PHARMACOLOGICAL TREATMENT OF MEMORY DEFICITS

Everyone experiences occasional memory lapses, which are often termed senior moments by those older than they care to be. While a frequent source of complaint, such events are generally not cause for worry. However, there are diseases that can cause much more profound and debilitating memory impairment. The most commonly recognized illness that causes memory loss is Alzheimer's disease (AD). In addition, other neurodegenerative diseases, such as Parkinson's, Huntington's and Pick's disease, include memory problems among their symptoms. Vascular disorders and stroke are common causes of memory impairment in the elderly. There is also a rapidly growing population of otherwise healthy elderly people who develop memory problems that are severe enough to interfere with their everyday lives. While these conditions are most commonly seen in the aged, many young people with depression or schizophrenia, or who suffer from AIDS, also experience impaired memory. All of these people could potentially benefit from drug therapies that would relieve memory deficits.

Many treatments for ailing memory, both pharmacological and nonpharmacological have been described. However, no drug has been discovered that is overwhelmingly effective in improving memory. A major reason for this is that there are different types of memory, each of which engages, at least to some degree, different brain regions. Similarly, while the biochemical mechanisms required for memory formation are not completely understood, there is evidence indicating that more than one system is involved. This suggests that different drugs will be needed to treat the memory impairments that arise from different illnesses. In practice, the problem is compounded by the possibility that different stages of a disease may have different underlying causes, and by situations where more than one disease is present. For example, Alzheimer's disease can be categorized as mild, moderate, or severe, and some patients with AD also have Parkinson's disease or vascular dementia; each of these situations may require a different drug, or different amounts of the same drug, to be treated effectively. Thus, in order to show that a drug with only modest activity is effective, it is important to test the drug under controlled conditions that include a uniform patient population. In addition, double-blind trials comparing placebo against active drug are essential for objective evaluation of a drug candidate because placebo effects are relatively common in memory studies.

Prescription Drugs to Treat Memory Impairment

Drugs that are currently available to treat memory impairments can be divided into two broad classes, according to whether a physician's prescription is necessary to obtain them. Prescription drugs have had to meet defined standards of safety and must be shown to be effective to treat a particular condition. In the United States, the Food and Drug Administration (FDA) currently recognizes only AD and, more recently (summer of 2001), mild cognitive impairment as indications for memory enhancing treatment. All currently marketed prescription drugs for memory improvement have shown statistically significant results in AD patients. However, while the effects of these compounds were significant in controlled trials, in actual practice they have generally been meager. The disappointing results of these drugs could be because their mechanism of action is not an effective way to enhance memory. More likely, the poor outcome results from variability in the real-world patient population. An additional problem is that currently available drugs do not treat the cause of the illness, so memory in AD patients is continually getting worse. It may be that existing drugs would be more effective for treating people with less severe, or more slowly deteriorating, memory impairments.

Compounds that act to inhibit acetylcholinesterase dominate the group of currently available therapeutics to treat memory impairment in AD. This enzyme degrades acetylcholine, a neurotransmitter used by a population of neurons that degenerates in the early stages of the disease. The rationale for the development of acetylcholinesterase inhibitors is that they would strengthen and prolong the weakened signals sent by remaining cholinergic neurons in the brain of AD patients. A problem with this approach is that acetylcholine is also used as a neurotransmitter in the neuromuscular and autonomic nervous systems. Overactivation of these latter systems induces profound side effects, including nausea, vomiting, diarrhea and dizziness, and thus limiting the useful dose range of anticholinesterase drugs.

Cognex(r) (tacrine and tetrahydroacridine) became the first FDA-approved treatment for AD in 1993. Unfortunately, its mild memory enhancing properties were more than offset by the need to dose four times per day and problems with toxicity that required regular monitoring of liver function. When Aricept(r) (donepezil) became available in 1997, its superior safety margin and longer half-life (once-a-day dosing) allowed it to quickly supplant Cognex(r) as the preferred therapy for AD. At the beginning of 2002, Aricept(r) remains the most-used agent in its class. Two more recently available anticholinesterase compounds are Exelon(r) (rivastigmine; 1998) and Reminyl(r) (galanthamine; 2000). In addition to inhibiting acetylcholinesterase, Reminyl(r) is described as acting on brain nicotinic cholinergic receptor to enhance neurotransmitter release. It is not yet clear whether this action gives Reminyl(r) memory-improving properties that are superior to other acetylcholinesterase inhibitors.

