Iron is particularly important in pregnancy and infancy to meet the high demands for hematopoiesis, growth and development. Much attention has been given to conditions of iron deficiency (ID) and iron deficient anemia (IDA) because of the high global prevalence estimated in these vulnerable life stages. Emerging and preliminary evidence demonstrates, however, a U-shaped risk at both low and high iron status for birth and infant adverse health outcomes including growth, preterm birth, gestational diabetes, gastrointestinal health, and neurodegenerative diseases during aging. Such evidence raises questions about the effects of high iron intakes through supplementation or food fortification during pregnancy and infancy in iron-replete individuals. This review examines the emerging as well as the current understanding of iron needs and homeostasis during pregnancy and infancy, uncertainties in ascertaining iron status in these populations, and issues surrounding U-shaped risk curves in iron-replete pregnant women and infants. Implications for research and policy are discussed relative to screening and supplementation in these vulnerable populations, especially in developed countries in which the majority of these populations are likely iron-replete.  Iron has long been recognized as essential, but its nutritional status is nonetheless characterized by many challenges and unknowns, especially when the focus is pregnancy and infancy. Iron plays key roles in oxygen transport by red blood cells (RBC), energy production, growth and development, functions particularly important during the demands in pregnancy and infancy for hematopoiesis, growth and development. Much attention has been given to conditions of iron deficiency (ID) during these vulnerable life stages, but more recently questions have arisen about the effects of iron supplementation when individuals are iron-replete. Resolving these questions in general as well as in the case of pregnancy and infancy requires better understanding of iron homeostasis, biological adaptations, approaches to determining iron status, and the risk from not only too little but also too much iron.The highly reactive chemical nature of the iron molecule, particularly its redox chemistry  and inteID, well recognized as a public health concern, results when iron stores are inadequate to meet tissue needs and culminates in iron deficiency anemia (IDA) and fatigue when stores are fully depleted and erythropoiesis is impaired. The risk of ID or IDA increases in physiologic states of high blood loss (reproductive aged women) or increased physiologic need (pregnancy and infancy). ID and IDA receive greater attention than iron excess, both in research and policy, because of their high global prevalence, especially in developing countries.Globally, over 40% of pregnant women and 47% of preschool children are anemic from all causes . The WorHowever, the environmental and health context for developed countries differs because the prevalence of ID and IDA is lower. The most recent analysis of 1999–2010 National Health and Nutrition Examination Survey (NHANES) data found a prevalence of 2.6% and 2.2% IDA in pregnant women and young children (12–23 months) in the United States . The preConcerns exist and continue to emerge, as discussed in detail below, about the risk of adverse outcomes including growth, gestational length, gestational diabetes mellitus, and gastrointestinal health ,13,14,15This review examines the emerging as well as the current understanding of iron needs and homeostasis during pregnancy and infancy, uncertainties in ascertaining iron status in these populations, and issues surrounding U-shaped risk curves in iron-replete pregnant women and infants. It concludes with a discussion of the implications for research and policy relative to screening and supplementation in these vulnerable populations.The physiologic demand for iron is especially high in pregnancy and infancy with an estimated 1000–1200 mg of iron needed during pregnancy ,11. AbouDespite this progressive physiologic need, established reference intake values for iron in several developed countries average the need for iron across pregnancy rather than varying requirements by trimester. The United States, Canada, Australia and New Zealand recommend 150% higher intakes for pregnant women than for reproductive age women beginning at the initial stages of pregnancy . HoweverAfter birth, the need for iron is met primarily from iron stores in the exclusively breastfed full-term infant for the first 4 to 6 months because human milk is low in iron even though this iron is highly bioavailable. These iron stores derive from a portion of the approximate 270–330 mg of iron transferred in utero. Typically, such infants have approximately 80 mg of iron per kg ,22 and aRecommendations for supplementation vary across developed countries  with no Iron homeostasis is the coordinated process through which key proteins regulate iron absorption, recycling, transport and storage to ensure iron availability without excess. The hepatic protein, hepcidin, functions as a master regulator in this homeostasis through its down-regulation of intestinal and tissue release of iron. It interacts with the cellular iron exporter, ferroportin (FPN) to reduce iron efflux and, thus, availability. When iron stores and availability are low, hepcidin is low; and more iron is released from that absorbed in the intestine or stored in tissues. In contrast when iron stores and availability are high, hepcidin is elevated; and less iron is released from that absorbed in the intestine or stored in tissues . HepcidiAdaptations in this iron homeostasis have been suggested both in pregnancy and early infancy, most likely to meet the substantive needs for iron during these periods. In pregnancy, physiologic adaptations appear to increase iron absorption . AlthougDevelopmental adaptations may also alter the homeostatic regulation of iron absorption by hepcidin in the young infant. Although both hepcidin and its target FPN are present , limitedThe relevance of these physiologic and developmental adaptations of iron homeostasis is not understood, but these may serve to facilitate iron availability during peak periods of erythropoiesis. Given the widespread recommendation and use of iron supplements in both pregnant women and infants and iron-fortified formula in developed countries, however, these adaptations may also limit the primary protective mechanisms against excessive iron uptake. What is even less well understood is the extent to which these might, therefore, enhance the risk of high or excess iron status in the context of largely iron-replete populations . Also unIn addition to the physiologic and developmental adaptations of this homeostatic regulation, developing tissues in the fetus and infant differentially acquire iron , such thIn summary, adaptations in iron homeostasis appear to occur physiologically in pregnancy and developmentally in young infants. They enhance iron absorption, but may limit feedback regulation in response to high iron status. The mechanisms of these adaptations are unknown. Moreover, the extent to which they might also enhance or not susceptibility to excessive absorption with high supplementation or iron-fortification is not understood.Assessing iron status is complex at any life stage, in part because no single indicator is sufficiently specific or sensitive to be used alone; thus, multiple indicators must be measured and integrated to estimate iron status. The most commonly used indicators are presented in Uncertainties exist in assessing iron status in pregnant women and infants, as well as in other life stages, because of analytic issues including lack of standardization of the assays; confounding especially by inflammation; and lack of established health outcomes relative to cutpoints. Unique to pregnancy are physiologic changes due to plasma volume expansion resulting in hemodilution and a mild inflammatory state . The extThe analytic issues surround the lack of harmonization and standardization of the indicator assays . The avaExacerbating these uncertainties is the documented confounding of SF and to a lesser extent sTfR, as well as indicators based on these two measures such as TBI, by inflammation. The Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) project reports linear regression algorithms to adjust SF based on cross-sectional data from multinational population indicators of acute (C-reactive protein) and chronic  inflammation ,50,51. AA major limitation in, and the resulting uncertainty for, current cutpoints stem from the lack of their established relationships to non-hematologic or clinically relevant health outcomes in pregnant women, infants and young children for all common measures of iron status. Currently, cutpoints for pregnancy and young children derive from the lowest percentile distribution of the population, typically below the 5th percentile for Hb concentrations for anemia and, thus, IDA. For pregnant women, the Centers for Disease Control and Prevention (CDC) trimester-specific cutpoints were informed by four small longitudinal studies from 30 years ago , These tEvaluation of these indicators relative to health outcomes, especially non-hematologic outcomes, could inform cutpoints with clinical and public health relevance for the full spectrum of iron status . In partCollectively, the lack of standardization and harmonization of assays, confounding by inflammation, impacts of physiologic changes on the indicators and lack of established relationship with non-hematologic outcomes introduce uncertainty in the measurement and interpretation of iron indicators in pregnant women, infants and young children. These uncertainties increase the risk of misclassification of ID and IDA and also limit interpretation of screening and monitoring of these vulnerable populations. Iron exhibits a U-shaped risk, typical of essential nutrients, in which risk of adverse outcomes in pregnant women, infants and young children increases not only with low or inadequate availability but also at higher availability ,56. ReseIn terms of low iron status during pregnancy, most of the evidence has examined the relationship of Hb concentration or anemia and increased risk of maternal and fetal adverse outcomes without consideration of concomitant inflammation . Low Hb ID even more so than IDA is a concern in the infant and young child because of the vulnerable period of brain development in the first 24 months. As discussed earlier, the differential prioritization of iron to erythropoiesis exacerbates the vulnerability of the brain when iron is limiting during this critical period. A limited number of studies find impaired cognitive and brain development with ID ,58,59,60Another important evaluation of the risk of low iron status is improvement in outcomes with iron supplementation of pregnant women, infants and young children with low iron status. Although such supplementation generally improves hematologic indicators, which can be viewed as intermediate outcomes for anemia ,54,62, tHigh iron status during pregnancy also associates with increased risk for maternal and fetal adverse outcomes. Across studies, high Hb concentrations, especially in the second trimester, associate with LBW as comprehensively reviewed by Dewey and Oaks  and BreyIn addition, preliminary evidence also links supplementation or high iron status to emerging adverse outcomes in pregnancy including gestational diabetes mellitus (GDM) in observational case-control and prospective cohort studies and limited RCTs . At presIron supplementation of iron-replete infants and young children increased the risk of vomiting and fever in a systematic review of the evidence  and alteAnother proposed adverse outcome of high neonatal exposure relates to cumulative high brain iron and neurodegeneration in older adults . SupportOverall, current evidence supports a U-shaped risk curve for a variety of adverse birth outcomes in mother and neonate as well as in young children. Emerging evidence also raise concerns about adverse short-term and long-term health outcomes with iron supplementation of iron-replete pregnant women and children. Uncertainties in this evidence, particularly the failure to consider concomitant inflammation and limited evidence for non-hematologic health outcomes, emphasizes the need for well-controlled cohort longitudinal studies and RCT to evaluate the benefits and harms of iron supplementation in iron-replete populations. A number of knowledge gaps and research needs were identified at the NIH Workshop on Iron Screening and Supplementation of Iron-Replete Pregnant Women and Young Children in 2016. Four major themes emerged from these gaps and research needs focusing on (1) elucidating adaptations of iron homeostasis in pregnancy and early infancy including their mechanisms, responsiveness to iron status, interaction with genetic and ethnic factors and implication’s for the differential prioritization of iron to developing tissues and hematopoiesis; (2) improving the assessment of