Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

Background: Alzheimer disease (AD) is the most common cause of dementia, which is an acquired cognitive and behavioral impairment of sufficient severity to interfere significantly with social and occupational functioning. At present, the disorder afflicts approximately 5 million people in the US and more than 30 million people worldwide. A larger number of individuals have lesser levels of cognitive impairment, which frequently evolve into a full-blown dementia, thereby increasing the number of affected persons. Prevalence of this disorder is expected to increase substantially in this century, since the disorder preferentially affects the elderly, who constitute the fastest growing age bracket in many countries, especially in industrialized nations. For example, statistical projections indicate that the number of persons affected by the disorder in the US will nearly triple by the year 2050.

This disorder also is a major public health problem when looked at from the economic perspective. In fact, the cost of caring for AD was over $110 billion in the early 1990s in the US, and the average yearly cost per patient is about $45,000.

Many excellent treatises have been published on this topic in recent years, in which many important aspects of the disorder are reviewed in considerable detail. Therefore, the reader is referred to these texts for extensive reviews of specific topics, since the present review is intended primarily as a comprehensive (but not necessarily exhaustive) overview of the matter.

Pathophysiology:

• Anatomic pathology

The anatomic pathology of AD includes cerebrocortical atrophy (predominantly at the expense of association regions), and neurofibrillary tangles (NFTs) and senile plaques (SPs) at the microscopic level. The co-occurrence of NFTs and SPs was described by Alois Alzheimer in his original description of the disorder and is now accepted universally as a hallmark of the disease. Note that while these lesions are characteristic of AD, they are not pathognomonic of the condition. In fact, numerous other neurodegenerative conditions that are distinct from AD have NFTs (eg, progressive supranuclear palsy, dementia pugilistica) or SPs (eg, normal aging), indicating that the mere presence of these lesions is not sufficient to make a diagnosis of AD.

In addition to NFTs and SPs, many other lesions of AD have been recognized since Alzheimer’s original papers. These include (1) the granulovacuolar degeneration of Shimkowicz, (2) the neuropil threads of Braak et al, and (3) both neuronal loss and synaptic degeneration that are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder.

NFTs in very low densities, confined to the hippocampus, are accepted by some authorities as within the broad range of normal aging. However, the relatively recent formulation of histologic stages for AD by Braak et al includes an early stage with a low density of NFTs in the entorhinal and perirhinal (ie, transentorhinal) cortices, meaning that even small numbers of NFTs in the cortices of the medial temporal lobe should be considered abnormal.

In contrast, the presence of even low numbers of NFTs in the cerebral neocortex is considered abnormal and indicative of AD if associated with SPs in that location, following a specific topographic pattern of disposition. Granulovacuolar degeneration occurs almost exclusively in the hippocampus and has received considerably less attention in recent years than neuropil threads, a relatively recently identified array of dystrophic neurites diffusely distributed in the cortical neuropil, more or less independently of plaques and tangles. This lesion points to neuropil alterations beyond those merely due to NFTs and SPs, indicating an even more widespread insult to cortical circuitry than could be visualized by studying only plaques and tangles.

Figure 1. Cerebral cortical atrophy in Alzheimer dementia (Click to magnify figure)

Despite the wide distribution of these lesions in the cerebral cortex, consensus is increasing that a relatively consistent pattern of topographic disposition is present in most patients with AD. NFTs are distributed initially and most densely in the medial aspect and in the pole of the temporal lobe, affecting most severely the entorhinal cortex and hippocampus. As the disease progresses, NFTs also accumulate in most other cortical regions, beginning in high-order association regions while affecting much less frequently the primary motor and sensory regions. SPs also accumulate primarily in association cortices, as well as in the hippocampus. Plaques and tangles have been noted to exhibit relatively discrete and stereotyped patterns of laminar distribution in the cerebral cortex, indicating predominant involvement of corticocortical connections as viewed by many investigators.

