scholarly journals Single-nucleus RNA-seq of normal-appearing brain regions in relapsing-remitting vs. secondary progressive multiple sclerosis

2022 ◽  
Author(s):  
Yasuyuki Kihara ◽  
Yunjiao Zhu ◽  
Deepa Jonnalagadda ◽  
William Romanow ◽  
Carter Palmer ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Single Cells ◽  
Brain Regions ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive ◽  
Relapsing Remitting ◽  
Sphingosine Kinases ◽  
Progressive Neurodegeneration ◽  
Single Nucleus

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2), the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

T1 relaxation maps allow differentiation between pathologic tissue subsets in relapsing-remitting and secondary progressive multiple sclerosis

2004 ◽  
Vol 10 (5) ◽  
pp. 556-561 ◽  
Author(s):  
A Castriota-Scanderbeg ◽  
F Fasano ◽  
M Filippi ◽  
C Caltagirone
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Relaxation Times ◽  
Brain Regions ◽  
Progressive Multiple Sclerosis ◽  
Clinical Group ◽  
Secondary Progressive ◽  
Normal Appearing White Matter ◽  
Relapsing Remitting ◽  
Normal White Matter

In an attempt to clarify whether T1 relaxation time mapping may assist in characterizing the pathological brain tissue substrate of multiple sclerosis (MS), we compared the T1 relaxation times of lesions, areas of normal-appearing white matter (NAWM) located proximal to lesions, and areas of NAWM located distant from lesions in 12 patients with the relapsing-remitting and 12 with the secondary progressive (SP) subtype of disease. Nine healthy volunteers served as controls. Calculated mean T1 values were averaged across all patients within each clinical group, and comparisons were made by means of the Mann-Whitney U-test. Significant differences were found between all investigated brain regions within each clinical subgroup. Significant differences were also detected for each investigated brain region among clinical subgroups. While T1 values of NAWM were significantly higher in patients with SP disease than in normal white matter (NWM) of controls, no differences were detected when corresponding brain areas of patients with RR MS were compared with NWM of controls. T1 maps identify areas of the brain that are damaged to a different extent in patients with MS, and may be of help in monitoring disease progression.

The pathology of primary progressive multiple sclerosis

2002 ◽  
Vol 8 (2) ◽  
pp. 93-97 ◽  
Author(s):  
W Brück ◽  
C Lucchinetti ◽  
H Lassmann
Keyword(s):  
Multiple Sclerosis ◽  
Demyelinating Disease ◽  
Current Knowledge ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
Secondary Progressive ◽  
Relapsing Remitting ◽  
Underlying Pathology ◽  
Clinical Subtype

The present review will focus on the current knowledge of the pathology of primary progressive multiple sclerosis lesions. Multiple sclerosis (MS) is an inflammatory demyelinating disease with a broad clinical variability. The main disease courses are relapsing-remitting, secondary progressive and primary progressive MS. Pathological studies examining the specific underlying pathology of a defined clinical subtype are rare. Here, we focus on the phatological characteristics of the MS lesions and summarize the current findings of the phatology of primary progressive MS with respect to inflammation, oligodendrocyte/myelin pathology, axon destruction and immunopathology of the lesions.

scholarly journals Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Isobel A. Scarisbrick ◽  
Rachel Linbo ◽  
Alexander G. Vandell ◽  
Mark Keegan ◽  
Sachiko I. Blaber ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cortical Neurons ◽  
Serine Proteases ◽  
Serum Levels ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive ◽  
Neurite Retraction ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Potential Activity

Abstract Tissue kallikrein KLK1 and the kallikrein-related peptidases KLK2–15 are a subfamily of serine proteases that have defined or proposed roles in a range of central nervous system (CNS) and non-CNS pathologies. To further understand their potential activity in multiple sclerosis (MS), serum levels of KLK1, 6, 7, 8 and 10 were determined in 35 MS patients and 62 controls by quantitative fluorometric ELISA. Serum levels were then correlated with Expanded Disability Status Scale (EDSS) scores determined at the time of serological sampling or at last clinical follow-up. Serum levels of KLK1 and KLK6 were elevated in MS patients (p≤0.027), with highest levels associated with secondary progressive disease. Elevated KLK1 correlated with higher EDSS scores at the time of serum draw and KLK6 with future EDSS worsening in relapsing remitting patients (p≤0.007). Supporting the concept that KLK1 and KLK6 promote degenerative events associated with progressive MS, exposure of murine cortical neurons to either kallikrein promoted rapid neurite retraction and neuron loss. These novel findings suggest that KLK1 and KLK6 may serve as serological markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death.

