS, influencing physiological and biochemical changes related to cognition, emotion, behavior, anxiety, depressive symptoms, and stress. Furthermore, the existence of mediators in the connection between intestinal microorganisms and the CNS is evident, which includes neural networks, signaling, immune, and endocrine responses. However, the mechanisms underlying the effects of gut microbiota on brain processes still need to be determined. Therefore, understanding the relationship between the gut and neurodegenerative diseases (NDs) is essential for developing effective prophylactic alternatives and disease-modifying drugs that can prevent or slow the progression of such diseases. Herein, this short review aimed to present the most recent data from the scientific literature associated with the physiological, biochemical, and cellular aspects involved in the interrelationship between the gut-brain axis and NDs, discussing the role of the intestinal microbiota, and its relationship with CNS disorders.

Acute ischemic stroke (AIS) is the leading cause of disability and one of the top causes of mortality worldwide. The current standard of care is reperfusion therapy including intravenous thrombolysis (IVT) and thrombectomy. However, these treatments have limitations as they have a limited therapeutic window. Hence, there is a vital need to develop neuroprotective agents to prevent brain injury, extend the reperfusion window, improve mortality, and reduce disability in AIS patients. Neuroprotective agents work by counteracting the detrimental biochemical and molecular events that result in irreversible ischemic damage. Numerous preclinical studies and clinical trials have been done on different agents. Thus far, all have been definitively unsuccessful in large trials. Currently, there are several challenges in translation from animal studies to human trials. It is important to understand the current evidence as well as past challenges in the development of neuroprotective strategies in AIS in order for a more strategic selection of agents to be studied, improve study designs and thus contribute to the development of effective neuroprotective agents. Newer agents have shown promise in neuroprotection, and human trials are ongoing. In this review, the mechanisms of action of different families of neuroprotective agents were discussed. The evidence for the efficacy of different drugs in each family of neuroprotective agents was also evaluated and the current research landscape in neuroprotection for AIS was summarized. The past challenges and limitations in clinical trials and proposed possible ways to address these issues were highlighted.

There is no approved drug capable of halting the progression of the most prevalent neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD). Current therapeutic strategies focus mainly on the inhibition of the formation of protein aggregates and their deposition in the central nervous system. However, after almost a hundred years, proper management of the disease is still lacking. The fact of not finding effective management tools in the various clinical trials already carried out suggests that new hypotheses and strategies should be explored. Although vast resources have been allocated to the investigation of protein aggregates and the pathophysiology is now better understood, clues to the actual etiology are lacking. It is well known that brain homeostasis is of paramount importance for the survival of neurons. Drugs that target the periphery are often not subject to evaluation for their potential effect on the central nervous system. While acute treatments may be irrelevant, pills used for chronic conditions can be detrimental to neurons, especially in terms of progressive damage leading to a long-term decline in neuronal survival. Due to the lack of advances in the search for a curative treatment for neurodegenerative diseases, and the lack of new hypotheses about their etiology, a novel hypothesis is here proposed. It consists of assuming that the effects of the drugs most commonly used by the elderly, such as antihypertensive, hypoglycemic, and hypocholesterolemic, could have a negative impact on neuronal survival.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD.

More than 600 different neurological diseases affect the human population. Some of these are genetic and can emerge even before birth, and some are caused by defects, infections, trauma, degeneration, inflammation, and cancer. However, they all share disabilities caused by damage to the nervous system. In the last decades, the burden of almost all neurological disorders has increased in terms of absolute incidence, prevalence, and mortality, largely due to the population’s growth and aging. This represents a dangerous trend and should become our priority for the future. But what new goals are we going to set and reach now, and how will we exploit thought-provoking technological skills for making these goals feasible? Machine learning can be at the root of the problem. Indeed, most recently, there has been a push towards medical data analysis by machine learning, and a great improvement in the training capabilities particularly of artificial deep neural networks (DNNs) inspired by the biological neural networks characterizing the human brain. This has generated competitive results for applications such as biomolecular target and protein structure prediction, structure-based rational drug design, and repurposing, all exerting a major impact on neuroscience and human well-being. By approaching early risks for diseases, non-invasive diagnosis, personalized treatment assessment, drug discovery, and automated science, the machine learning arena has thus the potential of becoming the new frontier for empowering neuroscience research and clinical practice in the years ahead.

