Feature Article
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Cholinergic Therapy for Alzheimer's Disease Abstract
Cholinergic therapies such as tacrine and donepezil improve memory, language, and praxis (higher-level control of motor function) in Alzheimer's disease. These drugs may delay nursing home placement and improve psychiatric symptoms such as apathy, anxiety, hallucinations, disinhibition, and aberrant motor behavior. Cholinergic agents are the first class of drugs specifically indicated for the treatment of Alzheimer's disease, and their mechanism of action involves replacement of the primary neurochemical deficit associated with this illness. Use of these drugs should reduce the need for psychotropic medications with side effects such as benzodiazepines and neuroleptics. Patient and caregiver distress and treatment costs are also likely to be reduced. Donepezil is generally well tolerated and easy to administer. (Annals of Long-Term Care 1998;6[3]:92)
Several disease states have pathologic changes in the nucleus basalis and associated nuclei in the brain resulting in a cortical cholinergic deficiency. Alzheimer's disease (AD) is the prototypical example, but other syndromes with a cholinergic deficit include dementia with Lewy bodies, Parkinson's disease with dementia, progressive supranuclear palsy with dementia, alcohol-related dementia, delirium, and some cases of Creutzfeldt-Jakob disease. The cortical deficit of acetylcholine is associated with cognitive impairment1 and psychiatric symptoms.2 New treatments aimed at restoring cholinergic activity are now available for clinical use. The use of these new agents is likely to improve the quality of life for patients and caregivers and may reduce the overall cost of treating these illnesses.
All patients with AD experience a progressive decline in cognitive function that is associated with brain atrophy. Cholinergic agents do not interfere with the underlying course of illness, nor do they prevent or retard the loss of neurons in the brain. They provide acetylcholine for use by surviving neurons, thereby shifting the decline curve in favor of greater cognitive function in mild to moderate AD (Figure).
Cholinergic Deficit
The nucleus basalis is the principal site in the brain where choline acetyltransferase is produced.3,4 Input to this nucleus comes primarily from limbic and paralimbic brain regions,5 and output is directed to the neocortex. Presynaptic cholinergic neurons in this nucleus are severely affected by AD, resulting in a cholinergic deficit at the cortical level, particularly in the parietal, temporal, and frontal lobar regions with relative sparing of the occipital cortex, brainstem, cerebellum, basal ganglia, and thalamus.6,7 Postsynaptic cholinergic neurons in the cortex are relatively intact.
Cognitive Impairment
Cognitive decline is the best marker of disease progression in AD; therefore, drugs used to treat AD must demonstrate efficacy in improving cognitive function. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) has been used to assess cognitive improvement in patients treated with cholinergic agents.8 Tacrine and donepezil are approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD, and they work by inhibiting the enzyme acetylcholinesterase, which normally breaks down acetylcholine in the synapse. They have approximately equal efficacy as determined by the ADAS-Cog, but donepezil may be more effective in practice because it is better tolerated.9,10 Tacrine has been studied more extensively, but the effects of the two drugs are probably similar. The ADAS-Cog measures memory, language, and praxis with the heaviest weighting towards memory.11,12 All three of these factors improve on tacrine therapy.13
The memory deficit in AD is an impairment of the ability to acquire new information and store it in short-term memory.14,15 For example, patients frequently forget the day and date or what they ate for breakfast. This type of memory is a function of the limbic system, specifically the hippocampus, mamillary bodies, and mediodorsal nucleus of the thalamus, and it is highly dependent on cholinergic function.16
Language is predominantly a left-brain function, and AD usually affects temporal and parietal areas more than frontal areas. The classic language of an AD patient may resemble the fluent paraphasic output of a transcortical sensory aphasia and is caused by atrophy of the angular gyrus.17
Apraxia is the inability to perform simple manual tasks, such as combing hair or brushing teeth, despite an intact sensory-motor system. In AD, it is usually the result of parietal lobe and/or general brain dysfunction.18 It is not clear if these are the only three cognitive domains improved by cholinesterase therapy. Visuospatial ability, executive function, and several other cognitive processes are not as well assessed by the ADAS-Cog.
