CoChat
Sign Up
Cited by 297Multiple Sclerosis Research StudiesAdvanced Neuroimaging Techniques and ApplicationsAdvanced MRI Techniques and Applications

Multiple sclerosis normal‐appearing white matter: Pathology–imaging correlations

Open access
Moll, Natalia M., Rietsch, Anna M., Thomas, Smitha, Ransohoff, Amy J., Lee, Jar‐Chi, Fox, Robert, Chang, Ansi, Ransohoff, Richard M. +1 more·2011·Annals of Neurology
DOI 10.1002/ana.22521PMC PMC3241216
Open this paper in CoChat — free account

Abstract

Objective: The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal‐appearing white matter (NAWM) in multiple sclerosis brains. Methods: Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI‐defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa‐WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa‐WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels. Results: Forty‐eight ROIs from 4 secondary progressive MS brains were analyzed. sa‐WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II+ microglia and macrophages detected in sa‐WM Far, sa‐WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity. Interpretation: The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities. ANN NEUROL 2011

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1002/ana.22521

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The data set of 48 data points suffices to fit the regression models and evaluate correlations.

    “Practically, this led to the construction of a data set of 48 data points, whose size suffices to fit the regression models and evaluate correlations (other high‐impact studies on MRI‐histopathology correlation relied on the same amount of data20 or even less17).”

    From Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology? (2017) · cites this paper as [20]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 44