Small fiber neuropathy (SFN) is a relatively common, but largely understudied neurological syndrome which has affected the lives of many globally. The common symptoms of SFN include pain, dysesthesia, and autonomic dysfunction, which are caused by damage to small nerve fibers. Due to its heterogeneous nature, SFN causes a multitude of symptoms which makes the disease and its subtypes difficult to diagnose. Furthermore, as the pathophysiology of SFN remains largely enigmatic, no cause is found in around 50% of the cases and these are classified as idiopathic SFN (iSFN). The difficult task of diagnosing SFN, and the even more elusive feat of hunting for the underlying etiology, demands accurate, precise, preferably noninvasive, and affordable tools, or a combination of them. Accordingly, appropriate biomarkers for SFN are needed to stratify patients and develop cause-centered treatments in addition to symptomatic treatments. As peripheral axons grow and repair, identifying underlying causes of SFN and intervening early may spur axonal regeneration in young patients, which can greatly improve their symptoms and improve quality of life. This narrative review aims to objectively highlight functional, histological, and molecular biomarkers to aid clinicians in discerning the diagnostic tests they should use to diagnose, confirm and determine the etiology of SFN. The strengths and limitations of each potential biomarker will be discussed. Clearer diagnostic criteria, guidelines, and work-up for SFN are required for clinicians to better identify the disease in patients presenting with non-specific symptoms.

Catatonia is a neuropsychiatric syndrome characterized by a broad range of motor, behavioral and cognitive abnormalities. Catatonia and Parkinson’s disease (PD) may show partially overlapping symptomatology. For this reason, catatonia could be misdiagnosed and overlooked in patients with severe PD, leading to a delay in proper treatment with benzodiazepines or electroconvulsive therapy (ECT). Two cases of women with PD and catatonia who have been admitted and treated with ECT at the University Hospital of Pisa are described here. Both had a history of bipolar disorder and developed withdrawn catatonia, in the context of affective episodes, approximately one year after the diagnosis of PD. In both cases, ECT was needed and successfully led to the remission of catatonic symptoms, without cognitive worsening. Since ECT appears to effectively treat catatonia in patients with PD, clinicians should consider it as a therapeutic option.

The patient was a 6-year-old child with spastic quadriplegic cerebral palsy (CP) categorized with the gross motor function classification system (GMFCS) as a level IV and a Modified Modified Ashworth Scale (MMAS) of 2 for the bilateral hamstring and hip adductor muscles, and 3 for the bilateral gastrocnemius muscles. This patient’s limited range of motion significantly affected the caregiver’s ability to perform activities of daily living (ADLs). Dry needling (DN) is considered a standard treatment (TX) when treating adults with poor range of motion. This article aims to place intramuscular electrical stimulation (IMES), the delivery of an electrical current through a monofilament needle into targeted trigger points (TrPs) within the context of treating children with spastic CP. Following IMES TXs over 32 months that totaled 12 left hamstring TXs, 13 right hamstring TXs, 13 hip adductor TXs, 21 left gastrocnemius TXs, and 18 right gastrocnemius TXs, the patient demonstrated an increase in passive range of motion (PROM) of the hamstring, hip adductors, and gastrocnemius muscles. These gains equated to ease in ADLs. Both the Pediatric Evaluation of Disability Inventory (PEDI, PEDI-Caregiver Assistance Scale) and the Goal Attainment Scale (GAS) demonstrated decreased caregiver burden. The child’s GMFCS level and the MMAS did not change. Further data collection related to treating children with spasticity using IMES is indicated to validate this type of TX with this patient population.

