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|Neuropsychopharmacology: The Fifth Generation of Progress|
Deborah B. Marin and Kenneth L. Davis
Several pharmacologic strategies have been used in attempts to treat the cognitive deficits in Alzheimer's disease. Trials with nootropics that presumptively alleviate the symptoms of mental aging and cerebral insufficiency exemplify nonspecific empirical treatments. In distinction, the neurotransmitter replacement strategies that have been explored are based on specific neurotransmitter deficits demonstrated in the brains of Alzheimer's disease patients. The consistently reported central cholinergic depletion in Alzheimer's disease in conjunction with the cholinergic system's involvement in learning have generated many studies that have focused on cholinergic enhancement. Although the cholinergic strategy has yielded some promising findings, including the approval of the first drug indicated for Alzheimer's disease, the results have not yet demonstrated robustness and universality. The results observed with cholinergic replacement may in part be due to the fact that other neurotransmitter systems are affected in Alzheimer's disease. It can therefore be argued that multiple neurotransmitter replacements may be more efficacious than a purely cholinergic approach.
An alternative to these palliative treatments of Alzheimer's disease is the development of approaches that interfere with the neurodegenerative process of the illness. This chapter will review the cholinergic and combined neurotransmitter approaches and will then discuss strategies designed to modify the course of Alzheimer's disease because of their presumed alteration of the fundamental pathophysiological processes in the disease.
THE CHOLINERGIC SYSTEM
There is a convergence of evidence supporting the critical role of the cholinergic system in Alzheimer's disease: (a) Centrally active anticholinergic agents produce attention and memory deficits; (b) cholinergic neurotransmission modulates memory and learning; (c) lesions of the central cholinergic system create learning and memory impairments which are attenuated with cholinergic agents; and (d) postmortem studies of Alzheimer's patients consistently document cholinergic abnormalities with the degree of cognitive impairment (45, 47).
Both muscarinic and nicotinic receptors have been implicated in cognition and in Alzheimer's disease. Five muscarinic receptor subtypes, known as m1–m5, have been demonstrated and localized in the central nervous system (CNS) (71). Studies with pharmacological antagonists have identified four classes of muscarinic receptors that are known as M1, M2, M3, and M4. The subtypes identified by antisera (m1–m5) show substantial overlap with the receptor types identified pharmacologically (M1–M4) (71). The postsynaptic M1 receptors, whose main subtype is found in the cerebral cortex, have been implicated in memory processes (42). Activation of the m1, m3, and m5 receptors causes cellular excitation, whereas activation of the m2 and m4 subtypes produces inhibitory effects. The excitatory role of the m1 and m3 receptors, combined with their location in the cortex and hippocampus, makes these sites potential targets for pharmacologic treatment of the cognitive deficits in Alzheimer's disease.
There exist at least three different subtypes of nicotinic receptors in the human frontal cortex. The nicotinic receptors can be divided into three types, termed super-high, high, and low affinity (42). Brains of patients with Alzheimer's disease demonstrate decrements in the high-affinity nicotinic sites (42). In animal studies, nicotinic antagonists produce a dose-dependent impairment of memory comparable to what is observed with scopolamine (17). The nicotinic and muscarinic systems appear to jointly modulate performance in learning and memory (51). Animal data suggest that presynaptic nicotinic receptors mediate a positive feedback mechanism that modulates cholinergic activity (17). The development and implementation of safe and effective pharmacologic treatments have not yet fully utilized the above basic science findings (see also Cholinergic Transduction, Structure and Function of Colonergic Pathways in the Cerebral Cortex, Limbic System, Basel Ganglia and thalamus of the Human Brain, Funcutional Heterogeneity of Centeral Cholinergic Systems, and Late-Onset Schizophrenia and related Psychoses).
The use of muscarinic agonists for the treatment of Alzheimer's disease is supported by their beneficial effects on memory and learning in animals in hypocholinergic states (25) and by the observed relative preservation of postsynaptic M1 sites in Alzheimer's disease (69).
RS-86 (2-ethyl-8-methyl-2,8-diazospiro-4,5-decan-1,3-dianhydrobromide) is a muscarinic receptor agonist that has a relatively higher affinity for M1 sites than for M2 sites. Oral administration of RS-86 has been shown to produce minimal or no effects in patients with Alzheimer's disease (26).
