In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
- Translational Neuroradiology Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
- Department of Neurology and Neurological Sciences, Stanford University, United States
- Department of Neurobiology, University of Pittsburgh, United States
- Section on Neural Function, National Institute of Mental Health, National Institutes of Health, United States
- Department of Neuroradiology, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich, Switzerland
- Viral Immunology Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
- Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
- Department of Radiology and Radiological Sciences, Uniformed Services University of the Health Sciences, United States
- Vertex Pharmaceuticals Incorporated, United States
- Neuroimaging Program, Department of Neurology, Cedars Sinai, United States
Figures
Figure 1
Example of an early active demyelinating EAE lesion with persistent hyperintensity on PDw MRI and active inflammatory demyelination on histopathology.
(A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter …
Figure 2
Example of a chronic, at least partially demyelinated EAE lesion core with long-lasting hyperintensity on serial PDw MRI and complete loss of myelin on histopathology.
(A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter …
Figure 3
Example of a nearly complete remyelinated EAE lesion with initial hyperintensity that returned to isointensity on serial PDw MRI.
(A) In vivo PDw MRI acquired before EAE induction (baseline) and at various timepoints leading up to the terminal scan. Images were processed as described in Methods. Red arrows: focal white matter …
Figure 4
Evolution of in vivo PDw MRI signal intensity of remyelinating EAE lesions shows a typical 4- to 9-week time course of remyelination.
Vertical axis: mean PDw signal intensity relative to gray matter. Horizontal axis: weeks post-immunization. Blue line corresponds to mean normalized PDw signal intensity (with standard deviation) of …
Figure 5
Histological quantification of myelin highlights different patterns across lesion categories and NAWM.
Cells were quantified in a region of interest of 1500 µm2 centered on each lesion core. Percentage of demyelination quantified for each lesion category and NAWM on PLP (A) and LFB (B). Number of …
Figure 6 with 2 supplements
In vivo (baseline) multicontrast marmoset brain magnetic resonance imaging (MRI).
The T1 subtraction image was obtained by voxelwise subtraction of pre-gadolinium from post-gadolinium T1-weighted (T1w) images. The magnetization transfer ratio (MTR) image was derived voxelwise as …
Figure 6—figure supplement 1
Workflow of the magnetic resonance imaging (MRI) postprocessing pipeline.
PD = proton density; MT = magnetization transfer; MTR = magnetization transfer ratio; N3=bias field correction.
Figure 6—figure supplement 2
Postprocessed proton-density weighted images used as input for the convolutional neural network-based lesion segmentation.
All hyperintense lesions that appeared on the follow-up magnetic resonance imaging (MRI) performed post-immunization (in this example, M#1, 22 weeks post-immunization) were captured by the automated …
Tables
Table 1
Classification of focal lesions by proton density-weighted magnetic resonance imaging.
| Animal | Predicted early active | Predicted chronic, at least partially demyelinated | Predicted remyelinated | Total |
|---|---|---|---|---|
| M#1 | 1 | 2 | 6 | 9 |
| M#2 | 1 | 1 | 6 | 8 |
| M#3 | 1 | 1 | 4 | 6 |
| M#4 | 0 | 1 | 2 | 3 |
| M#5 | 3 | 3 | 0 | 6 |
| M#6 | 6 | 2 | 0 | 8 |
| Total | 12 | 10 | 18 | 40 |
Table 2
Classification of focal lesions by histopathology.
| Animal | Early active | Chronic, at least partially demyelinated | Remyelinated | Total |
|---|---|---|---|---|
| M#2 | 1 | 3 | 4 | 8 |
| M#3 | 1 | 1 | 4 | 6 |
| M#4 | 0 | 2 | 1 | 3 |
| M#5 | 3 | 3 | 0 | 6 |
| M#6 | 7 | 1 | 0 | 8 |
| Total | 12 | 10 | 9 | 31 |
Table 3
Confusion matrix for PDw MRI prediction of demyelinated vs. remyelinated lesions compared to histology.
| n=31 | Predicted demyelination by MRI | Predicted remyelination by MRI | |
|---|---|---|---|
| Actual demyelination by histology | 19 | 3 | 22 |
| Actual remyelination by histology | 0 | 9 | 9 |
| 19 | 12 |
Table 4
Demographics and experimental information for the six marmosets included in this study.
Immunizations used human white matter homogenate. Experiment duration corresponds to the time between immunization and terminal MRI.
| Animal | Sex | Age (years) | First immunization | Second immunization | Corticosteroid treatment | Experiment duration (weeks) |
|---|---|---|---|---|---|---|
| M#1* | Male | 3.7 | 100 mg | 200 mg | Yes | 40 |
| M#2* | Male | 3.7 | 100 mg | 200 mg | No | 54 |
| M#3† | Male | 6.2 | 200 mg | – | Yes | 61 |
| M#4† | Male | 6.2 | 200 mg | – | No | 60 |
| M#5‡ | Female | 2.8 | 200 mg | – | Yes | 18 |
| M#6‡ | Female | 2.8 | 200 mg | – | No | 16 |
-
Denote the three different pairs of twin animals.
