Publications by authors named "Julien Valette"

57 Publications

Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations.

NMR Biomed 2020 Aug 26:e4325. Epub 2020 Aug 26.

Commissariat à l'Energie Atomique et aux Energies Alternatives, MIRCen, Fontenay-aux-Roses, France.

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 biochemistry, related disturbances and mechanisms taking place during or prior to symptoms and tissue changes. In this work, we focus on the main preclinical H, P and C MRS approaches to study brain metabolism in rodent models, with the aim of providing general experts' consensus recommendations (animal models, anesthesia, data acquisition protocols). An overview of the main practical differences in preclinical compared with clinical MRS studies is presented, as well as the additional biochemical information that can be obtained in animal models in terms of metabolite concentrations and metabolic flux measurements. The properties of high-field preclinical MRS and the technical limitations are also described.
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http://dx.doi.org/10.1002/nbm.4325DOI Listing
August 2020

Characterizing extracellular diffusion properties using diffusion-weighted MRS of sucrose injected in mouse brain.

NMR Biomed 2021 Apr 27;34(4):e4478. Epub 2021 Jan 27.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.

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 ICS by measuring the diffusion of purely intracellular endogenous metabolites (such as NAA), the absence of endogenous markers specific to ECS hampers similar analyses in this compartment. In past experiments, exogenous probes have therefore been injected into the brain to assess their apparent diffusion coefficient (ADC) and thus estimate tortuosity in ECS. Here, we use a similar approach in mice by injecting sucrose, a well-known ECS marker, in either the lateral ventricles or directly in the prefrontal cortex. For the first time, we propose a thorough characterization of ECS diffusion properties encompassing (1) short-range restriction by looking at signal attenuation at high b values, (2) tortuosity and long-range restriction by measuring ADC time-dependence at long diffusion times and (3) microscopic anisotropy by performing double diffusion encoding (DDE) measurements. Overall, sucrose diffusion behavior is strikingly different from that of intracellular metabolites. Acquisitions at high b values not only reveal faster sucrose diffusion but also some sensitivity to restriction, suggesting that the diffusion in ECS is not fully Gaussian at high b. The time evolution of the ADC at long diffusion times shows that the tortuosity regime is not reached yet in the case of sucrose, while DDE experiments suggest that it is not trapped in elongated structures. No major difference in sucrose diffusion properties is reported between the two investigated routes of injection and brain regions. These original experimental insights should be useful to better interpret and model the diffusion signal of molecules that are distributed between ICS and ECS compartments.
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http://dx.doi.org/10.1002/nbm.4478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988537PMC
April 2021

Inflammation-driven glial alterations in the cuprizone mouse model probed with diffusion-weighted magnetic resonance spectroscopy at 11.7 T.

NMR Biomed 2021 Apr 21;34(4):e4480. Epub 2021 Jan 21.

Center for Neuroimaging Research-CENIR, Paris Brain Institute (Institut du Cerveau-ICM), Paris, France.

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, as well as for evaluating the efficacy of personalized treatments. Due to their specific location in glial cells, myo-inositol (mIns) and choline compounds (tCho) seem to be the best candidates for probing glial-specific intra-cellular compartments. However, their concentrations quantified using conventional proton MRS are not specific for inflammation. In contrast, it has been recently suggested that mIns intra-cellular diffusion, measured using diffusion-weighted MRS (DW-MRS) in a mouse model of reactive astrocytes, could be a specific marker of astrocytic hypertrophy. In order to evaluate the specificity of both mIns and tCho diffusion to inflammation-driven glial alterations, we performed DW-MRS in a volume of interest containing the corpus callosum and surrounding tissue of cuprizone-fed mice after 6 weeks of intoxication, and evaluated the extent of astrocytic and microglial alterations using immunohistochemistry. Both mIns and tCho apparent diffusion coefficients were significantly elevated in cuprizone-fed mice compared with control mice, and histologic evaluation confirmed the presence of severe inflammation. Additionally, mIns and tCho diffusion showed, respectively, strong and moderate correlations with histological measures of astrocytic and microglial area fractions, confirming DW-MRS as a promising tool for specific detection of glial changes under pathological conditions.
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http://dx.doi.org/10.1002/nbm.4480DOI Listing
April 2021

Complementarity of gluCEST and H-MRS for the study of mouse models of Huntington's disease.

NMR Biomed 2020 07 21;33(7):e4301. Epub 2020 Mar 21.

Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut de biologie François Jacob, Molecular Imaging Research Center (MIRCen), Université Paris-Saclay, Fontenay-aux-Roses, France.

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 biomarkers by combining biological specificity provided by H-MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)-the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD-were used. Animals were scanned at 11.7 T using a protocol combining H-MRS and gluCEST imaging. We measured a significant decrease in levels of N-acetyl-aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that H-MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarkers.
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http://dx.doi.org/10.1002/nbm.4301DOI Listing
July 2020

Revisiting double diffusion encoding MRS in the mouse brain at 11.7T: Which microstructural features are we sensitive to?

