Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia
Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progr...
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2024-12-01
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| author | Xavier Morató Raquel Puerta Amanda Cano Adelina Orellana Itziar de Rojas María Capdevila Laura Montrreal Maitée Rosende-Roca Pablo García-González Claudia Olivé Fernando García-Gutiérrez Josep Blázquez Andrea Miguel Raúl Núñez-Llaves Vanesa Pytel Montserrat Alegret María Victoria Fernández Marta Marquié Sergi Valero Jose Enrique Cavazos Santos Mañes Mercè Boada Alfredo Cabrera-Socorro Agustín Ruiz |
| author_facet | Xavier Morató Raquel Puerta Amanda Cano Adelina Orellana Itziar de Rojas María Capdevila Laura Montrreal Maitée Rosende-Roca Pablo García-González Claudia Olivé Fernando García-Gutiérrez Josep Blázquez Andrea Miguel Raúl Núñez-Llaves Vanesa Pytel Montserrat Alegret María Victoria Fernández Marta Marquié Sergi Valero Jose Enrique Cavazos Santos Mañes Mercè Boada Alfredo Cabrera-Socorro Agustín Ruiz |
| author_sort | Xavier Morató |
| collection | DOAJ |
| description | Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progression, remains inconclusive. Moreover, there is debate on whether inflammation has a protective or detrimental effect on disease onset and progression. Indeed, distinct immunological mechanisms may govern protective and damaging effects at early and late stages, respectively.This study aims to (i) identify inflammatory mediators demonstrating robust correlations between peripheral and central nervous system (CNS) compartments by means of plasma and CSF analysis, respectively, and (ii) assess their potential significance in the context of AD and disease progression from mild cognitive impairment (MCI) to dementia. To achieve this, we have examined the inflammatory profile of a well-defined subcohort comprising 485 individuals from the Ace Alzheimer Center Barcelona (ACE). Employing a hierarchical clustering approach, we thoroughly evaluated the intercompartmental correlations of 63 distinct inflammation mediators, quantified in paired CSF and plasma samples, using advanced SOMAscan technology. Of the array of mediators investigated, only six mediators (CRP, IL1RAP, ILRL1, IL6RA, PDGFRB, and YKL-40) exhibited robust correlations between the central and peripheral compartments (proximity scores <400). To strengthen the validity of our findings, these identified mediators were subsequently validated in a second subcohort of individuals from ACE (n = 873). The observed plasma correlations across the entire cohort consistently have a Spearman rho value above 0.51 (n = 1,360, p < 1.77E-93).Of the high CSF-plasma correlated proteins, only soluble IL6RA (sIL6RA) displayed a statistically significant association with the conversion from MCI to dementia. This association remained robust even after applying a stringent Bonferroni correction (Cox proportional hazard ratio [HR] = 1.936 per standard deviation; p = 0.0018). This association retained its significance when accounting for various factors, including CSF amyloid (Aβ42) and Thr181-phosphorylated tau (p-tau) levels, age, sex, baseline Mini-Mental State Examination (MMSE) score, and potential sampling biases identified through principal component analysis (PCA) modeling. Furthermore, our study confirmed the association of both plasma and CSF levels of SPARC-related modular calcium-binding protein 1 (SMOC1) with amyloid and tau accumulation, indicating their role as early surrogate biomarkers for AD pathology. Despite the lack of a statistically significant correlation between SMOC1 levels in CSF and plasma, both acted as independent biomarkers of disease progression (HR > 1.3, p < 0.002).In conclusion, our study unveils that sIL6RA and SMOC1 are associated with MCI progression. The absence of correlations among inflammatory mediators between the central and peripheral compartments appears to be a common pattern, with only a few intriguing exceptions. |
| format | Article |
| id | doaj-art-cec0c618b8b14d4db849327800647c8b |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-cec0c618b8b14d4db849327800647c8b2024-12-02T05:06:44ZengElsevierBrain, Behavior, & Immunity - Health2666-35462024-12-0142100899Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementiaXavier Morató0Raquel Puerta1Amanda Cano2Adelina Orellana3Itziar de Rojas4María Capdevila5Laura Montrreal6Maitée Rosende-Roca7Pablo García-González8Claudia Olivé9Fernando García-Gutiérrez10Josep Blázquez11Andrea Miguel12Raúl Núñez-Llaves13Vanesa Pytel14Montserrat Alegret15María Victoria Fernández16Marta Marquié17Sergi Valero18Jose Enrique Cavazos19Santos Mañes20Mercè Boada21Alfredo Cabrera-Socorro22Agustín Ruiz23Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Universitat de Barcelona (UB), SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainSouth Texas Medical Science Training Program, University of Texas Health San Antonio, San Antonio, TX, USA; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USADepartment of Immunology and Oncology, Centro Nacional Biotecnología (CNB-CSIC), 28049, Madrid, SpainAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, SpainNeuroscience Therapeutic Area, Drug Discovery, Johnson & Johnson Innovative Medicine, USAAce Alzheimer Center Barcelona-Universitat Internacional de Catalunya, Barcelona, Spain; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA; Corresponding author. Ace Alzheimer Center Barcelona, Marquès de Sentmenat 57, 08039, Barcelona, Spain.Despite the central role attributed to neuroinflammation in the etiology and pathobiology of Alzheimer's disease (AD), the direct link between levels of inflammatory mediators in blood and cerebrospinal fluid (CSF) compartments, as well as their potential implications for AD diagnosis and progression, remains inconclusive. Moreover, there is debate on whether inflammation has a protective or detrimental effect on disease onset and progression. Indeed, distinct immunological mechanisms may govern protective and damaging effects at early and late stages, respectively.This study aims to (i) identify inflammatory mediators demonstrating robust correlations between peripheral and central nervous system (CNS) compartments by means of plasma and CSF analysis, respectively, and (ii) assess their potential significance in the context of AD and disease progression from mild cognitive impairment (MCI) to dementia. To achieve this, we have examined the inflammatory profile of a well-defined subcohort comprising 485 individuals from the Ace Alzheimer Center Barcelona (ACE). Employing a hierarchical clustering approach, we thoroughly evaluated the intercompartmental correlations of 63 distinct inflammation mediators, quantified in paired CSF and plasma samples, using advanced SOMAscan technology. Of the array of mediators investigated, only six mediators (CRP, IL1RAP, ILRL1, IL6RA, PDGFRB, and YKL-40) exhibited robust correlations between the central and peripheral compartments (proximity scores <400). To strengthen the validity of our findings, these identified mediators were subsequently validated in a second subcohort of individuals from ACE (n = 873). The observed plasma correlations across the entire cohort consistently have a Spearman rho value above 0.51 (n = 1,360, p < 1.77E-93).Of the high CSF-plasma correlated proteins, only soluble IL6RA (sIL6RA) displayed a statistically significant association with the conversion from MCI to dementia. This association remained robust even after applying a stringent Bonferroni correction (Cox proportional hazard ratio [HR] = 1.936 per standard deviation; p = 0.0018). This association retained its significance when accounting for various factors, including CSF amyloid (Aβ42) and Thr181-phosphorylated tau (p-tau) levels, age, sex, baseline Mini-Mental State Examination (MMSE) score, and potential sampling biases identified through principal component analysis (PCA) modeling. Furthermore, our study confirmed the association of both plasma and CSF levels of SPARC-related modular calcium-binding protein 1 (SMOC1) with amyloid and tau accumulation, indicating their role as early surrogate biomarkers for AD pathology. Despite the lack of a statistically significant correlation between SMOC1 levels in CSF and plasma, both acted as independent biomarkers of disease progression (HR > 1.3, p < 0.002).In conclusion, our study unveils that sIL6RA and SMOC1 are associated with MCI progression. The absence of correlations among inflammatory mediators between the central and peripheral compartments appears to be a common pattern, with only a few intriguing exceptions.http://www.sciencedirect.com/science/article/pii/S2666354624001777sIL6RASMOC1Alzheimer's diseaseInflammationMild cognitive impairmentDisease progression |
| spellingShingle | Xavier Morató Raquel Puerta Amanda Cano Adelina Orellana Itziar de Rojas María Capdevila Laura Montrreal Maitée Rosende-Roca Pablo García-González Claudia Olivé Fernando García-Gutiérrez Josep Blázquez Andrea Miguel Raúl Núñez-Llaves Vanesa Pytel Montserrat Alegret María Victoria Fernández Marta Marquié Sergi Valero Jose Enrique Cavazos Santos Mañes Mercè Boada Alfredo Cabrera-Socorro Agustín Ruiz Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia Brain, Behavior, & Immunity - Health sIL6RA SMOC1 Alzheimer's disease Inflammation Mild cognitive impairment Disease progression |
| title | Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia |
| title_full | Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia |
| title_fullStr | Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia |
| title_full_unstemmed | Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia |
| title_short | Associations of plasma SMOC1 and soluble IL6RA levels with the progression from mild cognitive impairment to dementia |
| title_sort | associations of plasma smoc1 and soluble il6ra levels with the progression from mild cognitive impairment to dementia |
| topic | sIL6RA SMOC1 Alzheimer's disease Inflammation Mild cognitive impairment Disease progression |
| url | http://www.sciencedirect.com/science/article/pii/S2666354624001777 |
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