Alzheimer Disease Eng

8/4/2019 Alzheimer Disease Eng

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Alzheimer Disease

Background

In 1901, a German psychiatrist named Alois Alzheimer observed a patientat the Frankfurt Asylum named Mrs. Auguste D. This 51-year-old womansuffered from a loss of short-term memory, among other behavioralsymptoms that puzzled Dr. Alzheimer. Five years later, in April 1906, thepatient died, and Dr. Alzheimer sent her brain and her medical records toMunich, where he was working in the lab of Dr. Emil Kraeplin. By stainingsections of her brain in the laboratory, he was able to identify amyloidplaques and neurofibrillary tangles.

A speech given by Dr. Alzheimer on November 3, 1906 was the first timethe pathology and the clinical symptoms of presenile dementia (later to berenamed Alzheimer disease [AD]) were presented together. Alzheimerpublished his findings in 1907.

AD is an acquired cognitive and behavioral impairment of sufficient severitythat markedly interferes with social and occupational functioning. It is anincurable disease with a long and progressive course. AD not only has

detrimental effects on the patient but tends to take a significant toll onpatients families and caretakers as well.

The most common form of dementia, AD affects about 4.5 million people inthe United States alone, and that number is projected to exceed 13 millionby the year 2050.Economically, it is a major public health problem. In theUnited States, the cost of caring for patients with dementia was $144 billionper year in 2009. The most recent data available on the cost for healthcareand long-term care services per patient, from 2004, show that the averageyearly cost was about $33,007.

In the past 15-20 years, dramatic progress has been made inunderstanding the neurogenetics and pathophysiology of AD (seePathophysiology). Four different genes have been associated with AD, andothers are likely to be discovered. The mechanisms by which alteredamyloid and tau protein metabolism, inflammation, oxidative stress, andhormonal changes may produce neuronal degeneration in AD are being


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identified, and rational pharmacological interventions based on thesediscoveries are being developed.

Currently, an autopsy or a brain biopsy is the only ways to make a definitivediagnosis of AD, although the diagnosis is usually made clinically from the

history and findings on Mental Status Examination (see Workup).

Symptomatic therapies are the only treatments available for AD. Thestandard medical treatments include cholinesterase inhibitors andpartial N-methyl-D-aspartate (NMDA) antagonists. Psychotropicmedications are often used to treat secondary symptoms of AD, such asdepression, agitation, and sleep disorders

Healthy neurons have an internal support structure partly made up ofstructures called microtubules. These microtubules act like tracks, guidingnutrients and molecules from the body of the cell down to the ends of theaxon and back. A special kind of protein, tau, makes the microtubulesstable.

In AD, tau is changed chemically. It begins to pair with other threads of tau,and they become tangled together. When this happens, the microtubulesdisintegrate, collapsing the neurons transport system (see the imagebelow). This may result first in malfunctions in communication between

neurons and later in the death of the cells.

Pathophysiology

AD affects the 3 processes that keep neurons healthy: communication,metabolism, and repair. This disruption causes certain nerve cells in thebrain to stop working, lose connections with other nerve cells, and finallydie. The destruction and death of these nerve cells causes the memoryfailure, personality changes, problems in carrying out daily activities, andother features of the disease.

The anatomic pathology of Alzheimer disease includes neurofibrillarytangles (NFTs); senile plaques (SPs; also known as beta-amyloid plaques)at the microscopic level; and cerebrocortical atrophy, which predominantlyinvolves the association regions and particularly the medial aspect of the


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temporal lobe. NFTs and SPs, which were described by Alois Alzheimer inhis original report on the disorder in 1907,are now universally accepted asa hallmark of the disease.

Considerable attention has been devoted to elucidating the composition of

NFTs and SPs to find clues about the molecular pathogenesis andbiochemistry of AD. The main constituent of NFTs is the microtubule-associated protein tau (see Anatomy). In AD, hyperphosphorylated tauaccumulates in the perikarya of large and medium pyramidal neurons.Somewhat surprisingly, mutations of the tau gene result not in AD but insome familial cases of frontotemporal dementia.

Since the time of Alois Alzheimer, SPs have been known to include astarch like (or amyloid) substance, usually in the center of these lesions,which is surrounded by a halo or layer of degenerating (dystrophic) neurites

and reactive glia (both astrocytes and microglia).

One of the most important advances in recent decades has been thechemical characterization of this amyloid protein, the sequencing of itsamino acid chain, and the cloning of the gene encoding its precursorprotein (on chromosome 21). These advances have provided a wealth ofinformation about the mechanisms underlying amyloid deposition in thebrain, including information about the familial forms of AD. (See Amyloidhypothesis versus tau hypothesis.)

Although the amyloid cascade hypothesis has gathered the most researchdollars, other interesting hypotheses have been proposed, including themitochondrial cascade hypothesis.

In addition to NFTs and SPs, many other lesions of AD have beenrecognized since Alzheimers original papers were published. Theseinclude the granulovacuolar degeneration of Shimkowicz; the neuropilthreads of Braak et al; and neuronal loss and synaptic degeneration, whichare thought to ultimately mediate the cognitive and behavioralmanifestations of the disorder.

Neurofibrillary tangles and senile plaques

Plaques are dense, mostly insoluble deposits of protein and cellularmaterial outside and around the neurons. Plaques are made of beta-amyloid (AB), a protein fragment snipped from a larger protein called


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amyloid precursor protein (APP). These fragments clump together and aremixed with other molecules, neurons, and non-nerve cells (see the imagesbelow).

The cause of AD is unknown. Several investigators now believe thatconverging risk factors trigger a pathophysiologic cascade that, overdecades, leads to Alzheimer pathology and dementia.

