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FIGURE 12 — 34. Palliative responders to cholinesterase inhibitor therapy in Alzheimer's disease. Yet another response to cholinesterase inhibition can be no immediate improvement but a definite slowing in the expected rate of decline.

Agents of unproven or limited efficacy for dementias

EARLY CHOLINERGIC THERAPIES The earliest attempts to boost cholinergic functioning in Alzheimer's disease were made with rather rudimentary cholinergic agents, namely, choline and lecithin (phospatidyl choline), the precursors for ACh synthesis. This was based on an analogy with Parkinson's disease, in which neuro-degeneration of dopaminergic neurons causes symptoms that can be successfully treated by administering L-DOPA, the precursor of dopamine. Multiple studies of cholinergic precursors have led to essentially negative results, which do not offer meaningful hope for improvement in patients with Alzheimer's disease.

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CEREBRAL VASODILATORS Cerebral vasodilators were originally explored as treatments for dementia based on the hypothesis that cognitive loss was caused by atherosclerosis of cerebral vessels. Thus, carbon dioxide, carbonic anhydrase inhibitors, anticoagulants, nicotinic acid (a vitamin B6 derivative), pyritinol, meclofenate, vitamin E, hyperbaric oxygen, papaverine, cyclandelate, isoxuprine, vincamine, and cinnarizine have all been tested to improve oxygen delivery to the brain. However, none of these strategies has proved to be effective, and the hypothesis that faulty circulation is implicated in the dementia process is no longer tenable. Some carryover use of these compounds, which were originally marketed in the era of the "faulty brain circulation hypothesis of dementia," includes use nafridrofuryl in some European countries for elderly confused patients, but improvement is inconsistent. Cin-nazine is a vasodilating and calcium antagonist compound prescribed in Europe for vertigo and dementia related to chronic ischemia, with equivocal efficacy. Pentoxi-fylline is a vasodilator, which may improve memory in animals but has not been conclusively shown to do so in patients with dementia. Nimodipine is a calcium channel blocker marketed for cerebrovascular disease in some countries and specifically for lessening vasospasm in subarachnoid hemorrhage in many countries. It may normalize cellular calcium levels or possibly affect another mechanism, such as calcium-activated enzymes involved in cognition. Nimodipine was therefore tested extensively in Alzheimer's disease, where it failed to show efficacy in improving cognitive functioning. Calcium channel blockers are used as possible neuroprotective and/or cognitive enhancing agents in Japan and in some European countries.

METABOLIC ENHANCERS So-called metabolic enhancers include Hydergine, the brand name of a mixture of ergot alkaloids, the first FDA-approved drug of this group, which was marketed for a while for the treatment of dementia, although not specifically for memory disturbances in Alzheimer's disease. It also was developed during the era when Alzheimer's disease and dementia in general were believed to result from vascular disease. Hydergine was marketed as a "cerebral vasodilator" owing to its putative but fairly weak alpha adrenergic antagonist actions, which might be expected to cause dilation of blood vessels. Subsequently, the drug was reclassified as a metabolic enhancer because of its ability to change second-messenger cAMP levels, and because of the possibility that it acts as a partial agonist at dopamine, serotonin, and norepinephrine receptors. Several studies of higher doses of Hydergine have shown some beneficial effects in dementia, especially when cognitive impairment is mild. Several reports indicate that improved mood is more pronounced than change in cognitive status. Currently, there is no current acceptance of how Hydergine or other putative metabolic enhancers or cerebral vasodilators might be useful, especially in the United States.

VITAMINS AND HORMONES Vitamins and hormones such as B12, thiamine, and zinc have been administered since abnormalities have been described in Alzheimer's disease. However, most studies of replacement therapy with these agents have been negative. Gingko biloba may improve cognitive functioning according to some reports, although the size of the effect and generalizability of the finding remain uncertain, as do the effects of other herbs. Chelation therapy is used by some practitioners to remove aluminum, based on speculation regarding the role of aluminum in Alzheimer's disease. Trials with chelating agents such as desferioxamine, however,

have been negative, and the potential efficacy of future chelation therapy is uncertain. Chelation therapy is now largely considered to be an expensive and elaborate placebo for Alzheimer's disease.

NOOTROPIC DRUGS Nootropic drugs are a class of psychotropic drugs that enhance learning acquisition and reverse learning impairments in experimental animals. The term nootropic was introduced to describe a group of drugs that have the ability to improve certain brain mechanisms postulated to be associated with mental performance. The hypothesized main features of nootropic agents, in addition to the ability to enhance memory and learning, are the following: (1) facilitation of the flow of information between the cerebral hemispheres; (2) enhancement of the resistance of the brain to physical and chemical assault; and (3) lack of sedative, analgesic, or neuroleptic activity. The naturally occurring agent acetyl-L-carnitine, formed by acetylation of carnitine in mitochondria, has an analogous structure to ACh and is sometimes classified as a nootropic agent or as a weak ACh agonist.