iron status particularly in these two vulnerable periods including the measurement uncertainties, need for indicators across the full continuum of iron status that are adjustable or independent of inflammation; (3) evaluating iron status relative to maternal and infant health outcomes, especially non-hematologic outcomes; and (4) determination of short and long term beneficial and adverse health outcomes, especially non-health outcomes such as GDM, LBW, SGA, postnatal growth and DOHaD, with iron supplementation of iron-replete pregnant women and young children ,48. In FIllustrated from this framework and the discussion above of the limitations of the evidence even from the benefit of improved hematologic outcomes with supplementation is the limited and preliminary nature of the current evidence. Clearly, well-controlled longitudinal cohort studies in iron-replete and generally well-nourished populations in developed countries are needed to understand the dynamic mobilization of iron stores and its impact on clinically-relevant and non-hematologic health outcomes. So too, are well-designed RCTs examining both the benefits and potential harms of iron supplementation on such health outcomes.Importantly, little if any research has considered the interaction of baseline iron status (and level of stores) and the beneficial or harmful response to iron supplementation. Critical to understand however regarding this interaction is the determination of who is at risk of adverse outcomes from low iron status and would benefit from iron supplementation. A parallel consideration is the amount and form of iron that is most effective with least adverse effect for either supplementation or food fortification. Based on emerging data, the interaction of the level of iron stores among iron-replete pregnant women and infants with high dietary iron intakes from supplementation or fortified foods may become important to understand relative to the possibility of adverse health outcomes. Until the needed research is available, well-informed public policy will be limited by the insufficiency of the evidence for benefit or harm of routine screening and supplementation. The historical focus on concerns for iron inadequacy remains critical for these vulnerable population groups. But, the concerns should now also begin to encompass the parallel interests in ensuring that those who are iron-replete are not put at risk in the broad-brush efforts to avoid iron deficiency. For many understandable reasons, pregnancy and infancy have been almost universally characterized as “automatically” resulting in ID. The situation, especially in more developed regions of the world, many be more nuanced. Research agendas, and in turn public policy, now need to more fully embrace the competing nature of the concerns and find the best balance. Examples of policy decisions that could be better informed by addressing these knowledge gaps and research needs include, but are not limited to clinical guidelines for screening and supplementation; decisions on supplements and food fortification  such as the type and amount of iron, dietary guidance both for recommended nutrient and food intakes for these two vulnerable populations. The dilemma at present for policy-decisions in developed countries is the duality both of the U-shaped risk and of the nature of iron status of their pregnant women and young children, most of whom are likely iron, but some of whom have sufficient low iron status to be a concern. In summary, our knowledge is limited by critical gaps and methodologic challenges that increase the uncertainty in the assessment of iron status across its full continuum in pregnant women and young children whose iron needs are high and in whom adaptations of iron homeostasis may affect their susceptibility to iron excess. Adding to this uncertainty is the lack of cutpoints across the full continuum of iron status that have been related to health outcomes, especially those clinically-relevant and beyond hematologic outcomes. Indicators are also needed that can be appropriated adjusted for or are not affected by inflammation. Advancing our knowledge on the benefits and adverse outcomes of iron supplementation in pregnant women and young children will also inform strong evidence-based policy that ensure sufficiency without excess iron availability in largely iron-replete pregnant women and children in developed countries.


Mixed dementia is the coexistence of Alzheimer's disease and cerebrovascular disease (CVD) in the same demented patient. Currently, its diagnosis and treatment remains a challenge for practitioners. To provide an overview of the epidemiology, pathogenesis, natural history, diagnosis, and therapy of Mixed Vascular-Alzheimer Dementia (MVAD). The literature was reviewed for articles published between 1990-2016 by using the keywords linked to MVAD. Neuropathological studies indicate that MVAD is a very common pathological finding in the elderly with a prevalence about of 22%. The distinction between Alzheimer's dementia and vascular dementia (VD) is complex because their clinical presentation can overlap. There are international criteria for the MVAD diagnosis. The pharmacologic therapy shows modest clinical benefits that are similar among all drugs used in patients with Alzheimer's dementia and VD. The non-pharmacologic therapy includes the rigorous management of cardiovascular risk factors  and the promotion of a healthy diet. The diagnosis and treatment of MVAD cannot be improved without further studies. Currently available medications provide only modest clinical benefits once a patient has developed MVAD. In subjects at risk, the antihypertensive therapy and healthy diet should be recommend for preventing or slowing the progression of MVAD. According to the American Heart Association/American Stroke Association (AHA/ASA), the vascular and neurodegenerative disorders are common in the elderly and it could coexist in the same patient. These processes underlying dementia are mutually potentiated for developing cognitive impairment and dementia, generating overlapped clinical phenotypes and neuroimaging.-,The mixed dementia, the Alzheimer's dementia, and the vascular dementia (VD) are the most frequent types of dementia,For an optimal treatment of dementia, the adequate diagnosis of each dementia type is essential. However, recognizing the distinction between these diseases can be difficult in clinical practice. This review provides an overview of the Mixed Vascular-Alzheimer Dementia  for the following terms: (Dementia) AND (“Alzheimer Disease”) AND . Abstracts of articles in any language were independently reviewed by the authors. The only inclusion criterion was that the study should be available as full text in any bibliographic or academic databases. We did secondary search of reference lists of identified studies and received additional references from international experts. The latest date of publication for inclusion of articles in the study was 31No approval from the ethics committee was required since the study was carried out solely with published data from the world literature.In the consulted databases our search strategy identified 357 scientific documents , which 26 articles addressed the topic of “mixed dementia” and 8 key articles were selected for this study, including a previous review about mixed dementia.--,,,Several autopsy-based studies reported a dementia prevalence of 39.5%-44.4%,Other autopsy-based studies showed that the dementia proportion increases from 57% to 75% due to the presence of large artery infarctions and up to 93% due to the presence of lacunar infarcts.,The MVAD, as well as other dementias, starts several years before the symptoms display, which allow their diagnosis.,,According to vascular theory, the chronic non-communicable diseases  and the sedentary lifestyle produce several vascular changes,,,There have been reports of different mechanisms of vascular damage such as small vessel atherosclerosis, large vessel arteriosclerosis, cortical and subcortical infarcts, lacunar infacts with gray/white matter lesions, WML (leukoaraoisis), demyelination, gliosis, amyloid angiopathy, and small brain hemorrhages.,,,-According several epidemiological studies, the main vascular risk factors are the age,-In the case of AD, some studies reported a set of brain changes during the presymptomatic phase, which includes accumulation of beta-amyloid protein, tau protein and phosphorylated tau protein, alterated glucose metabolism,There is no consensus for the diagnosis of MVAD. Thus, international referents such as the Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC)According to the ADDTC criteria, the diagnosis of MVAD requires the existence of a typical AD and closely dementia related CVD.,Additionally, we recommend an approach aimed to identify the dominant component (CVI or AD). Thus, in the majority of patients with predominance of CVI lesions, the initial clinical phenotype should be as VD ,,,The neuroimaging studies is useful for increasing the diagnostic certainty, particularly in silent lesions such as lacunar infarcts and WML.A definitive diagnosis warrants a neuropathologic verification. Regarding the clinical-pathological diagnosis of MVAD, we suggest to use the recommendations for the AD diagnosis based on morphological changes .52 AccorThere are no specific recommendations for the pathological diagnosis of VCI/VD. However, its importance lies in that allows to identify the type of underlying CVD. Additionally, it also allows to identify injuries in cases of non-detectable lesions by current neuroimaging technologies, such as small cystic infarctions, selective neuronal loss, and microinfarcts.In this context, Jellinger and Atems proposed as a criterion for pathological diagnosis of MVAD the combination of AD (confirmed by autopsy) with presence of multiple lacunar infarcts or CVI lesions located in the cortex, basal ganglia, thalamus, hippocampus and white matter, with an infarcted cerebral volume of 30 - 50 ml, approximately.-For the research purposes, the AD diagnosis requires the evidence of: 1) amyloid deposition in the autopsy study, low b-amyloid concentrations in cerebrospinal fluid (CSF), or b-amyloid deposition in positron emission tomography; and 2) neuro-degeneration in the autopsy study, high concentrations of phosphorylated Tau in CSF, or pattern of EA atrophy in the cerebral images.-,The AHA/ASA highlighted that there are several factors that affect diagnostic accuracy. For example, current imaging technologies are unable to detect microscopic infarctions (≤ 3 mm) and alterations in small vessels such as arteriosclerosis.,,Cognitive phenotypes. Due to the lack of consensus on the diagnostic criteria and the heterogeneous neuropathological characteristic of the MVAD, this entity has not been widely studied. However, establishing a cognitive profile in relation to AD can be useful for measuring the contribution of CVD/CVI to cognitive impairment and establishing clinical management and therapeutic strategies in patients with MVAD.,,,,,There are studies showing that the cognitive performance of patients with MVAD is lower than that observed in patients with Alzheimer's dementia,,Currently, the treatment is basically symptomatic and preventive. The use of acetylcholinesterase inhibitor drugs such as donepezil, galantamine and rivastigmine and antidemential drugs such as memantine can be used in patients with Alzheimer's dementia and VD.,Studies in patients with MVAD have shown a mild improvement, especially in cognition function, with contradictory results in daily living activities and global status, and showing no statistical superiority in the efficacy of either agent.,Although effective blood pressure control seems to decrease the progression rate of WML in hypertensive patients,,A healthy diet includes a greater amount of vegetables, fruits, nuts, soy proteins, grains and fish, as well as lower consumption of red meat. Longitudinal studies have shown that this dietary regimens can decrease both the progression rate of cognitive impairment and the risk of developing AD.Finally, psychological and social support is critical, particularly when the patient is working. This support should also cover the family, who must understand the progressive loss of independence of the patient.There is a public health need for new studies that address the diagnosis and treatment of MVAD. Currently, the available medications offer only a modest clinical benefits once a patient has developed MVAD, without any modification of its evolution. In subjects at risk, the antihypertensive therapy and healthy diet should be both recommend and promoted for preventing or slowing the progression of MVAD.For improving the health outcomes, we recommend thinking in MVAD as probable diagnosis in all demented patients with an atypical presentation of AD and coexistence of risk factors for CVD/CVI.For improving the value of image studies in the diagnosis of dementia, we recommend to assess the concordance between neuroimaging patterns and postmortem findings.


