Publications by authors named "Luisa Agnello"

52 Publications

Biomarkers for Prognosis and Treatment Response in COVID-19 Patients.

Ann Lab Med 2021 Nov;41(6):540-548

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences, and Advanced Diagnostics, University of Palermo, Palermo, Italy.

During a severe infection such as coronavirus disease 2019 (COVID-19), the level of almost all analytes can change, presenting a correlation with disease severity and survival; however, a biomarker cannot be translated into clinical practice for treatment guidance until it is proven to have a significant impact. Several studies have documented the association between COVID-19 severity and circulating levels of C-reactive protein (CRP) and interleukin-6, and the accuracy of the CRP level in predicting treatment responses has been evaluated. Moreover, promising findings on prothrombin and D-dimer have been reported. However, the clinical usefulness of these biomarkers in COVID-19 is far from proven. The burst of data generation during this pandemic has led to the publication of numerous studies with several notable drawbacks, weakening the strength of their findings. We provide an overview of the key findings of studies on biomarkers for the prognosis and treatment response in COVID-19 patients. We also highlight the main drawbacks of these studies that have limited the clinical use of these biomarkers.
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http://dx.doi.org/10.3343/alm.2021.41.6.540DOI Listing
November 2021

Preliminary reference intervals of Glycated Albumin in healthy Caucasian pregnant women.

Clin Chim Acta 2021 Aug 12;519:227-230. Epub 2021 May 12.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy. Electronic address:

Background And Aims: Glycated albumin (GA) could represent a useful biomarker in pregnant women for diagnosing and monitoring gestational diabetes mellitus (GDM). The establishment of reference intervals (RI) is mandatory before assessing its clinical usefulness. The RIs of GA in healthy pregnant women are not well defined. The aim of the current study was to establish the RI in a cohort consisting of Caucasian pregnant women without overt diabetes mellitus or gestational diabetes mellitus.

Methods: The study included 183 healthy pregnant women. GA was measured on plasma by an enzymatic method (quantILab Glycated Albumin, IL Werfen, Germany). The RI was calculated by the non-parametric and robust methods.

Results: The RI of GA in the whole population was 10.16% (90%CI 9.60-10.70) and 15.44% (90%CI 14.90-16.90). GA levels decreased during pregnancy, with lower levels in the third trimester: 10.11 (90%CI 9.48-10.79) and 15.72 (90%CI 15.15-16.27) in the first trimester, 10.49 (90%CI 10.05-10.96) and 15.49 (90%CI 15.05-15.92) in the second trimester, 9.84 (90%CI 9.50-10.22) and 14.57 (90%CI 14.11-15.01) in the third trimester. Finally, a weak negative correlation was found between GA levels and body mass index.

Conclusion: This is the first study establishing the RIs of GA in Caucasian healthy pregnant women.
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http://dx.doi.org/10.1016/j.cca.2021.05.009DOI Listing
August 2021

Clinical Utility of Midregional Proadrenomedullin in Patients with COVID-19.

Lab Med 2021 Apr 30. Epub 2021 Apr 30.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Objective: The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19.

Methods: We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated.

Results: Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001).

Conclusion: We found that MR-proADM could represent a prognostic biomarker of COVID-19.
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http://dx.doi.org/10.1093/labmed/lmab032DOI Listing
April 2021

A new tool for sepsis screening in the Emergency Department.

Clin Chem Lab Med 2021 Apr 13. Epub 2021 Apr 13.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Objectives: In this study, we developed and evaluated the diagnostic accuracy of the Sepsis Index for early sepsis screening in the Emergency Department (ED).

Methods: Sepsis Index is based on the combination of monocyte distribution width (MDW) and mean monocyte volume (MMV). Sepsis Index≥1 was selected to define sepsis. We tested its diagnostic accuracy in an ED population stratified in four groups: controls, Systemic Inflammatory Response Syndrome (SIRS), infection, and sepsis, according to Sepsis-2 criteria.

Results: Patients with sepsis displayed higher median Sepsis Index value than patients without sepsis. At the receiver operating characterictis (ROC) curve analysis for the prediction of sepsis, the area under the curve (AUC) of MDW and Sepsis Index were similar: 0.966 (95%CI 0.947-0.984), and 0.964 (95%CI 0.942-0.985), respectively. Sepsis Index showed increased specificity than MDW (94.7 vs. 90.6%), without any decrease in sensitivity (92.0%). Additionally, LR+ increased from 9.8 (MDW) to 17.4 (Sepsis Index), without any substantial change in LR- (respectively 0.09 vs. 0.08). Finally, PPV increased from 0.286 (MDW) to 0.420 (Sepsis Index).

Conclusions: Sepsis Index improves the diagnostic accuracy of MDW alone for sepsis screening.
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http://dx.doi.org/10.1515/cclm-2021-0208DOI Listing
April 2021

FOXP3 and GATA3 Polymorphisms, Vitamin D3 and Multiple Sclerosis.

