title: What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors?
abstract: The progression of Alzheimer disease (AD) corresponds to a prolonged course of neuronal loss in the cerebral cortex. Strategies aimed at reducing the rates of neuronal loss are therefore particularly important. The clinical measures to evaluate the disease-modifying effect of an intervention are readily confounded by any symptomatic benefit of the intervention. Thus, when testing putative neuroprotective agents that are known to have symptomatic effects, it can be difficult to separate the 2 effects. The hypothesis that cholinesterase inhibitors (ChEIs) only treat symptoms caused by cholinergic imbalances in AD is overly simplistic. Evidence has now accumulated that ChEIs have a neuroprotective, disease-modifying property. In this paper, to answer the question of what constitutes clinical evidence for neuroprotection in AD, we have reviewed clinical studies with specific designs, including "delaying end point," "withdrawal," and "randomized start" designs. We have also reviewed data on surrogate biomarkers of disease progression that may indicate a disease-modifying action. In addition, we have reviewed evidence indicating that ChEIs may protect cells in the brain of patients with AD. Among the clinical data suggesting a possible neuroprotective effect of ChEIs, the most rigorous published evidence comes from magnetic resonance imaging (MRI) hippocampal volumetric studies with donepezil.
authors.affiliation: Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan. mori@mail.tains.tohoku.ac.jp
authors.forename: Etsuro
authors.initials: E
authors.lastname: Mori
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hashimoto
authors.forename: K Ranga
authors.initials: KR
authors.lastname: Krishnan
authors.forename: P Murali
authors.initials: PM
authors.lastname: Doraiswamy
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D001921:Brain / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D018696:Neuroprotective Agents / Q000627:therapeutic use*
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents