Decreased levels of alpha-synuclein in cerebrospinal fluid of patients with clinically isolated syndrome and multiple sclerosis

Abstract Eighty-five percent of multiple sclerosis cases begin with a discrete attack termed clinically isolated syndrome, but 37% of clinically isolated syndrome patients do not experience a relapse within 20 years of onset. Thus, the identification of biomarkers able to differentiate between individuals who are most likely to have a second clinical attack from those who remain in the clinically isolated syndrome stage is essential to apply a personalised medicine approach. We sought to identify biomarkers from biochemical, metabolic, and proteomic screens that predict clinically defined conversion from clinically isolated syndrome to multiple sclerosis and generate a multi-omics-based algorithm with higher prognostic accuracy than any currently available test. An integrative multi-variate approach was applied to the analysis of cerebrospinal fluid samples taken from 54 individuals at the point of clinically isolated syndrome with 2–10 years of subsequent follow-up enabling stratification into clinical converters and non-converters. Leukocyte counts were significantly elevated at onset in the clinical converters and predict occurrence of a second attack with 70% accuracy. Myo-inositol levels were significantly increased in clinical converters while glucose levels were decreased, predicting transition to multiple sclerosis with accuracies of 72% and 63%, respectively. Proteomics analysis identified 89 novel gene products related to conversion. The identified biochemical and protein biomarkers were combined to produce an algorithm with predictive accuracy of 83% for the transition to clinically defined multiple sclerosis, outperforming any individual biomarker in isolation including oligoclonal bands. The identified protein biomarkers are consistent with an exaggerated immune response, perturbed energy metabolism, and multiple sclerosis pathology in the clinical converter group. The new biomarkers presented provide novel insight into the molecular pathways promoting disease while the multi-omics algorithm provides a means to more accurately predict whether an individual is likely to convert to clinically defined multiple sclerosis.

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Proteomic analysis of cerebrospinal fluid for relapsing-remitting multiple sclerosis and clinically isolated syndrome

Biomedical Reports ◽

10.3892/br.2016.668 ◽

2016 ◽

Vol 5 (1) ◽

pp. 35-40 ◽

Cited By ~ 7

Author(s):

ZBYŠEK PAVELEK ◽

OLDŘICH VYŠATA ◽

VOJTĚCH TAMBOR ◽

KRISTÝNA PIMKOVÁ ◽

DAI LONG VU ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Proteomic Analysis ◽

Clinically Isolated Syndrome ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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Intrathecal B-Cell Clonal Expansion, an Early Sign of Humoral Immunity, in the Cerebrospinal Fluid of Patients with Clinically Isolated Syndrome Suggestive of Multiple Sclerosis

Laboratory Investigation ◽

10.1097/01.lab.0000077008.24259.0d ◽

2003 ◽

Vol 83 (7) ◽

pp. 1081-1088 ◽

Cited By ~ 74

Author(s):

Yufen Qin ◽

Pierre Duquette ◽

Yiping Zhang ◽

Michael Olek ◽

Reng-Rong Da ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

B Cell ◽

Humoral Immunity ◽

Clonal Expansion ◽

Clinically Isolated Syndrome ◽

Early Sign ◽

Cell Clonal Expansion

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Cerebrospinal fluid mitochondrial DNA levels in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458518786055 ◽

2018 ◽

Vol 25 (11) ◽

pp. 1535-1538 ◽

Cited By ~ 1

Author(s):

Nicolas Fissolo ◽

Laura Cervera-Carles ◽

Luisa María Villar Guimerans ◽

Alberto Lleó ◽

Jordi Clarimón ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Mitochondrial Dna ◽

Clinically Isolated Syndrome ◽

Chain Reaction ◽

Pathological Conditions ◽

Polymerase Chain ◽

Digital Polymerase Chain Reaction

The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice.

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Cerebrospinal Fluid Findings in 541 Patients With Clinically Isolated Syndrome and Multiple Sclerosis: A Monocentric Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.675307 ◽

2021 ◽

Vol 12 ◽

Author(s):

Klaus Berek ◽

Gabriel Bsteh ◽

Michael Auer ◽

Franziska Di Pauli ◽

Anne Zinganell ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

White Blood Cells ◽

Clinically Isolated Syndrome ◽

The Novel ◽

Barrier Dysfunction ◽

Csf Pleocytosis ◽

Oligoclonal Igg ◽

Wbc Count ◽

Oligoclonal Igg Bands

BackgroundReports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS).ObjectiveTo assess routine CSF parameters in MS patients and the frequency of pathologic findings by applying novel RL.MethodsCSF white blood cells (WBC), CSF total protein (CSF-TP), CSF/serum albumin quotient (Qalb), intrathecal synthesis of immunoglobulins (Ig) A, M and G, oligoclonal IgG bands (OCB) were determined in patients with clinically isolated syndrome (CIS) and MS.ResultsOf 541 patients 54% showed CSF pleocytosis with a WBC count up to 40/μl. CSF cytology revealed lymphocytes, monocytes and neutrophils in 99%, 41% and 9% of patients. CSF-TP and Qalb were increased in 19% and 7% applying age-corrected RL as opposed to 34% and 26% with conventional RL. Quantitative intrathecal IgG, IgA and IgM synthesis were present in 65%, 14% and 21%; OCB in 95% of patients. WBC were higher in relapsing than progressive MS and predicted, together with monocytes, the conversion from CIS to clinically definite MS. Intrathecal IgG fraction was highest in secondary progressive MS.ConclusionsCSF profile in MS varies across disease courses. Blood-CSF-barrier dysfunction and intrathecal IgA/IgM synthesis are less frequent when the novel RL are applied.

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The Importance and Utility of Cerebrospinal Fluid Evaluation in the Diagnosis of Central Demyelinating Diseases

10.1093/med/9780199341016.003.0008 ◽

2016 ◽

Cited By ~ 1

Author(s):

Mark S. Freedman ◽

Mohammad Abdoli

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Prognostic Value ◽

Clinically Isolated Syndrome ◽

Demyelinating Diseases ◽

Response To Treatment ◽

Disease Subtype ◽

Csf Analysis ◽

Diagnostic And Prognostic Value ◽

Csf Findings

This chapter aims to highlight the diagnostic and prognostic value of cerebrospinal fluid (CSF) findings in multiple sclerosis with a special consideration of distinguishing it from neuromyelitis optica (NMO) and NMO spectrum disorder. Interpretation of CSF findings in daily clinical practice in patients with MS is thoroughly explained. New advances in CSF analysis and recently identified biomarkers may be helpful for diagnosis, help elucidate disease subtype and activity, or aid in prognosis and monitoring of the response to treatment. Characteristics of CSF changes in different subtypes of multiple sclerosis, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS) are discussed. CSF findings in NMO spectrum disease as a diagnostic and differentiating marker are explained separately.

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