Brain Sci 2021 Mar 25;11(4). Epub 2021 Mar 25.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, 90127 Palermo, Italy.

Background: Regulatory T cells (Tregs) alterations have been implicated in the pathogenesis of Multiple Sclerosis (MS). Recently, a crucial role of the X-Linked Forkhead Box P3 (FoxP3) for the development and the stability of Tregs has emerged, and FOXP3 gene polymorphisms have been associated with the susceptibility to autoimmune diseases. The expression of Foxp3 in Tregs is regulated by the transcription factor GATA binding-protein 3 (GATA3) and vitamin D. The aim of this retrospective case-control study was to investigate the potential association between FOXP3 and GATA3 genetic variants, Vitamin D, and MS risk.

Methods: We analyzed two polymorphisms in the FOXP3 gene (rs3761547 and rs3761548) and a polymorphism in the GATA3 gene (rs3824662) in 106 MS patients and 113 healthy controls. Serum 25(OH)D3 was also measured in all participants.

Results: No statistically significant genotypic and allelic differences were found in the distribution of FOXP3 rs3761547 and rs3761548, or GATA3 rs3824662 in the MS patients, compared with controls. Patients that were homozygous for rs3761547 had lower 25(OH)D3 levels.

Conclusions: Our findings did not show any association among FOXP3 and GATA3 SNPs, vitamin D, and MS susceptibility.
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http://dx.doi.org/10.3390/brainsci11040415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066599PMC
March 2021

The Role of Vitamin D as a Biomarker in Alzheimer's Disease.

Brain Sci 2021 Mar 6;11(3). Epub 2021 Mar 6.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy.

Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D's eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.
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http://dx.doi.org/10.3390/brainsci11030334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000099PMC
March 2021

COVID-19 and Alzheimer's Disease.

Brain Sci 2021 Feb 27;11(3). Epub 2021 Feb 27.

Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, University of Palermo, 90127 Palermo, Italy.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a neurotropic virus with a high neuroinvasive potential. Indeed, more than one-third of patients develop neurological symptoms, including confusion, headache, and hypogeusia/ageusia. However, long-term neurological consequences have received little interest compared to respiratory, cardiovascular, and renal manifestations. Several mechanisms have been proposed to explain the potential SARS-CoV-2 neurological injury that could lead to the development of neurodegenerative diseases, including Alzheimer's Disease (AD). A mutualistic relationship between AD and COVID-19 seems to exist. On the one hand, COVID-19 patients seem to be more prone to developing AD. On the other hand, AD patients could be more susceptible to severe COVID-19. In this review, we sought to provide an overview on the relationship between AD and COVID-19, focusing on the potential role of biomarkers, which could represent precious tool for early identification of COVID-19 patients at high risk of developing AD.
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http://dx.doi.org/10.3390/brainsci11030305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997244PMC
February 2021

Prognostic Role of CSF β-amyloid 1-42/1-40 Ratio in Patients Affected by Amyotrophic Lateral Sclerosis.

Brain Sci 2021 Feb 27;11(3). Epub 2021 Feb 27.

Unit of Neurology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90129, Palermo, Italy.

The involvement of β-amyloid (Aβ) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aβ accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aβ 1-42 and Aβ 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aβ 1-40 and Aβ 1-42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a significant correlation of the Aβ 42/40 ratio with age at onset and Mini Mental State Examination (MMSE) scores. No significant correlation of Aβ 1-42 or Aβ 42/40 ratios to the rate of progression of the disease were found. Furthermore, when we stratified patients according to Aβ 1-42 concentration and the Aβ 42/40 ratio, we found that patients with a lower Aβ 42/40 ratio showed a shorter survival. Our results support the hypothesis that Aβ 1-42 could be involved in some pathogenic mechanism of ALS and we suggest the Aβ 42/40 ratio as a potential prognostic biomarker.
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http://dx.doi.org/10.3390/brainsci11030302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997395PMC
February 2021

Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis.

Eur J Neurol 2021 Jun 19;28(6):1868-1875. Epub 2021 Mar 19.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Background And Purpose: To test the hypothesis that total tau (tTau), tau phosphorylated at threonine 181 (pTau) and pTau/tTau ratio in the cerebrospinal fluid (CSF) are diagnostic and prognostic biomarkers of amyotrophic lateral sclerosis (ALS), we performed a retrospective observational study in a large cohort of ALS patients and controls.

Methods: We enrolled 196 ALS patients and 91 controls, who included patients with ALS-mimicking diseases and those with non-neurodegenerative diseases. All patients underwent lumbar puncture for CSF analysis at the time of the diagnostic evaluation or to first referral. We measured tTau and pTau levels in the CSF by chemiluminescence enzyme immunoassay.