Bethanecol is a synthetic b-methyl analogue of acetylcholine that acts on both M1 and M2 receptors. Studies conducted on small samples of patients have demonstrated modest improvement with this agent (50). Variable dose responses may contribute to this agent's heterogeneous efficacy (50). Bethanecol must be administered by an intracerebroventricular (ICV) route because of its poor blood–brain barrier permeability. ICV administration carries substantial risks, including perioperative complications, pneumocephalus, seizures, and chronic subdural hematoma. Thus, ICV bethanecol treatment is not likely to be a viable option for cholinergic enhancement in Alzheimer's disease.
Arecoline is a natural alkaloid with both muscarinic and nicotinic agonist properties. Modest improvement in picture recognition, verbal memory, and visuospatial construction after arecoline infusion have been observed in patients with Alzheimer's disease (49).
Oxotremorine is a synthetic nonselective muscarinic agonist with a half-life lasting several hours. Oxotremorine administration to Alzheimer's disease patients did not have cognitive enhancing effects and was associated with significant side effects, including panic and depression (14).
AF102B [±cis-2-methyl-spiro(1,3-oxathiolane-5,3˘) quinuclidine] is a structurally rigid analogue of acetylcholine. Unlike most of the cholinergic agents described above, AF102B is a selective M1 agonist (21). This characteristic is desirable because activation of the M2 autoreceptors can result in decreased acetylcholine release. AF102B, like other cholinergic agonists, reverses the cognitive impairments observed in hypocholinergic animals (21). Azaspirodecanes (2-methyl-1,3-dioxaazaspiro[4,5]-decanes) are a group of muscarinic compounds that are analogues of the tertiary amine AF-30. Some of these analogues are potent muscarinic agonists that have yet to be clinically tested.
Intravenous nicotine administration to Alzheimer's disease patients has been shown to improve performance in recall (40). Unfortunately, the anxiety and depressive symptoms associated with nicotine administration represent toxic effects that lessen the clinical utility of this compound.
None of the cholinergic agonists have yielded robust clinical benefit. Yet, it may very well be that the potential benefits of cholinergic agonists have not been adequately tested. The diverse physiologic effects of muscarinic and nicotinic activation limit the clinical usefulness of the agents currently employed. Arecoline, RS-86, and bethanecol probably do not have much effect on the m1 and m3 receptor sites in the cortex. The importance of targeting the appropriate site is exemplified by the compound oxotremorine, which actually decreases acetylcholine release through its action on the presynaptic m2 receptor. Targeting the appropriate receptor subtype in order to enhance cognition may be true for nicotinic receptors as well because there exist at least three different subtypes of these receptors. Optimal pharmacological manipulation of cholinergic subtypes has yet to be attempted.
Future directions in cholinergic agonist development may include manipulation of the subtypes of muscarinic and nicotinic receptors that are most likely to enhance cognitive function without adverse side effects. Such agents may be used in conjunction with other cholinergic strategies to treat the cognitive deficits in Alzheimer's disease. Postsynaptic therapy, however, is limited by the fact that agonist administration provides a nonphysiologic tonic stimulation, whereas the physiologic state is characterized by phasic mechanisms.
Acetylcholinesterase inhibitor treatment for Alzheimer's disease is based on the rationale that cholinergic neurotransmission is enhanced through preventing the breakdown of acetylcholine. The agents to be reviewed are physostigmine, tetrahydroaminoacridine, HP 029, and galanthamine.
Physostigmine is a natural alkaloid that is absorbed in the gastrointestinal tract, subcutaneous tissue, and mucous membranes. Most studies using parenteral administration of physostigmine have documented transient cognitive improvement in at least a subgroup of patients with Alzheimer's disease (34). Oral administration of the compound has been shown to have some efficacy as well. It has been suggested that long-term treatment with physostigmine may delay deterioration in Alzheimer's disease (28). Obviously, these intriguing reports will stimulate further investigation. The limited efficacy of physostigmine may be due to several factors. The unpredictable blood, and therefore CNS, concentrations achieved with a given dose necessitate individual titration of medication. This agent's peripheral-to-brain partitioning also lessens its clinical utility. Blood levels required to achieve CNS concentrations necessary for cognitive enhancement may be associated with significant adverse effects. Physostigmine's short half-life is also problematic because this characteristic causes continuous fluctuations in blood levels and the need for frequent administration. The compound's inverted U-shape dose–response curve can lead to nonoptimal blood levels which also limit beneficial effects.
