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

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.

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Molecular signature of slowly expanding lesions in progressive multiple sclerosis

Brain ◽

10.1093/brain/awaa158 ◽

2020 ◽

Vol 143 (7) ◽

pp. 2073-2088 ◽

Cited By ~ 1

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.

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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

Multiple Sclerosis Journal ◽

10.1177/1352458520918978 ◽

2020 ◽

pp. 135245852091897 ◽

Cited By ~ 1

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.

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Conversion of diffusely abnormal white matter to focal lesions is linked to progression in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520912172 ◽

2020 ◽

pp. 135245852091217

Author(s):

Mahsa Dadar ◽

Sridar Narayanan ◽

Douglas L Arnold ◽

D Louis Collins ◽

Josefina Maranzano

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis ◽

Magnetic Resonance Images ◽

Secondary Progressive Multiple Sclerosis ◽

Clinical Progression ◽

Focal Lesions ◽

Secondary Progressive ◽

Over Time

Background: Diffusely abnormal white matter (DAWM) regions are observed in magnetic resonance images of secondary progressive multiple sclerosis (SPMS) patients. However, their role in clinical progression is still not established. Objectives: To characterize the longitudinal volumetric and intensity evolution of DAWM and focal white matter lesions (FWML) and assess their associations with clinical outcomes and progression in SPMS. Methods: Data include 589 SPMS participants followed up for 3 years (3951 time points). FWML and DAWM were automatically segmented. Screening DAWM volumes that transformed into FWML at the last visit (DAWM-to-FWML) and normalized T1-weighted intensities (indicating severity of damage) in those voxels were calculated. Results: FWML volume increased and DAWM volume decreased with an increase in disease duration ( p < 0.001). The Expanded Disability Status Scale (EDSS) was positively associated with FWML volumes ( p = 0.002), but not with DAWM. DAWM-to-FWML volume was higher in patients who progressed (2.75 cm3 vs. 1.70 cm3; p < 0.0001). Normalized T1-weighted intensity of DAWM-to-FWML was negatively associated with progression ( p < 0.00001). Conclusion: DAWM transformed into FWML over time, and this transformation was associated with clinical progression. DAWM-to-FWML voxels had greater normalized T1-weighted intensity decrease over time, in keeping with relatively greater tissue damage. Evaluation of DAWM in progressive multiple sclerosis provides a useful measure for therapies aiming to protect this at-risk tissue with the potential to slow progression.

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Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1818348116 ◽

2019 ◽

Vol 116 (18) ◽

pp. 9030-9039 ◽

Cited By ~ 45

Author(s):

Alexandra M. Nicaise ◽

Laura J. Wagstaff ◽

Cory M. Willis ◽

Carolyn Paisie ◽

Harshpreet Chandok ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Progenitor Cells ◽

Cellular Senescence ◽

Progenitor Cell ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis ◽

Cellular Aging ◽

Primary Progressive Multiple Sclerosis ◽

Cell Functions

Cellular senescence is a form of adaptive cellular physiology associated with aging. Cellular senescence causes a proinflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases. We had previously determined that neural progenitor cells (NPCs) derived from induced pluripotent stem cell (iPSC) lines from patients with primary progressive multiple sclerosis (PPMS) failed to promote oligodendrocyte progenitor cell (OPC) maturation, whereas NPCs from age-matched control cell lines did so efficiently. Herein, we report that expression of hallmarks of cellular senescence were identified in SOX2+ progenitor cells within white matter lesions of human progressive MS (PMS) autopsy brain tissues and iPS-derived NPCs from patients with PPMS. Expression of cellular senescence genes in PPMS NPCs was found to be reversible by treatment with rapamycin, which then enhanced PPMS NPC support for oligodendrocyte (OL) differentiation. A proteomic analysis of the PPMS NPC secretome identified high-mobility group box-1 (HMGB1), which was found to be a senescence-associated inhibitor of OL differentiation. Transcriptome analysis of OPCs revealed that senescent NPCs induced expression of epigenetic regulators mediated by extracellular HMGB1. Lastly, we determined that progenitor cells are a source of elevated HMGB1 in human white matter lesions. Based on these data, we conclude that cellular senescence contributes to altered progenitor cell functions in demyelinated lesions in MS. Moreover, these data implicate cellular aging and senescence as a process that contributes to remyelination failure in PMS, which may impact how this disease is modeled and inform development of future myelin regeneration strategies.

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

10.1101/584920 ◽

2019 ◽

Cited By ~ 1

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.

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Adult-onset vanishing white matter disease as differential diagnosis of primary progressive multiple sclerosis: A case report

Multiple Sclerosis Journal ◽

10.1177/1352458514546515 ◽

2014 ◽

Vol 21 (5) ◽

pp. 666-668 ◽

Cited By ~ 4

Author(s):

Marina Herwerth ◽

Benedikt J Schwaiger ◽

Kornelia Kreiser ◽

Bernhard Hemmer ◽

Rüdiger Ilg

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Diffusion Weighted Imaging ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis ◽

White Matter Disease ◽

Primary Progressive Multiple Sclerosis ◽

Adult Onset ◽

Vanishing White Matter Disease ◽

Vanishing White Matter

We report the case of a 42-year-old woman with a slowly progressive cerebellar syndrome. In contrast to a relatively mild clinical presentation, the magnetic resonance imaging (MRI) showed extensive leukencephalopathy with cystic degeneration. Initially primary progressive multiple sclerosis (PPMS) was suspected. Additional diffusion-weighted imaging revealed restricted diffusion in the white matter lesions with a reduced apparent diffusion coefficient. Genetic testing showed vanishing white matter disease (VWM) with c.260C>T EIF2B3 mutation. In conclusion, in cases with relatively mild symptoms and extensive white matter lesions, adult-onset VWM should be considered as differential diagnosis of PPMS and diffusion-weighted imaging may be helpful to identify suspected cases.

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