  1. [1]Noseworthy JH Lucchinetti C Rodriguez M Weinshenker BG Multiple sclerosis New England Journal of Medicine 28 Sep 2000 343 13 938 52 [Review] [104 refs] 11006371
  2. [2]Kutzelnigg A Lassmann H Cortical lesions and brain atrophy in MS Journal of the Neurological Sciences 15 Jun 2005 233 1-2 55 9 [Review] [62 refs] 15893328
  3. [3]Kutzelnigg A Lucchinetti CF Stadelmann C Bruck W Rauschka H Bergmann M Cortical demyelination and diffuse white matter injury in multiple sclerosis Brain Nov 2005 128 Pt 11 2705 12 16230320
  4. [4]Frohman EM Racke MK Raine CS Multiple sclerosis--the plaque and its pathogenesis New England Journal of Medicine 2 Mar 2006 354 9 942 55 [Review] [74 refs] 16510748
  5. [5]Ludwin SK The pathogenesis of multiple sclerosis: relating human pathology to experimental studies Journal of Neuropathology & Experimental Neurology Apr 2006 65 4 305 18 [Review] [76 refs] 16691112
  6. [6]Richert ND Ostuni JL Bash CN Duyn JH McFarland HF Frank JA Serial whole-brain magnetization transfer imaging in patients with relapsing-remitting multiple sclerosis at baseline and during treatment with interferon beta-1b Ajnr: American Journal of Neuroradiology 1998 9 1705 13 9802494 PMC8337498
  7. [7]Inglese M van Waesberghe JH Rovaris M Beckmann K Barkhof F Hahn D The effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS Neurology 11 Mar 2003 60 5 853 60 12629246
  8. [8]Allen IV McQuaid S Mirakhur M Nevin G Pathological abnormalities in the normal-appearing white matter in multiple sclerosis Neurological Sciences Apr 2001 22 2 141 4 [Review] [25 refs] 11603615
  9. [9]Evangelou N Konz D Esiri MM Smith S Palace J Matthews PM Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis Brain Sep 2000 123 Pt 9 1845 9 10960048
  10. [10]Evangelou N Konz D Esiri MM Smith S Palace J Matthews PM Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis Brain Sep 2001 124 Pt 9 1813 20 11522583
  11. [11]Filippi M Paty DW Kappos L Barkhof F Compston DA Thompson AJ Zhao GJ Wiles CM McDonald WI Miller DH Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study Neurology 1995 45 2 255 60 7854522
  12. [12]Rovaris M Bozzali M Santuccio G Ghezzi A Caputo D Montanari E In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis Brain Dec 2001 124 Pt 12 2540 9 11701606
  13. [13]McFarland HF Barkhof F Antel J Miller DH The role of MRI as a surrogate outcome measure in multiple sclerosis Multiple Sclerosis 2002 8 1 40 51 11936488
  14. [14]Bar-Zohar D Agosta F Goldstaub D Filippi M Magnetic resonance imaging metrics and their correlation with clinical outcomes in multiple sclerosis: a review of the literature and future perspectives Multiple Sclerosis Jul 2008 14 6 719 27 [Review] [116 refs] 18424478
  15. [15]Miller DH Thompson AJ Filippi M Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis Journal of Neurology Dec 2003 250 12 1407 19 [Review] [125 refs] 14673572
  16. [16]Ciccarelli O Werring DJ Barker GJ Griffin CM Wheeler-Kingshott CA Miller DH A study of the mechanisms of normal-appearing white matter damage in multiple sclerosis using diffusion tensor imaging--evidence of Wallerian degeneration J Neurol Mar 2003 250 3 287 92 12638018
  17. [17]Ge Y Grossman RI Babb JS He J Mannon LJ Dirty-appearing white matter in multiple sclerosis: volumetric MR imaging and magnetization transfer ratio histogram analysis Ajnr: American Journal of Neuroradiology Nov;-Dec 2003 24 10 1935 40 14625213 PMC8148922
  18. [18]Filippi M Campi A Dousset V Baratti C Martinelli V Canal N A magnetization transfer imaging study of normal-appearing white matter in multiple sclerosis Neurology Mar 1995 45 3 Pt 1 478 82 7898700
  19. [19]Davie CA Barker GJ Thompson AJ Tofts PS McDonald WI Miller DH 1H magnetic resonance spectroscopy of chronic cerebral white matter lesions and normal appearing white matter in multiple sclerosis Journal of Neurology, Neurosurgery & Psychiatry Dec 1997 63 6 736 42 PMC2169838 9416807
  20. [20]Droogan AG Clark CA Werring DJ Barker GJ McDonald WI Miller DH Comparison of multiple sclerosis clinical subgroups using navigated spin echo diffusion-weighted imaging Magnetic Resonance Imaging Jun 1999 17 5 653 61 10372518
  21. [21]Stevenson VL Parker GJ Barker GJ Birnie K Tofts PS Miller DH Variations in T1 and T2 relaxation times of normal appearing white matter and lesions in multiple sclerosis Journal of the Neurological Sciences 15 Sep 2000 178 2 81 7 11018698
  22. [22]Leary SM Silver NC Stevenson VL Barker GJ Miller DH Thompson AJ Magnetisation transfer of normal appearing white matter in primary progressive multiple sclerosis Multiple Sclerosis Oct 1999 5 5 313 6 10516773
  23. [23]van Buchem MA McGowan JC Kolson DL Polansky M Grossman RI Quantitative volumetric magnetization transfer analysis in multiple sclerosis: estimation of macroscopic and microscopic disease burden Magnetic Resonance in Medicine Oct 1996 36 4 632 6 8892218
  24. [24]Traboulsee A Dehmeshki J Peters KR Griffin CM Brex PA Silver N Disability in multiple sclerosis is related to normal appearing brain tissue MTR histogram abnormalities Multiple Sclerosis Dec 2003 9 6 566 73 14664468
  25. [25]Agosta F Rovaris M Pagani E Sormani MP Comi G Filippi M Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis Brain Oct 2006 129 Pt 10 2620 7 16951409
  26. [26]Dousset V Brochet B Vital A Gross C Benazzouz A Boullerne A Lysolecithin-induced demyelination in primates: preliminary in vivo study with MR and magnetization transfer Ajnr: American Journal of Neuroradiology Feb 1995 16 2 225 31 7726066 PMC8338338
  27. [27]Brochet B Dousset V Pathological correlates of magnetization transfer imaging abnormalities in animal models and humans with multiple sclerosis Neurology 1999 53 5 Suppl 3 S12 7 [Review] [17 refs] 10496205
  28. [28]Barkhof F Bruck W De Groot CJ Bergers E Hulshof S Geurts J Polman CH van der Valk P Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance Archives of Neurology 2003 60 8 1073 81 12925362
  29. [29]Schmierer K Scaravilli F Altmann DR Barker GJ Miller DH Magnetization transfer ratio and myelin in postmortem multiple sclerosis brain Annals of Neurology Sep 2004 56 3 407 15 15349868
  30. [31]Vrenken H Geurts JJ Knol DL Polman CH Castelijns JA Pouwels PJ Normal-appearing white matter changes vary with distance to lesions in multiple sclerosis Ajnr: American Journal of Neuroradiology Oct 2006 27 9 2005 11 17032884 PMC7977884
  31. [32]Fisher E Chang A Fox RJ Tkach JA Svarovsky T Nakamura K Imaging correlates of axonal swelling in chronic multiple sclerosis brains Annals of Neurology Sep 2007 62 3 219 28 17427920
  32. [33]Moll NM Cossoy MB Fisher E Staugaitis SM Tucky BH Rietsch AM Imaging correlates of leukocyte accumulation and CXCR4/CXCL12 in multiple sclerosis Archives of Neurology Jan 2009 66 1 44 53 19139298 PMC2792736
  33. [34]Young EA Fowler CD Kidd GJ Chang A Rudick R Fisher E Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions Annals of Neurology Apr 2008 63 4 428 35 18438950
  34. [37]Lovas G Szilagyi N Majtenyi K Palkovits M Komoly S Axonal changes in chronic demyelinated cervical spinal cord plaques Brain Feb 2000 123 Pt 2 308 17 10648438
  35. [38]Seewann A Vrenken H van d V Blezer EL Knol DL Castelijns JA Diffusely abnormal white matter in chronic multiple sclerosis: imaging and histopathologic analysis Archives of Neurology May 2009 66 5 601 9 19433660
  36. [41]Basser PJ Pierpaoli C Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI Journal of Magnetic Resonance Series B Jun 1996 111 3 209 19 8661285
  37. [42]Song SK Yoshino J Le TQ Lin SJ Sun SW Cross AH Demyelination increases radial diffusivity in corpus callosum of mouse brain Neuroimage 15 May 2005 26 1 132 40 15862213
  38. [43]Song SK Sun SW Ju WK Lin SJ Cross AH Neufeld AH Diffusion tensor imaging detects and differentiates axon and myelin degeneration in mouse optic nerve after retinal ischemia Neuroimage 2003 3 1714 22 14642481
  39. [44]Budde MD Kim JH Liang HF Schmidt RE Russell JH Cross AH Toward accurate diagnosis of white matter pathology using diffusion tensor imaging Magnetic Resonance in Medicine Apr 2007 57 4 688 95 17390365
  40. [45]Sun SW Liang HF Le TQ Armstrong RC Cross AH Song SK Differential sensitivity of in vivo and ex vivo diffusion tensor imaging to evolving optic nerve injury in mice with retinal ischemia Neuroimage Sep 2006 32 3 1195 204 16797189
  41. [46]Schmierer K Wheeler-Kingshott CA Boulby PA Scaravilli F Altmann DR Barker GJ Diffusion tensor imaging of post mortem multiple sclerosis brain Neuroimage 1 Apr 2007 35 2 467 77 17258908 PMC1892244
  42. [47]Schmierer K Wheeler-Kingshott CA Tozer DJ Boulby PA Parkes HG Yousry TA Quantitative magnetic resonance of postmortem multiple sclerosis brain before and after fixation Magnetic Resonance in Medicine Feb 2008 59 2 268 77 18228601 PMC2241759
  43. [48]Bo L Geurts JJ van d V Polman C Barkhof F Lack of correlation between cortical demyelination and white matter pathologic changes in multiple sclerosis Archives of Neurology Jan 2007 64 1 76 80 17210812
  44. [49]De Stefano N Matthews PM Filippi M Agosta F De Luca M Bartolozzi ML Evidence of early cortical atrophy in MS: relevance to white matter changes and disability Neurology 8 Apr 2003 60 7 1157 62 12682324

