Periodic Reporting for period 3 - LactaDiff (Assessing cellular compartmentation of brain lactate using diffusion MR spectroscopy in vivo)
Berichtszeitraum: 2022-05-01 bis 2023-10-31
Compartmentation of brain lactate, i.e. its distribution between neurons, glial cells (in particular astrocytes) and the extracellular space, is likely to play a critical role in neurotransmission and brain plasticity, and is presumably altered in neurodegenerative diseases such as Alzheimer's disease. However, these notions remain controversial, and the fundamental “astrocyte-to-neuron lactate shuttle” mechanism, whereby astrocytes export lactate to neurons to sustain neuronal energy needs or for signaling purposes, is still fiercely debated. This is largely due the lack of tools to evaluate cell-specific compartmentation of lactate in the living brain, in particular in Humans.
The goal of the LactaDiff project is to develop a strategy, based on measurements of lactate diffusion properties using NMR spectroscopy in vivo, to achieve such non-invasive measurement of brain lactate compartmentation. This would provide some new experimental tool for basic neuroscience, and also allow better understanding of neurodegenerative diseases, which impose a heavy burden to modern societies.
More specifically, the goals are:
- To develop new diffusion NMR spectroscopy measurement techniques optimized for lactate
- To model measured lactate diffusion to extract lactate fraction in each compartment, exploiting the unique ability of diffusion NMR spectroscopy to differentiate between different microstructural environments
- To validate these methods in rodent models, by comparison with invasive reference techniques
- To transpose these methods on a clinical MRI system at ultra-high magnetic field, to assess lactate compartmentation in the Human brain and its modifications during brain activity, plasticity, and in Alzheimer's disease.
The goal of the LactaDiff project is to develop a strategy, based on measurements of lactate diffusion properties using NMR spectroscopy in vivo, to achieve such non-invasive measurement of brain lactate compartmentation. This would provide some new experimental tool for basic neuroscience, and also allow better understanding of neurodegenerative diseases, which impose a heavy burden to modern societies.
More specifically, the goals are:
- To develop new diffusion NMR spectroscopy measurement techniques optimized for lactate
- To model measured lactate diffusion to extract lactate fraction in each compartment, exploiting the unique ability of diffusion NMR spectroscopy to differentiate between different microstructural environments
- To validate these methods in rodent models, by comparison with invasive reference techniques
- To transpose these methods on a clinical MRI system at ultra-high magnetic field, to assess lactate compartmentation in the Human brain and its modifications during brain activity, plasticity, and in Alzheimer's disease.
Significant work has been devoted to the development and evaluation of new diffusion NMR spectroscopy measurement techniques. In particular, we have introduced NMR sequences exploiting spectrally-selective radiofrequency pulses to enhance the signal of lactate, allowing the measurement of lactate diffusion with a ~two-fold increased precision compared to conventional approaches.
In parallel, we have also performed extensive experimental works to characterize extracellular diffusion in the rodent brain, which is of critical importance for modeling lactate diffusion to extract lactate fraction in each compartment. First modeling attempts of experimental data have also been proposed, although we are still at the early stages.
Regarding validation in rodent models: the invasive reference techniques, namely enzyme-electrodes to measure extracellular lactate, and FRET to measure neuronal and astrocytic lactate, have been set up, optimized and characterized. All ethics authorization have been granted, and experimental campaigns combining MR spectroscopy and reference techniques are about to start.
Finally, we have performed some preliminary works to evaluate the feasibility of transposing methods to a high-field clinical MRI scanner.
In parallel, we have also performed extensive experimental works to characterize extracellular diffusion in the rodent brain, which is of critical importance for modeling lactate diffusion to extract lactate fraction in each compartment. First modeling attempts of experimental data have also been proposed, although we are still at the early stages.
Regarding validation in rodent models: the invasive reference techniques, namely enzyme-electrodes to measure extracellular lactate, and FRET to measure neuronal and astrocytic lactate, have been set up, optimized and characterized. All ethics authorization have been granted, and experimental campaigns combining MR spectroscopy and reference techniques are about to start.
Finally, we have performed some preliminary works to evaluate the feasibility of transposing methods to a high-field clinical MRI scanner.
The new diffusion NMR spectroscopy sequences that have been introduced, using spectrally-selective radiofrequency pulses to cancel the effect of J-modulation, allow measuring lactate diffusion properties with unprecedented precision.
Data gathered about extracellular diffusion in the rodent brain are original and provide new insights about biophysical properties of this compartment. Beyond the current project, this may help refining modelling of diffusion MRI data, where strong assumptions need to be made about diffusion properties in the extracellular space. Furthermore, some of the methods we have proposed may potentially be used to assess extracellular diffusion in the Human brain.
Data gathered about extracellular diffusion in the rodent brain are original and provide new insights about biophysical properties of this compartment. Beyond the current project, this may help refining modelling of diffusion MRI data, where strong assumptions need to be made about diffusion properties in the extracellular space. Furthermore, some of the methods we have proposed may potentially be used to assess extracellular diffusion in the Human brain.