Neuroimage 2020 02 25;207:116399. Epub 2019 Nov 25.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), MIRCen, F-92260, Fontenay-aux-Roses, France; Neurodegenerative Diseases Laboratory, UMR9199, CEA, CNRS, Université Paris Sud, Université Paris-Saclay, F-92260, Fontenay-aux-Roses, France. Electronic address:

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 blocks, where gradient's direction in the second block is varied during the course of the experiment. Unlike single diffusion encoding, DDE measurements at long mixing time display some angular modulation of the signal amplitude which reflects microscopic anisotropy (μA), while requiring relatively low gradient strength. This angular dependence has been formerly used to quantify cell fiber diameter using a model of isotropically oriented infinite cylinders. However, how additional features of the cell microstructure (such as cell body diameter, fiber length and branching) may also influence the DDE signal has been little explored. Here, we used a cryoprobe as well as state-of-the-art post-processing to perform DDE acquisitions with high accuracy and precision in the mouse brain at 11.7 ​T. We then compared our results to simulated DDE datasets obtained in various 3D cell models in order to pinpoint which features of cell morphology may influence the most the angular dependence of the DDE signal. While the infinite cylinder model poorly fits our experimental data, we show that incorporating branched fiber structure in our model allows more realistic interpretation of the DDE signal. Lastly, data acquired in the short mixing time regime suggest that some sensitivity to cell body diameter might be retrieved, although additional experiments would be required to further support this statement.
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http://dx.doi.org/10.1016/j.neuroimage.2019.116399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014823PMC
February 2020

Longitudinal characterization of cognitive and motor deficits in an excitotoxic lesion model of striatal dysfunction in non-human primates.

Neurobiol Dis 2019 10 24;130:104484. Epub 2019 May 24.

MIRCen, CEA/IBFJ/DRF/LMN, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France; UMR CEA CNRS 9199-Université Paris Saclay, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France. Electronic address:

As research progresses in the understanding of the molecular and cellular mechanisms underlying neurodegenerative diseases like Huntington's disease (HD) and expands towards preclinical work for the development of new therapies, highly relevant animal models are increasingly needed to test new hypotheses and to validate new therapeutic approaches. In this light, we characterized an excitotoxic lesion model of striatal dysfunction in non-human primates (NHPs) using cognitive and motor behaviour assessment as well as functional imaging and post-mortem anatomical analyses. NHPs received intra-striatal stereotaxic injections of quinolinic acid bilaterally in the caudate nucleus and unilaterally in the left sensorimotor putamen. Post-operative MRI scans showed atrophy of the caudate nucleus and a large ventricular enlargement in all 6 NHPs that correlated with post-mortem measurements. Behavioral analysis showed deficits in 2 analogues of the Wisconsin card sorting test (perseverative behavior) and in an executive task, while no deficits were observed in a visual recognition or an episodic memory task at 6 months following surgery. Spontaneous locomotor activity was decreased after lesion and the incidence of apomorphine-induced dyskinesias was significantly increased at 3 and 6 months following lesion. Positron emission tomography scans obtained at end-point showed a major deficit in glucose metabolism and D2 receptor density limited to the lesioned striatum of all NHPs compared to controls. Post-mortem analyses revealed a significant loss of medium-sized spiny neurons in the striatum, a loss of neurons and fibers in the globus pallidus, a unilateral decrease in dopaminergic neurons of the substantia nigra and a loss of neurons in the motor and dorsolateral prefrontal cortex. Overall, we show that this robust NHP model presents specific behavioral (learning, execution and retention of cognitive tests) and metabolic functional deficits that, to the best of our knowledge, are currently not mimicked in any available large animal model of striatal dysfunction. Moreover, we used non-invasive, translational techniques like behavior and imaging to quantify such deficits and found that they correlate to a significant cell loss in the striatum and its main input and output structures. This model can thus significantly contribute to the pre-clinical longitudinal evaluation of the ability of new therapeutic cell, gene or pharmacotherapy approaches in restoring the functionality of the striatal circuitry.
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http://dx.doi.org/10.1016/j.nbd.2019.104484DOI Listing
October 2019

Diffusion-weighted magnetic resonance spectroscopy enables cell-specific monitoring of astrocyte reactivity in vivo.

Neuroimage 2019 05 25;191:457-469. Epub 2019 Feb 25.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), MIRCen, F-92260, Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260, Fontenay-aux-Roses, France. Electronic address:

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 magnetic resonance spectroscopy (DW-MRS) in vivo, depends on the structure of their micro-environment. Here we perform advanced DW-MRS in a mouse model of reactive astrocytes to determine how cellular compartments confining metabolite diffusion are changing. This reveals myo-inositol as a specific intra-astrocytic marker whose diffusion closely reflects astrocytic morphology, enabling non-invasive detection of astrocyte hypertrophy (subsequently confirmed by confocal microscopy ex vivo). Furthermore, we measure massive variations of lactate diffusion properties, suggesting that intracellular lactate is predominantly astrocytic under control conditions, but predominantly neuronal in case of astrocyte reactivity. This indicates massive remodeling of lactate metabolism, as lactate compartmentation is tightly linked to the astrocyte-to-neuron lactate shuttle mechanism.
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http://dx.doi.org/10.1016/j.neuroimage.2019.02.046DOI Listing
May 2019

Efficient GPU-based Monte-Carlo simulation of diffusion in real astrocytes reconstructed from confocal microscopy.

