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Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

ABSTRACT: OBJECTIVE:To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration. METHODS:A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR-SB change over two years (?3 points). RESULTS:Cerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL-10 pathway dysregulation. The ROC curves for ?3 points change in CDR-SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different. INTERPRETATION:Baseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL-10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI-AD. CCL2's utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline.

SUBMITTER: Pillai JA

PROVIDER: S-EPMC7359114 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

Pillai Jagan A JA Bena James J Bebek Gurkan G Bekris Lynn M LM Bonner-Jackson Aaron A Kou Lei L Pai Akshay A Sørensen Lauge L Neilsen Mads M Rao Stephen M SM Chance Mark M Lamb Bruce T BT Leverenz James B JB

Annals of clinical and translational neurology 20200707 7

<h4>Objective</h4>To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration.<h4>Methods</h4>A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predic ...[more]

PMID: 32634865

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Project description:BackgroundIn Alzheimer's disease, amyloid- β (A β) peptides aggregate in the lowering CSF amyloid levels - a key pathological hallmark of the disease. However, lowered CSF amyloid levels may also be present in cognitively unimpaired elderly individuals. Therefore, it is of great value to explain the variance in disease progression among patients with A β pathology.MethodsA cohort of n=2293 participants, of whom n=749 were A β positive, was selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to study heterogeneity in disease progression for individuals with A β pathology. The analysis used baseline clinical variables including demographics, genetic markers, and neuropsychological data to predict how the cognitive ability and AD diagnosis of subjects progressed using statistical models and machine learning. Due to the relatively low prevalence of A β pathology, models fit only to A β-positive subjects were compared to models fit to an extended cohort including subjects without established A β pathology, adjusting for covariate differences between the cohorts.ResultsA β pathology status was determined based on the A β42/A β40 ratio. The best predictive model of change in cognitive test scores for A β-positive subjects at the 2-year follow-up achieved an R2 score of 0.388 while the best model predicting adverse changes in diagnosis achieved a weighted F1 score of 0.791. A β-positive subjects declined faster on average than those without A β pathology, but the specific level of CSF A β was not predictive of progression rate. When predicting cognitive score change 4 years after baseline, the best model achieved an R2 score of 0.325 and it was found that fitting models to the extended cohort improved performance. Moreover, using all clinical variables outperformed the best model based only on a suite of cognitive test scores which achieved an R2 score of 0.228.ConclusionOur analysis shows that CSF levels of A β are not strong predictors of the rate of cognitive decline in A β-positive subjects when adjusting for other variables. Baseline assessments of cognitive function accounts for the majority of variance explained in the prediction of 2-year decline but is insufficient for achieving optimal results in longer-term predictions. Predicting changes both in cognitive test scores and in diagnosis provides multiple perspectives of the progression of potential AD subjects.

Project description:BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. Studies on MCI progression are important for Alzheimer's disease (AD) prevention. 18F fluoro-deoxy-glucose positron emission tomography (FDG-PET) has been proven to be a powerful tool for measuring cerebral glucose metabolism. In this study, we proposed a classification framework for MCI prediction with both baseline and multiple follow-up FDG-PET scans as well as cognitive scores of 33 progressive MCI (pMCI) patients and 46 stable MCI (sMCI) patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodFirst, PET images were normalized using the Yakushev normalization procedure and registered to the Brainnetome Atlas (BNA). The average metabolic intensities of brain regions were defined as static features. Dynamic features were the intensity variation between baseline and the other three time points and change ratios with the intensity obtained at baseline considered as reference. Mini-mental State Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive section (ADAS-cog) scores of each time point were collected as cognitive features. And F-score was applied for feature selection. Finally, support vector machine (SVM) with radial basis function (RBF) kernel was used for the three above features.ResultsDynamic features showed the best classification performance in accuracy of 88.61% than static features (accuracy of 78.48%). And the combination of cognitive features and dynamic features improved the classification performance in specificity of 95.65% and Area Under Curve (AUC) of 0.9308.ConclusionOur results reported that dynamic features are more representative in longitudinal research for MCI prediction work. And dynamic features and cognitive scores complementarily enhance the classification performance in specificity and AUC. These findings may predict the disease course and clinical changes in individuals with mild cognitive impairment.

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Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

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Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

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