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. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in 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. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on "Best Practices & Tools for Diffusion MR Spectroscopy" held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.

Assessing potential correlation between T2 relaxation and diffusion of lactate in the mouse brain.

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 spaces, which exhibit different diffusion properties and may also exhibit different T2 . Such a TE dependence would be crucial to account for when interpreting or modeling lactate diffusion. Here we propose to take advantage of a new diffusion sequence, where J-modulation of lactate is canceled even at long TE, thus retaining excellent signal, to assess potential T2 dependence on diffusion of lactate in the mouse brain. METHODS: Using a frequency-selective diffusion-weighted spin-echo sequence that removes J-modulation at 1.3 ppm, thus preserving lactate signal even at long TE, we investigate the effect of TE between 50.9 and 110.9 ms (while keeping diffusion time constant) on apparent diffusivity and kurtosis in the mouse brain. RESULTS: Regardless of the metabolites, no difference appears for the diffusion-weighted signal attenuation with increasing TE. For lactate, apparent diffusivity and kurtosis remain unchanged as TE increases. CONCLUSION: No significant TE dependence of diffusivity and kurtosis is measured for lactate in the 50-110 ms TE range, confirming that potential T2 effects can be ignored 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. In this work, we assess the benefits of using a diffusion-weighting spin echo block and spectrally selective refocusing pulses to suppress the effect of J-coupling on the 1.3 ppm lactate resonance, by not refocusing its coupling partner at 4.1 ppm. Two different kinds of spectrally selective pulses, either polychromatic or single-band, are evaluated in the mouse brain at 11.7 T. Almost complete suppression of J-modulation is shown, resulting in an approximately two-fold signal increase as compared to a reference STE-LASER sequence (for the specific diffusion times used in this work). Repeated measurements confirm that lactate diffusion-weighted signal attenuation is measured with an approximately two-fold precision.