Temporal diffusion spectroscopy in nonalcoholic steatohepatitis – STEDI-NASH
Time-resolved diffusion and MR elastography in metabolic disorder-associated steatotic liver disease: the "Stedi-NASH" project
Liver disease caused by metabolic dysfunction is an important and growing societal health concern in the context of the rise of obesity and diabetes. Still, noninvasive methods able to accurately diagnose liver disease hallmarks such as ballooning or inflammation, remain elusive. Stedi-NASH ambitions to develop advanced MRI methods based on diffusion and elastography and their accurate in silico modeling to improve the diagnostic capabilities available to doctors.
StediNASH proposes novel MRI diffusion and elastography tools for improved MASH diagnosis performance. These methods will be developed with advanced in silico simulations and experimentally validated.
While MRI proton density fat fraction is a reliable tool for steatosis, and elastography techniques such as MR or ultrasound elastography are increasingly accepted for diagnosing fibrosis, hepatocyte ballooning and hepatic inflammation remain difficult to diagnose despite being essential components of the disease. This is partially due to a lack of proper simulation tools that could enable a better understanding of the relationship between microstructual tissue alterations specific of MASH and the macroscopically measurable properties such as water diffusivity and mechanical (viscoelastic) properties. Water diffusivity, while promising, is currently limited to interrogating a large range of spatial scales, and hence lacks specificity. MR elastography, while quite successful in terms of diagnosis for fibrosis with stiffness measurements, remains underexploited since it additionally enables to reliably measure the true rheological properties of tissues, including their frequency dispersive properties. StediNASH thus aims to develop a better understanding of the effect of microstructural alterations in MASH and their effect on MRI-accessible biomarkers, using a solid simulation foundational work. The concepts are then validated in small animal models of the disease carried over to the clinic.
Time-resolved diffusion imaging is a development on top of diffusion imaging, whereby the diffusion-encoding gradients, typically short pulses separated by a long mixing time, are replaced by rapidly oscillating gradients. The time scale of the experiment then becomes the period of oscillation of the gradients, which can be made so short that distances smaller than 2µm can be probed. With this technique, the observer can selectively sensitize the measurement to a specific spatial range, and potentially observe a wider variety of tissue alterations.
In MR elastography, mechanical properties of tissues are probed via the propagation of an acoustic wave. This technique hold promise for the diagnosis of MASH especially, since MASH is known to alter many determinants of mechanical properties. For instance, fibrosis increases the stiffness of tissue via the deposition of collagen fibers. MR elastography enables the measurement of more than just tissue stiffness, being able to reliably determine storage modulus, loss modulus, damping ratio, and the way they vary with respect to actuation frequency.
Finally, accurate in silico modeling is important for understanding the relationship between tissue alterations and their consequences in terms of imaging biomarkers. Advanced agent-based methods enable to simulate large numbers of particles over finely resolved time dimension, enough so that an entire MRI experiment can reliably be entirely simulated in silico.
The following communications best highlight the many results that have been obtained in the pursuit of StediNASH's originally stated objectives:
Articles explicitly mentioning ANR StediNASH
• Saïd et al. “Fat-Corrected Non-Gaussian Diffusion MRI for Liver Fibrosis Assessment in Metabolic Dysfunction-Associated Steatotic Liver Disease.” JMRI, ahead of print, 2025. doi.org/10.1002/jmri.70148.
• Garteiser & al “Editorial for “Prospective Comparison of DWI‐Derived Virtual MR Elastography and Conventional MR Elastography in Metabolic Dysfunction−Associated Steatotic Liver Disease and Healthy Volunteers.” JMRI 2025, jmri.70193. doi.org/10.1002/jmri.70193.
• Zhao & al. “A Liver Digital Twin for in Silico Testing of Cellular and Inter-Cellular Mechanisms in Regeneration after Drug-Induced Damage.” iScience 2023, 108077. doi.org/10.1016/j.isci.2023.108077.
• Hoehme & al “Digital Twin Demonstrates Significance of Biomechanical Growth Control in Liver Regeneration after Partial Hepatectomy.” iScience 2023. doi.org/10.1016/j.isci.2022.105714.
• Dirk Drasdo & al “An Integrative Experimental and Computational Twin Modeling Approach to Understand Clonal Dynamics in the Normal Liver.” JHep 2023. doi.org/10.1016/j.jhep.2023.05.016.
Conferences
• Khalfallah & al “Suivi de la réponse au traitement de la stéatohépatite non alcoolique par mesures du coefficient de diffusion à échelle spatiale spécifique.” SFRMBM 2023, Paris. hal.science/hal-04248831.
• Khalfallah & al “Temporal Diffusion Spectroscopy with Oscillating Gradient Echoplanar MRI : Signal to Noise and ADC Repeatability in Mice Liver.” Paper presented at ISMRM 2021 online hal.science/hal-03360727
• Saïd & al “Hepatic Non-Gaussian Apparent Diffusion in NAFLD Patients: A Dual Role for Steatosis.” ESMRMB 2023, Basel. hal.science/hal-04523455.
• Saïd & al “Sévérité de La Fibrose Hépatique : Performance Diagnostique de La Diffusion Nongaussienne Dans l’hépatopathie Stéatosique.” JFR 2023, Paris.
• Garteiser & al "Characterization of the microstructural complexity of tumor tissue using time-dependent diffusion in the 60-240Hz range". SFRMBM 2025, Saint-Malo. hal.science/hal-05016574
• Saïd & al "Fat Correction in Diffusion MRI: Impact on ADC Estimation with time-dependent diffusion MRI". SFRMBM 2025, Saint-Malo. hal.science/view/index/docid/5493179
PhD Theses
Khalfallah, Meryem. “Development and Validation of Quantitative Magnetic Resonance Imaging (MRI) of Nonalcoholic Fatty Liver Disease (NAFLD).” Université Paris Cité, ED 563, 2023. www.theses.fr/s234143.
Technological developments into StediNASH have been carried over to other projects of the team, notably the PCSI "MistraXL", wherein the time-resolved diffusion and the MRE methods are used in the context of pancreatic ductal adenocarcinoma.
Nonalcoolic steatohepatitis causes an increasing number of hepatic cancers. It is characterized by hepatic steatosis, inflammation and hepatocyte ballooning, and can be associated with fibrosis. Some imaging methods can be used to diagnose steatosis, fibrosis or inflammation, but none is available for ballooning. STEDI-NASH aims to fill this need with temporal diffusion spectroscopy MRI, which enables to probe movements at the subcellular scale such as those generated by ballooning. The project starts with the development of a DTS MRI sequence and its multiplexing with MR elastography, supported by numeric and physical models. It is followed by an applicative, translational phase ex vivo and in vivo in mice. The project is completed with a proof of concept clinical study on a small number of patients. The STEDI-NASH consortium involves 4 high impact teams in modeling, imaging physics, applied imaging and clinical radiology.
Project coordination
Philippe Garteiser (Centre de recherche sur l'inflammation)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
CRI Centre de recherche sur l'inflammation
Inria de Paris Institut national de recherche en informatique et en automatique
LIB Laboratoire d'Imagerie Biomédicale
CRI Centre de recherche sur l'inflammation
Help of the ANR 376,964 euros
Beginning and duration of the scientific project:
- 36 Months
