Conversion of Diffusely Abnormal White Matter to Focal Lesions is Linked to Progression in Secondary Progressive Multiple Sclerosis

ABSTRACTObjectives1) To automatically segment focal white matter lesions (FWML) and Diffusely abnormal white matter (DAWM), i.e. regions of diffuse abnormality observed on conventional (T2-weighted) MRI and characterize their longitudinal volumetric and normalized T1-weighted (T1w) intensity evolution, 2) To assess associations of FWML and DAWM with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP).MethodsData includes 3951 timepoints of 589 SPMS participants followed for three years. FWML and DAWM were automatically segmented using a 2-weighted-intensity thresholding technique. Screening DAWM volumes that transformed into FWML at the last visit (DAWM-to-FWML) and normalized T1w intensities (as a marker of severity of damage) in those voxels were calculated.ResultsFWML volume significantly increased and DAWM volume significantly decreased as disease duration increased (p<0.001). Global EDSS scores were positively associated with FWML volumes (p=0.002), but not with DAWM volumes. Median volume of DAWM-to-FWML was significantly higher in patients who progressed (2.75 vs 1.70 cc; p<0.0001), and represented 14% of the total DAWM volume at screening, compared to 10% in patients who did not progress (p=0.001). Normalized T1w intensity values of DAWM-to-FWML were negatively associated with CDP status (p<0.00001).ConclusionDAWM transformed into FWML over time, and this transformation was significantly associated with clinical progression. DAWM voxels that transformed had greater normalized T1w intensity decrease over time, in keeping with relatively greater tissue damage evolution. Evaluation of DAWM in progressive MS provides a useful measure to evaluate therapies that aim to protect this at-risk tissue with the potential to slow progression.

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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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Reliability of Outcome Measures in Clinical Trials in Secondary Progressive Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000011123 ◽

2020 ◽

Vol 96 (1) ◽

pp. e111-e120 ◽

Cited By ~ 1

Author(s):

Marcus W. Koch ◽

Jop Mostert ◽

Pavle Repovic ◽

James D. Bowen ◽

Bernard Uitdehaag ◽

...

Keyword(s):

Multiple Sclerosis ◽

Outcome Measures ◽

Controlled Trial ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Disability Progression ◽

Secondary Progressive ◽

Randomized Controlled ◽

Disability Status ◽

Over Time

ObjectiveTo investigate the reliability of clinical outcomes in secondary progressive multiple sclerosis (SPMS) trials, we compared the frequency of progression and improvement events on different clinical outcome measures in the placebo arms of 2 large randomized controlled trial (RCT) datasets.MethodsUsing original trial data from the placebo arms of IMPACT (International MS Secondary Progressive Avonex Controlled Trial) and ASCEND (A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis), 2 large RCTs in SPMS, we compared disability progression and similarly defined improvement with and without 3- or 6-month confirmation on the outcome measures Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and their combinations.ResultsIn both datasets, the EDSS showed the highest rates of improvement over time, and the smallest difference between progression and improvement rates, followed by the T25FW and the 9HPT. For the T25FW and 9HPT, improvement rates were fairly stable over time and remained at below or around the 10% level. For the EDSS, improvement rates increased in parallel with disability progression rates.ConclusionsAll investigated outcome measures in SPMS showed some evidence of random variation and measurement error, the T25FW and 9HPT less so than the more established outcome EDSS. Our findings are relevant for the design and critical appraisal of trials in SPMS.

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

Annals of Clinical and Translational Neurology ◽

10.1002/acn3.750 ◽

2019 ◽

Vol 6 (5) ◽

pp. 854-862 ◽

Cited By ~ 7

Author(s):

Ajai Tripathi ◽

Christina Volsko ◽

Ushasi Datta ◽

Keren Regev ◽

Ranjan Dutta

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Progressive Multiple Sclerosis

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Ongoing microstructural changes in the cervical cord underpin disability progression in early primary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458519900971 ◽

2020 ◽

Vol 27 (1) ◽

pp. 28-38 ◽

Cited By ~ 1

Author(s):

Rosa Cortese ◽

Carmen Tur ◽

Ferran Prados ◽

Torben Schneider ◽

Baris Kanber ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Brain Mri ◽

Progressive Multiple Sclerosis ◽

Cervical Cord ◽

Primary Progressive Multiple Sclerosis ◽

Disability Progression ◽

Mixed Effect ◽

Primary Progressive ◽

Over Time

Background: Pathology in the spinal cord of patients with primary progressive multiple sclerosis (PPMS) contributes to disability progression. We previously reported abnormal Q-space imaging (QSI)-derived indices in the spinal cord at baseline in patients with early PPMS, suggesting early neurodegeneration. Objective: The aim was to investigate whether changes in spinal cord QSI over 3 years in the same cohort are associated with disability progression and if baseline QSI metrics predict clinical outcome. Methods: Twenty-three PPMS patients and 23 healthy controls recruited at baseline were invited for follow-up cervical cord 3T magnetic resonance imaging (MRI) and clinical assessment after 1 year and 3 years. Cord cross-sectional area (CSA) and QSI measures were obtained, together with standard brain MRI measures. Mixed-effect models assessed MRI changes over time and their association with clinical changes. Linear regression identified baseline MRI indices associated with disability at 3 years. Results: Over time, patients deteriorated clinically and showed an increase in cord QSI indices of perpendicular diffusivity that was associated with disability worsening, independently of the decrease in CSA. Higher perpendicular diffusivity and lower CSA at baseline predicted worse disability at 3 years. Conclusion: Increasing spinal cord perpendicular diffusivity may indicate ongoing neurodegeneration, which underpins disability progression in PPMS, independently of the development of spinal cord atrophy.