HP 029 (velnacrine maleate) is a tetrahydroaminoacridine derivative that inhibits true cholinesterase and pseudocholinesterase. The drug reverses scopolamine- or lesion-induced memory impairment in rodents (20). There is marked intersubject variability in tolerance to the drug within the therapeutic dose range. A double-blind, placebo-controlled, enriched population design consisting of a 7-week dose-ranging phase followed by a 6-week dose replication phase demonstrated modest clinical improvement in a subset of the 195 patients with Alzheimer's disease (39). Unfortunately, a high incidence of liver toxicity is observed with this agent.
Galanthamine is a tertiary amine of the phenthrene group. Administration of this medication results in cerebral concentrations that are three times higher than its plasma level. Galanthamine's half-life of 7 hr is longer than that observed with tetrahydroaminoacridine or physostigmine (65). Some studies have suggested the efficacy of galanthamine in AD (65), whereas others have not (12).
9-Amino-1,2,3,4-tetrahydroaminoacridine (THA) is a synthetic acetylcholinesterase inhibitor. THA has been shown to increase presynaptic acetylcholine release through blocking slow K channels and to increase postsynaptic monoaminergic stimulation by interfering with norepinephrine and serotonin uptake. These latter characteristics of THA occur at concentrations higher than those required to achieve acetylcholinesterase inhibition and therefore probably do not contribute to the drug's clinical effects.
Double-blind, placebo-controlled studies have assessed the efficacy of THA in large samples of Alzheimer's disease patients (7, 15, 16, 17, 19, 23). THA and lecithin administration produced statistically significant improvement in the Mini Mental State score in two investigations (16, 23) and minimal cognitive improvement in another study of Alzheimer's patients (17). A 6-week crossover trial using an enriched-population design with 215 patients (15) demonstrated that patients treated with THA showed significantly less decline in cognitive function than did the placebo-treated group, as assessed by the Alzheimer's Disease Assessment Scale cognitive subscale. A 12-week parallel group design that included 273 patients demonstrated a significant cognitive improvement with THA (19). Side effects with THA are nausea, abdominal distress, tachycardia, and liver toxicity. The liver damage noted with this agent is dose-dependent and reversible upon its discontinuation. The THA data indicate that anticholinesterase therapy is likely to benefit a subgroup of patients with Alzheimer's disease. The lack of efficacy in some patients in these investigations may be due to underdosing. Improvement with THA appears to be dose-dependent, with over 50% of patients improving at the highest doses (19). The results from these large-scale studies contributed to THA being the first FDA-approved drug for the treatment of Alzheimer's disease. Nonetheless, the ideal cholinesterase has not yet been tested. This agent would have (a) a long enough half-life that permits one dose per day, (b) minimal peripheral side effects and toxicity, and (c) good absorption and CNS penetration.
Cholinergic Releasing Agents
The use of acetylcholine releasers is based on their enhancement of stimulus-induced acetylcholine delivery into the synapse. Such an action would improve the signal-to-noise ratio during neuronal transmission without the toxicity associated with cholinesterase inhibitors or the distorted temporal pattern of neurotransmission observed with cholinergic agonists.
Linopirdine [DuP 996; 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one] enhances potassium-stimulated release of acetylcholine, dopamine, and serotonin without affecting basal neurotransmitter release. DuP 996 has been shown to protect against hypoxia-induced passive avoidance deficits in rodents. In humans, DuP 996 administration induces electroencephalographic changes consistent with vigilance-improving properties (56).
HP 749 [N-(n-propyl)-N-(4-pyridinyl)-1H-indol-1-amine] is an indole-substituted analogue of 4-aminopyridine which is well-absorbed after oral administration. Preclinical studies demonstrate that HP 749 reverses the passive avoidance deficit produced by nucleus basalis and dual lesions in rodents (10). Clinical trials to determine the efficacy of HP 749 in humans have yet to be performed.
Combined Treatment Approaches
Several lines of evidence demonstrate that multiple neurotransmitter systems are involved in cognition and in Alzheimer's disease, thereby suggesting that combined treatment approaches are likely to be more efficacious than cholinergic monotherapy. Animal studies demonstrate that noradrenergic brain lesions negate cholinomimetic enhancement of memory in hypocholinergic animals (25). Administration of the alpha-adrenergic agonist clonidine will, in turn, restore the efficacy of cholinomimetic treatment in animals with noradrenergic and cholinergic lesions (25). Furthermore, postmortem studies demonstrate major neurotransmitter losses of the noradrenergic system in Alzheimer's disease patients. All these findings support the use of a combination of cholinergic and noradrenergic agents to treat Alzheimer's disease. This combined approach has been shown to be safe in humans. A pilot study with clonidine and physostigmine treatment in nine patients demonstrated the feasibility and safety of combining these agents in Alzheimer's disease (13).
