Julien Valette

Atomic Energy and Alternative Energies Commission | CEA · Molecular Imaging Research Center (MIRCen)

Water diffusion MRI is a very powerful tool for probing tissue microstructure, but disentangling the contribution of compartment-specific structural disorder from cellular restriction and inter-compartment exchange remains an open challenge. Here, we use diffusion MR spectroscopy (dMRS) of water and metabolites as a function of diffusion time in vi...

This work demonstrates that metabolites diffusion and kurtosis time-dependence can be measured in vivo in the human brain using Diffusion-Weighted MR Spectroscopy (DW-MRS) and ultra-strong gradients. At short diffusion-times, DW-MRS is sensitive to cytoplasmic viscosity and short-range structures; at long diffusion-times to long-range structures. W...

Brain cell structure and function reflect neurodevelopment, plasticity and ageing, and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to non-invasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted...

Purpose: While diffusion and T2 relaxation are intertwined, little or no correlation exists between diffusion and T2 relaxation of intracellular metabolites in the rodent brain, as measured by diffusion-weighted MRS at different TEs. However, situation might be different for lactate, since it is present in both extracellular and intracellular spac...

Measurement of lactate diffusion properties using diffusion-weighted magnetic resonance spectroscopy in vivo may allow elucidating brain lactate cellular compartmentation, which would be of great importance for neuroscience. However, measuring lactate signal is complicated by low signal-to-noise ratio due to low lactate concentration and J-modulati...

The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we b...

Brain water and some critically important energy metabolites, such as lactate or glucose, are present in both intracellular and extracellular spaces (ICS/ECS) at significant levels. This ubiquitous nature makes diffusion MRI/MRS data sometimes difficult to interpret and model. While it is possible to glean information on the diffusion properties in...

Inflammation of brain tissue is a complex response of the immune system to the presence of toxic compounds or to cell injury, leading to a cascade of pathological processes that include glial cell activation. Noninvasive MRI markers of glial reactivity would be very useful for in vivo detection and monitoring of inflammation processes in the brain,...

In vivo MRS is a non‐invasive measurement technique used not only in humans, but also in animal models using high‐field magnets. MRS enables the measurement of metabolite concentrations as well as metabolic rates and their modifications in healthy animals and disease models. Such data open the way to a deeper understanding of the underlying biochem...

Inflammation of brain tissue is a complex response of the immune system to the presence of toxic compounds or to cell injury, leading to a cascade of pathological processes that include glial cell activation. Noninvasive magnetic resonance imaging markers of glial reactivity would be very useful for in vivo detection and monitoring of inflammation...

Ultrasound-induced blood-brain barrier (BBB) opening using microbubbles is a promising technique for local delivery of therapeutic molecules into the brain. The real-time control of the ultrasound dose delivered through the skull is necessary as the range of pressure for efficient and safe BBB opening is very narrow. Passive cavitation detection (P...

Identification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant...

Brain metabolites, such as N-acetylaspartate or myo-inositol, are constantly probing their local cellular environment under the effect of diffusion. Diffusion-weighted NMR spectroscopy therefore presents unparalleled potential to yield cell-type specific microstructural information. Double diffusion encoding (DDE) consists in applying two diffusion...

Brain metabolites, such as N-acetylaspartate or myo-inositol, are constantly probing their local cellular environment under the effect of diffusion. Diffusion-weighted NMR spectroscopy therefore presents unparalleled potential to yield cell-type specific microstructural information. Double diffusion encoding (DDE) relies on two diffusion blocks whi...

Reactive astrocytes exhibit hypertrophic morphology and altered metabolism. Deciphering astrocytic status would be of great importance to understand their role and dysregulation in pathologies, but most analytical methods remain highly invasive or destructive. The diffusion of brain metabolites, as non-invasively measured using diffusion-weighted m...

The primary goal of this work is to develop an efficient Monte-Carlo simulation of diffusion-weighted signal in complex cellular structures, such as astrocytes, directly derived from confocal microscopy. In this study, we first use an octree structure for spatial decomposition of surface meshes. Octree structure and radius-search algorithm help to...

Purpose: Quantifying multiple NMR properties of sodium could be of benefit to assess changes in cellular viability in biological tissues. A proof of concept of Quantitative Imaging using Configuration States (QuICS) based on a SSFP sequence with multiple contrasts was implemented to extract simultaneously 3D maps of applied flip angle (FA), total...

The diffusion of brain intracellular metabolites, as measured using diffusion-weighted magnetic resonance spectroscopy in vivo , is thought to specifically depend on the cellular structure constraining them. However, it has never been established that variations of metabolite diffusion, e.g. as observed in some diseases, could indeed be linked to a...

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by an abnormal expansion of a CAG repeat located in the gene encoding for huntingtin protein. This mutation induces the expression of a polyglutamine stretch in the mutated protein resulting in the modification of various biological properties of the wild-type protein and the...