Results: Patients with ALS showed significantly higher levels of CSF tTau and a lower pTau/tTau ratio than controls (tTau: 245 vs. 146 pg/ml; p < 0.001; pTau/tTau ratio: 0.12 vs. 0.18; p < 0.001, respectively). No differences in pTau levels were detected. Receiver-operating characteristic curve analysis showed a good diagnostic accuracy of tTau and pTau/tTau ratio (tTau: area under the curve [AUC] 0.685, 95% confidence interval [CI] 0.616-0.754, p = 0.039; pTau/tTau ratio: AUC 0.777, 95% CI 0.707-0.848, p < 0.001). Among ALS patients, increased tTau levels were associated with advanced age of onset, increased revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS) rate of progression, and spinal onset. Multivariate analysis showed that in ALS patients, this biomarker was an independent negative predictor of overall survival.

Conclusions: Our findings suggest that tTau and pTau/tTau ratio can be diagnostic biomarkers of ALS. In addition, CSF tTau level at diagnosis might play a relevant prognostic role in the disease.
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http://dx.doi.org/10.1111/ene.14789DOI Listing
June 2021

Validation of monocyte distribution width decisional cutoff for sepsis detection in the acute setting.

Int J Lab Hematol 2021 Feb 26. Epub 2021 Feb 26.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy.

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http://dx.doi.org/10.1111/ijlh.13496DOI Listing
February 2021

Vitamin D increases the production of IL-10 by regulatory T cells in patients with systemic sclerosis.

Clin Exp Rheumatol 2020 Nov-Dec;38(6):1276. Epub 2020 Dec 3.

Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, University of Palermo, Italy.

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December 2020

Recent Updates and Advances in the Use of Glycated Albumin for the Diagnosis and Monitoring of Diabetes and Renal, Cerebro- and Cardio-Metabolic Diseases.

J Clin Med 2020 Nov 11;9(11). Epub 2020 Nov 11.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, 90121 Palermo, Italy.

Diabetes mellitus is a heterogeneous and dysmetabolic chronic disease in which the laboratory plays a fundamental role, from diagnosis to monitoring therapy and studying complications. Early diagnosis and good glycemic control should start as early as possible to delay and prevent metabolic and cardio-vascular complications secondary to this disease. Glycated hemoglobin is currently used as the reference parameter. The accuracy of the glycated hemoglobin dosage may be compromised in subjects suffering from chronic renal failure and terminal nephropathy, affected by the reduction in the survival of erythrocytes, with consequent decrease in the time available for glucose to attach to the hemoglobin. In the presence of these renal comorbidities as well as hemoglobinopathies and pregnancy, glycated hemoglobin is not reliable. In such conditions, dosage of glycated albumin can help. Glycated albumin is not only useful for short-term diagnosis and monitoring but predicts the risk of diabetes, even in the presence of euglycemia. This protein is modified in subjects who do not yet have a glycemic alteration but, as a predictive factor, heralds the risk of diabetic disease. This review summarizes the importance of glycated albumin as a biomarker for predicting and stratifying the cardiovascular risk linked to multiorgan metabolic alterations.
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http://dx.doi.org/10.3390/jcm9113634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697299PMC
November 2020

Vitamin D and Genetic Susceptibility to Multiple Sclerosis.

Biochem Genet 2021 Feb 7;59(1):1-30. Epub 2020 Nov 7.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Via del Vespro, 129, CAP 90127, Palermo, Sicily, Italy.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS), resulting from the interaction among genetic, epigenetic, and environmental factors. Vitamin D is a secosteroid, and its circulating levels are influenced by environment and genetics. In the last decades, research data on the association between MS and vitamin D status led to hypothesize a possible role for hypovitaminosis D as a risk factor for MS. Some gene variants encoding proteins involved in vitamin D metabolism, transport, and function, which are responsible for vitamin D status alterations, have been related to MS susceptibility. This review explores the current literature on the influence of vitamin D-related genes in MS susceptibility, reporting all single-nucleotide polymorphisms (SNPs) investigated to date in 12 vitamin D pathway genes. Among all, the gene codifying vitamin D receptor (VDR) is the most studied. The association between VDR SNPs and MS risk has been reported by many Authors, with a few studies producing opposite results. Other vitamin D-related genes (including DHCR7/NADSYN1, CYP2R1, CYP27A1, CYP3A4, CYP27B1, CYP24A1, Megalin-DAB2-Cubilin, FGF-23, and Klotho) have been less investigated and achieved more conflicting evidence. Taken together, findings from the studies reviewed cannot clarify whether and to what extent vitamin D-related gene variants can influence MS risk.
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http://dx.doi.org/10.1007/s10528-020-10010-1DOI Listing
February 2021

Monocyte distribution width as a biomarker of sepsis in the intensive care unit: A pilot study.

Ann Clin Biochem 2021 01 16;58(1):70-73. Epub 2020 Nov 16.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Background: Monocyte distribution width has been recently proposed as a sepsis biomarker in the emergency department. The aim of this study was to assess the role of monocyte distribution width as a diagnostic biomarker of sepsis in the intensive care unit.