Figure 2. Senile plaques (Click to magnify figure)

According to this formulation, the pathophysiologic mechanism underlying the clinical manifestations of AD is corticocortical disconnection due to the loss of medium-sized pyramidal neurons effecting such connections. However, multiple lines of evidence suggest that several classes of local circuit neurons are lost selectively throughout the cerebral cortex as well, demonstrating that the corticocortical disconnection is not the only alteration in cortical circuitry mediating the symptoms of AD.

Frequency:

• In the US: The lifetime risk of developing AD is estimated at 1:4-1:2. More than 14% of individuals older than 65 years have AD, and the prevalence increases to at least 40% in individuals older than 80 years.

• Internationally: Similar rates of prevalence have been reported in industrialized nations, and the US rates are being approached by developing nations experiencing rapid increases in the elderly segments of their population.

Mortality/Morbidity:

• AD frequently is considered to be a leading cause of death in the US, after certain cancers and cardiovascular disease.

• The primary cause of death is intercurrent illness, such as pneumonia, in a patient who has experienced the debilitating effects of the illness for many years.

Race: Claims have been made that AD may affect certain ethnic and racial groups more severely than others, but this matter necessitates more study before reliable statements can be made.

Sex: AD affects both men and women. Many studies indicate that women are at a significantly higher risk. Some authorities have postulated that this is due to the loss of the neurotrophic effect of estrogen in postmenopausal women.

Age: As noted previously, the prevalence of AD increases with age. Interestingly, some studies with nonagenarians and centenarians suggest that the risk of AD decreases in individuals older than 80 or 90 years. If so, age is not an unqualified risk factor for the disease, but this matter needs further study.

CLINICAL PICTURE

History: AD most commonly presents with insidiously progressive memory loss, to which other spheres of cognitive impairment are added over the course of several years. Functions commonly affected after the development of memory loss include language disorders (eg, anomia, progressive aphasia) and impaired visuospatial skills and executive functions. Substantially rarer presentations include right parietal lobe syndrome, progressive aphasia, spastic paraparesis, and impaired visuospatial skills, subsumed under the so-called visual variant of AD. These latter, unusual presentations often present a diagnostic challenge, since they are not covered under the guidelines for the clinical diagnosis of the disease. Therefore, their diagnosis necessitates histopathologic confirmation or is made at the time of autopsy, disconfirming previous diagnoses (eg, primary progressive aphasia, cerebrovascular conditions, prion disorders) made on purely clinical grounds.

• The majority of patients follow the above-mentioned pattern of slowly progressive memory loss, to which additional spheres of cognitive impairment are added over the course of several years. For this most common pattern, several clinical guidelines for diagnosis exist, as formulated by the National Institutes of Health-Alzheimer’s Disease and Related Disorders Association (NIH-ADRDA); the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV); and the Consortium to Establish a Registry in Alzheimer’s Disease (CERAD).

  The main thrust of these diagnostic guidelines consists of verifying that the condition begins with a mild, slowly progressive memory disorder; that additional spheres of cognition become compromised later; and that other possible causes for dementia (eg, cerebrovascular disease, cobalamin deficiency, syphilis) have been ruled out by a combination of clinical examination and ancillary radiologic and laboratory tests. These guidelines are widely believed to be 90-95% accurate when followed carefully, as determined by histopathologic verification, and are very important not only for routine management but also for patient selection and enrollment in therapeutic trials.

Physical: The earliest evidence of Alzheimer disease is the onset of chronic, insidious memory loss that is slowly progressive over several years. This can be associated with slowly progressive behavioral changes. Although other neurological systems can be affected (eg, extrapyramidal, cerebellar) as the disease progresses to its moderate and severe changes the most prominent finding will be that of progressive memory impairment.

