Effect of Osteopathic Cranial Manipulative Medicine on an Aged Rat Model of Alzheimer Disease.

CONTEXT: In the aging brain, reduction in the pulsation of cerebral vasculature and fluid circulation causes impairment in the fluid exchange between different compartments and lays a foundation for the neuroinflammation that results in Alzheimer disease (AD). The knowledge that lymphatic vessels in the central nervous system play a role in the clearance of brain-derived metabolic waste products opens an unprecedented capability to increase the clearance of macromolecules such as amyloid ß proteins. However, currently there is no pharmacologic mechanism available to increase fluid circulation in the aging brain. OBJECTIVE: To demonstrate the influence of an osteopathic cranial manipulative medicine (OCMM) technique, specifically, compression of the fourth ventricle, on spatial memory and changes in substrates associated with mechanisms of metabolic waste clearance in the central nervous system using the naturally aged rat model of AD. RESULTS: Significant improvement was found in spatial memory in 6 rats after 7 days of OCMM sessions. Live animal positron emission tomographic imaging and immunoassays revealed that OCMM reduced amyloid ß levels, activated astrocytes, and improved neurotransmission in the aged rat brains. CONCLUSION: These findings demonstrate the molecular mechanism of OCMM in aged rats. This study and further investigations will help physicians promote OCMM as an evidence-based adjunctive treatment for patients with AD.

Low-Dose Imaging in a New Preclinical Total-Body PET/CT Scanner.

Ionizing radiation constitutes a health risk to imaging scientists and study animals. Both PET and CT produce ionizing radiation. CT doses in pre-clinical in vivo imaging typically range from 50 to 1,000 mGy and biological effects in mice at this dose range have been previously described. [18F]FDG body doses in mice have been estimated to be in the range of 100 mGy for [18F]FDG. Yearly, the average whole body doses due to handling of activity by PET technologists are reported to be 3-8 mSv. A preclinical PET/CT system is presented with design features which make it suitable for small animal low-dose imaging. The CT subsystem uses a X-source power that is optimized for small animal imaging. The system design incorporates a spatial beam shaper coupled with a highly sensitive flat-panel detector and very fast acquisition (<10 s) which allows for whole body scans with doses as low as 3 mGy. The mouse total-body PET subsystem uses a detector architecture based on continuous crystals, coupled to SiPM arrays and a readout based in rows and columns. The PET field of view is 150 mm axial and 80 mm transaxial. The high solid-angle coverage of the sample and the use of continuous crystals achieve a sensitivity of 9% (NEMA) that can be leveraged for use of low tracer doses and/or performing rapid scans. The low-dose imaging capabilities of the total-body PET subsystem were tested with NEMA phantoms, in tumor models, a mouse bone metabolism scan and a rat heart dynamic scan. The CT imaging capabilities were tested in mice and in a low contrast phantom. The PET low-dose phantom and animal experiments provide evidence that image quality suitable for preclinical PET studies is achieved. Furthermore, CT image contrast using low dose scan settings was suitable as a reference for PET scans. Total-body mouse PET/CT studies could be completed with total doses of <10 mGy.

Bismuth Infusion of ABS Enables Additive Manufacturing of Complex Radiological Phantoms and Shielding Equipment.

Radiopacity is a critical property of materials that are used for a range of radiological applications, including the development of phantom devices that emulate the radiodensity of native tissues and the production of protective equipment for personnel handling radioactive materials. Three-dimensional (3D) printing is a fabrication platform that is well suited to creating complex anatomical replicas or custom labware to accomplish these radiological purposes. We created and tested multiple ABS (Acrylonitrile butadiene styrene) filaments infused with varied concentrations of bismuth (1.2-2.7 g/cm³), a radiopaque metal that is compatible with plastic infusion, to address the poor gamma radiation attenuation of many mainstream 3D printing materials. X-ray computed tomography (CT) experiments of these filaments indicated that a density of 1.2 g/cm³ of bismuth-infused ABS emulates bone radiopacity during X-ray CT imaging on preclinical and clinical scanners. ABS-bismuth filaments along with ABS were 3D printed to create an embedded human nasocranial anatomical phantom that mimicked radiological properties of native bone and soft tissue. Increasing the bismuth content in the filaments to 2.7 g/cm³ created a stable material that could attenuate 50% of 99mTechnetium gamma emission when printed with a 2.0 mm wall thickness. A shielded test tube rack was printed to attenuate source radiation as a protective measure for lab personnel. We demonstrated the utility of novel filaments to serve multiple radiological purposes, including the creation of anthropomorphic phantoms and safety labware, by tuning the level of radiation attenuation through material customization.

Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice.

Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT) or quantitative nuclear magnetic resonance (QMR). Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR. First, an in vitro analysis of oil/water mixtures was used to calibrate and assess the overall accuracy of microCT vs. QMR data. Next, experiments were conducted with two cohorts of living mice (either homogenous or heterogeneous by sex, age and genetic backgrounds) to assess the microCT imaging technique for adipose tissue segmentation and quantification relative to QMR. Adipose mass values were obtained from microCT data with three different resolutions, after which the data were analyzed with different filter and segmentation settings. Strong linearity was noted between the adipose mass values obtained with microCT and QMR, with optimal parameters and scan conditions reported herein. Lean tissue (muscle, internal organs) was also segmented and quantified using the microCT method relative to the analogous QMR values. Overall, the rigorous calibration and validation of the microCT method for murine body composition, relative to QMR, ensures its validity for segmentation, quantification and visualization of both adipose and lean tissues.

