A review of clinical treatment considerations of donepezil in severe Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that affects over 45 million people worldwide. Patients with severe AD require help with daily activities and show severe memory impairment. Currently, donepezil is one of two drugs approved by FDA and Health Canada for the treatment of severe AD (MMSE score <10). It is prescribed as 5 or 10 mg/d and an FDA-approved 23-mg/d dose. METHOD: This review will discuss risks and benefits of donepezil at these doses in severe AD. Articles were identified using PubMed using the MeSH terms "donepezil" AND "Alzheimer Disease" AND "severe." Three double-blind, placebo-controlled, randomized studies, one post hoc analysis, and one subgroup analysis were selected. RESULTS: Donepezil was found to benefit patients in cognition and global functioning. The most consistent improvement was in severe impairment battery (SIB) scores. However, more patients treated with high dosage of donepezil discontinued their treatment due to various adverse events (AEs). CONCLUSION: Clinicians must weigh benefits against adverse events when determining the course of therapy, as recommendations for cholinesterase inhibitors in advanced AD remain unclear and vary with different guidelines.

NF-κB p50 subunit knockout impairs late LTP and alters long term memory in the mouse hippocampus.

BACKGROUND: Nuclear factor kappa B (NF-κB) is a transcription factor typically expressed with two specific subunits (p50, p65). Investigators have reported that NF-κB is activated during the induction of in vitro long term potentiation (LTP), a paradigm of synaptic plasticity and correlate of memory, suggesting that NF-κB may be necessary for some aspects of memory encoding. Furthermore, NF-κB has been implicated as a potential requirement in behavioral tests of memory. Unfortunately, very little work has been done to explore the effects of deleting specific NF-κB subunits on memory. Studies have shown that NF-κB p50 subunit deletion (p50-/-) leads to memory deficits, however some recent studies suggest the contrary where p50-/- mice show enhanced memory in the Morris water maze (MWM). To more critically explore the role of the NF-κB p50 subunit in synaptic plasticity and memory, we assessed long term spatial memory in vivo using the MWM, and synaptic plasticity in vitro utilizing high frequency stimuli capable of eliciting LTP in slices from the hippocampus of NF-κB p50-/- versus their controls (p50+/+). RESULTS: We found that the lack of the NF-κB p50 subunit led to significant decreases in late LTP and in selective but significant alterations in MWM tests (i.e., some improvements during acquisition, but deficits during retention). CONCLUSIONS: These results support the hypothesis that the NF-κ p50 subunit is required in long term spatial memory in the hippocampus.