Clinical application of magnetic resonance elastography in pediatric neurological disorders.

Magnetic resonance elastography is a relatively new, rapidly evolving quantitative magnetic resonance imaging technique which can be used for mapping the viscoelastic mechanical properties of soft tissues. MR elastography measurements are akin to manual palpation but with the advantages of both being quantitative and being useful for regions which are not available for palpation, such as the human brain. MR elastography is noninvasive, well tolerated, and complements standard radiological and histopathological studies by providing in vivo measurements that reflect tissue microstructural integrity. While brain MR elastography studies in adults are becoming frequent, published studies on the utility of MR elastography in children are sparse. In this review, we have summarized the major scientific principles and recent clinical applications of brain MR elastography in diagnostic neuroscience and discuss avenues for impact in assessing the pediatric brain.

Abusive Head Trauma Animal Models: Focus on Biomarkers.

Abusive head trauma (AHT) is a serious traumatic brain injury and the leading cause of death in children younger than 2 years. The development of experimental animal models to simulate clinical AHT cases is challenging. Several animal models have been designed to mimic the pathophysiological and behavioral changes in pediatric AHT, ranging from lissencephalic rodents to gyrencephalic piglets, lambs, and non-human primates. These models can provide helpful information for AHT, but many studies utilizing them lack consistent and rigorous characterization of brain changes and have low reproducibility of the inflicted trauma. Clinical translatability of animal models is also limited due to significant structural differences between developing infant human brains and the brains of animals, and an insufficient ability to mimic the effects of long-term degenerative diseases and to model how secondary injuries impact the development of the brain in children. Nevertheless, animal models can provide clues on biochemical effectors that mediate secondary brain injury after AHT including neuroinflammation, excitotoxicity, reactive oxygen toxicity, axonal damage, and neuronal death. They also allow for investigation of the interdependency of injured neurons and analysis of the cell types involved in neuronal degeneration and malfunction. This review first focuses on the clinical challenges in diagnosing AHT and describes various biomarkers in clinical AHT cases. Then typical preclinical biomarkers such as microglia and astrocytes, reactive oxygen species, and activated N-methyl-D-aspartate receptors in AHT are described, and the value and limitations of animal models in preclinical drug discovery for AHT are discussed.

Advanced Neuroimaging Approaches to Pediatric Brain Tumors.

Central nervous system tumors are the most common pediatric solid tumors; they are also the most lethal. Unlike adults, childhood brain tumors are mostly primary in origin and differ in type, location and molecular signature. Tumor characteristics (incidence, location, and type) vary with age. Children present with a variety of symptoms, making early accurate diagnosis challenging. Neuroimaging is key in the initial diagnosis and monitoring of pediatric brain tumors. Conventional anatomic imaging approaches (computed tomography (CT) and magnetic resonance imaging (MRI)) are useful for tumor detection but have limited utility differentiating tumor types and grades. Advanced MRI techniques (diffusion-weighed imaging, diffusion tensor imaging, functional MRI, arterial spin labeling perfusion imaging, MR spectroscopy, and MR elastography) provide additional and improved structural and functional information. Combined with positron emission tomography (PET) and single-photon emission CT (SPECT), advanced techniques provide functional information on tumor metabolism and physiology through the use of radiotracer probes. Radiomics and radiogenomics offer promising insight into the prediction of tumor subtype, post-treatment response to treatment, and prognostication. In this paper, a brief review of pediatric brain cancers, by type, is provided with a comprehensive description of advanced imaging techniques including clinical applications that are currently utilized for the assessment and evaluation of pediatric brain tumors.

Radiosynthesis of 1-(2-[18F]Fluoroethyl)-L-Tryptophan using a One-pot, Two-step Protocol.

The kynurenine pathway (KP) is a primary route for tryptophan metabolism. Evidence strongly suggests that metabolites of the KP play a vital role in tumor proliferation, epilepsy, neurodegenerative diseases, and psychiatric illnesses due to their immune-modulatory, neuro-modulatory, and neurotoxic effects. The most extensively used positron emission tomography (PET) agent for mapping tryptophan metabolism, α-[11C]methyl-L-tryptophan ([11C]AMT), has a short half-life of 20 min with laborious radiosynthesis procedures. An onsite cyclotron is required to radiosynthesize [11C]AMT. Only a limited number of centers produce [11C]AMT for preclinical studies and clinical investigations. Hence, the development of an alternative imaging agent that has a longer half-life, favorable in vivo kinetics, and is easy to automate is urgently needed. The utility and value of 1-(2-[18F]fluoroethyl)-L-tryptophan, a fluorine-18-labeled tryptophan analog, has been reported in preclinical applications in cell line-derived xenografts, patient-derived xenografts, and transgenic tumor models. This paper presents a protocol for the radiosynthesis of 1-(2-[18F]fluoroethyl)-L-tryptophan using a one-pot, two-step strategy. Using this protocol, the radiotracer can be produced in a 20 ± 5% (decay corrected at the end of synthesis, n > 20) radiochemical yield, with both radiochemical purity and enantiomeric excess of over 95%. The protocol features a small precursor amount with no more than 0.5 mL of reaction solvent in each step, low loading of potentially toxic 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane (K222), and an environmentally benign and injectable mobile phase for purification. The protocol can be easily configured to produce 1-(2-[18F]fluoroethyl)-L-tryptophan for clinical investigation in a commercially available module.

Unravelling neuroinflammation in abusive head trauma with radiotracer imaging.

