scholarly journals MS Atlas - A molecular map of brain lesion stages in progressive multiple sclerosis

2019 ◽  
Author(s):  
Tobias Frisch ◽  
Maria L. Elkjaer ◽  
Richard Reynolds ◽  
Tanja Maria Michel ◽  
Tim Kacprowski ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Drug Targets ◽  
De Novo ◽  
Neurodegenerative Disorder ◽  
Brain Lesion ◽  
White Matter Lesions ◽  
Progressive Multiple Sclerosis ◽  
Brain White Matter ◽  
The Central Nervous System

AbstractMultiple sclerosis (MS) is a chronic inflammatory neurodegenerative disorder of the central nervous system with an untreatable late progressive phase in a high percentage of patients. Molecular maps of different stages of brain lesion evolution in patients with progressive MS (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate of PMS on lesion basis. The MS Atlas gives means for testing research hypotheses, validating candidate biomarkers and drug targets. The MS Atlas data base comprises comprehensive high-quality transcriptomic profiles of 73 brain white matter lesions at different stages of lesion evolution from 10 PMS patients and 25 control white matter samples from five patients with non-neurological disease. The MS Atlas was assembled from next generation RNA sequencing of post mortem samples using strict, conservative preprocessing as well as advanced statistical data analysis. It comes with a user-friendly web interface, which allows for querying and interactively analyzing the PMS lesion evolution. It fosters bioinformatics methods for de novo network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures. We also demonstrate how its interface can interactively condense and visualize the atlas’ content. This compendium of mechanistic PMS white matter lesion profiles is an invaluable resource to fuel future multiple sclerosis research and a new basis for treatment development.

scholarly journals Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Maria L. Elkjaer ◽  
Tobias Frisch ◽  
Richard Reynolds ◽  
Tim Kacprowski ◽  
Mark Burton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
White Matter ◽  
De Novo ◽  
Progressive Multiple Sclerosis ◽  
Differentially Expressed ◽  
Molecular Signature ◽  
Immunoglobulin Gene ◽  
Brain White Matter ◽  
Cellular Source

AbstractTo identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.

scholarly journals Expression of disease‐related mi RNA s in white‐matter lesions of progressive multiple sclerosis brains

2019 ◽  
Vol 6 (5) ◽  
pp. 854-862 ◽  
Author(s):  
Ajai Tripathi ◽  
Christina Volsko ◽  
Ushasi Datta ◽  
Keren Regev ◽  
Ranjan Dutta
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
White Matter Lesions ◽  
Progressive Multiple Sclerosis

D313Y mutation in the differential diagnosis of white matter lesions: Experiences from a multiple sclerosis outpatient clinic

2016 ◽  
Vol 22 (11) ◽  
pp. 1502-1505 ◽  
Author(s):  
Jana Becker ◽  
Arndt Rolfs ◽  
Nesrin Karabul ◽  
Peter Berlit ◽  
Markus Kraemer
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Neurological Disorders ◽  
Lysosomal Storage Disorder ◽  
White Matter Lesions ◽  
Clinical Impact ◽  
Lysosomal Storage ◽  
Younger Patients ◽  
Neural Damage ◽  
The Central Nervous System

White matter lesions (WML) in younger patients might be due to a variety of neurological disorders. Fabry disease (FD), an x-linked inherited lysosomal storage disorder, happens to be misdiagnosed as multiple sclerosis (MS). In two middle-aged female patients, presenting bilateral WML, diagnosis of MS turned out to be doubtful. Human genetic analysis presented the Fabry mutation D313Y, in which clinical impact is still unclear. Disease manifestations outside the central nervous system were not detected. Our findings support the suspicion that Fabry mutation D313Y may be involved in neural damage resulting in WML.

Patient-specific 3D FLAIR for enhanced visualization of brain white matter lesions in multiple sclerosis

2016 ◽  
Vol 46 (2) ◽  
pp. 557-564
Author(s):  
Refaat E. Gabr ◽  
Amol S. Pednekar ◽  
Koushik A. Govindarajan ◽  
Xiaojun Sun ◽  
Roy F. Riascos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
White Matter Lesions ◽  
Patient Specific ◽  
Brain White Matter ◽  
3D Flair

scholarly journals 7 T imaging reveals a gradient in spinal cord lesion distribution in multiple sclerosis

Brain ◽  
2020 ◽  
Vol 143 (10) ◽  
pp. 2973-2987 ◽  
Author(s):  
Russell Ouellette ◽  
Constantina A Treaba ◽  
Tobias Granberg ◽  
Elena Herranz ◽  
Valeria Barletta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
White Matter ◽  
Cervical Spinal Cord ◽  
White Matter Lesions ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Spinal Cord Lesions ◽  
Secondary Progressive ◽  
Relapsing Remitting

Abstract We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.

scholarly journals Molecular signature of slowly expanding lesions in progressive multiple sclerosis

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2073-2088 ◽  
Author(s):  
Katharina Jäckle ◽  
Thomas Zeis ◽  
Nicole Schaeren-Wiemers ◽  
Andreas Junker ◽  
Franziska van der Meer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
White Matter Lesions ◽  
Progressive Multiple Sclerosis ◽  
Chronic Inflammatory Disease ◽  
Molecular Signature ◽  
Specific Marker ◽  
Preferential Accumulation ◽  
Upregulated Genes ◽  
M1 Type

Abstract Multiple sclerosis is an immune-mediated chronic inflammatory disease of the CNS that leads to demyelinated lesions in the grey and white matter. Inflammatory, active demyelinating white matter lesions predominate in the relapsing-remitting disease stages, whereas in the progressive stage the so-called slowly expanding lesion is characteristic. These lesions show an accumulation of macrophages/microglia at their borders, mediating the ongoing myelin breakdown and axonal degeneration. The exact pathogenetic mechanisms of lesion progression in chronic multiple sclerosis are still not clear. In the present study, we performed a detailed immunological and molecular profiling of slowly expanding lesions (n = 21) from 13 patients aged between 30 to 74 years (five females and eight males), focusing on macrophage/microglia differentiation. By applying the microglia-specific marker TMEM119, we demonstrate that cells accumulating at the lesion edge almost exclusively belonged to the microglia lineage. Macrophages/microglia can be subdivided into the M1 type, which are associated with inflammatory and degenerative processes, and M2 type, with protective properties, whereby also intermediate polarization phenotypes can be observed. By using a panel of markers characterizing M1- or M2-type macrophages/microglia, we observed a preferential accumulation of M1-type differentiated cells at the lesion edge, indicating a crucial role of these cells in lesion progression. Additionally, unbiased RNA microarray analyses of macrodissected lesion edges from slowly expanding and chronic inactive lesions as well as normal-appearing white matter were performed. In slowly expanding lesions, we identified a total of 165 genes that were upregulated and 35 genes that were downregulated. The upregulated genes included macrophage/microglia-associated genes involved in immune defence and inflammatory processes. Among the upregulated genes were ALOX15B, MME and TNFRSF25. We confirmed increased expression of ALOX15B by quantitative PCR, and of all three genes on the protein level by immunohistochemistry. In conclusion, the present study characterized in detail slowly expanding lesions in progressive multiple sclerosis and demonstrated a preferential accumulation of resident microglia with M1 differentiation at the lesion edge. Microarray analysis showed an increased expression of genes related to immune function, metabolic processes as well as transcription/translation. Thus, these genes may serve as future therapeutic targets to impede lesion progression.

scholarly journals Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study

2020 ◽  
pp. 135245852091897 ◽  
Author(s):  
Svenja Kiljan ◽  
Paolo Preziosa ◽  
Laura E Jonkman ◽  
Wilma DJ van de Berg ◽  
Jos Twisk ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Diffusion Tensor ◽  
Mean Diffusivity ◽  
White Matter Lesions ◽  
Progressive Multiple Sclerosis ◽  
Axonal Loss ◽  
Normal Appearing White Matter ◽  
Axonal Density ◽  
Neuroaxonal Degeneration

Background: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS). Objective: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS. Methods: Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models. Results: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices ( p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD ( p = 0.003; p = 0.02, respectively), and NAWM MD and AD ( p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity ( p = 0.002), explaining 34.4% of axonal loss variance. Conclusion: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.

scholarly journals Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis

2006 ◽  
Vol 20 (2) ◽  
pp. 90-103 ◽  
Author(s):  
Erwin L. A. Blezer ◽  
Jan Bauer ◽  
Herbert P. M. Brok ◽  
Klaas Nicolay ◽  
Bert A. 't Hart
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
White Matter Lesions ◽  
Quantitative Mri ◽  
Primate Model ◽  
Brain White Matter ◽  
Human Primate
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