J Magn Reson 2018 11 27;296:188-199. Epub 2018 Sep 27.

Molecular Imaging Research Center (MIRCen), Commissariat l'Energie Atomique, Fontenay-aux-Roses, France.

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 quickly identify the faces that particles can possibly encounter during the next time step, thus speeding up the Monte-Carlo simulation. Furthermore, we propose to use a three-dimensional binary marker to describe the complex cellular structure and optimize the particle trajectory simulation. Finally, a GPU-based version of these two approaches is implemented for more efficient modeling. It is shown that the GPU-based binary marker approach yields unparalleled performance, opening up new possibilities to better understand intracellular diffusion, validate diffusion models, and create dictionaries of intracellular diffusion signatures.
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http://dx.doi.org/10.1016/j.jmr.2018.09.013DOI Listing
November 2018

Simultaneous multi-parametric mapping of total sodium concentration, T, T and ADC at 7 T using a multi-contrast unbalanced SSFP.

Magn Reson Imaging 2018 11 25;53:156-163. Epub 2018 Jul 25.

NeuroSpin, CEA, DRF/JOLIOT, Université Paris-Saclay, Gif-sur-Yvette, France. Electronic address:

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 sodium concentration, T, T, and Apparent Diffusion Coefficient (ADC).

Methods: A 3D Cartesian Gradient Recalled Echo (GRE) sequence was used to acquire 11 non-balanced SSFP contrasts at a 6 × 6 × 6 mm isotropic resolution with carefully-chosen gradient spoiling area, RF amplitude and phase cycling, with TR/TE = 20/3.2 ms and 25 averages, leading to a total acquisition time of 1 h 18 min. A least-squares fit between the measured and the analytical complex signals was performed to extract quantitative maps from a mono-exponential model. Multiple sodium phantoms with different compositions were studied to validate the ability of the method to measure sodium NMR properties in various conditions.

Results: Flip angle maps were retrieved. Relaxation times, ADC and sodium concentrations were estimated with controlled precision below 15%, and were in accordance with measurements from established methods and literature.

Conclusion: The results illustrate the ability to retrieve sodium NMR properties maps, which is a first step toward the estimation of FA, T, T, concentration and ADC of Na for clinical research. With further optimization of the acquired QuICS contrasts, scan time could be reduced to be suitable with in vivo applications.
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http://dx.doi.org/10.1016/j.mri.2018.07.012DOI Listing
November 2018

In Vivo Multidimensional Brain Imaging in Huntington's Disease Animal Models.

Methods Mol Biol 2018 ;1780:285-301

CEA, DRF, Institut de biologie François Jacob, Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.

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 progressive appearance of motor, cognitive, and psychiatric disorders that are typically associated to this condition. Although the exact neuropathological mechanisms of degeneration are still not fully understood, HD pathology is characterized by severe neuronal losses in various brain regions including the basal ganglia and many cortical areas. Early signs of astrogliosis may precede actual neuronal degeneration. Early metabolic impairment at least in part associated with mitochondrial complex II deficiency may play a key role in huntingtin-induced mechanisms of neurodegeneration. Clinical trials are actively prepared including various gene-silencing approaches aiming at decreasing mutated huntingtin production. However, with the lack of a specific imaging biomarker capable of visualizing mutated huntingtin or huntingtin aggregates, there is a need for surrogate markers of huntingtin neurodegeneration. MRI and caudate nucleus atrophy is one of the most sensitive imaging biomarkers of HD. As such it can be used as a means to study disease progression and potential halting of the neurodegenerative process by therapeutic intervention, but this marker relies on actual neuronal loss which is a somewhat a late event in the pathology. As a means to develop, characterize and evaluate new, potentially earlier biomarkers of HD pathology we have recently embarked on a series of NMR developments looking for brain imaging techniques that allow for noninvasive longitudinal evaluation/characterization of functional alterations in animal models of HD. This chapter describes an assemblage of innovative NMR methods that have proved useful in detecting pathological cell dysfunctions in various preclinical models of HD.
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http://dx.doi.org/10.1007/978-1-4939-7825-0_15DOI Listing
February 2019

The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin.

Brain 2018 05;141(5):1434-1454

CEA, DRF, Institut François Jacob, Molecular Imaging Research Center (MIRCen), F-92265 Fontenay-aux-Roses, France.

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 data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
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http://dx.doi.org/10.1093/brain/awy057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917821PMC
May 2018

Brain Metabolite Diffusion from Ultra-Short to Ultra-Long Time Scales: What Do We Learn, Where Should We Go?

Front Neurosci 2018 19;12. Epub 2018 Jan 19.

Department of Computer Science and Centre for Medical Image Computing, University College of London, London, United Kingdom.

