Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-ß clearance in animal models of Alzheimer's disease.

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.

Neurodevelopment in Term Infants with Normal Birthweight following Postnatal Systemic Steroid Exposure.

INTRODUCTION: Studies investigating the potential impact of systemic steroid exposure during early infancy on neurological development in full-term infants with normal birth weight are lacking. METHODS: This population-based administrative cohort study used data of national health insurance and a health-screening program for infants and children and included full-term infants who were born in Korea between 2008 and 2012 with normal birth weight and did not have any specific perinatal or neurodevelopmental diseases. The prescription of systemic steroids within the first 3 months of age was mainly considered. The neurological development of children was assessed using the Korean Development Screening Test (K-DST) at 6 years of age. To balance the baseline characteristics of the control and exposed groups, stabilized inverse probability of treatment weighting with trimming was performed in the main cohort. Ordinal logistic regression was used to assess the association between systemic steroid exposure and unfavorable results in the K-DST. RESULTS: The control and exposure groups had 246,168 and 5,083 children, respectively. The K-DST suggested unfavorable results in 8.1% and 8.6% children in the control and exposure groups, respectively (weighted odds ratio, 95% confidence interval, 1.03, 0.93-1.14). When each domain of the K-DST was considered separately, the risk of unfavorable results in the exposed group was not significantly different from that in the control group. CONCLUSIONS: No significant association was observed between exposure to systemic steroids during early infancy and neurodevelopmental impairment at 6 years of age.

The impact of the COVID-19 pandemic era on children with primary headache: a questionnaire survey study and literature review.

Background: The coronavirus disease (COVID-19) pandemic has resulted in individual isolation and secondary problems, especially in children. Research on the effect of the social isolation on children with primary headache is limited. This study aimed at exploring the effects of environmental changes caused by COVID-19 on headache in children. Methods: This cross-sectional survey study enrolled school-aged children (age, 8-16 years) with headache who were able to complete the questionnaire from a Pediatric Headache Clinic between January 2021 and December 2022. Headache diaries for all patients were in their medical records and two questionnaire responses were requested at a 3-month interval. The questionnaires included headache type, frequency, previous medical conditions, family history, Pediatric Migraine Disability Assessment scores (PedMIDAS) scores, changes in daily life after COVID-19, and factors that aggravated headaches associated with social distancing. Results: We identified 35 patients who were diagnosed with primary headache and continued to visit our outpatient clinic for at least 3 months. Among them, 33 (15 males and 18 females) patients responded to the first survey. The average age (±SD) of patients was 12.5 ± 1.9 years. PedMIDAS scores were not affected by the COVID-19 infection history. Prolonged use of masks and increased use of digital devices were reported as the most common factors that aggravated headache during the pandemic era. Conclusion: COVID-19 did not affect in worsening primary headache in children. However, the pandemic can introduce various changes in daily life, which in turn can affect the management of headache. By gathering feedback regarding the thoughts of the patients on the impact of the current pandemic environment, patient counseling on the precautions and management can be conducted in advance in the case of repeated lockdown in the future.

PINK1 siRNA-loaded poly(lactic-co-glycolic acid) nanoparticles provide neuroprotection in a mouse model of photothrombosis-induced ischemic stroke.

PTEN-induced kinase 1 (PINK1) is a well-known critical marker in the pathway for mitophagy regulation as well as mitochondrial dysfunction. Evidence suggests that mitochondrial dynamics and mitophagy flux play an important role in the development of brain damage from stroke pathogenesis. In this study, we propose a treatment strategy using nanoparticles that can control PINK1. We used a murine photothrombotic ischemic stroke (PTS) model in which clogging of blood vessels is induced with Rose Bengal (RB) to cause brain damage. We targeted PINK1 with poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles loaded with PINK1 siRNA (PINK1 NPs). After characterizing siRNA loading in the nanoparticles, we assessed the efficacy of PINK1 NPs in mice with PTS using immunohistochemistry, 1% 2,3,5-triphenyltetrazolium chloride staining, measurement of motor dysfunction, and Western blot. PINK1 was highly expressed in microglia 24 h after PTS induction. PINK1 siRNA treatment increased phagocytic activity, migration, and expression of an anti-inflammatory state in microglia. In addition, the PLGA nanoparticles were selectively taken up by microglia and specifically regulated PINK1 expression in those cells. Treatment with PINK1 NPs prior to stroke induction reduced expression of mitophagy-inducing factors, infarct volume, and motor dysfunction in mice with photothrombotic ischemia. Experiments with PINK1-knockout mice and microglia depletion with PLX3397 confirmed a decrease in stroke-induced infarct volume and behavioral dysfunction. Application of nanoparticles for PINK1 inhibition attenuates RB-induced photothrombotic ischemic injury by inhibiting microglia responses, suggesting that a nanomedical approach targeting the PINK1 pathway may provide a therapeutic avenue for stroke treatment.