In a 30-week study, 263 patients with mild to moderate AD received placebo or 40 mg, 80 mg, 120 mg, or 160 mg of tacrine.9 The magnitude of improvement on tacrine in the group treated with 160 mg was a mean 2-point improvement on the ADAS-Cog compared to a mean 2-point decline in the placebo group. The Mini-Mental Status Examination (MMSE) was also administered, and the magnitude of difference between the group receiving 160 mg and the placebo group was 2.5 over 30 weeks. An untreated AD patient would be expected to decline by approximately 3 points on the MMSE over a one-year period. The magnitude of this cholinergic effect would theoretically increase if patients were followed for a longer period of time, but it appears that the average 3-point gain may represent maximal improvement.
These results are averaged and include patients who did not respond to tacrine therapy. Of those patients receiving 160 mg, 43% improved by 3 or more points on the ADAS-Cog. In my experience, it is possible for a patient to improve by as much as 7 to 10 points on the MMSE. With donepezil, the improvement will occur in the first month or two of treatment, and the amount of improvement over baseline function will remain stable over time. In other words, cognitive function will be set back by 6 months to 1 year, and it will then decline at the same rate that it would have otherwise declined.
Neuropsychiatric Symptoms
Neuropsychiatric symptoms in AD may result from a limbic-neocortical disconnection. Limbic input to the diseased nucleus basalis may result in an abnormal relay to the cortex, thereby disrupting the connection between emotions and cognitive processes. Apathy is the most frequent neuropsychiatric symptom in AD19 and is only weakly associated with depression.20 It is correlated with reduced perfusion of the medial frontal cortex,21 a region with reduced cholinergic function.6 Kaufer et al22 found that apathy was the symptom most responsive to tacrine in an open-label study. Depression, euphoria, or other emotional symptoms may involve abnormal limbic input to the neocortex, but apathy may result when limbic input to the neocortex is blocked.
Psychosis in AD correlates with reduced perfusion and metabolism in the temporal and frontal lobes23ú27 and neuropsychological impairments characteristic of frontal and temporal dysfunction.28 The cholinergic deficit in AD is most severe in the temporal lobes.7 Cholinergic drugs have been shown to reduce psychosis in patients with AD,29,30 and patients are particularly prone to develop psychosis when given anticholinergic drugs. Thus, psychosis in AD appears to be mediated by frontal and temporal cholinergic systems.
Agitation is difficult to define and has many causes, but patients with AD who have no other obvious cause of their agitation have hypometabolic frontal and temporal lobes compared to non- agitated patients with AD.27 Anticholinergic agents cause patients with Alzheimer's disease to become agitated,31 and cholinergic agents reduce agitation.30,32 Thus, like psychosis, agitation appears to be mediated by frontal and temporal cholinergic systems.
Major depression is rare in patients with AD who do not have a personal or family history of depression33 despite the involvement of serotonergic and adrenergic nuclei. An intact cholinergic system may be required for the full expression of a major depressive syndrome. Various studies with cholinergic medications have shown either no change22,30 or worsening of depressive symptoms.34,35
Functional Ability
A variety of measures have been used to assess functional level and have generally shown significant improvement on cholinergic therapy.9,10 Areas of demonstrated improvement include activities of daily living, such as toileting, eating, and personal hygiene. Several global measures of overall function have also shown significant improvement.9,10
Patients treated with tacrine in the 30-week study were followed in an unblinded manner, and nursing home placement and mortality were assessed. There was a doseúresponse relationship between tacrine therapy and time to nursing home placement and death.36 These results must be interpreted cautiously, because they may only represent a relationship between the ability to tolerate a higher dose and delayed nursing home placement and death. However, these patients had significant improvement on measures of cognitive function, behavior, and activities of daily living, and global improvement during the blinded and randomized portion of the study, which argues that the delay in nursing home placement and death may have been due to a salutary effect of the drug.
Caregivers
Caregivers of patients with Alzheimer's disease suffer stress-related illnesses, and their burden is related to neuropsychiatric symptoms in their loved one.37 Depression in adult caregivers may range from 14% to 47%, and anxiety disorders affect another 10%.38 Pillemer and Suitor39 found that one-fifth of 236 caregivers experienced violent feelings and feared they might physically hurt their loved one, and one-third of these caregivers reported that they actually engaged in violent behavior.
Financial Burden
The financial burden from AD in the United States is enormous. It is currently the third most expensive disease to treat after cancer and heart disease. The total cost to the health care system may be as high as $100 billion annually.40 Neuropsychiatric symptoms inflate these figures, and there would be significant cost savings if these symptoms could be managed more effectively.
