Hideki Kohno

Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease

We surveyed a total of 570 cerebrospinal fluid (CSF) samples from a variety of diseases, including Alzheimers disease (AD; n = 236), non‐AD‐demented and nondemented diseases (n = 239), and normal controls (n = 95) to quantitate levels of tau protein phosphorylated at serine 199 (CSF/phospho‐tau199) by a recently established sandwich ELISA. The CSF/phospho‐tau199 levels in the AD group were significantly elevated compared to those in all the other non‐AD groups. Receiver operating characteristics curves showed that the diagnostic sensitivity and specificity for the AD group versus all the other non‐AD groups using the CSF/phospho‐tau199 were 85.2% and 85.0%, respectively. Furthermore, there was a significant positive correlation between CSF/phospho‐tau199 and CSF/total‐tau levels in the AD group. Elevated CSF/phospho‐tau199 in the AD group was noted irrespective of age, gender, dementia severity, and number of apolipoprotein E4 alleles. Thus, we suggest that CSF/phospho‐tau199 may be a novel and logical biomarker in supporting antemortem diagnosis of AD.

Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease.

Microtubule-associated protein tau in cerebrospinal fluid (CSF) has been proposed as a diagnostic marker for Alzheimers disease (AD), but there is overlap between AD patients and non-AD controls. To improve the diagnostic accuracy, we measured phosphorylated tau in CSF, because phosphorylated tau accumulates as pathological paired helical filaments in neurons of the AD brain. Immunoblot showed that CSF contained a 32 kDa N-terminal fragment of tau that was partially phosphorylated on Ser199, Thr231 and Ser235. A sandwich enzyme immunoassay revealed that phosphorylated CSF-tau levels were significantly higher in AD patients than those in non-AD controls. Discrimination between the two groups was clearer in phosphorylated CSF-tau than in total CSF-tau. The data indicate that elevated phosphorylated CSF-tau level is a more specific diagnostic marker for AD.

CSF phosphorylated tau protein and mild cognitive impairment: a prospective study.

Cerebrospinal fluid (CSF) tau protein phosphorylated at both Thr231 and Ser235 sites (CSF/phospho-tau(231-235)) and total tau (CSF/total-tau) were quantified by sandwich ELISA in 20 patients with mild cognitive impairment (MCI) who eventually developed AD on follow-up as well as seven memory complainers with no objective memory loss. 13/20 (65%) of the MCI patients had high CSF/total-tau and detectable levels of CSF/phospho-tau(231-235), whereas these markers were low and under a detectable level in all of the memory complainers. Although either a total-tau, phospho-tau measurement or a combination of these can help in predicting if MCI will develop AD, our results suggest that the pathogenic steps of AD may be at the stage that finally leads to an accumulation of abnormally phosphorylated tau and neuron death, at least in some brain areas, when MCI patients present with the earliest detectable clinical symptoms of dementia.