Perinatal Brain Damage Research Articles

Melatonin modulates the Notch1 signaling pathway and Sirt3 in the hippocampus of hypoxic-ischemic neonatal rats

The Notch1 signaling pathway plays a crucial role in the development of the central nervous system, governing pivotal functional activities in the brain, such as neurogenesis. Sirt3 is instrumental in managing mitochondrial homeostasis and is essential to cell survival. Dysregulation of these signaling pathways is implicated in the pathogenesis of a wide range of diseases, including neurodegenerative disorders such as stroke. We have previously shown that melatonin significantly improved the perinatal brain damage caused by hypoxia-ischemia (HI) through the activation of several protective mechanisms such as restoring mitochondria status and increasing the hippocampal cell proliferation. This study assessed whether melatonin affects the Notch1 signaling pathway and Sirt3 after neonatal HI. Results show that HI significantly increased Notch1 expression both in hippocampal neurons and glial cells as well as the expression of the key proteins of the pathway NICD, HES1, and c-Myc. Melatonin significantly prevented the Notch1 signaling pathway activation induced by HI, maintaining NICD and HES1 expression to control levels. In the same neurons, melatonin also prevents the Sirt3 depletion caused by HI. In summary, this study provides new insights into the effects of melatonin on the Notch1 signaling pathway and Sirt3 in in vivo neonatal brain ischemia. We suggest that the rapid modulation of the Notch1 signaling pathway and Sirt3 induced by melatonin may support neuronal survival during ischemia.

Intellectual Development in Mexican Preterm Children at Risk of Perinatal Brain Damage: A Longitudinal Study.

Preterm birth accounts for about 10% of births worldwide. Studying risk factors for perinatal brain damage is essential, as findings suggest that almost 20% of disabilities are linked to risks in the early stages of development. This research aimed to study longitudinal changes in intelligence from 6 to 8 years of age in a sample of 39 preterm children with a history of risk of brain damage and a control group of 35 children born at term. The Wechsler Intelligence Scale (WISC-IV) was used to measure cognitive ability at six, seven, and eight years old. The results showed that the preterm group obtained significantly lower scores than the control group. The working memory indicator significantly affected the interaction between age and prematurity. We consider it crucial to expand the knowledge we have about the neurocognitive development of premature infants, both in specific cognitive domains and in age ranges, so that the information obtained can help predict the probability of presenting cognitive alterations from early stages. This, therefore, helps in implementing intervention strategies and programs based on scientific evidence, and their design is complemented by clinical experience and empirical and theoretical knowledge of the different professionals involved in infant cognitive intervention.

HISTORY OF PRETERM INFANTS WITH HYPOXIC BRAIN DAMAGE

Relevance. According to the experts of World Health Organization, diseases linked to perinatal hypoxic brain damage account for 70-80% of cases of childhood disability.
 This study aims to explore the historical records of heart rate and respiratory characteristics in preterm infants with hypoxic brain damage.
 Subjects and Methods. A prospective cohort study was conducted involving 160 preterm infants categorized into three groups: group I comprised conditionally healthy children, group II included children with hypoxic-ischemic central nervous system lesions, and group III involved children with hypoxic-hemorrhagic central nervous system lesions.
 Results. The analysis of heart rate parameters according to the data of daily monitoring of electrocardiogram has revealed a positive dynamic of reduction of heterotopic activity and a significant (p<0.05) improvement in the functional state of the conduction system of the heart in all preterm infants aged 20-30 months after a course of timely rehabilitation therapy of hypoxic brain damage. The presence of periodic breathing with respiratory pauses in preterm patients in the neonatal period was established, and a significantly longer duration of apnea was found in children with hypoxic-hemorrhagic central nervous system damage. There has been found an inverse correlation of moderate strength between gestational age and the amount of apnea during the day. Throughout the observation period, there was a gradual establishment of the sleep profile and its structural characteristics, indicating a physiological consolidation process marked by a regular alternation of stable rhythm phases. However, in newborns with hypoxic brain damage, autonomic dysregulation of heart rhythm persisted in the form of hypersympathicotonia. This suggests a high level of electrical instability of the myocardium, underscoring the necessity for ongoing clinical monitoring.