Translation as a notion and procedure is deeply embodied in medical science and education. Translation includes the possibility to translate data across disciplines to improve diagnosis and treatment procedures. The evidence accumulated using translation serves as a vehicle for reification of medical diagnoses. There are promising, established post hoc correlations between the different types of clinical tools (interviews and inventories) and neuroscience. The various measures represent statistical correlations that must now be integrated into diagnostic standards and procedures but this, as a whole, is a step forward towards a better understanding of the mechanisms underlying psychopathology in general and depression in particular. Here, we focus on functional magnetic resonance imaging studies using a trans-disciplinary approach and attempt to establish bridges between the different fields. We will selectively highlight research areas such as imaging genetics, imaging immunology and multimodal imaging, as related to the diagnosis and management of depression. Depression has a high social burden and affects over 350 million people worldwide. According to the World Health Organization (WHO), by 2030, depression is expected to be the second most common disease worldwide . The symTranslation as a notion and procedure is deeply embodied in medical science and education. Translation includes the possibility to translate data across disciplines and across domains within a single discipline to improve diagnosis and treatment procedures. The evidence accumulated using translation serves as a vehicle for reification of medical diagnoses. Reification and hypostatization in the sense of G. Lucacs refer to objectification  of constructs which are otherwise a matter of temporary social conventions . Below wMyocardial infarction as clinical nosology entails detailed translation across four bottom-up disciplinary domains  :Biochemistry: The hypostasis of infarction is reflected in biochemical mechanisms of hypoxia and ischemia, which results in necrosis. Damaged cells release creatinin-phosphokinase MB and troponin into the circulation. These substances are elevated in the acute phase of infarction (with up to 78% specificity), and they are considered biomarkers of disease. However, it should be emphasized that those biomarkers themselves do not belong to the realm of clinical cardiology per se, but are rather translated for use in clinical cardiology methods and data from biochemistry. Without translation to clinical symptoms and observations, they are meaningless and might be regarded as indirect measures of various processes in the living organism. To put it in the framework of reification, it is troponin that reifies the diagnosis, and it is the clinical hypothesis that reifies the troponin as a biomarker.Physiology: The other basic domain involved in this exemplary case is electrophysiology. On the electrocardiogram (ECG) record, a deviation is observed, known as elevation of the ST segment. Once again, taken as a sole measure, it has limited sense. It requires translation to interpret it as a marker of infarction in the context of the patient’s complaints. Furthermore, it needs to be translated to the other measures as discussed here.Radiology: Radiological scans include the x-ray contrast - the based technique of coronary angiography. This provides real-time images of where and to what extent are the coronary vessels are obstructed. In this sense, angiography reflects on the primary cause of infarction: the obstructed blood and oxygen supply. Radiology is not cardiology from an epistemological point of view. Yet the data acquired inside this domain are successfully translated to reify the diagnosis.Thus, a circular process of translation is implemented: radiography gives information about the effects of the cause, biochemistry and electrophysiology provide correlates of the mechanisms that cause this disorder, and (taken together) these measures reify the diagnosis, which in turn motivates therapeutic intervention.In the common case, not all medical settings have at their disposal a clinical laboratory or angiography facilities. For this reason, minimum resource methods are often use, such as ECG to perform the diagnostic assessment. What makes such an approach feasible is the triangulation of knowledge as acquired within discrete disciplinary matrices . Under tTranslation and reification in psychiatry are still out of reach. All data acquired externally to the domain of clinical psychopathology are regarded as irrelevant to diagnosis. This refers to most recent and current studies in basic neuroscience, which are supposed to be involved in translation  . In realAlthough psychological and psychiatric assessment tools  belong nominally to different disciplinary frameworks, they share the same matrix: the matrix of statistically quantified subjective and inter-subjective narratives.If we assume the case of depression, then the translation across disciplines to operationalize diagnosis will appear like this:Psychiatry and clinical psychology use four levels of clinical tools . Psychiatry more often operates with structured clinician-rated scales, while clinical psychology refers more frequently to self-evaluation instruments. The most common among the psychiatric tools in depression assessment are the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Scale for Depression (HAM-D). These consist of items rated according to a Likert scale, the score of which is taken to have diagnostic value. For instance, a score on MADRS over 20 is considered as a measure of mild or moderate depression and a score ranging above 30 to be an indicator of severe depression. The usual psychological tests (or inventories) that are implicated in depression are Beck’s and Zung’s inventories or Depression Scale by Von Zerssen .There is no agent of reification located in the realm of objective biological facts (bio-marker) in this framework, and thus much confusion is caused by diagnostic errors, overestimating or underestimating the clinical data . Any disHowever, there are established promising post hoc correlations between the different types of clinical tools (interviews and inventories) and neuroscience. Thus, the different kinds of measures represent statistical correlations that need to be integrated into diagnostic standards and procedures but this, as a whole, is a step forward towards a better understanding of the mechanisms underlying psychopathology in general and depression in particular. Below, we will focus on fMRI studies using a trans-disciplinary approach and attempt to establish bridges between the different fields. We will selectively highlight research areas such as imaging genetics, imaging immunology and multimodal imaging, as related to the diagnosis and management of depression.Imaging genetics is a rapidly developing field in which neuroimaging is used to elucidate variations in brain structure and function as they relate to genotype . ClassicThe s-allele has been related to negative emotions and increased amygdala activation during perception of aversive emotional stimuli, which is also characteristic for depression . AssociaThe dysfunction of the fronto-limbic circuit is a well-replicated finding in depression , and theAlso, the activation of the prefrontal cortex, as well as its connectivity with the amygdala, were different in depressed patients with low- and high-expression genotype . AccordiEarlier genetic studies have also addressed the question of the influence of the SCL6A4 variants on treatment response in depressed patients and have found that s-allele carriers had poorer response to antidepressants, such as escitalopram , and morThe catechol-O-methyltransferase (COMT) gene with its val158met polymorphism have been extensively studied in psychiatric genetics (mainly in relation to schizophrenia). Met-homozygotes have been associated with the lower enzymatic activity of COMT compared to val-homozygotes , with cofMRI research has explored the influence of the COMT genotype on both emotional processing and working memory in major depression . In healIn bipolar patients, implicit processing of fearful and angry faces elicited significant positive connectivity between the amygdala, dorsolateral prefrontal cortex (DLPFC) and supramarginal gyrus in Val/Val carriers and significant negative connectivity between DLPFC and AMG in Met carriers . InteresAnother widely studied genotype in depression is the Val66Met polymorphism of the gene for the brain-derived neurotrophic factor (BDNF) that plays a major role in neuroplasticity . In healSerum BDNF-levels are consistently found to be lower in depressed patients and to normalize following treatment with a variety of antidepressants, including venlafaxine, sertraline, fluoxetine, paroxetine, lithium and citalopram, as well as with vagus nerve stimulation, repetitive transcranial magnetic stimulation and electroconvulsive therapy ,41,42,43Recently, the interaction between single genetic variants became a focus of research, providing valuable insight into the pathophysiological mechanisms of psychopathology. In healthy subjects, an additive effect of COMT and 5-HTT risk variants polymorphisms (met and s - respectively) was observed, accounting for 40% of the inter-individual variance in the averaged blood-oxygen-level-dependent (BOLD) response of