Periodic Reporting for period 1 - METAJOINT (Metabolic imaging of the joint)
Período documentado: 2020-08-01 hasta 2022-01-31
The problem/issue being addressed and importance to society (taken from application):
Osteoarthritis is a painful and disabling life-altering joint disease and the most common form of
disability in our society. There are very limited treatment options for osteoarthritis and in most cases,
osteoarthritis is slowly progressive, sometimes over a period of decades. More than 10% of entire the
population in Europe has osteoarthritis in knee, hip or hands that leads to disability, pain and limited
quality of life. In the METAJOINT study we proposed to test new metabolic imaging methods of joints
using MRI that can visualize the distribution of specific metabolites and thereby elucidate biological
and/or biochemical processes in the joint. This new ground-breaking evaluation method for joint
disease will help pharmaceutical companies with better outcome measures in order to find disease
modifying medication that can treat osteoarthritis and it can be used by physicians and surgeons for
early detection of osteoarthritis and prediction of the course of the disease to better guide patients
with early or late phase osteoarthritis.
Objectives:
The aim of METAJOINT concerns the scanning with META-scan of a limited set of 5 patients for
three imaging methods (total number of 15 patients) to scan for respectively phosphorus, sodium
and deuterium. All three methods provide information regarding metabolic aspects of the joint.
Osteoarthritis is a painful and disabling life-altering joint disease and the most common form of
disability in our society. There are very limited treatment options for osteoarthritis and in most cases,
osteoarthritis is slowly progressive, sometimes over a period of decades. More than 10% of entire the
population in Europe has osteoarthritis in knee, hip or hands that leads to disability, pain and limited
quality of life. In the METAJOINT study we proposed to test new metabolic imaging methods of joints
using MRI that can visualize the distribution of specific metabolites and thereby elucidate biological
and/or biochemical processes in the joint. This new ground-breaking evaluation method for joint
disease will help pharmaceutical companies with better outcome measures in order to find disease
modifying medication that can treat osteoarthritis and it can be used by physicians and surgeons for
early detection of osteoarthritis and prediction of the course of the disease to better guide patients
with early or late phase osteoarthritis.
Objectives:
The aim of METAJOINT concerns the scanning with META-scan of a limited set of 5 patients for
three imaging methods (total number of 15 patients) to scan for respectively phosphorus, sodium
and deuterium. All three methods provide information regarding metabolic aspects of the joint.
Dedicated hardware had to be designed (originally not anticipated, but the setup of the NICI project was not capable to detect these metabolic MRI from joints)
1. a 2H setup was build composed of 4 loop transceivers tuned to 2H metabolic MRI that were driven with a home build power divider, and merged to an 8 channel 1H dipole array for conventional MRI
2. a 23Na coil setup was build as a double tuned birdcage resonator
3. a 31P setup was build composed of 16 receiver loops using the integrated bore transmitter and merged with 8 dipole 1H tranceivers
Scan protocols designed and tested in phantoms
Dedicated metabolic MRI scan protocols were designed focusing on 2H, 23Na and 31P, each optimized for the respective MR properties of the nuclei.
For 2H, the scans were tuned to assess dipolar coupling and their sensitivity to the orientation of the leg with respect to the direction of the main magnetic field of the MRI. (Fig1)
For 23Na, the echo time was minimized while maintaining a high resolution. Even shorter echo times were explored but resulted in so much blurring that consulted clinicians advised to maintain good resolution (Fig2)
For 31P, as a uniform excitation was used, short repetition times could be used to facilitate relatively fast scans with superb image quality (Fig3)
Metabolic 2H MRI tested in healthy volunteers (4 scans) published PMID: 34657308.
Three subjects were scanned in a supine position, with the right leg parallel with the B0 field. One subject was scanned twice; during the second scan, the subject was laying on his right side and the right knee was bent such that the angle between the right lower leg and B0 was approximately 45°. DTI was performed in the same subjects in the same positions at 3 Tesla to determine muscle fiber angles.
We observed splittings in the natural abundance deuterated water signal. The size of the splittings varied between different muscles in the lower leg but were mostly similar among subjects for each muscle.