Neurodevelopment at 6 years of age in children with atopic dermatitis.

BACKGROUND: Few studies have reported an association between atopic dermatitis and cognitive impairment in children. Therefore, we evaluated the association between atopic dermatitis (AD) and neurodevelopmental dysfunction in children. METHODS: We analyzed 2,395,966 children born between 2008 and 2012 in Korea. All data were acquired from the databases of the Korean National Health Insurance System. AD was defined as five or more diagnoses before age 24 months. The outcome was suspected neurodevelopmental dysfunction in the gross motor skill, fine motor skill, cognition, language, sociality, and self-care domains of the Korean Developmental Screening Test for Infants and Children at age 6 years. The positive control outcome was defined as attention deficit hyperactive disorder (ADHD). The associations were assessed using ordinal logistic regression, adjusting for asthma and allergic rhinitis. RESULTS: Among the eligible children, 89,452 and 30,557 were allocated to the control and AD groups, respectively. In the weighted data, the AD group showed a higher risk of suspected neurodevelopmental dysfunction in the total score (weighted adjusted odds ratio [95% CI] 1.10 [1.05-1.16]), gross motor skills (1.14 [1.04-1.25]), and fine motor skills (1.15 [1.06-1.25]) than the control group. The AD with steroids or hospitalization groups showed an increased risk of suspected neurodevelopmental dysfunction. In addition, the AD group showed a significant association with mental retardation, psychological development disorder, and behavioral and emotional disorders as well as ADHD. CONCLUSIONS: AD before age 2 years may be associated with an increased risk of neurodevelopmental dysfunction including gross and fine motor skills in the young childhood period.

Perampanel Reduces Brain Damage via Induction of M2 Microglia in a Neonatal Rat Stroke Model.

Purpose: Ischemic stroke is a leading cause of death and disability worldwide. Additionally, neonatal ischemia is a common cause of neonatal brain injury, resulting in cerebral palsy with subsequent learning disabilities and epilepsy. However, there is currently a lack of effective treatments available for patients with perinatal ischemic stroke. In this study, we investigated the effect of perampanel (PER)-loaded poly lactic-co-glycolic acid (PLGA) by targeting microglia in perinatal stroke. Methods: After formation of focal ischemic stroke by photothrombosis in P7 rats, PER-loaded PLGA was injected intrathecally. Proinflammatory markers (TNF-α, IL-1ß, IL-6, COX2, and iNOS) and M2 polarization markers (Ym1 and Arg1) were evaluated. We investigated whether PER increased M2 microglial polarization in vitro. Results: PER-loaded PLGA nanoparticles decreased the pro-inflammatory cytokines compared to the control group. Furthermore, they increased M2 polarization. Conclusion: PER-loaded PLGA nanoparticles decreased the size of the infarct and increased motor function in a perinatal ischemic stroke rat model. Pro-inflammatory cytokines were also reduced compared to the control group. Finally, this development of a drug delivery system targeting microglia confirms the potential to develop new therapeutic agents for perinatal ischemic stroke.

Transition from pediatric to adult care among patients with epilepsy: Cross-sectional surveys of experts and patients in Korea.

