Noninvasive Imaging of Transgene Expression in Neurons Using Chemical Exchange Saturation Transfer MRI.

Advances in gene therapy, especially for brain diseases, have created new imaging demands for noninvasive monitoring of gene expression. While reporter gene imaging using co-expression of fluorescent protein-encoding gene has been widely developed, these conventional methods face significant limitations in longitudinal in vivo applications. Magnetic resonance imaging (MRI), specifically chemical exchange saturation transfer (CEST) MRI, provides a robust noninvasive alternative that offers unlimited depth penetration, reliable spatial resolution, and specificity toward particular molecules.

Toward quantitative CEST imaging of glutamate in the mouse brain using a multi-pool exchange model calibrated by H-MRS.

Purpose: To develop a CEST quantification model to map glutamate concentration in the mouse brain at 11.7 T, overcoming the limitations of conventional glutamate-weighted CEST (gluCEST) contrast (magnetization transfer ratio with asymmetric analysis).

Methods: H-MRS was used as a gold standard for glutamate quantification to calibrate a CEST-based quantitative pipeline.

Capturing alterations of intracellular-extracellular lactate distribution in the brain using diffusion-weighted MR spectroscopy in vivo.

While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease.

Diffusion-weighted MR spectroscopy: Consensus, recommendations, and resources from acquisition to modeling.

Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations.

Answering Hospital Caregivers' Questions at Any Time: Proof-of-Concept Study of an Artificial Intelligence-Based Chatbot in a French Hospital.

Background: Access to accurate information in health care is a key point for caregivers to avoid medication errors, especially with the reorganization of staff and drug circuits during health crises such as the COVID‑19 pandemic. It is, therefore, the role of the hospital pharmacy to answer caregivers' questions. Some may require the expertise of a pharmacist, some should be answered by pharmacy technicians, but others are simple and redundant, and automated responses may be provided.

Assessing potential correlation between T relaxation and diffusion of lactate in the mouse brain.

Purpose: While diffusion and T relaxation are intertwined, little or no correlation exists between diffusion and T 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 spaces, which exhibit different diffusion properties and may also exhibit different T . Such a TE dependence would be crucial to account for when interpreting or modeling lactate diffusion.

Using spectrally-selective radiofrequency pulses to enhance lactate signal for diffusion-weighted MRS measurements in vivo.

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-modulation of its 1.3 ppm peak.

Zero Echo Time O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis.

The cerebral metabolic rate of oxygen consumption (CMRO) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO can be measured by direct O magnetic resonance imaging (O-MRI) of HO signal changes during inhalation of O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.

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

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.

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

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.

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

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.

Influence of the urban context on the relationship between neighbourhood deprivation and obesity.

Background: In middle- and high-income countries, obesity is positively associated with neighbourhood deprivation. However, the moderating effect of the broader urban residential context on this relationship remains poorly understood.

Methods: In this study, we have examined the nonlinear and geographically varying relationship between neighbourhood deprivation and the likelihood of being a person with overweight among participants of the French NutriNet-Santé adult cohort study (n = 68,698), adjusted for age, gender and educational level.

A new safety index based on intrapulse monitoring of ultra-harmonic cavitation during ultrasound-induced blood-brain barrier opening procedures.

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 (PCD) is a method proposed to monitor the microbubble activity during ultrasound exposure.

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

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.

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

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.

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

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.

Natives' Attitudes and Immigrants' Unemployment Durations.

In this study, we investigate how the attitude of natives-defined as the perceived trustworthiness of citizens from different countries-affects immigrants' labor market outcomes in Germany. Evidence in the literature suggests that barriers to economic assimilation might be higher for some groups of immigrants, but the role of natives' heterogeneous attitudes toward immigrants from different countries of origin has received little attention. Using individual-level panel data from the German Socio-Economic Panel covering the years 1984 to 2014, we apply survival analysis methods to model immigrants' unemployment durations.

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

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.

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

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.

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

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.

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

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.

The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin.

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.

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

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.

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

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).

Insights into brain microstructure from in vivo DW-MRS.

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.