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 and structure. However, interpretation and modeling of DW-MRS, and more generally of intracellular diffusion, remains difficult. In this perspective paper, we will focus on the study of the time-dependency of brain metabolite apparent diffusion coefficient (ADC). We will see how measuring ADC over several orders of magnitude of diffusion times, from less than 1 ms to more than 1 s, allows clarifying our understanding of brain metabolite diffusion, by firmly establishing that metabolites are neither massively transported by active mechanisms nor massively confined in subcellular compartments or cell bodies. Metabolites appear to be instead diffusing in long fibers typical of neurons and glial cells such as astrocytes. Furthermore, we will evoke modeling of ADC time-dependency to evaluate the effect of, and possibly quantify, some structural parameters at various spatial scales, departing from a simple model of hollow cylinders and introducing additional complexity, either short-ranged (such as dendritic spines) or long-ranged (such as cellular fibers ramification). Finally, we will discuss the experimental feasibility and expected benefits of extending the range of diffusion times toward even shorter and longer values.
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http://dx.doi.org/10.3389/fnins.2018.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780428PMC
January 2018

Feedback control of microbubble cavitation for ultrasound-mediated blood-brain barrier disruption in non-human primates under magnetic resonance guidance.

J Cereb Blood Flow Metab 2019 07 30;39(7):1191-1203. Epub 2018 Jan 30.

2 NeuroSpin, Institut des Sciences du Vivant Frédéric Joliot, Commissariat à l'Energie Atomique et aux Énergies Alternatives (CEA), Gif-sur-Yvette, France.

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)-guided FUS system designed for BBB disruption in non-human primates (NHP) with a robust feedback control based on passive cavitation detection (PCD). Contrast enhanced T-weighted MR images confirmed the BBB opening in NHP sonicated during 2 min with 500-kHz frequency, pulse length of 10 ms, and pulse repetition frequency of 5 Hz. The safe acoustic pressure range from 185 ± 22 kPa to 266 ± 4 kPa in one representative case was estimated from combining data from the acoustic beam profile with the BBB opening and hemorrhage profiles obtained from MR images. A maximum amount of MR contrast agent at focus was observed at 30 min after sonication with a relative contrast enhancement of 67% ± 15% (in comparison to that found in muscles). The feedback control based on PCD using relative spectra was shown to be robust, allowing comparisons across animals and experimental sessions. Finally, we also demonstrated that PCD can test acoustic coupling conditions, which improves the efficacy and safety of ultrasound transmission into the brain.
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http://dx.doi.org/10.1177/0271678X17753514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668523PMC
July 2019

Insights into brain microstructure from in vivo DW-MRS.

Neuroimage 2018 11 16;182:97-116. Epub 2017 Nov 16.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut de Biologie François Jacob, MIRCen, F-92260 Fontenay-aux-Roses, France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.

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 ubiquitous, non-specific water signal. By contrast, diffusion-weighted Magnetic Resonance Spectroscopy (DW-MRS) allows specific characterizations of tissues such as brain and muscle in vivo by quantifying the diffusion properties of MR-observable metabolites. Many brain metabolites are predominantly intracellular, and some of them are preferentially localized in specific brain cell populations, e.g., neurons and glia. Given the microstructural sensitivity of diffusion-encoding filters, investigation of metabolite diffusion properties using DW-MRS can thus provide exclusive cell and compartment-specific information. Furthermore, since many models and assumptions are used for quantification of water diffusion, metabolite diffusion may serve to generate a-priori information for model selection in DW-MRI. However, DW-MRS measurements are extremely challenging, from the acquisition to the accurate and correct analysis and quantification stages. In this review, we survey the state-of-the-art methods that have been developed for the robust acquisition, quantification and analysis of DW-MRS data and discuss the potential relevance of DW-MRS for elucidating brain microstructure in vivo. The review highlights that when accurate data on the diffusion of multiple metabolites is combined with accurate computational and geometrical modeling, DW-MRS can provide unique cell-specific information on the intracellular structure of brain tissue, in health and disease, which could serve as incentives for further application in vivo in human research and clinical MRI.
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http://dx.doi.org/10.1016/j.neuroimage.2017.11.028DOI Listing
November 2018

Can we detect the effect of spines and leaflets on the diffusion of brain intracellular metabolites?

Neuroimage 2017 05 8;182:283-293. Epub 2017 May 8.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut de Biologie François Jacob, MIRCen, F-92260 Fontenay-aux-Roses France; Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.

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 details which may have an important role. Some types of neurons present high density of spines; and astrocytes and macroglial cells processes present leaflets, which may all impact the diffusion process. Here, we use Monte-Carlo simulations of many particles diffusing in cylindrical compartments with secondary structures mimicking spines and leaflets of neuronal and glial cell fibers, to investigate to what extent the diffusion-weighted signal of intracellular molecules is sensitive to spines/leaflets density and length. In order to study the specificity of DW-MR signal to these kinds of secondary structures, beading-like geometry is simulated as "control" deviation from smooth cylinder too. Results suggest that: a) the estimated intracellular tortuosity increases as spines/leaflets density or length (beading amplitude) increase; b) the tortuosity limit is reached for diffusion time t>200 ms for metabolites and t>70 ms for water molecules, suggesting that the effects of these finer morphological details are negligible at t longer than these threshold values; c) fiber diameter is overestimated, while intracellular diffusivity is underestimated, when simple geometrical models based on hollow smooth cylinders are used; d) apparent surface-to-volume, S/V, ratio estimated by linear fit of high frequency OG data appears to be an excellent estimation of the actual S/V ratio, even in the presence of secondary structures, and it increases as spines and leaflets density or length increase (while decreasing as beadings amplitude increases). Comparison between numerical simulations and multimodal metabolites DW-MRS experiments in vivo in mouse brain shows that these fine structures may affect the DW-MRS signal and the derived diffusion metrics consistently with their expected density and geometrical features. This work suggests that finer structures of cell morphology have non-negligible effects on intracellular molecules' diffusion that may be measured by using multimodal DW-MRS approaches, stimulating future developments and applications.
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http://dx.doi.org/10.1016/j.neuroimage.2017.05.003DOI Listing
May 2017

