Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis

Objective: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing–remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS. Methods: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years. Results: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 – 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 – 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 – 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 – 20.83); p = 0.05). Conclusions: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.

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Cerebrospinal fluid neurofilament tracks fMRI correlates of attention at the first attack of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514546789 ◽

2014 ◽

Vol 21 (4) ◽

pp. 396-401 ◽

Cited By ~ 14

Author(s):

C Tortorella ◽

V Direnzo ◽

P Taurisano ◽

R Romano ◽

M Ruggieri ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Attentional Control ◽

Repeated Measures ◽

Imaging Data ◽

Neurofilament Light Chain ◽

Recruitment Pattern ◽

Neurofilament Light ◽

Random Effects Models ◽

In Cis

Background: Identifying markers of cognitive dysfunction in multiple sclerosis (MS) is extremely challenging since it means supplying potential biomarkers for neuroprotective therapeutic strategies. Objective: The aim of this study is to investigate the relationship between fMRI correlates of attention performance and cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels in patients with clinically isolated syndrome (CIS) suggestive of MS. Methods: Twenty-one untreated, cognitively preserved CIS patients underwent BOLD-fMRI while performing the Variable Attentional Control (VAC) task, a cognitive paradigm requiring increasing levels of attentional control processing. CSF NFL was assessed by ELISA technique. SPM8 random-effects models were used for statistical analyses of fMRI data ( p<0.05 corrected). Results: Repeated-measures ANOVA on imaging data showed an interaction between attentional control load and NFL levels in the right putamen. At the high level of attentional control demand CIS patients with “low NFL levels” showed greater activity in the putamen compared with subjects with “high NFL levels” ( p=0.001). These results are independent of cognitive impairment index. Conclusions: Our findings suggest a relationship between CSF NFL levels and load-dependent failure of putaminal recruitment pattern during sustained attention in CIS and suggest a role of CSF NFL as a marker of subclinical abnormality of cognitive pathway recruitment in CIS.

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Neuronal and glial CSF biomarkers in multiple sclerosis: a systematic review and meta-analysis

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0145 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Sara Momtazmanesh ◽

Parnian Shobeiri ◽

Amene Saghazadeh ◽

Charlotte E. Teunissen ◽

Joachim Burman ◽

...

Keyword(s):

Multiple Sclerosis ◽

Meta Analysis ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Meta Regression ◽

Meta Analyses ◽

Astroglial Activation ◽

In Cis ◽

T Tau

Abstract Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.

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Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/135248506ms1263oa ◽

2006 ◽

Vol 12 (2) ◽

pp. 143-148 ◽

Cited By ~ 72

Author(s):

J Brettschneider ◽

A Petzold ◽

A Junker ◽

H Tumani

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Clinically Isolated Syndrome ◽

Axonal Damage ◽

T2 Lesions ◽

Definite Multiple Sclerosis ◽

Relapsing Remitting ◽

Csf Levels ◽

Magnetic Resonance Imaging Mri ◽

In Cis

Clinically isolated syndrome (CIS) represents the earliest phase of multiple sclerosis (MS). This study tested whether biomarkers for axonal degeneration can improve upon sensitivity and specificity of magnetic resonance imaging (MRI) parameters in predicting conversion from CIS to MS. Patients with CIS ( n=52), relapsing-remitting MS (RRMS, n=38) and age-matched controls ( n=25) were included. Cerebrospinal fluid (CSF) levels of tau and neurofilaments (NfHSMI35) were measured using ELISA. The MRI T2-lesion load and the Expanded Disability Status Scale (EDSS) were recorded. CSF tau and NfHSMI35 were elevated in CIS compared to controls (p<0.05). RRMS patients with acute relapse had higher NfHSMI35 levels than stable patients. Tau and NfHSMI35 levels correlated with EDSS in CIS and RRMS. In RRMS, the number of T2-lesions correlated with tau levels ( R=0.53, P=0.01). The sensitivity predicting the conversion from CIS to MS was higher for the combination of CSF markers (either tau or NfHSMI35 elevated) than for MRI (40 versus 34%), but could be further increased to 60% if CSF and MRI criteria were combined. Similarly, the combination of tau and NfHSMI35 showed higher specificity (94%) than MRI (82%). Tau and NfHSMI35 are valuable biomarkers for axonal damage in the CIS patients. Predicting conversion from CIS to MS can be improved if CSF markers are combined with MRI.

