Multiple Sclerosis Atlas: A Molecular Map of Brain Lesion Stages in Progressive Multiple Sclerosis

Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Position emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation.

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Cognitive dysfunction in primary progressive multiple sclerosis: a neuropsychological and MRI study

Multiple Sclerosis Journal ◽

10.1177/1352458509106231 ◽

2009 ◽

Vol 15 (9) ◽

pp. 1055-1061 ◽

Cited By ~ 14

Author(s):

M Ukkonen ◽

T Vahvelainen ◽

P Hämäläinen ◽

P Dastidar ◽

I Elovaara

Keyword(s):

Multiple Sclerosis ◽

Cognitive Performance ◽

Cognitive Dysfunction ◽

Neuropsychological Tests ◽

Brain Lesion ◽

Progressive Multiple Sclerosis ◽

Primary Progressive Multiple Sclerosis ◽

Cognitive Domains ◽

Primary Progressive ◽

Mri Study

Although cognitive dysfunction is known to occur in multiple sclerosis (MS), only few studies have reported cognitive performance in patients with primary progressive MS (PPMS). To find out the pattern of cognitive performance in PPMS, 28 PPMS patients underwent an extensive battery of neuropsychological tests. The results were compared to those of healthy controls ( n = 20) and patients with secondary progressive MS (SPMS, n = 28). Furthermore, the results of neuropsychological tests in PPMS were correlated to magnetic resonance imaging findings. Our study showed that the PPMS patients have deficits in several cognitive domains when compared to age-matched and education-matched controls, but the cognitive impairment in the PPMS and SPMS patients appeared to be similar. Cognitive deficits in PPMS patients correlated with diffuse brain lesion, T1- and T2-lesion load, but no correlations were found with atrophy.

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Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217320972137 ◽

2020 ◽

Vol 6 (4) ◽

pp. 205521732097213 ◽

Cited By ~ 1

Author(s):

Dana Horáková ◽

Aaron Boster ◽

Antonio Bertolotto ◽

Mark S Freedman ◽

Isabel Firmino* ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Lesion ◽

Functional System ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Kaplan Meier ◽

Relapsing Remitting ◽

Core Study ◽

Few Data ◽

Post Hoc

Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. Conclusions The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

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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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