scholarly journals CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

2012 ◽  
Vol 19 (7) ◽  
pp. 877-884 ◽  
Author(s):  
Jeppe Romme Christensen ◽  
Lars Börnsen ◽  
Mohsen Khademi ◽  
Tomas Olsson ◽  
Poul Erik Jensen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Underlying Disease ◽  
Progressive Multiple Sclerosis ◽  
Axonal Damage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Csf Biomarkers ◽  
Relapsing Remitting ◽  
One Year

Background: The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. Objectives: To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Methods: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing–remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Results: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. Conclusion: CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

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.

CSF β-amyloid as a putative biomarker of disease progression in multiple sclerosis

2016 ◽  
Vol 23 (8) ◽  
pp. 1085-1091 ◽  
Author(s):  
Anna M Pietroboni ◽  
Francesca Schiano di Cola ◽  
Marta Scarioni ◽  
Chiara Fenoglio ◽  
Barbara Spanò ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Enzyme Linked Immunosorbent Assay ◽  
Csf Biomarkers ◽  
Newly Diagnosed ◽  
Potential Biomarker ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Brain Tissue Damage

Background: Neurodegeneration plays a major role in determining disability in multiple sclerosis (MS) patients. Hence, there is increasing need to identify reliable biomarkers, which could serve as prognostic measure of disease progression. Objectives: To assess whether cerebrospinal fluid (CSF) tau and β-amyloid (Aβ) levels were altered in newly diagnosed MS patients and correlated with disability. Moreover, we investigated whether these CSF biomarkers associate with macroscopic brain tissue damage measures. Methods: CSF Aβ and tau levels were determined by enzyme-linked immunosorbent assay in CSF samples from 48 newly diagnosed MS patients, followed-up clinically for 3 years by recording their Expanded Disability Status Scale score at 6-month intervals, and 45 controls. All patients underwent magnetic resonance imaging at baseline and at the end of follow-up to quantify their lesion load (LL). Results: CSF Aβ levels were significantly reduced in patients compared to controls ( p < 0.001). Lower CSF Aβ levels at baseline were a disability predictor at 3-year follow-up ( p = 0.009). CSF tau levels correlated with T2- and T1-LL ( p < 0.001). Conclusion: CSF Aβ reduction is a promising biomarker of neurodegeneration and may predict patients’ clinical outcome. Therefore, CSF Aβ should be considered as a potential biomarker of prognostic value.

scholarly journals CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage

2018 ◽  
Vol 25 (7) ◽  
pp. 937-946 ◽  
Author(s):  
Jeppe Romme Christensen ◽  
Mika Komori ◽  
Marina Rode von Essen ◽  
Rikke Ratzer ◽  
Lars Börnsen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Axonal Damage ◽  
Inflammatory Biomarkers ◽  
Enzyme Linked Immunosorbent Assay ◽  
Csf Biomarkers ◽  
Phase Ii Trials ◽  
Open Label ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

Background: Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. Objective: To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. Methods: CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). Results: In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. Conclusion: These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Neurofilaments and 10-year follow-up in multiple sclerosis

2018 ◽  
Vol 24 (10) ◽  
pp. 1301-1307 ◽  
Author(s):  
Alok Bhan ◽  
Cecilie Jacobsen ◽  
Kjell Morten Myhr ◽  
Ingvild Dalen ◽  
Kirsten Lode ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Outcome ◽  
Predictive Biomarker ◽  
Progressive Multiple Sclerosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Newly Diagnosed ◽  
Relapsing Remitting ◽  
Csf Levels ◽  
Relapsing Remitting Multiple Sclerosis

Background: The role of biomarkers to predict clinical outcome in multiple sclerosis (MS) is still debated. Objective: To test whether cerebrospinal fluid (CSF) light-chain neurofilament (NfL) levels in newly diagnosed patients with MS could predict clinical outcome over a 10-year period. Methods: Patients with newly diagnosed MS underwent standardized clinical assessments at baseline and 5 and 10 years of follow-up. Expanded Disability Status Scale (EDSS) progression between assessments was defined as an increase in one point or more if <6 and 0.5 or more if ≥6. CSF obtained at baseline was analyzed for levels of NfL using enzyme-linked immunosorbent assay technology. Results: A total of 44 patients were included. In all, 35 patients (80%) had relapsing–remitting multiple sclerosis (RRMS). Patients who progressed in EDSS showed a trend for higher median baseline CSF-NfL levels than patients who did not progress after 5 years (947 ng/L vs 246 ng/L, p = 0.05), and although not statistically significant, after 10 years (708 ng/L vs 265 ng/L, p = 0.28). Patients who converted from RRMS to secondary-progressive multiple sclerosis (SPMS) at 5 years had a statistical significant higher median CSF level of NfL (2122 ng/L vs 246 ng/L, p = 0.01). Conclusion: CSF levels of NfL at the time of diagnosis seems to be an early predictive biomarker of long-term clinical outcome and conversion from RRMS to SPMS.

scholarly journals Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment

2017 ◽  
Vol 24 (4) ◽  
pp. 472-480 ◽  
Author(s):  
Cyra E Leurs ◽  
Petar Podlesniy ◽  
Ramon Trullas ◽  
Lisanne Balk ◽  
Martijn D Steenwijk ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Progression ◽  
Progressive Multiple Sclerosis ◽  
Neurologic Disease ◽  
Brain Volumes ◽  
Multiple Sclerosis Disease ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Digital Polymerase Chain Reaction