Using P-MRI of hydroxyapatite for bone attenuation correction in PET-MRI: proof of concept in the rodent brain.

EJNMMI Phys 2017 Dec 2;4(1):16. Epub 2017 May 2.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomedicale (I2BM), MIRCen, Fontenay-aux-Roses, France.

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 of brain activity. The purpose of this study was to develop an alternate method for bone attenuation correction based on NMR. The proposed approach relies on the detection of hydroxyapatite crystals by zero echo time (ZTE) MRI of P, providing individual and quantitative assessment of bone density. This work presents a proof of concept of this approach. The first step of the method is a calibration experiment to determine the conversion relationship between the P signal and the linear attenuation coefficient μ. Then P-ZTE was performed in vivo in rodent to estimate the μ-map of the skull. F-FDG PET data were acquired in the same animal and reconstructed with three different AC methods: P-based AC, AC neglecting the bone and the gold standard, CT-based AC, used to comparison for the other two methods.

Results: The calibration experiment provided a conversion factor of P signal into μ. In vivo P-ZTE made it possible to acquire 3D images of the rat skull. Brain PET images showed underestimation of F activity in peripheral regions close to the skull when AC neglected the bone (as compared with CT-based AC). The use of P-derived μ-map for AC leads to increased peripheral activity, and therefore a global overestimation of brain F activity.

Conclusions: In vivo P-ZTE MRI of hydroxyapatite provides μ-map of the skull, which can be used for attenuation correction of F-FDG PET images. This study is limited by several intrinsic biases associated with the size of the rat brain, which are unlikely to affect human data on a clinical PET-MRI system.
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http://dx.doi.org/10.1186/s40658-017-0183-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413461PMC
December 2017

Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases.

J Cereb Blood Flow Metab 2017 Jun 9;37(6):1927-1943. Epub 2017 Mar 9.

1 Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), CNRS UMR 9199, Université Paris-Sud, Université Paris-Saclay, Fontenay-aux-Roses, France.

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 their probable neuronal origin without considering the cellular heterogeneity of the brain. Recent data point towards the existence of a tri-cellular compartmentation of brain energy metabolism between neurons, astrocytes, and oligodendrocytes, each cell type having a distinctive metabolic profile. Still, the number of methods to follow energy metabolism in patients is extremely limited and existing clinical techniques are blind to most cellular processes. There is a need to better understand how brain energy metabolism is regulated in health and disease through experiments conducted at different scales in animal models to implement new methods in the clinical setting. The purpose of this review is to offer a brief overview of the broad spectrum of methodological approaches that have emerged in recent years to probe energy metabolism in more detail. We conclude that multi-modal neuroimaging is needed to follow non-cell autonomous energy metabolism dysregulation in neurodegenerative diseases.
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http://dx.doi.org/10.1177/0271678X17697989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464722PMC
June 2017

Probing metabolite diffusion at ultra-short time scales in the mouse brain using optimized oscillating gradients and "short"-echo-time diffusion-weighted MRS.

NMR Biomed 2017 01 28;30(1). Epub 2016 Nov 28.

Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), MIRCen, F-92260, Fontenay-aux-Roses, France.

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 T . Here we propose a new kind of stretched oscillating gradient that allows us to increase diffusion-weighting b while preserving spectral and temporal properties of the gradient modulation. We used these optimized gradients to measure metabolite diffusion in the mouse brain down to effective diffusion times of 1 ms while keeping T relatively short (60 ms). At such T , a significant macromolecule signal could still be observed and used as an internal reference of approximately null diffusivity, which proved critical to discard datasets corrupted by some motion artifact. The methods introduced here may be useful to improve the accuracy and precision of metabolite apparent diffusion coefficient measurements with oscillating gradients.
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http://dx.doi.org/10.1002/nbm.3671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164933PMC
January 2017

Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion-weighting: Diffusion in long fibers (almost) accounts for non-monoexponential attenuation.

Magn Reson Med 2017 01 7;77(1):343-350. Epub 2016 Nov 7.

Commissariat a l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomedicale (I2BM), MIRCen, Fontenay-aux-Roses, France.

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 q = 1 μm at diffusion time t = 63.2 ms, corresponding to b = 60 ms/µm². We model cell fibers as randomly oriented cylinders, with radius a and intracellular diffusivity Dintracyl, and fit experimental data as a function of q to estimate Dintracyl and a.