Methods: In this prospective observational study, we included all consecutive patients admitted to the intensive care unit of the University Hospital "P. Giaccone" of Palermo. Patients were classified into three groups according to Sepsis-3 criteria: (1) patients without sepsis; (2) patients developing sepsis during their hospital stay; (3) patients admitted with sepsis. Monocyte distribution width was measured at admission (groups 1, 2, 3) and daily until the developing of sepsis (group 2) or the end of hospitalization (group 1).

Results: Monocyte distribution width was significantly higher in group 3 than group 1 and group 2 (30.9 [25.6-36.0] vs. 20.3 [18.3-23.6] and 21.4 [19.4-25.2]). Among patients belonging to group 2, monocyte distribution width values, measured at the day when sepsis was clinically diagnosed, were significantly higher than those found at admission: 29.4 (26.7-36.0) vs. 21.4 (19.4-25.2),  = 0.001.

Conclusion: Monocyte distribution width could represent a reliable biomarker of sepsis in the intensive care unit.
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http://dx.doi.org/10.1177/0004563220970447DOI Listing
January 2021

Comparison of a rapid immunochromatographic test with a chemiluminescence immunoassay for detection of anti-SARS-CoV-2 IgM and IgG.

Biochem Med (Zagreb) 2020 Oct;30(3):030901

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Introduction: The 2019 Coronavirus disease (COVID-19) has been characterized as a pandemic, representing a serious global public health emergency. Serological tests have been proposed as reliable tools for detecting Coronavirus SARS-CoV-2 antibodies in infected patients, especially for surveillance or epidemiological purposes. The aim of this study is to evaluate the agreement between the IgM/IgG rapid assays, based on lateral flow immunochromatographic assay, and the fully automated 2019-nCoV IgM and IgG, based on chemiluminescence immunoassay.

Materials And Methods: SARS-CoV-2 antibodies were measured with the BIOSYNEX COVID-19 BSS IgM/IgG test (BIOSYNEX, Illkirch-Graffenstaden, France) and the MAGLUMI CLIA (IgM and IgG) (SNIBE - Shenzhen New Industries Biomedical Engineering, Shenzhen, China) in 70 serum samples from patients with PCR-confirmed diagnosis. The strength of the agreement of the two methods was calculated by using the Cohen Kappa index.

Results: The results showed a good grade of concordance between the two immunoassays with a Cohen's kappa coefficient of 0.71 (95%CI: 0.54-0.87) for IgG SARS-CoV-2 antibodies and 0.70 (95%CI: 0.53-0.87) for IgM SARS-CoV-2 antibodies. In addition, the rapid assays BIOSYNEX COVID-19 BSS for detecting SARS-CoV-2 antibodies showed a positive likelihood ratio (LR) of 10.63 (95%CI: 2.79-40.57) for IgG and a LR of 6.79 (95%CI: 2.93-15.69) for IgM.

Conclusion: Our results suggest that the immunochromatographic rapid IgM/IgG test and the chemiluminescence IgM and IgG immunoassay have a good degree of concordance, suggesting that both could be considered as useful tools for epidemiologic surveillance.
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http://dx.doi.org/10.11613/BM.2020.030901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528641PMC
October 2020

Neurogranin as a Novel Biomarker in Alzheimer's Disease.

Lab Med 2021 Mar;52(2):188-196

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Background: In this study, we investigated the possible role of 2 novel biomarkers of synaptic damage, namely, neurogranin and α-synuclein, in Alzheimer disease (AD).

Methods: The study was performed in a cohort consisting of patients with AD and those without AD, including individuals with other neurological diseases. Cerebrospinal fluid (CSF) neurogranin and α-synuclein levels were measured by sensitive enzyme-linked immunosorbent assays (ELISAs).

Results: We found significantly increased levels of CSF neurogranin and α-synuclein in patients with AD than those without AD. Neurogranin was correlated with total tau (tTau) and phosphorylated tau (pTau), as well as with cognitive decline, in patients with AD. Receiver operating characteristic (ROC) curve analysis showed good diagnostic accuracy of neurogranin for AD at a cutoff point of 306 pg per mL with an area under the curve (AUC) of 0.872 and sensitivity and specificity of 84.2% and 78%, respectively.

Conclusions: Our findings support the use of CSF neurogranin as a biomarker of synapsis damage in patients with AD.
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http://dx.doi.org/10.1093/labmed/lmaa062DOI Listing
March 2021

Reference interval of monocyte distribution width (MDW) in healthy blood donors.

Clin Chim Acta 2020 Nov 22;510:272-277. Epub 2020 Jul 22.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy; Department of Laboratory Medicine, University Hospital "P. Giaccone", Palermo, Italy. Electronic address:

Background: The aim of the study was to accurately establish the reference interval (RI) of monocyte distribution width (MDW) in healthy blood donors by the direct method using different statistical approaches.

Methods: MDW was measured in 486 subjects. RI of MDW was calculated by the non-parametric method, the robust method and, the Harrell-Davis bootstrap method and using different tests to identify potential outliers (Dixon-Reed and Tukey).