Comorbidity of cerebral palsy and epilepsy with autism in children

Background. Cerebral palsy is often combined with epilepsy (up to about 50 % of children). The treatment of epilepsy limits the rehabilitation of cerebral palsy, and the rehabilitation of cerebral palsy often provokes epileptic seizures. Epilepsy in children with cerebral palsy is often manifested in a form of developmental and epileptic encephalopathy with spike-and-wave activation in sleep, which is characterized by epileptiform activity according to the type of benign epileptiform patterns of childhood with a high index on the electroencephalogram (up to 100 %), severe epileptic seizures of a status course, and mental disorders by type autism-like behavior (the so-called atypical autism) and disorders of speech communication. The problem of comorbidity of cerebral palsy, epilepsy and autism remains relevant and needs further study.Aim. To study the features of autism spectrum disorder in a group of children with a combination of cerebral palsy and epilepsy.Materials and methods. We examined 100 patients aged 3–10 years with various forms of cerebral palsy, combined with epilepsy, to identify the clinical features of autism spectrum disorder. Criteria for inclusion in the study: age 3–10 years; verified diagnosis of epilepsy in combination with cerebral palsy and autism spectrum disorder; informed consent of the patient’s parents to participate in the study. Criteria for exclusion from the study: severe somatic diseases and disorders of the sense organs (in particular, kyphoscoliosis, gastrostomy and others, as well as deafness, blindness); age less than 3 or more than 10 years.Results. The average age of visiting a psychiatrist was 5.4 ± 0.5 years. The reasons for visit were: violation of the communication (76 %), decreased eye contact (75 %), lack of compassion for surrounding or adjacent animals (100 %), dysphoric disorders (77.1 %), aggression (55 %), autoaggression (40 %), phobias (90 %), impaired speech development (18 %). Perinatal brain damage was diagnosed in 100 % of cases. Epilepsy was manifested by focal motor seizures. Patients with complex treatment (drugs and pedagogical correction) have more pronounced positive dynamics compared with patients who received only drug therapy or only rehabilitation (p <0.05).Conclusion. In children with a combination of cerebral palsy and epilepsy, the cause of autism is perinatal lesions of the central nervous system, as well as the severity of motor pathology and the presence of continued epileptiform activity on the electroencephalogram. Autism in this group of children requires timely recognition and medical and pedagogical correction.

A study on placental expression of neuronal markers in intrauterine growth restriction

Introduction and Aim: The restriction of intrauterine growth (IUGR) has a 20% recurrence rate and is one of the leading causes of postnatal illness and death. The diagnosis of intrauterine retardation refers to the infant's increased risk of neurological issues over an extended period, neonatal morbidity, and mortality, and in utero death. Materials and Methods: One hundred placenta samples were collected and divided into cases and controls. Clearance from the ethics committee was taken from the institute prior to the commencement of this study. Exclusion criteria include the patients with multiple pregnancies, unknown gestational age, gestational diabetes, and HIV. The inclusion criteria are the singleton pregnancy, normal and cesarean section, maternal age between 18-35 years and GA between 34 – 41 weeks. Standard immunohistochemistry protocols were followed for the study and glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) markers were used as neuronal markers. Results: Strong immunoreactivity of glial fibrillary acidic protein and neuron specific enolase was observed in fetal growth restriction placenta indicating perinatal brain damage of neonate. Conclusion: In our study we observed strong positive immunoreactivity of GFAP and NSE in IUGR only. This study suggests that these markers are used to predict brain damage in IUGR neonates.

The effectiveness of the early habilitation complex in premature infants according to N.A. Bernstein’s concept

