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Domains of Dementia: Expanding the Role of Cholinergic Enhancers

Diagnosing AD

Typically, the symptoms of AD originate from 1 to 4 years before an individual or a family member seeks medical assistance, and by the time of diagnosis as much as 30% of mental capacity may have been lost. This underscores the value of early diagnosis, as it may lead to medical treatment before the patient sustains extensive neuronal loss. Timely intervention may assist in preserving cognitive and functional abilities, postponing the need for long-term care, and enabling the patient to plan for the future prior to the loss of abilities. Although the disease process is irreversible, early diagnosis and intervention may preserve some degree of function or decelerate progression.

There are, however, several obstacles to early diagnosis. One of these is an outdated attitude that if AD cannot be reversed, there is little value in diagnosing it, an attitude that Dr. Blake characterized as “therapeutic nihilism among the public and health care workers.” Other obstacles are the time and expense of making the diagnosis, denial of deficits, and fear and lack of information among patients and families. “The day we diagnose AD,” Dr. Blake said, “is the day we have to come to terms with it.”

The diagnosis of AD is time-consuming. Taking the medical history includes seeking evidence of a family history of AD, genetic factors such as Down syndrome predisposing to AD, evidence of head trauma or repeated head trauma, vascular risk factors and educational attainment. (Low educational level appears to be a risk factor for AD.) The clinician should ask about and observe for behavioral signs of dementia because the primary complaint, failing memory, must be distinguished from benign age-related memory loss. The physical examination includes a thorough neurological evaluation. Neuropsycho-logical testing may help in distinguishing among different forms of dementia. Extensive laboratory testing includes a complete blood count, electrolytes, calcium, liver and thyroid function tests, BUN, creatinine, and Vitamin B12 and homocysteine levels. (Low Vitamin B12 levels and high homocysteine levels are important diagnostic clues.) Brain imaging may be helpful, primarily because it may rule out other potential causes of dementia-like symptoms. In addition, however, magnetic resonance imaging (MRI) is sometimes able to distinguish atrophy in the area of the hippocampus, a hallmark of AD.

In the differential diagnosis, the clinician must consider a spectrum of reversible and irreversible causes of AD-like symptoms. Among the reversible causes are psychiatric disorders such as depression; toxins such as alcohol, heavy metals and solvents; medications, especially those with anticholinergic effects; infections such as encephalitis; metabolic disorders including thyroid disease, hypoglycemia, and electrolyte abnormalities; nutritional disorders including pellagra and B12 deficiency; and normal pressure hydrocephalus. In addition to AD, irreversible conditions that may cause memory loss are other degenerative diseases such as frontotemporal dementia, Lewy body dementia, and Pick’s disease (which usually occurs in younger patients than does AD); vascular dementia; autoimmune diseases such as lupus and multiple sclerosis; malignancies, particularly brain metastases, meningioma and astrocytoma; and genetic causes such as Down syndrome.

Table 1 provides a comparative checklist of the features of different forms of dementia. In addition to those disorders listed, mild cognitive impairment (MCI) presents a new diagnostic challenge. In this condition, cognitive impairment is usually limited to memory, with other cognitive abilities remaining intact. Patients have no functional disability. Because MCI progresses to AD at a rate higher than the incidence of AD in the normal elderly, this may represent a pre-AD transitional state for some patients (Almkvist O et al. J Neural Transm Suppl 1998;54:21; Petersen RC et al. Arch Neurol 1999;56:303).

Despite its prevalence and the foregoing diagnostic process, AD is frequently misdiagnosed. In a review of records conducted in 1999 by the Alzheimer’s Caregiver Project of Consumer Health Sciences, LLC, only 28% of patients with AD were recorded as having had AD at an initial diagnosis. Of the remaining 72%, approximately one-third of patients were initially diagnosed as having non-Alzheimer’s dementia. Following a miscellaneous category comprising 21% of cases, depression and normal aging (14% each) were the next most common misdiagnoses. Stroke (9%) and no diagnosis (7%) made up the remainder.

Although it is commonly thought that neurologists and geriatric psychiatrists deal most frequently with AD, the National Disease and Therapeutic Index indicates that between 65% and 75% of cases at all levels of progression (mild, moderate, severe) are diagnosed by primary-care physicians. Neurologists diagnose between 15% and 25% of cases, principally at the mild state. Psychiatrists diagnose 10% or less of cases. Approximately an equal proportion is diagnosed by clinicians in other specialties, with gynecologists prominent among them.

