Loss of Perineuronal Net in ME7 Prion Disease

Microglial activation and behavioral abnormalities occur before neuronal loss in experimental murine prion disease; the behavioral changes coincide with a reduction in synaptic plasticity. Because synaptic plasticity depends on an intact perineuronal net (PN), a specialized extracellular matrix that surrounds parvalbumin (PV)-positive GABAergic (gamma-aminobutyric acid [GABA]) inhibitory interneurons, we investigated the temporal relationships between microglial activation and loss of PN and PV-positive neurons in ME7 murine prion disease. Anesthetized C57Bl/6J mice received bilateral intracerebral microinjections of ME7-infected or normal brain homogenate into the dorsal hippocampus. Microglial activation, PrP accumulation, the number of PV-positive interneurons, and Wisteria floribunda agglutinin-positive neurons (i.e. those with an intact PN) were assessed in the ventral CA1 and subiculum at 4, 8, 12, 16, and 20 weeks postinjection. Hippocampal areas and total neuron numbers in the ventral CA1 and subiculum were also determined. Loss of PN coincided with early microglial activation and with a reduction in synaptic plasticity. No significant loss of PV-positive interneurons was observed. Our findings suggest that the substrate of the earliest synaptic and behavioral abnormalities in murine prion disease may be inflammatory microglia-mediated degradation of the PN

Behavioral consequences of prion disease targeted to the hippocampus in a mouse model of scrapie

Sheep scrapie is an archetypal member of a group of chronic neurodegenerative diseases that can afflict both humans and animals and that are known collectively as the transmissible spongiform encephalopathies or prion diseases. The study of these diseases has been facilitated by the experimental transmission of sheep scrapie to laboratory rodents, and this has led to an ever-increasing literature on the pathogenesis and molecular biology of this unusual group of diseases. There is relatively little known about the relationship between the chronic neurodegenerative process and the development of clinical signs, the latter occurring very late in the course of the disease after a prolonged incubation period. We have previously shown that following intrahippocampal injection of scrapie brain homogenate, there is an early inflammatory response in the brains of affected mice. This develops long before there is neuronal loss and also before the mice develop any overt clinical signs of disease. It was surprising that despite the marked and evolving inflammatory response in the brains of scrapie-affected mice, indicative of underlying pathology, there were no outward signs that the mice had any form of central nervous system pathology. The present study shows that by using a number of behavioral tasks, including multitrial passive avoidance, open-field motor activity, and tests of muscle strength, it is possible to detect more subtle clinical signs much earlier during the course of disease in scrapie-affected mice. The relevance of this finding to the investigation of mouse scrapie is discussed.</p

Understanding the complex challenges in digital pathology and artificial intelligence integration

The hexagonal socio-technical framework was employed to understand the complex system of digital pathology (DP) workflow and artificial intelligence (AI) application while identifying the complex human factors challenges within the DP and AI integration process.</p

Systems thinking approach to the implementation of digital pathology and AI

A rapid rise in digitization and AI implementation in pathology services has been seen over the last decade, which is likely to bring a paradigm shift in these services in the near future. However, the process of implementing AI solutions to pathology practices has been relatively slow and somewhat problematic due to a technology-centered mindset, which leads to a focus on technology alone and neglecting systemic factors including a wide range of stakeholders involved, ethical issues and the overall workflow, etc. The aim of this project is to explore how a systems thinking approach can improve the implementation of digitalization and AI implementation in pathology services. The Royal College of Pathologists (RCPath) position statement on digital pathology and AI provides an essential foundation for understanding the perspective of the RCPath on the implementation of digital pathology and AI. A qualitative analysis of this foundational document using the Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework as a guiding system framework for analysis was conducted. The NASSS framework, rooted in implementation science and complexity science, was developed to aid in identifying dynamic systemic factors and their interrelationships within the implementation. It promises to offer a comprehensive understanding of the implementation process and its associated complexities. Based on our NASS framework analysis, a visual system map was produced showing how facilitators and barriers interact together and any gaps in the document. The analysis indicates that the position statement identified some significant facilitators and barriers to implementation, but it focused mainly on pathologists without considering a broader range of indirect adopters like biomedical scientists and associated clinicians within the system. The awareness of the wider healthcare systemic issues was lacking. This presentation will report on more detailed findings, the visual system map produced and further on-going case study work.</p