Cholinergic Therapies
Available cholinergic therapies appear to have approximately equal efficacy in AD (Table I). They do not affect the underlying course of illness but may improve or temporarily stabilize cognitive function; a few patients have marked cognitive improvement. Psychiatric symptoms such as apathy, psychosis, and agitation may be reduced, activities of daily living may be improved, and nursing home placement may be delayed.
Tacrine was the first drug specifically approved for the treatment of AD. It is a cholinesterase inhibitor with proven efficacy in improving memory, language, praxis, and activities of daily living.9,41 Kaufer et al,22 in an open-label study, found that tacrine improved apathy, anxiety, hallucinations, disinhibition, and aberrant motor behavior. It may also delay nursing home placement.36
Liver abnormalities occur in 40% of patients on tacrine.42 Liver function tests are required every 2 weeks for the first 16 weeks of treatment and periodically thereafter. Tacrine must be administered four times per day, and it takes 18 weeks to achieve a maximum dose if the medication is well tolerated. Cholinergic side effects such as nausea, vomiting, loose stools, increased sweating, and bradycardia can be moderate to severe in many patients, and maximum doses are frequently never achieved (Table II).
Donepezil is also a cholinesterase inhibitor that is approved for the treatment of Alzheimer's disease. It appears to be equally efficacious but more effective than tacrine due to its ease of administration, lack of effect on the liver, and rapid titration to maximum levels.10 The 5 mg dose is well tolerated, and if an increase to 10 mg is delayed 4 weeks, then this dose is also usually well-tolerated. The 5 mg dose is superior to placebo in the treatment of Alzheimer's disease, and patients who are unable to tolerate 10 mg should be maintained on 5 mg.
Exelon is a cholinesterase inhibitor that has been found to be safe and effective in patients with AD. It is administered once or twice per day and improves cognitive performance and activities of daily living. Pivotal phase III studies are complete, and FDA approval for use in the United States is pending.
Metrifonate is a cholinesterase inhibitor that is safe and well tolerated. It was approved in 1962 as an anthelminthic, and it has a half-life of about 50 days. Phase III trials have been completed, and FDA approval is pending for this indication.
Xanomeline is a selective M1 agonist. A multicenter double-blind study involving 300 patients showed that 75 mg tid was superior to placebo in the treatment of cognitive and noncognitive symptoms.30 It was well tolerated and is currently undergoing a second phase III trial. The potential advantage of a direct muscarinic agonist is that intact presynaptic neurons are not required. Postsynaptic cholinergic neurons in the cortex are relatively well preserved in AD and can be directly stimulated by xanomeline. Cognitive function improved significantly in a multicenter study of 343 patients. Neuropsychiatric symptoms (including vocal outbursts, suspiciousness, delusions, agitation, and hallucinations) also showed significant improvement.30 In addition, there is some laboratory evidence to suggest that xanomeline may enhance release of soluble APP and thereby affect the underlying course of AD.
Conclusion
Cognitive and neuropsychiatric symptoms in AD are a source of considerable morbidity in terms of patient distress, caregiver distress, premature nursing home placement, and increased health care costs. Cholinergic agents are the first drugs that improve cognitive function in patients with a degenerative dementia. Symptoms such as apathy, anxiety, hallucinations, disinhibition, and aberrant motor behavior also may improve with cholinergic therapy. A reduction in these neuropsychiatric symptoms may reduce the need for neuroleptic or benzodiazepine therapy, both of which have serious side effects in this population. Treatment with cholinergic agents also may reduce nursing home placement and health care utilization by these patients.
Acknowledgment
This project was supported by a Department of Veterans Affairs Neuroscience Fellowship.
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About the Author
Dr. Levy is a Clinical Instructor of Psychiatry and Neurosciences Research Fellow at the Department of Psychiatry and Biobehavioral Sciences, UCLA School of Medicine and the West Los Angeles Veterans Affairs Medical Center Psychiatry Service. Address for correspondence: Morgan L. Levy, MD, Neuropsychiatric Institute, UCLA School of Medicine, 760 Westwood Plaza, Rm 37-425, Los Angeles, CA 90095. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 6 - Issue 03 - March 1998 |