Atypical functional connectivity between the amygdala and visual, salience regions in infants with genetic liability for autism.

The amygdala undergoes a period of overgrowth in the first year of life, resulting in enlarged volume by 12 months in infants later diagnosed with ASD. The overgrowth of the amygdala may have functional consequences during infancy. We investigated whether amygdala connectivity differs in 12-month-olds at high likelihood (HL) for ASD (defined by having an older sibling with autism), compared to those at low likelihood (LL). We examined seed-based connectivity of left and right amygdalae, hypothesizing that the HL and LL groups would differ in amygdala connectivity, especially with the visual cortex, based on our prior reports demonstrating that components of visual circuitry develop atypically and are linked to genetic liability for autism. We found that HL infants exhibited weaker connectivity between the right amygdala and the left visual cortex, as well as between the left amygdala and the right anterior cingulate, with evidence that these patterns occur in distinct subgroups of the HL sample. Amygdala connectivity strength with the visual cortex was related to motor and communication abilities among HL infants. Findings indicate that aberrant functional connectivity between the amygdala and visual regions is apparent in infants with genetic liability for ASD and may have implications for early differences in adaptive behaviors.

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

White matter development and language abilities during infancy in autism spectrum disorder.

White matter (WM) fiber tract differences are present in autism spectrum disorder (ASD) and could be important markers of behavior. One of the earliest phenotypic differences in ASD are language atypicalities. Although language has been linked to WM in typical development, no work has evaluated this association in early ASD. Participants came from the Infant Brain Imaging Study and included 321 infant siblings of children with ASD at high likelihood (HL) for developing ASD; 70 HL infants were later diagnosed with ASD (HL-ASD), and 251 HL infants were not diagnosed with ASD (HL-Neg). A control sample of 140 low likelihood infants not diagnosed with ASD (LL-Neg) were also included. Infants contributed expressive language, receptive language, and diffusion tensor imaging data at 6-, 12-, and 24 months. Mixed effects regression models were conducted to evaluate associations between WM and language trajectories. Trajectories of microstructural changes in the right arcuate fasciculus were associated with expressive language development. HL-ASD infants demonstrated a different developmental pattern compared to the HL-Neg and LL-Neg groups, wherein the HL-ASD group exhibited a positive association between WM fractional anisotropy and language whereas HL-Neg and LL-Neg groups showed weak or no association. No other fiber tracts demonstrated significant associations with language. In conclusion, results indicated arcuate fasciculus WM is linked to language in early toddlerhood for autistic toddlers, with the strongest associations emerging around 24 months. To our knowledge, this is the first study to evaluate associations between language and WM development during the pre-symptomatic period in ASD.

Enlarged Perivascular Spaces in Infancy and Autism Diagnosis, Cerebrospinal Fluid Volume, and Later Sleep Problems.

Importance: Perivascular spaces (PVS) and cerebrospinal fluid (CSF) are essential components of the glymphatic system, regulating brain homeostasis and clearing neural waste throughout the lifespan. Enlarged PVS have been implicated in neurological disorders and sleep problems in adults, and excessive CSF volume has been reported in infants who develop autism. Enlarged PVS have not been sufficiently studied longitudinally in infancy or in relation to autism outcomes or CSF volume. Objective: To examine whether enlarged PVS are more prevalent in infants who develop autism compared with controls and whether they are associated with trajectories of extra-axial CSF volume (EA-CSF) and sleep problems in later childhood. Design, Setting, and Participants: This prospective, longitudinal cohort study used data from the Infant Brain Imaging Study. Magnetic resonance images were acquired at ages 6, 12, and 24 months (2007-2017), with sleep questionnaires performed between ages 7 and 12 years (starting in 2018). Data were collected at 4 sites in North Carolina, Missouri, Pennsylvania, and Washington. Data were analyzed from March 2021 through August 2022. Exposure: PVS (ie, fluid-filled channels that surround blood vessels in the brain) that are enlarged (ie, visible on magnetic resonance imaging). Main Outcomes and Measures: Outcomes of interest were enlarged PVS and EA-CSF volume from 6 to 24 months, autism diagnosis at 24 months, sleep problems between ages 7 and 12 years. Results: A total of 311 infants (197 [63.3%] male) were included: 47 infants at high familial likelihood for autism (ie, having an older sibling with autism) who were diagnosed with autism at age 24 months, 180 high likelihood infants not diagnosed with autism, and 84 low likelihood control infants not diagnosed with autism. Sleep measures at school-age were available for 109 participants. Of infants who developed autism, 21 (44.7%) had enlarged PVS at 24 months compared with 48 infants (26.7%) in the high likelihood but no autism diagnosis group (P = .02) and 22 infants in the control group (26.2%) (P = .03). Across all groups, enlarged PVS at 24 months was associated with greater EA-CSF volume from ages 6 to 24 months (ß = 4.64; 95% CI, 0.58-8.72; P = .002) and more frequent night wakings at school-age (F = 7.76; η2 = 0.08; P = .006). Conclusions and Relevance: These findings suggest that enlarged PVS emerged between ages 12 and 24 months in infants who developed autism. These results add to a growing body of evidence that, along with excessive CSF volume and sleep dysfunction, the glymphatic system could be dysregulated in infants who develop autism.