scholarly journals Onset of secondary progressive multiple sclerosis is not influenced by current relapsing multiple sclerosis therapies

2018 ◽  
Vol 4 (2) ◽  
pp. 205521731878334 ◽  
Author(s):  
Francisco Coret ◽  
Francisco C Pérez-Miralles ◽  
Francisco Gascón ◽  
Carmen Alcalá ◽  
Arantxa Navarré ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Secondary Progressive Multiple Sclerosis ◽  
Secondary Progressive ◽  
Disease Modifying Therapies ◽  
Relapsing Remitting ◽  
Disease Modifying ◽  
Remitting Multiple Sclerosis ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background Disease-modifying therapies are thought to reduce the conversion rate to secondary progressive multiple sclerosis. Objective To explore the rate, chronology, and contributing factors of conversion to the progressive phase in treated relapsing–remitting multiple sclerosis patients. Methods Our study included 204 patients treated for relapsing–remitting multiple sclerosis between 1995 and 2002, prospectively followed to date. Kaplan–Meier analysis was applied to estimate the time until secondary progressive multiple sclerosis conversion, and multivariate survival analysis with a Cox regression model was used to analyse prognostic factors. Results Relapsing–remitting multiple sclerosis patients were continuously treated for 13 years (SD 4.5); 36.3% converted to secondary progressive multiple sclerosis at a mean age of 42.6 years (SD 10.6), a mean time of 8.2 years (SD 5.2) and an estimated mean time of 17.2 years (range 17.1–18.1). A multifocal relapse, age older than 34 years at disease onset and treatment failure independently predicted conversion to secondary progressive multiple sclerosis but did not influence the time to reach an Expanded Disability Status Scale of 6.0. Conclusions The favourable influence of disease-modifying therapies on long-term disability in relapsing–remitting multiple sclerosis is well established. However, the time to progression onset and the subsequent clinical course in treated patients seem similar to those previously reported in natural history studies. More studies are needed to clarify the effect of disease-modifying therapies once the progressive phase has been reached.

Hopelessness Ratings in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis

2002 ◽  
Vol 32 (2) ◽  
pp. 155-165 ◽  
Author(s):  
Scott B. Patten ◽  
Luanne M. Metz
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trial ◽  
Interferon Beta ◽  
Progressive Multiple Sclerosis ◽  
Double Blind ◽  
Exact Probability ◽  
Secondary Progressive ◽  
Relapsing Remitting ◽  
Trial Participants ◽  
Over Time

Objective: Two recent randomized double-blind placebo controlled clinical trials of interferon beta-1a in multiple sclerosis have obtained hopelessness ratings using the Beck Hopelessness Scale (BHS). One of these studies, the PRISMS trial, evaluated interferon beta-1a in relapsing remitting multiple sclerosis (RRMS). Another, the SPECTRIMS trial, evaluated the same medication in secondary progressive (SP) MS. The objective of this analysis was to compare levels of hopelessness in persons with RRMS and SPMS, and to describe changes over time in the clinical trial participants. Method: Raw data from each clinical trial was obtained from the sponsor of the trials (Serono). Median BHS ratings, and the proportions at or above the BHS cut-point of 10 were calculated over a two (PRISMS) or three (SPECTRIMS) year period. Results: The analysis included n = 532 clinical trial participants. Ratings of hopelessness were higher in SPMS clinical trial participants (SPECTRIMS) than in the RRMS group (PRISMS) at baseline (Fisher's exact test, p = 0.0035). Furthermore, ratings of hopelessness were higher during follow-up than at baseline, in the SPMS group (McNemar's exact probability, p = 0.0015), but not in the RRMS group (McNemar's exact probability, p = 0.65). Depression was strongly associated with hopelessness in both RRMS ( z = 4.13, p < 0.001) and SPMS ( z = 5.24, p < 0.001). Conclusions: Hopelessness is associated with SPMS, and may increase over time in this group. Hopelessness may influence suicide risk in people with MS and may potentially have an impact on coping and quality of life. Additional research is necessary to define the clinical implications of hopelessness in persons with this condition.

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