Features of oxidative stress in alcoholism.

The review considers molecular mechanisms underlying formation and development of oxidative stress (OS) in patients with alcohol dependence. The major attention is paid to the effects of ethanol and its metabolite acetaldehyde associated with additional sources of generation of reactive oxygen species (ROS) in response to exogenous ethanol. The own results of studies of the in vitro effect of ethanol and acetaldehyde on the concentration of peripheral OS markers - products of oxidative modification of proteins (protein carbonyls), lipids (lipid peroxidation products), DNA (8-hydroxy-2-deoxyguanosine, 8-OHdG) in blood plasma are presented. The changes in these parameters and the activity of antioxidant enzymes (SOD, catalase) in patients with alcohol dependence were analyzed. Own and literature data indicate that at a certain stage of the disease OS can play a protective rather than pathogenic role in the body.

Blood-Based Biomarkers of Neuroinflammation in Alzheimer's Disease: A Central Role for Periphery?

Neuroinflammation represents a central feature in the development of Alzheimer's disease (AD). The resident innate immune cells of the brain are the principal players in neuroinflammation, and their activation leads to a defensive response aimed at promoting ß-amyloid (Aß) clearance. However, it is now widely accepted that the peripheral immune system-by virtue of a dysfunctional blood-brain barrier (BBB)-is involved in the pathogenesis and progression of AD; microglial and astrocytic activation leads to the release of chemokines able to recruit peripheral immune cells into the central nervous system (CNS); at the same time, cytokines released by peripheral cells are able to cross the BBB and act upon glial cells, modifying their phenotype. To successfully fight this neurodegenerative disorder, accurate and sensitive biomarkers are required to be used for implementing an early diagnosis, monitoring the disease progression and treatment effectiveness. Interestingly, as a result of the bidirectional communication between the brain and the periphery, the blood compartment ends up reflecting several pathological changes occurring in the AD brain and can represent an accessible source for such biomarkers. In this review, we provide an overview on some of the most promising peripheral biomarkers of neuroinflammation, discussing their pathogenic role in AD.

Breakdown of blood brain barrier as a mechanism of post-traumatic epilepsy.

Traumatic brain injury (TBI) accounts for approximately 16% of acute symptomatic seizures which usually occur in the first week after trauma. Children are at higher risk for post-traumatic seizures than adults. Post-traumatic seizures are a risk factor for delayed development of epilepsy. Delayed, chronic post-traumatic epilepsy is preceded by a silent period during which therapeutic interventions may arrest, revert or prevent epileptogenesis. A number of recent review articles summarize the most important features of post-traumatic seizures and epilepsy; this review will instead focus on the link between cerebrovascular permeability, epileptogenesis and ictal events after TBI. The possibility of acting on the blood-brain barrier (BBB) and the neurovascular unit to prevent, disrupt or treat post-traumatic epilepsy is also discussed. Finally, we describe the latest quest for biomarkers of epileptogenesis which may allow for a more targeted intervention.

Peripheral Biomarker for Vascular Disorders.

Atherosclerosis is the underlying cause of most myocardial infarction (MI) and ischaemic stroke episodes. An early sign of atherosclerosis is hypertrophy of the arterial wall. It is known that increased intima media thickness (IMT) is a non-invasive marker of arterial wall alteration, which can easily be assessed in the carotid arteries by high-resolution B-mode ultrasound. Similarly, the other key element of MI and ischaemic strokes is the N-methyl-D-aspartate (NMDA) receptor which is an ionotropic glutamate receptor that mediates the vast majority of excitatory neurotransmission in the brain. NMDA activation requires the binding of both glutamate and a coagonist like D-serine to its glycine site. A special enzyme, serine racemase (SR), is required for the conversion of L-serine into D-serine, and alterations in SR activities lead to a variety of physiological and pathological conditions ranging from synaptic plasticity to ischemia, MI, and stroke. The amount of D-serine available for the activation of glutamatergic signalling is largely determined by SR and we have developed ways to estimate its levels in human blood samples and correlate it with the IMT. This research based short communication describes our pilot study, which clearly suggests that there is a direct relationship between the SR, D-serine, and IMT. In this article, we will discuss whether the activity of SR can determine the future consequences resulting from vascular pathologies such as MI and stroke.