Brain Injury Outcomes after Adjuvant Erythropoietin Neuroprotection for Moderate or Severe Neonatal Hypoxic-Ischemic Encephalopathy: A Report from the HEAL Trial.

INTRODUCTION: Erythropoietin (Epo) is a putative neuroprotective therapy that did not improve overall outcomes in a phase 3 randomized controlled trial for neonates with moderate or severe hypoxic-ischemic encephalopathy (HIE). However, HIE is a heterogeneous disorder, and it remains to be determined whether Epo had beneficial effects on a subset of perinatal brain injuries. METHODS: This study was a secondary analysis of neuroimaging data from the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, which was conducted from 2016 - 2021 at 17 sites involving 23 US academic medical centers. Participants were neonates >36 weeks' gestation undergoing therapeutic hypothermia for moderate or severe HIE who received 5 doses of study drug (Epoetin alpha 1000 U/kg/dose) or placebo in the first week of life. Treatment assignment was stratified by trial site and severity of encephalopathy. The primary outcome was the locus, pattern and acuity of brain injury as determined by three independent readers using a validated HIE Magnetic Resonance Imaging (MRI) scoring system. RESULTS: Of the 500 infants enrolled in HEAL, 470 (94%) had high quality MRI data obtained at a median of 4.9 days of age (IQR 4.5 - 5.8). The incidence of injury to the deep grey nuclei, cortex, white matter, brainstem and cerebellum was similar between Epo and placebo groups. Likewise, the distribution of injury patterns was similar between groups. Among infants imaged at less than 8 days (n=414), 94 (23%) evidenced only acute, 93 (22%) only subacute and 89 (21%) both acute and subacute injuries, with similar distribution across treatment groups. CONCLUSION: Adjuvant erythropoietin did not reduce the incidence of regional brain injury. Subacute brain injury was more common than previously reported, which has key implications for the development of adjuvant neuroprotective therapies for this population.

Deep Learning to Optimize Magnetic Resonance Imaging Prediction of Motor Outcomes After Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for outcome prediction after hypoxic-ischemic encephalopathy (HIE). Published scoring systems contain duplicative or conflicting elements. METHODS: Infants ≥36 weeks gestational age (GA) with moderate to severe HIE, therapeutic hypothermia treatment, and T1/T2/diffusion-weighted imaging were identified. Adverse motor outcome was defined as Bayley-III motor score <85 or Alberta Infant Motor Scale <10th centile at 12 to 24 months. MRIs were scored using a published scoring system. Logistic regression (LR) and gradient-boosted deep learning (DL) models quantified the importance of clinical and imaging features. The cohort underwent 80/20 train/test split with fivefold cross validation. Feature selection eliminated low-value features. RESULTS: A total of 117 infants were identified with mean GA = 38.6 weeks, median cord pH = 7.01, and median 10-minute Apgar = 5. Adverse motor outcome was noted in 23 of 117 (20%). Putamen/globus pallidus injury on T1, GA, and cord pH were the most informative features. Feature selection improved model accuracy from 79% (48-feature MRI model) to 85% (three-feature model). The three-feature DL model had superior performance to the best LR model (area under the receiver-operator curve 0.69 versus 0.75). CONCLUSIONS: The parsimonious DL model predicted adverse HIE motor outcomes with 85% accuracy using only three features (putamen/globus pallidus injury on T1, GA, and cord pH) and outperformed LR.