amygdala, hippocampal and limbic cortical regions elicited by unpleasant stimuli . In a fMApart from gene × gene interactions, gene × environment interactions have recently attracted increasing scientific attention. Amongst the most prominent is the interaction between stressful life events and the serotonin genotype in the development of depression . IndividThe above findings support existing hypothesis of depression as a polygenic multifactorial disorder  that is the endpoint of diverse combinations of genetic susceptibility  and environmental influences (stress), which converge into dysfunctional neurotransmitter systems and neurocircuits. Stress has been associated with the development of depression, as well as other psychiatric and somatic disorders, most probably through its influence on the immune system .There is growing evidence of increased inflammatory biomarkers in depressed patients, including elevation of acute-phase proteins and the production of inflammatory cytokines, as well as increased cellular markers of immune activation . It is iAnother major body of data in support of inflammation’s role in depression comes from the findings that administration of inflammatory cytokines or cytokine inducers can cause a depressive-like behaviour in both laboratory animals and humans. Also, treatment with interferon-alfa results in a clinically significant depression in up to 40% of the cases . SeveralThe neurotransmitters serotonin, dopamine, and glutamate all seem to be affected by cytokines. The serotonin system, for instance, might be influenced by metabolic changes , as welSimilarly, the metabolism of dopamine seems to be affected by cytokines, as evidenced by a recent study in patients treated with interferon (IFN) alpha, where increased IL-6 in the cerebro-spinal fluid (CSF) was associated with decreased CSF tetrahydrobiopterin (BH4) - an essential enzyme co-factor for tryptophan hydroxylase and tyrosine hydroxylase, which are the rate-limiting enzymes for the synthesis of serotonin and dopamine, respectively. In this study, significant correlations were found between the phenylalanine (Phe) to tyrosine (Tyr) ratio and CSF concentrations of both dopamine and its metabolite, homovanillic acid .The Phe/Tyr ratio has been used as an indirect measure of BH4 activity in the brain and has been correlated with symptoms of depression in elderly individuals .Following IFN-alpha treatment, patients with hepatitis C demonstrated significantly decreased activation of ventral striatal regions during a hedonic reward task, which in turn was highly correlated with anhedonia, depression, and fatigue . A complWhile exploring inflammation induced mood change in healthy controls with fMRI, Harrison et al.  found thA recent magnetic resonance spectroscopy (MRS) study on unmedicated MDD patients revealed an interesting positive correlation between C-reactive protein (CRP) levels and the concentration of glutamate in the basal ganglia, which was associated with anhedonia and psychomotor slowing . In a saInvestigation of patients with IFN-induced depression has provided valuable insight into inflammation’s effects on neurogenesis and neurodevelopment. BDNF levels were reduced following treatment with IFN-alpha, and lower pretreatment BDNF was associated with higher depression symptoms . In animChanges in the activity of hypothalamus-pituitary axis (HPA) has been found both in stress and depression . Also, sThe activity of the HPA has been linked to the functional changes in brain areas involved in emotion processing in bipolar and MDD patients, as well as healthy controls during a facial emotion perception paradigm. In both groups, cortisol was associated with greater activation in several regions involved in the perception and control of emotion . However, in the patient group, cortisol responsivity was associated with hypoactivation of the insula, postcentral gyrus, precuneus, and putamen for fearful faces and the medial frontal gyrus for angry faces .The findings highlighted so far reveal some of the more specific mechanisms of the pathophysiology of depression and its interplay with stress and inflammation, which again is influencing the same neurotransmitter systems and neurocircuits, as well as neurogenesis and neuroplasticity, that are affected by the genetic predisposition. Below, we will move from the molecular level to the systems levels, as reflected by electrophysiology and multimodal functional imaging.Combined EEG-fMRI investigates neural activity, providing both high spatial and high temporal resolution specific to each of the techniques separately ,77. MoreSimultaneous EEG-fMRI acquisition during working memory (WM) task revealed a functional relation between WM-induced right posterior alpha increases and decreases in BOLD activity of the right middle temporal gyrus and primary visual cortex. The WM-induced frontal theta power, on the other hand, was associated with decreased activity in a set of regions that together form the default mode network (DMN) . The incThe activity of the DMN was found to be positively correlated with visual alpha power in the eyes-open condition but not in the eyes-closed condition, which is the most common in resting state fMRI . This laAbout emotional picture processing, a combined EEG-fMRI approach revealed interesting valence-specific findings. During the pleasant condition, the late positive potential  was correlated with BOLD in the occipitotemporal junction, medial prefrontal cortex, amygdala, and precuneus. For the unpleasant condition, the significant LPP-BOLD correlation was found in the ventrolateral prefrontal cortex, insula, and posterior cingulate cortex . In a seThe neural correlates of anhedonia have been studied using EEG, as well as structural and fMRI, during execution of monetary reward task in healthy individuals . A negatExploring a novel real-time fMRI-neurofeedback (rtfMRI-nf) procedure for the treatment of depression, the authors of this recent study implemented simultaneous EEG recordings to reveal objective measures of its efficacy . A positAn increasing amount of data supports the utility of combined fMRI-MRS techniques that could reveal the molecular underpinnings of observed BOLD activity changes in both resting state and task-related functional imaging. In this way, for instance, the concentration of GABA was found to be correlated with the negative BOLD activity of the ACC during emotional processing . MoreoveIn healthy subjects, BOLD signal changes during empathy task in the supragenual ACC (task-positive region) were related to the level of glutamate in the perigenual ACC (task-negative region). Moreover, there was no opposite relationship between activity in the pgACC and the level of glutamate in the sgACC . MDD patA recent multimodal imaging study combining resting-state fMRI, aversion task fMRI, glutamate MRS, and diffusion MRI explored the impact of negative childhood events [as measured by childhood trauma questionnaire (CTQ) on brain activity in healthy subjects] . Higher As evidenced by the findings reviewed, the application of combined EEG-fMRI and MRS-fMRI provides a valuable insight into the intimate pathophysiological mechanisms of depression, underscoring the engagement of the same neurotransmitter systems and neurocircuits on both molecular and functional/anatomical levels. However, a critical point in every research in psychiatry is the definition of the diagnostic categories.Compared to healthy controls, depressed patients are characterized by increased activity and resting-state FC between nodes of the DMN . HoweverOne of the reasons for these and other inconsistencies might be the fundamental lack of validity of psychiatric diagnoses in contemporary diagnostic classifications ,104. To Recently, we have been able to test our hypothesis on a sample of healthy controls and depressed patients with a new fMRI paradigm, specifically developed for this purpose. We implemented a standard block design where the Diagnostically Specific (DS) blocks consisted of four statements from the von Zerssen Depression Scale (DS), and the DN blocks consisted of four statements from an interest questionnaire. When contrasting the DS with the DN blocks (DS>DN), depressed patients demonstrated residual activations in frontal and central regions, while control subjects had no residual activations. The between-group analysis revealed significant activation in the middle frontal gyrus, parahippocampal gyrus, hippocampus and thalamus in patients compared to controls . These iIn this selective review, we have elaborated some of the most recent advances in the field of translational neuroimaging and, in particular, in the translation across genetic imaging, psychoneuroimmunology and multimodal imaging, as well as to the more conceptual issue of reification of diagnosis in psychiatry by means of inter-disciplinary translation. Although these topics appear to be discrete, they have the ultimate potential to further bridge the gap between neuroscience and psychiatry by co-producing a meta-language between disciplines, similar to other fields of medical expertise. We believe that our own approach of translational cross-validation of psychological assessment instruments is just one of many possible solutions to be discovered at the intersections between translational psychiatry and basic neuroscience, thereby transforming it into clinical utility.