Results: Lower and upper reference limits of the RI calculated by the non-parametric method were, 16.22 (90%CI 15.78-16.47) - 23.15 (90%CI 22.80-24.10) (without outlier removal), and 16.44 (90%CI 16.21-16.67) - 22.99 (90%CI 22.33-23.22) (after outlier removal). The RIs based on the robust method were, respectively, 16.29-22.98 (without) and 16.50-22.67 (with outlier removal). Finally, the RIs calculated by the Harrell-Davis bootstrap method, without or after outlier removal, were 16.19-23.24 and 16.43-22.93. Thus, the RIs obtained by the three calculation methods were very similar. Additionally, no RI partition was done since no significant gender or age association was found.

Conclusions: Our results support the use of a unique RI of MDW, independently of sex and age.
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http://dx.doi.org/10.1016/j.cca.2020.07.036DOI Listing
November 2020

Monocyte distribution width (MDW) as a screening tool for sepsis in the Emergency Department.

Clin Chem Lab Med 2020 10;58(11):1951-1957

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy.

Objectives The diagnosis of sepsis in the Emergency Department (ED) is challenging and a reliable biomarker is needed. The current study aimed to evaluate the diagnostic accuracy of monocyte distribution width (MDW) for the early identification of sepsis in the ED. Methods We performed a large observational study including consecutive adult patients (≥18 years of age) presenting to the ED between September and November 2019, with an order for complete blood count (CBC) evaluation. A total of 2,215 patients were enrolled and classified based on Sepsis-2 criteria as the control group (1,855), infection group (172), Systemic Inflammatory Response Syndrome (SIRS) group (100), and sepsis group (88). Results MDW levels were higher in patients with sepsis than in all other groups (p<0.001). ROC curve analysis showed an optimal diagnostic accuracy of MDW for sepsis prediction at a cut-off point of 23.5, with an AUC of 0.964, sensitivity and specificity of 0.920 and 0.929, respectively. Conclusions Our findings encourage further investigation to validate the use of MDW as a screening tool for the early identification of patients at risk of sepsis in the ED.
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http://dx.doi.org/10.1515/cclm-2020-0417DOI Listing
October 2020

Biochemical biomarkers alterations in Coronavirus Disease 2019 (COVID-19).

Diagnosis (Berl) 2020 Nov;7(4):365-372

Department of Laboratory Medicine, AOUP "P. Giaccone", Palermo, Italy.

Coronavirus Disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory disease, which can evolve into multi-organ failure (MOF), leading to death. Several biochemical alterations have been described in COVID-19 patients. To date, many biomarkers reflecting the main pathophysiological characteristics of the disease have been identified and associated with the risk of developing severe disease. Lymphopenia represents the hallmark of the disease, and it can be detected since the early stage of infection. Increased levels of several inflammatory biomarkers, including c-reactive protein, have been found in COVID-19 patients and associated with an increased risk of severe disease, which is characterised by the so-called "cytokine storm". Also, the increase of cardiac and liver dysfunction biomarkers has been associated with poor outcome. In this review, we provide an overview of the main biochemical characteristics of COVID-19 and the associated biomarkers alterations.
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http://dx.doi.org/10.1515/dx-2020-0057DOI Listing
November 2020

Klotho and vitamin D in multiple sclerosis: an Italian study.

Arch Med Sci 2020 2;16(4):842-847. Epub 2019 Aug 2.

Department of Biomedicine, Neuroscience, and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine, and Laboratory Medicine, University of Palermo, Palermo, Italy.

Introduction: Low vitamin D levels have been recognised as an important risk factor for autoimmune diseases, including multiple sclerosis (MS). MS is a multifactorial disease, the pathogenesis of which contributes both to genetic and environmental factors. Polymorphisms in genes codifying molecules involved in vitamin D homeostasis have been associated with hypovitaminosis D. However, the influence of polymorphisms of Klotho, which codify a protein with a pivotal role in vitamin D metabolism, have never been investigated. The aim of this study was to evaluate the association among genetic variants of Klotho, namely rs1207568 and rs9536314, serum 25(OH)D levels, and multiple sclerosis (both risk and disease progression).

Material And Methods: 107 patients with MS and 133 healthy controls were enrolled in this study. Serum 25(OH)D levels and genotyping of Klotho SNPs were evaluated in all participants by high-performance liquid chromatography and real-time polymerase chain reaction, respectively.

Results: Allelic and genotypic frequencies did not differ between patients and controls. Concerning rs1207568, we found a trend toward lower serum 25(OH)D levels in MS patients with A allele (mutant), both in heterozygosis (AG) and in homozygosis (AA), in comparison to MS patients with G allele in homozygosis (GG) (AG + AA 20.5 ±6.3 µg/l; GG 22.5 ±7.5 µg/l, = 0.07).

Conclusions: Our findings did not identify a role of Klotho in the genetic susceptibility to MS.
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http://dx.doi.org/10.5114/aoms.2019.86969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286339PMC
August 2019

Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis.

Scand J Clin Lab Invest 2020 Jul 7;80(4):313-317. Epub 2020 Apr 7.

