Chronic Mycobacterium avium infection differentially affects the cytokine expression profile of three mouse strains, but has no effect on behavior.

One of the most remarkable findings in the immunology and neuroscience fields was the discovery of the bidirectional interaction between the immune and the central nervous systems. This interplay is tightly regulated to maintain homeostasis in physiological conditions. Disruption in this interplay has been suggested to be associated with several neuropsychiatric disorders. Most studies addressing the impact of an immune system disruption on behavioral alterations focus on acute pro-inflammatory responses. However, chronic infections are highly prevalent and associated with an altered cytokine milieu that persists over time. Studies addressing the potential effect of mycobacterial infections on mood behavior originated discordant results and this relationship needs to be further addressed. To increase our understanding on the effect of chronic infections on the central nervous system, we evaluated the role of Mycobacterium avium infection. A model of peripheral chronic infection with M. avium in female from three mouse strains (Balb/c, C57BL/6, and CD-1) was used. The effect of the infection was evaluated in the cytokine expression profile (spleen and hippocampus), hippocampal cell proliferation, neuronal plasticity, serum corticosterone production and mood behavior. The results show that M. avium peripheral chronic infection induces alterations not just in the peripheral immune system but also in the central nervous system, namely in the hippocampus. Interestingly, the cytokine expression profile alterations vary between mouse strains, and are not accompanied by hippocampal cell proliferation or neuronal plasticity changes. Accordingly, no differences were observed in locomotor, anxious and depressive-like behaviors, in any of the mouse strains used. We conclude that the M. avium 2447 infection-induced alterations in the cytokine expression profile, both in the periphery and the hippocampus, are insufficient to alter hippocampal plasticity and behavior.

Association Between Iron-Related Protein Lipocalin 2 and Cognitive Impairment in Cerebrospinal Fluid and Serum.

A worldwide increase in longevity is bringing novel challenges to public health and health care professionals. Cognitive impairment in the elderly may compromise living conditions and precede Alzheimer's disease (AD), the most prevalent form of dementia. Therefore, finding molecular markers associated with cognitive impairment is of crucial importance. Lipocalin 2 (LCN2), an iron-related protein, has been suggested as a potential marker for mild cognitive impairment (MCI) and AD. This study aimed at investigating the association between LCN2 measured in serum and cerebrospinal fluid (CSF) with cognitive impairment. A cross-sectional design based on two aging cohorts was used: individuals diagnosed with subjective cognitive complaints (SCC), MCI, and AD from a Swedish memory clinic-based cohort, and individuals diagnosed with SCC and AD from a Portuguese cohort. Binary logistic [for the outcome cognitive impairment (MCI + AD) in the Swedish cohort and AD in the Portuguese cohort] and multinomial logistic (for the outcomes MCI and AD) regression analyses were used. No associations were found in both cohorts when controlling for sex, education, and age. This explanatory study suggests that the association between serum and CSF LCN2 concentrations with cognitive impairment reported in the literature must be further analyzed for confounders.

Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part I: which parameters from human studies are most relevant for toxicological assessments?

The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.

Adult Body Height Is a Good Predictor of Different Dimensions of Cognitive Function in Aged Individuals: A Cross-Sectional Study.

Background: Adult height, weight, and adiposity measures have been suggested by some studies to be predictors of depression, cognitive impairment, and dementia. However, the presence of confounding factors and the lack of a thorough neuropsychological evaluation in many of these studies have precluded a definitive conclusion about the influence of anthropometric measures in cognition and depression. In this study we aimed to assess the value of height, weight, and abdominal perimeter to predict cognitive impairment and depressive symptoms in aged individuals. Methods and Findings: Cross-sectional study performed between 2010 and 2012 in the Portuguese general community. A total of 1050 participants were included in the study and randomly selected from local area health authority registries. The cohort was representative of the general Portuguese population with respect to age (above 50 years of age) and gender. Cognitive function was assessed using a battery of tests grouped in two dimensions: general executive function and memory. Two-step hierarchical multiple linear regression models were conducted to determine the predictive value of anthropometric measures in cognitive performance and mood before and after correction for possible confounding factors (gender, age, school years, physical activity, alcohol consumption, and smoking habits). We found single associations of weight, height, body mass index, abdominal perimeter, and age with executive function, memory and depressive symptoms. However, when included in a predictive model adjusted for gender, age, school years, and lifestyle factors only height prevailed as a significant predictor of general executive function (ß = 0.139; p < 0.001) and memory (ß = 0.099; p < 0.05). No relation was found between mood and any of the anthropometric measures studied. Conclusions and Relevance: Height is an independent predictor of cognitive function in late-life and its effects on the general and executive function and memory are independent of age, weight, education level, gender, and lifestyle factors. Altogether, our data suggests that modulators of adult height during childhood may irreversibly contribute to cognitive function in adult life and that height should be used in models to predict cognitive performance.

