CIBM Pre-Clinical Imaging EPFL SECTION

Metabolic Imaging

Section Head: Dr. Cristina Cudalbu (EPFL)

The CIBM Pre-Clinical Imaging EPFL Metabolic Imaging Section focuses on advancing Magnetic Resonance (MR) and Positron Emission Tomography (PET) technologies and their applications in biomedical research. MR spectroscopy, MR Spectroscopic Imaging and PET represent most of the current non-invasive imaging techniques used to follow metabolism in vivo. They are complemented by MR Imaging bringing complementary information on tissue structure, microstructure and function. The multidisciplinary team thrives to improve our understanding, interalia, of the steady-state and dynamic metabolism (metabolite concentrations, kinetic fluxes), structure and microstructure, and cognitive function in healthy and diseased subjects, at preclinical level, as well as bringing technological and methodological innovations to the community.  

CIBMPCIEPFL overview
Main research areas
  •  mapping of steady-state brain metabolism in vivo and its regional vulnerability in neurological diseases using MR Spectroscopy and whole-brain accelerated MR Spectroscopic Imaging
  • dynamic mapping of brain glucose metabolism in neurological diseases using MR Spectroscopy and Positron Emission Tomography
  • dynamic whole-brain energy metabolic imaging of neurological diseases using phosphorous, deuterium MR Spectroscopy and whole-brain accelerated MR Spectroscopic Imaging
  • in vivo brain microstructural changes in neurological diseases using MR Diffusion Weighted Spectroscopy, MR Diffusion Weighted Imaging and Microscopy
  • study of oxidative stress in neurological diseases using MR Spectroscopy, Electron Paramagnetic Resonance and Microscopy
  • high resolution MR Imaging and volumetry
  • state-of-the art hardware and method developments
Infrastructure

Expertise and access to two preclinical ultra-high field Magnetic Resonance Imaging scanners and small-animal PET systems are also provided to the community , namely:

  • 9.4T / 31cm horizontal bore PET/MR scanner equipped with cryogenic coils to deliver unmatched MR sensitivity and a PET insert to enable multimodal metabolic studies, more info.
  • 14.1T / 26cm horizontal bore MR scanner with ultra-strong gradients for exceptional spectral and microstructural details, more info.
  • Small-animal PET scanner, more info.

These scanners are complemented with the following ancillary infrastructure:

  • Two adjacent preparation rooms fully equipped for surgeries, anaesthesia, scan preparation and physiology monitoring of small rodents.
  • Type C laboratory for the handling and preparation of radiotracers.
  • Veterinary support for small rodent experiments, in particular the preparation of the animal, monitoring to ensure proper physiological parameters during the scan, as well as, compliance with ethical rules.
  • Fully equipped radiofrequency (RF) laboratory and workshop, providing CIBM-wide RF coils and electronics support.
  • Neurochemistry laboratory, providing infrastructure for sample/tissue preparation and analysis, biochemical assays, sample storage, biohazardous materials handling (P2 level).
  • X-band electron paramagnetic resonance spectrometer, for the characterization of radical species.
  • Fluorescence microscopy laboratory, for tissue analysis.
  • On-site animal housing facility, managed by the EPFL Center for Phenogenomics.

RESEARCH TOPICS

CIBM PCI EPFL

Mapping brain microstructure in vivo using diffusion MR Spectroscopy and MR Imaging

Description: The temporal and regional evolution of the brain during development, disease or injury is characterized by numerous microstructural and metabolic changes, for which new non-invasive methods advancing the quantification of brain microstructure are necessary. Diffusion MRI (dMRI) of water provides information about tissue microstructure non-invasively, but its specificity is limited due to ubiquitous presence of water. The biggest challenge remains the validation of the biological accuracy of estimated parameters. In contrast, brain metabolites measured by MR spectroscopy (MRS) are predominantly intracellular and some have a reportedly preferential localization in specific brain cell types. Diffusion MRS (dMRS) can thus provide quantification of cell-type specific microstructure. Taking advantage of this specificity to tag microstructure across the brain, however, still requires thorough validation.
Our overall goal is therefore to push further a new concept for quantification and validation of brain microstructure through diffusion of brain metabolites and water at cellular and sub-cellular scale, by implementing an in vivo innovative multi-modal approach combining novel dMRS acquisitions, state-of-the-art postprocessing and metabolite diffusion modeling techniques validated with 2-photon microscopy and mass spectrometry. Our target application is the critical period of brain development and associated potential injury, that we will assess using both 3D brain cell organoids (validation of metabolite diffusion metrics) and in vivo rodent models.

