Author Of 2 Presentations
FC03.03 - Depicting multiple sclerosis pathology at 160μm isotropic resolution by human whole-brain postmortem 3T magnetic resonance imaging
Abstract
Background
Postmortem magnetic resonance imaging (MRI) of formalin-fixed healthy and diseased human brains with ultra-high spatial resolution has the great potential to depict tissue architecture in fine detail, allowing a deeper understanding of pathological processes. Whole-brain imaging is important since it provides neuroanatomic relationships, reference points across distant brain regions, and a comprehensive view of pathologies affecting the brain. However, ultra-high-resolution whole-brain postmortem MRI is challenging and has been so far almost exclusively performed at 7T with specialized hardware.
Objectives
To develop a 3D isotropic 160µm ultra-high-resolution imaging (URI) approach for human whole-brain ex vivo acquisitions on a standard clinical 3T MRI system. To explore the sensitivity and specificity of the approach to specific pathological features of multiple sclerosis (MS).
Methods
A fixed whole human brain from a patient with secondary progressive MS was investigated. Acquisitions were performed on a clinical 3T Siemens Prismafit MRI system with standard hardware components. URI is based on a gradient echo sequence similar to the 7T approach by Edlow et al. 2019. However, it allows to acquire an isotropic 160µm resolution with low hardware demands and to directly reconstruct the image data on the standard 3T MRI system. URI images display a strong, susceptibility-enhanced tissue contrast.
Results
The reconstructed URI images depicted with remarkable quality the diseased human MS brain at 3T field strength. URI allowed to distinguish fine anatomical details such as the subpial molecular layer, the stria of Gennari as well as some intrathalamic nuclei. Additionally, because of the unprecedented spatial resolution and contrast at 3T, URI permitted to easily identify the presence of subpial lesions, detailed features of intracortical lesions such the presence of incomplete/complete iron rims or patterns of iron accumulation in the entire lesion core in both cortical and white matter lesions (CLs/WMLs), lesions affecting the convoluted layers of the cerebellar cortex and nascent submillimetric CLs/WMLs.
Conclusions
URI provides a comprehensive microscopic insight into the whole-human brain at 3T through the micrometric resolution and a tissue-specific, susceptibility-enhanced contrast. We propose URI as an excellent approach to investigate microscopic brain changes of complex pathologies like MS.
LB01.01 - Primary astrocytopathy has a detrimental effect on remyelination efficacy of parenchymal oligodendrocyte precursor cells.
Abstract
Background
Astrocytic impairment is a common feature of neuromyelitis optica and possibly also multiple sclerosis (MS) lesions and initiates even prior to demyelination. Repopulation of early active plaques with aquaporin 4-negative astrocyte precursors has been recorded, implying astrocytic loss in pre-active lesion stages.
Objectives
Therefore, we aimed at investigating effects of a primary astrocytic loss on lesion regeneration and remyelination.
Methods
Osmolytic shifts induce severe astrocytic loss in certain CNS regions, leading to a secondary oligodendrocyte loss and demyelination, in the absence of antigen-specific lymphocyte activation. In patients, this is referred to as central pontine myelinolysis (CPM). Studying autopsy material from patients with CPM, as well as an experimental rat model, we characterized the oligodendrocyte precursor cell (OPC) activation and differentiation. Using injections of the thymidine-analogue BrdU, we traced the maturation of OPCs activated in early lesions.
Results
Animal experiments revealed rapid activation of the parenchymal NG2+ OPC reservoir in the widely astrocyte-free lesion, leading to extensive OPC proliferation. One week after lesion initiation, most cells derived from parenchymal OPCs expressed breast carcinoma amplified sequence 1 (BCAS1), indicating the transition into a pre-myelinating state. Though, cells derived from the early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and without evidence for process extension, that were sparsely found among myelin producing or mature oligodendrocytes. Correspondingly, also early human CPM lesions showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the animal model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already repopulated with OPCs, giving rise to nestin+ progenitors that partially generated oligodendroglial lineage cells in the lesion, that was finally successively refilled with astrocytes and remyelinated. Those nestin+ stem cell-derived progenitors were absent in human CPM cases possibly contributing to the rather inefficient lesion repair.
Conclusions
The present study underpins the importance of astrocyte-oligodendrocyte interactions for remyelination, thus stressing the necessity to further determine the impact of astrocyte dysfunction on remyelination efficiency in demyelinating disorders like MS.
Author Of 1 Presentation
P0624 - Quantitative multiparametric 3T-MRI of postmortem multiple sclerosis whole brains (ID 1583)
Abstract
Background
Postmortem MRI provides precious insights into the relation of MRI metrics to pathoanatomical features of multiple sclerosis (MS) and can help to understand the basis of damage and repair.
Objectives
To investigate the respective features of MS lesions in the cortex and in the white matter using multiparametric postmortem MR imaging at 3T and identify discriminant characteristics of white matter lesion subgroups.
Methods
We scanned three fixed brains of secondary-progressive MS patients (mean disease duration 15.3 years) on a standard clinical 3T-MRI scanner with following sequences: Magnetization Transfer Saturation (MTsat), T1-relaxometry (T1-rt), Myelin Water Fraction (MWF) and Diffusion Tensor - Fractional Anisotropy (DTI-FA). We compared these metrics between (i) cortical lesions (CL, n=118) and normal-appearing grey matter (NAGM, n=186) and (ii) white matter lesions (WML, n=140) and normal-appearing white matter (NAWM, n=53) using a Mann-Whitney U test. Then, we analyzed the differences between different subgroups of WML (periventricular lesions -PVL-, n=38, WM part of leukocortical lesions -WMLCL-, n=36, subcortical lesions -SCL-, n=66, and areas of “dirty white matter” -DWM-, n=15) by performing a Kruskal-Wallis test and a Mann-Whitney U tests for direct comparison. Bonferroni correction for multiple-testing was applied.
Results
CL exhibited lower MTsat (p<0.001), higher T1-rt (p<0.001) and MWF (p<0.01) than normal appearing cortical tissue. WML showed lower MTsat (p<0.001), higher T1-rt (p<0.001), and lower MWF (p<0.001) than normal appearing white matter. DTI-FA did not differ between CL/WML and NAWM/NAGM. MTsat values were lower in the PVL (p<0.001) and higher in the DWM (p<0.001) in comparison to all other lesion subgroups. T1-rt were higher in PVL (p<0.001) compared to the other lesion subgroups. MWF values were higher in DWM and SCL (p<0.01), not statistically different between PVL and WMLCL. DTI-FA values were lower in WMLCL in comparison to all other subgroups (p<0.01) and did not differ between the other categories.
Conclusions
Postmortem MRI metrics in WML/CL as well as in different subgroups of WML, are compatible with myelin damage and tissue destruction. Interestingly, MWF was higher in CL than in NAGM, which might correspond to a predominance of “myelin blistering” pathology in the cortex. Ongoing work aims to directly correlate our findings with detailed histopathological characterization including electron microscopy of myelin damage.