Background: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

Diffusion tensor imaging in multiple sclerosis: a tool for monitoring changes in normal-appearing white matter

2004 ◽  
Vol 10 (2) ◽  
pp. 188-196 ◽  
Author(s):  
Emmanuelle Cassol ◽  
Jean-Philippe Ranjeva ◽  
Danielle Ibarrola ◽  
Claude Mékies ◽  
Claude Manelfe ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Diffusion Tensor ◽  
Lesion Load ◽  
Normal Appearing White Matter ◽  
Relapsing Remitting ◽  
One Year ◽  
Diffusion Tensor Imaging Dti

Our objectives were to determine the reproducibility of diffusion tensor imaging (DTI) in volunteers and to evaluate the ability of the method to monitor longitudinal changes occurring in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS). DTI was performed three-mo nthly for one year in seven MS patients: three relapsing-remitting (RRMS), three secondary progressive (SPMS) and one relapsing SP. They were selected with a limited cerebral lesion load. Seven age- and sex-matched controls also underwent monthly examinations for three months. Diffusivity and anisotropy were quantified over the segmented whole supratentorial white matter, with the indices of trace (Tr) and fractional anisotropy (FA). Results obtained in volunteers show the reproducibility of the method. Patients had higher trace and lower anisotropy than matched controls (P B-0.0001). O ver the follow-up, both Tr and FA indicated a recovery after the acute phase in RRMS and a progressive shift towards abnormal values in SPMS. A lthough this result is not statistically significant, it suggests that DTI is sensitive to microscopic changes occurring in tissue of normal appearance in conventional images and could be useful for monitoring the course of the disease, even though it was unable to clearly distinguish between the various physiopathological processes involved.

Increased plasma 8,12-iso-iPF2alpha- VI levels in relapsing multiple sclerosis patients are not predictive of disease progression

2012 ◽  
Vol 18 (8) ◽  
pp. 1092-1098 ◽  
Author(s):  
CE Teunissen ◽  
M Sombekke ◽  
L van Winsen ◽  
J Killestein ◽  
F Barkhof ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Disease Progression ◽  
Plasma Levels ◽  
Lesion Load ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
In Cis

Background: Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression. Objective: To study whether plasma isoprostane levels were related to disease progression in MS. Methods: Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing–remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters. Results: Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7–77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9–82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1–49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS). Conclusion: These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.

Dalfampridine improves walking speed, walking endurance, and community participation in veterans with multiple sclerosis: a longitudinal cohort study

2013 ◽  
Vol 20 (6) ◽  
pp. 733-738 ◽  
Author(s):  
Michelle H Cameron ◽  
Mary Fitzpatrick ◽  
Shannon Overs ◽  
Charles Murchison ◽  
Jane Manning ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Community Participation ◽  
Walking Speed ◽  
Medical Center ◽  
Community Integration ◽  
Short Term ◽  
Relapsing Remitting ◽  
One Year ◽  
Walking Endurance

Background: In short-term trials, dalfampridine extended release (ER) improves walking in people with multiple sclerosis (MS). The tolerability and effects of dalfampridine-ER in clinical practice have not been reported. Objectives: The objective of this paper is to determine the clinical tolerability and effects of dalfampridine on walking and community participation. Methods: All patients at the Portland VA Medical Center prescribed dalfampridine-ER over one year completed the Timed 25-Foot Walk (T25FW), Multiple Sclerosis Walking Scale-12 (MSWS-12), Two-Minute Timed Walk (2MTW), and Community Integration Questionnaire (CIQ) at baseline and follow-up clinic visits. Ongoing use and measures over one year were analyzed. Results: A total of 39 patients (mean age 56.5 years, mean disease duration 19.5 years, 82% male, 38% relapsing–remitting MS, 62% progressive MS) were prescribed dalfampridine-ER. Twenty-four (62%) continued to take dalfampridine-ER. At initial follow-up, all measures improved significantly from baseline (T25FW: –2.7 s, p = 0.004; 2MTW: 41 feet (ft), p = 0.002; MSWS12: –11, p < 0.001; CIQ: 1.2, p = 0.003). At one year, walking endurance and self-perceived walking were still significantly improved (2MTW: 33 ft, p = 0.03; MSWS-12: 5.9, p = 0.007). Conclusions: Dalfampridine-ER was associated with short-term improvements in walking speed and community participation, and sustained improvements in walking endurance and self-perceived impact of MS on walking for one year. Our study supports the utility of this medication in late MS.

Effect of drugs in secondary disease progression in patients with multiple sclerosis

2004 ◽  
Vol 10 (3_suppl) ◽  
pp. S46-S55 ◽  
Author(s):  
Ludwig Kappos
Keyword(s):  
Multiple Sclerosis ◽  
Disease Progression ◽  
Progressive Multiple Sclerosis ◽  
Positive Effects ◽  
Secondary Progressive ◽  
The North ◽  
Disability Status ◽  
Relapsing Remitting ◽  
Effect Of Therapy ◽  
Almost All

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN b) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN b-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN b-1a) in MS (SPEC TRIMS), the North A merican Study of IFN b-1b in SPMS (NA SPMS), and the Internatio nal MS Secondary Progressive Avonex C linical Trial (IMPAC T). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN b has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly IV Ig were disappointing, positive effects on disease progression have been reported with the applicatio n of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.

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