CHAPTER 13 Cognitive Disorders and Dementia

Alzheimer’s disease (AD), first described in 1907, is defined as progressive loss of mental function and memory accompanied by a decline in cognitive function. More than 4 million Americans are afflicted with the condition. Related health care costs exceed $100 billion per year, according to the Alzheimer’s Association. Millions more are afflicted worldwide. AD is classified as a primary degenerative dementia, with senile onset occurring after age 65 and presenile onset taking place before age 65. The incidence of dementia may be as high as 10% among people older than 65 years and 40% among individuals older than 80.

Cognitive impairment is thought to be associated with the degeneration of cholinergic neurons. AD involves disturbances in the amygdala, hippocampus, cerebral cortex, and basal forebrain. The main structural changes are neuronal loss, cortical atrophy, and the presence of neurofibrillary tangles and plaques. Tangles are twisted fibers caused by changes in a protein called tau. Plaques are dense, sticky substances comprising accumulations of a protein called β-amyloid. The β-amyloid plaques reside in the spaces between the billions of neurons in the brain and the neurofibrillary tangles clumped together inside the neurons. Plaques and tangles block the normal transport of electrical messages between neurons that enable us to think, remember, talk, and move. Neuronal structures deteriorate, which in turn affects the transport of neurotransmitters and alters receptor activity in specific areas of the brain. As AD progresses, nerve cells die, the brain shrinks, and the ability to function deteriorates.¹ Reduced cerebral blood flow has also been noted in subjects with AD. It appears that the more severe the reduction in blood flow, the more severe the dementia.

Specific changes in brain neurotransmitter levels occur in patients with AD. Levels of the enzyme choline acetyltransferase (ChAt) are reduced, as are muscarinic receptors types 1 and 2 (M₁ and M₂) and presynaptic nicotinic receptors in the cerebral cortex. The M₂ receptor, when bound, inhibits adenylate cyclase, causing the release and synthesis of acetylcholine. The activated nicotinic receptor facilitates the release of acetylcholine from the neuron. As a result, neuronal transmission in the brain is diminished because of reduced levels of acetylcholine, a neurotransmitter important in memory and cognitive function.

The locus ceruleus consists primarily of adrenergic nuclei that play a pivotal role in the processing of information and tolerance of stress and anxiety. Subjects with AD often experience neuronal loss in the locus ceruleus accompanied by an increase in the activity of monoamine oxidase, the enzyme responsible for the degradation of noradrenergic and dopaminergic neurotransmitters. Serotonin levels also are reduced in AD. The raphe system contains serotonergic nuclei that become overrun with neurofibrillary tangles.

DIAGNOSIS

AD occurs gradually, starting with mild memory loss, changes in personality and behavior, and a decline in cognition. It progresses to loss of speech and movement, then total incapacitation and eventually death. It is normal for memory to decline and for the ability to absorb complex information to slow as we age, but AD is not a part of normal aging. The impact on both the individual and his or her family is devastating.

IDENTIFYING ALZHEIMER’S DISEASE

A patient with AD often presents with the following difficulties:

Learning and retaining new information. The individual is more repetitive; has trouble remembering recent conversations, events, or appointments; and frequently misplaces objects.

Handling complex tasks: The individual with AD has trouble following a complex train of thought or performing tasks that require many steps (e.g., balancing a checkbook, cooking a meal).

Reasoning ability: The individual is unable to respond with a reasonable plan to problems at work or home, such as knowing what to do if the house is cold; shows uncharacteristic disregard for rules of social conduct and behavior.

Spatial ability and orientation: An individual with AD has trouble driving, organizing objects around the house, or finding his or her way around familiar places.

Language: The individual experiences increasing difficulty in finding the words to express himself or herself.

Behavior: The individual appears more passive and less responsive, is more irritable or suspicious than usual, and misinterprets visual or auditory stimuli.

