Dataset Information

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.

ABSTRACT:

Introduction

This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau₁₈₁ /Aβ₄₂ status (+/-) and explored their value in predicting cognition.

Methods

CSF biomarkers amyloid beta (Aβ)₄₂ , pTau₁₈₁ , tTau, Aβ₄₀ , neurogranin, neurofilament light (NfL), α-synuclein, glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), S100 calcium binding protein B (S100B), and interleukin 6 (IL6), were measured with the NeuroToolKit (NTK) for 720 adults ages 40 to 93 years (mean age = 63.9 years, standard deviation [SD] = 9.0; 50 with dementia; 54 with mild cognitive impairment [MCI], 616 unimpaired).

Results

Neurodegeneration and glial activation biomarkers were elevated in pTau₁₈₁ /Aβ₄₂ + MCI/dementia participants relative to all pTau₁₈₁ /Aβ₄₂ - participants. Neurodegeneration biomarkers increased with clinical severity among pTau₁₈₁ /Aβ₄₂ + participants and predicted worse cognitive performance. Glial activation biomarkers were unrelated to cognitive performance.

Discussion

The NTK contains promising markers that improve the pathophysiological characterization of AD. Neurodegeneration biomarkers beyond tTau improved statistical prediction of cognition and disease stages.

SUBMITTER: Van Hulle C

PROVIDER: S-EPMC8016695 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.

Van Hulle Carol C Jonaitis Erin M EM Betthauser Tobey J TJ Batrla Richard R Wild Norbert N Kollmorgen Gwendlyn G Andreasson Ulf U Okonkwo Ozioma O Bendlin Barbara B BB Asthana Sanjay S Carlsson Cynthia M CM Johnson Sterling C SC Zetterberg Henrik H Blennow Kaj K

Alzheimer's & dementia : the journal of the Alzheimer's Association 20201218 3

<h4>Introduction</h4>This study examines the utility of a multipanel of cerebrospinal fluid (CSF) biomarkers complementing Alzheimer's disease (AD) biomarkers in a clinical research sample. We compared biomarkers across groups defined by clinical diagnosis and pTau<sub>181</sub> /Aβ<sub>42</sub> status (+/-) and explored their value in predicting cognition.<h4>Methods</h4>CSF biomarkers amyloid beta (Aβ)<sub>42</sub> , pTau<sub>181</sub> , tTau, Aβ<sub>40</sub> , neurogranin, neurofilament light ...[more]

PMID: 33336877

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Project description:BackgroundClusterin is a multifunctional protein, which is associated with the pathogenesis and the development of Alzheimer's disease (AD). Compared with normal controls, inconsistent results have yielded in previous studies for concentration of cerebrospinal fluid (CSF) clusterin in AD patients. We explored CSF clusterin levels in different pathological processes of AD.MethodsFollowing the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria, we employed on the levels of CSF Aβ42(A), phosphorylated-Tau (T), and total-tau (N). Based on previously published cutoffs and the close correlation between CSF p-tau and t-tau, 276 participants from the publicly available ADNI database with CSF biomarkers were divided into four groups: A-(TN)- (normal Aβ42 and normal p-tau and t-tau; n = 50), A+(TN)- (abnormal Aβ42 and normal p-tau and t-tau; n = 39), A+(TN) + (abnormal Aβ42 and abnormal p-tau or t-tau; n = 147), A-(TN) + (normal Aβ42 and abnormal p-tau or t-tau; n = 40). To assess CSF clusterin levels in AD continuum, intergroup differences in four groups were compared. Pairwise comparisons were conducted as appropriate followed by Bonferroni post hoc analyses. To further study the relationships between CSF clusterin levels and AD core pathological biomarkers, we employed multiple linear regression method in subgroups.ResultsCompared with the A-(TN)- group, CSF clusterin levels were decreased in A+ (TN)- group (P = 0.002 after Bonferroni correction), but increased in the A+(TN) + group and the A-(TN) + group (both P < 0.001 after Bonferroni correction). Moreover, we found CSF clusterin levels are positively associated with CSF Aβ42 (β = 0.040, P < 0. 001), CSF p-tau (β = 0.325, P < 0.001) and CSF t-tau (β = 0.346, P < 0.001).ConclusionsOur results indicated that there are differences levels of CSF clusterin in different stages of AD pathology. The CSF clusterin level decreased at the early stage are related to abnormal Aβ pathology; and the increased levels are associated with tau pathology and neurodegeneration.

Project description:BackgroundClinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ?10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (A?42, tau, p-tau181).Methods and findingsUsing a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-?, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/A?42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, A?42, and age.Conclusions/significanceUsing a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential.

Dataset Information

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.

Introduction

Methods

Results

Discussion

Publications

An examination of a novel multipanel of CSF biomarkers in the Alzheimer's disease clinical and pathological continuum.

Similar Datasets

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