Memory Dysfunction, Drug Treatment
MEMORY DYSFUNCTION, DRUG TREATMENT
Memory deficits in the adult can develop from lesions that disrupt circuits that interconnect structures involved in encoding and retrieving recently acquired information, as well as from those involved in transferring information to long-term storage. The most important structure of this memory system is the hippocampalentorhinal complex. Other areas involved in memory processes include the amygdala, paralimbic cortices, thalamic nuclei, mammillary bodies, fornix, hypothalamic nuclei, basal forebrain, and ventral striatum. Therefore, amnestic, or memory, disorders can occur from lesions at any part of this system and have a wide variety of causes, including infections, exposure to toxic substances, medications, vitamin deficiency, head trauma, cerebrovascular disease, tumors, and some neurodegenerative disorders. However, the most frequent cause of amnestic disorders in the adult is Alzheimer's disease (AD). Indeed, focal memory deficits precede the development of dementia, and episodic memory deficits (i.e., inability to recall recent events) and semantic memory deficits (i.e., loss of factual knowledge and object recognition) are the hallmark characteristics of the AD dementia syndrome, with episodic memory deficits preceding semantic memory deficits. AD has been reported in up to 10 percent of the population age sixty-five or older, and it is estimated that by the year 2040, 14 million Americans will have AD. Therefore, there is a significant effort to develop medications that can treat or ameliorate AD symptoms.
Neuropathological basis for cognitive disorders in Alzheimer's disease
Although the primary causes (or cause) of AD are not known, significant advances have furthered our understanding of the genetic and environmental factors, as well as the pathophysiological mechanisms, that can lead to AD. The latter has been a critical area of research, as it has given rise to therapies aimed at slowing the progression of AD. The neuropathological and biochemical changes in AD can be divided into two general areas: (1) structural changes and (2) alterations in neurotransmitter systems.
Structural changes. Structural changes in AD are concentrated in the cortical association regions and portions of the limbic system, and involve amyloid metabolism alterations, neurofibrillary tangles, neuritic plaques, synapse loss, and neuronal death. In the neocortex, large neurons are preferentially lost, relative to small neurons. Beta-amyloid proteins (they are major constituent neurotic plaques, which are the key lesion in Alzheimer's disease) accumulate in affected and unaffected regions of brain, but only in the association cortices and limbic regions does it evoke an inflammatory response that leads to tissue destruction and formation of neurofibrillary tangles.
Neurotransmitter systems. One of the most consistent findings in the brain of AD patients is the loss of cholinergic neurons (neurons that produce the neurotransmitter acetylcholine) in the nucleus basalis of Meynert (nbM). The nbM sends cholinergic projections to all areas of the neocortex, especially the temporal lobes and frontal and parietal association areas, and the indemnity of this system is essential for normal cognitive functioning. However, the major depletion of cholinergic neurons occurs in the temporal lobes. Other neurotransmitters are affected in AD, such as serotonin and norepinephrine, and they are though to be associated with the noncognitive behavioral symptoms of AD.
Pharmacological therapy for cognition
Drugs that can modify structural changes in AD. The understanding of molecular pathology and neurotransmitter dysfunction has led researchers to delineate several therapeutic approaches for AD. One such approach involves the highly suspected inflammatory mechanisms thought to contribute to AD pathology. It has been suggested the inflammatory process is necessary in amyloid metabolism, and population studies have shown that the use of steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD. However, two clinical trials have shown that neither prednisone (a corticosteroid) nor diclofenac (a NSAID) and misoprosol ("a prostanglandin E1 analogue that reduces the NSAID related gastrointestinal ulcers" or "medication that reduces gastrointestinal side effects of NSAID") improve cognition in AD patients. Studies investigating a new type of anti-inflammatory drug called cyclo-oxygenase 2 (COX2) inhibitors are under way.
It has been reported that ovarian steroids, especially estrogens, play a critical role in the memory process of normal individuals and individuals with AD. Experimental studies have found that estrogens and progestins stimulate neuronal growth in the hippocampus of animal models and modulate the cholinergic system and levels of beta-amyloid in the human brain. However, placebo-controlled studies have shown that estrogen replacement therapy (ERT) does not modify the course and progression of AD. Therefore, current evidence suggests that while ERT can delay AD onset (although this needs to be confirmed in prospective studies), it has no effect on the course of AD.
Modulation of neurotransmitter systems in AD patients. Acetylcholine is the most affected neurotransmitter in patients with AD. Its synthesis is begun at the presynaptic level by the enzyme acetylcholine transferase. The acetylcholine diffuses across the synaptic membrane and stimulates the postsynaptic cholinergic receptor. Its activity is then halted by the enzyme acetylcholine esterase, which is present on both presynaptic and postsynaptic membranes. Therefore, administration of acetylcholine esterase inhibitors can prolong the half-life of acetylcholine and have been found to be an effective treatment of AD.