Table 5
Main parameters used for the different MRI contrasts acquired in vivo.
| MRI contrast | PDw | T1w | T2w | T2*w | MTR* |
|---|---|---|---|---|---|
| Sequence | 2D RARE | 2D MDEFT | 2D RARE | 2D MGE | 3D MGE |
| FOV (mm) | 32×24 | 32×24 | 32×24 | 32×24 | 38.4×38.4 |
| Matrix | 214×160 | 214×160 | 214×160 | 214×160 | 256×256 |
| Number of slices | 36 | 36 | 36 | 36 | 36 |
| Slice thickness (mm) | 1 | 1 | 1 | 1 | 1 |
| TR (ms) | 2300 | 12.5 | 8000 | 2150 | 20 |
| TE (ms) | 16 | 4.2 | 72 | 18 | 5 |
| TI (ms) | N/A | 1200 | N/A | N/A | N/A |
| ETL | 1 | N/A | 4 | N/A | N/A |
| Excitation pulse (shape, FA) | Sinc3, 90° | Sinc3, 12° | Sinc3, 90° | Sinc3, 70° | Sinc3, 10° |
| Refocusing pulse (shape, FA) | Sinc3, 180° | N/A | Sinc3, 180° | N/A | N/A |
| Preparation pulse (type, shape, FA, offset) | N/A | Excitation/inversion, Sech, 90°/180° | N/A | N/A | MT, Gauss, 1500 Hz |
| NEX | 1 | 1 | 2 | 1 | 2 |
| AT | 7 min 40 s | 6 min 56 s | 13 min 20 s | 7 min 10 s | 7 min 58 s |
-
FOV = field of view; TR = repetition tine; TE = echo time; TI = inversion time; ETL = echo train length (or RARE factor); FA = flip angle; NEX = number of repetitions; AT = acquisition time; RARE = rapid acquisition with relaxation and enhancement; MDEFT = modified drive equilibrium Fourier transform; MGE = multi-gradient echo.
-
*
Sequence was performed twice: with (MSAT) and without (M0) the MT pre-pulse.
Additional files
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Supplementary file 1
Immunohistochemistry methodology.
For each of the immunohistochemical targets, respective source, clonalities and hosts, and methods for antigen retrieval, blocking, and primary and secondary antibody inoculation are listed. HIER = heat-induced epitope retrieval; RT = room temperature; P=polyclonal antibody; M=monoclonal antibody; Rb = rabbit; Ms = mouse
- https://cdn.elifesciences.org/articles/73786/elife-73786-supp1-v2.docx
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Transparent reporting form
- https://cdn.elifesciences.org/articles/73786/elife-73786-transrepform1-v2.docx
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Source data 1
First part of serial in vivo magnetic resonance images of animal #1, including proton density-weighted sequence, used for analysis and figure generation.
Uploaded into two separate source data for size of files. Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data1-v2.zip
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Source data 2
Second part of serial in vivo magnetic resonance images of animal #1, including proton density-weighted sequence, used for analysis and figure generation.
Uploaded into two separate source data for size of files. Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data2-v2.zip
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Source data 3
First part of serial in vivo magnetic resonance images of animal #2, including proton density-weighted sequence, used for analysis and figure generation.
Uploaded into two separate source data for size of files. Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data3-v2.zip
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Source data 4
Second part of serial in vivo magnetic resonance images of animal #2, including proton density-weighted sequence, used for analysis and figure generation.
Uploaded into two separate source data for size of files. Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data4-v2.zip
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Source data 5
Serial in vivo magnetic resonance images of animal #3, including proton density-weighted sequence, used for analysis and figure generation.
Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data5-v2.zip
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Source data 6
Serial in vivo magnetic resonance images of animal #4, including proton density-weighted sequence, used for analysis and figure generation.
Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data6-v2.zip
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Source data 7
Serial in vivo magnetic resonance images of animal #5, including proton density-weighted sequence, used for analysis and figure generation.
Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data7-v2.zip
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Source data 8
Serial in vivo magnetic resonance images of animal #6, including proton density-weighted sequence, used for analysis and figure generation.
Files are in neuroimaging informatics technology initiative (NIFTI) format.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data8-v2.zip
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Source data 9
Iba1 and proteolipid protein (PLP) immunohistochemistry images of animals #2–6 used for analysis and figure generation.
- https://cdn.elifesciences.org/articles/73786/elife-73786-data9-v2.pdf