Investigator: Cristina Cudalbu, Tan Toi Phan, Eloise Mougel, Thi Ngoc Anh Dinh, Thanh Phong Lê (EPFL).

Collaborators: Ileana Jelescu (CHUV, UNIL), Julien Valette (CEA, Paris), Olivier Braissant (CHUV, UNIL), Stephane Sizonenko (HUG, UNIGE)

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High resolution ex vivo brain MRI

Description:  Animal models of brain diseases are powerful means to address fundamental neuroscientific questions on the genesis and progression of neurological diseases and on the effect of potential treatments. To track changes in brain subregions morphology and volumetry as well as to define new brain atlases for tissue segmentation in new animal models with altered brain morphology, ultra-high resolution 3D imaging of the intact brain is instrumental. Typically, to push the limits in terms of signal-to-noise for an enhanced spatial resolution and to avoid any artefact due to motion, long acquisitions can be undertaken on extracted brains or still in situ in the cranium, for rats or mice. These measurements can also be extended to diffusion-weighted MRI.

The brains are prepared in dedicated supports and surrounded with MR-invisible oil, to optimize field homogeneity and minimize image distortion. Taking advantage of the enhance receive sensitivity of the 9.4T cryoprobe, 3D isotropic high resolution (50 µm) T2-weighted images can then be acquired overnight over the full brain, resulting in anatomical contrast and resolution approaching histology, but on the intact brain.

Investigator: Bernard Lanz (EPFL), Katarzyna Pierzchala (EPFL).

Collaborators: Antoine Philippides (EPFL), Viviana Aureli (CHUV), Grégoire Courtine (EPFL).

CIBM PCI EPFL

The role of brain glutamine on brain microstructure and energy metabolism in juvenile chronic hepatic encephalopathy

Description:  Chronic hepatic encephalopathy (CHE) is a clinical challenge in adults, and is increasingly recognized in children with congenital porto-systemic shunts (CPSS) and chronic liver disease (CLD). Its underlying pathophysiology – both at the molecular and tissue levels- is incompletely understood leading to insufficient recognition, treatment and outcomes. Our group applied its expertise to filling the gap in our understanding of neurometabolism in CHE in the adult and developing brain (animal models and children): osmotic stress caused by glutamine (Gln) increase (stronger in the developing brain), alterations in brain microstructure in a rat model of CHE, increase in brain Gln and decrease in the energy metabolite creatine, as well as decreased cerebral glucose metabolism (CMRglc) in CHE rats. It remains unclear how the increased osmotic pressure triggered by Gln accumulation in juvenile CHE alters the morphology of brain cells (microstructure) and brain energy metabolism, and how they might contribute to observed neurocognitive complications. We hypothesize that early brain Gln increase in CHE causes reduction of neural network complexity and arborization and energy dysfunction.
We aim to investigate the impact of increased Gln on brain microstructure and energy metabolism using an innovative multimodal approach combining diffusion MRS and imaging (dMRS, dMRI) with proton and deuterium 3D spectroscopic imaging (1H&2H-MRSI), and PET-MRSI. We will work in a fully translational framework integrating 3D brain cell organoids, animal models and children with CLD and CPSS.

Investigator: Cristina Cudalbu, Bernard Lanz, Thanh Phong Lê, Tan Toi Phan, Eloise Mougel, Thi Ngoc Anh Dinh, Gianna Nossa, Alessio Siviglia, Omar Zenteno (EPFL).

Collaborators: Valerie McLin (HUG UNIGE), Olivier Braissant (CHUV UNIL).

Dynamic 2H MRSI measurement of brain oxidative metabolism

Description: Deuterium imaging (2H-MRS/MRSI) emerged as a promising in vivo tool to study glucose metabolism by the use of deuterium-labelled substrates. Although research to date has shed some light on the usefulness of deuterium imaging in animal models and humans, current 2H-MRSI acquisitions and reconstructions are often limited to static acquisitions at labelling steady-state.

To enable dynamic measurement of deuterium turnover through the brain oxidative metabolic pathway, our research focuses on implementing accelerated MRSI strategies to 3D 2H-MRSI. All developments are aiming at obtaining dynamic and quantitative 3D images of glucose metabolites 2H turnover, enabling further quantitative determination of cerebral oxidative metabolic rate of glucose CMRglc(ox) through advanced metabolic modelling.

Investigator: Bernard Lanz, Alessio Siviglia, Cristina Cudalbu, Gianna Nossa, Thanh Phong Lê (EPFL).

