Translating from Macro-scale to Micro-scale in Multiple Sclerosis: Histological underpinnings of macroscopic structural and functional alterations in MS
https://research.vu.nl/en/publications/ ... -sclerosis
https://research.vu.nl/ws/portalfiles/p ... dacted.pdf
Abstract
1. What are the cellular substrates of DTI measured diffusivity alterations in normal appearing and lesioned cortex in MS?
- Chapter 2.1 showed that axonal orientation may be an important driver of diffusivity measures, such as FA, not only in white matter but also in grey matter in MS and in control cortex
- Chapter 2.1 showed that the typical diffusivity pattern of MRI measured low FA in NAGM compared to controls and increased FA in grey matter lesions compared to NAGM in MS is associated with cortical axonal degeneration.
2. What are the cellular substrates of DTI based network measures of integration and segregation in MS?
- Chapter 2.2 showed that cortical regions with segregative properties are characterized by small neurons and a low axonal density, while regions with integrative properties contain large neurons and high axonal densities.
- Chapter 2.2 showed that MS patients with a higher whole brain WM lesion volume showed higher more pronounced segregative properties and less integrative properties and correspondingly also smaller neurons and a lower axonal densities on average.
3. To what extent do remote white matter and local grey matter pathology explain cortical neuroaxonal degeneration in MS?
- Chapter 3 showed that both white matter damage and cortical demyelination contribute to cortical axonal loss. Variance in cortical axonal density in NAGM is explained for 22.6% by remote axonal diffusivity in WML and for 12.6% by axonal diffusivity in NAWM. Furthermore, local cortical demyelination was associated with additional axonal loss in lesioned cortex and explained 34.4% of variance in axonal loss, while microglia showed no association.
4. What are possible histological substrates of altered brain function in MS?
- Chapter 4 showed that GAD67 immuno-reactivity is increased in WM astrocytes, inhibitory interneurons and synapses in inflamed and demyelinated hippocampi of MS patients. This is possibly related to cognitive functioning according to the medical history of the donors.
- Preliminary data showed that inhibitory synaptic and excitatory synaptic densities are reduced in layer 6 of the cortex. This may reflect ongoing processes such as synaptic displacement, synaptic stripping and neurodegeneration
Thesis: Underpinnings of macroscopic structural alterations in MS
Related: DAWM in MS
It seems that DAWM is something in the middle between NAWM and lesions and appears in 25% of the patients. Maybe it could be a marker of a new MS pathological variant. (https://onlinelibrary.wiley.com/doi/abs ... /jon.12900)(https://www.sciencedirect.com/science/a ... 482100688X)
Diffusely abnormal white matter in multiple sclerosis
https://onlinelibrary.wiley.com/doi/ful ... /jon.12945
Abstract
MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades.
A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM).
DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2-weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS.
Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins.
This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS.
Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.
Diffusely abnormal white matter in multiple sclerosis
https://onlinelibrary.wiley.com/doi/ful ... /jon.12945
Abstract
MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades.
A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM).
DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2-weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS.
Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins.
This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS.
Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.
Last edited by frodo on Wed Jan 26, 2022 11:58 am, edited 2 times in total.
Related: MRI spectroscopy at 7Tesla
Extensive Brain Pathologic Alterations Detected with 7.0-T MR Spectroscopic Imaging Associated with Disability in Multiple Sclerosis
https://pubs.rsna.org/doi/full/10.1148/radiol.210614
Abstract
Background: MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity.
Purpose: To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability.
Materials and Methods: Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability.
Results: Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0–1: 0.86 ± 0.03 [P = .02]; EDSS 1.5–3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5–3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004).
Conclusion: MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability.
https://pubs.rsna.org/doi/full/10.1148/radiol.210614
Abstract
Background: MR spectroscopic imaging (MRSI) allows in vivo assessment of brain metabolism and is of special interest in multiple sclerosis (MS), where morphologic MRI cannot depict major parts of disease activity.
Purpose: To evaluate the ability of 7.0-T MRSI to depict and visualize pathologic alterations in the normal-appearing white matter (NAWM) and cortical gray matter (CGM) in participants with MS and to investigate their relation to disability.
Materials and Methods: Free-induction decay MRSI was performed at 7.0 T. Participants with MS and age- and sex-matched healthy controls were recruited prospectively between January 2016 and December 2017. Metabolic ratios were obtained in white matter lesions, NAWM, and CGM regions. Subgroup analysis for MS-related disability based on Expanded Disability Status Scale (EDSS) scores was performed using analysis of covariance. Partial correlations were applied to explore associations between metabolic ratios and disability.
Results: Sixty-five participants with MS (mean age ± standard deviation, 34 years ± 9; 34 women) and 20 age- and sex-matched healthy controls (mean age, 32 years ± 7; 11 women) were evaluated. Higher signal intensity of myo-inositol (mI) with and without reduced signal intensity of N-acetylaspartate (NAA) was visible on metabolic images in the NAWM of participants with MS. A higher ratio of mI to total creatine (tCr) was observed in the NAWM of the centrum semiovale of all MS subgroups, including participants without disability (marginal mean ± standard error, healthy controls: 0.78 ± 0.04; EDSS 0–1: 0.86 ± 0.03 [P = .02]; EDSS 1.5–3: 0.95 ± 0.04 [P < .001]; EDSS ≥3.5: 0.94 ± 0.04 [P = .001]). A lower ratio of NAA to tCr was found in MS subgroups with disabilities, both in their NAWM (marginal mean ± standard error, healthy controls: 1.46 ± 0.04; EDSS 1.5–3: 1.33 ± 0.03 [P = .03]; EDSS ≥3.5: 1.30 ± 0.04 [P = .01]) and CGM (marginal mean ± standard error, healthy controls: 1.42 ± 0.05; EDSS ≥3.5: 1.23 ± 0.05 [P = .006]). mI/NAA correlated with EDSS (NAWM of centrum semiovale: r = 0.47, P < .001; parietal NAWM: r = 0.43, P = .002; frontal NAWM: r = 0.34, P = .01; frontal CGM: r = 0.37, P = .004).
Conclusion: MR spectroscopic imaging at 7.0 T allowed in vivo visualization of multiple sclerosis pathologic findings not visible at T1- or T2-weighted MRI. Metabolic abnormalities in the normal-appearing white matter and cortical gray matter were associated with disability.
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