CSF phospho-tau correlates with behavioural decline and brain insoluble phospho-tau levels in a rat model of tauopathy.

The aim of the present study was to identify the relationship between progressive neurobehavioural decline and phospho-tau levels (p-tau(181)) in the cerebrospinal fluid (CSF) and the brain in transgenic rats expressing human truncated tau protein. Behavioural analyses, as quantified using the NeuroScale scoring method, revealed that the transgenic rats fell into two main groups based on the baseline behavioural functioning: (1) mild neurobehavioural impairment (MNI, score 3.3-26) and (2) severe neurobehavioural impairment (SNI, score 36-44). SNI transgenic rats showed a significant increase in brain sarkosyl insoluble p-tau(181) when compared to their MNI counterparts. In order to determine whether CSF phospho-tau reflects the behavioural decline and increase in sarkosyl insoluble tau in the brain, p-tau(181) was measured in the CSF in a longitudinal study. The study showed a significant increase in CSF p-tau(181) during the progression of the disease from MNI to SNI. Moreover, increased levels of p-tau(181) in CSF correlated with an increase in the sarkosyl insoluble p-tau(181) levels in the brain. The increase in the CSF level of p-tau(181) during progressive behavioural decline suggests that it may represent a useful surrogate biomarker for preclinical drug development and a potential surrogate endpoint for clinical trials of disease-modifying therapy for Alzheimer's disease and related human tauopathies.