Limited data exist in patients with cerebral ischemia in Japan, some of which suggest improvements in functioning. One idea is that a nootropic drug enhances cellular protection by inhibiting the formation of damaging lipid peroxides in cellular ischemia as well as the increased lactate production that follows interrupted blood flow. The chemical structure of the prototype nootropic, piracetam, is a derivative of gamma aminobutyric acid (GABA). As yet, however, there is no established mechanism of action for nootropics at GABA neurons, GABA receptors, or elsewhere. Some scientists hypothesize that nootropics act as metabolic enhancers by influencing cerebral energy reserves and by increasing energy-containing chemicals such as ATP in the brain. The initial nootropic compound was piracetam, but several more have since been developed, including pramiracetam, oxiracetam, and aniracetam. Limited data suggest that nootropics may be useful in improving memory,

mood, or behavioral functioning in patients with mild to moderate senile dementia but not in severely demented patients. These agents are used primarily Outside the United States, as no nootropic is approved for any use in the United States.

Research strategies for age-associated memory impairment, mild cognitive impairment, and presymptomatic or early symptomatic treatment of Alzheimer's disease. If we live long enough, will we all be demented? Is aging hazardous to our cholinergic neurons? Over half of elderly residents living in the community complain of memory impairment. They have four common complaints; namely, as compared with their functioning of 5 or 10 years ago, they experience a diminished ability (1) to remember names, (2) to find the correct word, (3) to remember where objects are located, and (4) to concentrate. When such complaints occur in the absence of dementia or depression, it is called age-associated memory impairment. Fortunately, it does not appear that the majority of those with such complaints go on to develop Alzheimer's disease, but there is intense interest in early recognition and prevention of progression for those who are destined to have Alzheimer's disease. Thus, we are embarking on an era of extensive presymptomatic and very early symptomatic treatments. This was mentioned briefly as well in Chapter 11 on schizophrenia. The idea here is not to remove current symptoms but to prevent future symptoms and deterioration. There are many methodological and logistical problems with conducting such studies in both schizophrenia and Alzheimer's disease, including the difficulty in decid-

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ing which subjects to enter into the study; the expense (because these studies need huge numbers of patients and take a very long time to conduct); the problems in defining satisfactory end points (when does one have early schizophrenia or Alzheimer's disease, etc.?) Assuming that all these methodological points can be addressed, nevertheless a number of novel psychopharmacological agents are being used to test several provocative hypotheses.

First, of course, the cholinesterase inhibitors are being administered to see if they can prevent or delay the onset of dementia. Also, estrogen (in women) and antiinflammatory agents (in rheumatoid arthritis and in uncontrolled use) have already suggested a lowered incidence of Alzheimer's disease, so these agents are similarly being tested in randomized trials. The idea behind the estrogen trials is that estrogen may be a neurotrophic factor (see Chapter 14 on psychopharmacology of the sexes). The hypothesis behind the anti-inflammatory trials is that amyloid deposition precipitates an inflammatory reaction, which leads to further neuronal damage, but interruption of this reaction, could halt the degenerative process. Thus, a whole host of agents that could theoretically interrupt such an inflammatory cascade are all currently being tested in this manner, including old-fashioned nonsteroidal antiinflammatory drugs (NSAIDS), the new generation version called cyclooxygenase type 2 (COX-2) inhibitors, the free-radical scavenger vitamin E, and the potential neuroprotective and monoamine oxidase B inhibitor deprenyl.

A theoretical off-shoot of this strategy is to use neuroprotective agents, such as glutamate antagonists, to interrupt a theoretically excitotoxic neurodegenerative process in Alzheimer's disease. This has been discussed extensively in Chapter 10 for schizophrenia (Figs. 10—26 to 10—31), along with potential treatment strategies (Figs. 10—32 and 10—33) that apply to Alzheimer's disease as well. A major research strategy for the discovery of novel therapeutics in Alzheimer's disease is to target the glutamate system, which might mediate progressive neurodegeneration by an excitotoxic mechanism. The therapeutic idea underlying the development of neuroprotective agents is that such drugs could stop inappropriate or excessive excitatory neurotransmission and thereby halt the progressive neurodegenerative course of various neurodegenerative disorders. No such agents are currently available for clinical use. In the long run, it may also be possible to interrupt the loss of degenerating neurons in Alzheimer's disease through apoptotic demise by the administration of caspase inhibitors, as mentioned in Chapter 11 in our discussion of possible novel therapeutics for schizophrenia as well.