OBJECTIVES: Many pediatric patients with epilepsy require treatment beyond the pediatric age. These patients require transition to an adult epilepsy center. Currently, many centers worldwide run epilepsy transition programs. However, a standardized protocol does not exist in Korea. The basic data required to establish a transition program are also unavailable. We aimed to assess the status and perceptions of patients and epilepsy care providers on transition. METHODS: To assess the status of epilepsy transition, we retrospectively collected data from patients with epilepsy older than 18 years who visited our pediatric epilepsy clinic between March 1990 and July 2019. To assess the perception of transition, we surveyed patients, parents, pediatric neurologists (PN), and adult epileptologists (AE). RESULTS: In a retrospective chart review, 39 of 267 (14.6%) patients visited the adult epilepsy clinic after consulting a pediatric neurologist, and three patients returned to the pediatric center. The average patient age at transition was 23.29 ± 5.10 years. A total of 94 patients or their guardians and 100 experts participated in the survey. About half of the patients or guardians (44.7%) did not want to transition and emotional dependence was the commonest reason. Most patients (52.1%) thought that the appropriate age of transition was above 20 years. PNs had greater concerns about patients' compliance than AEs. Regarding the age of transition, AEs believed that a younger age (18 years) was more appropriate than PNs (20 years). SIGNIFICANCE: This study describes difficulties in the transition from pediatric to adult epilepsy centers without appropriate support. There were differences in perspectives among patients, parents, and adult and pediatric epilepsy care providers. This study can assist in creating a standardized protocol in Korea.

Preventive Effects of Neuroprotective Agents in a Neonatal Rat of Photothrombotic Stroke Model.

Neonatal ischemic stroke has a higher incidence than childhood stroke. Seizures are the first sign for the need for clinical assessment in neonates, but many questions remain regarding treatments and follow-up modalities. In the absence of a known pathophysiological mechanism, only supportive care is currently provided. Stroke-induced microglia activation and neuroinflammation are believed to play a central role in the pathological progression of neonatal ischemic stroke. We induced a photothrombotic infarction with Rose Bengal in neonatal rats to investigate the effects of pre- and post-treatment with Aspirin (ASA), Clopidogrel (Clop), and Coenzyme Q10 (CoQ10), which are known for their neuroprotective effects in adult stroke. Pre-stroke medication ameliorates cerebral ischemic injury and reduces infarct volume by reducing microglia activation, cellular reactive oxygen species (ROS) production, and cytokine release. Post-stroke administration of ASA, Clop, and CoQ10 increased motor function and reduced the volume of infarction, and the statistical evidence was stronger than that seen in the pre-stroke treatment. In this study, we demonstrated that ASA, Clop, and CoQ10 treatment before and after the stroke reduced the scope of stroke lesions and increased behavioral activity. It suggests that ASA, Clop, and CoQ10 medication could significantly have neuroprotective effects in the neonates who have suffered strokes.

Behavioral and intelligence outcome in 8- to 16-year-old born small for gestational age.

PURPOSE: We investigated behavioral problems, attention problems, and cognitive function in children and adolescents born small for gestational age (SGA). METHODS: Forty-six SGA children born at term and 46 appropriate for gestational age (AGA) children born at term were compared. Psychiatric symptoms were examined with reference to the Korean-Child Behavior Checklist, Korean-Youth Self Report, and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). Cognitive function was estimated using the Wechsler Intelligence Scale. Sociodemographic data were recorded from interviews. RESULTS: SGA children had high scores on delinquent behavior, aggressive behavior, and the externalizing scale, and they also showed a propensity for anxiety and depression. The SGA group had a higher mean ADHD-RS score than the AGA group (10.52±8.10 vs.9.93±7.23), but the difference was not significant. The SGA group had a significantly lower verbal intelligence quotient (IQ) than the AGA group, but the mean scores of both groups were within normal limits. CONCLUSION: This study indicates marked behavioral problems, such as delinquency, aggressiveness, and anxiety and depression, as well as low verbal IQ in the SGA group than in the AGA group. Even in cases in which these symptoms are not severe, early detection and proper treatment can help these children adapt to society.

Screening for depression and anxiety disorder in children with headache.