The Editorial on the Research TopicNew Insights into the Pathophysiology and Treatment of Neonatal Hypoxic–Ischemic EncephalopathyNeonatal hypoxic–ischemic encephalopathy (HIE) is one of the leading causes of death and disability-adjusted life years (DALYs) in term infants , 2. ThisDavidson et al. addressed the utilization of therapeutic hypothermia for HIE. They discussed the evolution of hypoxic–ischemic brain damage and the optimal moment to start the hypothermic treatment, as well as the length and intensity of the intervention. The authors pointed out that, although hypothermia protocols are fairly close to optimal (starting within the first 6 h of life and continuing for 48–72 h), they are only partly effective, since the number needed to treat is currently of approximately eight patients. Therefore, they argued that additional enhancements may come from better detection of patients who could benefit from the therapy, and by determining the optimal rate of rewarming. Moreover, the authors examined the possibility of combining therapeutic hypothermia with other promising experimental therapies such as erythropoietin and cell transplantation.In an elegant review, Lange discussed the possibility of combining peptidylarginine deiminases (PADs) inhibition with therapeutic hypothermia to improve its results. PADs are responsible for posttranslational deimination, which impact structural and functional properties of proteins. Consequently, PADs have a role in different developmental processes, and their dysfunction has been linked with many degenerative and inflammatory disorders. The author discussed the roles of PADs after a hypoxic–ischemic insult, including aspects such as epigenetics, phagoptosis, and autophagy, and commented on the possible therapeutic applications of selective or non-selective PAD inhibition for HIE.In this regard, a mini-review by Rumajogee et al. summarized the etiology and pathophysiology of cerebral palsy, and then described the Rice-Vannucci model and 12 other rodent models of HIE, detailing the characteristics, advantages, and limitations of each one of them. The authors mentioned important clinical improvements for HIE that were based on extensive studies in preclinical models, including therapeutic hypothermia and the importance of maintaining cerebral perfusion. Moreover, they discussed sex-related distinctions in response to perinatal injury as well as the main limitations of rodent models, including differences in brain structure and development between rodents and humans, which may have important implications for the development of new therapies. Finally, they compared rodent versus large animal models and intra- versus extra-uterine models.The review article by Kang and Kadam have also pointed out the need for establishing preclinical models to study long-term effects and to develop novel therapies for neonatal seizures. The authors described diverse etiologies of neonatal seizures, including central nervous system infections and genetic diseases, while focusing on HIE. They provided a detailed discussion of the consequences of neonatal seizures on neurodevelopmental outcomes according to lesion type and severity, and called to the attention relevant aspects such as the evidence that prolonged seizures apparently lead to worsened brain injuries in HIE. The authors also reasoned that, because neonatal seizures are mostly subclinical, electroencephalographic monitoring and other parameters such as original lesion severity, antiepileptic drug efficacy, and follow-up magnetic resonance imaging are extremely important to estimate seizure burden and long-term outcomes.In their review paper, Looney et al., who presented evidence that glial fibrillary acidic protein (GFAP) levels in umbilical cord blood serum samples do not differ among infants with perinatal asphyxia, infants with HIE, and healthy controls. Their data showed that GFAP levels were associated neither with the grade of HIE nor with the presence of developmental abnormalities at 36 months of age. Taken together with previous findings [Douglas-Escobar et al.; (This research topic also features an original article by  et al.; , 5. TherIn conclusion, the articles that comprise this research topic provide new insights into different aspects related to HIE and may be useful for researchers, and health-care students and professionals who want to stay updated.PR-d-C, RM-O, and PP-C drafted and made substantial contributions to the conception of the work, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Corticotrophin releasing factor, vasopressin, oxytocin, natriuretic hormones, angiotensin, neuregulins, some purinergic substances, and some cytokines contribute to the long-term modulation and restructuring of cardiovascular regulation networks and, at the same time, have relevance in situations of comorbid abnormal stress responses. The synthesis, release, and receptor expression of these mediators seem to be under epigenetic control since early stages of life, possibly underlying the comorbidity to coronary artery disease (CAD) and stress-related disorders (SRD). The exposure to environmental conditions, such as stress, during critical periods in early life may cause epigenetic programming modifying the development of pathways that lead to stable and long-lasting alterations in the functioning of these mediators during adulthood, determining the risk of or resilience to CAD and SRD. However, in contrast to genetic information, epigenetic marks may be dynamically altered throughout the lifespan. Therefore, epigenetics may be reprogrammed if the individual accepts the challenge to undertake changes in their lifestyle. Alternatively, epigenetics may remain fixed and/or even be inherited in the next generation. In this paper, we analyze some of the common neuroendocrine functions of these mediators in CAD and SRD and summarize the evidence indicating that they are under early programming to put forward the theoretical hypothesis that the comorbidity of these diseases might be epigenetically programmed and modified over the lifespan of the individual. The interest in the relation between the heart and the emotions comes from ancient times. Aristotle mistakenly thought that the brain was an organ that cooled down the passions from the heart; however, he also noted that negative emotions adversely impacted upon the health/disease processes . In 1628Cardiovascular (CV) diseases are the main cause of premature death and chronic disability in the world  and mentThe common origin of risk/resilience to CAD and SRD could involve: (a) common anatomical brain structures participating in CV and behavioral responses; (b) common mechanisms at subcellular structures  which are regulated by reactive oxygen species (ROS), inflammation, and intracellular calcium in myocytes and neural cells; (c) microbiome effects on the brain and the CV systems; and (d) common chemical mediators. Most of these mechanisms shall be dealt with in future reviews, while the participation of common neuro-immune-hormonal mediators constitutes the aim of the present review.Epigenetic programming of the synthesis, release, and receptor expression of common mediators participating in the alternative risk of or resilience to comorbidity to CAD and SRD since early life stages, might contribute to the long-term modulation and restructuring of CV regulation networks and, at the same time, have relevance in situations of comorbid abnormal responses to stress. The term epigenetic refers to heritable traits of the expression of genes and to the subsequent phenotypic changes without there being alterations in the DNA sequence ,18. The Epigenetic programming refers to the influence produced by the exposure to specific conditions during critical periods of early life that modify the developmental pathways of the organism, leading to stable and long-lasting alterations that have effects when the individual reaches adulthood . The lanIn 2002, Barker et al.  suggesteEpigenetic regulation plays an important role in the determination of the adaptive or mal adaptive neural functioning and the behavioral responses to environmental stressors and maternal mental disorders may alter fetal development . The mecBriefly, summarizing the common brain anatomical structures that participate in CV and behavioral responses, there are at least three instances playing a regulatory role in the functioning of the brain-heart axis. They are the central nervous system (CNS), which is the main instrument to explore and evaluate environmental situations and in which the prefrontal cortex (PFC) plays a central role; the amygdala with its extension in the bed nucleus of the stria terminalis (BNST); the insula and the autonomous nervous system (ANS) with its sympathetic (SNS), parasympathetic, and enteric divisions ; and theIn addition to the above mentioned neuronal structures and as mentioned previously, neuroinmunoendocrine mediators have been proposed to jointly participate in the common origin of SRD and CMD, including CAD. The systems responding to stress include a complex network of mediators with complex interactions whose knowledge is continually expanding. The variations in the production of these mediators could be programmed since the early stages of development, leading to the appearance of complex diseases in adulthood or to resilience to them, and could also be reprogrammed. In this paper, we analyze some of the common mediators of SRD and CAD involved in the comorbidity of these diseases and their mechanisms of action, the evidence of their programming in early development, and the possibility to act upon this predisposition and modify the outcome. Although studies on epigenetics of the comorbidity are absent, there are enough data on the epigenetics of each of the molecules participating in these diseases. Therefore, we are putting forward the theoretical hypothesis that epigenetics might contribute to their simultaneous appearance.Cells from the whole body and those pertaining to neural structures synthesize and release different amounts of chemical molecules, depending on the tissue to which they belong. These molecules mediate communication between cells from the same tissue and with those of other tissues. Communication also depends on the expression of specific receptors that receive the signals. Cells from the heart and brain require similar chemical mediators.Many neuroactive substances modulate the CV system through their action on the CNS or act directly on the heart and vessels. Some neurotransmitters, including some of the classical ones , are among them. Neuropeptides are also included, such as vasopressin, oxytocin, natriuretic peptides (NPs), corticotrophin, angiotensin, thyroxin, Y neuropeptide, leptin, endothelin, orexins, apelins, interleukin 1b, and tumor necrosis factor-α (TNF-α) as well as steroids such as mineralo- and glucocorticoids, estrogens, and testosterone . Other sThe effect of neurotransmitters is usually of a short duration and can be stimulatory or inhibitory. In contrast, the effects of neuropeptides are long lasting and may contribute to the long-term modulation and restructuring of regulatory CV networks, whilst also having relevance in stress situations . Since tAfter a stressful event, the HHA axis is activated. The hypothalamus secretes the corticotrophin releasing factor (CRF) which, in turn, regulates the secretion of the adrenocorticotrophic hormone (ACTH) by the hypophysis. ACTH regulates the secretion by the adrenal cortex of important stress reaction mediators such