Jonathan D. Thiessen

Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination

The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2‐weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone‐fed (n = 5) mice, with significant increases in signal intensity in T2‐weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone‐fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone‐fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone‐fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (ρ = −0.90), the bound pool fraction (ƒ) versus the myelin sheath fraction (ρ = 0.93), and axial diffusivity versus the non‐myelinated cell fraction (ρ = 0.92). Using Pearsons correlation coefficient, ƒ was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37ƒ − 0.25). Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Copyright

Evidence for the involvement of calbindin D28k in the presenilin 1 model of Alzheimer's disease.

Pathological hallmarks of Alzheimers disease include memory deficits, accumulation of amyloid beta (Abeta) plaques, the appearance of neurofibrillary tangles, and dysregulation of calcium homeostasis, which has been linked to mutations in the presenilin gene that code for presenilin (PS) proteins. PSs are a family of multi-pass transmembrane proteins where normal presenilins (PS1 and PS2) are highly localized in the endoplasmic reticulum (ER). Several past studies have explored alterations in long-term potentiation (LTP), a proposed molecular correlate of memory, and in behavioral tests of spatial memory in a variety of PS1 models. These reports suggest that calcium plays a role in these alterations, but mechanistic explanations for changes in LTP and in behavioral tests of memory are still lacking. To test the hypothesis that calcium-related mechanisms, such as changes in calcium buffering, are associated with alterations in LTP and memory, we utilized in vitro experimental paradigms of LTP in hippocampal slices obtained from the PS1-M146V transgenic mouse model of Alzheimers disease (AD). We also used the in vivo Morris water maze (MWM), a test for hippocampal dependent spatial memory. In addition, we used cellular assays to explore molecular mechanisms. We confirm that PS1 mutations (M146V) enhance LTP. We also find increases in some parameters of the MWM, and alterations in other parameters, such as path length indicating impairment in cognitive functioning in PS1-M146V mice. In addition, these findings are observed in association with increased calbindin D28K expression in the CA1 hippocampus of PS1-M146V mice.

Development and evaluation of a LOR-based image reconstruction with 3D system response modeling for a PET insert with dual-layer offset crystal design

In this study we present a method of 3D system response calculation for analytical computer simulation and statistical image reconstruction for a magnetic resonance imaging (MRI) compatible positron emission tomography (PET) insert system that uses a dual-layer offset (DLO) crystal design. The general analytical system response functions (SRFs) for detector geometric and inter-crystal penetration of coincident crystal pairs are derived first. We implemented a 3D ray-tracing algorithm with 4π sampling for calculating the SRFs of coincident pairs of individual DLO crystals. The determination of which detector blocks are intersected by a gamma ray is made by calculating the intersection of the ray with virtual cylinders with radii just inside the inner surface and just outside the outer-edge of each crystal layer of the detector ring. For efficient ray-tracing computation, the detector block and ray to be traced are then rotated so that the crystals are aligned along the X-axis, facilitating calculation of ray/crystal boundary intersection points. This algorithm can be applied to any system geometry using either single-layer (SL) or multi-layer array design with or without offset crystals. For effective data organization, a direct lines of response (LOR)-based indexed histogram-mode method is also presented in this work. SRF calculation is performed on-the-fly in both forward and back projection procedures during each iteration of image reconstruction, with acceleration through use of eight-fold geometric symmetry and multi-threaded parallel computation. To validate the proposed methods, we performed a series of analytical and Monte Carlo computer simulations for different system geometry and detector designs. The full-width-at-half-maximum of the numerical SRFs in both radial and tangential directions are calculated and compared for various system designs. By inspecting the sinograms obtained for different detector geometries, it can be seen that the DLO crystal design can provide better sampling density than SL or dual-layer no-offset system designs with the same total crystal length. The results of the image reconstruction with SRFs modeling for phantom studies exhibit promising image recovery capability for crystal widths of 1.27-1.43 mm and top/bottom layer lengths of 4/6 mm. In conclusion, we have developed efficient algorithms for system response modeling of our proposed PET insert with DLO crystal arrays. This provides an effective method for both 3D computer simulation and quantitative image reconstruction, and will aid in the optimization of our PET insert system with various crystal designs.