• Other commonly affected neurological systems

  • Language: anomia, progressive aphasia

  • Impaired visuospatial skills

  • Impaired executive function

• Less common presentations

  • Right parietal lobe syndrome

  • Spastic paraparesis

• Examination in the clinic (or at the bedside)

  • Long discussion not only with the patient to confirm cognitive impairment and language function but also with the spouse/caregivers to confirm memory dysfunction and problems with activities of daily living (eg, cooking, cleaning, money management, getting lost, confusion, self care)

  • Screening language examination

  • Mini-mental status testing (see Table 1)

• Mini – Mental Status Testing

A score <20 is indicative of a dementia. Patients with the benign forgetfulness of senility generally score > 25

Causes:

• Considerable attention has been devoted to elucidating the composition of NFTs and SPs in the expectation that this would yield clues about the molecular pathogenesis and biochemistry of AD. In fact, it was known since the time of Alois Alzheimer that SPs include a starchlike (or amyloid) substance–usually in the core, or center, of these lesions–surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia. Following this lead, one of the most important advances in recent decades has been the characterization of the amyloid protein, the sequencing of its amino-acid chain, and the cloning of the gene for its precursor protein situated in chromosome 21. This has resulted in a wealth of information on the mechanisms underlying amyloid deposition in the brain, including information on the familial forms of AD.

• Familial forms of AD are known to account for less than 10% of all cases of AD, the majority being sporadic (ie, not inherited). To date, 4 major loci in chromosomes 21, 14, 1, and 12 have been found to be responsible for AD: (1) the amyloid precursor protein (APP; chromosome 21), (2) presenilin I (chromosome 14), (3) presenilin II (chromosome 1), and (4) another protein encoded in chromosome 12. These mutations have been postulated by many investigators to result in alterations of the mechanisms processing APP, leading to the deposition and eventual fibrillar aggregation of one of its processing peptides, the 40-43 residue known as the beta-amyloid peptide. This beta-pleated form of the peptide is postulated by many to have neurotoxic properties and to lead to an incompletely understood cascade of events that results in neuronal death, synapse loss, and formation of NFTs and SPs.

• A considerable amount of attention also has been devoted to the mechanisms leading to the development of the NFTs, whose main constituent is the associated tubule that is hyperphosphorylated and accumulates in the perikarya of large- and medium-sized pyramidal neurons. Several studies have shown that both exonic and intronic mutations of the tau gene result not in AD, but in familial frontotemporal dementia associated with parkinsonism. These mutations have been presumed to modify the properties of the neuronal cytoskeleton, eventually leading to dysfunction and death.

INVESTIGATION

Lab Studies:

• Blood cell count, cobalbumin – abnormalities in this measurement require further workup to rule out hematological disease.

• Liver enzyme screening – abnormalities in this measurement require further workup to rule out hepatic disease.

• Blood cortisol level – abnormalities in this measurement require further workup to rule out adrenal system disease.

• Thyroid stimulating hormone (TSH) – abnormalities in this measurement require further workup to rule out thyroid disease.

• Rapid plasma reagent (RPR) – abnormalities in this measurement require further workup to rule out syphilis.

Imaging Studies:

• Brain MRI or CT scan – diffuse cortical/cerebral atrophy expected. Enlargement of temporal horn with medial temporal lobe atrophy is occasionally present. also used to rule out other CNS disease.

Figure 3. Alzheimer’s disease. T2-weighted images of brain atrophy with prominent hippocampal atrophy (A and B). (Click to magnify figure)

• Single-photon emission computed tomography (SPECT) scan: This is used in qualified cases, usually in those with atypical presentations such as language disorders (eg, progressive aphasia), visuospatial dysfunction syndromes, and other conditions that may be confused with cerebrovascular disease or other neurodegenerative conditions. Under most circumstances, however, SPECT is an optional study and is not considered mandatory for the routine work-up of typical presentations of Alzheimer’s disease

Other Tests:

• EEG – findings for Alzheimer’s disease and other dementias have been described; please see the EEG in Dementia and Encephalopathy chapter; can help to rule out other dementing diseases such as prion related diseases (eg, Jakob-Creutzfeldt disease)