BACKGROUND: Currently, the incidence of developmental disorders and the level of disability in premature infants, especially those born with a low and extremely low body weight, remain high, that determines the relevance of habilitation methods.
 AIM: to develop and evaluate the effectiveness of the early habilitation complex in premature infants with a perinatal brain damage when transferring to the stage III of rehabilitation.
 MATERIALS AND METHODS: The study included 86 patients born with a very low and extremely low body weight, who had a hypoxic-ischemic or hemorrhagic brain damage and were observed at the Children's Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan during the first three years of life. A comparative analysis of the development and functional outcomes of the disease was carried out for children of two groups. The first group, when transferred to the stage III of rehabilitation, was assigned a complex of early sensorimotor habilitation, developed on the basis of N.A. Bernsteins concept to be carried out at home for three months after an appropriate training. The second group was not prescribed such a complex.
 RESULTS: The effect of the early sensorimotor rehabilitation complex on the functional (motor, speech and cognitive) outcomes in prematurely born patients was evaluated and described. In the first group with an assigned complex of sensorimotor exercises, despite the absence of a significant effect by the age of 6 months, it was found by the age of one and a half years, that the average indices of the development of large (p=0.022) and fine motor skills (p=0.023), expressive speech (p=0.006) and cognitive functions (p=0.040) were higher, while, by the age of three years, the differences in speech (p=0.001) and cognitive (p=0.001) outcomes retained their statistical significance compared to the development indicators in children who did not receive the same early habilitation complex.
 CONCLUSION: It was found that premature infants who received the early habilitation complex had better speech and cognitive outcomes by the age of three, compared to patients who did not receive the complex. The significance of the positive influence on the ontogenesis of motor skills persists during the second year of life.

Diagnostic significance of serum erythropoietin as a marker of perinatal brain damage in premature newborns with very low birth weight

The search for promising markers of brain damage in premature newborns is important for the development and optimization of individual diagnostic and therapeutic approaches to neuroprotection in neonatology. Objective: to evaluate the diagnostic significance of serum erythropoietin (sEPO) on the 1st day of life as a marker of perinatal brain damage in premature infants with very low birth weight (VLBW). The study protocol was approved by the Biomedical Research Ethics Committee (Minutes No.12 of 17 November 2016) and the Scientific Council (Minutes No.19 of 29 November 2016) of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after the Academician V.I. Kulakov of Ministry of Healthcare of the Russian Federation. Written informed consent to the patients' participation in the study was obtained from their parents. The study included 47 premature infants with VLBW born in 2018 at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Healthcare of the Russian Federation. In these patients, sEPO was determined on the 1st day of life. Depending on the level of sEPO, infants were divided into 3 groups: group 1 – premature infants with VLBW with a low sEPO level on the 1st day of life (< 20 IU/L, n = 24); group 2 – premature infants with VLBW with an average sEPO level of 20–39 IU/L (reference values) (n = 14) – control group; group 3 – premature infants with VLBW with an elevated sEPO level (≥ 40 IU/L, n = 9). We determined the frequency of brain damage, including intraventricular hemorrhages (IVH) and periventricular leukomalacia. sEPO was not correlated with gestational age. In group 1, IVH ≤ Grade II was observed in 4/24 (16.7%) infants; in group 2, IVH ≤ Grade II was observed in 3/14 (21.4%) infants, and 1/14 (7.1%) infant had IVH Grade III; in group 3, IVH ≤ Grade II was noted in 1/9 (11.1%) infant, and IVH Grade III – in 1/9 (11.1%) infant, p > 0.05. There were no cases of periventricular leukomalacia. A high sEPO level on the 1st day of life in premature infants with VLBW was not associated with an increased risk of perinatal brain damage. The clinical value and practical significance of the determination of sEPO on the 1st day of life as a marker of perinatal brain damage in premature infants with VLBW did not demonstrate any benefits. Further studies are required to assess the role of sEPO in predicting neonatal outcomes.

Effectiveness of Polyphenols on Perinatal Brain Damage: A Systematic Review of Preclinical Studies.

Polyphenol supplementation during early life has been associated with a reduction of oxidative stress and neuroinflammation in diseases caused by oxygen deprivation, including cerebral palsy, hydrocephaly, blindness, and deafness. Evidence has shown that perinatal polyphenols supplementation may alleviate brain injury in embryonic, fetal, neonatal, and offspring subjects, highlighting its role in modulating adaptative responses involving phenotypical plasticity. Therefore, it is reasonable to infer that the administration of polyphenols during the early life period may be considered a potential intervention to modulate the inflammatory and oxidative stress that cause impairments in locomotion, cognitive, and behavioral functions throughout life. The beneficial effects of polyphenols are linked with several mechanisms, including epigenetic alterations, involving the AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and phosphoinositide 3-kinase (PI3K) pathways. To highlight these new perspectives, the objective of this systematic review was to summarize the understanding emerging from preclinical studies about polyphenol supplementation, its capacity to minimize brain injury caused by hypoxia-ischemia in terms of morphological, inflammatory, and oxidative parameters and its repercussions for motor and behavioral functions.

