Pathology


Canine amyloid-Aβ (Aβ) protein is identical to the human protein and the pattern and quantity of isoforms is analogous to that seen in humans.

Endogenous Aβ is naturally deposited into plaques of the diffuse subtype in aged dogs, which are vulnerable to post translational modification and are fibrillar at the ultrastructural level – cerebral amyloid angiopathy is also found in aged dogs. The pattern of Aβ deposition parallels that seen in humans and occurs over a 3 to 4 year window permitting the examination of interventions that may slow or halt deposition.

Cognitive deficits are positively correlated with Aβ deposition in Beagles. Oligomeric forms of Aβ, may correlate with cognitive decline occurring prior to Aβ deposition.

Drug Screening


A β-amyloid cleaving enzyme (BACE) inhibitor acutely reduces CSF and plasma levels of Aβ in a dose dependent manner.

The administration of a vaccine targeting fibrillar Aβ reduced Aβ deposition, but did not significantly modify longitudinal cognitive measures.

The effects of putative AD therapeutics on CSF biomarkers in aged dogs provides a rapid screen in a higher mammalian model that naturally develops AD-like pathology. We have experience in conducting relatively rapid screens for studying the effect of multiple NCEs on CSF biomarkers to support the lead optimization process which can be followed up with more extensive studies on selected compounds.

Imaging


  • MRI or CT to demonstrate structural changes in response to interventions
  • T1, T2. PD sequences
  • Diffusion Tensor Imaging to evaluate changes in myelination
  • Quantitative and qualitative assessment of morphological features or regions of interest by image processing
T1 weighted

Bar chart of diffusion tensor imaging data showing increasing fractional anisotropy
Diffusion Tensor Imaging data showing increasing fractional anisotropy in the frontal lobe, implying increasing myelination with increasing age in young beagle dogs.
Graph showing landmark allocentric learning improves with increased myelination in one year old beagle dogs
Data indicating performance on the landmark allocentric learning improves with increased myelination in one year old beagle dogs.
  • Dynamic contrast perfusion to assess blood brain barrier permeability and regional cerebral blood flow using either MRI or CT
  • PET/CT imaging with additional coregistration to MRI images if required to quantify glucose uptake
  • Imaging of brain tissues using standard PET radiopharmaceuticals eg F-18 DOPA
  • Imaging of brain tissues with custom developed radiopharmaceuticals linked to specific naturally occurring brain chemicals or novel compounds
F-18 DOPA

Dynamic perfusion CT (A)
Dynamic perfusion CT (B)

Dynamic perfusion CT images of a dog brain with cerebral blood flow (CBF) maps demonstrating an increase in CBF when end tidal CO2 is increased from 35mmHg (A) to 68mm Hg(B).

  • Chemical shift graph
    Quantification of changes in brain chemistry associated with the development and decline of neural function in response to therapeutics
  • MRS concentration bar chart
    Magnetic resonance spectroscopy data showing changes in brain metabolites associated with brain development in growing beagles, including markers of neuronal health. Effects of therapeutics can be assessed in attenuating or improving brain development
  • Percent change chart across metabolites
    Data showing change in concentration of brain metabolites in 10 year old compared to 2 year old beagle dogs

Quantitative magnetic resonance (QMR) is a non invasive method of determining body composition in awake animals. The principles of the method are similar to magnetic resonance imaging (MRI), except that the output is numerical rather than an image. Non sedated rodents are restrained in a Plexiglas tube that is placed within the bore of a low field magnet. Data collection takes two minutes, allowing a high throughput and repeated measurement for longitudinal study designs. During the data collection, hydrogen atoms in fat and lean tissue respond differently to radiofrequency energy, allowing the determination of the subject’s fat, lean and total body water mass.

Fat: Zucker vs. Lean control Rodents

Whole body imaging protocols are used for assessing the effects of therapeutics on metabolism and feeding behavior. Using dual energy x-ray absorptiometry (DEXA) body composition can be determined non invasively in longitudinal studies. These studies give body composition in terms of the percentage of fat, lean and bone tissue. Body composition is an important component in obesity studies.

DEXA image of a dog and MR images

From left to right: DEXA image of a dog; MR Image of rat abdomen; MR image segmented into visceral (yellow) and subcutaneous (blue) fat.

Several imaging protocols can be used to quantify the efficacy of new therapeutics. These can be conventional anatomic measures of tumor size using MRI, ultrasound or radiographs. Other functional measures that can be used on a quantitative basis pre and post treatment as a measure of the therapeutic effect of a new agent include:

  • FDG PET imaging of glucose metabolism in tumors. Reduced glucose metabolism is a measure of therapeutic success.
  • Dynamic contrast enhanced MRI to quantify effect of agents on angiogenesis. Reduced angiogenesis is a measure of therapeutic success

Depending on the research question to be answered several different imaging modalities can be used in musculoskeletal imaging. Magnetic Resonance Imaging provides images of the greatest range of tissues including bone marrow and changes in the internal structure of a joint, including articular cartilage changes, whereas CT can provide detailed images of bone structure.

Our range of magnets available allows MR imaging of beagles at up to 9.4T. Plain radiographs can illustrate basic morphometric changes with either contrast radiography or ultrasound adding details of the internal structure of joints. Nuclear medicine studies provide quantitative information on bone metabolic turnover and studies can be focused on a specific area or can include the entire skeletal system.

Dog knee radiograph

From left to right: Radiograph of a dog knee with osteoarthritis; MR image of a normal dog knee.

Our comprehensive imaging capabilities allow evaluation of any organ or body system. In addition to the sophisticated cross sectional imaging modalities we have extensive experience in plain and contrast radiography and ultrasound, including endocavitory, evaluation. These modalities continue to have applications in the development of new therapeutic applications and we can help you to select the most appropriate and cost effective imaging method for your study. Morphometric measures can be made from the images and some measures of echogencitiy can be made from ultrasound images.

Dog chest radiograph

From left to right: Dog chest radiograph; image of dog prostate with benign prostatic hypertrophy; dog kidney with chronic infection.

Interventional imaging provides minimally invasive methods of collecting tissue or depositing cells in virtually any organ system. We have extensive experience in interventional procedures with all imaging modalities. The complexity can range from simple collection of fluid or cells to implantation of cells within a fetus to create chimera or place a device within an organ or vessel using an endovascular approach. Biopsies can be collected from both bone and soft tissues. We can also develop instrumentation and methodology for unique procedures.

Ultrasound guided biopsy collection; catheter delivery of cells into the renal artery in a dog; 25 day canine fetus yolk sac injection.

From left to right: Dog chest radiograph; image of dog prostate with benign prostatic hypertrophy; dog kidney with chronic infection.

Segmented Brain
Dog brain segmented into grey matter, white matter and cerebrospinal fluid

InterVivo Solutions has experience in image processing of all modalities. Image processing extracts quantitative data from images. This can range from basic morphometric measurements made from images such as bone length or hippocampal volume to complex segmentation based on image signal intensities.

Project specific image processing routines are developed using scripts in standard software packages or can be custom developed according to the needs of the project. Interpretation of the data is routinely provided.

We are able to co-register images to enable low resolution quantitative images to be co-located with high resolution anatomical mages to allow accurate regions of interest to be drawn of the low resolution images. Brain images can be segmented into grey matter, white matter and cerebrospinal fluid. Regional blood flow and blood volume can be determined using either an MRI or a CT acquisition. Time activity curves can be generated from nuclear medicine studies to determine first pass kinetics.