No abstract

Ten individuals suspected of having possible Alzheimer disease underwent PET imaging using 18F-Flubetapir. Only one of ten individuals had a pattern typical for normal elderly control subjects with 9 of the 10 showing a Alzheimer type pattern for the cerebral cortex yet all 10 subjects had uniformly low to absent tracer localization to the cerebellar cortex; significantly high tracer activity was noted within the subcortical white matter of the cerebellum in a symmetric manner in all cases. In consideration of studies that have shown amyloid deposits within the cerebellar cortex in 90% of pathologically proven cases of Alzheimer’s disease, these findings raise questions about the actual clinical value of florbetapir PET imaging in evaluating cerebellar involvement and raises questions whether PET imaging of this tracer accurately portrays patterns of amyloid deposition, as there is rapid hepatic metabolism of the parent compound after intravenous injection. Possible links to Alzheimer’s disease related alterations in blood-brain barrier permeability to the parent compound and subsequent radiolabelled metabolites are discussed as potential mechanisms that could explain the associated localization of the tracer to the brainstem and subcortical white matter within the cerebrum and cerebellum of Alzheimer’s disease patients.

Preliminary data demonstrated that a greater percentage of female mice infected with F. tularensis succumbed to disease and developed symptoms faster than male mice. Increases in the serum inflammatory cytokine levels corresponded to this enhanced sensitivity in females consistent with a stronger inflammatory. Herein, we sought to understand the cellular basis for this sex difference in the inflammatory response between males and females. We used a combination of in vivo and ex vivo cellular analysis to determine differences in the cellular response to F. tularensis. Multiparametric cytokine analysis was used to quantify changes in serum and supernatant cytokines, real-time RT-PCR was used to measure cytokine mRNA expression in tissues, and multiparametric flow cytometry was used to discriminate cell populations responsive to infection. Despite a tendency for fewer T regulatory (Treg) cells, males had fewer inflammatory macrophage and an increase in regulatory macrophages. This corresponded with an overall decrease in the transcripts of IL-10, IL-5, and IL-4 in the tissues of mice succumbing to disease and an increase in IL-6 transcripts, a marker for the level of inflammation. The functional deficiency of regulatory macrophages and increase of M1 macrophages may enhance the inflammatory response to F. tularensis ultimately leading to decreased survival. Further investigations will focus on understanding the interactions between these myeloid populations with F. tularensis and other cells of the immune system. Development of therapeutics that activate or induce expansion of regulatory macrophages or that suppress the activity/activation of M1 macrophages may prevent death from this disease.

Francisella tularensisis the causative agent of the human disease tularemia. F. tularensisinfects a variety of cells, including macrophages, in order to cause pathogenicity. As few as 10 inhaled microorganisms cause a lethal infection by over-activating the host’s own inflammatory response. Differences in the intensity of the inflammatory response exist between the sexes which leads to differences in sensitivity to autoimmune and infectious disease. Males tend to be more susceptible to infectious diseases whereas females tend to be more susceptible to autoimmune diseases. However, our preliminary data unexpectedly demonstrated that female mice were more susceptible to F. tularensis-mediated disease than male mice. We hypothesize that the elevated inflammatory state of females may make them more susceptible to F. tularensis disease and that the M1 and M2 macrophage subsets may determine this differential inflammatory response. Naïve M1 and M2 macrophages will be purified from male and female mice and infected in vitro to directly compare cellular responses between male and female mice. In parallel, M0 macrophages will be differentiated in vitro prior to infection for similar comparison.

The zoonotic infectious disease, Francisella tularensis, the causative agent for human tularemia, elicits high cytokine levels as a result of rampant inflammation, a condition referred to as “cytokine storm.” This cytokine storm is responsible for the severity of symptoms and ultimately for the death of the host. Though men have a tendency to be exposed to the pathogen more frequently than women, do to its presence in wild animals, women have a significantly greater inflammatory response than do men. Therefore, we asked whether their enhanced inflammatory response might make women more susceptible to tularemia-mediated death. Male and female mice were infected with F. tularensis and their survival and inflammatory response monitored. Subsequently, the role of sex hormones was considered by infecting gonadectomized mice. On average, 15% female mice survived infection compared with 90% of male mice. In addition, the female mice displayed an increased serum cytokine storm compared with male mice despite similar levels of bacterial growth. We seek to identify the factors controlling this increased susceptibility of female mice. This line of investigation may lead to the development of novel therapeutics and/or treatment strategies specific to women exposed to F. tularensis.