Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

Puthenparampil, Marco; Tomas-Ojer, Paula; Hornemann, Thorsten; Lutterotti, Andreas; Jelčić, Ilijas; Ziegler, Mario; Hülsmeier, Andreas J.; Cruciani, Carolina; Faigle, Wolfgang; Martin, Roland; Sospedra, Mireia

doi:10.1212/nxi.0000000000000951

Cited by 20 publications

(19 citation statements)

References 29 publications

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“…Interestingly, we observed that the presence of monocytes/macrophages was associated with conversion to CDMS. This underlines findings on Chitinase 3like 1 (CHI3L1), a glycoprotein secreted by macrophages (41), which was determined as a biomarker in MS (42)(43)(44) and which was also associated with the conversion from CIS to CDMS (45).…”

Section: Discussionsupporting

confidence: 76%

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

et al. 2021

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BackgroundReports on typical routine cerebrospinal fluid (CSF) findings are outdated owing to novel reference limits (RL) and revised diagnostic criteria of Multiple Sclerosis (MS).ObjectiveTo assess routine CSF parameters in MS patients and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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Section: Discussionsupporting

confidence: 76%

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

et al. 2021

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“…Albumin quotients and CSF-specific oligoclonal bands were analyzed as previously reported. 20 Intrathecal Ig synthesis (Ig[loc]) was calculated according to Reiber. 21 …”

Section: Methodsmentioning

confidence: 99%

“…Ex vivo immunophenotyping of intrathecal and paired circulating lymphocytes was performed as previously reported 20 , 22 in a subcohort of 66 patients with MS (eTable 1, links.lww.com/NXI/A590 ). We added SPHERO AccuCount Particles (Spherotech, Inc., Lake Forest, IL) to count absolute numbers following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

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T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis

Cruciani

Puthenparampil

Tomas-Ojer

et al. 2021

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesEncouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management.MethodsThe proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features.ResultsBy testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-l-fucose synthase peptides, we identified GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7− CD45RA−) CD27− Th1 CD4+ cell subset in GDP-l-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture.DiscussionOur observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.

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“… 4 , 5 , 7 , 28 Acute BBB disruption (CSF/serum albumin quotient) in patients with MS is known to correlate with CNS inflammation injury and was recently linked to increased intrathecal neurofilament light chain, chitinase 3-like 1, metalloproteinase 2, and interleukin-6 levels. 29 , 30 However, although levels of fibrinogen in CSF correlate with levels of acute (or past) BBB dysfunction, they do not necessarily reflect the extent of fibrinogenic pathway activation, e.g., processing of fibrinogen into fibrin, which effectively exerts proinflammatory effects. 5 By contrast, D-dimer in CSF is not only a substrate passing the BBB but also a product of the coagulation cascade.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis

Schaller‐Paule

Yalachkov

Steinmetz

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesProteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.MethodsPatients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.ResultsOf 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.DiscussionD-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.Classification of EvidenceThis study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.

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Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS

Cited by 20 publications

References 29 publications

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

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

T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis

Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis

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