• Determinations of levels of tau protein (a constituent of neurofibrillary tangles) and amyloid protein (contained, among other lesions, in senile plaques) in cerebrospinal fluid have been advocated by some for the diagnosis of Alzheimer’s disease. However, since there is a considerable overlap in these levels among normal elderly individuals, patients with a variety of neurodegenerative disorders and those with Alzheimer’s disease, such levels are not useful as an unequivocal biological marker of Alzheimer’s disease. Similarly, commercially available determinations of tau protein levels in the urine are not reliable or unanimously agreed upon aids in the diagnosis and management of Alzheimer’s disease. None of these tests should consequently be considered mandatory nor reliable, and cannot be considered a substitute for a clinical diagnosis of Alzheimer’s disease. In addition, these tests have no unanimously agreed upon role in the management of patients.

• Genotyping for apolipoproteins is a research tool helpful to determine the risk of populations of patients to develop Alzheimer’s disease, but is of little if any value in formulating a clinical diagnosis and in formulating a management plan in individual patients.

Procedures:

• Lumbar puncture: Perform lumbar puncture in selected cases to rule out conditions such as normal pressure hydrocephalus, neurosyphilis, and cryptococcosis.

Histologic Findings: See Pathophysiology for a discussion of the salient histopathologic features of AD.

Figure 4. Alzheimer’s Disease; cerebral atrophy: The leptomeninges have been removed from one hemisphere in this specimen, disclosing a marked degree of narrowing of gyri and widening of sulci. These are the typical external features in Alzheimer’s disease. (Click to magnify figure)

MANAGEMENT

Medical Care: Therapeutic approaches to AD follow from the developing hypotheses on pathogenesis and the need to alleviate the cognitive and behavioral manifestations of the disease. The predominantly symptomatic approach preceded by many decades the more recent interventions based on improved understanding of the pathogenesis and pathophysiology of AD.

• Psychotropic medications and behavioral interventions

  • The symptomatic approach is based on behavioral interventions and psychotropic medications that temporarily alleviate clinical manifestations of the disorder, such as anxiety, agitation, depression, and psychotic behavior, are best approached symptomatically.

  • A variety of both behavioral and pharmacologic interventions have been shown to be useful in the management of AD, although their impact is often modest and temporary and does not prevent the eventual relentless deterioration of patients.

  • Behavioral interventions range from patient-centered approaches to caregiver training to help manage cognitive and behavioral manifestations of the disorder. Often, these are combined with the more widely employed pharmacologic interventions, which include anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations such as spells of anger or rage.

  • No unanimously agreed agents or specific dosage of individual agents exist for this wide array of clinical manifestations. At the time of this writing, no Food and Drug Administration (FDA)-approved agent exists for this challenging and common clinical situation. However, medications preferred by many practitioners include haloperidol, risperidone, olanzapine and, more recently quetiapine. In general, the recommendation is to use such agents as infrequently and at doses as low as possible to minimize adverse effects in frail, elderly patients.

  • Particular concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations in patients with so-called Lewy body dementia, or dementia with cortical Lewy bodies (DCLB), also known as Lewy Body dementia (LBD) since such patients are said to be extremely sensitive to such agents. These adverse reactions to conventional neuroleptics have fueled the search for new agents that alleviate disruptive behavior while minimizing the occurrence of extrapyramidallike manifestations and the worsening of motor and behavioral performance observed frequently in DCLB. This is the basis for the recent trend to use the new-generation agents to alleviate the behavioral manifestations of AD, usually into the more advanced stages of the disorder.

  • Several recent studies indicate that anticonvulsants (eg, gabapentin) may have a role in the treatment of behavioral problems in Alzheimer patients.