Studies evaluating the efficacy of combination treatment have primarily been performed with cholinesterase inhibitors and the monoamine oxidase B inhibitor 1-deprenyl. Double-blind, placebo-controlled trials with small patient samples suggest that subchronic treatment with 1-deprenyl (10 mg/day) improves performance on attention, memory, and learning tasks (32).
A double-blind, placebo-controlled 4 week crossover study demonstrated that 1-deprenyl augmentation of either THA or physostigmine treatment significantly improved performance on the cognitive subscale scores of the Alzheimer's Disease Assessment Scale (59), suggesting possible additive effects of 1-deprenyl and cholinesterase inhibitors. However, another study of 16 Alzheimer's disease patients found no significant improvement with the combination of physostigmine and deprenyl (63). Inadequate physostigmine levels achieved in this latter trial might have led to spuriously poor results.
Future studies are needed to determine the potential efficacy of combination treatments. The 1-deprenyl results need to be replicated with larger patient samples and longer treatment trials to determine if this agent alone or in combination with other agents have clinically significant effects on cognition in patients with Alzheimer's disease.
APPROACHES TO SLOW PROGRESSION
The approaches described above generally offer palliative treatment to augment the functioning of deficient neurotransmitter systems in Alzheimer's disease. However, the suggestion that restoring either cholinergic transmission or some other property of cholinesterase inhibitors may slow the course of the illness needs to be pursued. Advances in the understanding of the biology of Alzheimer's disease permit the development of strategies that interfere with the underlying pathophysiology of the illness. The rationale for, and description of, potential neuroprotective strategies will be discussed.
Glutamate is the major excitatory neurotransmitter of the pyramidal neurons. The postsynaptic effects of glutamate are mediated via several different receptor subtypes that can be classified according to their prototypic agonists, namely, N-methyl-D-aspartate (NMDA), quisqualate (QUIS), and kainate (KAIN). Extensive loss of NMDA sites has been demonstrated in some, but not all, studies of brains of Alzheimer's disease patients (61). These findings suggest that development of glutamatergic treatment strategies must consider whether there is a glutamate deficiency to treat in Alzheimer's disease.
The glutamatergic system has been implicated in learning and memory (30). NMDA receptor blockade with aminophosphonopentanoic acid disrupts spatial learning and prevents long-term potentiation, which is considered a physiological model for memory. In addition to its beneficial properties, glutamate is neurotoxic and implicated in the pathogenesis of several CNS neurodegenerative disorders. The neurotoxic effects of glutamate can occur via both NMDA and non-NMDA receptors.
Given that glutamate can enhance learning as well as produce neurotoxicity, determination of the optimal glutamatergic strategy has to consider the complex functions of glutamate and the various glutamatergic receptors. Both NMDA and non-NMDA sites could be potential targets for therapeutic approaches. A strategy that enhances glutamatergic transmission is supported by the presynaptic glutamatergic losses observed in Alzheimer's disease. However, augmentation of glutamatergic functioning could increase neuronal damage. Glutamatergic blockade could protect against neurotoxic effects, yet potentially interfere with memory processing.
Antagonism of the glycine modulatory site of the NMDA receptor could decrease neurotoxicity mediated by glutamate. 1-Hydroxy-3-amino-2-pyrrolidone (HA-966) and 1-aminocyclobutane (ACBC) appear to inhibit NMDA-specific binding and block NMDA responses (27, 68). An optimal antagonist at the glycine site would interfere with glutamate's neurotoxicity without causing cognitive impairment.
Non-NMDA antagonism may provide a potential therapeutic strategy to interfere with glutamatergic functioning and neurotoxicity. Antagonists of the non-NMDA receptors include 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline (NBQX), 6, 7-dinitroquinoxaline-2, 3-dione (DNQX), and 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) (60). These agents have been shown to protect against the effects of ischemia (60). Clinical trials are necessary to determine whether these agents can alter the course of Alzheimer's disease.