Development of a PET Scanner for Simultaneously Imaging Small Animals with MRI and PET

Recently, positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of cancer. Combined PET and X-ray computed tomography (PET-CT) scanners are now the modality of choice in cancer treatment planning. More recently, the combination of PET and magnetic resonance imaging (MRI) is being explored in many sites. Combining PET and MRI has presented many challenges since the photo-multiplier tubes (PMT) in PET do not function in high magnetic fields, and conventional PET detectors distort MRI images. Solid state light sensors like avalanche photo-diodes (APDs) and more recently silicon photo-multipliers (SiPMs) are much less sensitive to magnetic fields thus easing the compatibility issues. This paper presents the results of a group of Canadian scientists who are developing a PET detector ring which fits inside a high field small animal MRI scanner with the goal of providing simultaneous PET and MRI images of small rodents used in pre-clinical medical research. We discuss the evolution of both the crystal blocks (which detect annihilation photons from positron decay) and the SiPM array performance in the last four years which together combine to deliver significant system performance in terms of speed, energy and timing resolution.

Performance evaluation of SensL SiPM arrays for high-resolution PET

Silicon photomultipliers (SiPMs) have high gain, excellent timing performance, and are well suited to PET/MRI applications due, in part, to their MR-compatibility and small form factor. Within the constraints of a resistor-based multiplexing circuit, it is useful to evaluate the four generations of SiPM arrays manufactured by SensL: the SPMArray4, ArraySL-4, ArraySM-4, and ArraySB-4. Breakdown voltage and dark current were measured as a function of temperature in two each of the four generations of SensL SiPM arrays. Flood histograms were created with a 68Ge-irradiated 9×9 LYSO crystal array at temperatures of 5 °C to 45 °C in 5 °C increments and overvoltages of 2 to 4 V in 0.5 V increments. Measurements of dark current vs. bias voltage increased as temperature increased, with a corresponding increase in the breakdown voltage, Vb. The temperature dependence of Vb is similar between all four generations of SiPM arrays with slopes ranging from 17.0 to 23.8 mV/°C. Notably, the ArraySB-4 has lower values for the breakdown voltage, with Vb = 24 V at 0 °C. Mean energy resolution for individual LYSO crystals showed improvements in each successive generation. The average energy resolution of the ArraySB-4 was 11.9% after correcting for non-linearity in the SiPM pixels. The linearity of the SensL SiPM arrays as a function of temperature and breakdown voltage makes them a suitable choice for a high-resolution, small animal PET/MRI system. Based on its improved resolvability and energy resolution, lower sensitivity to temperature and higher PDE, the ArraySB-4 will be used in our PET system.

Characterization of a New MR Compatible Small Animal PET Scanner Using Monte-Carlo Simulations

We are currently designing a small animal PET insert for use in an MRI with a bore size that constrains the insert inner diameter to be no larger than 66 mm while leaving 25 mm for ring thickness. The insert will be made from 10 mm thick DOI-capable Dual Layer Offset LYSO blocks coupled to MR-compatible SiPMs. The block is made from a 9 × 9 array of 1.345 × 4 mm3 crystals in the front layer and a 10 × 10 array of 1.345 × 1.345 × 6 mm3 crystals in the back layer (crystal pitch = 1.422 mm). A ring of blocks is made by repeating a block around a ring with inner diameter of 64.776 mm 16 times. Here, GATE simulations have been made to estimate mousenoise-equivalent count rate (NECR), mouse-scatter fraction (SF), peak sensitivity (Sp) resolution, and resolution uniformity to evaluate the design of our PET insert. These simulations make use of hardware performance estimates measured from a prototype block. For the one, three, and six ring tomographs, NECR curves, SF, and fígures were produced for the best and worst expected hardware performance. Simulations of a point source in a one-ring tomograph were made to estimate resolution across the field of view (FOV). For a six-ring tomograph with a 250-750 keV energy window and best expected hardware performance, the peak NECR, peak NECR activity, and Sp were 1273 kcps, 96 MBq and 10.0%. With three rings, these figures were 389 kcps at 95 MBq, and 5.9%. And with one-ring, they were 43 kcps, 85 MBq, and 2.0%. SF was ~ 16% in these three cases. Spatial resolution in the radial direction was found to change from 1.0 to 1.9 mm FWHM moving from the center of the FOV to a 15 mm offset. These results indicate that our scanner design is highly suited for high-resolution preclinical mouse imaging.