• Cholinesterase inhibitors

  • A widely employed strategy to address the symptoms of AD consists of trying to palliate the deficiency in the cholinergic innervation to the cerebral cortex. In fact, numerous lines of evidence indicate that the corticipetal cholinergic system is targeted relatively early and more or less selectively in AD. For example, it has been shown for over 2 decades that AD is characterized by (1) substantial loss of acetylcholine content in the cerebral cortex, (2) progressive decline in the cortical levels of the biosynthetic enzyme necessary for the synthesis of acetylcholine (choline acetyltransferase), and (3) severe loss of neurons in the subcortical cholinergic nuclei that project to the cerebral neocortex (basal nucleus of Meynert) and hippocampus (medial septal nuclei).

  • These observations have led to the hypothesis that part of the clinical manifestations of AD are due to a loss of the cholinergic innervation to the cerebral cortex. This hypothesis has in turn led to the development of an increasing number of compounds capable of palliating the cholinergic defect by interfering with the degradation of acetylcholine by acetylcholinesterase (AChE), the synaptic or so-called specific form of cholinesterase. More recently available compounds have included, in some cases, substances capable of blocking the nonsynaptic, or nonspecific cholinesterases, frequently subsumed under the designation of butyrylcholinesterase (BuChE).

  • Products currently in clinical use that inhibit AChE are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (a.k.a., galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy, since BuChE levels have been shown to increase during the course of AD and this enzyme is contained in some AD lesions, including senile plaques.

  • An increasing number of clinical studies demonstrate that cholinesterase inhibition can have modest but detectable effects, such as improvement in cognitive performance, as measured by selected tools such as the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). More recent evidence indicates that cholinesterase inhibitors (ChEIs) also may alleviate the noncognitive manifestations of AD. For example, they can ameliorate behavioral manifestations of the disease, as assessed by tools such as the Neuropsychiatric Inventory, and improve performance in activities of daily living as evinced by the Progressive Deterioration Scale.

  • In general, however, these benefits are temporary, since ChEIs do not address the underlying cause of the degeneration of cholinergic neurons, which continues during the disease. Interestingly, although the increasingly large family of cholinesterase inhibitors originally was expected to help only in the early and intermediate stages of AD, recent studies indicate, unexpectedly, that they (1) improve cognitive performance in advanced stages of the disease, (2) significantly improve behavioral manifestations such as wandering, agitation, and socially inappropriate behavior associated with advanced stages of the disease, and (3) also help in patients with presumed vascular components added to a dementia due to AD.

  • Thus, the admittedly modest benefits of ChEIs seem to extend beyond the relatively restricted sphere of low-level cognitive impairment in the relatively early stages of AD. This was an unexpected phenomenon that has not been explained satisfactorily yet. Interesting speculations, which remain to be tested experimentally, include the possibility that some of the newly recognized benefits in advanced behavioral and cognitive performance may be associated with the inhibition of BuChE, in addition to AChE, a characteristic of only some of the ChEIs currently in use, as mentioned above.

  • The ChEIs share a common profile of adverse effects, the most frequent of which include nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated by slow upward titration of the dose to the desired maintenance dose. Drugs whose absorption peaks are blunted by food (eg, rivastigmine) can further mitigate the adverse effects and improve the tolerability of ChEI treatment.

  • At the time of this writing, only tacrine, donepezil, rivastigmine and galantamine have been approved by the FDA for use in AD. The former is used seldom now, if at all, since it has been superseded by the introduction of donepezil, rivastigmine and galantamine. To date, ChEI are the only class of drugs that have been approved formally for use in AD.

  An often neglected aspect in regards to palliation of cholinergic deficits pertains to the avoidance of centrally acting anticholinergic medications. It is not uncommon to see patients that are receiving both cholinesterase inhibitors and anticholinergic agents, the latter negating or at least counteracting the effects of the former. A careful listing of the medications taken by the patient is therefore important for practical management, in order to reduce the dose, or ideally eliminate, all centrally acting anticholinergic agents.