In vivo X-ray computed tomographic imaging of soft tissue with native, intravenous, or oral contrast.

X-ray Computed Tomography (CT) is one of the most commonly utilized anatomical imaging modalities for both research and clinical purposes. CT combines high-resolution, three-dimensional data with relatively fast acquisition to provide a solid platform for non-invasive human or specimen imaging. The primary limitation of CT is its inability to distinguish many soft tissues based on native contrast. While bone has high contrast within a CT image due to its material density from calcium phosphate, soft tissue is less dense and many are homogenous in density. This presents a challenge in distinguishing one type of soft tissue from another. A couple exceptions include the lungs as well as fat, both of which have unique densities owing to the presence of air or bulk hydrocarbons, respectively. In order to facilitate X-ray CT imaging of other structures, a range of contrast agents have been developed to selectively identify and visualize the anatomical properties of individual tissues. Most agents incorporate atoms like iodine, gold, or barium because of their ability to absorb X-rays, and thus impart contrast to a given organ system. Here we review the strategies available to visualize lung, fat, brain, kidney, liver, spleen, vasculature, gastrointestinal tract, and liver tissues of living mice using either innate contrast, or commercial injectable or ingestible agents with selective perfusion. Further, we demonstrate how each of these approaches will facilitate the non-invasive, longitudinal, in vivo imaging of pre-clinical disease models at each anatomical site.

Bacterial infection probes and imaging strategies in clinical nuclear medicine and preclinical molecular imaging.

At present, a limited number of strategies exist for diagnostic imaging of patients with bacterial infection. While radiolabeled probes and white blood cells provide robust solutions to detect bacteria in humans, they also give false positives in cases of sterile inflammation. With the onset of bacterial drug resistance, and a clinical trend toward reducing the prescription of antibiotics, the need for highly specific infection detection protocols has been renewed. The preclinical research community has recently utilized new optical imaging strategies, alongside traditional radioimaging research, to develop novel infection probes with translational potential. Here we review the current clinical methods for imaging bacteria in humans, and discuss the efforts within the preclinical community to validate new strategies. The review of preclinical infection imaging probes is limited to those probes that could be feasibly adapted for use in humans with currently available clinical modalities.

Dual tracer imaging of SPECT and PET probes in living mice using a sequential protocol.

Over the past 20 years, multimodal imaging strategies have motivated the fusion of Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) scans with an X-ray computed tomography (CT) image to provide anatomical information, as well as a framework with which molecular and functional images may be co-registered. Recently, pre-clinical nuclear imaging technology has evolved to capture multiple SPECT or multiple PET tracers to further enhance the information content gathered within an imaging experiment. However, the use of SPECT and PET probes together, in the same animal, has remained a challenge. Here we describe a straightforward method using an integrated trimodal imaging system and a sequential dosing/acquisition protocol to achieve dual tracer imaging with (99m)Tc and (18)F isotopes, along with anatomical CT, on an individual specimen. Dosing and imaging is completed so that minimal animal manipulations are required, full trimodal fusion is conserved, and tracer crosstalk including down-scatter of the PET tracer in SPECT mode is avoided. This technique will enhance the ability of preclinical researchers to detect multiple disease targets and perform functional, molecular, and anatomical imaging on individual specimens to increase the information content gathered within longitudinal in vivo studies.

Segmentation and measurement of fat volumes in murine obesity models using X-ray computed tomography.

Obesity is associated with increased morbidity and mortality as well as reduced metrics in quality of life. Both environmental and genetic factors are associated with obesity, though the precise underlying mechanisms that contribute to the disease are currently being delineated. Several small animal models of obesity have been developed and are employed in a variety of studies. A critical component to these experiments involves the collection of regional and/or total animal fat content data under varied conditions. Traditional experimental methods available for measuring fat content in small animal models of obesity include invasive (e.g. ex vivo measurement of fat deposits) and non-invasive (e.g. Dual Energy X-ray Absorptiometry (DEXA), or Magnetic Resonance (MR)) protocols, each of which presents relative trade-offs. Current invasive methods for measuring fat content may provide details for organ and region specific fat distribution, but sacrificing the subjects will preclude longitudinal assessments. Conversely, current non-invasive strategies provide limited details for organ and region specific fat distribution, but enable valuable longitudinal assessment. With the advent of dedicated small animal X-ray computed tomography (CT) systems and customized analytical procedures, both organ and region specific analysis of fat distribution and longitudinal profiling may be possible. Recent reports have validated the use of CT for in vivo longitudinal imaging of adiposity in living mice. Here we provide a modified method that allows for fat/total volume measurement, analysis and visualization utilizing the Carestream Molecular Imaging Albira CT system in conjunction with PMOD and Volview software packages.