For several years, researchers have been able to modulate cholinergic system activity, especially using acetylcholine esterase inhibitors such as physostigmine, in nondemented individuals. Coupled with the fact that acetylcholine is the most affected neurotransmitter in AD, this has made it possible to develop acetylcholine esterase inhibitors as the main line of treatment of AD. Indeed, in 1986, Summers et al. demonstrated that the long-term (twelve months) use of tacrine can improve cognition in AD patients, and in 1993 this drug was approved by the Food and Drug Administration as the first palliative treatment for AD. Since then, three other acetlcholine esterase inhibitors have been approved: donepezil, rivastigmine, and galantamine.
Experimental Compounds that modulate oxidative stress. There are a number of mechanisms that protect the human body from free-radical damage at the molecular level—including enzymes such as superoxide dismutase and catalase, and reduced gluthatione. Because free-radical damage increases with age, and because evidence exists that suggests increased lipid peroxidation (oxidation of fat tissue) in AD cases, the use of medication that can modulate oxidative stress has been a logical approach to the treatment of AD. Most importantly, the majority of the compounds that can modulate the oxidative stress can also have effects in other metabolic pathways that lead to neuronal loss.
A study investigating two antioxidants, alpha-tocopherol (vitamin E) and selegiline (an antiodixant commonly used in the treatment of Parkinson's disease), showed a possible beneficial effect of vitamin E on AD. The authors found that the amount of time before patients reached any of the primary outcomes (death, nursing home admission, or loss of the ability to perform two activities of daily living) was longer in patients taking vitamin E than in those taking selegiline, both drugs, or a placebo. However, the use of either vitamin E or seleginine did not modify cognitive decline. Interestingly, prevention studies have shown that the combination of vitamin E and C can lower the risk of developing vascular dementia, but not AD.
Neuroprotective agents. There are several lines of research that suggest that there is a common pathway for neuronal damage in neurological disorders. For example, a noxious stimulus can activate the N-methyl-D-aspartate (NMDA) receptor-operated channels, resulting in an excessive influx of calcium leading to neuronal damage. This results in the release of glutamate (the excitator neurotransmitter that activates NMDA receptors), and the cycle continues causing more nonreversible neuronal damage. Because it is believed that amyloid deposits can activate the NMDA receptor, it has been proposed that NMDA receptor blockers can prevent neuronal death in AD. Menantine is a noncompetitive NMDA receptor blocker that also modulates the glutamargic system. As of 2001, it was available in Europe, Canada, and Latin America. However, clinical trials have shown that memantine is effective only in the late stages of AD.
Herbal alternative medicine. There has been a considerable increase in the use of herbal medicines in neuropsychiatry (see Lafrance, et al.). The most commonly used herbal medicine for the treatment of AD is ginkgo biloba. It was estimated that 10 million Americans took ginkgo biloba in 1998. In the United States, ginkgo biloba is considered an herbal preparation, and it is regulated as a dietary supplement. Therefore, its manufacturers are not obligated to complete the strict approval process that the Food and Drug Administration require for drugs.
The major components of ginkgo biloba are flavonoids and terpenoids, which act as scavengers, are antagonists of platelet-activating factor, provide membrane protection, increase γ-aminobutiric acid and glutamic (or glutamate) decarboxilase levels, and increase the muscarinic receptor population. Multiple publications have found a cognitive improvement from the use of ginkgo biloba in the treatment of AD, and a few have reported a lack of efficacy. However, the majority of these studies did not use current standardized measures to determine cognitive improvement, and they have been conducted in mixed populations. In other words, patients with Alzheimer's disease associated with other brain disorders that can cause dementia (e.g., strokes).
The goal of the treatment of AD is to prevent, slow, or reverse the neurodegenerative process, and practically all suspected mechanisms of the metabolic cascade of AD have been explored with specific and nonspecific treatments. There have been significant advances in the treatment of AD over the past twenty years. However, as of 2001, only medications that can slow down the process for an unknown period of time exist. Nevertheless, there is a significant effort underway to develop new cholinergic compounds, nerve growth factors, anti-inflammatories, antioxidant agents, and drugs that may affect the production of neurofibrillary tangles and neuritic plaques (including peripherally administered antibodies against beta-amyloid proteins, providing hope for improved treatment of AD.
See also Alzheimer's Disease; Dementia; Herbal Therapy; Memory; Memory Training; Neurotransmitters.
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