Myasthenia gravis (MG) is a rare auto-immune neuromuscular junction (NMJ) disorder which is caused by formation of autoantibodies and destruction of NMJ components. The MG diagnosis is based on the symptoms, autoantibodies detection and paraclinical tests. Given that MG patients have so many differential diagnosis and various medication responses, choosing an accurate diagnosis and the therapy plan in MG is challenging. According to the studies, there are the immunologic, genetic, microRNAs, gut microbiome, and other established or newly proposed biomarkers for diagnosis and prognosis of MG. More studies are needed to provide better collection of biomarkers in MG patients and evaluate their role in MG pathology.

Neuropathic pain (NP), which is difficult to treat, remains a heavy burden for both individuals and society. The efficacy of current treatments is insufficient. The pathophysiology of NP is still not fully elucidated, and there is a need to explore new therapeutic targets to develop more effective treatment strategies. Recent studies showed that thrombospondin 4 (TSP4) protein expression is increased in the spinal cord following nervous system injury and that blocking or inhibiting this increase improves NP. In this review, it has been aimed to present the evidence for the role of TSP4 in the mechanisms of NP development and to evaluate the therapeutic potential of TSP4 blockade in the treatment of NP.

Different stressors can elicit neuroinflammatory responses modulated by innate immunity receptors, such as the family of Toll-like receptors (TLRs). The TLR4, a pattern recognition receptor (PRR), is involved in many diseases, such as inflammatory and central nervous system (CNS) diseases. Stress exposure can regulate the expression of PRRs, including TLR4, in the brain of animals, especially in the hippocampus and prefrontal cortex. Moreover, TLR4 modulates behavior and neuroinflammatory responses in the brain. In addition, to TLR4, the endocannabinoid (eCB) system plays a role in stress response and immunity, acting as a regulatory, stress-buffer system. This system is involved in many TLRs-mediated immune responses, such as microglia activation. Therefore, pharmacological approaches targeting the eCB system could modulate neuroinflammatory responses to stress by interfering with the TLR4 pathway. Although the connection between TLR4, stress, and neuroinflammation is well documented, almost no pre-clinical studies investigate the possible direct relationship between TLR4, behavior, stress, and the eCB system. Studies exploring the relationship between stress, neuroinflammation, TLR4, and the eCB system were searched using Pubmed, Web of Science, and Embase databases. Based on this search, this review is focused on the involvement of TLR4 receptors and signaling in neuroinflammation and the behavioral consequences of stress exposure. Moreover, evidence of the eCB system modulating TLR4-mediated responses was brought to the attention, pointing out a possible regulatory role of these responses by eCBs in behavior changes related to mood disorders.

The global prevalence of intracranial aneurysms (IA) ranges from 5–10%, with a demographic variation. Large and giant aneurysms typically involve cavernous and paraclinoid segments of the internal carotid artery (ICA), and represent 5% of IA. Typically, these lesions involve segments of the ICA, especially the cavernous and paraclinoid segments. The remaining cases affect the vertebrobasilar region, middle cerebral artery (MCA), and anterior cerebral artery (ACA). From the morphological point of view, they are divided into saccular and fusiform. In cases of rupture, the subarachnoid hemorrhage (SAH) is the most common presentation followed by intracerebral hemorrhage (ICH), or both. Other manifestations can occur as occlusion of perforating vessels, embolic events, seizures, and mass effects. The management of unruptured intracranial aneurysms (UIA) is controversial, and the aim of treatment is to exclude the lesions and preserve neurological function. Endovascular techniques for the treatment of paraclinoid aneurysms, in particular, ICA reconstruction using flow-diverting stents, have become a valid option. However, surgery or endovascular treatment has a number of limitations and the choice of treatment is individual in each case. This type of lesion has an extremely poor natural history, and treatment is a challenge regardless of the technique used.