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

In the last decades, an important role of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) diagnosis has emerged. The evaluation of the triad consisting of 42 aminoacid-long amyloid-beta peptide (Aβ42), total Tau (tTau) and Tau phosphorylated at threonine 181 (pTau) have been recently integrated into the research diagnostic criteria of AD. For a long time, the enzyme-linked immunosorbent assay (ELISA) has represented the most commonly used method for the measurement of CSF biomarkers levels. This study aimed to assess the diagnostic accuracy of CSF biomarkers, namely Aβ42, tTau and pTau and their ratio, measured by fully automated CLEIA assay (Lumipulse). We included 96 patients clinically diagnosed as AD (48) and non-AD (48). All CSF biomarkers levels were measured on Lumipulse G1200 fully automated platform (Fujirebio Inc. Europe, Gent, Belgium). Aβ42 levels, 42/40 ratio, 42/tTau ratio, 42/PTau ratio were significantly reduced, and tTau and PTau levels were significantly increased in AD patients in comparison with non-AD patients. The receiving operator curve (ROC) analysis showed good diagnostic accuracy of all CSF biomarkers and their ratios for discriminating AD patients from non-AD patients, with 42/40 ratio having the best AUC (0.724, 95%CI 0.619-0.828;  < 0.001). Our findings support the use of CSF biomarkers measured by CLEIA method on a fully automated platform for AD diagnosis.
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http://dx.doi.org/10.1080/00365513.2020.1740939DOI Listing
July 2020

Presepsin and Midregional Proadrenomedullin in Pediatric Oncologic Patients with Febrile Neutropenia.

Lab Med 2020 Nov;51(6):585-591

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Objective: In this study, we investigated the roles of presepsin (PSP) and midregional proadrenomedullin (mr-proADM) in children with febrile neutropenia (FN) due to chemotherapy.

Methods: We assessed 36 FN episodes in 26 children. Patients were classified into bacteremia (B) and fever of unknown origin (FUO) groups. We evaluated PSP and mr-proADM at admission (T0), after 24/48 h (T1), and after 5 days (T2).

Results: PSP and mr-proADM levels were elevated at T0 and significantly decreased at T2. mr-proADM levels did not significantly differ between the B and FUO groups. PSP levels significantly differed between the B and FUO groups only at T1. Both PSP and mr-proADM levels at T0 were a predictor of length of hospital stay but not of the duration of fever. Finally, receiver operating characteristic curve analysis showed that PSP and mr-proADM had low diagnostic accuracy for blood culture positivity.

Conclusion: PSP and mr-proADM display poor clinical usefulness for FN in oncologic children.
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http://dx.doi.org/10.1093/labmed/lmaa011DOI Listing
November 2020

Clinical Use of κ Free Light Chains Index as a Screening Test for Multiple Sclerosis.

Lab Med 2020 Jul;51(4):402-407

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Italy.

Objective: To assess the usefulness of the κ free light chain index (κFLCi) as a screening test to identify patients with suspected MS.

Methods: The study included 56 patients with a request to test for oligoclonal bands (OCBs). OCBs were detected by isoelectric focusing, followed by immunofixation. Cerebrospinal fluid (CSF) and serum κFLC were measured by a turbidimetric assay. Also, the κFLC index (κFLCi) was calculated.

Results: CSF κFLC levels and κFLCi were significantly higher in patients with multiple sclerosis (MS) than in patients with other neurological diseases (NDs; P < .001 and P < .001, respectively). At the cutoff value of 2.9, the κFLCi detected MS with sensitivity of 97% and specificity of 65%. Overall, 92% patients with κFLCi of 2.9 or greater and who had tested positive for OCBs were diagnosed as having MS.

Conclusion: Our findings support the use of κFLCi as a screening test when MS is suspected, followed by OCB detection as a confirmatory test for the diagnosis of MS.
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http://dx.doi.org/10.1093/labmed/lmz073DOI Listing
July 2020

Aging and Neuroinflammatory Disorders: New Biomarkers and Therapeutic Targets.

Curr Pharm Des 2019 ;25(39):4168-4174

Department of Biomedicine, Neurosciences and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Palermo, Italy.

Chronic neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative age-associated disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, and dementia. In particular, persistent low-grade inflammation may disrupt the brain endothelial barrier and cause a significant increase of pro-inflammatory cytokines and immune cells into the cerebral tissue that, in turn, leads to microglia dysfunction and loss of neuroprotective properties. Nowadays, growing evidence highlights a strong association between persistent peripheral inflammation, as well as metabolic alterations, and neurodegenerative disorder susceptibility. The identification of common pathways involved in the development of these diseases, which modulate the signalling and immune response, is an important goal of ongoing research. The aim of this review is to elucidate which inflammation-related molecules are robustly associated with the risk of neurodegenerative diseases. Of note, peripheral biomarkers may represent direct measures of pathophysiologic processes common of aging and neuroinflammatory processes. In addition, molecular changes associated with the neurodegenerative process might be present many decades before the disease onset. Therefore, the identification of a comprehensive markers panel, closely related to neuroinflammation, could be helpful for the early diagnosis, and the identification of therapeutic targets to counteract the underlying chronic inflammatory processes.
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http://dx.doi.org/10.2174/1381612825666191112093034DOI Listing
July 2020

Vitamin D increases the production of IL-10 by regulatory T cells in patients with systemic sclerosis.