The Oxygen and Glucose Deprivation of Immature Cells of the Nervous System Exerts Distinct Effects on Mitochondria, Mitophagy, and Autophagy, Depending on the Cells’ Differentiation Stage

Perinatal brain damage, one of the most common causes of lifelong impairment, is predominantly caused by a lack of oxygen and glucose during early development. These conditions, in turn, affect cells of the nervous tissue through various stages of their maturation. To quantify the influence of these factors on cell differentiation and mitochondrial parameters, we exposed neural cell precursors to oxygen and glucose deprivation (OGD) during three stages of their differentiation: day 1, day 7, and day 14 (D1, D7, and D14, respectively). The obtained results show that OGD slows down cellular differentiation and causes cell death. Regardless of the level of cell maturity, the overall area of the mitochondria, their length, and the branching of their filaments decreased uniformly when exposed to OGD-related stress. Moreover, the cells in all stages of differentiation exhibited an increase in ROS production, hyperpolarization of the mitochondrial membrane, and autophagy. Interestingly, day 7 was the only stage in which a significant increase in mitochondrial fission, along with measurable instances of mitophagy, were detected. Taken together, the results of this study suggest that, apart from common reactions to a sudden lack of oxygen and glucose, cells in specific stages of neural differentiation can also exhibit increased preferences for mitochondrial fission and mitophagy. Such findings could play a role in guiding the future development of novel therapeutic approaches targeting perinatal brain damage during specific stages of nervous system development.

Indicators of The Dynamics of Perinatal Hypoxia in Newborns

A comprehensive study of clinical and neurological changes in newborns in the relationship between the nature and duration of perinatal hypoxia (PH) was carried out. To assess the state of clinical and neurological changes, 52 newborns who underwent perinatal hypoxia were examined. The anamnesis of mothers who underwent combined perinatal hypoxia was significantly worse than in the group of children with acute asphyxia. Anemia, acute respiratory viral infection (ARVI), preeclampsia, fetoplacental insufficiency (FPI), the duration of the anhydrous interval, pathological childbirth served as predisposing factors contributing to the development of perinatal hypoxia. For an objective quantitative assessment of the dynamics of the neurological status of newborns, the “Scoring of the severity of perinatal encephalopathy”, developed at the Research Institute of Pediatrics of the Russian Academy of Medical Sciences by A.A. Stepanov (1998), was used. It is based on an integrated assessment of motor activity, innate reflexes and behavioral reactions of newborns, taking into account the quantitative characteristics of each newborn. The data obtained indicate that the duration of hypoxia, the state of health, the course of pregnancy and childbirth in the mother determine the severity of perinatal brain damage and affect the severity of clinical and neurological patterns. Combined perinatal hypoxia leads to deeper brain disorders and contributes to the formation of two or more syndromes in one child.

Development of BOLD Response to Motion in Human Infants.

Behavioral studies suggest that motion perception is rudimentary at birth and matures steadily over the first few years. We demonstrated previously that the major cortical associative areas serving motion processing, like middle temporal complex (MT+), visual cortex area 6 (V6), and PIVC in adults, show selective responses to coherent flow in 8-week-old infants. Here, we study the BOLD response to the same motion stimuli in 5-week-old infants (four females and four males) and compare the maturation between these two ages. The results show that MT+ and PIVC areas show a similar motion response at 5 and 8 weeks, whereas response in the V6 shows a reduced BOLD response to motion at 5 weeks, and cuneus associative areas are not identifiable at this young age. In infants and in adults, primary visual cortex (V1) does not show a selectivity for coherent motion but shows very fast development between 5 and 8 weeks of age in response to the appearance of motion stimuli. Resting-state correlations demonstrate adult-like functional connectivity between the motion-selective associative areas but not between primary cortex and temporo-occipital and posterior-insular cortices. The results are consistent with a differential developmental trajectory of motion area respect to other occipital regions, probably reflecting also a different development trajectory of the central and peripheral visual field.SIGNIFICANCE STATEMENT How the cortical visual areas attain the specialization that we observed in human adults in the first few months of life is unknown. However, this knowledge is crucial to understanding the consequence of perinatal brain damage and its outcome. Here, we show that motion selective areas are already functioning well in 5-week-old infants with greater responses for detecting coherent motion over random motion, suggesting that very little experience is needed to attain motion selectivity.

FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress.

The impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined. Lipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying. Upon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs. Our findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Perinatal brain damage- what the obstetrician needs to know.

Perinatal brain damage is still one of the leading contributors to perinatal death and postnatal disability worldwide. However, the term perinatal brain damage encompasses very different aetiological entities that result in an insult to the developing brain and does not differentiate between the onset, cause and severity of this insult. Hypoxic-ischemic encephalopathy (HIE), intraventricular haemorrhage, periventricular leukomalacia and perinatal stroke are often listed as the major aetiologies of perinatal brain damage. They differ by type and timing of injury, neuropathological and imaging findings and their clinical picture. Along the timeline of neurodevelopment in utero, there appears to be a specific "window of vulnerability" for each type of injury, but clinical overlap does exist. In the past, peripartum acute hypoxia was believed to be the major, if not the only, cause of perinatal brain damage, but intrauterine inflammation, prematurity, chronic hypoxia/growth retardation and genetic abnormalities appear to be at least equally important contributors.

Brain Damage in Preterm and Full-Term Neonates: Serum Biomarkers for the Early Diagnosis and Intervention

The Brain is vulnerable to numerous insults that can act in the pre-, peri-, and post-natal period. There is growing evidence that demonstrate how oxidative stress (OS) could represent the final common pathway of all these insults. Fetuses and newborns are particularly vulnerable to OS due to their inability to active the antioxidant defenses. Specific molecules involved in OS could be measured in biologic fluids as early biomarkers of neonatal brain injury with an essential role in neuroprotection. Although S-100B seems to be the most studied biomarker, its use in clinical practice is limited by the complexity of brain damage etiopathogenesis and the time of blood sampling in relation to the brain injury. Reliable early specific serum markers are currently lacking in clinical practice. It is essential to determine if there are specific biomarkers that can help caregivers to monitor the progression of the disease in order to active an early neuroprotective strategy. We aimed to describe, in an educational review, the actual evidence on serum biomarkers for the early identification of newborns at a high risk of neurological diseases. To move the biomarkers from the bench to the bedside, the assays must be not only be of a high sensitivity but suitable for the very rapid processing and return of the results for the clinical practice to act on. For the best prognosis, more studies should focus on the association of these biomarkers to the type and severity of perinatal brain damage.

Кардиальная дисфункция у плода: влияние на исходы в перинатальном периоде у недоношенных детей

Objective. To study the importance of fetal cardiac dysfunction in the genesis of perinatal brain damage in premature newborns. Patients and methods. A prospective cohort comparative study included 59 preterm infants with gestational age from 26 to 32 weeks and body weight from 590 to 1990. Newborns were divided into 2 groups at the 1st month of life: the main group (n = 38), which included children with structural brain lesions, and the control group (n = 21) with favorable neurological outcomes. There were no statistically significant differences in either body weight or gestational age between the groups. At the antenatal stage, all underwent ultrasound doppler sonography of uteroplacental blood flow, and the cerebral-placental ratio was calculated. The following markers were determined at the 1st day of postnatal life: levels of lactate, cerebral natriuretic propeptide and soluble type 2 tumor suppressor in the umbilical cord blood of a newborn (enzyme-linked immunosorbent assay); neurosonography of the brain with the determination of blood flow and doppler echocardiography. Neurological outcomes were assessed after 1 month of life after the control neurosonography of brain. The data are presented in the form of median, maximum and minimum values – Me [min; max]. The obtained data were processed using the Statistica 6.1 program. The Mann–Whitney and Fisher χ2 criteria with the Yeats correction were calculated. The differences were considered significant at p equal to 0.05. Results. The pulsation index in the umbilical cord artery was significantly higher (1.270 [1.120; 1.320] versus 0.984 [0.798; 1.120]) in the fetuses of the main group, Its values indicating severe disorders of fetal-placental hemodynamics were more often recorded (in 15–39.5% cases versus 4–19.1%). The significant decrease in the cerebroplacental ratio was significantly more often recorded (in 18–47.4% cases versus 2–9.5%) in the same group. The levels of lactate (3.6 [2.1; 5.2] versus 2.25 [1.3; 3.05] mmol/L) and cerebral natriuretic propeptide (243.2 [84.17; 1385] versus 111.6 [64.8; 2903] pg/ml, respectively) were significantly elevated in the umbilical cord blood, in newborns of the main group. The newborns of the main group had significantly lower levels of systolic, diastolic and mean blood pressure, at the first hours of life. They also had a reduced level of blood flow in the superior vena cava (Me = 65 ml/kg/min; 9 (23.7%) children had a periventricular leukomalacia, 18 (47.4%) – intraventricular hemorrhages of the II–III degree, and 2 (5.3%) had a stroke. Conclusion. It is very important to pay attention of pediatricians-neonatologists to the antenatal period. Treating the fetus as a patient, early assessment of hemodynamics and timely diagnosis of fetal cardiac dysfunction and other developmental abnormalities will reduce the incidence of disabling perinatal diseases and the level of perinatal mortality. Key words: antenatal diagnosis, umbilical cord blood lactate, prematurity, perinatal brain damage, placental insufficiency, fetal cardiac dysfunction