The report described a clinical case of a 55-year-old female, with a personal history of hypertension, hyperthyroidism, and depressive syndrome. The patient started complaints of moderate-intensity right frontal headache, progressively worsening with two months of evolution. She also reported blurred vision and diplopia. Brain computed tomography (CT) documented a partially calcified sellar and parasellar lesion. Subsequently, magnetic resonance imaging (MRI)/MRI angiographies were performed and showed a saccular aneurysm of the right ICA, cavernous segment. The patient underwent a diagnostic and therapeutic angiography with stent placement. Clinical and imaging improvements were documented by angiography and MRI angiography with progressive reduction of the aneurysm during the period of follow-up.

Delayed cerebral ischemia after subarachnoid hemorrhage is one of the most important causes of mortality and poor functional outcome in patients. Initially, the etiology and treatment of delayed cerebral ischemia focused primarily on cerebral vasospasm. However, recent studies have detected that depolarization, microcirculation, and autoregulation disorder, which spreads together with cerebral vasospasm, also play a role in the etiology. The main treatment strategies in the prevention and treatment of delayed cerebral ischemia are the regulation of blood pressure and the use of calcium channel blockers, especially nimodipine. The main step in the early diagnosis and treatment of the disease is to monitor the neurological clinical status. In addition to transcranial Doppler ultrasonography, computed tomography, or magnetic resonance imaging angiography, continuous electroencephalography and invasive brain multimodal examination may be required in the follow-up period of the disease. In addition to blood pressure regulation, optimization of cardiac output, endovascular interventions, angioplasty, and/or intra-arterial vasodilator infusion are other treatment methods. This review aimed to evaluate delayed cerebral ischemia, one of the most important complications of subarachnoid hemorrhage, in the light of current literature.

Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders (NDD) characterized by deficits in three domains: impairments in social interactions, language, and communication, and increased stereotyped restrictive/repetitive behaviors and interests. The exact etiology of ASD remains unknown. Genetics, gestational exposure to inflammation, and environmental stressors, which combine to affect mitochondrial dysfunction and metabolism, are implicated yet poorly understood contributors and incompletely delineated pathways toward the relative risk of ASD. Many studies have shown a clear male bias in the incidence of ASD and other NDD. In other words, being male is a significant yet poorly understood risk factor for the development of NDD. This review discusses the link between these factors by looking at the current body of evidence. Understanding the link between the multiplicity of hits—from genes to environmental stressors and possible sexual determinants, contributing to autism susceptibility is critical to developing targeted interventions to mitigate these risks.

Stroke is one of the most common causes of disability and exerts a high burden of direct and indirect costs. Stroke may cause spasticity, which limits patients’ abilities and affects their activities of daily living, decreasing their quality of life. Conventional treatments are based on physical therapy, anti-spasticity medication, and botulinum toxin type A (BTX-A). However, recently, non-pharmacological approaches have been used, such as dry needling (DN) of myofascial trigger points. BTX-A and DN are two treatments that aim to decrease spasticity in patients with stroke, but their mode of action, application, and costs differ. Thus, there is a need to determine the comparative economics of post-stroke spasticity treatments. For this purpose, a search for all types of cost-effectiveness studies (randomized controlled trials, matched controls, and cohorts) and models of epidemiological data was performed. Studies were selected if they included economic outcomes in stroke patients treated with BTX-A or DN. As a result, 7 studies of BTX-A and 2 of DN were selected. Similarities were found in the outcomes used to assess the effectiveness of both treatments in most studies, with modifications of the Ashworth Scale [Modified Ashworth Scale (MAS)/Modified Modified Ashworth Scale (MMAS)] and quality-adjusted life year (QALY) being the main indicators of effectiveness. However, both the duration of the studies and the evaluation of costs were highly heterogeneous, making comparison difficult. In conclusion, both BTX-A and DN are cost-effective to treat spasticity in patients with stroke, but there is a need for comparative studies to make direct comparisons of cost-effectiveness with the most frequently used outcomes such as the MMAS and QALYs.

