L. Dean Chapman

Mapping metals in Parkinson's and normal brain using rapid-scanning x-ray fluorescence

Rapid-scanning x-ray fluorescence (RS-XRF) is a synchrotron technology that maps multiple metals in tissues by employing unique hardware and software to increase scanning speed. RS-XRF was validated by mapping and quantifying iron, zinc and copper in brain slices from Parkinsons disease (PD) and unaffected subjects. Regions and structures in the brain were readily identified by their metal complement and each metal had a unique distribution. Many zinc-rich brain regions were low in iron and vice versa. The location and amount of iron in brain regions known to be affected in PD agreed with analyses using other methods. Sample preparation is simple and standard formalin-fixed autopsy slices are suitable. RS-XRF can simultaneously and non-destructively map and quantify multiple metals and holds great promise to reveal metal pathologies associated with PD and other neurodegenerative diseases as well as diseases of metal metabolism.

Memory and survival after microbeam radiation therapy

BACKGROUND Disturbances of memory function are frequently observed in patients with malignant brain tumours and as adverse effects after radiotherapy to the brain. Experiments in small animal models of malignant brain tumour using synchrotron-based microbeam radiation therapy (MRT) have shown a promising prolongation of survival times. MATERIALS AND METHODS Two animal models of malignant brain tumour were used to study survival and memory development after MRT. Thirteen days after implantation of tumour cells, animals were submitted to MRT either with or without adjuvant therapy (buthionine-SR-sulfoximine=BSO or glutamine). We used two orthogonal 1-cm wide arrays of 50 microplanar quasiparallel microbeams of 25 microm width and a center-to-center distance of about 200 microm, created by a multislit collimator, with a skin entrance dose of 350 Gy for each direction. Object recognition tests were performed at day 13 after tumour cell implantation and in monthly intervals up to 1 year after tumour cell implantation. RESULTS In both animal models, MRT with and without adjuvant therapy significantly increased survival times. BSO had detrimental effects on memory function early after therapy, while administration of glutamine resulted in improved memory.

Synchrotron X-ray Fluorescence Reveals Abnormal Metal Distributions in Brain and Spinal Cord in Spinocerebellar Ataxia: A Case Report

For the first time, synchrotron rapid-scanning X-ray fluorescence (RS-XRF) was used to simultaneously localize and quantify iron, copper, and zinc in spinal cord and brain in a case of spinocerebellar ataxia (SCA). In the normal medulla, a previously undescribed copper enrichment was seen associated with spinocerebellar fibers and amiculum olivae. This region was virtually devoid of all metals in the SCA case. Regions with neuronal loss and gliosis in the cerebellar cortex, inferior olivary, and dentate nuclei and areas showing loss of myelinated fibers were also low in all metals in SCA compared to control. In contrast, the ventral columns of the spinal cord that exhibited only moderate myelin pallor had increased metal levels. Iron and zinc were also elevated in the globus pallidus pars externa in SCA relative to control. We hypothesize that metals increase as part of the initial neurodegenerative process, but once degeneration is advanced, the metal levels drop. This implies a role for multiple metals in SCA neurodegeneration, but further study is required to establish a causative role. We suggest that if these findings are generally true of at least some cases of SCA, not only iron but also copper and zinc should be considered as possible therapeutic targets.

Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) channel, which can result in chronic lung disease. The sequence of events leading to lung disease is not fully understood but recent data show that the critical pathogenic event is the loss of the ability to clear bacteria due to abnormal airway surface liquid secretion (ASL). However, whether the inhalation of bacteria triggers ASL secretion and whether this is abnormal in cystic fibrosis has never been tested. Here we show, using a novel synchrotron-based in vivo imaging technique, that wild-type pigs display both a basal and a Toll-like receptor-mediated ASL secretory response to the inhalation of cystic fibrosis relevant bacteria. Both mechanisms fail in CFTR−/− swine, suggesting that cystic fibrosis airways do not respond to inhaled pathogens, thus favoring infection and inflammation that may eventually lead to tissue remodeling and respiratory disease.Cystic fibrosis is caused by mutations in the CFTR chloride channel, leading to reduced airway surface liquid secretion. Here the authors show that exposure to bacteria triggers secretion in wild-type but not in pig models of cystic fibrosis, suggesting an impaired response to pathogens contributes to infection.

