Faculty Bibliography

In recent years, time-varying inhomogeneous point process models have been introduced for assessment of instantaneous heartbeat dynamics as well as specific cardiovascular control mechanisms and hemodynamics. Assessment of the model's statistics is established through the Wiener-Volterra theory and a multivariate autoregressive (AR) structure. A variety of instantaneous cardiovascular metrics, such as heart rate (HR), heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and baroreceptor-cardiac reflex (baroreflex) sensitivity (BRS), are derived within a parametric framework and instantaneously updated with adaptive and local maximum likelihood estimation algorithms. Inclusion of second-order non-linearities, with subsequent bispectral quantification in the frequency domain, further allows for definition of instantaneous metrics of non-linearity. We here present a comprehensive review of the devised methods as applied to experimental recordings from healthy subjects during propofol anesthesia. Collective results reveal interesting dynamic trends across the different pharmacological interventions operated within each anesthesia session, confirming the ability of the algorithm to track important changes in cardiorespiratory elicited interactions, and pointing at our mathematical approach as a promising monitoring tool for an accurate, non-invasive assessment in clinical practice. We also discuss the limitations and other alternative modeling strategies of our point process approach.

Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, an in vivo strategy is described that has been successfully used to map amyloid-beta deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing both the endogenous contrast induced by the plaques attributed to their iron content and by selectively enhancing the signal from amyloid-beta plaques using molecular-targeting vectors labeled with MRI contrast agents. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency and dictate the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Two-dimensional (2D) multi-slice and three-dimensional (3D) MRI acquisitions are described and their advantages and limitations are discussed. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse's head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies and for subsequent matching of MRI with histology.

Background: Immunotherapy targeting hyperphosphorylated tau is a promising prospect to mitigate the neurodegenerative effects of tauopathies. Assessing the effectiveness of such immunotherapies often involves sacrifice of the animal. However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Methods: Twenty-five homozygous JNPL3 tangle transgenic mice underwent MEMRI at 6 months of age. Thirteen of the mice received tau immunotherapy with Tau379-408[P-Ser396,404] in alum adjuvant from 3 months of age, and twelve controls received an adjuvant alone. Imaging studies were performed on a 7-T micro-MRI. Mice were imaged pre-injection, then injected in one nostril with a solution of 2.5 M MnCl 2, under isoflurane anesthesia. Image sets were acquired at 1, 4, 8, 12, 24, 36 and 48 hours, and finally at 7 days (Fig 1). The datasets were processed using ImageJ. Normalized measurements for each mouse were plotted and fitted to a tract tracing bolus model using MATLAB. Fitting enabled the estimation of the timing (Pt) and intensity (Pv) of the bolus peak of Mn, and maximal slope of uptake (Sv). Results: A significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer (35%, P <.005) and glomerular layer (36%, P <0.02) in treated JNPL3 mice compared to identical controls. There was also a significant increase in bolus peak value, Pv, in the mitral layer in the treated group (7%, P = 0.02). Furthermore, in the immunized mice, there was a strong trend for a decrease in the time to peak value, Pt (-9%P = 0.10), in the mitral cell layer, compared to the controls. Conclusions: Utilizing MEMRI's non-invasive, longitudinal measurements from 1 hour to 7 days, allowed us to detect substantial improvements in neuronal transport following tau immunotherapy. We are analyzing tau pathology in olfactory sections from these mice to assess the correlation of these benefits with clearance of tau lesions, which we have shown previously to occur with this treatment

The adult brain functions within a well-controlled stable environment, the properties of which are determined by cellular exchange mechanisms superimposed on the diffusion restraint provided by tight junctions at interfaces between blood, brain and cerebrospinal fluid (CSF). These interfaces are referred to as "the" blood-brain barrier. It is widely believed that in embryos and newborns, this barrier is immature or "leaky," rendering the developing brain more vulnerable to drugs or toxins entering the fetal circulation from the mother. New evidence shows that many adult mechanisms, including functionally effective tight junctions are present in embryonic brain and some transporters are more active during development than in the adult. Additionally, some mechanisms present in embryos are not present in adults, e.g., specific transport of plasma proteins across the blood-CSF barrier and embryo-specific intercellular junctions between neuroependymal cells lining the ventricles. However developing cerebral vessels appear to be more fragile than in the adult. Together these properties may render developing brains more vulnerable to drugs, toxins, and pathological conditions, contributing to cerebral damage and later neurological disorders. In addition, after birth loss of protection by efflux transporters in placenta may also render the neonatal brain more vulnerable than in the fetus.

We report the elusive X-ray structure of the Dess-Martin periodinane (DMP), a hypervalent iodine reagent popular amongst synthetic chemists. In the solid state, the highly crystalline compound forms an intricate coordination polymer held together by intermolecular halogen and hydrogen bonds.