A thorough history and physical examination, laboratory studies (including assessments of folate and vitamin B₁₂ levels; liver, thyroid, and kidney function; complete blood-cell count; a screen for advanced syphilis (Venereal Disease Research Laboratory [VDRL] slide test) and human immunodeficiency virus testing; and imaging studies such as magnetic resonance imaging (MRI) and computed tomography are conducted as necessary. The diagnosis of AD is made only after other causes of dementia have been ruled out. This diagnosis of exclusion is performed so that a potentially treatable problem (e.g., hypothyroidism, depression) is not missed and also because, at this time, the diagnosis of AD can only be conclusively made at autopsy.

New research may change this, however. Researchers have found that a radioactive compound known as FDDNP has a special affinity for the neurofibrillary tangles and β-amyloid plaques found in the brains of AD patients. The compound was first tested in vitro, then in animals, and finally in a small number of patients. If the accuracy of this test can be confirmed in larger studies, the test will become an invaluable tool for the early diagnosis of AD, enabling earlier initiation of treatment.

INTEGRATIVE TREATMENT STRATEGIES

Cognitive Stimulation

Some studies have shown that participation in mentally stimulating activities (e.g., reading, doing crossword puzzles, going to social events) may be associated with a reduced risk of AD. Stimulating activity, either mentally or socially oriented, may protect against dementia, indicating that both social interaction and intellectual stimulation may be important for preservation of mental function in the elderly.² Researchers speculate that repetition improves certain cognitive skills, making them less susceptible to brain damage.¹

In a study funded by the National Institutes on Aging and published in the Journal of the American Medical Association in 2002, frequent cognitive activity in elderly people was found to reduce the risk of AD by almost 50%. The study included 801 Catholic nuns, priests, and brothers (at least 65 years old) without dementia, recruited from 40 religious organizations across the United States. Researchers documented the frequency of cognitive activity at baseline using a 5-point scale (e.g., doing crossword puzzles, reading books and newspapers, going to museums). Cognitive function (e.g., memory, language, attention, spatial ability) and physical activity were also documented. After 4.5 years of follow-up, researchers found that frequency of cognitive activity was inversely related to the risk of AD. After controlling for age, sex, and education, the investigators found that each one-point increase in cognitive activity was associated with a 33% reduction in risk for AD, and slowed the decline in cognitive function by 47%, working memory by 60%, and that of perceptual speed by 30%.³

Acetylcholinesterase Inhibitors

The cholinergic hypothesis has provided the rationale for our current pharmacotherapy for AD. Among the possible strategies for enhancing brain cholinergic activity, acetylcholinesterase inhibitors (AChEIs) have been studied most extensively. Cholinesterase inhibitors increase the amount of acetylcholine present in the neuronal synaptic cleft by inhibiting the enzyme responsible for the hydrolysis of acetylcholine, thus improving neuronal transmission. At the time of this writing, the U.S. Food and Drug Administration has approved four prescription drugs for people with mild to moderate AD: tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl).⁴

CURRENT DRUG THERAPY FOR ALZHEIMER’S DISEASE

Although many practitioners consider the drugs now available for the treatment of AD to be equivalently effective, with similar side-effect profiles, a systematic review by the Cochrane group revealed the following:

No convincing evidence indicates that tacrine is a useful treatment for the symptoms of AD.⁴

Rivastigmine appears to be beneficial for subjects with mild to moderate AD.⁵ Improvements were noted in cognitive function, ability to carry out activities of daily living, and severity of dementia with daily dosages of 6 to 12 mg compared with placebo. Adverse events were consistent with the cholinergic actions of the drug.

In patients with mild or moderate AD who were treated for 12, 24, or 52 weeks, donepezil produced modest improvements in cognitive function.⁶ No improvements were seen with regard to patient-assessed quality-of-life, and data on other important outcomes are not available.

Positive effects of galantamine were found in trials lasting 3, 5, and 6 months. Improvements with dosages greater than 8 mg/day were, for the most part, consistently statistically significant.⁷

Although these drugs offer hope for individuals with AD, the relatively short duration of action, frequent side effects, and dose-dependent hepatotoxicity have made the search for better-tolerated medications and treatments desirable.