as the glucocorticoid, cortisol in humans (or corticosterone in rats), and of mineralocorticoids. Although CRF was initially characterized as a regulator of ACTH, it is nowadays known that it participates in the control of the CV and gastrointestinal function, in behavioral and physiological responses to stress, and in the control of food intake ,54,55,56N-methyl-d-aspartate (NMDA) receptors [When stress is persistent and severe, the signaling from CRF promotes a decrease in dendritic branching which requires glutamatergic stimulation mediated through eceptors . ACTH sieceptors ,60 and tThe HHA axis activity can be modified at different levels, including its basal functioning, its circadian cycles, and/or the degree of response to acute stress. Changes in circadian rhythms, including that of the HHA axis, have been associated with the development of metabolic syndrome and its CV consequences . AlthougCRF and urocortins might participate in the mediation of a variety of pathophysiological conditions involving abnormal responses to stressors such as AD. Mice over-expressing CRF show anxiogenic-like responses compared to wild-type mice. The CRF-1 receptor may mediate CRF-like neuropeptide effects on the behavioral profile . Results2 receptors [CRF and urocortins also have cardioprotective effects that are mediated by cardiac CRFeceptors . Urocorteceptors . Urocorteceptors . Urocorteceptors  and alsoeceptors . The careceptors . Urocorteceptors ,73. Cardeceptors .Furthermore, insulin signaling, in the hypothalamus, whose malfunction constitutes a CV risk factor, regulates the HHA axis after stress through a negative feedback loop. Insulin normally provides an inhibitory tone to the axis and is regulated in a reciprocal manner by corticosterone. Altered signaling through the insulin receptor in the hypothalamus modifies the neuroendocrine response to acute psychological stress. Insulin signaling may promote or inhibit the release of other hormones such as vasopressin, depending on the region to which it binds ,76.The regulation of comorbid cardiac and brain conditions might be the consequence of the anatomical and functional relation between the HHA axis and the BNST . The BNSNR3C1 [GR in the hypothalamus and modify the impact of stressful events in adulthood [CRF or arginine vasopressin (AVP) [GR and MR such as FKBP5 [The HHA axis constitutes a good example of early programming since fetal exposure to maternal cortisol during development modifies the neuroendocrine system response related to stress and leads to psychopathology in adulthood. There are numerous evidences of early programming of CV disease triggered by changes in early life of the functioning of the HHA axis. High fasting cortisol levels during early development determine low birth weight which is associated with CMD in the adult . EpigeneNR3C1 ,80. Expodulthood ; (2) Acedulthood ,82; (3) in (AVP)  or of chas FKBP5 ,83  to the BNST ,106 and Regarding early programming of oxytocin and vasopressin, it has been reported that the elevated estrogen levels during pregnancy modify the oxytocin receptors in the limbic system, reducing maternal fear to new stimuli, thus rendering the mother more receptive to social signals from the newborn, which favor a better environment for child development . ChangesThe oxytocin and vasopressin neuroendocrine systems are involved in sensibility adaptations to stress and their functioning during adulthood might be programmed from the early stages of life. Postnatal chronic stress induces a behavior similar to that of depression when offspring reach adulthood and stimulates the expression of the vasopressin receptor-1 in the hippocampus in the young adult stage. Furthermore, when two sources of stress are combined during early life, the expression of the oxytocin gene receptor is increased in the hippocampus when the individuals reach adulthood . RegardiNPs are compounds that act in an endocrine or paracrine way to regulate extracellular liquid volume and arterial pressure through stimulation of the sodium excretion by the kidney. Peripheral atrial natriuretic peptides (ANP) and their bioactive fragments, together with their corresponding receptors , are involved in diuresis and blood pressure regulation. NPRs are also found in the brain. NPR-A and NPR-C are found on neurons and astrocytes, while NPR-B is mainly located on neurons and partially co-localizes with NPR-A. In the CNS of man and rodents, NPR-A is mainly found in the cortex and hippocampus, whereas NPR-B is present in the amygdala and several brainstem regulatory sites. NPR-C is widely found within the CNS, i.e., in neocortex, limbic cortex, the hippocampal area, and the amygdala. Besides the important cardio-renal function of NPs, they also have vasorelaxant effects and they inhibit the renin–angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) ,109. CirNPs preserve vascular health in both endothelial and vascular smooth muscle cells by interfering with the key mechanisms that promote atherosclerosis including inflammation, thus participating in CAD ,109. MorNPs also participate in numerous brain functions. They are found throughout the CNS, where they represent an important neuromodulatory system regulating emotional behavior, such as anxiety and arousal, and the consequences of stress hormone release and ANS activation. NPs are specifically involved in the regulation of the HHA system. The effects of ANP seem to be mediated through the inhibition of the HHA axis by decreasing the liberation of CRF and ACTH, which in turn stimulate the liberation of ANP, establishing a feedback circuit. In man and rodents, ANP inhibits the HHA system at all regulatory levels and reduces anxiety levels. The central or peripheral administration of ANP diminishes anxiety-related behavior in rats . In healSimilar to ANP, BNP also has anxiolytic effects . By contImmunocytochemistry studies have found NP synthesizing neurons in the BNST, which regulates both CV function and emotions  Figure . TherefoBNP gene in the heart of subjects with rheumatic diseases [ANP and BNP genes at the beginning of the development of heart failure [Among the evidence suggesting that the secretion of NPs is under programming since early stages is the finding of epigenetic modifications in the patterns of NPs secretion between the right and left ventricles and of other proteins that determine the difference in the force of contraction that ventricles exert . There idiseases . There i failure .The renin-angiotensin system (RAAS) is a circulating and tissue-based hormonal system with a pathway that can be divided into the classic RAAS and the non-classic RAAS. Both pathways play a key role in CV regulation, but are also involved in neurological diseases through peripheral and/or central control systems . The RAAThe RAAS plays an important role in blood pressure control and volume homeostasis. Inappropriate activation of the RAAS has been implicated in the pathogenesis of hypertension and related CV diseases . In addiRegarding the regulation of comorbidity of cardiometabolic and neuropsychiatric disorders, angiotensin peptides play an important role in direct CV regulation and are also involved in the central regulation of the CV system. All of the components of the RAS and their receptors are present in the brain and particularly in structures involved in the regulation of the CV system . Ang II The secretion levels of the RAAS are subjected to early programming. The abolishment or improper activation of the RAAS may unleash an increase in oxidative stress and in the production of endothelin, which are implied in the development of hypertension, whose origin is linked to the fetal stage .NRGs comprise a family formed of four members of signaling molecules  that are similar in structure to the epithelial growth factor (EGF). NRGs participate in the communication between cells during development and in diseases. NRGs transmit their signals to target cells through their interaction with tyrosine kinase activity receptors pertaining to EGF, the ErbB family . This faOf the NRGs, NRG1 is the most studied and it plays an important role in the early development of the nervous system, heart, and breast gland . In the NRG1 and stress in adult humans have been reported [TnNrg1 rats, it was found that male TnNrg1 rats have significantly higher basal corticosterone levels, while female TnNrg1 rats show enhanced suppression of corticosteroid secretion after recovery from acute restraint stress [TnNrg1 rats may be more sensitive to changes in their environment, while female rats are less impacted by mildly stressful aspects in their environment [Type II NRG1 is expressed in the neurocircuitry involved in regulating the HHA axis response to stressors, including the hypothalamic PVN, which integrates and controls the neuroendocrine responses to stress ,146, thureported ,146. Whereported . NRG1-Erreported . Moreovet stress . In addit stress . These fironment .Regarding the participation of neuregulins in CAD, endothelial cells produce neuregulins. The activation of ErbB by NRG can also protect from the ischaemic damage of heart tissue in vivo ,150 and Evidence of a possible programming by neuregulins during the early stages of risk/resilience to diseases has been found. Alterations in the peripheral signals from NRG1 during neural development also modify the behavioral traits, inducing their early programming . The devThe peripheral administration of NRG1 increases the ErbB4 levels in the brain of neonatal mice and elevates the expression, phosphorylation, and enzymatic activity of tyrosine hydroxylases, which increase dopamine levels. The hyperdopaminergic state is maintained until after adolescence in the medial PFC. Therefore, NRG1 neurotrophically contributes to an altered dopaminergic system and to the posterior pathogenesis of neuropsychiatric diseases . Further+), and ADPribose (ADPR). It is difficult to identify which of these molecules is participating in each case as a mediator since purines are present in all types of cells and are generated by a great variety of sources and liberated by numerous pathways [Purinergic mediators include molecules such as adenine, adenosine triphosphate (ATP), diadenosine polyphosphates (ApnA adenosine), β-nicotinamide adenine dinucleotide , potassium (K+), and calcium (Ca2+). The P2Y receptors are linked to G proteins which activate the phospholipase C/inositol triphosphate intracellular Ca2+ liberating pathway [There are a great variety of purine receptors, which have been classified as receptors for P1 and nucleotide receptors P2. P1 receptors are linked to G proteins and comprise the A1, A2A, A2B, and A3 subtypes. The A1 and A3 receptors are coupled to the Gi/o family of G proteins which inhibit the cyclic AMP production, while A2A and A2B receptors stimulate cyclic adenosine mono phosphate (AMP) production through the Gs protein. P2 receptors are subdivided into the seven ionotropic P2X receptors (P2X1-7) and the eight metabotropic P2Y receptors . The P2X receptors are classical ionic channels whose opening is ligand-dependent and are permeable to ions such as sodium  or to hypoxia acting upon P2 receptors of the same endothelial cells to produce nitric oxide, endothelial derived hyperpolarizing factor, or prostaglandins to cause vasodilation .With respect to early programming, there are very few molecules with a higher potential of having an influence on mammalian development than adenine nucleosides. Adenosine levels rapidly increase under hypoxic or inflammatory conditions. When pregnant mice