Linking Functional impact and Microstructural properties of fiber tract demyelination and remyelination in a rodent model of multiple sclerosis

Project Information

LinkFM

Grant agreement ID: 843352

DOI

10.3030/843352

Project closed

EC signature date 30 April 2019

Start date 1 May 2019

End date 30 April 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 219 312,00

EU contribution

€ 219 312,00

Coordinated by

REGION HOVEDSTADEN
Denmark

Periodic Reporting for period 1 - LinkFM (Linking Functional impact and Microstructural properties of fiber tract demyelination and remyelination in a rodent model of multiple sclerosis)

Reporting period: 2019-05-01 to 2021-04-30

Summary of the context and overall objectives of the project

Demyelination of multiple sclerosis (MS) affects not only the white matter (WM) but also the cortex and deep grey matter (DGM). Magnetic resonance imaging (MRI) is the modality of choice to assess brain damage in Multiple sclerosis, but there is an unmet need in MRI for achieving higher sensitivity and specificity to MS-related microstructural alterations in WM and GM. We explored whether advanced tensor-valued diffusion MRI (dMRI) can yield sensitive microstructural readouts for focal demyelination in cerebral WM and DGM. We found that tensor-valued dMRI bears considerable potential for microstructural imaging in MS, suggesting a regional microscopic fractional anisotropy decrease may be a sensitive indicator of MS lesions, while a regional isotropic mean kurtosis increase may be particularly sensitive in detecting DGM lesions of MS. These biomarkers will have great potential for monitoring MS disease activity, informing personalized treatment in patients with multiple sclerosis. The overall objectives of the LinkFM project are to evaluate microstructure and functional changes in the MS animal model by multi-modal MRI and validate microstructure changes in MS by 2D Histology and 3D Synchrotron imaging.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The work performed from the beginning to the end of the period are as follows:
A) Establishing a focal MS rodent model
We injected lysolecithin (LPC) to induce focal demyelination in the white and deep grey matter of the rodent’s brains. Then we used myelin-sensitive bound pool fraction mapping to evaluate the myelin loss in the focal lesions. Our results confirm that LPC treatment induces focal demyelination in WM and DGM CPu and not in the saline-injected hemisphere.
B) Evaluating the MS model by multi-modal MRI
We combined multi-modal MRI approaches (advanced diffusion MRI (dMRI), quantitative MRI (qMRI), and MR spectroscopy (MRS)) to track microstructural changes caused by focal demyelination in cerebral white matter and deep grey matter.
Publication 1: Yi He (The fellow), Susana Aznar, Hartwig R. Siebner, Tim B. Dyrby, In vivo tensor-valued diffusion MRI of focal demyelination in white and deep grey matter of rodents, NeuroImage: Clinical, Volume 30, 2021, https://doi.org/10.1016/j.nicl.2021.102675.
C) Setting up an acquisition pipeline of small animal fMRI
we established an acquisition pipeline of small animal fMRI, including invasive blood gas analysis, ventilator, and real-time fMRI, and then acquired high-quality fMRI in rodents.
D) Validation (Synchrotron imaging and Histology)
We have performed 2D histology and 3D synchrotron imaging in the focal demyelinating lesions to validate the microstructural imaging of MRI.

The overview of the results and their exploitation and dissemination:
During the LinkFM project, we combined in vivo tensor-valued diffusion MRI, MRS, and quantitative myelin-sensitive MRI in MS rodent models. We found that tensor-valued dMRI bears considerable potential for microstructural imaging in MS, suggesting a regional microscopic fractional anisotropy decrease may be a promising biomarker of both white and deep gray matter lesions, whereas isotropic mean kurtosis may be particularly suited in detecting gray matter lesions in MS. We published the main results in the journal NeuroImage: Clinical and disseminated the research findings through Twitter. Moreover, we presented the tensor-valued dMRI method in the 2020 ISMRM annual meeting and achieved the ISMRM awards Summa cum laude Awards (Top 5% Abstract).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The LinkFM project suggests a regional microscopic fractional anisotropy decrease may be a sensitive indicator of MS lesions, while a regional isotropic mean kurtosis increase may be particularly sensitive in detecting DGM lesions of MS. The LinkFM project has the potential to provide 3D nanoscale ground truth acquired by synchrotron imaging for interpreting diffusion MRI. The results are expected to advance the field of MRI and provide new insights into MS disease pathways and disease progression. The LinkFM project will promote early diagnosis, assessment, and therapy monitoring in multiple sclerosis, directly benefiting over one million MS patients in Europe. An early diagnosis of MS is crucial to promote early treatment, which reduces the total costs to the healthcare system and society.

Moreover, the fellow has gained teaching skills in fMRI and research skills in multi-modal MRI (advanced diffusion MRI, qMRI, and MRS), hands-on training in MS animal model, and synchrotron imaging. The long-term goal of the fellow is to integrate and optimize multi-modal brain mapping technologies to investigate functional and structural properties of the brain in multiple scale levels (cell, microstructure, global network) and translate them to clinical application. After the fellowship, the fellow will work on a funded one-year Lundbeck postdoc project, parallelly apply for one faculty position, and one starting grant to pursue further and achieve the long-term goal in the multiple-scale & multi-modal MRI field.

Main Results of LinkFM