Given the complex sequelae of glutamatergic activation, a partial agonist approach is rational. The glycine agonist milacemide enhances learning in normal and amnestic rodents. One clinical trial of this drug, however, did not enhance cognition and was accompanied by significant liver toxicity (48). As with other glutamatergic modulating agents, further clinical studies are necessary to test their potential efficacy (also see Excitatory Amino Acid Neurotransmission, for related topic).
Several studies demonstrate increased free radical production in aging and Alzheimer's disease. Metal ions, increased superoxide-dismutase-derived hydrogen peroxide fluxes, and damaged mitochondria can contribute to cell damage mediated by free radicals. Free radical production in Alzheimer's disease might also be caused by amyloid beta protein, glutamate, increased levels of monoamine oxidase, or another toxic event (3). All these findings suggest the use of antioxidants to treat Alzheimer's disease.
L-Deprenyl's inhibition of monoamine oxidase B support its use as a free radical scavenger for the treatment of Alzheimer's disease. Vitamin E and idebenone are also potential antioxidant treatments for Alzheimer's disease. Alpha tocopherol, a biologically active constituent of vitamin E, interferes with the effects of lipid peroxidation by trapping free radicals (70). Vitamin E and idebenone have been shown to prevent cell death caused by glutamate and amyloid beta protein (3, 43). Because of their antioxidant properties, L-deprenyl and vitamin E have been investigated as therapies to slow the progression of Parkinson's disease. A multicenter double-blind, placebo-controlled trial has demonstrated that deprenyl given at 10 mg/day delays the onset of disability associated with early Parkinson's disease (46). A multicenter double-blind, placebo-controlled trial is now underway to determine the ability of L-deprenyl and vitamin E, administered alone or in combination, to slow the progression of Alzheimer's disease.
Several lines of evidence demonstrate the involvement of the immune system and inflammation in Alzheimer's disease. Histochemical studies demonstrate the presence of several markers of inflammation in Alzheimer's disease brains. Furthermore, components of the immune response have been localized in senile plaques, suggesting a role for the immune response in the pathophysiology of Alzheimer's disease. The implication of the presence of an immune response in the brain is that host cells can be inadvertently attacked and destroyed by these molecules.
Increased numbers of reactive glia and microglia (believed to be related to macrophages) have been observed in postmortem brain tissue (24). Of particular relevance is that complement proteins, including the membrane attack components C5–C9, have also been identified in senile plaques, tangles, and dystrophic neurites (36). These findings suggest that the complement system could be involved in the tissue destruction in Alzheimer's disease. Although the stimulus for complement activation in Alzheimer's disease brains is unclear, it has been shown that amyloid beta (Ab) protein can activate the classical complement pathway (54).
Elevated concentrations of cytokines, agents which signal cell proliferation and the production of mediators of the inflammatory response, exist in Alzheimer's disease patients. Because interleukins can enhance amyloid precursor protein (APP) production, their presence in the Alzheimer's disease brain may have substantial import (1). Acute-phase proteins, inflammatory response molecules that are induced by cytokines, are elevated in Alzheimer's disease. Alpha-2 macroglobulin and alpha-1 antichymotrypsin (ACT) have been demonstrated in amyloid deposits in Alzheimer's disease (2). Increased ACT concentrations is particularly intriguing because it is a proteinase inhibitor.
Clinical data derived from other illnesses support the use of antiinflammatory agents to treat Alzheimer's disease. The prevalence of Alzheimer's disease in rheumatoid arthritis clinic patients, a population who was very likely to have received chronic anti-inflammatory therapy, was significantly less than that observed in the general population over age 64 (37). Thus, therapies for autoimmune diseases can serve as models for the choice of anti-inflammatory treatment strategies in Alzheimer's disease.
Given the host of immunological reactions noted in AD and their implication in cell death, immunomodulatory therapies might offer treatments to slow the course of the illness. A 6-month double-blind study with the nonsteroidal anti-inflammatory agent indomethacin demonstrated that Alzheimer's disease patients who received active drug declined significantly less than did patients who received placebo (53). Steroids offer a logical antiinflammatory therapy for Alzheimer's disease, because these agents are widely used and efficacious for several inflammatory diseases in the CNS, including lupus cerebritis and multiple sclerosis. Unfortunately, the systemic toxicity of steroids limits the use of high doses or long-term treatments with these agents. Animal studies suggest that prolonged exposure to high doses of glucocorticoids is toxic to hippocampal neurons (57). Low-dose steroid therapy (e.g., 10 mg/day of prednisone) may be the safest strategy because this dose is well-tolerated and effective in patients with rheumatoid arthritis.
