Phosphorylated Tau-A尾₄₂ Ratio as a Continuous Trait for Biomarker Discovery for Early-Stage Alzheimer鈥檚 Disease in Multiplex Immunoassay Panels of Cerebrospinal Fluid

详细信息    查看全文

• 作者：Oscar Harari^a ; Carlos Cruchaga^a ; ^g ; John S.K. Kauweⁱ ; Benjamin J. Ainscough^h ; Kelly Bales^j ; Eve H. Pickering^j ; Sarah Bertelsen^a ; Anne M. Fagan^b ; ^f ; ^g ; David M. Holtzman^b ; ^e ; ^f ; ^g ; John C. Morris^b ; ^c ; ^f ; ^g ; Alison M. Goate^a ; ^b ; ^d ; ^f ; ^g ; ^{goatea@psychiatry.wustl.edu" class="auth_mail} ; Alzheimer&rsquo ; s Disease Neuroimaging Initiative
• 关键词：Alzheimer&rsquo ; s disease ; biomarkers ; brain proteome&mdash ; Rules Based Medicine Discovery Multi-Analyte Profile 1.0 ; cerebrospinal fluid (CSF) ; heart-type fatty acid binding protein ; ptau-A尾42 ratio
• 刊名：Biological Psychiatry
• 出版年：1 May, 2014
• 年：2014
• 卷：75
• 期：9
• 页码：723-731
• 全文大小：1697 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Background

Identification of the physiologic changes that occur during the early stages of Alzheimer鈥檚 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.

Methods

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鈥檚 Disease Research Center (N = 311) and the Alzheimer鈥檚 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尾₄₂ was used as a continuous trait in these analyses.

Results

The ptau₁₈₁-A尾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尾₄₂) compared with elderly control subjects with no pathology (low ptau₁₈₁, high A尾₄₂). The FABP-A尾₄₂ ratio demonstrates a similar hazard ratio for disease conversion to ptau₁₈₁-A尾₄₂ even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD.

Conclusions

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.