Collaborators: Bernhard Strasser, Fabian Niess, Wolfgang Bogner (Medical University of Vienna)

Quantitative metabolic mapping of glucose uptake

Description: A novel 18FDG PET-based methodology was developed to quantitate regional cerebral metabolic rate of glucose (CMRglc) in μmol/g/min, using image-derived input function from the vena cava in rodents. This method enables with minimal invasiveness to create 3D metabolic maps of glucose uptake from dynamic PET acquisitions that can be used not only as a quantitative metabolic imaging approach in itself, but can be combined with MRS and MRSI metabolic measurements.
Initially developed on the LabPET4 standalone PET scanner, the approach is currently extended to be used on the newly installed PET-MR equipment of the preclinical 9.4T scanner and for metabolic imaging in various organs.

Investigator: Bernard Lanz (EPFL), Omar Zenteno (EPFL).

Collaborators: Volumina Medical SA

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In vivo brain metabolism and it’s regional differences in disease by 1H MRS

Description: Chronic hepatic encephalopathy (chronic HE) is a neurological disease caused by chronic liver disease (CLD). Unlike adults, children grow up with significant neurological deficits even after liver transplantation, suggesting that the immature brain is uniquely vulnerable to the insults associated with CLD.
Despite considerable advances in understanding the pathogenesis of many neurological diseases, key questions remain unanswered for chronic HE. What makes the developing brain more vulnerable? What regional brain metabolic changes occur in response to elevated ammonium and its metabolic product glutamine (Gln)? How do these affect the morphology and function of brain cells?
Current therapies aimed at lowering peripheral ammonium load are insufficient to avoid long-term clinical consequences in children. Therefore, identifying novel molecular pathways involved in chronic HE that might be amenable to therapeutic intervention would be a major advance.
The current project aims to address the molecular, regional, and age-dependence changes in chronic HE in vivo and longitudinally using a multi-modal approach based on dynamic multinuclear MRS(I) and MRI at ultra-high filed, PET and ex-vivo histological measures in the adult and developing brain under chronic HE.

Investigator: Cristina Cudalbu (EPFL), Bernard Lanz (EPFL), Thanh Phong Lê (EPFL), Katarzyna Pierzchala (EPFL), Brayan Alves (EPFL), Gianna Nossa (EPFL).

Collaborators: Olivier Braissant (CHUV, UNIL), Valerie McLin (HUG UNIGE)

Hardware and method development for preclinical MR

Description: We develop custom tools and methods for preclinical MR at 9.4T and 14.1T, for example:

  • Design, electromagnetic simulations and manufacturing of single- and multi-tuned radiofrequency coils.
  • Development of acquisition sequences and processing pipelines for MR spectroscopic imaging.
  • Animal and phantom fixation apparatus tailored to specific experimental requirements.
  • Ancillary devices for MR experiments, such as stimulation interfaces for functional MR, animal physiological support and monitoring system, fluidic pumps, …

Investigator: Thanh Phong Lê (EPFL), Cristina Cudalbu (EPFL), Bernard Lanz (EPFL) 

Fast high-resolution metabolic imaging in the brain at ultra-high magnetic field

Description: MR spectroscopic imaging (MRSI) is a powerful tool that enables the simultaneous noninvasive acquisition of MR spectra from multiple spatial locations inside the brain, with one drawback the long measurement times.

Several methods have been proposed to accelerate 1H MRSI UHF for clinical applications (i.e. FID-MRSI and spatial-spectral encoding), with in plane spatial resolutions of 1.7-10 mm and the detection of several metabolites.

High resolution 1H MRSI preclinical data quantitatively mapping an extended number of metabolites are still acquired using traditional phase encode MRSI, as pioneered by our group, while 31P MRSI in preclinical models is non-existent.

MRSI is highly challenging due to metabolites low concentration, long measurement times, signal-to-noise ratio (SNR), hardware limitations (B0 and gradients strength, RF coils, B0 inhomogeneities), advanced pulse sequences and processing that need to be developed in-house, quality assessment of a huge number of spectra, and precision and reliability of derived metabolite maps.

The main goal is therefore to develop 3D fast and highly spatially resolved MRSI of the whole rodent brain combined with an automatic processing pipeline and automatic quality control. 

Investigator: Cristina Cudalbu (EPFL), Thanh Phong Lê (EPFL), Brayan Alves (EPFL), Gianna Nossa (EPFL), Tan Toi Phan (EPFL)

Collaborators: Bernard Lanz (EPFL), Bernhard Strasser (Medical University of Vienna), Wolfgang Bogner (Medical University of Vienna)