Clin Exp Rheumatol 2019 Jul-Aug;37 Suppl 119(4):76-81. Epub 2019 Oct 3.

Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, University of Palermo, Italy.

Objectives: Vitamin D status influences the risk to develop autoimmune diseases affecting the percentage and/or functions of regulatory T cells (Tregs). Since low levels of 25 (OH) D have been decreased in patients with systemic sclerosis (SSc), we aimed to study the effect of Vitamin D3 (cholecalciferol) supplementation on Tregs frequencies and functions.

Methods: Peripheral blood and sera samples were obtained from 45 SSc patients and controls (HC). A number of eighteen SSc patients had consumed Cholecalciferol (orally) at the dose of 25.000 UI/month for 6 months at the time of enrollment. 25(OH)D serum levels were measured and VDR polymorphisms, were genotyped by polymerase chain reaction (PCR). Tregs isolated from peripheral blood mononuclear cells were in vitro expanded and a suppression assay was performed. Flow cytometry analysis was then carried out. Finally, IL-10 production was assayed by ELISA.

Results: Low serum levels of 25(OH)D were detected in SSc patients. The percentage of Tregs in SSc patients was similar to controls, but, among SSc patients, it was higher in those patients taking cholecalciferol. Tregs capability to suppress T cell proliferation was impaired in SSc patients and not restored after in vitro pre-treatment with the active form of Vitamin D (1,25(OH)2D3); but at the same time the production of IL-10 was increased in treated samples obtained from patients. The lack of response of Tregs from SSc patients to 1,25(OH)2D3 treatment in vitro was not due to altered Vitamin D/VDR signalling.

Conclusions: Altogether, our results indicate that the increased production of IL-10 by 1,25(OH)2D3 -treated Tregs could provide a "suppressive" cytokine milieu able to modulate immune response but it is not sufficient to restore the immune suppressive functions of Tregs.
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October 2019

Standardized measurement of circulating vitamin D [25(OH)D] and its putative role as a serum biomarker in Alzheimer's disease and Parkinson's disease.

Clin Chim Acta 2019 Oct 19;497:82-87. Epub 2019 Jul 19.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, University of Palermo, Via del Vespro 129, 90141 Palermo, Italy; Department of Laboratory Medicine, University-Hospital, Via del Vespro 129, 90141 Palermo, Italy. Electronic address:

The current review provides an overview on the development of 25(OH)D measurement standardization tools over the last three decades and clarifies whether there is a role as a serum biomarker for vitamin D in neurological diseases. In the past, a lack of internationally recognized 25(OH)D reference measurement procedures and reference standard materials led to unstandardized serum total 25(OH)D results among research and clinical care laboratories. The vitamin D Standardization Program (VDSP) has been introduced in 2010 to address this problem, however, vitamin D External Quality Assessment Scheme (DEQAS) reports still show substantial sample- to- sample variability. Further, immunoassays, which are mainly used in clinical care laboratories, display analytical issues, including matrix-effects interferences, which cannot be overcome by the standardization process. Hence, liquid chromatography-tandem mass spectrometry (LC/MS-MS) methods should be used to measure 25(OH)D. Low vitamin D serum levels have been found in patients affected by Alzheimer's disease and Parkinson's disease, suggesting a role for vitamin D as a serum biomarker in these diseases. However, few studies reported 25(OH)D standardized results, thus, no clear evidence on the potential role of 25(OH)D serum levels in these diseases exists.
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http://dx.doi.org/10.1016/j.cca.2019.07.022DOI Listing
October 2019

Non-Skeletal Activities of Vitamin D: From Physiology to Brain Pathology.

Medicina (Kaunas) 2019 Jul 5;55(7). Epub 2019 Jul 5.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy.

Vitamin D is a secosteroid hormone regulating the expression of almost 900 genes, and it is involved in the regulation of calcium and phosphate metabolism, immune response, and brain development. Low blood vitamin D levels have been reported in patients affected by various diseases. Despite a large amount of literature data, there is uncertainty surrounding the role of vitamin D as a serum biomarker in Alzheimer's disease (AD) and Parkinson's disease (PD). Indeed, the lack of internationally recognized 25(OH)D reference measurement procedures and standard materials in the past led to unstandardized serum total 25(OH)D results among research and clinical care laboratories. Thus, most of the literature studies reported unstandardized data, which are of little use and make it difficult to draw conclusions of the role of vitamin D in AD and PD. This review summarizes the extra-skeletal actions of vitamin D, focusing its role in immunomodulation and brain function, and reports the issue of lacking standardized literature data concerning the usefulness of vitamin D as a biomarker in AD and PD.
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http://dx.doi.org/10.3390/medicina55070341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680897PMC
July 2019

Establishing the 99 percentile for high sensitivity cardiac troponin I in healthy blood donors from Southern Italy.

