Seeing and Treating Cholinergic Deficits in AD
abstracts & commentary
Sources: Imbimbo BP, et al. Efficacy and safety of epistigmine for the treatment of patients with AD. Neurology 1999;52(4):700-708; Kuhl DE, et al. In vivo mapping of cerebral acetylcholinesterase activity in aging and AD. Neurology 1999;52(4):691-699.
Alzheimer’s disease (ad) progresses slowly, necessitating many years to fully assess the efficacy of new treatments. One small step consists of the outcome of a randomized trial of epistigmine, yet another acetylcholinesterase inhibitor (AChEI) being tested for ameliorating AD-related dementia. Epistagmine given 15 mg tid previously showed marginal improvement in AD patients, but failed to produce a significant change in global function (Imbimbo BP, et al. Alz Dis Assoc Disord 1998:12:313-322). In a new study involving 463 AD patients, treatment with placebo was compared to either 15 mg or 20 mg epistigmine tid. The effects were comparable to those of the previous study, but the higher dose significantly improved activities of daily living over a 24-week period, apparently the first reported improvement in instrumental activities by a drug of this class. A similar dropout rate occurred between epistigmine- and placebo-treated patients. A low rate of gastrointestinal side effects with epistigmine was nearly comparable to that of placebos. Unfortunately, 6.2% of patients treated with 20 mg tid of epistigmine developed neutropenia, which Imbimbo and colleagues acknowledge will limit the drug’s clinical use.
Cholinergic therapy is an established treatment for AD, but the exact mechanisms of its beneficial effects are not completely understood. Accordingly, optimal candidates for such drugs cannot be identified in advance. To clarify this issue, Kuhl and colleagues developed a PET technique similar to that first proposed by Irie and colleagues in 1994 (Irie T, et al. Nucl Med Biol 1994;21:801-808) for mapping brain acetylcholinesterase in the brains of living subjects. The radioligand used was N [11C] methylpiperidin-4-yl propionate, a highly selective substrate for the AchE enzyme that enters the brain after intravenous injection. Kuhl et al studied 26 normal controls and 14 patients with AD. They correlated their findings with other PET measures of cholinergic terminal density and glucose metabolism. The [11C]PMP PET results agreed reasonably well with postmortem data on the distribution of cholinergic activity in normals and AD patients, and changed in the expected manner when physostigmine was administered. Kuhl et al speculate that the [11C]PMP PET technique may prove valuable in identifying responders to cholinergic therapies, thereby facilitating other aspects of drug development and use.
Commentary
Two AChEIs (tacrine, donepezil) are already FDA approved for treating symptoms of AD. Last year, Neurology Alert reported the positive results of Phase III clinical trials of metrifonate, an irreversible AChEI, which showed comparable efficacy to the tacrine and donepezil (Relkin, NR. Neurol Alert 1998;16:84-85). All human studies with metrifonate were stopped voluntarily by Bayer, Inc. when a small fraction of patients developed unexpected muscle weakness. Rivastigmine, a chemically unrelated AChEI that requires twice-daily dosing, has shown comparable efficacy to other agents in its class and is currently used to treat AD patients in Europe. Rivastigmine has yet to receive approval for use in the United States. Other cholinesterase inhibitors like galanthamin are currently under large-scale study in Europe and the United States.
The positive effects of epistigmine on the performance of daily activities and the low incidence of gastrointestinal side effects represent potential selling points. The negative problems include a three-time-daily dosing and the drug’s dose-dependent neutropenic effect. It seems unlikely that epistigmine will replace drugs like donepezil, which can be dosed once daily with comparable efficacy and greater safety. The data on epistigmine corroborate the cognitive benefits of cholinergic therapy for AD, and may provide modest improvements in daily function when receiving this type of medication.
The direct clinical applicability of the [11C]PMP PET technique is questionable in light of the complexity, expense, and limited availability of quantitative PET. The real value of this method would appear to be as an investigational tool. Although cholinergic deficiency is well-documented as a biological correlate of AD, the benefits of cholinergic therapy are inconsistent across both symptoms and patients for unexplained reasons. A specific and quantitative in vivo measure of central acetylcholinesterase activity could assist in the further development of cholinergic therapies. By more directly measuring the brain’s response to these agents, the [11C]PMP PET method could facilitate dose finding and other aspects of new drug development.
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