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

Brain ◽

10.1093/brain/awaa249 ◽

2020 ◽

Vol 143 (10) ◽

pp. 2973-2987 ◽

Cited By ~ 1

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.

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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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Slow Progression of White-Matter Changes

International Psychogeriatrics ◽

10.1017/s1041610203009153 ◽

2003 ◽

Vol 15 (S1) ◽

pp. 173-176 ◽

Cited By ~ 2

Author(s):

Reinhold Schmidt ◽

Helena Schmidt ◽

Peter Kapeller ◽

Franz Fazekas

Keyword(s):

White Matter ◽

Test Performance ◽

Statistical Power ◽

White Matter Lesions ◽

White Matter Hyperintensity ◽

Prevention Study ◽

Clinical Predictors ◽

Time Period ◽

Slow Progression

A three-year follow-up of 273 participants (mean age 60 years) of the Austrian Stroke Prevention Study provides the first information on the rate, clinical predictors, and cognitive consequences of MRI white-matter lesions in elderly individuals without neuropsychiatric disease. Lesion progression was found in 17.9% of individuals over a time period of 3 years. Diastolic blood pressure and early confluent or confluent white-matter hyperintensities at baseline were the only significant predictors of white-matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychologic test performance over the observational period, but the statistical power of this analysis was low.

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Myelin in SIDS: Assessment of Development and Damage using MRI

PEDIATRICS ◽

10.1542/peds.95.3.409 ◽

1995 ◽

Vol 95 (3) ◽

pp. 409-413

Author(s):

Phillipa Lamont ◽

Toos Sachinwalla ◽

Roger Pamphlett

Keyword(s):

White Matter ◽

White Matter Lesions ◽

Sudden Infant Death ◽

Sudden Infant ◽

Proton Density ◽

Resonance Imaging ◽

Focal Lesions ◽

White Matter Development ◽

Magnetic Resonance Imaging Mri ◽

And Inversion

Objective. Abnormalities of myelin that have been reported in Sudden Infant Death Syndrome (SIDS) include a delay in development and focal lesions presumed to be secondary to hypoxia. Magnetic resonance imaging (MRI) gives excellent images of white matter and can be used to map the progress of myelination and to demonstrate focal lesions. It was the aim of this study to determine whether any MRI abnormality of myelin could be detected in the brains of SIDS compared to control infants. Methods. The brains of 28 SIDS and 14 control infants were fixed in formalin and scanned with MRI. The proton density, T2-weighted, and inversion recovery scans were assessed for the presence of focal white matter lesions. The amount of myelin in 26 sites was measured in the proton density scans, using a densitometer. The amount of myelin present could be assessed in 21 of 26 sites. Results. In 15 of 21 sites the amount of myelin for age was the same in SIDS and controls. In three sites the rate of myelination was greater in SIDS than control and in another three sites the amount of myelin for age was greater in SIDS than control infants, but these differences were not seen in infants aged less than 8 months. No focal abnormalities of white matter were seen in either SIDS or control infants. Conclusions. The development of white matter in brains of SIDS infants less than 8 months old is the same as in controls, and in older SIDS infants white matter development may be slightly advanced compared to controls. No hypoxic changes can be seen in SIDS white matter on MRI.

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Covarying patterns of white matter lesions and cortical atrophy predict progression in early MS

Neurology Neuroimmunology & Neuroinflammation ◽

10.1212/nxi.0000000000000681 ◽

2020 ◽

Vol 7 (3) ◽

pp. e681

Author(s):

Muthuraman Muthuraman ◽

Vinzenz Fleischer ◽

Julia Kroth ◽

Dumitru Ciolac ◽

Angela Radetz ◽

...

Keyword(s):

White Matter ◽

Computational Models ◽

Functional Disability ◽

White Matter Lesions ◽

Cortical Atrophy ◽

Support Vector ◽

Study Cohort ◽

Disability Progression ◽

Replication Cohort ◽

Characteristic Analysis

ObjectiveWe applied longitudinal 3T MRI and advanced computational models in 2 independent cohorts of patients with early MS to investigate how white matter (WM) lesion distribution and cortical atrophy topographically interrelate and affect functional disability.MethodsClinical disability was measured using the Expanded Disability Status Scale Score at baseline and at 1-year follow-up in a cohort of 119 patients with early relapsing-remitting MS and in a replication cohort of 81 patients. Covarying patterns of cortical atrophy and baseline lesion distribution were extracted by parallel independent component analysis. Predictive power of covarying patterns for disability progression was tested by receiver operating characteristic analysis at the group level and support vector machine for individual patient outcome.ResultsIn the study cohort, we identified 3 distinct distribution types of WM lesions (cerebellar, bihemispheric, and left lateralized) that were associated with characteristic cortical atrophy distributions. The cerebellar and left-lateralized patterns were reproducibly detected in the second cohort. Each of the patterns predicted to different extents, short-term disability progression, whereas the cerebellar pattern was associated with the highest risk of clinical worsening, predicting individual disability progression with an accuracy of 88% (study cohort) and 89% (replication cohort), respectively.ConclusionThese findings highlight the role of distinct spatial distribution of cortical atrophy and WM lesions predicting disability. The cerebellar involvement is shown as a key determinant of rapid clinical deterioration.

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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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