Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords
Open accessAbstract
Objective Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. Background In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. Methods DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). Conclusions Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.
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DTI metrics highlight focal pathology with increased diffusivity and changes in FA.
“DTI metrics highlight focal pathology as well, with increased diffusivity and changes in FA, similarly to what has been previously reported.36”
From Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? (2017) · cites this paper as [36]
The Results (§3.4 Myelin analysis; page unavailable) show increased diffusivity in demyelinated regions and a change in relative anisotropy (RA), supporting the focal-pathology point. The study did not report a corresponding FA result of its own; FA findings appear in its discussion of other studies (§4 Discussion). (LLM, conf=0.86)
Experimental — accuracy not yet measuredDTI is very sensitive to multiple sclerosis pathology, as shown by strong changes of FA, AD, RD, and MD.
“Both correlation and linear regression analyses confirm once more that DTI is very sensitive to multiple sclerosis pathology, as shown by strong changes of FA, AD, RD, and MD noticeable on simple visual inspection.36”
From Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? (2017) · cites this paper as [36]
The Results (sections 3.2 and 3.4; page unavailable) report changes in axial and radial diffusivity and ADC/mean diffusivity in MS spinal cords, with radial diffusivity tracking demyelination. But the study measured relative anisotropy rather than FA, found no significant overall relative-anisotropy difference between MS and control tracts, and does not establish that changes in all four named measures were noticeable on simple visual inspection. (LLM, conf=0.87)
Experimental — accuracy not yet measuredRadial diffusivity (RD) has been suggested as a surrogate biomarker associated with the level of white matter myelination.
“While axial diffusivity (AD) has been linked to axonal pathology, radial diffusivity (RD) has been suggested as a surrogate biomarker associated with the level of white matter myelination [1–3].”
From Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis (2021) · cites this paper as [2]
Axial diffusivity (AD) has been linked to axonal pathology.
“While axial diffusivity (AD) has been linked to axonal pathology, radial diffusivity (RD) has been suggested as a surrogate biomarker associated with the level of white matter myelination [1–3].”
From Differentiating axonal loss and demyelination in chronic MS lesions: A novel approach using single streamline diffusivity analysis (2021) · cites this paper as [2]
In control spinal cord specimens, DTI metrics show higher diffusion anisotropy in white matter compared with gray matter.
“DTI metrics show known trends,36 such as higher diffusion anisotropy in white as compared with gray matter.”
From Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? (2017) · cites this paper as [36]
The Results (§3.2) compare DTI measurements in white-matter tracts from control and MS spinal cords, not white matter with gray matter in controls. A search for gray matter found only its use as an anatomical boundary in Methods (§2.5); our copy does not report the claimed anisotropy comparison. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Known contrasts are observed between controls' gray and white matter for DTI metrics.
“Regarding DTI metrics, known contrasts are observed between controls’ gray and white matter.27, 36”
From Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? (2017) · cites this paper as [36]
Methods §2.3 describes control DTI measurements in white-matter tracts, and Methods §2.5 mentions gray–white matter boundaries as registration landmarks; neither compares DTI metrics between the two tissues. Results §3.2 compares white-matter tracts in controls and MS subjects, not gray and white matter within controls. A search for control gray–white matter DTI contrasts found no passage addressing the claim; page numbers were unavailable. (LLM, conf=0.74)
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- Authors
- Klawiter, E. C., Schmidt, R. E., Trinkaus, K., Liang, H.-F., Budde, M. D., Naismith, R. T., Song, S.-K., Cross, A. H., & Benzinger, T. L.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Klawiter, Eric C.
- ORCID
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 55
- Issue
- 4
- Pages
- 1454-1460
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC3062747
- OpenAlex
- W2142255966
- Cited by
- 364
- References
- 5
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 12 · 2023: 20 · 2022: 23 · 2021: 21 · 2020: 26 · 2019: 30 · 2018: 26 · 2017: 27 · 2016: 33 · 2015: 31 · 2014: 30 · 2013: 27 · 2012: 20
- FWCI
- 22.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 NS054194, P01 NS059560, R01 DK19645, K23NS052430-01A1, UL1RR024992)
- National MS Society (CA1012, RG 3670A3/2)
- American Academy of Neurology Foundation Clinical Research Training Fellowship
- Manny and Rosalyn Rosenthal-Dr. John L. Trotter Chair in Neuroimmunology of Barnes-Jewish Hospital Foundation
- Bracco/American Roentgen Ray Society Scholar Award
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- multiple sclerosis, demyelination, radial diffusivity, diffusion tensor imaging, axonal injury, cervical spinal cord, relative anisotropy, apparent diffusion coefficient, axon density, histopathological correlation
- MeSH terms
- Female, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Nerve Fibers, Myelinated, Retrograde Degeneration, Sensitivity and Specificity, Spinal Cord, Reproducibility of Results
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