scholarly journals A metabolic perspective on CSF-mediated neurodegeneration in multiple sclerosis

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2756-2774 ◽  
Author(s):  
Maureen Wentling ◽  
Carlos Lopez-Gomez ◽  
Hye-Jin Park ◽  
Mario Amatruda ◽  
Achilles Ntranos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Damage ◽  
Morphological Changes ◽  
Progressive Multiple Sclerosis ◽  
Functional Screening ◽  
Disease Course ◽  
Post Translational Modification ◽  
Neurodegenerative Process ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients

Abstract Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of ‘virtual hypoglycosis’ induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.

scholarly journals Retrospective unbiased plasma lipidomic of progressive multiple sclerosis patients-identifies lipids discriminating those with faster clinical deterioration

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mario Amatruda ◽  
Maria Petracca ◽  
Maureen Wentling ◽  
Benjamin Inbar ◽  
Kamilah Castro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Disease Course ◽  
Primary Progressive ◽  
T2 Lesions ◽  
Relapsing Remitting ◽  
One Year ◽  
Multiple Sclerosis Patients

Abstract The disease course of patients with a confirmed diagnosis of primary progressive multiple sclerosis (PPMS) is uncertain. In an attempt to identify potential signaling pathways involved in the evolution of the disease, we conducted an exploratory unbiased lipidomic analysis of plasma from non-diseased controls (n = 8) and patients with primary progressive MS (PPMS, n = 19) and either a rapid (PPMS-P, n = 9) or slow (PPMS-NP, n = 10) disease course based on worsening disability and/or MRI-visible appearance of new T2 lesions over a one-year-assessment. Partial least squares-discriminant analysis of the MS/MSALL lipidomic dataset, identified lipids driving the clustering of the groups. Among these lipids, sphingomyelin-d18:1/14:0 and mono-hexosylceramide-d18:1/20:0 were differentially abundant in the plasma of PPMS patients compared to controls and their levels correlated with MRI signs of disease progression. Lyso-phosphatidic acid-18:2 (LPA-18:2) was the only lipid with significantly lower abundance in PPMS patients with a rapidly deteriorating disease course, and its levels inversely correlated with the severity of the neurological deficit. Decreased levels of LPA-18:2 were detected in patients with more rapid disease progression, regardless of therapy and these findings were validated in an independent cohort of secondary progressive (SPMS) patients, but not in a third cohorts of relapsing–remitting (RRMS) patients. Collectively, our analysis suggests that sphingomyelin-d18:1/14:0, mono-hexosylceramide-d18:1/20:0, and LPA-18:2 may represent important targets for future studies aimed at understanding disease progression in MS.

scholarly journals Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery

2018 ◽  
Vol 4 (4) ◽  
pp. 205521731881551 ◽  
Author(s):  
L De Meijer ◽  
D Merlo ◽  
O Skibina ◽  
EJ Grobbee ◽  
J Gale ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cognitive Change ◽  
Progressive Multiple Sclerosis ◽  
Healthy Controls ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Serial Addition ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Cognitive Monitoring

Background Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. Objectives The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. Methods Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing–remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing–remitting multiple sclerosis patients were evaluated using linear mixed models. Results Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline ( p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test ( p<0.001). In relapsing–remitting multiple sclerosis patients, reaction time slowed over 12 months ( p<0.001) for the CogState Brief Battery Detection (mean change –34.23 ms) and Identification (–25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. Conclusions The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting.

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.

Pixantrone: a B-cell-depleting immunosuppressant for multiple sclerosis patients with active disease

2015 ◽  
Vol 22 (6) ◽  
pp. 817-821 ◽  
Author(s):  
Richard Gonsette ◽  
Marc Debouverie ◽  
Christian Sindic ◽  
Jean-Christophe Ferré ◽  
Gilles Edan
Keyword(s):  
Multiple Sclerosis ◽  
Lymphocyte Subsets ◽  
Progressive Multiple Sclerosis ◽  
Left Ventricular ◽  
Open Label ◽  
Annual Relapse Rate ◽  
Cerebral Mri ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients

Background: Mitoxantrone has been approved for patients with worsening relapsing–remitting (RR) or secondary progressive multiple sclerosis (SPMS), but its long-term use is limited by its cardiotoxicity. Pixantrone (PIX) is an analog of mitoxantrone. Objectives: The aim of this open-label, multicenter, noncomparative Phase I/II trial was to explore the immunosuppressive effect of PIX, its impact on clinical disease activity and cerebral gadolinium-enhanced (Gd+) lesions, and its safety. Methods: Eighteen patients with active RRMS and SPMS (⩾ 1 cerebral Gd+ lesion) despite approved immunomodulatory therapy received four intravenous PIX injections every 21 days. A neurological examination, hematology, lymphocyte subsets, and biochemistry were performed at Day 1, Weeks 3, 6 and 9, and Months 3, 6, 9 and 12. Echocardiography was performed before each infusion, at Months 3, 6 and 12. Cerebral MRI was performed at baseline, and at Months 6 and 12. Results: CD19+ cells were reduced by 95% at Month 3 and by 47% at Month 12. Gd+ lesions were reduced by 86% at Month 12 ( p = 0.01). The annual relapse rate was reduced by 87% ( p < 10−4). Two patients experienced a transient reduction in left ventricular fraction. Conclusion: These preliminary data indicate the efficacy of PIX in active RRMS and SPMS.

