Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1β (IL-1β) responses to subsequent LPS stimulation.Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1β. Systemic LPS triggered microglial IL-1β, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1β disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1β and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

Evidence for the effectiveness of mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) is rapidly growing as interest in this field expands. By contrast, there are few empirical analyses of the pedagogy of MBSR and MBCT. Development of the evidence base concerning the teaching of MBCT or MBSR would support the integrity of the approach in the context of rapid expansion. This paper describes an applied conversation analysis (CA) of the characteristics of inquiry in the MBSR and MBCT teaching process. Audio-recordings of three 8-week MBCT and MBSR classes, with 24, 12, and 6 participants, were transcribed and systematically examined. The study focused on the teacher-led interactive inquiry which takes place in each session after a guided meditation practice. The study describes and analyzes three practices within the inquiry process that can be identified in sequences of talk: turn-taking talk involving questions and reformulations; the development of participant skills in a particular way of describing experience; and talk that constructs intersubjective connection and affiliation within the group. CA enables fine-grained analysis of the interactional work of mindfulness-based inquiry. Inquiry is a process of disciplined improvisation which is both highly specific to the conditions of the moment it took place in and uses repeated and recognizable patterns of interaction.

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Acknowledgements. This study was supported by a Wellcome Trust Senior ResearchFellowship to CC (SRF090907) and by NIH R01AG050626. The technical assistance of Gavin MacManus in the Biomedical Sciences Imaging suite is gratefully acknowledged. AbstractAlzheimer's disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by -amyloid pathology to induce exaggerated IL-1 responses to acute stimulation with LPS or IL-1. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1 induction nor NFĸB p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1, NFĸB-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1 we demonstrate that astrocytes proximal to A-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

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