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Summary: Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies. : Gupta and colleagues show that transplantation with allogeneic central nervous system stem cells can be performed safely in humans with minimal morbidity. Immunologic data, however, show that neural stem cells can elicit an immune response following transplantation, suggesting the importance of monitoring immunologic parameters. Keywords: Pelizaeus-Merzbacher disease, neural stem cells, leukodystrophy, myelin, oligodendrocyte, transplantation, pediatric, neurodegenerative disease

Background Impairments in fetal oxygen delivery have been implicated in brain dysmaturation seen in congenital heart disease (CHD), suggesting a role for in utero transplacental oxygen therapy. We applied a novel imaging tool to quantify fetal cerebral oxygenation by measuring T2* decay. We compared T2* in fetuses with CHD with controls with a focus on cardiovascular physiologies (transposition or left‐sided obstruction) and described the effect of brief administration of maternal hyperoxia on T2* decay. Methods and Results This is a prospective study performed on pregnant mothers with a prenatal diagnosis of CHD compared with controls in the third trimester. Participants underwent a fetal brain magnetic resonance imaging scan including a T2* sequence before and after maternal hyperoxia. Comparisons were made between control and CHD fetuses including subgroup analyses by cardiac physiology. Forty‐four mothers (CHD=24, control=20) participated. Fetuses with CHD had lower total brain volume (238.2 mm3, 95% CI, 224.6–251.9) compared with controls (262.4 mm3, 95% CI, 245.0–279.8, P=0.04). T2* decay time was faster in CHD compared with controls (beta=−14.4, 95% CI, −23.3 to −5.6, P=0.002). The magnitude of change in T2* with maternal hyperoxia was higher in fetuses with transposition compared with controls (increase of 8.4 ms, 95% CI, 0.5–14.3, P=0.01), though between‐subject variability was noted. Conclusions Cerebral tissue oxygenation is lower in fetuses with complex CHD. There was variability in the response to maternal hyperoxia by CHD subgroup that can be tested in future larger studies. Cardiovascular physiology is critical when designing neuroprotective clinical trials in the fetus with CHD.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a “two-hit” model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Global patterns of brain injury correlate with motor, cognitive, and language outcomes in survivors of neonatal encephalopathy (NE). However, it is still unclear whether local changes in brain structure predict specific deficits. We therefore examined whether differences in brain structure at 6months of age are associated with neurodevelopmental outcomes in this population. We enrolled 32 children with NE, performed structural brain MR imaging at 6months, and assessed neurodevelopmental outcomes at 30months. All subjects underwent T1-weighted imaging at 3T using a 3D IR-SPGR sequence. Images were normalized in intensity and nonlinearly registered to a template constructed specifically for this population, creating a deformation field map. We then used deformation based morphometry (DBM) to correlate variation in the local volume of gray and white matter with composite scores on the Bayley Scales of Infant and Toddler Development (Bayley-III) at 30months. Our general linear model included gestational age, sex, birth weight, and treatment with hypothermia as covariates. Regional brain volume was significantly associated with language scores, particularly in perisylvian cortical regions including the left supramarginal gyrus, posterior superior and middle temporal gyri, and right insula, as well as inferior frontoparietal subcortical white matter. We did not find significant correlations between regional brain volume and motor or cognitive scale scores. We conclude that, in children with a history of NE, local changes in the volume of perisylvian gray and white matter at 6months are correlated with language outcome at 30months. Quantitative measures of brain volume on early MRI may help identify infants at risk for poor language outcomes. Keywords: Neonatal encephalopathy, Hypoxic-ischemic encephalopathy, Language, Deformation based morphometry

Background Tube‐assisted feeding in infancy is common in patients with single‐ventricle physiology (SVP). Postnatal brain development is delayed, and injury is common, in patients with SVP. The role of brain findings in feeding outcomes remains unclear. We sought to determine the association between neonatal perioperative brain injury and postnatal brain maturation with feeding‐tube dependency in patients with SVP at neonatal discharge and just before the stage‐2 palliation. Methods and Results We evaluated a cohort of 48 term neonates with SVP who underwent pre‐ and postoperative brain magnetic resonance imaging. Perioperative brain injury and microstructural brain development were measured with diffusion tensor imaging including fractional anisotropy in white matter and apparent diffusion coefficient in gray matter. The primary outcome was defined as being 100% orally fed (binary). Of the patients 79% (38/48) were tube fed at hospital discharge, and 27% (12/45) were tube fed before stage‐2 palliation. Perioperative brain injury did not differ by group. Orally fed patients had a faster rate of decrease in apparent diffusion coefficient (3%, 95% CI 1.7% to 4.6%, P

