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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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