Correlating Quantitative MRI-based Apparent Diffusion Coefficient Metrics with 24-month Neurodevelopmental Outcomes in Neonates from the HEAL Trial.

Background Multiple qualitative scoring systems have been created to capture the imaging severity of hypoxic ischemic brain injury. Purpose To evaluate quantitative volumes of acute brain injury at MRI in neonates with hypoxic ischemic brain injury and correlate these findings with 24-month neurodevelopmental outcomes and qualitative brain injury scoring by radiologists. Materials and Methods In this secondary analysis, brain diffusion-weighted MRI data from neonates in the High-dose Erythropoietin for Asphyxia and Encephalopathy trial, which recruited participants between January 2017 and October 2019, were analyzed. Volume of acute brain injury, defined as brain with apparent diffusion coefficient (ADC) less than 800 × 10-6 mm2/sec, was automatically computed across the whole brain and within the thalami and white matter. Outcomes of death and neurodevelopmental impairment (NDI) were recorded at 24-month follow-up. Associations between the presence and volume (in milliliters) of acute brain injury with 24-month outcomes were evaluated using multiple logistic regression. The correlation between quantitative acute brain injury volume and qualitative MRI scores was assessed using the Kendall tau-b test. Results A total of 416 neonates had available MRI data (mean gestational age, 39.1 weeks ± 1.4 [SD]; 235 male) and 113 (27%) showed evidence of acute brain injury at MRI. Of the 387 participants with 24-month follow-up data, 185 (48%) died or had any NDI. Volume of acute injury greater than 1 mL (odds ratio [OR], 13.9 [95% CI: 5.93, 32.45]; P < .001) and presence of any acute injury in the brain (OR, 4.5 [95% CI: 2.6, 7.8]; P < .001) were associated with increased odds of death or any NDI. Quantitative whole-brain acute injury volume was strongly associated with radiologists' qualitative scoring of diffusion-weighted images (Kendall tau-b = 0.56; P < .001). Conclusion Automated quantitative volume of brain injury is associated with death, moderate to severe NDI, and cerebral palsy in neonates with hypoxic ischemic encephalopathy and correlated well with qualitative MRI scoring of acute brain injury. Clinical trial registration no. NCT02811263 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

Toward Automated Detection of Silent Cerebral Infarcts in Children and Young Adults With Sickle Cell Anemia.

BACKGROUND: Silent cerebral infarcts (SCI) in sickle cell anemia (SCA) are associated with future strokes and cognitive impairment, warranting early diagnosis and treatment. Detection of SCI, however, is limited by their small size, especially when neuroradiologists are unavailable. We hypothesized that deep learning may permit automated SCI detection in children and young adults with SCA as a tool to identify the presence and extent of SCI in clinical and research settings. METHODS: We utilized UNet-a deep learning model-for fully automated SCI segmentation. We trained and optimized UNet using brain magnetic resonance imaging from the SIT trial (Silent Infarct Transfusion). Neuroradiologists provided the ground truth for SCI diagnosis, while a vascular neurologist manually delineated SCI on fluid-attenuated inversion recovery and provided the ground truth for SCI segmentation. UNet was optimized for the highest spatial overlap between automatic and manual delineation (dice similarity coefficient). The optimized UNet was externally validated using an independent single-center prospective cohort of SCA participants. Model performance was evaluated through sensitivity and accuracy (%correct cases) for SCI diagnosis, dice similarity coefficient, intraclass correlation coefficient (metric of volumetric agreement), and Spearman correlation. RESULTS: The SIT trial (n=926; 31% with SCI; median age, 8.9 years) and external validation (n=80; 50% with SCI; age, 11.5 years) cohorts had small median lesion volumes of 0.40 and 0.25 mL, respectively. Compared with the neuroradiology diagnosis, UNet predicted SCI presence with 100% sensitivity and 74% accuracy. In magnetic resonance imaging with SCI, UNet reached a moderate spatial agreement (dice similarity coefficient, 0.48) and high volumetric agreement (intraclass correlation coefficient, 0.76; ρ=0.72; P<0.001) between automatic and manual segmentations. CONCLUSIONS: UNet, trained using a large pediatric SCA magnetic resonance imaging data set, sensitively detected small SCI in children and young adults with SCA. While additional training is needed, UNet may be integrated into the clinical workflow as a screening tool, aiding in SCI diagnosis.