Abusive head trauma (AHT) is a leading cause of mortality and morbidity in child abuse, with a mortality rate of approximately 25%. In survivors, the prognosis remains dismal, with high prevalence of cerebral palsy, epilepsy and neuropsychiatric disorders. Early and accurate diagnosis of AHT is challenging, both clinically and radiologically, with up to one-third of cases missed on initial examination. Moreover, most of the management in AHT is supportive, reflective of the lack of clear understanding of specific pathogenic mechanisms underlying secondary insult, with approaches targeted toward decreasing intracranial hypertension and reducing cerebral metabolism, cell death and excitotoxicity. Multiple studies have elucidated the role of pro- and anti-inflammatory cytokines and chemokines with upregulation/recruitment of microglia/macrophages, oligodendrocytes and astrocytes in severe traumatic brain injury (TBI). In addition, recent studies in animal models of AHT have demonstrated significant upregulation of microglia, with a potential role of inflammatory cascade contributing to secondary insult. Despite the histological and biochemical evidence, there is a significant dearth of specific imaging approaches to identify this neuroinflammation in AHT. The primary motivation for development of such imaging approaches stems from the need to therapeutically target neuroinflammation and establish its utility in monitoring and prognostication. In the present paper, we discuss the available data suggesting the potential role of neuroinflammation in AHT and role of radiotracer imaging in aiding diagnosis and patient management.

Artificial intelligence in child abuse imaging.

There have been rapid advances in artificial intelligence (AI) technology in recent years, and the field of diagnostic imaging is no exception. Just as digital technology revolutionized how radiology is practiced, so these new technologies also appear poised to bring sweeping change. As AI tools make the transition from the theoretical to the everyday, important decisions need to be made about how they will be applied and what their role will be in the practice of radiology. Pediatric radiology presents distinct challenges and opportunities for the application of these tools, and in this article we discuss some of these, specifically as they relate to the prediction, identification and investigation of child abuse.

Birth-related subdural hemorrhage: prevalence and imaging morphology.

BACKGROUND: Birth trauma accounts for 1-2% of the mortality in newborns with significant intracranial injuries presenting in the immediate postnatal period. However, a significant number of asymptomatic neonates harbor birth-related intracranial hemorrhage (ICH), with birth-related subdural hemorrhage (SDH) being a common occurrence on infant brain CT and MRI studies performed as a standard of care for a variety of reasons. Although clinically insignificant, birth-related SDH is frequently brought up in courts as an alternative explanation for SDH in suspected abusive head trauma. OBJECTIVE: The aim of this study was to determine prevalence, imaging morphology and distribution of birth-related SDHs on brain CT and MRI studies obtained as a standard of care in infants up to 1 month old. We further tried to ascertain the relationship of birth-related SDHs with mode of delivery and birth weight. MATERIALS AND METHODS: Infants up to the age of 1 month who had CT or MRI of the brain performed between Jan. 1, 2018, and March 29, 2020, were included in this retrospective observational study. In addition to the imaging data, we reviewed clinical history, birth history including birth weight and mode of delivery, and final diagnoses. RESULTS: Two hundred six infants younger than 30 days (range 0-29 days, mean 11.9 days, median 11 days and standard deviation [SD] 8.4 days) had a CT or MRI study during the study period. Among these, 58 infants were excluded as per the exclusion criteria. Among the included 148 infants, 88 (59.5%) had no imaging evidence of SDH. An additional 56 (37.8%) infants were assessed as having birth-related SDH based on review of clinical data. Within the birth-related SDH cohort (56 infants), only supratentorial SDH was identified in 5 (8.9%), only infratentorial SDH was identified in 14 (25%), while SDHs within both compartments were identified in 37 (66.1%) infants. The most common location for supratentorial birth-related SDH was along the occipital lobes (31/42, 73.8%), with other common locations being along the posterior interhemispheric fissure (30/42, 71.4%) and fronto-parietal convexity (9/42, 21.4%). The distribution of posterior fossa SDH was along the tentorium (38/51, 74.5%), along the cerebellum (38/51, 74.5%) and in both the locations (25/51, 49.0%). The rate of SDH was significantly higher in vaginal delivery group (46/84, 54.7%) as compared to caesarean section group (10/57, 17.5%) (P<0.05). We did not find any statistically significant difference between the birth weights of normal and birth-related SDH cohorts (P>0.05). CONCLUSION: Birth-related SDH is a common occurrence, with our study suggesting a prevalence of 37.8%. The most common distribution of birth-related SDH is within both the supra- and infratentorial compartments (66.1%) followed by infratentorial compartment (25%). The rate of birth-related SDH was significantly higher in vaginal delivery group as compared to caesarean section group.

Imaging phenotype of multiple mitochondrial dysfunction syndrome 2, a rare BOLA3-associated leukodystrophy.

Multiple mitochondrial dysfunction syndrome (MMDS) is a rare disorder of systemic energy metabolism associated with mutations in genes having a vital role in production of iron-sulfur clusters, important for the normal maturation of lipoate-containing 2-oxoacid dehydrogenases and for the assembly of the mitochondrial respiratory chain complexes. MMDS 2 associated with BOLA3 mutation presents in early infancy and is characterized by developmental regression, severe encephalopathy, optic atrophy, and cardiomyopathy. Neuroimaging phenotype associated with MMDS 2 has never been described in its entirety in literature, with few reported cases till date. None of the published cases mention findings demonstrated in our case, a proband with biallelic BOLA3 variants, such as necrotic/cavitary lesions within the centrum semiovale, restricted diffusivity within the white matter, areas of central enhancement within the centrum semiovale presumably related to leakage of contrast within the necrotic center, enhancement of bilateral optic nerves, and markedly elevated lactate on magnetic resonance spectroscopy.