Abstract
BackgroundThere is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer’s disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD.MethodsWe have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts.ResultsIn the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 ± 0.166 pg/ml in AD versus 0.0405 ± 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p-tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 ± 1.26 pg/ml in DS versus 0.0415 ± 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p-tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023).ConclusionsWe report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well-controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD.
Highlights
There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer’s disease (AD) pathology
Cohort 3 consisted of 8 AD, 2 vascular dementia (VaD) and 1 Parkinson’s disease (PD) patients (Table 3), whose cerebrospinal fluid (CSF) and plasma samples were collected simultaneously in each patient to determine the correlation between CSF and plasma levels of p-tau181 as measured with our novel immunoassay
Intra-assay precision was determined (Additional file 1), and it was robust with coefficient of variations (CVs) between 2.8 and 11.2% (Additional file 2)
Summary
There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer’s disease (AD) pathology. The current consensus is that these CSF and PET biomarkers can differentiate AD from normal aging and from other dementing disorders, and changes in these biomarkers can facilitate detection of AD many years before any overt clinical symptoms become clear [7,8,9,10]. There is still a substantial unmet need for less invasive and lower-cost alternatives, for high-throughput screening of people at risk of developing AD. For this reason, there have been many studies of blood-based molecular markers, including plasma Aβ species, as a potential alternative and less invasive method for the diagnosis of AD. The reported results have been very contradictory [11,12,13,14,15] and so the prevailing view is that AD (or preclinical AD) cannot be distinguished from controls without AD pathology on the basis of plasma levels of Aβ40 and Aβ42 [16]
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