are treated with an adenosine antagonist such as methylxanthines (caffeine or theophylline) during embryogenesis, upon reaching adulthood, pretreated mice show abnormal cardiac function. Adenosine acts through A1ARs receptors in the protection of embryos against intrauterine stress . These rThere are also a growing number of studies showing evidence that the nucleotide signaling plays an important role in the development of the nervous system. Nucleotide signaling is associated with progenitor cell proliferation, cellular migration, interaction and differentiation of neurons and glia, and in the formation of synaptic nets. Nucleotide receptors might play a relevant role in the epigenetic regulation of genes .Inflammation is a physiopathologic process accompanying depression, anxiety, and CV diseases ,169. DieAlso, important brain functions such as neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and the neural circuitry of mood are regulated by cytokine signaling in the brain. Dysregulation in cytokine signaling might lead to anxiety and cognitive dysfunction. There is a bidirectional interaction between the immune system and the CNS in which psychological stress modulates cytokine production and cytokines determine psychological stress, and its presence is one of the most relevant findings in the last decades. The role of neuroimmunology in anxiety has been studied and oxidative stress has been found to work as a sensor of distress leading to neuroinflammation, thus participating in anxiety disorders . In physThe CV and nervous systems share a large group of mediators, among which cytokines and their receptors are counted. Thus, the altered expression of these molecules in any of these systems influences the other in a reciprocal manner. Among the inflammatory mediators that may play a role in the co joint appearance of CAD and SRD are IL-6, TNFα, soluble cell adhesion molecule 1, and acute phase proteins, particularly C-reactive protein (PCR), as well as a decrease in the anti-inflammatory cytokines IL-4 and IL-10. The cytokine profile that underlies the psychiatric disorder present in patients showing acute post stroke anxiety might account for the increased risk condition to develop new CV events. In chronic inflammatory diseases (such as multiple sclerosis), the permeability of the hematoencephalic barrier is disrupted, allowing for the flow of cytokines and other proinflammatory molecules ,176. ThiRegarding early programming, for more than a decade, it has been considered that inflammation is one of the mechanisms that alters the structure of chromatin through signaling pathways activated by necrosis factor-κB (NF-κB) . These pAt present, epigenetics is considered as a novel area for new therapies ,183,184 In contrast to genetic mutations, the plasticity of epigenetic changes makes them attractive candidates for prevention or reversion by non-pharmacological intervention. The free will of the individuals to undertake healthy eating habits, perform exercise, and increase mental activity might help induce epigenetic modifications. Dietary lifestyles may alter epigenetic cues in neuropsychiatric and CMD risk in utero, after birth, or during life, since they contribute to the risk of developing these diseases by metabolic re programming of the epigenome .Several studies have reported that intestinal microbial steady-state imbalances can cause a range of metabolic diseases ,187,188.This gut-brain connection could have clinical implications, as influencing the gut microbiome through diet may serve to ameliorate some psychiatric disorders. Dinan et al. coined the term “psychobiotics” in 2013  to descrDietary interventions using natural compounds have been proposed to modify epigenetic cues. A growing number of epidemiologic studies point to a link between the ingestion of nutritional polyphenols and health benefits . A mixtuCrh gene [Other interventions proposed include the reduction of glutamatergic receptor activation. This intervention has been found to be enough to counteract the negative effects of increased maternal care on increased CRF signaling . This efCrh gene ,198. NRSCrh gene . These mGR gene expression, was Trichostatin A and L-methionine administration. They influenced the epigenetic status of critical loci in the brain [Another pharmacological manipulation in the adult that was able to reverse some of the effects of environmental influences such as maternal behavior and diet that caused epigenetic changes in neurons by altering histone acetylation, DNA methylation, and nerve growth factor-inducible protein A transcription factor binding, thus inducing long-term changes in he brain .Perinatal exposure to endocrine disrupting compounds such as xenoestrogens increases the risk of diseases by (re)programming the epigenome via alterations in DNA and histone methylation. Xenoestrogens induce nongenomic signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase, thus providing a direct link to disruption of the epigenome . Thus, iSeveral drugs with a potential capacity to modulate the epigenetic machinery and that could be suggested as new drugs for the treatment of several diseases have been proposed ,206,207.The area of study of epigenetic therapies is still in its beginnings and new and effective treatments will follow in the near future as experimental data accumulates and is tested for human use. Furthermore, the response of the epigenome to environmental insults throughout life seems not to be an accidental aberration happening only in early life and always leading to pathology, but a biological mechanism that helps adaptability of the genome to altered environments during life. It would be important to delineate if only chemical exposures such as diet or drugs or toxins can affect the epigenome or if the social environment can also act on it. This would imply that there might be signaling pathways which link extracellular environmental exposures and epigenetic machineries in mature somatic cells and that correct environmental exposures, including changes in the social environment, which might reverse damaging signals. The prospect that the social environment or individual behavior might alter our genome by modifying the epigenome might provide an explanation for the relationship between socioeconomic status and physical health. Hence new therapies that modify the social environment might be possible and are an intriguing possibility .Neuro-cardio-immune-endocrine mediators that participate in the comorbidity of CAD and SRD can be subject to early programming and later reprograming. The synthesis, release, and/or expression of receptors of these mediators may be the subject of epigenetic marks. Although there are no studies on the epigenetics of the comorbidity, there are enough data on each of the epigenetics of the molecules participating in these diseases. Therefore, here we put forward the hypothesis that epigenetics might contribute to their comorbidity. At present, more studies have been done on the programming of CMD than of SRD. The study of possible re programming therapies is an area of opportunity for the treatment of neuropsychiatric and CV diseases offering great relevance. The knowledge of the mechanisms underlying CMD and SRD is important for decision making to safeguard health. This could favor comprehensive health guidelines including actions that influence not only the brain-heart axis parameters, but the entire economy of the organism.


The gut and brain form the gut-brain axis through bidirectional nervous, endocrine, and immune communications. Changes in one of the organs will affect the other organs. Disorders in the composition and quantity of gut microorganisms can affect both the enteric nervous system and the central nervous system (CNS), thereby indicating the existence of a microbiota-gut-brain axis. Due to the intricate interactions between the gut and the brain, gut symbiotic microorganisms are closely associated with various CNS diseases, such as Parkinson's disease, Alzheimer's disease, schizophrenia, and multiple sclerosis. In this paper, we will review the latest advances of studies on the correlation between gut microorganisms and CNS functions & diseases. The human gut contains various microorganisms, such as bacteria, fungi, parasites, and viruses, and more than 100 million bacteria reside in human gastrointestinal tract, which is 10-100 times the number of eukaryotic cells in our body. After years of common development with the human body, the gut bacteria have reached a mutually beneficial symbiotic state with the human body. The gut bacteria mainly include six major phyla of Firmicutes, Bacteroidetes, Proteobacteria, Actinomycetes, Verrucomicrobia, and Fusobacteria, with Bacteroidetes and Firmicutes being the dominant flora [Gut microorganisms play an important role in promoting adult development and homeostasis; for example, they can affect human metabolic functions by decomposing the complex polysaccharides in food. In addition, gut microorganisms can regulate gut movement, the gut barrier system and fat distribution . Gut micAge and diet, in particular, can have a significant impact on gut microbiota , 5, and There are three main methods for detecting gut microorganisms: the bacteria culture technique, the traditional molecular biology technique that is independent of culture, and high-throughput sequencing technology. The former is mainly used for stool culture, this method is time-consuming, and the bacterial species obtained are limited. The latter two mainly isolate the bacterial DNA from the stool for the detection, the detection is fast, and the bacterial species are complete.The central nervous system (CNS) is closely related to the gastrointestinal tract, and the CNS plays an important role in regulating gut function and homeostasis. In turn, the gut flora may affect the CNS and nerve cells, participate in the regulation of nervous system function, affect the pathogenesis and progression of nervous system-related diseases. Due to the complex relationship between the gut microorganism population and the host, the authors proposed a new concept: the microbiota gut-brain axis. The microbiota gut-brain axis is the focus of recent research on the gut microecology. In addition to studies of the relationship between the gut microecology and neurological function, recent studies have emphasized how this relationship affects human health.The brain and gut can be connected through a variety of pathways, including the enteric nervous system (ENS), vagus nerve, the immune system, or the metabolic processes of gut microorganisms.The gastrointestinal tract is an organ that is co-dominated by the CNS, the autonomic nervous system, and the ENS. Regulation of enteric nerves consists of four levels of nervous regulation . The firThe vagus nerve of the body can control the function of multiple organs, such as heart rate and gut motility; the vagus nerve can also transmit peripheral immune signals to the CNS. The vagus signal from the gut can trigger an anti-inflammatory response against the sepsis induced by microorganisms. Gut microorganisms can affect brain functions through the vagus nerve; after a vagotomy, the microorganisms will not be able to regulate behaviors . After vBecause gut microorganisms can directly affect the immune system, immune activation may be the pathway for transmitting microbial actions to the CNS . MicroorMicroorganisms can also cause neurophysiological changes in the host by producing chemical substances that bind to the receptors inside and