Biochem Med (Zagreb) 2019 Jun;29(2):020901

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy.

Introduction: The knowledge of high sensitivity cardiac troponin I (hsTnI) distribution in a reference population is mandatory for its introduction in clinical practice. The aim of this study was to define the Upper Reference Limit (URL) of hsTnI measured by Single Molecule Counting technology (SMC) in an accurately selected reference population.

Materials And Methods: In the study 1140 blood donors were included and selected on the basis of medical history and biomarkers. High sensitivity cardiac troponin I was measured by SMC technology (Clarity, Singulex, Alamed, USA). The 99th percentile was calculated by the non-parametric method according to the Clinical and Laboratory Standard Institute - CLSI C28-A3.

Results: The median age was 41 years (IQR: 28 - 50) and 69% were males. The overall 99th percentile was 5 ng/L (90% CI: 4.2 - 5.6). When considering sex-related differences, we found slight differences between the 99th percentile in males and females. Moreover, the 99th percentile trended with age, especially in females.

Conclusions: We defined the 99th percentile of hs-cTnI measured by SMC technology in a highly selected healthy population, with only minor differences between males and females. Our findings provide the basic criteria for the reliable interpretation of hsTnI concentrations measured by the SMC technology in clinical settings.
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http://dx.doi.org/10.11613/BM.2019.020901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559611PMC
June 2019

Reference interval by the indirect approach of serum thyrotropin (TSH) in a Mediterranean adult population and the association with age and gender.

Clin Chem Lab Med 2019 Sep;57(10):1587-1594

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy.

Background The serum concentration of thyrotropin (TSH) represents a first-line test in diagnostic algorithms. The estimation of TSH reference intervals (RIs) is still a matter of debate due to the high prevalence of subclinical disease making difficult the definition of truly healthy subjects. The aim of this study was to estimate TSH RIs in healthy subjects and to evaluate the effect of age and gender on TSH concentration. Methods Forty-four thousand one hundred and fifty-six TSH data were collected between July 2012 and April 2018 at the Department of Laboratory Medicine, University-Hospital, Palermo. Common and sex-specific RIs were estimated by Arzideh's indirect method after exclusion of individuals younger than 15 years, subjects with repeated TSH tests and with abnormal free thyroxine (fT4), free triiodothyronine (fT3) or anti-thyroid-peroxidase antibodies. The combined effect of age and gender on TSH values was evaluated. Results RIs estimated in the selected individuals (n = 22602) were, respectively, 0.18-3.54 mIU/L (general), 0.19-3.23 mIU/L (men) and 0.18-3.94 mIU/L (women). Women showed significantly higher median TSH than men (1.46 vs. 1.39 mIU/L; p < 0.0001). Both in men and in women, median TSH decreased along with age; however, although up to 60 years in both men and women showed similar values, afterwards women showed constantly higher TSH than men. Accordingly, statistical analysis showed a significant interaction between gender and age (p = 0.001), suggesting that the effect of age on TSH is different between genders. Conclusions Our findings suggest that the indirect method, with appropriate cleaning of data, could be useful to define TSH RIs.
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http://dx.doi.org/10.1515/cclm-2018-0957DOI Listing
September 2019

Cerebrospinal Fluid Analysis in Multiple Sclerosis Diagnosis: An Update.

Medicina (Kaunas) 2019 Jun 4;55(6). Epub 2019 Jun 4.

Institute of Clinical Biochemistry, Clinical Molecular Medicine and Laboratory Medicine, Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90100 Palermo, Italy.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with brain neurodegeneration. MS patients present heterogeneous clinical manifestations in which both genetic and environmental factors are involved. The diagnosis is very complex due to the high heterogeneity of the pathophysiology of the disease. The diagnostic criteria have been modified several times over the years. Basically, they include clinical symptoms, presence of typical lesions detected by magnetic resonance imaging (MRI), and laboratory findings. The analysis of cerebrospinal fluid (CSF) allows an evaluation of inflammatory processes circumscribed to the CNS and reflects changes in the immunological pattern due to the progression of the pathology, being fundamental in the diagnosis and monitoring of MS. The detection of the oligoclonal bands (OCBs) in both CSF and serum is recognized as the "gold standard" for laboratory diagnosis of MS, though presents analytical limitations. Indeed, current protocols for OCBs assay are time-consuming and require an operator-dependent interpretation. In recent years, the quantification of free light chain (FLC) in CSF has emerged to assist clinicians in the diagnosis of MS. This article reviews the current knowledge on CSF biomarkers used in the diagnosis of MS, in particular on the validated assays and on the alternative biomarkers of intrathecal synthesis.
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http://dx.doi.org/10.3390/medicina55060245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630948PMC
June 2019