Long-term effect of phenserine treatment in Alzheimer patients as assessed by PET and CSF biomarkers

Background: Beta amyloid is one of the major histopathological hallmarks of AD. Imaging with 11C-PIB PET ligand has open up the new possibilities to understand the pathological mechanism in AD. Reduction of Aβ plaque formation is a major focus in the design and development of effective therapies for AD. Previously we have shown that PiB tracer could be used to evaluate the anti-amyloid therapy in AD. The new novel drug phenserine works as an inhibitor of the formation of β-amyloid precursor protein (β-APP) and hence reduces the formation of Aβ plaque as well as an inhibitor of the acetylcholinesterase. The aim of this study is to investigate the long-term effects of phenserine treatment on regional cerebral metabolic rate for glucose (rCMRglc) as assessed by PET and cerebrospinal fluid (CSF) in patients with mild AD in relation to brain amyloid load as assessed by 11C-PiB and cognitive function. Methods: Twenty patients with mild AD were included in this 12 months study and treated with phenserine (30 mg/day). The patients underwent PET examinations to measure rCMRglc by 18F-FDG at baseline and after 3, 6 and 12 months of treatment. Brain amyloid load was assessed by 11C-PIB at baseline and after 3 and 6 months of the treatment. Neuropsychological and biomarkers data were collected through out the study. Results: The 6 months data has recently been published (Kadir et al. Annals of Neurology 2008: 63: 621). After 12 months of phenserine treatment a stabilization of cerebral glucose metabolism was observed as well as a significant increased in CSF Aβ 40, sAPP-α and sAPP-β was observed. CSF Aβ 40 and sAPP levels significant positively correlated with rCMRglc and cognitive function while CSF Aβ 42, 42/40 ratio, P-tau and t-tau negatively correlated with rCMRglc and cognitive function. Patients who showed reduction in PiB binding after 3 months of phenserine treatment showed increased in CSF Aβ 40 level and improved cognitive function at 12 months treatment. Conclusions: long-term phenserine treatment was associated with stabilization in rCMRglc and increased in CSF Aβ 40 and sAPP. Indicating that reduction of PiB binding at 3 months may predict the 12 months outcome.