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Clinically accurate diagnosis of Alzheimer's disease via multiplexed sensing of core biomarkers in human plasma.

ABSTRACT: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting one in ten people aged over 65 years. Despite the severity of the disease, early diagnosis of AD is still challenging due to the low accuracy or high cost of neuropsychological tests and neuroimaging. Here we report clinically accurate and ultrasensitive detection of multiple AD core biomarkers (t-tau, p-tau₁₈₁, A?₄₂, and A?₄₀) in human plasma using densely aligned carbon nanotubes (CNTs). The closely packed and unidirectionally aligned CNT sensor array exhibits high precision, sensitivity, and accuracy, evidenced by a low coefficient of variation (<6%), a femtomolar-level limit of detection, and a high degree of recovery (>93.0%). By measuring the levels of t-tau/A?₄₂, p-tau₁₈₁/A?₄₂, and A?₄₂/A?₄₀ in clinical blood samples, the sensor array successfully discriminates the clinically diagnosed AD patients from healthy controls with an average sensitivity of 90.0%, a selectivity of 90.0%, and an average accuracy of 88.6%.

SUBMITTER: Kim K

PROVIDER: S-EPMC6949261 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Clinically accurate diagnosis of Alzheimer's disease via multiplexed sensing of core biomarkers in human plasma.

Kim Kayoung K Kim Min-Ji MJ Kim Da Won DW Kim Su Yeong SY Park Steve S Park Chan Beum CB

Nature communications 20200108 1

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting one in ten people aged over 65 years. Despite the severity of the disease, early diagnosis of AD is still challenging due to the low accuracy or high cost of neuropsychological tests and neuroimaging. Here we report clinically accurate and ultrasensitive detection of multiple AD core biomarkers (t-tau, p-tau181, Aβ42, and Aβ40) in human plasma using densely aligned carbon nanotub ...[more]

PMID: 31913282

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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.

Project description:Plasma biomarkers for Alzheimer's disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. To define Alzheimer's disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer's disease instead of the risk of dementia. In a cohort of Alzheimer's disease cases [n = 1439, mean age 68 years (standard deviation = 8.2)] and screened controls [n = 508, mean age 82 years (standard deviation = 6.8)], we measured plasma concentrations of the 40 and 42 amino acid-long amyloid-β (Aβ) fragments (Aβ40 and Aβ42, respectively), tau phosphorylated at amino acid 181 (P-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) using state-of-the-art Single molecule array (Simoa) technology. We tested the relationships between the biomarkers and Alzheimer's disease genetic risk, age at onset and disease duration. We also conducted a genome-wide association study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer's disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10-5). Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011-4.78 × 10-8), except NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer's disease.

Project description:BackgroundLipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer's disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer's disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer's disease, differential diagnoses, other biomarkers, and clinical data.MethodsFor this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer's disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer's disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28).ResultsPlasma Lipocalin-2 was significantly lower in Alzheimer's disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer's pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer's disease and healthy controls were 0.783 (95%CI: 0.712-0.855) in the study cohort and 0.766 (95%CI: 0.627-0.905) in the validation cohort. The area under the curve for Alzheimer's disease versus vascular dementia was 0.778 (95%CI: 0.667-0.890) in the study cohort. In Alzheimer's disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer's disease (p = 0.013).ConclusionsPlasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer's disease and seems to be independent from currently employed biomarkers.

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Clinically accurate diagnosis of Alzheimer's disease via multiplexed sensing of core biomarkers in human plasma.

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Clinically accurate diagnosis of Alzheimer's disease via multiplexed sensing of core biomarkers in human plasma.

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