Biomarkers in traumatic brain injury (TBI): a review.

Biomarkers can be broadly defined as qualitative or quantitative measurements that convey information on the physiopathological state of a subject at a certain time point or disease state. Biomarkers can indicate health, pathology, or response to treatment, including unwanted side effects. When used as outcomes in clinical trials, biomarkers act as surrogates or substitutes for clinically meaningful endpoints. Biomarkers of disease can be diagnostic (the identification of the nature and cause of a condition) or prognostic (predicting the likelihood of a person's survival or outcome of a disease). In addition, genetic biomarkers can be used to quantify the risk of developing a certain disease. In the specific case of traumatic brain injury, surrogate blood biomarkers of imaging can improve the standard of care and reduce the costs of diagnosis. In addition, a prognostic role for biomarkers has been suggested in the case of post-traumatic epilepsy. Given the extensive literature on clinical biomarkers, we will focus herein on biomarkers which are present in peripheral body fluids such as saliva and blood. In particular, blood biomarkers, such as glial fibrillary acidic protein and salivary/blood S100B, will be discussed together with the use of nucleic acids (eg, DNA) collected from peripheral cells.

Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study.

We aimed to profile a broad panel of inflammatory markers in patients with schizophrenia and healthy controls. Additionally, we performed a meta-analysis of chemokine alterations that have not been subjected to quantitative synthesis so far. We recruited 78 patients with schizophrenia and 78 healthy controls, and measured inflammatory markers using the Luminex technology. After adjustment for multiple testing, we found elevated levels of interleukin (IL)-1 receptor antagonist (IL-1RA), IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, interferon-γ, eotaxin-1, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), platelet-derived growth factor with two B subunits (PDGF-BB), macrophage inflammatory protein (MIP)-1α, MIP-1ß, vascular endothelial growth factor A (VEGF-A) and RANTES in multiple-episode schizophrenia (MES) patients. These differences, except for the difference in eotaxin-1 levels, appeared to be significant after co-varying for the dosage of antipsychotics. There were no significant differences in the levels of immune markers between first-episode schizophrenia (FES) patients and controls. Our meta-analysis revealed elevated levels of MCP-1 in first-episode psychosis (FEP) patients and MES individuals. Other chemokine alterations (elevated levels of IL-8, eotaxin-1 and MIP-1ß) were present only in MES patients. Our results indicate that dysregulation of immune response in schizophrenia develops with illness progression or appears as a long-term medication effect. Chemokine alterations are another example of aberrant immune response in schizophrenia patients. Elevated levels of MCP-1 might represent trait markers since these alterations were found in FEP and MES patients. Other chemokine alterations might be the markers of disease progression or might represent medication effects.

Levels of Serum Brain-Derived Neurotropic Factor in Individuals at Ultra-High Risk for Psychosis-Findings from the Longitudinal Youth at Risk Study (LYRIKS).

BACKGROUND: Identifying biomarkers to enrich prognostication and risk predictions in individuals at high risk of developing psychosis will enable stratified early intervention efforts. Brain-derived neurotrophic factor has been widely studied in schizophrenia and in first-episode psychosis with promising results. The aim of this study was to examine the levels of serum brain-derived neurotrophic factor between healthy controls and individuals with ultra-high risk of psychosis. METHODS: A sample of 106 healthy controls and 105 ultra-high risk of psychosis individuals from the Longitudinal Youth at Risk Study was included in this study. Ultra-high risk of psychosis status was determined using the Comprehensive Assessment of At-Risk Mental State at recruitment. Calgary Depression Scale for Schizophrenia was used to assess the severity of depression. All participants were followed up for 2 years, and ultra-high risk of psychosis remitters were defined by ultra-high risk of psychosis individuals who no longer fulfilled Comprehensive Assessment of At-Risk Mental State criteria at the end of the study period. Levels of brain-derived neurotrophic factor were measured in the serum by enzyme-linked immunosorbent assay method. RESULTS: The ultra-high risk of psychosis group had significantly higher baseline levels of serum brain-derived neurotrophic factor compared with the control group (3.7 vs 3.3 ng/mL, P=.018). However, baseline levels of serum brain-derived neurotrophic factor did not predict the development of psychosis (OR=0.64, CI=0.40-1.02) or remission (OR=0.83, CI=0.60-1.15) from ultra-high risk of psychosis status. CONCLUSION: Findings from our study did not support a role for serum brain-derived neurotrophic factor in predicting outcomes in ultra-high risk of psychosis individuals. However, the finding of higher levels of serum brain-derived neurotrophic factor in ultra-high risk of psychosis individuals deserves further study.