Two other prescription drugs are marketed for the treatment of memory impairments, but these agents have not been approved by the FDA and so are not currently available in the United States. The first of these is Alcar(r) (acetyl-l-carnitine), which was first introduced in Italy in 1985; its mechanism of action seems, like that of the acetylcholinesterase inhibitors described above, also to involve enhancing cholinergic neurotransmission in the brain. However, the effect appears to be achieved by elevating levels of nerve growth factor (NGF), a neurotrophin that is critical to maintaining the survival and normal functioning of cholinergic neurons. (NGF administration is being explored as a therapy in its own right.) Akatinol(r) (memantine), first available in Germany in 1982, is different from all of the previously discussed drugs in that its primary action does not appear to involve cholinergic neurons. Akatinol(r) interacts in a complex way with glutamate-mediated neurotransmission, the most important excitatory system in the brain. Over-activation of glutamate receptors, particularly those of the NMDA (n-methyl-d-aspartate) type, leads to neuronal death. Akatinol(r) acts as an antagonist to prevent this overactivation, yet seems not to interfere with normal synaptic function. At this point it is not possible to compare the efficacy of Alcar(r) or Akatinol(r) to marketed anticholinesterase drugs, but observations based upon the long existing period of clinical experience suggest that neither drug will turn out to be a substantially better memory enhancer.

Nonprescription Drugs to Treat Memory Impairment

In addition to prescription drugs, a large number of over-the-counter agents are advertised as benefiting memory. Many nonprescription memory boosters are formulations containing several compounds. While it is not possible to discuss all of these compounds individually, some of them deserve mention. Huperzine A is a potent acetylcholinesterase inhibitor that is derived from a particular type of club moss and sold as a dietary supplement for memory loss and mental impairment. While Huperzine A has been shown to be an effective memory enhancer, its side effects are identical to other anticholinesterase drugs. In contrast to the agents that will be described in the remainder of this section, there are substantial risks associated with the use of Huperzine A.

Extracts from leaves of the Ginkgo biloba tree have been shown to improve memory in several studies of healthy volunteers and patients with dementia. How Ginkgo works is not entirely clear, but it seems to involve a combination of effects including increasing cerebral blood flow and antioxidant action. The latter reduces or prevents neuronal damage caused by the generation of chemical-free radical species. The active agents in Ginkgo extracts have not been completely characterized, and the extraction procedure is not standardized, so it is likely that currently marketed products have varying effectiveness. Two compounds derived from the ergot fungus, hydergine and nicergoline, share the enhancement of cerebral circulation that has been described for Ginkgo extracts. Both hydergine and nicergoline have shown some beneficial effects in treating memory impairments, but the compounds have not been evaluated as rigorously as Ginkgo.

Compounds that enhance learning and memory by an undefined mechanism are often termed nootropics. Although there are many agents that could be called nootropic, the name is most often applied to piracetam and its relatives: aniracetam, oxiracetam, and pramiracetam. Memory-enhancing effects of piracetam in animals were first described in the late 1960s. In the intervening years these drugs have been used to treat many conditions with memory impairment, including AD, but no convincing improvements have been described. Another nootropic, idebenone, shares a similar history.

A final compound of note is vitamin E. Low serum levels of vitamin E have been correlated with memory impairments. In addition, a high dose of vitamin E has been shown to be effective in slowing cognitive deterioration in AD patients. Vitamin E has antioxidant properties, so its beneficial properties are ascribed to reducing free radical damage. It is likely that vitamin E will not be shown to be particularly effective at improving memory; rather, its use seems better suited to protect against age-or disease-related memory impairments.

Conclusion

In the 1990s, a significant breakthrough in the treatment of memory disorders occurred with FDA approval of several acetylcholinesterase inhibitors for symptomatic treatment of AD. Although the currently marketed drugs are only modestly effective, they have refocused attention on the problem of memory impairment and the possibility that it can be treated. This, in turn, has provided a strong stimulus for research to develop more useful pharmacological treatments for memory impairment. Several promising drugs are currently undergoing clinical trials, and it is likely that substantial advances in the treatment of memory deficits will take place before 2010.

See also:ALZHEIMER'S DISEASE: BEHAVIORAL ASPECTS; ALZHEIMER'S DISEASE: HUMAN DISEASE AND THE GENETICALLY ENGINEERED ANIMAL MODELS; COGNITIVE ENHANCERS

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Gregory M.Rose