Statins and Cholesterol Management

Accumulation of β-amyloid is associated with AD, and medicines that inhibit this peptide have been researched as a potential treatment. Recent evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly known as statins, can inhibit β-amyloid production. In vitro and animal data show that a reduction in cholesterol reduces the production of β-amyloid, and in human subjects lovastatin, however, some has been shown to reduce blood peptide levels by as much as 40%.⁸ Some researchers question whether blood levels of β-amyloid adequately correspond to levels found in the brain or signify the progression of AD. Two retrospective epidemiological studies have linked statin use with a reduction in risk for AD of 40% to 79%.⁹ One study showed that individuals ages 50 years and older who were prescribed statins had a substantially decreased risk of dementia, independent of the presence or absence of untreated hyperlipidemia, or exposure to nonstatin lipid-lowering agents.¹⁰ However, a prospective study of 4740 individuals older than age of 65 found that although statin use was associated with a reduced prevalence of dementia, statins had no statistically significant effect on the incidence of AD.¹¹ (Incidence is the number of new occurrences of a condition in a population over a given period.) This study also raised the issue of equal efficacy among statins and questioned the necessity of a drug to cross the blood-brain barrier. Atorvastatin, which does not penetrate the blood-brain barrier, was actually shown to offer a greater risk-reducing effect than statins that do enter into the brain.

At this time, evidence is insufficient to recommend statins as a means of reducing the risk of AD. However, a growing body of biologic, epidemiologic, and clinical evidence indicates that decreasing the serum cholesterol level may retard the pathogenesis of AD.¹² Rigorous research is needed to determine what role, if any, is played by statins in the prevention and treatment of AD.

Antiinflammatory Medications

People who take large doses of nonsteroidal antiinflammatory drugs (NSAIDs), commonly used to relieve joint pain, have been shown to have a reduced likelihood of developing AD in some studies.

A systematic review and metaanalysis of nine studies of NSAID use among adults ages 55 and older showed that NSAIDs offer some protection against the development of AD.¹³ The authors note, however, that the optimal dosage, duration of use, and ratios of risk to benefit are unknown. A 12-month study of 351 patients with mild to moderate AD given rofecoxib (25 mg) once daily, naproxen sodium (220 mg) twice daily, or placebo failed to show any slowing of cognitive decline among the members of the treatment groups compared with subjects taking placebo. Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, hypertension, and more serious adverse events were more common in the active treatment groups.¹⁴

None of the studies performed to date with antiinflammatory drugs is definitive. The Alzheimer’s Disease Anti-Inflammatory Prevention Trial was launched in 2001 to test the effectiveness of some NSAIDs in preventing AD. The study, comprising more than 2500 healthy participants ages 70 and older, is sponsored by the National Institute on Aging and is scheduled to run 5 to 7 years.¹⁵

Micronutrients

Folate and reduction of homocysteine.

Folate is essential to the healthy development of the central nervous system. Recently it has been found that folate deficiency is associated with high blood levels of the amino acid homocysteine. Folate deficiency can occur because of insufficient folate in the diet, inefficient absorption, or altered metabolic use related to genetic variations. High blood levels of homocysteine have been linked to increased risk for arterial disease and dementia.

A prospective, observational study monitored 1092 patients (mean age 76 years), free of dementia at the time of enrollment, for approximately 8 years. Participants’ homocysteine levels were measured near the beginning of the study (1979-1982) and again between 1986 and 1990. At the end of the study, it was found that dementia had developed in 111 participants. AD was thought to be the cause in 83 cases. This study found that patients with the highest levels of homocysteine were roughly twice as likely to experience dementia, compared with those with the lowest levels. The correlation between homocysteine level and dementia was present even after age, sex, blood levels of vitamins, and the presence of lipoprotein E genotype were accounted for. In fact, each 5 μmol/L increase in homocysteine concentration was associated with a 40% increased risk for AD.¹⁶

But does a reduction in homocysteine level prevent AD or slow its progression? A review by the Cochrane group showed no beneficial effect of 750 μg/day folic acid on measures of cognition or mood in older healthy women and no benefit on measures of cognition or mood among patients with mild to moderate cognitive decline and different forms of dementia receiving 2 mg/day folate.¹⁷ The reviewers noted that one trial reported a significant decline, compared with patients taking placebo, in two cognitive-function tasks performed by dementia patients who had received high doses of folic acid (10 mg/day) for unspecified periods. Although no benefit was seen, folic acid plus vitamin B₁₂ was effective in reducing the serum homocysteine concentration, and the treatment was well tolerated. Limitations of the currently available research include short duration of studies, which ranged from 5 to 12 weeks and may not have been long enough to see a treatment effect.

