Temporal Kinetics of CSF Phosphorylated Tau (ptau-181, Ptau-199) in Novel PS1 Mutant FAD Cases

PS1 is a major causative gene as early onset FAD. In the view of diagnosis and molecular mechanism AD, it is important to analyze the kinetics in longitudinal time process of CSF phophorylated tau in FAD patients. We investigate the relationship clinical features, cognitive function, radiological findings and CSF phosphorylated tau. We disclose causative gene mutations and CSF phosphorylated tau (ptau-181, ptau-199) and radiological findings in four FAD families. We analyzed gene sequences as causative genes of these FAD families (FAD1-4). We also analyzed the correlation between temporal profiles of neurological symptoms and radiological findings of MRI/CT and SPECT. We analyzed CSF phosphorylated tau (ptau-181) for every 3-4 years respectively. After gene analyis, we have found four different PS1 mutations in all five FAD cases (H131R, H163R, L219R, M233L). Two siblings in FAD1 family (M233L) had common initial phenotype characterized by neurological symptoms (dementia, apraxia, apathy), with severe motor deficits since onset of the disease. A proband of FAD2 family (H163R) presented dementia and parkinsonism. MRI of two siblings in FAD1 family showed that the temporo-parietal lobes and hippocampus were atrophied at the initial stage, then atrophies of the frontal lobe were followed. Phosphorylated ptau-199 and ptau-181 in CSF slightly increased in three patints except one FAD3 case. MRI of the proband of FAD2 family showed severe temporal and fronto-temporal atrophy, corresponding to low CBF in SPECT. While two cases of FAD3 (L219R) resemble clinical and radiological findings of FAD1, FAD4 (H131R) case is reminiscent of FAD1. In time process of 5 AD cases, ptau-181 have slight decreased since initial CSF examination. We have demonstrated four PS1 mutations including two novel mutations (L219R, H131R) in four FAD. FAD patients showed common initial phenotype characterized by dementia, apraxia, apathy with severe motor deficits since onset of the disease. In time process of 5 AD cases, CSF ptau-181 and ptau-199 have slight decreased since initial CSF examination. We consider that AD clinical progress and CSF ptau-181 may close relationship in time process, and that further deterioration of dmentia and pathological/clinical stable AD condition might decrease ptau-181.