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A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.

ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previously validated multiplexed 10-min, targeted proteomic assay to assess 54 candidate cerebrospinal fluid (CSF) biomarkers in two independent cohorts comprising individuals with neurodegenerative dementias and healthy controls. Individuals were classified as 'AD' or 'non-AD' on the basis of their CSF T-tau and amyloid A?1-42 profile measured using enzyme-linked immunosorbent assay; biomarkers of interest were compared using univariate and multivariate analyses. In all, 35/31 individuals in Cohort 1 and 46/36 in Cohort 2 fulfilled criteria for AD/non-AD profile CSF, respectively. After adjustment for multiple comparisons, five proteins were elevated significantly in AD CSF compared with non-AD CSF in both cohorts: malate dehydrogenase; total APOE; chitinase-3-like protein 1 (YKL-40); osteopontin and cystatin C. In an independent multivariate orthogonal projection to latent structures discriminant analysis (OPLS-DA), these proteins were also identified as major contributors to the separation between AD and non-AD in both cohorts. Independent of CSF A?1-42 and tau, a combination of these biomarkers differentiated AD and non-AD with an area under curve (AUC)=0.88. This targeted proteomic multiple reaction monitoring (MRM)-based assay can simultaneously and rapidly measure multiple candidate CSF biomarkers. Applying this technique to AD we demonstrate differences in proteins involved in glucose metabolism and neuroinflammation that collectively have potential clinical diagnostic utility.

SUBMITTER: Paterson RW

PROVIDER: S-EPMC5314115 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.

Paterson R W RW Heywood W E WE Heslegrave A J AJ Magdalinou N K NK Andreasson U U Sirka E E Bliss E E Slattery C F CF Toombs J J Svensson J J Johansson P P Fox N C NC Zetterberg H H Mills K K Schott J M JM

Translational psychiatry 20161115 11

Alzheimer's disease (AD) is the most common cause of dementia. Biomarkers are required to identify individuals in the preclinical phase, explain phenotypic diversity, measure progression and estimate prognosis. The development of assays to validate candidate biomarkers is costly and time-consuming. Targeted proteomics is an attractive means of quantifying novel proteins in cerebrospinal and other fluids, and has potential to help overcome this bottleneck in biomarker development. We used a previ ...[more]

PMID: 27845782

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Project description:Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (rSp205 = 0.67, rSp202 = 0.45) than Aβ-PET (rSp205 = 0.40, rSp202 = 0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P < 0.01), whereas p-tau202 only increased in Braak V-VI (P < 0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V-VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R2 = 69.7%; CSF p-tau202: R2 = 85.6%) Both biomarkers associated with brain atrophy measurements globally (rSp205 = - 0.36, rSp202 = - 0.33) and regionally, and correlated with cognition (rSp205 = - 0.38/- 0.40, rSp202 = - 0.20/- 0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials.

Project description:BackgroundUnderstanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.MethodsCross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [18F]-FDG, and [18F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.ResultsThe prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.ConclusionsThere are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.Trial registrationNCT02485730.

Dataset Information

A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.

Publications

A targeted proteomic multiplex CSF assay identifies increased malate dehydrogenase and other neurodegenerative biomarkers in individuals with Alzheimer's disease pathology.

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