PURPOSE: The purpose of this study was to investigate the importance of initial screening tests for depression and anxiety disorders in children with headache. In addition, this study evaluated whether the Children's Depression Inventory (CDI) and Revised Children's Manifest Anxiety Scale (RCMAS) are suitable for screening symptoms of depression and anxiety. METHODS: A retrospective chart review was conducted of 720 children aged 7-17 years who had visited a pediatric neurology clinic for headaches and were referred to a pediatric psychiatric clinic for psychiatric symptoms from January 2010 to December 2011. All patients completed the CDI and RCMAS. Among them, charts of patients with clinically significant total scores (cutoff>15) for psychiatric symptoms, as defined by the CDI and RCMAS scoring scales, were reviewed. RESULTS: Nineteen patients had headaches and clinically significant total scores for psychiatric symptoms. The mean age at headache diagnosis was 11.7 years, and 57% were male. Mean duration of headache was 11.5 months. Two point eight percent of the patients were diagnosed with psychiatric disorders including major depression (1.7%), generalized anxiety disorder (1.1%), and bipolar disorder (0.1%). Four patients (0.6%) were diagnosed with attention deficit/hyperactivity disorder (ADHD). Total mean CDI and RCMAS scores of patients referred to the psychiatric clinic were 18.8 and 22.2, respectively. There was no correlation between CDI or RCMAS total scores and headache frequency, duration, or severity. CONCLUSION: We recommend that all patients with headache should be screened for depression and anxiety by CDI and RCMAS scores.

Psychological problems and clinical outcomes of children with psychogenic non-epileptic seizures.

PURPOSE: Our purpose was to investigate psychological problems and clinical outcomes in children with psychogenic non-epileptic seizures (PNES). MATERIALS AND METHODS: We retrospectively reviewed the data of 25 patients who were diagnosed with PNES between 2006 and 2012. RESULTS: Twenty-five children with PNES, aged 8 to 19 years (mean 13.82), were referred to psychiatrists for psychiatric assessment. On their initial visit, 72% of patients had comorbid psychological problems, including depression, anxiety, conduct disorder, adjustment disorder, Attention Deficit Hyperactivity Disorder, schizophrenia, and bipolar disorder. Among these, depression was the most frequent (36%). Predisposing and triggering factors included familial distress (40%), social distress (24%), and specific events (20%). The following treatment was advised based on the results of the initial psychological assessment: 3 patients regularly visited psychiatric clinic to assess their clinical status without treatment, nine underwent psychotherapy, and 13 received a combination of psychotherapy and psychopharmacological therapy. At the mean follow-up of 31.5 months after diagnosis, 20 patients (80%) were event-free at follow-up, three (12%) showed reduced frequency, and two (8%) experienced persistent symptoms. CONCLUSION: The outcomes of PNES in children are much better than those in adults, despite a high rate of psychological comorbidities.

Wernicke's encephalopathy in a child with high dose thiamine therapy.

Wernicke's encephalopathy is an acute neurological disorder characterized by mental confusion, oculomotor dysfunction, and ataxia. It has been reported in individuals with alcohol dependence, hyperemesis gravidarum, and prolonged parenteral nutrition without vitamin supplementation. Here we present the case of a 13-year-old male patient with neuroblastoma and a history of poor oral intake and nausea for 3 months. After admission, he showed gait disturbances, nystagmus, and excessive dizziness; his mental state, however, indicated he was alert, which did not fit the classical triad of Wernicke's encephalopathy. A diagnosis of Wernicke's encephalopathy was made only after brain magnetic resonance imaging and serum thiamine level analyses were performed. The patient's symptoms remained after 5 days of treatment with 100-mg thiamine once daily; thus, we increased the dosage to 500 mg 3 times daily, 1,500 mg per day. His symptoms then improved after 20 days of replacement therapy. This case report describes a pediatric patient who was promptly diagnosed with Wernicke's encephalopathy, despite only 2 suspicious symptoms, and who completely recovered after high doses of thiamine were given intravenously.

Clinical outcomes of cerebral infarctions in neonates.

Cerebral infarctions are uncommon in neonates. However, they should be considered among causes of neonatal seizures. We describe seven neonates with cerebral infarctions. Clinical presentations, perinatal history, perinatal risk factors, cranial magnetic resonance imaging and electroencephalography findings, thrombophilic factors, and clinical outcomes were reviewed. Six patients manifested seizures, whereas one exhibited cyanosis. Six neonates manifested left middle cerebral artery infarctions, and one exhibited a borderzone infarction between the anterior cerebral and middle cerebral arteries. Electroencephalograms indicated epileptiform discharges on the left hemisphere in three neonates with left middle cerebral artery territory infarctions, and epileptiform discharges on both hemispheres in one patient. At most recent follow-up visit, five patients had achieved normal development, whereas one exhibited right hemiparesis and aphasia, and another manifested toe-in gait. These findings may help predict neurodevelopmental outcomes in neonates with cerebral infarctions.