Dataset Information

Phosphorylated tau-A?42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.

ABSTRACT: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and A?42 was used as a continuous trait in these analyses.The ptau181-A?42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low A?42) compared with elderly control subjects with no pathology (low ptau181, high A?42). The FABP-A?42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-A?42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD.Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.

SUBMITTER: Harari O

PROVIDER: S-EPMC4007142 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.

Harari Oscar O Cruchaga Carlos C Kauwe John S K JS Ainscough Benjamin J BJ Bales Kelly K Pickering Eve H EH Bertelsen Sarah S Fagan Anne M AM Holtzman David M DM Morris John C JC Goate Alison M AM

Biological psychiatry 20140119 9

<h4>Background</h4>Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.<h4>Methods</h4>A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Dis ...[more]

PMID: 24548642

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Project description:Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/A?1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/A?1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/A?1-42 ratios in the patients in our cohort.We found that high ptau/A?1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/A?1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.

Project description:BACKGROUND:A relationship quantitative trait locus exists when the correlation between multiple traits varies by genotype for that locus. Relationship quantitative trait loci (rQTL) are often involved in gene-by-gene (G×G) interactions or gene-by-environmental interactions, making them a powerful tool for detecting G×G. METHODS:We performed genome-wide association studies to identify rQTL between tau and A?42 and ptau and A?42 with over 3000 individuals using age, gender, series, APOE ?2, APOE ?4, and two principal components for population structure as covariates. Each significant rQTL was separately screened for interactions with other loci for each trait in the rQTL model. Parametric bootstrapping was used to assess significance. RESULTS:We found four significant tau/A?42 rQTL from three unique locations and six ptau/A?42 rQTL from five unique locations. G×G screens with these rQTL produced four significant G×G interactions (one A?42, two ptau, and one tau) with four rQTL where each second locus was from a unique location. On follow-up, rs1036819 and rs74025622 were associated with Alzheimer's disease (AD) case/control status; rs15205 and rs79099429 were associated with rate of decline. CONCLUSIONS:The two most significant rQTL (rs8027714 and rs1036819) for ptau/A?42 are on different chromosomes and both are strong hits for pelvic organ prolapse. While diseases of the nervous system can cause pelvic organ prolapse, it is unlikely related to the ptau/A?42 relationship but may suggest that these two loci share a pathway. In addition to a ptau/A?42 rQTL and association with AD case/control status, rs1036819 is a strong rQTL for case/control status/A?42 and for tau/A?42. It resides in the ZFAT gene, which is related to autoimmune thyroid disease. For tau, rs9817620 interacts with the tau/A?42 rQTL rs74025622. It is in the CHL1 gene, which is a neural cell adhesion molecule and may be involved in signal transduction pathways. CHL1 is related to BACE1, which is a ?-secretase enzyme that initiates production of the ?-amyloid peptide involved in AD and is a primary drug target. Overall, there are numerous loci that affect the relationship between these important AD endophenotypes and some are due to interactions with other loci. Some affect the risk of AD and/or rate of progression.

Dataset Information

Phosphorylated tau-A?42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.

Publications

Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.

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