Colchicine is another possible candidate for the treatment of Alzheimer's disease. This drug effectively treats familial Mediterranean fever, a condition in which recurrent inflammation and renal amyloidosis occur. Although the amyloid constituents in familial Mediterranean fever and Alzheimer's disease differ, both illnesses involve chronic inflammation, elevated acute-phase proteins, and abnormal processing of a precursor protein leading to deposition of insoluble amyloid fragments. These similarities suggest the potential therapeutic efficacy of colchicine for patients with Alzheimer's disease.
Hydroxychloroquine has been used as an antimalarial agent, but it has been adopted as a safe and effective second-line agent for the treatment of rheumatoid arthritis and lupus erythematosus. This agent suppresses cytokine and acute-phase reactant levels in these illnesses. The efficacy of hydroxychloroquine is thought to be related to its effects on the immune response and lysosomal functioning. Hydroxychloroquine is a lysomotropic agent that interferes with lysosomal enzymatic activity by increasing the pH in these organelles and by stabilizing lysosomal membranes. Hydroxychloroquine's safe clinical profile as a chronic treatment for rheumatoid arthritis supports it as a possible candidate for the treatment of Alzheimer's disease.
Alzheimer's disease is characterized by neurofibrillary tangles and extracellular deposits of (Ab) protein. Ab protein is derived from processing of APP (52). The presence of Ab protein in Alzheimer's disease may result from several causes. APP can undergo secretory processing that occurs within the domain of Ab protein, thereby precluding amyloidogenesis (64). In contrast, lysosomal processing of APP can produce amyloidogenic fragments (18). Increased synthesis of APP could, in turn, overwhelm the capacity of the cell to degrade its substrate through the regular pathway. A disrupted balance between protease and protease inhibitors in the brain could lead to abnormal degradation of APP and increased production of Ab (52). Two forms of APP contain a Kunitz-type protease inhibitor (KPI) insert that may provide protease inhibitor activity to APP. Protease inhibitors have been shown to modulate cell growth and might be involved in the neuronal sprouting activity associated with plaques (35). The presence of ACT in plaques further supports a role of plasma proteinase inhibitors in amyloidogenesis.
Agents that interfere with Ab's production or deposition offer potential therapeutic strategies to alter the course of Alzheimer's disease. The lysomotropic properties of colchicine and hydroxychloroquine suggest these agents as candidates to interfere with Ab protein production. Although colchicine is used as a neurotoxin in laboratory studies, no significant CNS toxicity has been reported with clinical use of this agent. A study using cell cultures suggests that a lysosomal inhibitor may shunt APP to the secretase pathway, thereby leading to the release of nonamyloidogenic fragments (5). Numerous pharmaceutical companies have active drug discovery programs directed at inhibiting amyloidogenesis through specific protease inhibitors. The findings that apolipoprotein type 4 allele is a risk factor for the development of Alzheimer's disease and is localized in senile plaques suggest that modulation of this chaperone may prevent amyloid deposition (62) (see also Issues in the Long-Term Treatment of Anxiety Disorders).
The cell loss in Alzheimer's disease and in other neurodegenerative illnesses suggests a role of neurotrophic factors in their pathophysiology and treatment. Several neurotrophic factors (i.e., proteins capable of altering neuronal survival, innervation, and function) have been identified (67). Nerve growth factor (NGF) represents one of these neurotrophins and has been most studied in relation to AD. NGF is primarily located in the basal forebrain, hippocampus, and cortex and acts selectively on cholinergic neurons (67). The basal forebrain cholinergic neurons possess the NGF receptor and express increased choline acetyltransferase activity in response to NGF. NGF administration has been shown to attenuate degenerative changes in cholinergic cells caused by transections of the septohippocampal pathway. NGF treatment also elevates choline acetyltransferase activity, acetylcholine synthesis, and release following partial lesions of the fimbria.
The basic and preclinical findings support the utility of NGF for the treatment of Alzheimer's disease. A case report of a patient treated subchronically with NGF demonstrates that one month of treatment was associated with improvement in verbal episodic memory, increased nicotine binding in frontal and temporal cortices, and increased cerebral blood flow (44). Limitations of NGF treatment, however, include the morbidity associated with the required intraventricular dosing, and the unknown neuronal and behavioral sequelae of its long term administration (see Neuronal Growth and Differentiation Factors and Synaptic Placidity for related topic).