Exploring Female Mice Interstrain Differences Relevant for Models of Depression.

Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain.

From the periphery to the brain: Lipocalin-2, a friend or foe?

Lipocalin-2 (LCN2) is an acute-phase protein that, by binding to iron-loaded siderophores, acts as a potent bacteriostatic agent in the iron-depletion strategy of the immune system to control pathogens. The recent identification of a mammalian siderophore also suggests a physiological role for LCN2 in iron homeostasis, specifically in iron delivery to cells via a transferrin-independent mechanism. LCN2 participates, as well, in a variety of cellular processes, including cell proliferation, cell differentiation and apoptosis, and has been mostly found up-regulated in various tissues and under inflammatory states, being its expression regulated by several inducers. In the central nervous system less is known about the processes involving LCN2, namely by which cells it is produced/secreted, and its impact on cell proliferation and death, or in neuronal plasticity and behaviour. Importantly, LCN2 recently emerged as a potential clinical biomarker in multiple sclerosis and in ageing-related cognitive decline. Still, there are conflicting views on the role of LCN2 in pathophysiological processes, with some studies pointing to its neurodeleterious effects, while others indicate neuroprotection. Herein, these various perspectives are reviewed and a comprehensive and cohesive view of the general function of LCN2, particularly in the brain, is provided.

The choroid plexus transcriptome reveals changes in type I and II interferon responses in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a marked decline in cognition and memory function. Increasing evidence highlights the essential role of neuroinflammatory and immune-related molecules, including those produced at the brain barriers, on brain immune surveillance, cellular dysfunction and amyloid beta (Aß) pathology in AD. Therefore, understanding the response at the brain barriers may unravel novel pathways of relevance for the pathophysiology of AD. Herein, we focused on the study of the choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, in aging and in AD. Specifically, we used the PDGFB-APPSwInd (J20) transgenic mouse model of AD, which presents early memory decline and progressive Aß accumulation, and littermate age-matched wild-type (WT) mice, to characterize the CP transcriptome at 3, 5-6 and 11-12months of age. The most striking observation was that the CP of J20 mice displayed an overall overexpression of type I interferon (IFN) response genes at all ages. Moreover, J20 mice presented a high expression of type II IFN genes in the CP at 3months, which became lower than WT at 5-6 and 11-12months. Importantly, along with a marked memory impairment and increased glial activation, J20 mice also presented a similar overexpression of type I IFN genes in the dorsal hippocampus at 3months. Altogether, these findings provide new insights on a possible interplay between type I and II IFN responses in AD and point to IFNs as targets for modulation in cognitive decline.

Co-expression network of neural-differentiation genes shows specific pattern in schizophrenia.

BACKGROUND: Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls. METHODS: We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that were non-conserved between adult cases and controls brain samples. RESULTS: We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation. CONCLUSION: This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. We showed that, although generated by different approaches, both sets of DEG associated to schizophrenia were involved with neocortical development. The results add to the hypothesis that critical metabolic changes may be occurring during early neurodevelopment influencing faulty development of the brain and potentially contributing to further vulnerability to the illness.

The behavioral and immunological impact of maternal separation: a matter of timing.