Results: Randomly oriented cylinders account well for measured attenuation, giving fiber radii and Dintracyl in the expected ranges (0.5-1.5 µm and 0.30-0.45 µm/ms, respectively). The only exception is N-acetyl-aspartate (NAA) (extracted a∼0), which we show to be compatible with a small fraction of the NAA pool being confined in highly restricted compartments (with short T).

Conclusion: The non-monoexponential signal attenuation of intracellular metabolites in the mouse brain can be described by diffusion in long and thin cylinders, yielding realistic D and fiber diameters. However, this simple model may require small "corrections" for NAA, in the form of a small fraction of the NAA signal originating from a highly restricted compartment. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.
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http://dx.doi.org/10.1002/mrm.26548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326576PMC
January 2017

Energy defects in Huntington's disease: Why "in vivo" evidence matters.

Biochem Biophys Res Commun 2017 02 14;483(4):1084-1095. Epub 2016 Sep 14.

CEA, DRF, I(2)BM, Molecular Imaging Research Center (MIRCen), F-92265, Fontenay-aux-Roses, France; CEA, CNRS, Paris-Sud University, Paris-Saclay University, UMR9199, Neurodegenerative Diseases Laboratory, F-92265, Fontenay-aux-Roses, France. Electronic address:

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, including the cerebral cortex. Changes are also seen outside the brain, in particular weight loss/cachexia despite high dietary intake. The disease is caused by an abnormal expansion of a CAG repeat in the gene encoding the huntingtin protein (Htt). This mutation leads to the expression of a poly-glutamine stretch that changes the biological functions of mutant Htt (mHtt). The mechanisms underlying neurodegeneration in HD are not totally elucidated. Here, we discuss recent results obtained in patients, animal and cellular models suggesting that early disturbance in energy metabolism at least in part associated with mitochondrial defects may play a central role, even though all data are not congruent, possibly because most findings were obtained in cell culture systems or using biochemical analyses of post mortem tissues from rodent models. Thus, we put a particular focus on brain imaging studies that could identify biomarkers of energy defects in vivo and would be of prime interest in preclinical and clinical trials testing the efficacy of new therapies targeting energy metabolism in HD.
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http://dx.doi.org/10.1016/j.bbrc.2016.09.065DOI Listing
February 2017

Paclitaxel-loaded PEGylated nanocapsules of perfluorooctyl bromide as theranostic agents.

Eur J Pharm Biopharm 2016 Nov 2;108:136-144. Epub 2016 Sep 2.

Institut Galien Paris-Sud, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 92296 Châtenay-Malabry, France.

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 prone to crystallization. Encapsulation is performed by a modified emulsion-evaporation method leading to 120nm diameter nanocapsules with a drug loading compatible with tumor treatment. The optimized formulation tested in vitro on CT-26 colon cancer cells yields a similar IC50 as the generic Taxol® formulation. In vivo, F-MRI shows that PTX encapsulation does not modify the ability of nanocapsules to accumulate passively in CT-26 tumors in mice by the enhanced permeation and retention (EPR) effect. This accumulation leads to a promising and statistically significant twofold reduction in tumor growth as compared with negative control and generic Taxol® group. Altogether these results advocate for an interesting potential of these paclitaxel-loaded theranostic agents.
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http://dx.doi.org/10.1016/j.ejpb.2016.08.017DOI Listing
November 2016

Experimental strategies for in vivoC NMR spectroscopy.

Anal Biochem 2017 07 8;529:216-228. Epub 2016 Aug 8.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), NeuroSpin, F-91190 Gif-sur-Yvette, France.

In vivo carbon-13 (C) MRS opens unique insights into the metabolism of intact organisms, and has led to major advancements in the understanding of cellular metabolism under normal and pathological conditions in various organs such as skeletal muscles, the heart, the liver and the brain. However, the technique comes at the expense of significant experimental difficulties. In this review we focus on the experimental aspects of non-hyperpolarized C MRS in vivo. Some of the enrichment strategies which have been proposed so far are described; the various MRS acquisition paradigms to measure C labeling are then presented. Finally, practical aspects of C spectral quantification are discussed.
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http://dx.doi.org/10.1016/j.ab.2016.08.003DOI Listing
July 2017

Evidence for a "metabolically inactive" inorganic phosphate pool in adenosine triphosphate synthase reaction using localized 31P saturation transfer magnetic resonance spectroscopy in the rat brain at 11.7 T.

J Cereb Blood Flow Metab 2016 09 28;36(9):1513-8. Epub 2016 Jun 28.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France.

With the increased spectral resolution made possible at high fields, a second, smaller inorganic phosphate resonance can be resolved on (31)P 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 triphosphate synthase, the second pool is inactive for this reaction. Accounting for this new pool may not only help us understand (31)P magnetic resonance spectroscopy metabolic profiles better but also better quantify adenosine triphosphate synthesis.
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http://dx.doi.org/10.1177/0271678X16657095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012527PMC
September 2016

In vivo imaging of brain glutamate defects in a knock-in mouse model of Huntington's disease.

Neuroimage 2016 Oct 16;139:53-64. Epub 2016 Jun 16.

