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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD. [ABSTRACT FROM AUTHOR]

Inositol is a natural sugar-like compound, commonly present in many plants and foods. It is involved in several biochemical pathways, most of them controlling vital cellular mechanisms, such as cell development, signaling and nuclear processes, metabolic and endocrine modulation, cell growth, signal transduction, etc. In this narrative review, we focused on the role of inositol in human brain physiology and pathology, with the aim of providing an update on both potential applications and current limits in its use in psychiatric disorders. Overall, imaging and biomolecular studies have shown the role of inositol levels in the pathogenesis of mood disorders. However, when administered as monotherapy or in addition to conventional drugs, inositol did not seem to influence clinical outcomes in both mood and psychotic disorders. Conversely, more encouraging results have emerged for the treatment of panic disorders. We concluded that, despite its multifaceted neurobiological activities and some positive findings, to date, data on the efficacy of inositol in the treatment of psychiatric disorders are still controversial, partly due to the heterogeneity of supporting studies. Therefore, systematic use of inositol in routine clinical practice cannot be recommended yet, although further basic and translational research should be encouraged.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-β plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the "neuronal system" (R-HSA-112316) and the "synaptic signaling" (GO:0099536), while the "regulation of protein catabolic process" (GO:00042176) and "transport of small molecules" (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients.

The COVID-19 pandemic and the related infodemic generated confusion and increased demand of various pharmaceuticals, ushering in the opportunity for illicit online vendors to fill a gap in the marketplace using potentially dangerous products. The aim of our study is to provide evidence regarding increased demand, online availability and consumer accessibility of ivermectin, an anthelmintic agent, without substantiated indications in reference to SARS-CoV-2. In our study, we combined infodemiology methodology aligned with search engine result assessment and website analytics to evaluate patient safety risks. Users' Google queries regarding ivermectin were trending and peaked during the last week of November 2020 and March 2021. Consumers more likely found links leading directly or indirectly (via redirection) to illegal online retailers representing nearly half (53.3%) of search engine result links regarding the first three result pages in December 2020 and topped off at 73.3% by March 2021. Illicit medicine retailers outnumbered and outranked their legitimate counterparts and dominated the first search engine results page. A vast majority (77.7%) of the identified online pharmacies were characteristically rogue; more than half (55.5%) offered prescription-only products without a valid medical prescription. Our results illustrate connection between infodemic and its consequences on the illicit online pharmacy market.

Background: Neuroinvasive properties of SARS-CoV-2 have allowed the hypothesis of several pathogenic mechanisms related to acute and chronic neurological sequelae. However, neuropathological correlates have been poorly systematically investigated, being retrieved from reports of single case or limited case series still., Methods: A PubMed search was carried out to review all publications on autopsy in subjects with "COronaVIrus Disease-19" (COVID-19). Among them, we focused on histological findings of the brain, which were compared with those from the authors' autoptic studies performed in some COVID-19 patients., Results: Only seven studies reported histological evidence of brain pathology in patients deceased for COVID-19, including three with reverse transcription-quantitative polymerase chain reaction evidence of viral infection. All these studies, in line with our experience, showed vascular-related and infection-related secondary inflammatory tissue damage due to an abnormal immune response. It is still unclear, however, whether these findings are the effect of a direct viral pathology or rather reflect a non-specific consequence of cardiovascular and pulmonary disease on the brain., Conclusions: Notwithstanding the limited evidence available and the heterogeneity of the studies, we provide a preliminary description of the relationship between SARS-CoV-2 and brain sequelae. Systematic autoptic investigations are needed for accurate detection and adequate management of these patients.