scholarly journals Phonological Fluency Strategy of Switching Differentiates Relapsing-Remitting and Secondary Progressive Multiple Sclerosis Patients

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
L. Messinis ◽  
M. H. Kosmidis ◽  
C. Vlahou ◽  
A. C. Malegiannaki ◽  
G. Gatzounis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Verbal Fluency ◽  
Progressive Multiple Sclerosis ◽  
Word Production ◽  
Secondary Progressive Multiple Sclerosis ◽  
Healthy Controls ◽  
Secondary Progressive ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
Fluency Task

The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls.

An MRI study of Chlamydia pneumoniae infection in Italian multiple sclerosis patients

2003 ◽  
Vol 9 (5) ◽  
pp. 467-471 ◽  
Author(s):  
L ME Grimaldi ◽  
A Pincherle ◽  
F Martinelli-Boneschi ◽  
M Filippi ◽  
F Patti ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Chlamydia Pneumoniae ◽  
Neurological Diseases ◽  
Disease Onset ◽  
Progressive Multiple Sclerosis ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Magnetic Resonance Imaging Mri ◽  
Multiple Sclerosis Patients ◽  
Mri Study

We amplified sequences of the Chlamydia pneumoniae (C P) major-outer membrane protein in the cerebrospinal fluid (CSF) from 23 of 107 (21.5%) relapsing-remitting or secondary progressive multiple sclerosis (MS) patients and two of 77 (2.6%) patients with other neurological diseases (OND) (P =0.00022). C P+ patients showed magnetic resonance imaging (MRI) evidence of more active disease (P =0.02) compared to CP-MS patients and tended to have an anticipation of age at disease onset (32.39-12 versus 28.59-10 years; P =ns) causing a longer disease duration (7.59-5 versus 4.49-4 years; P =0.016) at the time of clinical evaluation. These findings, although indirectly, suggest that C P infection of the central nervous system (C NS) might affect disease course in a subgroup of MS patients.

Progressive multiple sclerosis patients have a higher burden of autonomic dysfunction compared to relapsing remitting phenotype

2018 ◽  
Vol 129 (8) ◽  
pp. 1588-1594 ◽  
Author(s):  
Ivan Adamec ◽  
Luka Crnošija ◽  
Anamari Junaković ◽  
Magdalena Krbot Skorić ◽  
Mario Habek
Keyword(s):  
Multiple Sclerosis ◽  
Autonomic Dysfunction ◽  
Progressive Multiple Sclerosis ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients

scholarly journals Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis

2018 ◽  
Vol 4 (4) ◽  
pp. 205521731881953 ◽  
Author(s):  
Madhurima Chatterjee ◽  
Marleen JA Koel-Simmelink ◽  
Inge MW Verberk ◽  
Joep Killestein ◽  
Hugo Vrenken ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Progressive Multiple Sclerosis ◽  
Clinically Isolated Syndrome ◽  
Resonance Imaging ◽  
Secondary Progressive ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Background Contactin-1 and contactin-2 are important for the maintenance of axonal integrity. Objective To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration. Methods Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing–remitting multiple sclerosis ( n = 41), secondary progressive multiple sclerosis ( n = 26) and primary progressive multiple sclerosis patients ( n = 13) and controls ( n = 18), and in a second cohort with clinically isolated syndrome patients ( n = 88, median clinical follow-up period of 2.3 years) and controls ( n = 20). Correlations/linear regressions were analysed with other baseline cerebrospinal fluid axonal damage markers and cross-sectional/longitudinal magnetic resonance imaging features. Results Contactin-1 and contactin-2 levels were up to 1.4-fold reduced in relapsing–remitting multiple sclerosis (contactin-1: p = 0.01, contactin-2: p = 0.02) and secondary progressive multiple sclerosis (contactin-1: p = 0.05, contactin-2: p = 0.02) compared to controls. In clinically isolated syndrome patients, contactin-1 tended to increase when compared to controls ( p = 0.07). Both contactin-1 and contactin-2 correlated with neurofilament light, neurofilament heavy and magnetic resonance imaging metrics differently depending on the disease stage. In clinically isolated syndrome patients, baseline contactin-2 level (β = –0.42, p = 0.04) predicted the longitudinal decline in cortex volume. Conclusion Cerebrospinal fluid contactin-1 and contactin-2 reveal axonal dysfunction in various stages of multiple sclerosis and their inclusion to the biomarker panel may provide better insight into the extent of axonal damage/dysfunction.

Sign in / Sign up

Export Citation Format

Share Document