Partial molecular alignment in skeletal muscle leads to residual deuteron quadrupolar couplings in deuterated water, the size of which depends on the angle between the muscle fibers and B0.
Metabolic 31P MRI tested in healthy volunteers (2scans). published PMID: 33522635
With the optimal order of processing steps, we show that the effective SNR of in vivo phosphorus 3D chemical shift imaging data can be increased.
In this study, we have shown that principal component analysis-based denoising in combination with regularized Wiener deconvolution allows increasing the effective spectral SNR of in vivo phosphorus 3D chemical shift imaging data, with reduction of the FWHM of the voxel point spread function. Processing increased the effective SNR by at least threefold compared to Hamming weighted acquired data and minimized voxel bleeding. With these methods, fitting of metabolite amplitudes became more robust with decreased fitting residuals.
Metabolic 23Na MRI tested in healthy volunteers (4scans). Publised PMID: 33180225
Four human tibial plateaus were retrieved from patients undergoing total knee replacement (TKR), and their cartilage stiffness mapped with indentation testing, after which samples were scanned in a 7 T MRI to determine sodium concentration.
Weak correlations of GAG concentration with apparent peak modulus (p = 0.0057) and apparent equilibrium modulus (p = 0.0181) were observed. A moderate correlation of MRI sodium concentration with permeability was shown (p = 0.0014).
If the correlation between MRI sodium imaging and GAG concentration could be resolved, this strategy for assessing cartilage functional quality still holds promise.
Ethical considerations
31P: While it was assumed that high levels of phosphate in bone could be detected with metabolic MRI, our 31P study in healthy subjects show no detectable 31P signal from bone, yet high levels were observed in muscle. We think that the potential signal in bone decays so fast (T2*) that the signal is vanished in our optimized short time between our pulse and start of acquisition. Consequently, it would be unethical to ask patients to participate if we will only detect noise.
2H: Our current best spatial resolution is 14 × 14 × 25 mm; sufficient for muscle, but much too poor for the 3mm thin layer of cartilage. Efforts are taking place to increase the spatial resolution using echo planar imaging and compressed sensing.
23Na: The spatial resolution, sensitivity and accuracy of the sodium MRI in volunteers was sufficient to justify ethical clearance for patient inclusion. Considering the no longer required patients for 2H and 31P, we increased the number of patients in the sodium study and also to allow scanning before and after therapy. The ethical approval required sufficient sample size to justify clinical study outcome. At the moment of completing the METAJOINT project, metabolic MRI (sodium, GagCEST) was performed in 12 patients scheduled for knee distraction (4 scanned twice). The departments of radiology and orthopedics will continue the patient inclusion after completion of the METAJOINT project.
1. a 2H setup was build composed of 4 loop transceivers tuned to 2H metabolic MRI that were driven with a home build power divider, and merged to an 8 channel 1H dipole array for conventional MRI
2. a 23Na coil setup was build as a double tuned birdcage resonator
3. a 31P setup was build composed of 16 receiver loops using the integrated bore transmitter and merged with 8 dipole 1H tranceivers
Scan protocols designed and tested in phantoms
Dedicated metabolic MRI scan protocols were designed focusing on 2H, 23Na and 31P, each optimized for the respective MR properties of the nuclei.
For 2H, the scans were tuned to assess dipolar coupling and their sensitivity to the orientation of the leg with respect to the direction of the main magnetic field of the MRI. (Fig1)
For 23Na, the echo time was minimized while maintaining a high resolution. Even shorter echo times were explored but resulted in so much blurring that consulted clinicians advised to maintain good resolution (Fig2)
For 31P, as a uniform excitation was used, short repetition times could be used to facilitate relatively fast scans with superb image quality (Fig3)
Metabolic 2H MRI tested in healthy volunteers (4 scans) published PMID: 34657308.
Three subjects were scanned in a supine position, with the right leg parallel with the B0 field. One subject was scanned twice; during the second scan, the subject was laying on his right side and the right knee was bent such that the angle between the right lower leg and B0 was approximately 45°. DTI was performed in the same subjects in the same positions at 3 Tesla to determine muscle fiber angles.