Магнитно-резонансная томография при гипоксически-ишемических поражениях мозга у новорожденных: эволюция взглядов и перспективы развития

Aim: Based on the study of a large amount of available information, to create an idea of the use of magnetic resonance imaging (MRI) in hypoxic-ischemic brain lesions in newborns, to present the available research algorithms, classifications, the scope of the technique and its information content in the named pathology. Key points. MRI has long been a common practice in a neuropediatric hospital. To date, examination by this method has absolute significance in the diagnosis of perinatal hypoxic-ischemic brain lesions. In addition, MRI data help to objectify the effectiveness of therapeutic interventions and predict the further development of a child with perinatal brain damage. There are several classifications of MRI changes in hypoxic-ischemic brain lesions in newborns. These classifications have varying degrees of sensitivity to the initial hypoxic-ischemic changes in the child's brain, however, allow us to roughly represent the process of their formation in dynamics in the morphological aspect according to the scheme “periventricular white matter — subcortical ganglia and thalamus — subcortical structures of the hemispheres and cerebral cortex”. Thus, the target structures of hypoxic ischemic lesions allow us to identify its main patterns: lesions of neuronal structures, leukopathy, and their combination. Conclusion. Studies of MRI phenomena as predictors of developmental pathology show that an increase in detail increases the accuracy of the prognosis. However, the available data do not currently allow us to form a spatial model for the development of hypoxic-ischemic changes in the brain of a newborn. It seems necessary to create such a model depending on the time and intensity of the impact of the ischemic process. This will allow developing a morphological and pathophysiological classification of perinatal encephalopathies. Keywords: magnetic resonance imaging, hypoxia-ischemia, hypoxic-ischemic brain damage, newborns, cerebral palsy.

From Fetal to Neonatal Neuroimaging in TORCH Infections: A Pictorial Review.

Congenital infections represent a challenging and varied clinical scenario in which the brain is frequently involved. Therefore, fetal and neonatal neuro-imaging plays a pivotal role in reaching an accurate diagnosis and in predicting the clinical outcome. Congenital brain infections are characterized by various clinical manifestations, ranging from nearly asymptomatic diseases to syndromic disorders, often associated with severe neurological symptoms. Brain damage results from the complex interaction among the infectious agent, its specific cellular tropism, and the stage of development of the central nervous system at the time of the maternal infection. Therefore, neuroradiological findings vary widely and are the result of complex events. An early detection is essential to establishing a proper diagnosis and prognosis, and to guarantee an optimal and prompt therapeutic perinatal management. Recently, emerging infective agents (i.e., Zika virus and SARS-CoV2) have been related to possible pre- and perinatal brain damage, thus expanding the spectrum of congenital brain infections. The purpose of this pictorial review is to provide an overview of the current knowledge on fetal and neonatal brain neuroimaging patterns in congenital brain infections used in clinical practice.