Hypertensive crisis, defined as an increase in systolic blood pressure >179 mmHg or diastolic blood pressure >109 mmHg, typically causes end-organ damage; the brain is an elective and early target, among others. The strong relationship between arterial hypertension and cerebrovascular diseases is supported by extensive evidence, with hypertension being the main modifiable risk factor for both ischemic and hemorrhagic stroke, especially when it is uncontrolled or rapidly increasing. However, despite the large amount of data on the preventive strategies and therapeutic measures that can be adopted, the management of high BP in patients with acute cerebrovascular diseases presenting at the emergency department is still an area of debate. Overall, the outcome of stroke patients with high blood pressure values basically depends on the occurrence of hypertensive emergency or hypertensive urgency, the treatment regimen adopted, the drug dosages and their timing, and certain stroke features. In this narrative review, we provide a timely update on the current treatment, debated issues, and future directions related to hypertensive crisis in patients referred to the emergency department because of an acute cerebrovascular event. This will also focus greater attention on the management of certain stroke-related, time-dependent interventions, such as intravenous thrombolysis and mechanic thrombectomy.

Background: While the association between motor-evoked potential (MEP) abnormalities and motor deficit is well established, few studies have reported the correlation between MEPs and signs of pyramidal tract dysfunction without motor weakness. We assessed MEPs in patients with pyramidal signs, including motor deficits, compared to patients with pyramidal signs but without weakness., Methods: Forty-three patients with cervical spondylotic myelopathy (CSM) were dichotomized into 21 with pyramidal signs including motor deficit (Group 1) and 22 with pyramidal signs and normal strength (Group 2), and both groups were compared to 33 healthy controls (Group 0). MEPs were bilaterally recorded from the first dorsal interosseous and tibialis anterior muscle. The central motor conduction time (CMCT) was estimated as the difference between MEP latency and peripheral latency by magnetic stimulation. Peak-to-peak MEP amplitude and right-to-left differences were also measured., Results: Participants were age-, sex-, and height-matched. MEP latency in four limbs and CMCT in the lower limbs were prolonged, and MEP amplitude in the lower limbs decreased in Group 1 compared to the others. Unlike motor deficit, pyramidal signs were not associated with MEP measures, even when considering age, sex, and height as confounding factors., Conclusions: In CSM, isolated pyramidal signs may not be associated, at this stage, with MEP changes.

Background: Patients with Fabry's disease (FD) may be asymptomatic or show a spectrum of clinical manifestations, including cerebrovascular disease, mainly affecting posterior circulation. Few and conflicting studies on cerebral blood flow (CBF) velocity by transcranial Doppler sonography (TCD) in asymptomatic FD (aFD) subjects have been published. Our study aims to assess TCD in aFD subjects to identify any preclinical CBF change., Methods: A total of 30 aFD subjects were consecutively recruited and compared to 28 healthy controls. Brain magnetic resonance imaging was normal in all participants. TCD was used to study blood flow velocity and indices of resistance of intracranial arteries from the middle cerebral artery (MCA), bilaterally, and from the basilar artery (BA). Cerebral vasomotor reactivity (CVR) was also evaluated from MCA., Results: No difference was found between groups for MCA parameters of CBF velocity and CVR. Compared to controls, a higher mean blood flow velocity and a lower resistance index from BA were observed in FD subjects. No correlation was found between any BA-derived TCD parameter and the level of lyso-globotriaosylceramide., Conclusions: aFD subjects show evidence of altered CBF velocity in posterior circulation. Preclinical detection of neurovascular involvement in FD might allow appropriate management and prevention of future cerebrovascular complications and disability.

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called "cytokine storm"), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

In the last years, there has been a significant growth in the literature exploring the pathophysiology of vascular cognitive impairment (VCI). As an "umbrella term" encompassing any degree of vascular-related cognitive decline, VCI is deemed to be the most common cognitive disorder in the elderly, with a significant impact on social and healthcare expenses. Interestingly, some of the molecular, biochemical, and electrophysiological abnormalities detected in VCI seem to correlate with disease process and progression, eventually promoting an adaptive plasticity in some patients and a maladaptive, dysfunctional response in others. However, the exact relationships between vascular lesion, cognition, and neuroplasticity are not completely understood. Recent findings point out also the possibility to identify a panel of markers able to predict cognitive deterioration in the so-called "brain at risk" for vascular or mixed dementia. This will be of pivotal importance when designing trials of disease-modifying drugs or non-pharmacological approaches, including non-invasive neuromodulatory techniques. Taken together, these advances could make VCI a potentially preventable cause of both vascular and degenerative dementia in late life. This review provides a timely update on the recent serological, cerebrospinal fluid, histopathological, imaging, and neurophysiological studies on this "cutting-edge" topic, including the limitations, future perspectives and translational implications in the diagnosis and management of VCI patients.

