Dynamic Measurement Of Soluble Human Aβ In A Combined Microdialysis-Experimental Traumatic Brain Injury Mouse Model

The amyloid-β peptide: Aβ) plays a central pathophysiological role in Alzheimer\u27s disease, but little is known about its dynamics in the brain\u27s extracellular space. A recent microdialysis-based study in human patients with severe brain injuries found that extracellular Aβ dynamics correlate with changes in neurological status. Because neurological status is generally diminished following injury, this correlation suggests that extracellular Aβ is reduced relative to baseline. However, human studies cannot assess pre-injury Aβ levels, very early post-injury Aβ levels, nor the relationship between extracellular Aβ and total tissue levels. Therefore, we developed a mouse model that combines experimental TBI with microdialysis to address these gaps. In this model, Aβ levels were stable at baseline and after sham-injury. Following controlled cortical impact TBI, we found that Aβlevels were immediately and persistently decreased in the ipsilateral hippocampus. These results were found in both wild-type mice and young pre-plaque PDAPP mice that produce human-sequence Aβ. Similar decreases were observed in PBS-soluble hippocampal extracts, but no changes were found in carbonate or guanidine extracts. Reductions in Aβ were not due to changes in microdialysis probe function, APP levels nor Aβ deposition. Hippocampal depth electrode recordings demonstrated that electroencephalographic activity was decreased over 24 hours following TBI. Thus, we propose that in mice and likely injured human patients, post-injury extracellular Aβ levels are acutely decreased relative to baseline. Reduced neuronal activity may contribute, though the underlying mechanisms have not been definitively determined. One hypothesized mechanism for reduced extracellular levels is that Aβ is retained at the synapse following injury. To test this, we prepared synaptosomes in sham and injured PDAPP mice and measured levels of Aβ and APP by ELISA. No significant differences between sham and 2.0 mm-injured mice were detected. Future experiments will determine whether enhanced clearance accounts for decreased extracellular Aβ. In summary, we have designed a mouse model to address questions that cannot be answered in patients. Using this model, we measured Aβ dynamics and their relationship to tissue levels and a possible relationship with neuronal activity. Studies of other peptides and treatment strategies might benefit from use of this model

Ring-enhancing Brain Lesions in a Patient with Advanced Human Immunodeficiency Virus from the Central United States of America

Background: Histoplasmosis is an endemic fungus found worldwide. It most commonly causes pulmonary infections. In patients with defects in cellular immunity it can cause disseminated infections including central nervous system infections. Case presentation: We present a case of a 44-year-old with advanced human immunodeficiency virus who presented with neurologic complaints. Magnetic resonance imaging of the brain revealed ring-enhancing brain lesions. He underwent brain biopsy of one of the ring-enhancing lesions and histopathology revealed Histoplasma capsulatum. Conclusion: Ring-enhancing brain lesions due to endemic fungi in patients with advanced HIV are uncommon. Nonetheless, this should remain a diagnostic consideration in endemic areas.D. Matthew Shoemaker (1), Katherine Schwetye (2) ; 1. University of Kansas Medical Center. Assistant Professor, Infectious Diseases. 2. Saint Louis University. Assistant Professor, Pathology.Includes bibliographical reference

LATE-NC staging in routine neuropathologic diagnosis: An update

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer\u27s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience

Melanoma mimicking malignant peripheral nerve sheath tumor with spread to the cerebellopontine angle: Utility of next-generation sequencing in diagnosis

Cutaneous spindle cell malignancy is associated with a broad differential diagnosis, particularly in the absence of a known primary melanocytic lesion. We present an unusually challenging patient who presented with clinical symptoms involving cranial nerves VII and VIII and a parotid-region mass, which was S100-positive while lacking in melanocytic pigment and markers. Over a year after resection of the parotid mass, both a cutaneous primary lentigo maligna melanoma and a metastatic CP angle melanoma were diagnosed in the same patient, prompting reconsideration of the diagnosis in the original parotid-region mass. Next-generation sequencing of a panel of cancer-associated genes demonstrated 19 identical, clinically significant mutations as well as a high tumor mutation burden in both the parotid-region and CP angle tumors, indicating a metastatic relationship between the two and a melanocytic identity of the parotid-region tumor

On Edge Computing for Remote Pathology Consultations and Computations

Telepathology aims to replace the pathology operations performed on-site, but current systems are limited by their prohibitive cost, or by the adopted underlying technologies. In this work, we contribute to overcoming these limitations by bringing the recent advances of edge computing to reduce latency and increase local computation abilities to the pathology ecosystem. In particular, this paper presents LiveMicro, a system whose benefit is twofold: on one hand, it enables edge computing driven digital pathology computations, such as data-driven image processing on a live capture of the microscope. On the other hand, our system allows remote pathologists to diagnosis in collaboration in a single virtual microscope session, facilitating continuous medical education and remote consultation, crucial for under-served and remote hospital or private practice. Our results show the benefits and the principles underpinning our solution, with particular emphasis on how the pathologists interact with our application. Additionally, we developed simple yet effective diagnosis-aided algorithms to demonstrate the practicality of our approach