The corpus callosum is the major axon tract that connects and integrates neural activity between the two cerebral hemispheres. Although ∼1:4,000 children are born with developmental absence of the corpus callosum, the primary etiology of this condition remains unknown. Here, we demonstrate that midline crossing of callosal axons is dependent upon the prior remodeling and degradation of the intervening interhemispheric fissure. This remodeling event is initiated by astroglia on either side of the interhemispheric fissure, which intercalate with one another and degrade the intervening leptomeninges. Callosal axons then preferentially extend over these specialized astroglial cells to cross the midline. A key regulatory step in interhemispheric remodeling is the differentiation of these astroglia from radial glia, which is initiated by Fgf8 signaling to downstream Nfi transcription factors. Crucially, our findings from human neuroimaging studies reveal that developmental defects in interhemispheric remodeling are likely to be a primary etiology underlying human callosal agenesis.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments.Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

In recent years, the concept of hypomyelinating disorders has been proposed as a group of disorders with varying systemic manifestations that are identified by MR findings of absence or near absence of the T2 hypointensity that develops in white matter as a result of myelination. Initially proposed as a separate group because they were the largest single category of undiagnosed leukodystrophies, their separation as a distinct group that can be recognized by looking for a specific MRI feature has resulted in a marked increase in their diagnosis and a better understanding of the different causes of hypomyelination. This review will discuss the clinical presentations, imaging findings on standard MRI, and new MRI-related techniques that allow a better understanding of these disorders and proposed methods for quantifying the myelination as a potential means of assessing disease course and the effects of proposed treatments.Disorders with hypomyelination of white matter, or hypomyelinating disorders (HMDs), represent the single largest category among undiagnosed genetic leukoencephalopathies (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010). This group of inborn errors of metabolism is characterized by a magnetic resonance imaging (MRI) appearance of reduced or absent myelin development: delay in the development of T2 hypointensity and, often, T1 hyperintensity in the white matter of the brain. The concept of hypomyelination was first conceptualized by (Schiffmann and van der Knaap, 2009; Steenweg et al., 2010; Schiffmann et al., 1994) in a series of papers that showed that these MRI characteristics were easily recognized, were different from the MRI characteristics of dysmyelinating and demyelinating disorders, and that the combination of these imaging findings with specific other clinical and imaging features could be used to make diagnoses with some confidence. In this manuscript, we will discuss the physiologic and genetic bases of hypomyelinating disorders, as well as their classification, clinical manifestations and imaging characteristics.

BackgroundWe previously reported that increasing severity of watershed (WS) injury in neonatal magnetic resonance imaging (MRI) is associated with worse language outcomes in early childhood. In the present study, we investigated the relationship between neonatal injury patterns and cognitive profile in adolescents with neonatal encephalopathy.MethodsTerm neonates with encephalopathy were prospectively enrolled and imaged using brain MRI from 1999 to 2008. Neonatal brain injury was scored according to the degree of injury in WS and basal ganglia/thalamus (BG/T) areas. The children underwent a neurocognitive assessment and follow-up brain MRI at the age of 10-16 years. The relationship between neonatal brain injury patterns and adolescent cognitive outcomes was assessed.ResultsIn a cohort of 16 children, neonatal MRI showed WS injury in 7, BG/T injury in 2, and normal imaging in 7. Children with WS injury had lower estimated overall cognitive ability than those with normal imaging. Increasing WS injury score was associated with decreasing estimated overall cognitive ability, Perceptual Reasoning Index, and digit span score.ConclusionsChildren with the WS injury are at an increased risk of having problems in long-term intellectual ability. These cognitive outcomes may underlie early language difficulties seen in children with neonatal WS injury.ImpactAdolescents with a history of neonatal encephalopathy and watershed pattern of injury on neonatal brain magnetic resonance imaging (MRI) had lower overall cognitive ability, perceptual reasoning skills, and auditory working memory than those with normal neonatal imaging. Children with post-neonatal epilepsy and cerebral palsy had the worst cognitive outcomes. Watershed pattern of injury confers high long-term differences in intellectual ability.

Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD. We found up to 800-fold enrichment of genetic risk in CBD across different levels of significance for PSP or FTD. In addition to NSF (tagging the MAPT H1 haplotype), we observed that SNPs in or near MOBP, CXCR4, EGFR, and GLDC showed significant genetic overlap between CBD and PSP, whereas only SNPs tagging the MAPT haplotype overlapped between CBD and FTD. The risk alleles of the shared SNPs were associated with expression changes in cis-genes. Evaluating transcriptome levels across adult human brains, we found a unique neuroanatomic gene expression signature for each of the five overlapping gene loci (omnibus ANOVA p