The role of infections in the pathogenesis of autism spectrum disorder (ASD) is still controversial. In this study, we aimed to evaluate markers of infections and immune activation in ASD by performing a meta-analysis of publicly available whole-genome transcriptomic datasets of brain samples from autistic patients and otherwise normal people. Among the differentially expressed genes, no significant enrichment was observed for infectious diseases previously associated with ASD, including herpes simplex virus-1 (HSV-1), cytomegalovirus and Epstein-Barr virus in brain samples, nor was it found in peripheral blood from ASD patients. Interestingly, a significant number of genes belonging to the "prion diseases" pathway were found to be modulated in our ASD brain meta-analysis. Overall, our data do not support an association between infection and ASD. However, the data do provide support for the involvement of pathways related to other neurodegenerative diseases and give input to uncover novel pathogenetic mechanisms underlying ASD.

Neuroblastoma (NB) is the most frequent extracranial pediatric tumor. Despite the current available multiple therapeutic options, the prognosis for high-risk NB patients remains unsatisfactory and makes the disease a clear unmet medical need. Thus, more tailored therapeutic approaches are warranted to improve both the quality of life and the survival of the patients. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that plays a key role in several diseases, including cancer. Preclinical and clinical studies in NB patients convergently indicate that MIF exerts pro-tumorigenic properties in NB. MIF is upregulated in NB tumor tissues and cell lines and it contributes to NB aggressiveness and immune-escape. To date, there are only a few data about the role of the second member of the MIF family, the MIF homolog d-dopachrome tautomerase (DDT), in NB. Here, we review the preclinical and clinical studies on the role of the MIF family of cytokines in NB and suggest that MIF and possibly DDT inhibitors may be promising novel prognostic and therapeutic targets in NB management.

Background: Cervical myelopathy (CM) is a common cause of morbidity and disability in patients with mucopolysaccharidosis (MPS) and, therefore, early detection is crucial for the best surgical intervention and follow-up. Transcranial magnetic stimulation (TMS) non-invasively evaluates the conduction through the cortico-spinal tract, also allowing preclinical diagnosis and monitoring., Methods: Motor evoked potentials (MEPs) to TMS were recorded in a group of eight patients with MPS-related CM. Responses were obtained during mild tonic muscular activation by means of a circular coil held on the "hot spot" of the first dorsal interosseous and tibialis anterior muscles, bilaterally. The motor latency by cervical or lumbar magnetic stimulation was subtracted from the MEP cortical latency to obtain the central motor conduction time. The MEP amplitude from peak to peak to cortical stimulation and the interside difference of each measure were also calculated., Results: TMS revealed abnormal findings from both upper and lower limbs compatible with axonal damage and demyelination in six of them. Notably, a subclinical cervical spinal disease was detected before the occurrence of an overt CM in two patients, whereas TMS signs compatible with a CM of variable degree persisted despite surgery in all treated subjects., Conclusions: TMS can be viewed as an adjunct diagnostic test pending further rigorous investigations.

Celiac disease is a systemic disorder with multifactorial pathogenesis and multifaceted symptomatology. In response to gluten exposure, a significant part of the general population produces antibodies that have been hypothesized to be deleterious to the brain. Among the well-known neurological manifestations, adult celiac patients often complain cognitive symptoms, ranging from the so-called "brain fog" till an overt dementia. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that can contribute to the assessment and monitoring of celiac patients, even in those without a clear neurological involvement. The studies here reviewed seem to converge on an impaired central motor conductivity and a "hyperexcitable celiac brain" to TMS, which partially reverts back after a long-term gluten restriction. Notably, a clear hyperexcitability is a stably reported feature of both degenerative and vascular dementia. Therefore, given its potential neuroprotective effect, the gluten-free diet should be introduced as early as possible, although the overall response of neurological symptoms (and cognition in particular) is still controversial. Identifying new and possibly modifiable risk factors may be of crucial importance for patients, clinicians, and researchers.