Given the comparatively low cost of vitamin supplements, it makes sense to study the possible relationship between high serum homocysteine levels and dementia. The National Institute on Aging is funding an 18-month clinical trial designed to test whether reduction of homocysteine levels with high-dose vitamin supplements can slow the rate of cognitive decline in people with AD. Although these vitamin supplements are relatively safe, folic acid given to people with undiagnosed vitamin B₁₂ deficiency may cause neurologic damage. Vitamin B₁₂ deficiency produces an anemia identical to that seen in folate deficiency but also causes irreversible damage to the central and peripheral nervous systems.¹⁸ Folic acid corrects the anemia associated with vitamin B₁₂ deficiency and so delays diagnosis but does not prevent progression to neurologic damage. For this reason, folic-acid supplementation should be accompanied by the simultaneous administration of vitamin B₁₂.

Antioxidants.

Antioxidants help neutralize the free radicals produced through normal metabolism, helping prevent damage to important cell components. As people age, free radicals become increasingly prevalent, and many researchers believe that it is the inability to buffer against the effects of this oxidative stress that leads to age-related neuronal decline.¹⁹

If antioxidants reduce the damaging effects of free radicals that occur with aging, and if memory decline is related to oxidative neuronal destruction, perhaps antioxidants can help slow memory decline and improve memory.²⁰ Though frank vitamin deficiency is uncommon in the United States, suboptimal vitamin status is prevalent and puts aged individuals at high risk for such diseases as cardiovascular disease, dementia, and osteoporosis.²¹

Although researchers have revealed an association between high dietary antioxidant intake and decreased risk for AD,^22,²³ clinical trials have failed to show a significant benefit in patients with AD.²⁰ Some researchers postulate that by the time clinical symptoms of AD appear, a large proportion of neuronal cells may have already been destroyed and, therefore, intervention with antioxidants represents a case of too little, too late.²⁴ Some experts note other potential flaws with clinical trials, citing a lack of design specificity to test a particular antioxidant, short duration of treatment and inappropriate choice of “time window” (for efficacy to be achieved, the antioxidant must be given during the time available between the damaging event and irreversible cell loss), the synthetic or natural source of antioxidant used, and the absence of evaluation of markers of oxidative stress as intermediate end points.²⁴

Many unexplored issues warrant research. Because antioxidants work as a system, their effectiveness depends on adequate levels of other vitamins and minerals. Also, intake of an antioxidant may not directly translate to its serum level. Therefore, to find reliable benefits, researchers may need to be sensitive to levels of other micronutrients, as well as the serum level of the target antioxidant, not just the amount being supplemented.²⁵ Until more definitive answers are available, it would seem to be a common sense practice for most adults to take a daily multivitamin that provides adequate levels of antioxidants and other nutrients as part of a healthy diet and lifestyle.

Herbal Remedies

Ginkgo (Ginkgo biloba).

Ginkgo biloba extract (GBE) is one of the most heavily researched of all herbal remedies, and the most heavily researched herb for the treatment of dementia (Figure 13-1). A standardized extract of ginkgo leaf is widely prescribed by health care providers in Germany and France for relief of age-related conditions, peripheral vascular disorders, and dementia. The German Commission E has endorsed the use of gingko for the “symptomatic treatment of disturbed performance in organic brain syndrome within the regimen of a therapeutic concept in cases of demential syndromes with the following principal symptoms: memory deficits, disturbances in concentration, depressive emotional condition, dizziness, tinnitus and headache. The primary target groups are dementia syndromes, including primary degenerative dementia, vascular dementia and mixed forms of both.”²⁶