The Pathology and Treatment of AD

The three consistent neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles of tau protein, and neuronal degeneration. These changes eventually lead to clinical symptoms, but they begin years before the onset of symptoms and perhaps as early as age 20 years. The most prominent neurotransmitter abnormalities are cholinergic, consisting of reduced activity of choline acetyltransferase in the synthesis of acetylcholine (ACh). In advanced AD, there appears a reduction of cholinergic neurons, particularly in the basal forebrain. In addition, there is a selective loss of nicotinic receptor subtypes in the hippocampus and the cerebral cortex. The significance of this loss is that presynaptic nicotinic receptors control the release of neurotransmitters (ACh, glutamate, serotonin, norepinephrine) important for memory and mood. Blocking nicotinic receptors impairs cognition, whereas stimulating them improves memory (Levin ED et al. Psychopharmacol (Berl) 1998;138:217; Levin ED et al. Eur J Pharmacol 2000; 393:141).

The treatment objectives in AD are to manage associated psychiatric conditions and behaviors, and to optimize outcomes by improving cognitive abilities, improving function and quality of life, stabilizing the patient’s condition, and slowing disease progression.

At present, the only FDA-approved drug class for treating AD is the acetylcholinesterase inhibitors. Their development was based on the cholinergic hypothesis. This posits that ACh deficiency is primarily responsible for cognitive impairment, and that the course of the disease may be improved by increasing the synthesis of ACh, blocking ACh degradation, and increasing cholinergic transmission. Cholinesterase inhibitors may slow the loss of functional abilities, and they yield their maximum benefit with early initiation and continuous treatment. The efficacy of these agents has been demonstrated in moderately-to-severely impaired individuals, including residents of nursing facilities (Mohs R et al. Neurology 2001;57;481; Raskind M et al. Neurology 2000;54: 2261; Feldman H et al. Neurology 2001;57:613; Tariot PN et al. J Am Geriatr Soc 2001;49:1590). Only galantamine is available as an oral solution, a formulation that may be easier for some patients to take than tablets.

The mechanisms of action of the currently-available cholinesterase inhibitors vary. Tacrine, an older and rarely used drug, decelerates the degradation of ACh. Donepezil is an ACh inhibitor as is galantamine, but the latter also modulates nicotinic receptors in the brain. Rivastigmine is an inhibitor of both acetylcholinesterase and butyrylcholinesterase. This may result in psychological changes by increasing brain levels of other neurotransmitters such as dopamine, serotonin and glutamine in addition to ACh. Elimination times of cholinesterase inhibitors also differ, ranging from 1.5 hours to 4 hours for tacrine to 70 hours for donepezil. Rivastigmine, which must be taken with meals, clears in 1.5 hours and frequently interacts with nonsteroidal anti-inflammatory drugs (NSAIDs). The elimination time of galantamine is 7 hours in younger adults and 8 hours to 10 hours in the elderly. Galantamine, which may be taken with or without food, has no significant drug/drug interactions. Adverse events affecting more than 10% of patients are headache, nausea and diarrhea with donepezil; nausea, agitation and diarrhea with galantamine; and dizziness, headache, nausea, vomiting, diarrhea, anorexia and abdominal pain with rivastigmine. The broader spectrum of adverse events associated with rivastigmine is probably due to butyrylcholinesterase inhibition.

The efficacy of donepezil, galantamine and rivastigmine with respect to activities of daily living and cognition in AD has been studied extensively. In one placebo-controlled study (Figure 1), a mean of 1 hour of caregivers’ time supervising patients was saved (p<0.001 vs. baseline) by treating patients with galantamine 24 mg/day (Lilienfeld S et al. Dement Geriatr Cog Disord 2000; 11(Suppl 1):19). In another study, there was a significant saving of caregiver time (p<0.05) assisting patients with activities of daily living. Other studies have demonstrated significant preservation of activities of daily living with galantamine, donepezil and rivastigmine over periods ranging from 26 to 30 weeks in residents of nursing homes (Tariot PN et al. Neurology 2000;54:2269; Burns A at al. Dement Geriatr Cog Disord 1999;10:237; Corey-Bloom J et al. Int J Psychopharmacol 1998;1:55).

Although the optimum duration of cholinergic enhancement therapy for preserving cognitive abilities in AD has not been determined, early evidence suggests that there may be clinically important benefits to long-term therapy with cholinesterase inhibitors. In an open-label treatment phase following a 6-month double-blind and placebo-controlled trial with galantamine, patients with mild-to-moderate AD maintained their baseline cognitive status for 12 months and their rate of cognitive decline was slowed by approximately 50% over 3 years of treatment (Figure 2). Similar results have been observed with other cholinesterase inhibitors such as donepezil and rivastigmine, but cognition scores of patients treated with other agents fell below baseline prior to the completion of 12 months’ treatment. Nevertheless, the rate of deterioration was less than that of the natural course of disease.