Other research strategies for Alzheimer's disease and other dementias

CHOLINERGIC STRATEGIES (NONCHOLINESTERASE INHIBITION) One approach

that still has only met with limited success is to target cholinergic receptors selectively with a cholinergic agonist. Various agonists are under investigation, especially agonists for the Ml cholinergic receptor (Fig. 12 — 35). Nicotinic agonists are also being tested (Fig. 12 — 36). The possible advantage of stimulating nicotinic cholinergic receptors is suggested by several epidemiological studies finding a lower risk for Alzheimer's disease among smokers. In addition, central nicotinic receptors are reduced in brains of Alzheimer patients. In Chapter 11, we discussed the development of alpha-7-nicotinic cholinergic agonists as a novel therapeutic strategy for schizophrenia. This could be useful for cognitive enhancement in Alzheimer's disease

FIGURE 12-35. Use of agonists for the muscarinic 1 receptor for the treatment of Alzheimer's disease. Another approach that still has only met with limited success is to target cholinergic receptors selectively with a cholinergic agonist. Various agonists are under investigation, especially agonists for the M1 cholinergic receptor.

as well. Yet another possibility is to develop an agent that can release acetylcholine, perhaps through blocking potassium channels. This approach is heavily dependent, however, on the presence of intact remaining presynaptic cholinergic nerve terminals and may therefore only be effective in the early stages of the disease. Several such agents are under clinical investigation.

ALTERING AMYLOID PRECURSOR PROTEIN OR APO-E BIOSYNTHESIS Current

therapeutics are aimed at the possibility that altering the synthesis of APP (Fig. 12 — 37) or APO-E (Fig. 12 — 38) might change the deposition of beta amyloid (see

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FIGURE 12-36. Use of agonists for the nicotinic cholinergic receptor for the treatment of Alzheimer's disease. Nicotinic agonists are also being tested in Alzheimer's disease. The possible advantage of stimulating nicotinic cholinergic receptors is suggested by several epidemiological studies finding a lower risk for Alzheimer's disease among smokers. In addition, central nicotinic receptors are reduced in brains of Alzheimer's patients. To date, no such agents have been licensed for the treatment of Alzheimer's disease.

Figs. 12—16 to 12—22) and prevent the progressive course of Alzheimer's disease. Direct inhibition of gene expression for the biosynthesis of these proteins is not currently possible and is currently not a very feasible therapeutic possibility. Perhaps a more realistic therapeutic possibility would be to inhibit the synthesis of beta amyloid, in much the same way that lipid-lowering agents act to inhibit the biosynthesis of cholesterol in order to prevent atherosclerosis. This could be done by means of enzyme inhibitors, such as protease inhibitors, which are at least a theoretical possibility.

FIGURE 12 — 37. One current therapeutic approach to preventing the neuronal destruction in Alzheimer's disease is based on the molecular neurobiology of beta amyloid formation and the involvement of amyloid precursor protein (APP) in this process. If the synthesis of APP could be prevented, it might change the deposition of beta amyloid and prevent the progressive course of Alzheimer's disease. Another possibility is to inhibit the synthesis of beta amyloid itself, in much the same way that lipid-lowering agents act to inhibit the biosynthesis of cholesterol in order to prevent atherosclerosis.

FIGURE 12 — 38. Another current therapeutic approach to preventing the neuronal destruction in Alzheimer's disease is also based on the molecular neurobiology of beta amyloid formation but emphasizes the involvement of APO-E binding protein in this process. If the synthesis of "good" APO-E could be ensured or the synthesis of "bad" APO-E prevented, possibly amyloid would not accumulate in the neuron. Changing the deposition of beta amyloid would hopefully prevent the progressive course of Alzheimer's disease.

antipsychotics), the future treatment for Alzheimer's disease is not likely to consist of one drug acting by a single pharmacological mechanism. Despite the economic incentives for developing a single treatment of choice and the methodological incentives for studying one drug at a time, it seems likely that a disorder with cognitive and memory disturbance, behavioral disturbance, and a degenerative component will require some kind of combination of drugs, such as a procholinergic agent for memory working with an atypical antipsychotic for behavior and a neuroprotec-tive agent for neurodegeneration, or some such blend. Perhaps psychopharmaco-logical treatments for cognitive disorders in the future will need to borrow a chapter out of the book of cancer chemotherapy and HIV/AIDS therapy, as we have argued as well for new therapies in schizophrenia, where the standard of treatment is to use multiple drugs simultaneously so that several independent therapeutic mechanisms work synergistically to provide a total therapeutic response that is greater than the sum of its parts.

Summary

In this chapter, we have looked at two topics in cognitive enhancement: attention and memory. We have first reviewed the role of dopamine and norepinephrine/ noradrenaline in the neuropharmacology of attention, and then the syndrome of attention deficit disorder as a common problem associated with a disorder of attention. We then discussed the use of stimulants for improving attention, primarily in attention deficit disorder, and reviewed the pharmacological mechanisms of action of methylphenidate, d and 1 amphetamine, pemoline, and secondary therapies such as clonidine and guanfacine.

The second major topic of this chapter was the role of acetylcholine in memory, and how cholinergic systems are disrupted in Alzheimer's disease by a number of processes that form plaques and tangles in the cholinergic neurons projecting from the nucleus basalis of Meynert, and more diffusely throughout the brain as well. We then reviewed the major cholinergic strategies for enhancing memory and slowing the rate of memory loss in Alzheimer's disease, namely, cholinesterase inhibition by a number of agents including donepezil and tacrine as well as promising new therapies such as rivastigmine, metrifonate, physostigmine and galanthamine. Finally, numerous strategies for treating Alzheimer's disease based on current understanding of pathophysiologic mechanisms of this disorder were reviewed.