Maternal separation (MS), an early life stressful event, has been demonstrated to trigger neuropsychiatric disorders later in life, in particular depression. Experiments using rodents subjected to MS protocols have been very informative for the establishment of this association. However, the mechanism by which MS leads to neuropsychiatric disorders is far from being understood. This is probably associated with the multifactorial nature of depression but also with the fact that different research MS protocols have been used (that vary on temporal windows and time of exposure to MS). In the present study, MS was induced in rats in two developmental periods: for 6 h per day for 14 days between postnatal days 2-15 (MS2-15) and 7-20 (MS7-20). These two periods were defined to differ essentially on the almost complete (MS2-15) or partial (MS7-20) overlap with the stress hypo-responsive period. Behavioral, immunological, and endocrine parameters, frequently associated with depressive-like behavior, were analyzed in adulthood. Irrespectively from the temporal window, both MS exposure periods led to increased sera corticosterone levels. However, only MS2-15 animals displayed depressive and anxious-like behaviors. Moreover, MS2-15 was also the only group presenting alterations in the immune system, displaying decreased percentage of CD8(+) T cells, increased spleen T cell CD4/CD8 ratio, and thymocytes with increased resistance to dexamethasone-induced cell death. A linear regression model performed to predict depressive-like behavior showed that both corticosterone levels and T cell CD4/CD8 ratio explained 37% of the variance observed in depressive-like behavior. Overall, these findings highlight the existence of "critical periods" for early life stressful events to exert programing effects on both central and peripheral systems, which are of relevance for distinct patterns of susceptibility to emotional disorders later in life.

Clinical, physical and lifestyle variables and relationship with cognition and mood in aging: a cross-sectional analysis of distinct educational groups.

It is relevant to unravel the factors that may mediate the cognitive decline observed during aging. Previous reports indicate that education has a positive influence on cognitive performance, while age, female gender and, especially, depressed mood were associated with poorer performances across multiple cognitive dimensions (memory and general executive function). Herein, the present study aimed to characterize the cognitive performance of community-dwelling individuals within distinct educational groups categorized by the number of completed formal school years: "less than 4," "4, completed primary education," and "more than 4." Participants (n = 1051) were randomly selected from local health registries and representative of the Portuguese population for age and gender. Neurocognitive and clinical assessments were conducted in local health care centers. Structural equation modeling was used to derive a cognitive score, and hierarchical linear regressions were conducted for each educational group. Education, age and depressed mood were significant variables in directly explaining the obtained cognitive score, while gender was found to be an indirect variable. In all educational groups, mood was the most significant factor with effect on cognitive performance. Specifically, a depressed mood led to lower cognitive performance. The clinical disease indices cardiac and stroke associated with a more negative mood, while moderate increases in BMI, alcohol consumption and physical activity associated positively with improved mood and thus benefitted cognitive performance. Results warrant further research on the cause-effect (longitudinal) relationship between clinical indices of disease and risk factors and mood and cognition throughout aging.

Telephone-based screening tools for mild cognitive impairment and dementia in aging studies: a review of validated instruments.

The decline of cognitive function in old age is a great challenge for modern society. The simultaneous increase in dementia and other neurodegenerative diseases justifies a growing need for accurate and valid cognitive assessment instruments. Although in-person testing is considered the most effective and preferred administration mode of assessment, it can pose not only a research difficulty in reaching large and diverse population samples, but it may also limit the assessment and follow-up of individuals with either physical or health limitations or reduced motivation. Therefore, telephone-based cognitive screening instruments can be an alternative and attractive strategy to in-person assessments. In order to give a current view of the state of the art of telephone-based tools for cognitive assessment in aging, this review highlights some of the existing instruments with particular focus on data validation, cognitive domains assessed, administration time and instrument limitations and advantages. From the review of the literature, performed using the databases EBSCO, Science Direct and PubMed, it was possible to verify that while telephone-based tools are useful in research and clinical practice, providing a promising approach, the methodologies still need refinement in the validation steps, including comparison with either single instruments or neurocognitive test batteries, to improve specificity and sensitivity to validly detect subtle changes in cognition that may precede cognitive impairment.

Day and night: diurnal phase influences the response to chronic mild stress.

Chronic mild stress (CMS) protocols are widely used to create animal models of depression. Despite this, the inconsistencies in the reported effects may be indicative of crucial differences in methodology. Here, we considered the time of the diurnal cycle in which stressors are applied as a possible relevant temporal variable underlying the association between stress and behavior. Most laboratories test behavior during the light phase of the diurnal cycle, which corresponds to the animal's resting period. Here, rats stressed either in their resting (light phase) or active (dark phase) periods were behaviorally characterized in the light phase. When exposure to CMS occurred during the light phase of the day cycle, rats displayed signs of depressive and anxiety-related behaviors. This phenotype was not observed when CMS was applied during the dark (active) period. Interestingly, although no differences in spatial and reference memory were detected (Morris water maze) in animals in either stress period, those stressed in the light phase showed marked impairments in the probe test. These animals also showed significant dendritic atrophy in the hippocampal dentate granule neurons, with a decrease in the number of spines. Taken together, the observations reported demonstrate that the time in which stress is applied has differential effects on behavioral and neurostructural phenotypes.