Vascular depression consensus report - a critical update.

BACKGROUND: Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition - a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term "MRI-defined vascular depression". DISCUSSION: This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal-subcortical-limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed. CONCLUSION: The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.

Update on bipolar disorder biomarker candidates.

INTRODUCTION: Bipolar disorder is a chronic and disabling mood disorder with a complex pathophysiological basis. A significant percentage of patients do not receive correct diagnosis which directly influences therapeutic response, rendering recovery troublesome. There is a long-standing need for proper non-clinically based tools for diagnosis, treatment selection and follow-up of such patients. Areas covered: In the past decade, the scientific community has shown a great interest in biomarker development. Here, we highlight the different potential biomarkers and we discuss their feasibility and their possible clinical relevance. Expert commentary: To date, despite the major ongoing trials and consortia with promising future perspectives, no reliable biomarker of bipolar disorder has been fully defined.

Global changes in DNA methylation in Alzheimer's disease peripheral blood mononuclear cells.

Changes in epigenetic marks may help explain the late onset of Alzheimer's disease (AD). In this study we measured genome-wide DNA methylation by luminometric methylation assay, a quantitative measurement of genome-wide DNA methylation, on DNA isolated from peripheral blood mononuclear cells of 37 subjects with late-onset AD (LOAD) and 44 healthy controls (CT). We found an increase in global DNA methylation in LOAD subjects compared to CT (p=0.0122), associated with worse cognitive performances (p=0.0002). DNA hypermethylation in LOAD group was paralleled by higher DNA methyltransferase 1 (DNMT1) gene expression and protein levels. When data were stratified on the basis of the APOE polymorphisms, higher DNA methylation levels were associated with the presence of APOE ε4 allele (p=0.0043) in the global population. Among the APOE ε3 carriers, a significant increase of DNA methylation was still observed in LOAD patients compared to healthy controls (p=0.05). Our data suggest global DNA methylation in peripheral samples as a useful marker for screening individuals at risk of developing AD.

Peripheral biomarkers of oxidative stress in aging and Alzheimer's disease.

Aging is associated with a greatly increased incidence of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). These conditions are associated with chronic inflammation, which generates oxygen reactive species, ultimately responsible for a process known as oxidative stress. It is well established that this process is the culprit of neurodegeneration, and there are also mounting evidences that it is not restricted to the central nervous system. Indeed, several studies, including some by our group, have demonstrated that increased peripheral oxidative stress markers are associated to aging and, more specifically, to AD. Therefore, it is very instigating to regard aging and AD as systemic conditions that might be determined by studying peripheral markers of oxidative stress.

O envelhecimento está associado a uma alta incidência de doenças neurodegenerativas, incluindo doença de Alzheimer (DA), doença de Parkinson (DP) e esclerose lateral amiotrófica (ELA). Estas condições estão relacionadas à inflamação crônica que gera espécies reativas de oxigênio, responsáveis por um processo denominado de estresse oxidativo. Está bem estabelecido que este processo está envolvido na neurodegeneração, e existem várias evidências de que ele não é restrito ao sistema nervoso central. De fato, muitos estudos, inclusive alguns de nosso grupo, demonstraram que o aumento de marcadores do estresse oxidativo periférico está associado ao envelhecimento e, mais intensamente, à DA. Assim, é muito instigante pensar no envelhecimento e na DA como doenças sistêmicas que possam ser investigadas por meio de marcadores periféricos de estresse oxidativo.