Possible MCI Therapies

Most attempts to treat MCI in the elderly focus on the possible conversion of MCI into AD. Multiple potential treatment alternatives are under investigation. Estrogen, modulators of glutamate receptors, nootropic agents, anti-inflammatory agents, antiox-idant agents, monoaminergic enhancers, ergot alkaloids, neuropeptides, and cholinergic agents are some of the possible treatments being evaluated. Large trials are underway with cholinesterase inhibitors, COX-2 inhibitors, and vitamin E (Shah et al., 2000).

Using estrogen as a treatment for memory difficulties has been debated in the literature for a number of years. The hippocampus and basal forebrain possess estrogen and progestin receptors that are believed to play a role in memory. Basic science research has shown that estrogen increases the formation of dendritic spines and new synapses in the ventromedial hypothalamus and hippocampus. Estrogen may also facilitate the growth of cholinergic neurons by influencing nerve growth factor (NGF), which is synthesized by the hippocampus and transported to the basal forebrain where it promotes neuronal growth (Sherwin, 2000). Estrogen may also have a role in inhibiting lipid peroxidation, acting as a free radical scavenger and limiting the toxicity of beta-amyloid (Sramek et al., 2001).

Despite promising basic science research, estrogen has not consistently shown benefits in treating or preventing cognitive disorders. The data currently do not support the use of this agent for the treatment of AD. In one meta-analysis (LeBlanc et al., 2001) examining nine randomized controlled trials and eight cohort studies with respect to the role of estrogen and cognition, women with menopausal symptoms showed improvement in verbal memory, vigilance, reasoning, and motor speed but no benefit in other cognitive domains. Asymptomatic women did not improve. Likewise, clinical trials have failed to demonstrate benefits for coronary artery disease, cerebrovascular disease, osteoporosis, and cognition. Further, its long-term use may be contraindicated in women with intact uteruses due to the potential risk of endometrial hyperplasia, endometrial cancer, gallstones, and breast cancer.

Glutamate, a major excitatory amino acid (EAA) neurotransmitter in the mammalian brain, is also believed to affect cognition. The N-methyl-D-aspartate (NMDA) receptor, which binds glutamate and other neurotransmitters, is involved in learning, memory, and hippocampal synaptic plasticity. Studies in animals suggest that facilitating NMDA receptor functioning should improve cognition.

There are two EAA receptor agonists that have been used for memory enhancement: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and NMDA.

Direct activation of NMDA receptors can lead to neurotoxicity; therefore, glycine-like agonists, which indirectly activate NMDA receptors, are deemed more promising. In one study of milacemide, mildly positive, but equivocal, results were observed, suggesting improvement in source memory (Schwartz et al., 1992).

Ginkgo biloba has received attention in the lay press and the medical literature. Initial reports appeared promising. However, more recent controlled studies have been negative when ginkgo was compared to placebo in the normal elderly, as well as persons with MCI or dementia (Solomon et al., 2002; van Dongen et al., 2000).

Vitamin E can ameliorate oxidative stress, and a primary event in AD pathology is believed to be oxidative stress involving the production of free radicals. Postmortem examinations of individuals with AD have revealed oxidative damage in neurofibrillary plaques and tangles as well as pyramidal neurons. Vitamin E is a lipid-soluble antioxi-dant that interacts with cell membranes, traps free radicals, and inhibits beta-amyloid-induced cell death. So far, trials have produced mixed results. One placebo-controlled study revealed benefits in treating moderately impaired AD patients with vitamin E (alpha-tocopherol) at 2000 IU/day: This yielded delays in functional decline, particularly in terms of the need for placement in long-term care facilities (Sano et al., 1997).

Cholinesterase inhibitors are being investigated in large multicenter trials for the treatment of MCI. Loss of neurons in the nucleus basalis of Meynert and other basal forebrain cholinergic nuclei is correlated with cognitive deficits in MCI and AD. Acetylcholinesterase inhibitors prevent the enzymatic breakdown of ACh, enhancing cholinergic transmission and thereby improving cognition. As discussed below, cholinesterase inhibitors are currently the only Food and Drug Administration (FDA)-approved medications for treating AD. Can cholinesterase inhibitors also benefit MCI patients and/or prevent their conversion to AD? These questions are currently under investigation in a large-scale, multisite study conducted by the National Institute on Aging comparing donepezil with vitamin E or placebo (Sramek et al., 2001).

Our understanding of MCI has increased greatly over the last decade, but implications for the early detection and prevention of dementia require further clarification. A comprehensive review of the current state of knowledge is available (Petersen, 2003).

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