First Results From a High-Resolution Small Animal SiPM PET Insert for PET/MR Imaging at 7T

We present the initial results from a small animal PET insert designed to be operated inside a 7T MRI. The insert fits within the 114 mm inner diameter of the Bruker BGA-12S gradient coil while accommodating the Bruker 35 mm volume RF coil (outer diameter 60 mm), both used in the Bruker 70/20 MRI systems. The PET insert is a ring comprising 16 detectors. Each detector has a dual-layer offset (DLO) lutetium-yttrium oxyorthsilicate (LYSO) scintillator array read out by two SensL SPMArray4B SiPM arrays. The DLO scintillator has bottom (top) layers of: 22 × 10 (21 × 9) crystals of size 1.2 × 1.2 × 6 (4) mm3 for a total of 409 crystals per block, providing an axial extent of 28.17 mm. The detector outputs are multiplexed to four signals using a custom readout board and digitized using the OpenPET data acquisition platform. The detector flood images successfully resolve over 99% of the crystals, with average energy resolution of 12.5 ± 2.0% at 511 keV. Testing of the PET system inside the MRI showed that the PET insert had no effect on MRI image homogeneity and only a small effect on echo planar images (EPI) signal to noise ratio (SNR) (-9%), with neither PET nor MRI images showing obvious artefacts. These acquisitions used the OpenPET operating in “oscilloscope mode” with USB2.0 interface, allowing a maximum total singles event rate of 280 kcps, strongly limiting the count rate capabilities of the system. The PET radial spatial resolution (as measured with a 22Na point source and FBP-3DRP reconstruction) is 1.17 mm at the centre, degrading to 1.86 mm at a 15 mm radial offset. Simultaneous phantom and mouse PET/MR imaging produced good quality images that were free of any obvious artefacts.

A PET detector interface board and slow control system based on the Raspberry Pi

Construction of a full PET system requires scaling up from a few detectors on the bench top to dozens or even hundreds of detectors all operating simultaneously and connected to high channel count electronics. Our collaboration is building a MRI compatible PET insert system that will contain 16 detector modules in the prototype phase and 64 detector modules in the final phase. This number of detectors makes it difficult, if not impossible, to manually configure and monitor each detector in the system. In order to make possible the scaling of the system for up to 64 detectors, we require a scalable slow control system to manage the low level functions of the PET system, such as controlling detector bias and monitoring temperature and power consumption, that can be interfaced to and controlled by a host computer. We have implemented this slow control system in conjunction with a detector interface board (DIB) that is an intermediary between the detectors and the OpenPET digitizer system. Each DIB is connected to four detector modules and is controlled by a Raspberry Pi® computer directly attached to it. The Raspberry Pi® computers report to a host PC software program developed in National Instruments LabWindows™/CVI to provide the capability of central monitoring and control.

Comparison of manual and semi-automated segmentation methods to evaluate hippocampus volume in APP and PS1 transgenic mice obtained via in vivo magnetic resonance imaging

BACKGROUND Magnetic resonance imaging (MRI) of transgenic mouse models of Alzheimers disease is valuable to understand better the structural changes that occur in the brain and could provide a means to test drug treatments. A hallmark pathological feature of Alzheimers disease is atrophy of the hippocampus, which is an early biomarker of the disease. MRI can be used to detect and monitor this biomarker. METHOD Repeated measurements using in vivo 3D T2-weighted imaging of mice were used to assess the methods. Each mouse was imaged twice in one week and twice the following week and no changes in volume were expected. The hippocampus was segmented both manually and semi-automatically. Registration was done to gain information on shape changes. The volumes from each mouse were compared intra-mouse, between mice and to hippocampus volume values in the literature. RESULTS A reliable method was developed which was able to detect difference in volumes of hippocampus between mice when performed by a single individual. The semi-automated segmentation was unable to detect the same level of differences. The semi-automated segmentation method gave larger hippocampus volumes, with 78-87% reliability between the manual and semi-automated segmentation. Although more accurate, the manual segmentation is laborious and suffers from inter- and intra-variability. CONCLUSION These results suggest that manual segmentation is still considered the most reliable segmentation method for small structures. However, if performing longitudinal studies, where there is at least one year between imaging sessions, the segmentation should be done all at once at the end of all the imaging sessions. If segmentation is done after each imaging session, with at least a year passing between segmentations, very small variations in volumes can be missed. This method provides a means to quantify the volume of the hippocampus in a live mouse using manual segmentation, which is the first step toward studying hippocampus atrophy in a mouse model of Alzheimers disease.

Longitudinal Brain Size Measurements in APP/PS1 Transgenic Mice

There appear to be species differences among the effects of gene mutations related to familial Alzheimers disease on the brain during aging. To gain a better understanding of the effects of the Swedish mutation of amyloid precursor protein and the mutant form of human presenilin 1 on mice, commercially available mice from Jackson Laboratory were studied. Three dimensional T2*-weighted imaging was used to monitor the size of brains of APP/PS1 mice monthly, from 6 to 13 months of age. No significant difference was measured in the size of the medial-lateral width, dorsal-ventral height, rostral-caudal length or the volume of the APPSwe/ PS1 mouse brain. Faster and higher-resolution imaging methods are needed to accurately determine if small volume or shape changes occur in mouse brains with age or gene mutations.