Faculty Bibliography

The GRIN2B gene encodes Glutamate Ionotropic Receptor N-methyl-D-aspartate (NMDA) subunit 2B, a component of the agonist binding site for glutamate. It plays a role in brain development, circuit formation, and synaptic plasticity, as well as cellular migration and differentiation. Pathogenic variants are accompanied by a range of disorders, such as intellectual disability, autism spectrum disorder, and seizures, inherited in an autosomal dominant manner. GRIN2B is frequently analyzed in commercial epilepsy panels and was included in the panel of 132 genes tested by the CAP-accredited Molecular Genetics Laboratory in our office. We report the autopsy neuropathology of a 11yo boy with marked developmental delay and seizures since infancy, who died suddenly from mucus plugging of his tracheostomy. Externally, the brain (280g) had temporal lissencephaly, frontal gyral complexity, and flattened basis pontis and pyramids. On section, the hemispheric white matter volume was markedly diminished, and the deep gray structures were poorly demarcated and firm. Hippocampi were indistinct. Brainstem and cerebellar structures were ill-defined and firm. Microscopically, the cerebral cortex was dyslaminated and disorganized, with cytomegalic, ballooned, and scattered binucleate neurons, sulcal fusion, and tangentially oriented myelinated axon bundles in the cortical plate. There were also heterotopic neurons in white matter, periventricular and subarachnoid locations. Hypotrophy of cerebral hemispheric white matter, including corpus callosum and descending tracts, disorganization of deep gray nuclei with focal scarring, hippocampal dysgenesis and gliosis, dentato-olivary simplification and rhombic lip heterotopia were also evident. The patterns of dysgenesis did not fit well with any previously described neuronal migration disorders. Molecular genetic analysis revealed a novel missense variant (p.Met654Val) in Exon 9 (transmembrane domain) of the GRIN2B gene (NM-000834.3), with multiple in silico function analyses predicted to be consistently deleterious. Testing of the biological parents is being pursued to determine whether the mutation is de novo

Background/UNASSIGNED:Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality. Although the rate has plateaued, any unexpected death of an infant is a family tragedy thus finding causes and contributors to risk remains a major public health concern. The primary objective of this investigation was to determine patterns of drinking and smoking during pregnancy that increase risk of SIDS. Methods/UNASSIGNED:The Safe Passage Study was a prospective, multi-center, observational study with 10,088 women, 11,892 pregnancies, and 12,029 fetuses, followed to 1-year post delivery. Subjects were from two sites in Cape Town, South Africa and five United States sites, including two American Indian Reservations. Group-based trajectory modeling was utilized to categorize patterns of drinking and smoking exposure during pregnancy. Findings/UNASSIGNED: = 0·02) for smoking only beyond the first trimester as compared to those unexposed or reported quitting early in pregnancy. Interpretation/UNASSIGNED:Infants prenatally exposed to both alcohol and cigarettes continuing beyond the first trimester have a substantially higher risk for SIDS compared to those unexposed, exposed to alcohol or cigarettes alone, or when mother reported quitting early in pregnancy. Given that prenatal drinking and smoking are modifiable risk factors, these results address a major global public health problem. Funding/UNASSIGNED:National Institute of Child Health and Human Development, and the National Institute on Deafness and Other Communication Disorders.

We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of scan time (25 hours per flip angle), allowing derivation of synthesized FLASH volumes. This dataset provides an unprecedented view of the three-dimensional neuroanatomy of the human brain. To optimize the utility of this resource, we warped the dataset into standard stereotactic space. We now distribute the dataset in both native space and stereotactic space to the academic community via multiple platforms. We envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance understanding of human brain anatomy in health and disease.

Introduction: Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. A consensus panel funded by the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering (NINDS/NIBIB) was convened to define the neuropathological criteria for CTE.
Method(s): Twenty-five cases of various tauopathies were selected. The cases included 10 cases of suspected CTE and other cases that may have overlapped or be confused with CTE included Alzheimer disease (n = 5), progressive supranuclear palsy (n = 2), corticobasal degeneration (n = 2), parkinsonism/dementia complex of Guam (n = 2), argyrophilic grain disease (n = 2), and primary age-related tauopathy (n = 2). From 27 representative areas, sections were stained with Luxol fast blue counterstained with hematoxylin and eosin and a Bielschowsky silver impregnation; immunohistochemistry was performed using anti-Abeta42, anti-phosho- tau and anti-phospho- TDP- 43. The 671 glass slides were scanned into digital images using an Aperio scanner (Leica Biosystems, Buffalo Grove, IL. No clinical or demographic information was provided to the evaluating neuropathologists.
Result(s): There was good agreement regarding the overall neuropathological diagnosis of all 25 cases (Cohen's kappa, 0.67), and even better agreement regarding the specific diagnosis of CTE (Cohen's kappa, 0.78), using the proposed criteria. Three initial diagnoses of non-CTE were changed to CTE and nine diagnoses of co-morbid CTE in non-CTE cases were changed to no CTE after revealing the clinical and gross neuropathological features.
Conclusion(s): A consensus panel of seven neuropathologists concluded that the pathology of CTE is distinct from other tauopathies. The panel described the pathognomonic lesion of CTE as an accumulation of abnormal tau in neurons and astroglia distributed perivascularly at the depths of sulci in the isocortex in an irregular pattern

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

While next-generation sequencing has accelerated the discovery of human disease genes, progress has been largely limited to the "low hanging fruit" of mutations with obvious exonic coding or canonical splice site impact. In contrast, the lack of high-throughput, unbiased approaches for functional assessment of most noncoding variants has bottlenecked gene discovery. We report the integration of transcriptome sequencing (RNA-seq), which surveys all mRNAs to reveal functional impacts of variants at the transcription level, into the gene discovery framework for a unique human disease, microcephaly-micromelia syndrome (MMS). MMS is an autosomal recessive condition described thus far in only a single First Nations population and causes intrauterine growth restriction, severe microcephaly, craniofacial anomalies, skeletal dysplasia, and neonatal lethality. Linkage analysis of affected families, including a very large pedigree, identified a single locus on Chromosome 21 linked to the disease (LOD > 9). Comprehensive genome sequencing did not reveal any pathogenic coding or canonical splicing mutations within the linkage region but identified several nonconserved noncoding variants. RNA-seq analysis detected aberrant splicing in DONSON due to one of these noncoding variants, showing a causative role for DONSON disruption in MMS. We show that DONSON is expressed in progenitor cells of embryonic human brain and other proliferating tissues, is co-expressed with components of the DNA replication machinery, and that Donson is essential for early embryonic development in mice as well, suggesting an essential conserved role for DONSON in the cell cycle. Our results demonstrate the utility of integrating transcriptomics into the study of human genetic disease when DNA sequencing alone is not sufficient to reveal the underlying pathogenic mutation.

Upon detection of foreign-body embolization to the central nervous system (CNS) following a specific invasive cardiovascular procedure in 1 autopsied child, we undertook a quality assurance analysis to determine whether other patients had had similar events. Autopsies of all infants and children with history of cardiac catheterization, heart surgery on cardiopulmonary bypass, and/or extracorporeal membrane oxygenation over a 5-year period at a single tertiary care institution were reviewed for light-microscopic evidence of foreign material. Of the 24 patients meeting clinical criteria (13 females, 11 males; ages 6 days to 20 years, median age 7.5 months), 8 (33%) had foreign embolic material to the CNS. The material was associated with a cellular inflammatory reaction in all cases, with a subset associated with infarcts. No embolic foreign material was detected in 14 age-matched patients without history of cardiovascular procedures. Particles acquired from ex vivo manipulation of a catheter type utilized in at least 1 of the affected patients demonstrated similar histologic characteristics. We conclude that, in addition to recognized risks of hypoxic-ischemic brain damage in congenital cardiopulmonary disease, potential brain insult exists in the form of instrumentation-related foreign emboli to the cerebral vasculature. Cardiac catheters are a potential source of foreign embolic material.