The benefit of cholinergic enhancement on behavior has also been studied extensively. Multiple environmental, psychosocial and physical factors may trigger agitation, so potential causes such as pain, constipation, urinary retention, anticholinergic medications and comorbid psychiatric disorders should be considered before concluding that behavioral change is attributable to the dementing illness. Nonetheless, agitation frequently occurs with advancing AD. In placebo-controlled studies using the Neuropsychiatric Inventory as an instrument for tracking behavioral deterioration or improvement, donepezil, galantamine and rivastigmine have all yielded statistically significant improvement over periods ranging from 8 weeks to 20 weeks (Mega MS et al. Arch Neurol 1999;56:1388; Tariot PN et al. Neurology 2000;54:2269; McKeith et al. Lancet 2000;356:2031).

Vascular dementia (VaD), which is marked by acute impairment of cortical function, may develop in patients who are at high risk for vascular disease because of diabetes, hyperlipidemia, hypertension or cardiodysmetabolic syndrome (Syndrome X). Patients may have both AD and cerebrovascular disease, a combination comprising “mixed dementia.” Mixed dementia is present in 10% to 20% of all dementia cases, and 90% of patients with mixed dementia have histories of CVA. Urinary and gait disturbances may be early markers for development of VaD or mixed dementia.

Although acetylcholinesterase inhibitors do not have current approval for use in the setting of VaD or mixed dementia, they are showing considerable promise in clinical trials involving these populations.


Treatment of Dementia in the Future

The clinical evidence reviewed here indicates that cholinesterase inhibitors decrease the time required of caregivers, preserve independent conduct of the activities of daily living, and initially improve and transiently maintain cognitive abilities in patients with mild-to-moderate AD and potentially VaD and mixed dementia. Cognitive abilities worsen over time, however, indicating that treatment does not stop, but may delay, progression of AD. Thus, new treatments that maintain cognitive ability and stop disease progression are needed.

Already there is inconclusive evidence that some medications commonly taken may prevent or postpone the onset of AD symptoms. For example, retrospective reviews of large populations designed to identify potential trends correlating treatment histories with the development of AD suggest that NSAIDs may be one such drug class. Studies have indicated as high as 30% to 70% reduction in the incidence of AD in populations taking NSAIDs regularly for the relief of chronic pain. There is no evidence, however, that NSAID therapy following the diagnosis of AD contributes to effective management.

Early studies found evidence that estrogen replacement therapy might also delay the biological processes leading to symptomatic AD, but subsequent studies have yielded less hopeful evidence. Recent evidence implicating estrogen replacement in both cardiovascular disease and breast malignancies may disqualify it as a means of AD prevention anyway.

A high antioxidant diet or antioxidant supplementation may postpone AD symptoms. Although there is no evidence based on phase III trials that Vitamin E has a role in either the prevention or management of AD, anecdotal evidence and observation suggest that daily use at a dose of 1,500 to 2,000 units may be important in management. Selegiline, another antioxidant, may also have a role.

Although ginkgo biloba is popularly thought to enhance cognitive function, there is no scientific evidence of this claim and none that it contributes to either the prevention or treatment of AD.

Dr. Blake and Dr. Simonson commented on several drugs now in development as potential addition options in the prevention and treatment of AD. One promising medication is huperzine A, an anti-inflammatory and possible acetylcholinesterase agent that has been used in China historically. At a recent meeting in China, investigators presented evidence of its effectiveness from a double- blind study. Memantine, a product that has been used in Germany for several years, is likely to be approved by the FDA for use in the treatment of AD in 2003.

Another promising avenue of research is beta- and gamma-secretases. The cellular suicide that occurs in AD consists of many processes, one of which is the conversion of amyloid precursor protein into beta-amyloid protein. This protein, one of the critical factors in cellular destruction, is dependent on the secretases for its synthesis. Hypothetically, therefore, pharmacologic degradation of the enzymes may alter the course of AD. However, amyloid synthesis is not solely responsible for AD, so other targets are also under study. Tau protein, for example, is a potential treatment target. In addition, although vaccine development has been curtailed as a result of some recent disappointing trial outcomes, it is likely that AD vaccine research will resume in the future. Moreover, gilatide, a derivative of gila monster saliva, has been shown to improve memory in rodents, and it may have a role in AD.

Dr. Simonson concluded the presentation by citing cost statistics related to AD. It is estimated that cost savings associated with treatment of either mild or severe AD is small. However, prevention of even a small decline in cognition for patients with moderate AD would save approximately $3,700 per patient annually; and relatively small improvements in patients with moderate AD would save approximately $7,100 per patient annually (Ernst RL et al. Arch Neurol 1997;54:687). As important, however, preventing functional decline preserves quality of life, prevents some falls and fractures, postpones behavioral symptoms affecting both the patient and others, and delays the need for long-term care and relocation from home.

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