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Multiple system atrophy – Are cerebrospinal fluid cytokines reliable potential diagnostic marker?

Published:September 17, 2019DOI:https://doi.org/10.1016/j.parkreldis.2019.09.019
      The lack of a reliable marker that might help clinicians diagnose multiple system atrophy (MSA) early and distinguish it from other α-synucleinopathies, especially Parkinson's disease (PD), resulted in a much-needed search for diagnostic and prognostic biomarkers. Body fluids, including blood plasma and cerebrospinal fluid (CSF), are the main focus regarding biomarker search, given that they are easily accessible. The attention has turned to α-synuclein (AS) levels in plasma and CSF, however with no conclusive outcome. CSF levels of AS are diminished in PD compared to controls and Alzheimer's disease (AD) [
      • Gao L.
      • Tang H.
      • Nie K.
      • Wang L.
      • Zhao J.
      • Gan R.
      • et al.
      Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis.
      ], yet no differentiation between PD and other synucleinopathies is possible to date [
      • Aerts M.B.
      • Esselink R.A.
      • Abdo W.F.
      • Bloem B.R.
      • Verbeek M.M.
      CSF α-synuclein does not differentiate between parkinsonian disorders.
      ]. Furthermore, the light chain of neurofilament (NfL), a marker of neurodegenerative processes and coenzyme Q10 levels in CSF and peripheral blood were examined. NfL was significantly increased in MSA compared to PD in blood and CSF samples [
      • Marques T.M.
      • van Rumund A.
      • Oeckl P.
      • Kuiperij H.B.
      • Esselink R.A.J.
      • Bloem B.R.
      • et al.
      Serum NFL discriminates Parkinson disease from atypical parkinsonisms.
      ,
      • Hansson O.
      • Janelidze S.
      • Hall S.
      • Magdalinou N.
      • Lees A.J.
      • Andreasson U.
      • et al.
      Blood-based NfL: a biomarker for differential diagnosis of parkinsonian disorder.
      ,
      • Hu X.
      • Yang Y.
      • Gong D.
      Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson's disease: a meta-analysis.
      ], whereas coenzyme Q10 was significantly reduced in MSA compared to PD and control CSF [
      • Compta Y.
      • Giraldo D.M.
      • Muñoz E.
      • Antonelli F.
      • Fernández M.
      • Bravo P.
      • et al.
      Cerebrospinal fluid levels of coenzyme Q10 are reduced in multiple system atrophy.
      ]. Both markers show potential as probable diagnostic markers, however further validation studies have to be performed to confirm their sensitivity as diagnostic tool. Moreover, various studies investigating inflammatory markers in peripheral blood and CSF were conducted, given that α-synucleinopathies show prominent inflammation. A significant increase of pro-inflammatory and microglial-related cytokines in MSA compared to PD was reported in two separate studies using CSF samples, including C reactive protein (CRP) [
      • Hall S.
      • Janelidze S.
      • Surova Y.
      • Widner H.
      • Zetterberg H.
      • Hansson O.
      Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders.
      ,
      • Starhof C.
      • Winge K.
      • Heegaard N.H.H.
      • Skogstrand K.
      • Friis S.
      • Hejl A.
      Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes.
      ], tumor necrosis factor α (TNF-α), Interleukin-1β (IL-1β), and Il-6 [
      • Starhof C.
      • Winge K.
      • Heegaard N.H.H.
      • Skogstrand K.
      • Friis S.
      • Hejl A.
      Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes.
      ] as well as Chitinase-3-like protein 1 (CHI3-L1, YKL-40) [
      • Hall S.
      • Janelidze S.
      • Surova Y.
      • Widner H.
      • Zetterberg H.
      • Hansson O.
      Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders.
      ]. In the current issue of Parkinsonism & Related Disorders, Compta and colleagues present the measurement of 38 cytokine levels in CSF of MSA patients compared to PD patients and controls [
      • Compta Y.
      • Dias S.P.
      • Giraldo D.M.
      • Perez-Soriano A.
      • Munoz E.
      • Saura J.
      • et al.
      Cerebrospinal fluid cytokines in multiple system atrophy: a cross-sectional Catalan MSA registry study.
      ]. The sample size of MSA patients is high compared to other studies and MSA-P (parkinsonian variant of MSA) and MSA-C (cerebellar variant of MSA) were separately examined. Furthermore, the number of cytokines measured was comparatively high. Yet, CRP and YKL-40 levels in CSF have not been investigated in the current study. In future investigations, it might be of interest if the MSA patient cohort of this study shows a similar increase of CRP and YKL-40 amount compared to PD patients as shown in the aforementioned studies [
      • Hall S.
      • Janelidze S.
      • Surova Y.
      • Widner H.
      • Zetterberg H.
      • Hansson O.
      Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders.
      ,
      • Starhof C.
      • Winge K.
      • Heegaard N.H.H.
      • Skogstrand K.
      • Friis S.
      • Hejl A.
      Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes.
      ]. Another strength of the study is clearly the exclusion of patients treated with non-steroidal anti-inflammatory drugs (NSAIDs), which was not executed in other studies, though the treatment with NSAIDs could interfere with the release of cytokines into CSF or peripheral blood. Three cytokines were significantly elevated in MSA compared to PD CSF (monocyte chemotactic protein 3 (MCP-3), macrophage derived chemokine (MDC) and IL-12p40); MCP-3 and MDC showed the highest levels in MSA, also when comparing MSA-P to PD and therefore may be useful as MSA-P predictors [
      • Compta Y.
      • Dias S.P.
      • Giraldo D.M.
      • Perez-Soriano A.
      • Munoz E.
      • Saura J.
      • et al.
      Cerebrospinal fluid cytokines in multiple system atrophy: a cross-sectional Catalan MSA registry study.
      ]. Since there is often a misdiagnosis of early MSA-P as PD, a marker to distinguish these two disorders at an early time-point would be an enormous help for clinical diagnosis. However, validation studies with a larger cohort of patients would be necessary to confirm MCP-3 and MDC as markers for MSA-P.
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