The glymphatic system, first described in 2012, is a brain-wide perivascular network that plays an important role in promoting interstitial metabolic waste removal from the brain. Glymphatic pathway function has been reported to be dramatically diminished in the aging brain. Furthermore, glymphatic system dysfunction has been linked to a spectrum of neurodegenerative diseases including Alzheimer’s disease (AD). This waste clearance pathway of the brain is most active during sleep and is largely disengaged during wakefulness. While norepinephrine (NE) is responsible for suppressing the glymphatic function, electroencephalographic slow-wave (delta) activity has a facilitating effect. An intriguing question is whether these regulators of glymphatic activity can be modulated by meditation-based approaches and whether such approaches have the ability to increase glymphatic function in the awake brain. The present article hypothesizes that meditation-based approaches, such as immersive sound meditation, may have the potential to enhance glymphatic pathway transport and solute clearance by reducing NE and increasing slow-wave activity. If confirmed, meditation could be an attractive approach to promoting healthy brain aging and to preventing neurodegenerative conditions like AD.

The glymphatic system, or glial-lymphatic system, is a waste clearance system composed of perivascular channels formed by astrocytes that mediate the clearance of proteins and metabolites from the brain. These channels facilitate the movement of cerebrospinal fluid throughout brain parenchyma and are critical for homeostasis. Disruption of the glymphatic system leads to an accumulation of these waste products as well as increased interstitial fluid in the brain. These phenomena are also seen during and after subarachnoid hemorrhages (SAH), contributing to the brain damage seen after rupture of a major blood vessel. Herein this review provides an overview of the glymphatic system, its disruption during SAH, and its function in recovery following SAH. The review also outlines drugs which target the glymphatic system and may have therapeutic applications following SAH.

Several studies investigated the side effect of adjuvant cancer treatments, and different types of preventive techniques or treatments have been assessed. Chemotherapy-induced peripheral neuropathy (CIPN) is the most common neurological side effect. Exercise training has been widely studied as an adjuvant therapy to prevent CIPN and improve post-chemotherapy functional outcome and quality of life (QoL). This narrative review aims to summarize the data obtained from the latest studies about physical activity (PA) for the prevention and treatment of CIPN and associated QoL measures. Literature research was conducted to obtain studies including PA interventions for patients with CIPN. Ten studies met inclusion criteria and were therefore summarized and discussed, focusing on exercise type and functional outcome. It seems clear that, regardless of the type of exercise, PA plays a positive role in the treatment of CIPN, providing a significant symptom improvement. There has been no standardization of type, quantity, and intensity of PA administered to the subjects in the various studies probably due to a physiological difference between samples, grade of neuropathy, and difference among therapies.

Altered immunity may have destructive consequences for the integrated central nervous system. This immune response often affects progressive neurodegenerative diseases such as Parkinson’s disease and/or psychiatric disorders such as schizophrenia. In particular, schizophrenia pathogenesis may be mediated by multiple neuro-immune interaction pathways. Gut microbiota might affect the brain and/or immune function. Significant machineries of immunity are commonly affected by the commensal gut microbiota. Therefore, schizophrenia may be connected with the gut-immune system. In addition, the brain and immune systems cooperate on multiple levels. The brain could save several pieces of information about specific inflammation in a body. This immunological memory named “engrams”, also called memory traces, could restore the initial disease state, which may help to explain key features of schizophrenia. Based on this concept, therapeutic strategies for schizophrenia could be the modification of the gut microbiota. Probiotics and/or fecal microbiota transplantation are now emerging as the most promising treatments for the modification. More consideration of the roles of gut microbiota will conduct the further development of immune-based therapeutics for the prevention and/or treatments of psychiatric disorders.

Subarachnoid hemorrhage (SAH) has deleterious outcomes for patients, and during the hospital stay, patients are susceptible to vasospasm and delayed cerebral ischemia. Coronavirus disease 2019 (COVID-19) has been shown to worsen hypertension through angiotensin-converting enzyme 2 (ACE2) activity, therefore, predisposing to aneurysm rupture. The classic renin-angiotensin pathway activation also predisposes to vasospasm and subsequent delayed cerebral ischemia. Matrix metalloproteinase 9 upregulation can lead to an inflammatory surge, which worsens outcomes for patients. SAH patients with COVID-19 are more susceptible to ventilator-associated pneumonia, reversible cerebral vasoconstriction syndrome, and respiratory distress. Emerging treatments are warranted to target key components of the anti-inflammatory cascade. The aim of this review is to explore how the COVID-19 virus and the intensive care unit (ICU) treatment of severe COVID can contribute to SAH.