There is evidence to suggest an association between aluminum and neurodegenerative diseases, including Alzheimer's disease. Aluminum administration has been shown to be neurotoxic to the cholinergic system (9). These data suggest the use of chelating agents for the treatment of Alzheimer's disease.
Desferrioxamine mesylate has been investigated as a chelating agent to treat Alzheimer's disease. This compound has a high stability constant for aluminum and has been extensively used to treat iron and aluminum overload (6). In a study of 48 Alzheimer's patients, intramuscular administration of desferrioxamine was compared to placebo or no treatment over a 2-year period (38). Patients who received desferrioxamine treatment evidenced a significant reduction in the rate of decline of daily living skills when compared to the placebo group, suggesting that this agent may slow the clinical progression of Alzheimer's disease. The therapeutic effects observed with this agent, however, may not necessarily be due to its chelating action because it has been shown to inhibit free radical formation and inflammation (38). In addition, it was hard to keep the blind in that investigation because patients receiving active treatment received injections, whereas the controls did not. The required intramuscular administration and toxic side effects of this compound do limit its clinical utility. In addition, the role of aluminum in Alzheimer's disease has been questioned (29).
Calcium Channel Blockers
Neurotransmitter synthesis and release, neuron action potentials, receptor affinity, and memory storage are calcium-dependent functions. Therefore, the age-related deficits in calcium homeostasis have been implicated in the pathophysiology of neurodegenerative conditions, including Alzheimer's disease. It has been suggested that excessive calcium influx represents the final common pathway of neuronal death after a variety of insults, including hypoglycemia, excitotoxin release, and hypoxia (8). Calcium influx has also been associated with neurofibrillary tangle-like changes in tau (8).
Calcium channel antagonists are logical choices to prevent excessive calcium influx into neurons. Alzheimer's patients treated with nimodipine at 30 mg t.i.d. have been shown to experience a prophylactic benefit from the agent (66). Higher doses of nimodipine were not as efficacious. NGF administration also is protective against cell death associated with excessive calcium influx (8). These findings suggest further investigation of calcium antagonists for the treatment of Alzheimer's disease.
METHODOLOGICAL PROBLEMS IN DRUG DEVELOPMENT
Animal models have been very useful in determining the cognitive results of disruption of neurotransmitter systems in the CNS. These studies have supported the role of the cholinergic, noradrenergic, and glutamatergic systems in memory and learning and have been used for drug development for the treatment of Alzheimer's disease. However, there are limitations inherent in these models. Lesion experiments provide only an approximation of the neurodegenerative process in Alzheimer's disease. In addition, the tasks used to assess learning and memory in animals do not necessarily represent the complex cognitive processes disrupted in Alzheimer's disease. The discrepancy between animal study findings and clinical trials can be understood in light of these limitations. The development of an animal model that has the pathophysiology observed in Alzheimer's disease will undoubtedly enhance development of new strategies to treat the illness. It is hoped that transgenic animals will offer such a model, although thus far these efforts have been disappointing (see also Issues in the Long-Term Treatment of Anxiety Disorders).
The nature of the assessments used to determine medication response needs to be considered when reviewing the efficacy of pharmacotherapies for Alzheimer's disease. Neuropsychological tests that require the patient to perform specific tasks are often used to assess drug effects on cognitive symptoms. Clinician ratings that rely on interviews with patients and caregivers are usually used to determine psychiatric symptoms, activities of daily living, and global impressions of clinical improvement. These approaches are useful and complement each other. However, the use of different measures to evaluate drug efficacy can contribute to variable treatment outcomes. A "dual outcome" strategy that measures both improvement on core cognitive symptoms and the overall magnitude of clinical improvement has been suggested as the most comprehensive assessment of the efficacy of antidementia drugs (31).
The severity of cognitive compromise in Alzheimer's disease is best evaluated with neuropsychological assessments. An instrument that measures outcome of drug trials should provide a valid measurement of cognitive impairment across several stages of the illness, have alternate forms to avoid practice effects, and have high inter-rater and retest reliability. The instruments discussed below are those that have been most often used in clinical trials.