Electromagnetic controlled cortical impact device for precise, graded experimental traumatic brain injury

Genetically modified mice represent useful tools for traumatic brain injury (TBI) research and attractive preclinical models for the development of novel therapeutics. Experimental methods that minimize the number of mice needed may increase the pace of discovery. With this in mind, we developed and characterized a prototype electromagnetic (EM) controlled cortical impact device along with refined surgical and behavioral testing techniques. By varying the depth of impact between 1.0 and 3.0 mm, we found that the EM device was capable of producing a broad range of injury severities. Histologically, 2.0-mm impact depth injuries produced by the EM device were similar to 1.0-mm impact depth injuries produced by a commercially available pneumatic device. Behaviorally, 2.0-, 2.5-, and 3.0-mm impacts impaired hidden platform and probe trial water maze performance, whereas 1.5-mm impacts did not. Rotorod and visible platform water maze deficits were also found following 2.5- and 3.0-mm impacts. No impairment of conditioned fear performance was detected. No differences were found between sexes of mice. Inter-operator reliability was very good. Behaviorally, we found that we could statistically distinguish between injury depths differing by 0.5 mm using 12 mice per group and between injury depths differing by 1.0 mm with 7-8 mice per group. Thus, the EM impactor and refined surgical and behavioral testing techniques may offer a reliable and convenient framework for preclinical TBI research involving mice

BRAF mutations may identify a clinically distinct subset of glioblastoma

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Prior studies examining the mutational landscape of GBM revealed recurrent alterations in genes that regulate the same growth control pathways. To this regard, ~ 40% of GBM harbor EGFR alterations, whereas BRAF variants are rare. Existing data suggests that gain-of-function mutations in these genes are mutually exclusive. This study was designed to explore the clinical, pathological, and molecular differences between EGFR- and BRAF-mutated GBM. We reviewed retrospective clinical data from 89 GBM patients referred for molecular testing between November 2012 and December 2015. Differences in tumor mutational profile, location, histology, and survival outcomes were compared in patients with EGFR- versus BRAF-mutated tumors, and microarray data from The Cancer Genome Atlas was used to assess differential gene expression between the groups. Individuals with BRAF-mutant tumors were typically younger and survived longer relative to those with EGFR-mutant tumors, even in the absence of targeted treatments. BRAF-mutant tumors lacked distinct histomorphology but exhibited unique localization in the brain, typically arising adjacent to the lateral ventricles. Compared to EGFR- and IDH1-mutant tumors, BRAF-mutant tumors showed increased expression of genes related to a trophoblast-like phenotype, specifically HLA-G and pregnancy specific glycoproteins, that have been implicated in invasion and immune evasion. Taken together, these observations suggest a distinct clinical presentation, brain location, and gene expression profile for BRAF-mutant tumors. Pending further study, this may prove useful in the stratification and management of GBM

The role of vaccination route with an adenovirus-vectored vaccine in protection, viral control, and transmission in the SARS-CoV-2/K18-hACE2 mouse infection model

IntroductionVaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites.MethodsUtilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival.ResultsMice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed that animals vaccinated intranasally had improved cellular and mucosal antibody responses. Additionally, intranasally vaccinated animals had significantly better viremic control, and protection from lethal infection compared to intramuscularly vaccinated animals. Notably, in a novel transmission model, intranasal vaccination reduced viral transmission to naïve co-housed mice compared to intramuscular vaccination.DiscussionOur data provide convincing evidence for the use of intranasal vaccination in protecting against SARS-CoV-2 infection and transmission

Distinct Temporal and Anatomical Distributions of Amyloid-β and Tau Abnormalities following Controlled Cortical Impact in Transgenic Mice

Traumatic brain injury (TBI) is a major environmental risk factor for Alzheimer's disease. Intracellular accumulations of amyloid-β and tau proteins have been observed within hours following severe TBI in humans. Similar abnormalities have been recapitulated in young 3xTg-AD mice subjected to the controlled cortical impact model (CCI) of TBI and sacrificed at 24 h and 7 days post injury. This study investigated the temporal and anatomical distributions of amyloid-β and tau abnormalities from 1 h to 24 h post injury in the same model. Intra-axonal amyloid-β accumulation in the fimbria was detected as early as 1 hour and increased monotonically over 24 hours following injury. Tau immunoreactivity in the fimbria and amygdala had a biphasic time course with peaks at 1 hour and 24 hours, while tau immunoreactivity in the contralateral CA1 rose in a delayed fashion starting at 12 hours after injury. Furthermore, rapid intra-axonal amyloid-β accumulation was similarly observed post controlled cortical injury in APP/PS1 mice, another transgenic Alzheimer's disease mouse model. Acute increases in total and phospho-tau immunoreactivity were also evident in single transgenic TauP301L mice subjected to controlled cortical injury. These data provide further evidence for the causal effects of moderately severe contusional TBI on acceleration of acute Alzheimer-related abnormalities and the independent relationship between amyloid-β and tau in this setting

LATE-NC staging in routine neuropathologic diagnosis : an update

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.Peer reviewe