• New classes of drugs under development

  • Newer categories of drugs based on entirely different mechanisms of action are under development. One example of these is memantine, an N-methyl-D-aspartate (NMDA) antagonist, which is in phase III clinical trials for AD. This agent is under evaluation for advanced stages of the disorder, in contrast with ChEIs, which have been approved formally only for the early and intermediate stages of AD. Interestingly, memantine also may be helpful in other neurodegenerative conditions, such as Huntington disease, AIDS-related dementia, and vascular dementia.

  • Other classes of agents that offer some promise for the future treatment of AD include clioquinoline, an antibiotic that may help reduce the amyloid deposits in the brain of patients with AD, and a number of unrelated compounds under development which also are expected to reduce or eliminate cerebral amyloid deposits and possibly also NFTs.

  Finally, the role of antidepressants in the treatment of mood disorders, and especially depression, cannot be overemphasized. Patients with Alzheimer’s disease suffer from unusually high rates of depression, and palliation of this frequent co-morbidity can help considerably to improve both their cognitive and non-cognitive performance. Other “mood modulators” such as valproic acid can be helpful for the management of disruptive behaviors and outbursts of anger with beset patients in moderately advanced and advanced stages of the disorder.

• Other therapeutic interventions

  • Apart from psychotropic medications and behavioral intervention, ChEIs, NMDA antagonists, and inhibitors of amyloid deposition, numerous other agents are proposed for the treatment of AD. These include free radical scavengers (based on the proposal that AD is caused by oxidative stress) and estrogen or selective estrogen receptor agonists (based on emerging evidence that estrogen has a trophic effect on certain neuronal populations that is lost after menopause). The latter 2 proposals justify many practitioners’ recommendation to employ high doses of tocopherol (1000 IU PO bid) in all patients and estrogen replacement therapy in postmenopausal women with AD. Emphasis should be placed on the fact that the common use of these agents in clinical practice is not mandated by federal or other institutional policy but reflects the widespread belief that they may be beneficial to patients.

  • An additional treatment avenue consists of anti-inflammatory agents, based on the postulation that inflammatory phenomena are necessary for many of the lesions seen in AD, especially SPs, to develop and progress through hypothetical stages of increasing severity. This hypothesis has received considerable support, including many studies purportedly showing lack of progression or improvement of AD manifestations over relatively short periods of observation during anti-inflammatory therapy.

• To date, no interventions have been shown convincingly to slow down or prevent AD.

Surgical Care: No accepted surgical treatments exist for AD. An unconfirmed recent claim postulated that omental transposition to the brain may be beneficial in AD, but most experts remain skeptical. Potential surgical treatments in the future may include devices to infuse neurotrophic factors, such as growth factors, to palliate AD.

Diet: No special dietary considerations exist for AD.

Activity:

• Both physical and mental activities are recommended for patients with AD. In particular, many experts recommend mentally challenging activities, such as crossword puzzles and brainteasers, both to prevent and to attempt to slow down the rate of deterioration of AD. These mental activities should be kept within reasonable levels of difficulty for the patient, preferably be interactive, and of a nature such that the patient can recognize and correct mistakes. Most importantly, these activities should be administered in a manner that does not cause excessive frustration, and ideally motivates the patient to engage in them frequently.

• A small number of investigators have attempted various forms of so-called cognitive retraining, also known as cognitive rehabilitation. The results of this approach remain controversial, and a substantial amount of experimental study remains to be performed to determine whether it may be useful to patients with AD.

MEDICATION

The mainstay of therapy is centrally acting inhibitors of cholinesterase to palliate the depletion of acetylcholine in the cerebral cortex and hippocampus. Because the clinical manifestations of AD are believed to be due to a loss of the cholinergic innervation to the cerebral cortex, compounds have been developed that palliate the cholinergic defect by interfering with the degradation of acetylcholine by acetylcholinesterase (AChE), the synaptic or so-called specific form of cholinesterase. Many of the more recently available compounds have included substances that block the nonsynaptic, or nonspecific, cholinesterases, frequently subsumed under the designation of butyrylcholinesterase (BuChE).