Neudesin is involved in anxiety behavior: structural and neurochemical correlates.

Neudesin (also known as neuron derived neurotrophic factor, Nenf) is a scarcely studied putative non-canonical neurotrophic factor. In order to understand its function in the brain, we performed an extensive behavioral characterization (motor, emotional, and cognitive dimensions) of neudesin-null mice. The absence of neudesin leads to an anxious-like behavior as assessed in the elevated plus maze (EPM), light/dark box (LDB) and novelty suppressed feeding (NSF) tests, but not in the acoustic startle (AS) test. This anxious phenotype is associated with reduced dopaminergic input and impoverished dendritic arborizations in the dentate gyrus granule neurons of the ventral hippocampus. Interestingly, shorter dendrites are also observed in the bed nucleus of the stria terminalis (BNST) of neudesin-null mice. These findings lead us to suggest that neudesin is a novel relevant player in the maintenance of the anxiety circuitry.

Lipocalin-2 is involved in emotional behaviors and cognitive function.

Lipocalin-2 (LCN2), an iron-related protein well described to participate in the innate immune response, has been shown to modulate spine morphology and to regulate neuronal excitability. In accordance, LCN2-null mice are reported to have stress-induced anxiety. Here we show that, under standard housing conditions, LCN2-null mice display anxious and depressive-like behaviors, as well as cognitive impairment in spatial learning tasks. These behavioral alterations were associated with a hyperactivation of the hypothalamic-pituitary-adrenal axis and with an altered brain cytoarchitecture in the hippocampus. More specifically, we found that the granular and pyramidal neurons of the ventral hippocampus, a region described to be associated with emotion, were hypertrophic, while neurons from the dorsal hippocampus, a region implicated in memory and cognition, were atrophic. In addition, LCN2-null mice presented synaptic impairment in hippocampal long-term potentiation. Whether the LCN2 effects are mediated through modulation of the level of corticosteroids or through a novel mechanism, the present observations bring further into light this immune-related protein as a player in the fine-tuning of behavior and of synaptic activity.

Plasticity of resting state brain networks in recovery from stress.

Chronic stress has been widely reported to have deleterious impact in multiple biological systems. Specifically, structural and functional remodeling of several brain regions following prolonged stress exposure have been described; importantly, some of these changes are eventually reversible. Recently, we showed the impact of stress on resting state networks (RSNs), but nothing is known about the plasticity of RSNs after recovery from stress. Herein, we examined the "plasticity" of RSNs, both at functional and structural levels, by comparing the same individuals before and after recovery from the exposure to chronic stress; results were also contrasted with a control group. Here we show that the stressed individuals after recovery displayed a decreased resting functional connectivity in the default mode network (DMN), ventral attention network (VAN), and sensorimotor network (SMN) when compared to themselves immediately after stress; however, this functional plastic recovery was only partial as when compared with the control group, as there were still areas of increased connectivity in dorsal attention network (DAN), SMN and primary visual network (VN) in participants recovered from stress. Data also shows that participants after recovery from stress displayed increased deactivations in DMN, SMN, and auditory network (AN), to levels similar to those of controls, showing a normalization of the deactivation pattern in RSNs after recovery from stress. In contrast, structural changes (volumetry) of the brain areas involving these networks are absent after the recovery period. These results reveal plastic phenomena in specific RSNs and a functional remodeling of the activation-deactivation pattern following recovery from chronic-stress, which is not accompanied by significant structural plasticity.

Do genes and environment meet to regulate cerebrospinal fluid dynamics? Relevance for schizophrenia.

Schizophrenia is a neurodevelopment disorder in which the interplay of genes and environment contributes to disease onset and establishment. The most consistent pathological feature in schizophrenic patients is an enlargement of the brain ventricles. Yet, so far, no study has related this finding with dysfunction of the choroid plexus (CP), the epithelial cell monolayer located within the brain ventricles that is responsible for the production of most of the cerebrospinal fluid (CSF). Enlarged brain ventricles are already present at the time of disease onset (young adulthood) and, of notice, isolated mild ventriculomegaly detected in utero is associated with subsequent mild neurodevelopmental abnormalities similar to those observed in children at high risk of developing schizophrenia. Here we propose that altered CP/CSF dynamics during neurodevelopment may be considered a risk, causative and/or participating factor for development of schizophrenia.