The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent da...

Focused ultrasound (FUS) in combination with microbubbles is capable of noninvasive, site-targeted delivery of drugs through the blood–brain barrier (BBB). Although acoustic parameters are reproducible in small animals, their control remains challenging in primates due to skull heterogeneity. This study describes a 7-T magnetic resonance (MR)-guide...

In vivo diffusion-weighted MR spectroscopy (DW-MRS) allows measuring diffusion properties of brain metabolites. Unlike water, most metabolites are confined within cells. Hence, their diffusion is expected to purely reflect intracellular properties, opening unique possibilities to use metabolites as specific probes to explore cellular organization a...

Many developmental processes, such as plasticity and aging, or pathological processes such as neurological diseases are characterized by modulations of specific cellular types and their microstructures. Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) is a powerful technique for probing microstructure, yet its information arises from the ubiq...

Background The correction of γ-photon attenuation in PET-MRI remains a critical issue, especially for bone attenuation. This problem is of great importance for brain studies due to the density of the skull. Current techniques for skull attenuation correction (AC) provide indirect estimates of cortical bone density, leading to inaccurate estimates o...

Can we detect the effect of spines, leaflets and beads on the diffusion of brain Can we detect the effect of spines, leaflets and beads on the diffusion of brain intracellular metabolites? A confrontation between high b-values and high-intracellular metabolites? A confrontation between high b-values and high-frequencies diffusion-weighted MRS in th...

Synopsis While most brain metabolites detected by in vivo MRS are intracellular, some of them, in particular energy metabolism substrates such as glucose, lactate and acetate, are also known to be significantly present in the extracellular space. Although of high metabolic signiӠcance and of practical importance for metabolic flux quantification in...

Synopsis At ultra-short time scales, intracellular metabolites are expected to experience less restriction, so that their apparent diffusion coefficient (ADC) as measured by diffƒusion-weighted MRS should approach the free intracellular diffusivity in a manner which depends on small microstructural features. In this work we use a unique gradient in...

Synopsis In this work we use in vivo MRS and diffusion-weighted MRS (DW MRS) on a model of astrocytic activation induced by the ciliary neutrophic factor (CNTF) in mice striatum. We observe a massive metabolic remodeling in CNTF mice in comparison with control mice. We demonstrate the intrinsic potential of DW MRS to detect alterations in cellular...

Prior models used to clarify which aspects of tissue microstructure mostly affect intracellular diffusion and corresponding diffusion-weighted magnetic resonance (DW-MR) signal have focused on relatively simple geometrical descriptions of the cellular microenvironment (spheres, randomly oriented cylinders, etc…), neglecting finer morphological deta...

Introduction La correction de l’atténuation osseuse en TEP/IRM est un problème non résolu, particulièrement critique au niveau cérébral en raison de la boîte crânienne. Les techniques actuelles de correction de l’atténuation crânienne en TEP-IRM fournissent des estimations indirectes de l’os et restent entachées d’erreurs sur l’activité cérébrale....

SYNOPSIS Animal models of neurodegenerative diseases are useful tools to investigate neurodegenerative diseases. However, there is often a wide variety of described models for a same pathology, each model exhibiting its own characteristics. In this work, we used two mouse models of Huntington's disease exhibiting very different alterations. Using a...

SYNOPSIS GluCEST imaging has been proposed to image brain glutamate distribution with a better resolution than spectroscopic methods and has many potential applications for the study of neurodegenerative diseases. In this study, we pushed further the limits of gluCEST imaging by combining high magnetic field and high performance cryoprobe to acquir...

Changes in energy metabolism are generally considered to play an important role in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Whether these changes are causal or simply a part of self-defense mechanisms is a matter of debate. Furthermore, energy defects have often been discussed solely in the context of...

Measuring diffusion at ultra-short time scales may yield information about short-range intracellular structure and cytosol viscosity. However, reaching such time scales usually requires oscillating gradients, which in turn imply long echo times TE . Here we propose a new kind of stretched oscillating gradient that allows us to increase diffusion-we...

Purpose: To investigate how intracellular metabolites diffusion measured in vivo up to very high q/b in the mouse brain can be explained in terms of simple geometries. Methods: 10 mice were scanned using our new STE-LASER sequence, at 11.7 Tesla (T), up to qmax = 1 μm(-1) at diffusion time td = 63.2 ms, corresponding to bmax = 60 ms/µm². We mode...

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive and psychiatric symptoms. Atrophy of the striatum has been proposed for several years as a biomarker to assess disease progression in HD gene carriers. However, it does not provide any information about the biological mechanisms linked to HD pathog...

We optimize the encapsulation of paclitaxel (PTX) into nanocapsules made of a shell of poly(lactide-co-glycolide)-polyethylene glycol and a core of perfluorooctyl bromide (PFOB) to serve as theranostic agents. Two main challenges were met: keeping the imaging moiety (PFOB) encapsulated while loading the polymer shell with a hydrophobic drug very pr...

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder associated with involuntary abnormal movements (chorea), cognitive deficits and psychiatric disturbances. The most striking neuropathological change in HD is the early atrophy of the striatum. While the disease progresses, other brain structures also degenerate, includ...

Huntington’s disease (HD) is an inherited neurodegenerative disease characterised by motor, cognitive and psychiatric symptoms. Although classically considered as a good biomarker of disease progression in HD gene carriers, atrophy of the striatum does not provide any information about the biological mechanisms linked to HD pathogenesis. Consequent...

With the increased spectral resolution made possible at high fields, a second, smaller inorganic phosphate resonance can be resolved on 31P magnetic resonance spectra in the rat brain. Saturation transfer was used to estimate de novo adenosine triphosphate synthesis reaction rate. While the main inorganic phosphate pool is used by adenosine triphos...

Significance Characterizing the microstructure of an organ noninvasively using molecular diffusion measurements represents a major challenge in medical imaging and life science. In this work, we propose concepts in diffusion magnetic resonance to noninvasively extract morphological properties of brain cells that are out of reach of existing neuroim...

Synopsis Localized 31 P MRS with progressive saturation transfer was performed in the rat brain to estimate the exchange rate between inorganic phosphate (Pi) and adenosine-tri-phosphate (ATP). It was found that two Pi pools, tentatively intra and extracellular pools, can be resolved at 11.7 T, and that only the intracellular Pi signal varies with...

Synopsis We introduce a novel paradigm for non-invasive brain microstructure quantification, where original diffusion modeling is merged with cutting-edge diffusion-weighted spectroscopy (DW-MRS) experiments to capture features of cellular morphology that have remained largely ignored by DW-MRI. A compact description of long-range cellular morpholo...

Synopsis A new diffusion-weighted MRS paradigm, combining advanced modeling with metabolites diffusion measurements at long diffusion times, is applied in the mouse and macaque brain in vivo. Resulting synthetic astrocytes and neurons (derived from cell-specific metabolite diffusion) can be compared with histological data. Very good agreement betwe...

Modeling diffusion of intracellular metabolites in the mouse brain up to very high b: diffusion in long fibers (almost) accounts for non-monoexponential attenuation Palombo M, Ligneul C, Valette J CEA/DSV/I2BM/MIRCen; CNRS Universite Paris-Saclay UMR 9199 Synopsis We investigate how metabolite diffusion measured up to very high b (60 ms/µm 2) at re...

In this work we use in vivo MRS and diffusion-weighted MRS to detect alterations in cellular metabolism and structure in a triple transgenic APP/PS1/tauP301L mouse model of Alzheimer’s disease. We are able to detect massive remodeling of metabolic content in the hippocampus, as well as subtle but significant variations in diffusion properties of as...

Synopsis Localized 31 P MRS with progressive magnetization transfer (MT) is performed in the BACHD transgenic rat model of Huntington's disease to assess energy metabolism. Localized measurements of the ATP formation rate through creatine kinase and oxidative phosphorylation (ATPsynthase) are performed in the rat brain for the first time. Results s...

Purpose: To assess the potential correlation between metabolites diffusion and relaxation in the mouse brain, which is of importance for interpreting and modeling metabolite diffusion based on pure geometry, irrespective of relaxation properties (multicompartmental relaxation or surface relaxivity). Methods: A new diffusion-weighted magnetic res...

Background Alzheimer’s disease (AD) is the most frequent form of dementia in the elderly and no effective treatment is currently available. The mechanisms triggering AD onset and progression are still imperfectly dissected. We aimed at deciphering the modifications occurring in vivo during the very early stages of AD, before the development of amyl...

Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) is a unique tool for the noninvasive exploration of the structure and physiology of the intracellular space in vivo. The method combines sensitization to diffusion using magnetic field gradients with a variety of localized MRS sequences, and thus provides the means to measure and quantify...

Most current brain metabolic models are not capable of taking into account the dynamic isotopomer information available from fine structure multiplets in 13C spectra, due to the difficulty of implementing such models. Here we present a new approach that allows automatic implementation of multi-compartment metabolic models capable of fitting any num...

This work aims to develop a bi-compartmental model that best explains isotopomer data on the basis of biologically sound hypotheses.

Ciliary neurotrophic factor (CNTF) is neuroprotective against multiple pathologic conditions including metabolic impairment, but the mechanisms are still unclear. To delineate CNTF effects on brain energy homeostasis, we performed a multimodal imaging study, combining in vivo proton magnetic resonance spectroscopy, high-performance liquid chromatog...

To introduce a new outer volume suppression (OVS) technique that uses a single pulse and rotating gradients to accomplish frequency-swept excitation. This new technique, which is called gradient rotating outer volume excitation (GROOVE), produces a circular or elliptical suppression band rather than suppressing the entire outer volume. Theoretical...