Language exposure during infancy is negatively associated with white matter microstructure in the arcuate fasciculus.

Decades of research have established that the home language environment, especially quality of caregiver speech, supports language acquisition during infancy. However, the neural mechanisms behind this phenomenon remain under studied. In the current study, we examined associations between the home language environment and structural coherence of white matter tracts in 52 typically developing infants from English speaking homes in a western society. Infants participated in at least one MRI brain scan when they were 3, 6, 12, and/or 24 months old. Home language recordings were collected when infants were 9 and/or 15 months old. General linear regression models indicated that infants who heard the most adult words and participated in the most conversational turns at 9 months of age also had the lowest fractional anisotropy in the left posterior parieto-temporal arcuate fasciculus at 24 months. Similarly, infants who vocalized the most at 9 months also had the lowest fractional anisotropy in the same tract at 6 months of age. This is one of the first studies to report significant associations between caregiver speech collected in the home and white matter structural coherence in the infant brain. The results are in line with prior work showing that protracted white matter development during infancy confers a cognitive advantage.

How well does neonatal neuroimaging correlate with neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy?

BACKGROUND: In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. METHODS: Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4-6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. RESULTS: Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5-5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. CONCLUSION: In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. IMPACT: Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

A Prospective Evaluation of Infant Cerebellar-Cerebral Functional Connectivity in Relation to Behavioral Development in Autism Spectrum Disorder.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder diagnosed based on social impairment, restricted interests, and repetitive behaviors. Contemporary theories posit that cerebellar pathology contributes causally to ASD by disrupting error-based learning (EBL) during infancy. The present study represents the first test of this theory in a prospective infant sample, with potential implications for ASD detection. Methods: Data from the Infant Brain Imaging Study (n = 94, 68 male) were used to examine 6-month cerebellar functional connectivity magnetic resonance imaging in relation to later (12/24-month) ASD-associated behaviors and outcomes. Hypothesis-driven univariate analyses and machine learning-based predictive tests examined cerebellar-frontoparietal network (FPN; subserves error signaling in support of EBL) and cerebellar-default mode network (DMN; broadly implicated in ASD) connections. Cerebellar-FPN functional connectivity was used as a proxy for EBL, and cerebellar-DMN functional connectivity provided a comparative foil. Data-driven functional connectivity magnetic resonance imaging enrichment examined brain-wide behavioral associations, with post hoc tests of cerebellar connections. Results: Cerebellar-FPN and cerebellar-DMN connections did not demonstrate associations with ASD. Functional connectivity magnetic resonance imaging enrichment identified 6-month correlates of later ASD-associated behaviors in networks of a priori interest (FPN, DMN), as well as in cingulo-opercular (also implicated in error signaling) and medial visual networks. Post hoc tests did not suggest a role for cerebellar connections. Conclusions: We failed to identify cerebellar functional connectivity-based contributions to ASD. However, we observed prospective correlates of ASD-associated behaviors in networks that support EBL. Future studies may replicate and extend network-level positive results, and tests of the cerebellum may investigate brain-behavior associations at different developmental stages and/or using different neuroimaging modalities.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease.

Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (-19.4 mL/100 g/min) and OEF (-8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, -0.9 mL/100 g/min; P = .024; OEF, -3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Neurodevelopmental patterns of early postnatal white matter maturation represent distinct underlying microstructure and histology.

Cerebral white matter undergoes a rapid and complex maturation during the early postnatal period. Prior magnetic resonance imaging (MRI) studies of early postnatal development have often been limited by small sample size, single-modality imaging, and univariate analytics. Here, we applied nonnegative matrix factorization, an unsupervised multivariate pattern analysis technique, to T2w/T1w signal ratio maps from the Developing Human Connectome Project (n = 342 newborns) revealing patterns of coordinated white matter maturation. These patterns showed divergent age-related maturational trajectories, which were replicated in another independent cohort (n = 239). Furthermore, we showed that T2w/T1w signal variations in these maturational patterns are explained by differential contributions of white matter microstructural indices derived from diffusion-weighted MRI. Finally, we demonstrated how white matter maturation patterns relate to distinct histological features by comparing our findings with postmortem late fetal/early postnatal brain tissue staining. Together, these results delineate concise and effective representation of early postnatal white matter reorganization.