outside of the gut. Bravo et al. found that mice fed L. rhamnosus (JB-1) probiotics exhibited fewer anxiety-like and depressive behaviors and a change in the GABA Aα2 mRNA content in the brain area that controls specific behaviors . Short-cIn addition, studies have shown that the microbiota may affect the CNS by altering adult hippocampal neurogenesis (AHN). The adult hippocampus and lateral ventricle have the function of generating new neurons. AHN has a role in learning and memory and can have affect on the pathogenesis of many neurological disorder-related diseases and symptoms, such as epilepsy, depression, Alzheimer's disease (AD), and Parkinson's disease (PD) . In a reThe impact of microorganisms on behavior and cognition has been increasingly recognized. Microbial signals can regulate important functions of healthy human bodies, and growing evidence has demonstrated that many diseases are due to disturbances of gut microorganisms . Early sIn 2004, Sudo et al. were the first to report that symbiotic gut microorganisms were associated with the hypothalamic-pituitary-adrenal (HPA) axis . In respThe change in gut microorganisms found in sterile animals or with the use of probiotics, antibiotics, and colonization with fecal microorganisms can influence the cognitive function of the host. For example, supplementation with probiotics for a week prior to infection can not only prevent the microorganism disturbance caused by the infection but also prevent the changes in cognitive behavior caused by stress . Liang eSchizophrenia is a neuropsychological disorder, and whole-genome analysis suggests that immunity-related genes may be changed in schizophrenia patients. Song et al.  found thGut bacteria can also produce harmful substances that damage the intestinal epithelial barrier, causing neurotoxic bacterial products and proteins to enter the circulatory system . SeveranAutism spectrum disorder (ASD) is a type of extensive brain function development disorder that begins during the early stages of growth (< 36 months), and it is manifested as different levels of interpersonal barriers, language development disorders, and stereotyped behavior. Environmental factors  are involved in the development of ASD, and as many as 70% of autistic patients exhibit gastrointestinal tract-related symptoms; therefore, it is thought that ASD is associated with impairment of the gut-brain axis . The majObese pregnant mice exhibit changes in social behavior, oxytocin cells, synaptic plasticity, and the microorganism composition of the microbiota, but Lactobacillus reuteri could reverse these changes . BecauseThe bacterial metabolites, 4-ethyl-phenylsulfate and 3-(3-hydroxy phenyl)-3-hydroxypropionic acid, can cause mice to develop ASD-like symptoms , 50. In Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the nervous system, and its etiology is still unclear. MS is associated with a significant increase in the number of cells that have immune response to the patients’ own nervous system because gut microorganisms play an important role in the development of the autoimmune system and are associated with a variety of autoimmune and metabolic diseases. Therefore, it is speculated that gut symbiotic microorganisms play an important role in the susceptibility to MS.Experiments have been performed to study the role of gut microorganisms in an animal model MS-experimental allergic encephalomyelitis (EAE). Ochoa-Reparaz et al.  used a mThe drug resistance of ε-toxin in the plasma of MS patients is also higher than that of normal people. Vartanian et al.  found thPD is an extensive neurodegenerative disease, its pathogenic mechanism is complex, and a change in α-synuclein is an important pathogenic mechanism of this disease. Changes in the gut microbial composition may affect the gut barrier function and gut permeability, thereby affecting intestinal epithelial cells and the immune system. The primed immune response initiated by gut microorganisms can enhance the inflammatory response to brain amyloid (α-synuclein), thereby causing the misfolding of α-synuclein . Firelanα-synuclein. The inflammatory changes observed in PD patients and PD animal models are associated with increased gut permeability [Proinflammatory factors associated with chronic bowel diseases can induce intracranial inflammation, lead to the death of dopaminergic neurons, and eventually cause the development of PD . Schepereability . LPS is eability . Similareability  used higAD is a degenerative disease of the CNS, its onset is recessive, and its disease course is chronically progressive. The pathological markers of AD include extracellular β-amyloid (Aβ) senile plaques and intracellular neurofibrillary tangles. The number and maturation of microglial cells in sterile mice are abnormal, resulting in damage to the immune system and ultimately leading to the development of neurological diseases, such as AD . CognitiThe integrity of the BBB is important for brain function and development. The inflammation caused by the changes in gut microorganisms will lead to changes in BBB integrity, which in turn affects brain function. Under normal conditions, LPS cannot enter the bloodstream due to the tight junction between intestinal epithelial cells. However, when the tight junction of cells is disrupted and the permeability is increased, LPS can enter the bloodstream and induce inflammatory response. Studies found that the plasma LPS concentration in AD patients is three times that of normal patients . FurtherGut microorganisms can also affect brain functions through the synthesis of various substances. Serotonin is very important for cognitive function, 95% of serotonin is synthesized in the gut, and gut microorganisms play an important role in serotonin synthesis. The gut serotonin level in sterile mice was 60% lower than the normal value . The useThe interactive relationship between the brain and the gut includes neurology, metabolism, hormones, immunity, and other aspects, and changes in any component may lead to a functional change in the two interactive systems. The normal ecological balance of gut microorganisms plays an important role in the maintenance of this relationship. Microorganisms affect the development and function of the CNS through the microbiota-gut-brain axis. The mechanisms of many CNS diseases are still unclear, and the discovery of this complex relationship, the microbiota gut-brain axis, has provided a new research direction for the study of CNS diseases that do not have a clear pathogenic mechanism.


Ticks and the pathogens they transmit constitute a growing burden for human and animal health worldwide. Vector competence is a component of vectorial capacity and depends on genetic determinants affecting the ability of a vector to transmit a pathogen. These determinants affect traits such as tick-host-pathogen and susceptibility to pathogen infection. Therefore, the elucidation of the mechanisms involved in tick-pathogen interactions that affect vector competence is essential for the identification of molecular drivers for tick-borne diseases. In this review, we provide a comprehensive overview of tick-pathogen molecular interactions for bacteria, viruses, and protozoa affecting human and animal health. Additionally, the impact of tick microbiome on these interactions was considered. Results show that different pathogens evolved similar strategies such as manipulation of the immune response to infect vectors and facilitate multiplication and transmission. Furthermore, some of these strategies may be used by pathogens to infect both tick and mammalian hosts. Identification of interactions that promote tick survival, spread, and pathogen transmission provides the opportunity to disrupt these interactions and lead to a reduction in tick burden and the prevalence of tick-borne diseases. Targeting some of the similar mechanisms used by the pathogens for infection and transmission by ticks may assist in development of preventative strategies against multiple tick-borne diseases. Ectoparasites that derive nutrition through blood feeding (haematophagy) are efficient vectors of disease. Ticks are haematophagous ectoparasites of vertebrates. Approximately 10% of the 900 currently known tick species are of significant medical or veterinary importance. Besides causing direct damage associated with blood feeding and in some cases through the excretion of toxins within their saliva, the main relevance of ticks lies in the wide variety of pathogens they can transmit, including bacteria, viruses, protozoa, and helminths  , viruses , and protozoa (Babesia spp.) to illustrate their impact on vector competence, behavior and transmission , equine, and canine granulocytic anaplasmosis, and tick-borne fever (TBF)  or by direct contact with blood or tissues of viremic patients or animals, causing a disease characterized by fever, headache, myalgia, and hemorrhagic manifestations  and major surface protein 4 (MSP4) interact and bind to tick cells, thus playing a role in tick-pathogen interactions  as well as a tick receptor for the B. burgdorferi protein BBE31 (TRE31) help spirochetes traverse from the tick midgut into the hemocoel , produced when bacteria leave the tick midgut, binds to tick salivary protein 15   pathway, which inhibits apoptosis and promotes pathogen infection , counteracting the tick cell response to infection. However, tick cells respond by activating protein targeting and degradation, which reduces ER stress and apoptosis, thus favoring A. phagocytophilum infection  inhibition that results in lower glucose metabolism and the reduction in the availability of essential metabolites for bacterial growth, which leads to the inhibition of cell apoptosis that increases infection in tick cells . Infection of I. ricinus cells with flaviviruses leads to the differential expression of a large number of genes involved in a variety of cellular functions, including up-regulation of genes such as cytochrome c associated with cellular stress and apoptosis  suggest that flavivirus infection inhibits tick cell apoptosis in order to promote cell survival during infection as previously shown for A. phagocytophilum  levels to preserve a protein that is important for tick feeding  interacts with the E2 conjugating enzyme Bendless affecting positive and negative regulators of the immune deficiency (IMD) pathway resulting in protection against infection by A. phagocytophilum  belongs to a protein family with complement-inhibitory activity that blocks the host alternative complement pathway and assists in Borrelia transmission , histone acetyltransferases , and histone deacetylases (HDACs and Sirtuins) resulting in the inhibition of cell apoptosis to facilitate pathogen infection and multiplication  and modifies neutrophils gene expression  and heat shock proteins (HSPs) to increase tick survival and feeding fitness , has antimicrobial activity against biofilm-forming bacteria, particularly Staphylococcus aureus and Enterococcus faecalis. They further showed that by targeting biofilm-forming bacteria, A. phagocytophilum modifies the composition of gut microbiota and alters tick midguts permeability, which results in higher A. phagocytophilum infection in the vector  grant BFU2016-79892-P and the European Union (EU) Seventh Framework Programme (FP7) ANTIGONE project number 278976. SA and AD would like to acknowledge FCT for funds to GHTM - UID/Multi/04413/2013. MV was supported by the Research Plan of the University of Castilla-La Mancha (UCLM), Spain. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.