Season of birth and vulnerability to the pathology of Alzheimer's disease: an in vivo positron emission tomography study.

This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer's disease (AD) pathology in the elderly. We analysed datasets from the Alzheimer's Disease Neuroimaging Initiative, which included the data for 234 cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) (n=114) and AD dementia (n=38). As an index of amyloid β (Aβ)/tau accumulation, the 18 F-AV-45- and 18 F-AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. In addition, a multiple linear regression analysis was performed to determine whether the season of birth was a predictor of 18 F-AV-45 and/or 18 F-AV-1451 SUVRs, for which a difference was observed. Seasonal birth difference was a good predictor of 18 F-AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower 18 F-AV-1451 SUVRs than those with a spring-to-summer birth in both the CN and MCI/AD groups, after correcting for the effect of age, sex, years of education, and Alzheimer's Disease Assessment Scale cognitive subscale score, that could possibly affect tau accumulation. Participants with a fall-to-winter birth showed less tau accumulation than those with a spring-to-summer birth after accounting for the factors that could affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model.

Hypoxic-ischemic encephalopathy (HIE) mainly affects preterm and term newborns, leading to a high risk of brain damage. Coexisting infection/inflammation and birth asphyxia are key factors associated with intracerebral increase of proinflammatory cytokines linked to HIE. Microglia are key mediators of inflammation during perinatal brain injury, characterized by their phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with pro- and anti-inflammatory cytokines as well as the nucleotide-binding domain, leucine-rich repeat protein (NLRP-3) inflammasome from microglia cells. For this purpose, we used our established neonatal rat model of inflammation-sensitized hypoxic-ischemic (HI) brain injury in seven-day-old rats. We assessed gene expression profiles of 11 cytokines and for NLRP-3 using real-time PCR from sorted CD11b/c microglia of brain samples at different time points (3.5 h after LPS injection and 0, 5, 24, 48, and 72 hours post HI) following different treatments: vehicle, E. coli lipopolysaccharide (LPS), vehicle/HI, and LPS/HI. Our results showed that microglia are early key mediators of the inflammatory response and exacerbate the inflammatory response following HI, polarizing into a predominant proinflammatory M1 phenotype in the early hours post HI. The brains only exposed to HI showed a delay in the expression of proinflammatory cytokines. We also demonstrated that NLRP-3 plays a role in the inflammatory resolution with a high expression after HI insult. The combination of both, a preinfection/inflammation condition and hypoxia-ischemia, resulted in a higher proinflammatory cytokine storm, highlighting the significant contribution of acute inflammation sensitizing prior to a hypoxic insult on the severity of perinatal brain damage.

Extreme prematurity: Risk and resiliency

Individuals born extremely preterm (before 28 weeks of gestation) comprise only about 0.7% of births in the United States and an even lower proportion in other high resource countries. However, these individuals account for a disproportionate number of children with cerebral palsy, intellectual deficit, autism spectrum disorder, attention deficit hyperactivity disorder, and epilepsy. This review describes two large multiple center cohorts comprised of individuals born extremely preterm: the EPICURE cohort, recruited 1995 in the United Kingdom and the Republic of Ireland, and the Extremely Low Gestational Age Newborn (ELGAN), recruited 2002-2004 in five states in the United States. The primary focus of these studies has been neurodevelopmental disorders, but also of interest are growth, respiratory illness, and parent- and self-reported global health and well-being. Both of these studies indicate that among individuals born extremely preterm the risks of most neurodevelopmental disorders are increased. Early life factors that contribute to this risk include perinatal brain damage, some of which can be identified using neonatal head ultrasound, bronchopulmonary dysplasia, and neonatal systemic inflammation. Prenatal factors, particularly the family's socioeconomic position, also appear to contribute to risk. For most adverse outcomes, the risk is higher in males. Young adults born extremely preterm who have neurodevelopmental impairment, as compared to those without such impairment, rate their quality of life lower. However, young adults born extremely preterm who do not have neurodevelopmental impairments rate their quality of life as being similar to that of young adults born at term. Finally, we summarize the current state of interventions designed to improve the life course of extremely premature infants, with particular focus on efforts to prevent premature birth and on postnatal efforts to prevent adverse neurodevelopmental outcomes.