Magnetic resonance imaging of the supra-cervical fetal membrane detects an increased risk of prelabor rupture of membranes.

Objective: In 10% of term deliveries and 40% of preterm deliveries, the fetal membrane (FM) ruptures before labor. However, the ability to predict these cases of premature rupture of membranes (PROM) and preterm premature rupture of membranes (PPROM) is very limited. In this paper, our objective was to determine whether a prediction method based on T2 weighted magnetic resonance imaging (MRI) of the supra-cervical FM could predict PROM and PPROM. Methods: This prospective cohort study enrolled 77 women between the 28th and 37th weeks of gestation. Two indicators of fetal membrane defects, including prolapsed depth >5 mm and signal abnormalities, are investigated for our prediction. Fisher's exact test was used to determine whether prolapsed depth >5 mm and/or signal abnormalities were associated with PROM and PPROM. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for prolapsed depth >5 mm, signal abnormalities, and the combination of prolapsed depth >5 mm and signal abnormalities. Result: Among 12 women with PROM (5 preterm and 7 term, prior to labor onset), 9 had membrane prolapse >5 mm and 5 had FM signal abnormalities. Among 65 women with rupture of membranes at term, 2 had membrane prolapse >5 mm and 1 had signal abnormalities. By Fisher's exact test both indicators, membrane prolapse >5 mm and signal abnormalities, were associated with PROM (P<0.001, P<0.001) and PPROM (P=0.001, P<0.001). Additionally, membrane prolapse >5 mm, signal abnormalities, and the combination of the two indicators all demonstrated high specificity for predicting PROM (96.9%, 98.5%, and 100%, respectively) and PPROM (90.3%, 97.2%, and 100%, respectively). Conclusion: MRI can distinguish the supra-cervical fetal membrane in vivo and may be able to identify women at high risk of PPROM.

Case Report: A Novel EIF2B3 Pathogenic Variant in Central Nervous System Hypomyelination/Vanishing White Matter.

Leukodystrophies are a group of heterogeneous disorders affecting brain myelin. Among those, childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM) is one of the more common inherited leukodystrophies. Pathogenic variants in one of the genes encoding five subunits of EIF2B are associated with CACH/VWM. Herein, we presented a case of CACH/VWM who developed ataxia following a minor head injury. Brain magnetic resonance imaging showed extensive white matter signal abnormality. Diagnosis of CACH/VWM was confirmed by the presence of compound heterozygous variants in EIF2B3: the previously known pathogenic variant c c.260C>T (p.Ala87Val) and the novel variant c.673C>T (p.Arg225Trp). Based on the American College of Medical Genetics (ACMG) recommendations, we classified p.Arg225Trp as likely pathogenic. We report a novel variant in a patient with CACH/VWM and highlight the importance of genetic testing in patients with leukodystrophies.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Mild hypoxic-ischemic encephalopathy (HIE): timing and pattern of MRI brain injury.

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE. METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age. RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on MRI at median age 5 (IQR 4-6) days. Watershed (23%), deep gray (20%) and punctate white matter (18%) injury were most common. Among the 125 (88%) infants who received a brain MRI at ≤8 days, mild (44%) injury was more common than moderate (11%) or severe (4%) injury. Subacute (37%) lesions were more commonly observed than acute (32%) or chronic lesions (1%). CONCLUSION: Subacute brain injury is common in newborn infants with mild HIE. Novel neuroprotective treatments for mild HIE will ideally target both subacute and acute injury mechanisms. IMPACT: Almost two-thirds of infants with mild HIE have evidence of brain injury on MRI obtained in the early neonatal period. Subacute brain injury was seen in 37% of infants with mild HIE. Neuroprotective treatments for mild HIE will ideally target both acute and subacute injury mechanisms.

Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy.

OBJECTIVE: Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown. METHODS: Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans). RESULTS: Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen's d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors. CONCLUSIONS: This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.