Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification

• Published in: Alzheimer's research & therapy 2020-03, Vol.12 (1), p.26-11, Article 26
• Main Authors: Barthélemy, Nicolas R, Bateman, Randall J, Hirtz, Christophe, Marin, Philippe, Becher, François, Sato, Chihiro, Gabelle, Audrey, Lehmann, Sylvain
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - diagnostic imaging; Alzheimer's disease; Amyloid beta-Peptides; Biological markers; Biomarkers; Biomarkers - analysis; Brain research; Cerebrospinal fluid; Dementia; Diagnosis; Diagnosis, Differential; Differential diagnosis; Disabilities; Diseases; Female; Health aspects; Humans; Identification and classification; Immunoassay; Life Sciences; Lumbar puncture; Male; Mass spectrometry; Medical diagnosis; Methods; Neurodegenerative diseases; Peptide Fragments; Peptides; Phosphorylation; Positron emission tomography; Proteins; Scientific imaging; Spectroscopy; Tau proteins; tau Proteins - analysis
• ISSN: 1758-9193; 1758-9193
• DOI: 10.1186/s13195-020-00596-4

Cerebrospinal fluid biomarker profiles characterized by decreased amyloid-beta peptide levels and increased total and phosphorylated tau levels at threonine 181 (pT181) are currently used to discriminate between Alzheimer's disease and other neurodegenerative diseases. However, these changes are not entirely specific to Alzheimer's disease, and it is noteworthy that other phosphorylated isoforms of tau, possibly more specific for the disease process, have been described in the brain parenchyma of patients. The precise detection of these isoforms in biological fluids remains however a challenge. In the present study, we used the latest quantitative mass spectrometry approach, which achieves a sensitive detection in cerebrospinal fluid biomarker of two phosphorylated tau isoforms, pT181 and pT217, and first analyzed a cohort of probable Alzheimer's disease patients and patients with other neurological disorders, including tauopathies, and a set of cognitively normal controls. We then checked the validity of our results on a second cohort comprising cognitively normal individuals and patients with mild cognitive impairments and AD stratified in terms of their amyloid status based on PiB-PET imaging methods. In the first cohort, pT217 but not pT181 differentiated between Alzheimer's disease patients and those with other neurodegenerative diseases and control subjects much more specificity and sensitivity than pT181. T217 phosphorylation was increased by 6.0-fold in patients with Alzheimer's disease whereas T181 phosphorylation was only increased by 1.3-fold, when compared with control subjects. These results were confirmed in the case of a second cohort, in which the pT217 cerebrospinal fluid levels marked out amyloid-positive patients with a sensitivity and a specificity of more than 90% (AUC 0.961; CI 0.874 to 0.995). The pT217 concentrations were also highly correlated with the PiB-PET values (correlation coefficient 0.72; P