Cited by

Sorted by citations

Authors
Moll, N. M., Rietsch, A. M., Thomas, S., Ransohoff, A. J., Lee, J., Fox, R., Chang, A., Ransohoff, R. M., & Fisher, E.
Affiliations
  • Cleveland Clinic (US)
  • Cleveland Clinic Lerner College of Medicine (US)
  • Cleveland Clinic Research (US)
Corresponding author
Fisher, Elizabeth
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2011-11
Volume
70
Issue
5
Pages
764-773
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.22521
PMC
PMC3241216
OpenAlex
W2044677981
Cited by
297
References
4
Citations by year
2026: 15 · 2025: 16 · 2024: 15 · 2023: 21 · 2022: 24 · 2021: 26 · 2020: 20 · 2019: 27 · 2018: 25 · 2017: 13 · 2016: 17 · 2015: 18 · 2014: 25 · 2013: 24 · 2012: 10
FWCI
13.24
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 36 d)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cleveland Clinic
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (P50NS38667, P50NS038667)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
Keywords
multiple sclerosis, normal-appearing white matter, magnetization transfer ratio, diffusion tensor imaging, axonal swellings, microglial activation, myelin density, secondary progressive multiple sclerosis, postmortem brain, axonal pathology
MeSH terms
Adult, Astrocytes, Axons, Blood Proteins, Blood Vessels, Brain, Female, Humans, Macrophages, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Nerve Fibers, Myelinated, Postmortem Changes, Biomarkers, Microglia, Diffusion Tensor Imaging

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review