Stroke causes acute neurological deficit which is an important cause of morbidity and mortality. Neurorehabilitation is an important dimension in the management of post-stroke deficits. Spasticity, pain, and neurological deficits are contributors to post-stroke disability. Dry needling (DN) is a technique commonly used in the management of myofascial pain. Recent evidence suggests its efficacy in the management of post-stroke disability. The descriptive review on the use of DN summarises the evidence for the management of post-stroke patients such as spasticity, balance, pain, functional outcome, tremor, and ultrasonographic evidence. The filiform needle is inserted into the target muscle until a local twitch response is obtained. The effects of DN are produced by the local stretch of the spastic muscle and afferent modulation of the reflex arc that decreases the excitability of the alpha motor neuron. The DN reduces muscle spasticity in post-stroke patients. The improved spasticity is translated to better functional outcomes and balance. The procedure is also shown to reduce pain including post-stroke shoulder pain. It is also shown to improve tremors in post-stroke patients. Ultrasonographic evidence of the beneficial effects of DN shows improved measures in the pennate angle and mean muscle thickness. Concurrent use of DN and electrical stimulation improve spasticity, the effect which may be seen for longer periods. DN is emerging as a useful and cost-effective technique in the management of post-stroke patients. The evidence for the use of DN in the management of post-stroke spasticity is high. However, more research is required to assess its efficacy in functional outcomes and other aspects of the stroke.

The cholesterol is a vital component of cell membranes and myelin sheaths, and a precursor for essential molecules such as steroid hormones. In humans, cholesterol is partially obtained through the diet, while the majority is synthesized in the body, primarily in the liver. However, the limited exchange between the central nervous system and peripheral circulation, due to the presence of the blood-brain barrier, necessitates cholesterol in the brain to be exclusively acquired from local de novo synthesis. This cholesterol is reutilized efficiently, rendering a much slower overall turnover of the compound in the brain as compared with the periphery. Furthermore, brain cholesterol is regulated independently from peripheral cholesterol. Numerous enzymes, proteins, and other factors are involved in cholesterol synthesis and metabolism in the brain. Understanding the unique mechanisms and pathways involved in the maintenance of cholesterol homeostasis in the brain is critical, considering perturbations to these processes are implicated in numerous neurodegenerative diseases. This review focuses on the developing understanding of cholesterol metabolism in the brain, discussing the sites and processes involved in its synthesis and regulation, as well as the mechanisms involved in its distribution throughout, and elimination from, the brain.

Cholesterol serves as an essential lipid molecule in various membrane organelles of mammalian cells. The metabolites of cholesterol also play important functions. Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), also named as sterol O-acyltransferase 1, is a membrane-bound enzyme residing at the endoplasmic reticulum (ER). It converts cholesterol to cholesteryl esters (CEs) for storage, and is expressed in all cells. CEs cannot partition in membranes; they can only coalesce as cytosolic lipid droplets. Excess CEs are found in the vulnerable region of the brains of patients with late-onset Alzheimer’s disease (AD), and in cell and mouse models for AD. Reducing CE contents by genetic inactivation of ACAT1, or by pharmacological inhibition of ACAT is shown to reduce amyloidopathy and other hallmarks for AD. To account for the various beneficial actions of the ACAT1 blockade (A1B), a working hypothesis is proposed here: the increase in CE contents observed in the AD brain is caused by damages of cholesterol-rich lipid rafts that are known to occur in neurons affected by AD. These damages cause cholesterol to release from lipid rafts and move to the ER where it will be converted to CEs by ACAT1. In addition, the increase in CE contents may also be caused by overloading with cholesterol-rich substances, or through activation of ACAT1 gene expression by various pro-inflammatory agents. Both scenarios may occur in microglia of the chronically inflamed brain. A1B ameliorates AD by diverting the cholesterol pool destined for CE biosynthesis such that it can be utilized more efficiently to repair membrane damage in various organelles, and to exert regulatory actions more effectively to defend against AD. To test the validity of the A1B hypothesis in cell culture and in vivo, the current status of various anti-ACAT1 agents that could be further developed is briefly discussed.