The Mini Mental State (MMSE) and Blessed test (4, 22) are easy to administer, measure relevant areas of cognition, are available in multiple languages, and have available longitudinal data. However, both instruments do not comprehensively cover all domains of cognitive functioning and don't offer enough sensitivity to detect subtle changes in cognition. They also do not have alternate forms, leading to nonspecific carry-over effects that are problematic in clinical trials with multiple assessments.
The Alzheimer's Disease Assessment Scale (ADAS; see ref. 55) provides broad coverage of cognitive functioning and has alternate forms for the memory tests. The greater length of the ADAS relative to the Blessed and the MMSE enables this instrument to assess in more depth a range of cognitive domains. Because of its greater sensitivity to cognitive change over a broad range of severity, the ADAS has been accepted as a standard outcome measure for treatment and longitudinal studies. Longitudinal studies that have been conducted with the ADAS provide data on the expected rate of cognitive decline in Alzheimer's patients. This information permits investigators to estimate the sample size required to determine the presence of a desired drug effect over varying time intervals. For example, power calculations can be done to determine the sample size needed to detect the effect of a drug which slows the rate of deterioration by one-half relative to placebo. The sample size needed for such a study is over twice as large when drug and placebo treated patients are compared for 6 months than when they are compared for 12 months.
The rate of change in cognition observed with these tests is not independent of the baseline severity of dementia. For the ADAS, the rate of change is slower for both mild and severe dementia than for moderate dementia (33). The implication for clinical trial development is that the expected amount of deterioration for patients in a study will depend substantially upon the dementia severity at entry, suggesting stratifying patients by their severity at entry (33). Modifications of these instruments might be required for special populations, such as very mildly or severely impaired patients.
Global Change and Staging Instruments
These instruments assess both the cognitive status and the overall clinical condition of a patient. Used alone, these instruments cannot determine the cognitive efficacy of a drug because improvement on these measures may reflect noncognitive outcomes (15, 19). In addition, use of such global measures hampers quantification of the magnitude of drug effect. Global scales can be highly reliable when administered with specified procedures. However, there are few studies that evaluate the reliability and sensitivity of global change measures.
These assessments measure the patient's ability to perform everyday activities of daily living (ADLs). In clinical trials, these instruments are used to document the functional or clinical impact of therapeutic agents. The ADL instruments are not very sensitive for documenting subtle deficits in the very mildly impaired patients and usually show little change in clinical trials with this subgroup. Instruments which evaluate higher level activities [e.g., Instrumental Activities of Daily Living (IADL)] tend to be more specific for less impaired individuals. Scores on IADL change substantially at follow-up with mildly impaired patients, but then change very little in moderate-to-severe patients because of a ceiling effect. Although ADL impairment is well-documented in Alzheimer's disease, no specific instrument is accepted as a valid measurement of clinical efficacy of agents that treat the cognitive deficits in Alzheimer's disease (31). An ADL scale that would be optimal for clinical trials would be sensitive over a broad range of disease severity and include items to assess both basic and instrumental ADLs.
While rigorous efforts are made to document the presence of Alzheimer's disease in all subjects entered into treatment trials, patients diagnosed with this illness are a heterogeneous population because of the following factors. The criteria used to determine the presence of the illness do not have 100% concordance with neuropathological findings at autopsy. The cognitive deficits in the illness have variable presentations and course. The severity of cognitive compromise in patients at entry is not uniform. All these issues introduce heterogeneity into the patient population that can increase variability into the results of clinical trials.
The study designs used to assess drug efficacy also introduce methodological problems. The crossover designs which are often employed for drug studies may create carry-over effects that lessen the drug's effect in comparison to placebo. The repeated assessments used in trials lead to learning effects that can erroneously inflate a patient's response to medication. Practice effects can be avoided by administration of the key outcome measures at longer time intervals and by the use of parallel design studies. Finally, another problem is the shifting baseline due to the progression of the severity of Alzheimer's disease. The longer the study, the more this becomes a factor that needs to be addressed.
Several strategies for cognitive enhancement have been attempted with Alzheimer's disease patients. An adequate acetylcholinesterase inhibitor has not yet been tested with all the necessary parameters. Combined neurotransmitter therapies have also not been adequately tested to determine the level of efficacy that could be achieved with this approach. Strategies to delay progression of the illness are beginning to be explored and may provide the most effective means to treat the cognitive deterioration observed in Alzheimer's disease. It is essential to choose the appropriate measures and optimal study designs in order to determine drug efficacy.