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Cerebrospinal fluid neurofilament light chain in multiple sclerosis and its subtypes: a meta-analysis of case–control studies

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-319190 ◽

2019 ◽

Vol 90 (9) ◽

pp. 1059-1067 ◽

Cited By ~ 14

Author(s):

Sarah-Jane Martin ◽

Sarah McGlasson ◽

David Hunt ◽

James Overell

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Light Chain ◽

Meta Analysis ◽

Grey Literature ◽

Case Control ◽

Disease Stage ◽

Case Control Studies ◽

Neurofilament Light Chain ◽

Neurofilament Light

ObjectiveNeurofilament is a biomarker of axonal injury proposed as a useful adjunct in the monitoring of patients with multiple sclerosis (MS). We conducted a systematic review and meta-analysis of case–control studies that have measured neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of people with MS (pwMS), in order to determine whether, and to what degree, CSF NfL levels differentiate MS from controls, or the subtypes or stages of MS from each other.MethodsGuidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses were followed. Electronic databases were searched for published and ‘grey’ literature, with 151 hits. Of 51 full articles screened, 20 were included in qualitative analysis, and 14 in meta-analysis.ResultsCSF NfL was higher in 746 pwMS than 435 (healthy and disease) controls, with a moderate effect size of 0.61 (p < 0.00001). Mean CSF NfL levels were significantly higher in 176 pwMS with relapsing disease than 92 with progressive disease (2124.8 ng/L, SD 3348.9 vs 1121.4 ng/L, SD 947.7, p = 0.0108). CSF NfL in 138 pwMS in relapse (irrespective of MS subtype) was double that seen in 268 pwMS in remission (3080.6 ng/L, SD 4715.9 vs 1541.7 ng/L, SD 2406.5, p < 0.0001).ConclusionsCSF NfL correlates with MS activity throughout the course of MS, reflecting the axonal damage in pwMS. Relapse is more strongly associated with elevated CSF NfL levels than the development of progression, and NfL may be most useful as a marker of disease ‘activity’ rather than as a marker of disability or disease stage.

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Should We Use Clinical Tools to Identify Disease Progression?

Frontiers in Neurology ◽

10.3389/fneur.2020.628542 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hernan Inojosa ◽

Undine Proschmann ◽

Katja Akgün ◽

Tjalf Ziemssen

Keyword(s):

Multiple Sclerosis ◽

Clinical Markers ◽

Disability Progression ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Secondary Progressive ◽

Disability Status ◽

Relapsing Remitting ◽

Clinical Tools

The presence of disability progression in multiple sclerosis (MS) is an important hallmark for MS patients in the course of their disease. The transition from relapsing remitting (RRMS) to secondary progressive forms of the disease (SPMS) represents a significant change in their quality of life and perception of the disease. It could also be a therapeutic key for opportunities, where approaches different from those in the initial phases of the disease can be adopted. The characterization of structural biomarkers (e.g., magnetic resonance imaging or neurofilament light chain) has been proposed to differentiate between both phenotypes. However, there is no definite threshold between them. Whether the risk of clinical progression can be predicted by structural markers at early disease phases is still a focus of clinical research. However, several theories and pathological evidence suggest that both disease phenotypes are part of a continuum with common pathophysiological mechanisms. In this case, the clinical evaluation of the patients would play a preponderant role above destruction biomarkers for the early identification of disability progression and SPMS. For this purpose, the use of clinical tools beyond the Expanded Disability Status Scale (EDSS) should be considered. Besides established functional tests such as the Multiple Sclerosis Functional Composite (MSFC), patient's neurological history or digital resources may help neurologists in the decision-taking. In this article, we discuss arguments for the use of clinical markers in the detection of secondary progressive MS and the characterization of progressive disease activity.

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Cerebrospinal fluid transferrin levels are reduced in patients with early multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514530020 ◽

2014 ◽

Vol 20 (12) ◽

pp. 1569-1577 ◽

Cited By ~ 8

Author(s):

M Khalil ◽

B Riedlbauer ◽

C Langkammer ◽

C Enzinger ◽

S Ropele ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Iron Metabolism ◽

Iron Homeostasis ◽

Biochemical Study ◽

Iron Deposition ◽

Lesion Load ◽

Transporter Protein ◽

In Cis ◽

The Brain

Background: Previous magnetic resonance imaging (MRI) studies have demonstrated increased iron deposition in the basal ganglia of multiple sclerosis (MS) patients. However, it is not clear whether these alterations are associated with changes of iron metabolism in body fluids. Objectives: The purpose of this study was to investigate if iron metabolism markers in cerebrospinal fluid (CSF) and serum of clinically isolated syndrome (CIS) and MS patients differ from controls and how they relate to clinical and imaging parameters. Methods: We analysed serum ferritin, transferrin and soluble transferrin-receptor and CSF ferritin and transferrin by nephelometry in non-anaemic CIS ( n=60) or early MS ( n=14) patients and 68 controls. In CIS/MS we additionally assessed the T2 lesion load. Results: CSF transferrin was significantly decreased in CIS/MS compared to controls ( p<0.001), while no significant differences were seen in serum. Higher CSF transferrin levels correlated with lower physical disability scores ( r= −0.3, p<0.05). CSF transferrin levels did not correlate with other clinical data and the T2 lesion load. Conclusion: Our biochemical study provides evidence that altered iron homeostasis within the brain occurs in the very early phases of the disease, and suggests that the transporter protein transferrin may play a role in the increased iron deposition known to occur in the brain of MS patients.