Lipocalin 2 is present in the EAE brain and is modulated by natalizumab.

Multiple sclerosis (MS) is a demyelinating disease that causes major neurological disability in young adults. A definitive diagnosis at the time of the first episode is still lacking, but since early treatment leads to better prognosis, the search for early biomarkers is needed. Here we characterized the transcriptome of the choroid plexus (CP), which is part of the blood-brain barriers (BBBs) and the major site of cerebrospinal fluid production, in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. In addition, cerebrospinal fluid samples from two cohorts of patients with MS and with optic neuritis (ON) were analyzed to confirm the clinical relevance of the findings. Genes encoding for adhesion molecules, chemokines and cytokines displayed the most altered expression, supporting the role of CP as a site of immune-brain interaction in MS. The gene encoding for lipocalin 2 was the most up-regulated; notably, the cerebrospinal fluid lipocalin 2 levels coincided with the active phases of the disease. Immunostaining revealed that neutrophils infiltrating the CP were the source of the increased lipocalin 2 expression in this structure. However, within the brain, lipocalin 2 was also detected in astrocytes, particularly in regions typically affected in patients with MS. The increase of lipocalin 2 in the cerebrospinal fluid and in astrocytes was reverted by natalizumab treatment. Most importantly, the results obtained in the murine model were translatable into humans since patients from two different cohorts presented increased cerebrospinal fluid lipocalin 2 levels. The findings support lipocalin 2 as a valuable molecule for the diagnostic/monitoring panel of MS.

The path from the choroid plexus to the subventricular zone: go with the flow!

IN ADULT MAMMALS, UNDER PHYSIOLOGICAL CONDITIONS, NEUROGENESIS, THE PROCESS OF GENERATING NEW FUNCTIONAL NEURONS FROM PRECURSOR CELLS, OCCURS MAINLY IN TWO BRAIN AREAS: the subgranular zone in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) lining the walls of the brain lateral ventricles. Taking into account the location of the SVZ and the cytoarchitecture of this periventricular neural progenitor cell niche, namely the fact that the slow dividing primary progenitor cells (type B cells) of the SVZ extend an apical primary cilium toward the brain ventricular space which is filled with cerebrospinal fluid (CSF), it becomes likely that the composition of the CSF can modulate both self-renewal, proliferation and differentiation of SVZ neural stem cells. The major site of CSF synthesis is the choroid plexus (CP); quite surprisingly, however, it is still largely unknown the contribution of molecules specifically secreted by the adult CP as modulators of the SVZ adult neurogenesis. This is even more relevant in light of recent evidence showing the ability of the CP to adapt its transcriptome and secretome to various physiologic and pathologic stimuli. By giving particular emphasizes to growth factors and axonal guidance molecules we will illustrate how CP-born molecules might play an important role in the SVZ niche cell population dynamics.

Modulation of iron metabolism in aging and in Alzheimer's disease: relevance of the choroid plexus.

Iron is essential for mammalian cellular homeostasis. However, in excess, it promotes free radical formation and is associated with aging-related progressive deterioration and with neurodegenerative disorders such as Alzheimer's disease (AD). There are no mechanisms to excrete iron, which makes iron homeostasis a very tightly regulated process at the level of the intestinal absorption. Iron is believed to reach the brain through receptor-mediated endocytosis of iron-bound transferrin by the brain barriers, the blood-cerebrospinal fluid (CSF) barrier, formed by the choroid plexus (CP) epithelial cells and the blood-brain barrier (BBB) formed by the endothelial cells of the brain capillaries. Importantly, the CP epithelial cells are responsible for producing most of the CSF, the fluid that fills the brain ventricles and the subarachnoid space. Recently, the finding that the CP epithelial cells display all the machinery to locally control iron delivery into the CSF may suggest that the general and progressive senescence of the CP may be at the basis of the impairment of regional iron metabolism, iron-mediated toxicity, and the increase in inflammation and oxidative stress that occurs with aging and, particularly, in AD.

Gene expression of peripheral blood lymphocytes may discriminate patients with schizophrenia from controls.

To identify a classifier in schizophrenia, blood gene expression profiling was applied to patients with schizophrenia under different treatments and to controls. Expression of six genes discriminated patients with sensitivity of 89.3% and specificity of 90%, supporting the use of peripheral blood as biological material for diagnosis in schizophrenia.