Multi-scale MRI Assessment of Bone Quality and Function in a Chronic Rat Spinal Cord Injury Model

After traumatic spinal cord injury (SCI), significant deterioration of bone tissue is seen in most patients. This
continues throughout life and about 50% of chronic SCI patients will sustain a low-impact or spontaneous fracture
at some point, typically occurring around the knee. Traditionally, the pathogenesis of osteoporosis after SCI has
been focused on mechanical unloading and its effect on bone quantity, but advances in the field of skeletal
biology have revealed the involvement of a much broader array of bone physiology—in particular the critical
roles that the structural, physiological, and chemical properties of bone contribute to bone health. Evaluating the
multi-scale changes that occur in bone tissue components such as the organic matrix and water, which together
occupy approximately 60% of bone by volume, can provide critical information on chronic SCI risks including
osteoporotic fracture, as well as the anemia and immune dysfunction associated with the “acquired bone marrow
failure syndrome.” Unfortunately, such crucial information on bone structure, vascularity, and chemical properties
is all but inaccessible using the standard imaging modalities available in clinics today. Magnetic resonance
imaging (MRI), particularly ultrashort echo time (UTE) techniques, continues to gain interest for the investigation
of numerous structural and physiological properties of bone. The development and application of quantitative
UTE MRI techniques to measure multi-scale features of bone, including macro- and micro-scale structure (UTE),
micro-scale vascularity (UTE double echo steady state [UTE-DESS]), and molecular-scale chemical properties
(UTE acido-chemical exchange saturation transfer [UTE-acidoCEST]), would represent a revolutionary step
forward in the care of SCI patients. The goal of this proposal is to establish a panel of non-invasive MRI
biomarkers tailored for bone quality assessment in SCI and test its effectiveness on a novel chronic SCI rat
model. In the first Aim, cadaveric knee samples from SCI and healthy donors will be used to optimize a panel of
novel, quantitative MRI techniques for fast and accurate volumetric evaluation of bone quality and health. The
first hypothesis is that multi-scale bone quality and health measures can be reliably assessed using the new
techniques. The second hypothesis is that the new biomarkers will be highly correlated with reference standards,
including bone structure, composition, biomechanical properties, vascular density, and pH measures. In the
second Aim, a longitudinal rat model with chronic, complete T8 SCI will be used and investigations will focus on
validating the new MRI biomarker panel to assess bone recovery after induction of functional locomotion through
manipulation of activity level in propriospinal neurons (via Designer Receptors Exclusively Activated by Designer
Drugs) with and without sympathetic inhibition. The third hypothesis is that the biomarker panel will be highly
correlated with µCT, histology, and behavioral outcomes, and will accurately detect longitudinal changes in bone
quality associated with chronic complete thoracic SCI. The fourth hypothesis is that alterations in local
sympathetic control of hindlimbs make substantial contributions to bone remodeling and dysfunction, which can
be mitigated with sympathetic inhibition. After the successful completion of this grant, we expect to provide an
optimized MRI panel that is tailored for multi-scale evaluation of bone in SCI, use an animal model to provide
insight into the degree of bone recovery that may be expected with neuromodulation, and be the first to explore
the effects of sympathetic nervous system activity in sublesional bone in vivo.

Grant Number: 5I01BX005952-04
NIH Institute/Center: VA
Principal Investigator: Eric Chang