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CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-322286 ◽

2020 ◽

Vol 91 (6) ◽

pp. 605-611

Author(s):

Iris Kleerekooper ◽

Megan K Herbert ◽

H Bea Kuiperij ◽

Douglas Kazutoshi Sato ◽

Kazuo Fujihara ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Glutamine Synthetase ◽

Glial Fibrillary Acidic Protein ◽

Optic Neuritis ◽

Disease Activity ◽

Similar Pattern ◽

Myelin Oligodendrocyte Glycoprotein ◽

Neuromyelitis Optica Spectrum Disorder ◽

Csf Levels

ObjectiveTo explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis.MethodsCerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37).ResultsGFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased.ConclusionsOur data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.

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Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21176298 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6298

Author(s):

Petar Podlesniy ◽

Franc Llorens ◽

Margalida Puigròs ◽

Nuria Serra ◽

Diego Sepúlveda-Falla ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Mitochondrial Dna ◽

Clinical Diagnosis ◽

Neuronal Damage ◽

Clinical Signs ◽

Amyloid Peptide ◽

Slow Progression ◽

Csf Levels ◽

T Tau ◽

The Relationship

Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.

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Inflammation-related plasma and CSF biomarkers for multiple sclerosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912839117 ◽

2020 ◽

Vol 117 (23) ◽

pp. 12952-12960 ◽

Cited By ~ 6

Author(s):

Jesse Huang ◽

Mohsen Khademi ◽

Lars Fugger ◽

Örjan Lindhe ◽

Lenka Novakova ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Diseases ◽

Area Under The Curve ◽

Csf Biomarkers ◽

Healthy Controls ◽

Protein Biomarkers ◽

Neurofilament Light Chain ◽

Diagnostic Efficacy ◽

Neurofilament Light

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease (PCSF< 4 × 10−5,Pplasma< 4 × 10−5), and plasma CCL20 was associated with disease severity (P= 4 × 10−5), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.

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Protein biomarkers for multiple sclerosis: semi-quantitative analysis of cerebrospinal fluid candidate protein biomarkers in different forms of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458511433303 ◽

2012 ◽

Vol 18 (8) ◽

pp. 1081-1091 ◽

Cited By ~ 31

Author(s):

Timucin Avsar ◽

Didem Korkmaz ◽

Melih Tütüncü ◽

N Onat Demirci ◽

Sabahattin Saip ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Process ◽

Underlying Disease ◽

Protein Biomarkers ◽

Serum Samples ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Protein Levels ◽

Clinical Subtype

Background: The complex pathogenesis of multiple sclerosis, combined with an unpredictable prognosis, requires identification of disease-specific diagnostic and prognostic biomarkers. Objective: To determine whether inflammatory proteins, such as neurofilament light chain, myelin oligodendrocyte glycoprotein and myelin basic protein, and neurodegenerative proteins, such as tau and glial fibrillary acidic protein, can serve as biomarkers for predicting the clinical subtype and prognosis of MS. Methods: Cerebrospinal fluid and serum samples were collected from patients with a diagnosis of clinically isolated syndrome ( n = 46), relapsing–remitting MS ( n = 67) or primary-progressive MS ( n = 22) along with controls having other non-inflammatory neurological disease ( n = 22). Western blot analyses were performed for the listed proteins. Protein levels were compared among different clinical subtypes using one-way analysis of variance analysis. The k-nearest neighbour algorithm was further used to assess the predictive use of these proteins for clinical subtype classification. Results: The results showed that each of tau, GFAP, MOG and NFL protein concentrations differed significantly ( p < 0.001) in multiple sclerosis clinical subtypes compared with the controls. Levels of the proteins also differed between the multiple sclerosis clinical subtypes, which may be associated with the underlying disease process. Classification studies revealed that these proteins might be useful for identifying multiple sclerosis clinical subtypes. Conclusions: We showed that select biomarkers may have potential in identifying multiple sclerosis clinical subtypes. We also showed that the predictive value of the prognosis increased when using a combination of the proteins versus using them individually.

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