Products currently in clinical use that inhibit AChE are tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine (ie, galanthamine, Reminyl). Among these, only tacrine and rivastigmine also inhibit BuChE. This may be important for their therapeutic efficacy, since BuChE levels have been shown to increase during the course of AD and this enzyme is contained in some AD lesions, including senile plaques.

Cholinesterase inhibitors (ChEIs) can have modest but detectable effects, such as improvement in cognitive performance and possibly alleviation of the noncognitive manifestations of AD. In general, however, these benefits are temporary, since ChEIs do not address the underlying cause of the progressive degeneration of cholinergic neurons. Interestingly, although the increasingly large family of ChEIs originally was expected to help only in the early and intermediate stages of AD, recent studies indicate, unexpectedly, that they (1) improve cognitive performance in advanced stages of the disease, (2) significantly improve behavioral manifestations such as wandering, agitation, and socially inappropriate behavior associated with advanced stages of the disease, and (3) help in patients with presumed vascular components added to a dementia due to AD.

The ChEIs share a common profile of adverse effects, the most frequent of which include nausea, vomiting, diarrhea, and dizziness. These are typically dose related and can be mitigated by slow upward titration of the dose to the desired maintenance dose. Drugs whose absorption peaks are blunted by food (eg, rivastigmine) can further mitigate the adverse effects and improve the tolerability of ChEI treatment.

At the time of this writing, only tacrine, donepezil, and rivastigmine have been approved by the FDA for use in AD. The former seldom is used now, if at all, since it has been superseded by the introduction of donepezil and rivastigmine. Approval of galantamine for use in AD may be given during the year 2001. To date, ChEI are the only class of drugs that have been approved formally for use in AD.

Patients with clinical manifestations of AD such as anxiety, agitation, depression, and psychotic behavior may respond to symptomatic treatment with a psychotropic medication that will temporarily relieve such symptoms. A variety of pharmacologic interventions have been shown to be useful in the management of AD, although their impact is often modest and temporary and they do not prevent the progressive deterioration associated with the disease.

Pharmacologic interventions include anxiolytics for anxiety and agitation, neuroleptics for aberrant and/or socially disruptive behavior, and antidepressants or mood stabilizers for mood disorders and specific manifestations such as spells of anger or rage.

No unanimously agreed agents or specific dosage of individual agents exist for this wide array of clinical manifestations. At the time of this writing, no FDA-approved agent exists for this challenging and common clinical situation. Many practitioners prefer medications such as haloperidol, risperidone, olanzapine and, more recently, quetiapine. In general, such agents should be used as infrequently as possible and at the lowest effective doses to minimize adverse effects in frail, elderly patients.

Concern has been raised about the potential for dopamine-depleting agents to aggravate the manifestations in patients with the so-called Lewy body dementia, or dementia with cortical Lewy bodies (DCLB), since such patients are said to be extremely sensitive to such agents. These adverse reactions to conventional neuroleptics have fueled the search for new agents capable of alleviating disruptive behavior while minimizing the occurrence of extrapyramidallike manifestations and the worsening of motor and behavioral performance observed frequently in DCLB. This is the basis for the recent trend to use newer generation agents such as risperidone, olanzapine, and quetiapine to alleviate the behavioral manifestations of AD, usually into the more advanced stages of the disorder.

Medical/Legal Pitfalls:

• Patients with dementia in general and those with AD in particular usually experience progressive deterioration in their abilities to perform activities of daily living, behavior, and cognition. These may result in inappropriate or adverse psychosocial decisions, such as mismanagement of funds or serious default in the patient’s family, social, and occupational responsibilities. Medical advice should include a warning about these possibilities both to the patient and to at least the most directly responsible caregiver to minimize the risk of adverse legal effects on the patient or others.

• Particular attention should be given to the need to make a legal statement about the competency of patients to handle their own affairs and to the role that assigning power of attorney may have in the management of the patient’s estate and other responsibilities. Obviously, these delicate decisions must be individualized and coupled with legal advice.

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