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers—cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)]—has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also been proved useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

Peroxisomes are actively involved in the metabolism of various lipids including fatty acids, ether phospholipids, bile acids as well as the processing of reactive oxygen and nitrogen species. Recent studies show that peroxisomes can regulate cholesterol homeostasis by mediating cholesterol transport from the lysosomes to the endoplasmic reticulum and towards primary cilium as well. Disruptions of peroxisome biogenesis or functions lead to peroxisomal disorders that usually involve neurological deficits. Peroxisomal dysfunction is also linked to several neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In many peroxisomal disorders and neurodegenerative diseases, aberrant cholesterol accumulation is frequently encountered yet largely neglected. This review discusses the current understanding of the mechanisms by which peroxisomes facilitate cholesterol trafficking within the cell and the pathological conditions related to impaired cholesterol transport by peroxisomes, with the hope to inspire future development of the treatments for peroxisomal disorders and neurodegenerative diseases.

Familial early-onset Alzheimer’s disease (AD) is more probable in individuals coming from mothers diagnosed with AD than from fathers diagnosed with AD. Studies in animal models have shown maternal imprinting due to the transmission to the embryo of altered material in the ovum. In the case of transgenic animals harboring a mutated form of the human amyloid precursor protein (APP), offspring from crosses with wild-type (WT) fathers and transgenic mothers display more abnormalities than offspring from crosses with transgenic fathers and WT mothers. Expression of the mutated APP in the ovum may lead to alterations that may be genetic and/or epigenetic in the nuclear and/or the mitochondrial DNA. These modifications that are transmitted to the new living beings affect more mitochondrial proteins and, therefore, the mitochondrial function may be affected in adulthood by trends present in the ovum.

Spinal cord injury (SCI) induces several destructive events that develop immediately after the primary insult. These phenomena increase tissue damage; that is why, numerous therapeutic approaches are studied in order to neutralize these destructive mechanisms. In line with this, several studies indicate that after injury, neural tissue could be protected by an adaptive immune response directed against self-antigens. Immunization with neural-derived peptides (INDP) reduces secondary degeneration of neurons after spinal cord insult and promotes a significant motor recovery. The combination of antioxidants or other immunomodulatory peptides after SCI can improve the protective effect induced by INDP. INDP in acute SCI is a promising strategy, so further studies should be addressed to be able to formulate the best strategy.

Phosphoinositides are membrane phospholipids involved in a variety of cellular processes like growth, development, metabolism, and transport. This review focuses on the maintenance of cellular homeostasis of phosphatidylinositol 4,5-bisphosphate (PIP₂), and phosphatidylinositol 3,4,5-trisphosphate (PIP₃). The critical balance of these PIPs is crucial for regulation of neuronal form and function. The activity of PIP₂ and PIP₃ can be regulated through kinases, phosphatases, phospholipases and cholesterol microdomains. PIP₂ and PIP₃ carry out their functions either indirectly through their effectors activating integral signaling pathways, or through direct regulation of membrane channels, transporters, and cytoskeletal proteins. Any perturbations to the balance between PIP₂ and PIP₃ signaling result in neurodevelopmental and neurodegenerative disorders. This review will discuss the upstream modulators and downstream effectors of the PIP₂ and PIP₃ signaling, in the context of neuronal health and disease.