Human factors design for the BMIT biomedical beamlines

Operation of a biomedical beamline poses a unique set of operational and instrumentation challenges for a synchrotron facility. From proper handling and care of live animals and animal tissues, to a user community drawn primarily from the medical and veterinary realms, the work of a biomedical beamline is unique when compared to other beamlines. At the Biomedical Imaging and Therapy (BMIT) beamlines at Canadian Light Source (CLS), operation of the beamlines is geared towards our user community of medical personnel, in addition to basic science researchers. Human factors considerations have been incorporated wherever possible on BMIT, including in the design of software and hardware, as well as ease-of-use features of beamline control stations and experiment hutches. Feedback from users continues to drive usability improvements to beamline operations.

25+2 poles, 4.3 T wiggler at BMIT – 7 years operational experience

The research program at the Biomedical Imaging and Therapy (BMIT) Facility at the Canadian Light Source (CLS) required a unique radiation source that would provide a wide beam fan with high critical energy and high dose rates. A superconductive wiggler was the only practical solution that could be installed inside the CLS ring. Design requirements were defined in 2005 [1-2]. The wiggler, optimized for a 3 GeV ring, was to match operating parameters of an equivalent hard X-ray source on a 6 GeV ring. Manufacturing started in 2006 and the wiggler was installed in November of 2007 [3-5]. Several modifications to external hardware and to the power supplies’ controls were implemented to address the air leaks into the He space and to provide the ability to change the field of the wiggler during normal operation without affecting other research groups. The original burst disk and pressure relief valves were replaced with commercial units. Most of the buna O-rings were replaced with metal O-rings, helping to prov...

Preliminary Bone Imaging on 05B1-1 Beamline at the Canadian Light Source: Exploration of Diffraction Enhanced Imaging

The bending magnet line (05B1-1) of the BioMedical Imaging and Therapy (BMIT) facility of the Canadian Light Source saw initial research application (Figure 1) during commissioning which began in December 2008 and continued intermittently through May 2010. Following an initial run based upon letters of intent (June-Dec. 2010), the bending magnet line is now available for regular user access. The mandate to advance research related to human and animal health, combined with an active bone imaging community at the University of Saskatchewan, has resulted in a strong representation of skeletal imaging during initial experiments at BMIT. To date, specific manifestations of bone imaging have ranged from micro-CT imaging of human cortical bone samples to in vitro diffraction enhanced imaging (DEI) of rat and pig bones and, ultimately, to in vivo DEI of bones within young chickens. In this article we focus on the diffraction enhanced imaging capabilities of BMIT and describe our efforts to apply this technology to human trabecular bone microarchitecture – a potential clinical application in the future.

Design of a mouse restraint for synchrotron-based computed tomography imaging

High-resolution computed tomography (CT) imaging of a live animal within a lead-lined synchrotron light hutch presents several unique challenges. In order to confirm that the animal is under a stable plane of anaesthesia, several physiological parameters (e.g. heart rate, arterial oxygen saturation, core body temperature and respiratory rate) must be remotely monitored from outside the imaging hutch. In addition, to properly scan the thoracic region using CT, the animal needs to be held in a vertical position perpendicular to the fixed angle of the X-ray beam and free to rotate 180°-360°. A new X-ray transparent mouse restraint designed and fabricated using computer-aided design software and three-dimensional rapid prototype printing has been successfully tested at the Biomedical Imaging and Therapy bending-magnet (BMIT-BM) beamline at the Canadian Light Source.