Commissariat à l'Energie Atomique (CEA), Direction de la Recherche Fondamentale (DRF), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France; Institut national de la santé et de la recherche médicale (Inserm), UMS 27, F-92260 Fontenay-aux-Roses, France. Electronic address:

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 pathogenesis. Changes in brain metabolites have been also consistently seen in HD patients and animal models using Magnetic Resonance Spectroscopy (MRS), but metabolite measurements are generally limited to a single voxel. In this study, we used Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) in order to map glutamate distribution in the brain of a knock-in mouse model (Ki140CAG) with a precise anatomical resolution. We demonstrated that both heterozygous and homozygous mice with pathological CAG repeat expansion in gene encoding huntingtin exhibited an atrophy of the striatum and a significant alteration of their metabolic profile in the striatum as compared to wild type littermate controls. The striatal decrease was then confirmed by gluCEST imaging. Surprisingly, CEST imaging also revealed that the corpus callosum was the most affected structure in both genotype groups, suggesting that this structure could be highly vulnerable in HD. We evaluated for the first time gluCEST imaging as a potential biomarker of HD and demonstrated its potential for characterizing metabolic defects in neurodegenerative diseases in specific regions.
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http://dx.doi.org/10.1016/j.neuroimage.2016.06.023DOI Listing
October 2016

New paradigm to assess brain cell morphology by diffusion-weighted MR spectroscopy in vivo.

Proc Natl Acad Sci U S A 2016 06 25;113(24):6671-6. Epub 2016 May 25.

MIRCen, Institut d'Imagerie Biomédicale, Direction de la Recherche Fondamentale, Commissariat à l'Energie Atomique et aux Energies Alternatives, F-92260 Fontenay-aux-Roses, France; Unité Mixte de Recherche (UMR) 9199 (Neurodegenerative Diseases Laboratory), Université Paris-Sud, Université Paris-Saclay, CNRS, F-92260 Fontenay-aux-Roses, France;

The brain is one of the most complex organs, and tools are lacking to assess its cellular morphology in vivo. Here we combine original diffusion-weighted magnetic resonance (MR) spectroscopy acquisition and novel modeling strategies to explore the possibility of quantifying brain cell morphology noninvasively. First, the diffusion of cell-specific metabolites is measured at ultra-long diffusion times in the rodent and primate brain in vivo to observe how cell long-range morphology constrains metabolite diffusion. Massive simulations of particles diffusing in synthetic cells parameterized by morphometric statistics are then iterated to fit experimental data. This method yields synthetic cells (tentatively neurons and astrocytes) that exhibit striking qualitative and quantitative similarities with histology (e.g., using Sholl analysis). With our approach, we measure major interspecies difference regarding astrocytes, whereas dendritic organization appears better conserved throughout species. This work suggests that the time dependence of metabolite diffusion coefficient allows distinguishing and quantitatively characterizing brain cell morphologies noninvasively.
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http://dx.doi.org/10.1073/pnas.1504327113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914152PMC
June 2016

Metabolite diffusion up to very high b in the mouse brain in vivo: Revisiting the potential correlation between relaxation and diffusion properties.

Magn Reson Med 2017 04 28;77(4):1390-1398. Epub 2016 Mar 28.

Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Direction des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Fontenay-aux-Roses, France.

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 resonance spectroscopy sequence is introduced, dubbed "STE-LASER," which presents several nice properties, in particular the absence of cross-terms with selection gradients and a very clean localization. Metabolite diffusion is then measured in a large voxel in the mouse brain at 11.7 Tesla using a cryoprobe, resulting in excellent signal-to-noise ratio, up to very high b-values under different echo time, mixing time, and diffusion time combinations.

Results: Our results suggest that the correlation between relaxation and diffusion properties is extremely small or even nonexistent for metabolites in the mouse brain.

Conclusion: The present work strongly supports the interpretation and modeling of metabolite diffusion primarily based on geometry, irrespective of relaxation properties, at least under current experimental conditions. Magn Reson Med 77:1390-1398, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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http://dx.doi.org/10.1002/mrm.26217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008464PMC
April 2017

Alzheimer's disease-like APP processing in wild-type mice identifies synaptic defects as initial steps of disease progression.

Mol Neurodegener 2016 Jan 12;11. Epub 2016 Jan 12.

INSERM UMR1169, Université Paris-Sud, Université Paris-Saclay, Orsay, 94100, France.

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 amyloid deposits, neurofibrillary tangles, neuronal death and inflammation. Most current AD models based on Amyloid Precursor Protein (APP) overproduction beginning from in utero, to rapidly reproduce the histological and behavioral features of the disease within a few months, are not appropriate to study the early steps of AD development. As a means to mimic in vivo amyloid APP processing closer to the human situation in AD, we used an adeno-associated virus (AAV)-based transfer of human mutant APP and Presenilin 1 (PS1) genes to the hippocampi of two-month-old C57Bl/6 J mice to express human APP, without significant overexpression and to specifically induce its amyloid processing.

Results: The human APP, βCTF and Aβ42/40 ratio were similar to those in hippocampal tissues from AD patients. Three months after injection the murine Tau protein was hyperphosphorylated and rapid synaptic failure occurred characterized by decreased levels of both PSD-95 and metabolites related to neuromodulation, on proton magnetic resonance spectroscopy ((1)H-MRS). Astrocytic GLT-1 transporter levels were lower and the tonic glutamatergic current was stronger on electrophysiological recordings of CA1 hippocampal region, revealing the overstimulation of extrasynaptic N-methyl D-aspartate receptor (NMDAR) which precedes the loss of long-term potentiation (LTP). These modifications were associated with early behavioral impairments in the Open-field, Y-maze and Morris Mater Maze tasks.

Conclusions: Altogether, this demonstrates that an AD-like APP processing, yielding to levels of APP, βCTF and Aβ42/Aβ40 ratio similar to those observed in AD patients, are sufficient to rapidly trigger early steps of the amyloidogenic and Tau pathways in vivo. With this strategy, we identified a sequence of early events likely to account for disease onset and described a model that may facilitate efforts to decipher the factors triggering AD and to evaluate early neuroprotective strategies.
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http://dx.doi.org/10.1186/s13024-016-0070-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709894PMC
January 2016

Metabolic Modeling of Dynamic (13)C NMR Isotopomer Data in the Brain In Vivo: Fast Screening of Metabolic Models Using Automated Generation of Differential Equations.

Neurochem Res 2015 Dec 9;40(12):2482-92. Epub 2015 Nov 9.

Center for Magnetic Resonance Research (CMRR), University of Minnesota, 2021 6th St SE, Minneapolis, MN, 55455, USA.

Most current brain metabolic models are not capable of taking into account the dynamic isotopomer information available from fine structure multiplets in (13)C 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 number of (13)C isotopomer curves in the brain. The new automated approach also makes it possible to quickly modify and test new models to best describe the experimental data. We demonstrate the power of the new approach by testing the effect of adding separate pyruvate pools in astrocytes and neurons, and adding a vesicular neuronal glutamate pool. Including both changes reduced the global fit residual by half and pointed to dilution of label prior to entry into the astrocytic TCA cycle as the main source of glutamine dilution. The glutamate-glutamine cycle rate was particularly sensitive to changes in the model.
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http://dx.doi.org/10.1007/s11064-015-1748-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447462PMC
December 2015

The neuroprotective agent CNTF decreases neuronal metabolites in the rat striatum: an in vivo multimodal magnetic resonance imaging study.

J Cereb Blood Flow Metab 2015 Jun 1;35(6):917-21. Epub 2015 Apr 1.

1] Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), MIRCen, Fontenay-aux-Roses, France [2] Neurodegenerative Diseases Laboratory, Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Fontenay-aux-Roses, France.

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 chromatography analysis, and in situ glutamate imaging by chemical exchange saturation transfer. Unexpectedly, we found that CNTF expression through lentiviral gene transfer in the rat striatum significantly decreased the levels of neuronal metabolites (N-acetyl-aspartate, N-acetyl-aspartyl-glutamate, and glutamate). This preclinical study shows that CNTF remodels brain metabolism, and suggests that decreased levels of neuronal metabolites may occur in the absence of neuronal dysfunction.
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http://dx.doi.org/10.1038/jcbfm.2015.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640256PMC
June 2015

Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T.

Brain Struct Funct 2016 Apr 18;221(3):1245-54. Epub 2014 Dec 18.

Commissariat à l'Energie Atomique (CEA), Molecular Imaging Research Center (MIRCen), Institut d'Imagerie Biomédicale (I2BM), BP no. 6, Bâtiment 61, 18 route du panorama, 92265, Fontenay-aux-Roses, France.

Due to the specific compartmentation of brain metabolites, diffusion-weighted magnetic resonance spectroscopy opens unique insight into neuronal and astrocytic microstructures. The apparent diffusion coefficient (ADC) of brain metabolites depends on various intracellular parameters including cytosol viscosity and molecular crowding. When diffusion time (t d) is long enough, the size and geometry of the compartment in which the metabolites diffuse strongly influence metabolites ADC. In a previous study, performed in the macaque brain, we measured neuronal and astrocytic metabolites ADC at long t d (from 86 to 1,011 ms) in a large voxel enclosing an equal proportion of white and grey matter. We showed that metabolites apparently diffuse freely along the axis of dendrites, axons and astrocytic processes. To assess potential differences between these two tissue types, here we measured for the first time in the Human brain the t d-dependency of metabolites trace/3 ADC at 7 teslas using a localized diffusion-weighted STEAM sequence, in parietal and occipital voxels, respectively, containing mainly white and grey matter. We show that, in both tissues and over the observed timescale (t d varying from 92 to 712 ms) metabolite ADC reaches a non-zero plateau, suggesting that metabolites are not confined inside subcellular regions such as cell bodies, or inside subcellular compartments such as organelles, but are rather free to diffuse in the whole fiber-like structure of neurons and astrocytes. Beyond the fundamental insights into intracellular compartmentation of metabolites, this work also provides a new framework for interpreting results of neuroimaging techniques based on molecular diffusion, such as diffusion-weighted magnetic resonance spectroscopy and imaging.
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http://dx.doi.org/10.1007/s00429-014-0968-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878649PMC
April 2016