Current evidence indicates that neurodegeneration of dopaminergic neurons of the substantia nigra associated to Parkinson’s disease is a consequence of a neuroinflammatory process in which microglial cells play a central role. The initial activation of microglial cells is triggered by pathogenic protein inclusions, which are mainly composed by α-synuclein. Importantly, these pathogenic forms of α-synuclein subsequently induce a T-cell-mediated autoimmune response to dopaminergic neurons. Depending on their functional phenotype, these autoreactive T-cells might shape the functional features of activated microglia. T-cells bearing pro-inflammatory phenotypes such as T-helper (Th)1 or Th17 promote a chronic inflammatory behaviour on microglia, whilst anti-inflammatory T-cells, such as regulatory T-cells (Treg) favour the acquisition of neuroprotective features by microglia. Thus, T-cells play a fundamental role in the development of neuroinflammation and neurodegeneration involved in Parkinson’s disease. This review summarizes the evidence indicating that not only CD4⁺ T-cells, but also CD8⁺ T-cells play an important role in the physiopathology of Parkinson’s disease. Next, this review analyses the different T-cell epitopes derived from the pathogenic forms of α-synuclein involved in the autoimmune response associated to Parkinson’s disease in animal models and humans. It also summarizes the requirement of specific alleles of major histocompatibility complexes (MHC) class I and class II necessaries for the presentation of CD8⁺ and CD4⁺ T-cell epitopes from the pathogenic forms of α-synuclein in both humans and animal models. Finally, this work summarizes and discusses a number of experimental immunotherapies that aim to strengthen the Treg response or to dampen the inflammatory T-cell response as a therapeutic approach in animal models of Parkinson’s disease.

Since the identification and cloning of the cannabinoid receptor 2 (CB₂R), several studies focused on the characterization of its physiological and pathological role. Initially, CB₂R was considered as the peripheral cannabinoid receptor due to its detection in the rat spleen and leukocyte subpopulation in humans. Later, CB₂R was identified in different brain regions significantly modifying the landscape and pointing out its role in a wide variety of central physiological functions and pathological conditions. Additional research also detected the expression of CB₂R in neurons, microglia, and astroglia in different brain regions. Indeed, the findings collected to date support a significant function of CB₂R in anxiety, depression, schizophrenia, and additional neuropsychiatric disorders. This review gathers the most relevant literature regarding new advances about the role of CB₂R in a variety of neuropsychiatric conditions, with special emphasis on its potential as a new therapeutic target for the treatment of different psychiatric disorders.

The pathogenic basis behind some of the most prevalent neurodegenerative diseases in advanced societies, known as proteinopathies, deals with alterations in protein homeostasis. Despite the broad diversity of clinical symptoms, they share a remarkably common feature that is the serious neuronal loss in several disease-specific brain regions due to the presence of toxic aggregations of misfolded proteins. So far, research efforts have been insufficient to decipher the exact molecular mechanisms that trigger the conformational change from a functional healthy protein to its pathological version. This is a sine qua non condition to progress in developing new approaches and treatments for these diseases for which there is no cure. Currently, it is well accepted that perturbations in gut microbiota composition negatively impact a wide range of brain processes via the gut-brain axis which increases host susceptibility to neurodegenerative disorders. In this context, modulate the microbial ecosystem colonizing the gastrointestinal tract may be a promising therapeutic approach in the management of proteinopathies. This review aims to provide an updated view of the role that gut microbiota poses in the pathogenesis of Parkinson’s disease, Alzheimer’s disease and Huntington’s disease, the most common neurodegenerative proteinopathies, and of the possibility of translating this knowledge into effective and safe clinical microbiota-based interventions, especially those designed to afford neuroprotection.

Early in the course of infection, human immunodeficiency virus (HIV) is able to enter the central nervous system where it stablishes a permanent reservoir. Current antiretroviral therapies do not efficiently cross the blood-brain barrier and therefore do not reach the HIV located in the central nervous system. Consequently, HIV infection can often be associated with neurocognitive impairment and HIV-associated dementia. The purpose of this review is to brief the reader into the world of neurological complications arising from HIV infection. Mechanisms by which HIV directly or indirectly impairs the central nervous system are discussed, as well as other factors influencing or contributing to the impairment, and the animal models currently used to perform research on the topic.

The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism.