Faculty Bibliography

Two years into the COVID-19 pandemic, there are few published accounts of postmortem SARS-CoV-2 pathology in children. We report 8 such cases (4 infants aged 7-36 weeks, 4 children aged 5-15 years). Four underwent ex vivo magnetic resonance neuroimaging, to assist in identification of subtle lesions related to vascular compromise. All infants were found unresponsive (3 in unsafe sleeping conditions); all but 1 had recent rhinitis and/or influenza-like illness (ILI) in the family; 1 had history of sickle cell disease. Ex vivo neuroimaging in 1 case revealed white matter (WM) signal hyperintensity and diffuse exaggeration of perivascular spaces, corresponding microscopically to WM mineralization. Neurohistology in the remaining 3 infants variably encompassed WM gliosis and mineralization; brainstem gliosis; perivascular vacuolization; perivascular lymphocytes and brainstem microglia. One had ectopic hippocampal neurons (with pathogenic variant in DEPDC5). Among the children, 3 had underlying conditions (e.g., obesity, metabolic disease, autism) and all presented with ILI. Three had laboratory testing suggesting multisystem inflammatory syndrome (MIS-C). Two were hospitalized for critical care including mechanical ventilation and extracorporeal membrane oxygenation (ECMO); one (co-infected with adenovirus) developed right carotid stroke ipsilateral to the ECMO cannula and the other required surgery for an ingested foreign body. Autopsy findings included: acute lung injury in 3 (1 with microthrombi); and one each with diabetic ketoacidosis and cardiac hypertrophy; coronary and cerebral arteritis and aortitis, resembling Kawasaki disease; and neuronal storage and enlarged fatty liver. All 4 children had subtle meningoencephalitis, focally involving the brainstem. On ex vivo neuroimaging, 1 had focal pontine susceptibility with corresponding perivascular inflammation/expanded perivascular spaces on histopathology. Results suggest SARS-CoV-2 in infants may present as sudden unexpected infant death, while in older children, signs and symptoms point to severe disease. Underlying conditions may predispose to fatal outcomes. As in adults, the neuropathologic changes may be subtle, with vascular changes such as perivascular vacuolization and gliosis alongside sparse perivascular lymphocytes. Detection of subtle vascular pathology is enhanced by ex vivo neuroimaging. Additional analysis of the peripheral/autonomic nervous system and investigation of co-infection in children with COVID-19 is necessary to understand risk for cardiovascular collapse/sudden death.

Individuals with dementia may come to forensic autopsy, partly because of non-natural deaths (e.g. fall-related), and/or concerns of abuse/neglect. At the New York City Office of Chief Medical Examiner (NYC OCME), brains from such cases are submitted for neurodegenerative disease (ND) work-up. Seventy-eight sequential cases were evaluated using a recently published condensed protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer disease (AD), a cost-cutting innovation in diagnostic neuropathology. ND was identified in 74 (94.9%) brains; the most common were AD (n = 41 [52.5%]), primary age-related tauopathy (n = 26 [33.3%]), and Lewy body disease ([LBD], n = 25 [32.1%]). Others included age-related tau astrogliopathy, hippocampal sclerosis of aging, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, argyrophilic grain disease, and Creutzfeldt-Jakob disease. 26.8% of AD cases involved a non-natural, dementia-related death, versus 40.0% for LBD. Finally, 70 (89.7%) cases had chronic cerebrovascular disease, 53 (67.9%) being moderate-to-severe. We present a diverse distribution of NDs notable for a high rate of diagnoses associated with falls (e.g. LBD), a potential difference from the hospital neuropathology experience. We also report a high burden of cerebrovascular disease in demented individuals seen at the NYC OCME. Finally, we demonstrate that the aforementioned condensed protocol is applicable for a variety of ND diagnoses.

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by ¹²⁵I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in ¹²⁵I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002-0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, ¹²⁵I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on ¹²⁵I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla-a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

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.