We observed splittings in the natural abundance deuterated water signal. The size of the splittings varied between different muscles in the lower leg but were mostly similar among subjects for each muscle.
Partial molecular alignment in skeletal muscle leads to residual deuteron quadrupolar couplings in deuterated water, the size of which depends on the angle between the muscle fibers and B0.
Metabolic 31P MRI tested in healthy volunteers (2scans). published PMID: 33522635
With the optimal order of processing steps, we show that the effective SNR of in vivo phosphorus 3D chemical shift imaging data can be increased.
In this study, we have shown that principal component analysis-based denoising in combination with regularized Wiener deconvolution allows increasing the effective spectral SNR of in vivo phosphorus 3D chemical shift imaging data, with reduction of the FWHM of the voxel point spread function. Processing increased the effective SNR by at least threefold compared to Hamming weighted acquired data and minimized voxel bleeding. With these methods, fitting of metabolite amplitudes became more robust with decreased fitting residuals.
Metabolic 23Na MRI tested in healthy volunteers (4scans). Publised PMID: 33180225
Four human tibial plateaus were retrieved from patients undergoing total knee replacement (TKR), and their cartilage stiffness mapped with indentation testing, after which samples were scanned in a 7 T MRI to determine sodium concentration.
Weak correlations of GAG concentration with apparent peak modulus (p = 0.0057) and apparent equilibrium modulus (p = 0.0181) were observed. A moderate correlation of MRI sodium concentration with permeability was shown (p = 0.0014).
If the correlation between MRI sodium imaging and GAG concentration could be resolved, this strategy for assessing cartilage functional quality still holds promise.
Ethical considerations
31P: While it was assumed that high levels of phosphate in bone could be detected with metabolic MRI, our 31P study in healthy subjects show no detectable 31P signal from bone, yet high levels were observed in muscle. We think that the potential signal in bone decays so fast (T2*) that the signal is vanished in our optimized short time between our pulse and start of acquisition. Consequently, it would be unethical to ask patients to participate if we will only detect noise.
2H: Our current best spatial resolution is 14 × 14 × 25 mm; sufficient for muscle, but much too poor for the 3mm thin layer of cartilage. Efforts are taking place to increase the spatial resolution using echo planar imaging and compressed sensing.
23Na: The spatial resolution, sensitivity and accuracy of the sodium MRI in volunteers was sufficient to justify ethical clearance for patient inclusion. Considering the no longer required patients for 2H and 31P, we increased the number of patients in the sodium study and also to allow scanning before and after therapy. The ethical approval required sufficient sample size to justify clinical study outcome. At the moment of completing the METAJOINT project, metabolic MRI (sodium, GagCEST) was performed in 12 patients scheduled for knee distraction (4 scanned twice). The departments of radiology and orthopedics will continue the patient inclusion after completion of the METAJOINT project.
Metabolic MRI performed in 12 patients scheduled for knee distraction (4 scanned twice); 4 for thumb surgery and 2 for wrist. Data is used to discuss with surgeons and orthopedics on added value to prepare for clinical trials.
In summary, hardware was purchased to build the dedicated RF coils, and a total of 30 scans were performed.
Project is ended and resulted in convincing evidence of the feasibility of 2H, 23Na and 31P metabolic MRI in joints. Moreover, the results have attracted surgeons and orthopedics to perform metabolic scans on their patients and prepare for clinical trials.
The 31P metabolic MRI results were used to convince a company to apply for an EIC transition to explore the clinical potential in an expert center in Italy (Pisa). The grant is awarded and has started in April 2022. Here, the impact is to stratify patients on the basis of the metabolic MRI for specific treatments.
In summary, hardware was purchased to build the dedicated RF coils, and a total of 30 scans were performed.
Project is ended and resulted in convincing evidence of the feasibility of 2H, 23Na and 31P metabolic MRI in joints. Moreover, the results have attracted surgeons and orthopedics to perform metabolic scans on their patients and prepare for clinical trials.
The 31P metabolic MRI results were used to convince a company to apply for an EIC transition to explore the clinical potential in an expert center in Italy (Pisa). The grant is awarded and has started in April 2022. Here, the impact is to stratify patients on the basis of the metabolic MRI for specific treatments.