The following risk factors for Alzheimer-type dementia have beenidentified:

Advancing age Family history

Apolipoprotein E epsilon 4 genotype Obesity Insulin resistance Vascular factors Dyslipidemia Hypertension Inflammatory markers Down syndrome

In addition, epidemiology studies have suggested some possible riskfactors (such as aluminumand previous depression) and some protective

factors (education,, anti-inflammatory drugs). Moderate-to-severe headtrauma appears to be linked to the development of AD as well as otherforms of dementia later in life. A study that followed over 7,000 US veteransfrom World War II showed that those who had sustained head injuries hadtwice the risk of developing dementia later in life, with veterans whosuffered more severe head trauma being at an even higher risk. The studyalso found that the presence of the apolipoprotein E gene and sustaininghead trauma seemed to act additively to increase the risk of developingAD, although there was no direct correlation.


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Insulin resistance

A small study by Baker et al implies that insulin resistance as evidenced by

decreased cerebral glucose metabolic rate measured by a specific type ofpositron emission tomography (PET) scan may be useful as an earlymarker of AD risk, even before the onset of MCI.The PET scan revealed aqualitatively different activation pattern in patients with prediabetes or type2 diabetes mellitus during a memory encoding task compared with healthyindividuals who were not insulin resistant. Although their results were notstatistically significant due to the small number of subjects (n=23) in thestudy, this certainly warrants further study because it may lead to anoninvasive test that could help to quantify risk for development of AD in

presymptomatic patients.A similar study was performed in a much larger population of 3,139participants to investigate the association of diabetes mellitus with anincreased risk of AD and to assess whether the risk is constant over time.Adifferent measure of insulin resistance was calculated, using thehomeostasis model assessment. They found a similar association betweeninsulin resistance and AD over 3 years, which then disappeared after thattime. Disturbances in insulin metabolism may not cause neurologicalchanges but may influence and accelerate these changes, leading to an

earlier onset of AD.

Genetic causes

Although most cases of AD are sporadic (ie, not inherited), familial forms of

AD do exist; however, they account for less than 7% of all cases.

Mutations in genes coding for 3 proteins unequivocally cause AD. Thesegenes (which code for amyloid precursor protein [APP, on chromosome21], for PS1 [on chromosome 14], and for PS2 [on chromosome 1]) all leadto a relative excess in the production of the stickier 42-amino acid form ofthe AB peptide over the less sticky 40-amino acid form.


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This beta-pleated peptide is postulated to have neurotoxic properties and tolead to a cascade of events (as yet incompletely understood) that results inneuronal death, synapse loss, and the formation of NFTs and SPs, amongother lesions. Nonetheless, the mutations that have been found to dateaccount for less than half of all cases of early-onset AD. Other than theapolipoprotein E epsilon 4 (APOE E4) genotype, no polymorphisms in othergenes have been consistently found to be associated with late-onset AD.

Genetic factors associated or potentially associated with AD aresummarized in Tables 1 and 2.

Table 1. Genetic Factors Associated With Alzheimer Disease

ChromosomeGene

DefectOnset Putative Mechanisms

21 APP Early Increased production of AB 42

19 APOE E4 Late Tau hyperphosphosphorylation

Impaired production/

-polymerzation/ clearance of AB

14 PS-1 Early Early increased production of AB 42

1 PS-2 Early Early altered AB metabolism


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Table 2. Other Locus or Susceptibility Genes PotentiallyAssociated with Alzheimer Disease

Chromosome Gene Onset Putative Mechanisms

12 Unidentified Late Unknown

6 HLA A2 Late Possible relationship with

immune system and

inflammatory response

14 a1-

antichymotrypsin A

allele

Late AB aggregation

12 LRP Late Endocytosis of APOE/APP

APP mutations

The observation that patients with Down syndrome (trisomy 21) developcognitive deterioration and typical pathological features of AD by middleage led to the discovery of the APPgene on chromosome 21.Simultaneously, a locus segregating with a minority of early-onset familialAD kindreds was mapped to this chromosome in the same region asthe APPgene. Subsequently, several missense mutations withinthe APPgene that resulted in amino acid substitutions in APP wereidentified in these FAD kindreds. Such mutations appear to alter the

previously described proteolytic processing of APP, generatingamyloidogenic forms of AB. Skin fibroblasts from subjectscarrying APPmutations produce increased AB 42/43. Increased plasmaconcentration of AB 42/43 is also seen in these patients regardless of age,sex, or clinical status. Interestingly, some patients with sporadic AD mayexhibit similar elevations of plasma AB 42/43.


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PS1 and PS2 mutations

In cases of early-onset autosomal-dominant AD cases, 50-70% appear tobe associated with a locus (AD3) mapped by genetic linkage to the longarm of chromosome 14 (14q24.3). Numerous missense mutations havebeen identified on a strong candidate gene, called PS1. At the same time,another autosomal dominant locus responsible for early-onset AD waslocalized to chromosome 1. Two mutations were identified on the candidategene, designated PS2.

The physiological role of presenilins and the pathogenic effects of their

mutations are not yet well understood.

APOE E4 allele

The gene encoding the cholesterol-carrying apolipoprotein E (APOE) onchromosome 19 has been linked to early-onset familial and sporadic AD.The gene is inherited as an autosomal codominant trait with 3 alleles. Thisarticle focuses on the allele that may have a direct correlation to AD.

APOE E4gene dose is correlated with increased risk and earlier onset ofAD.Persons with 2 copies of the APOE E4 allele (4/4 genotype) havesignificantly greater risk of developing AD than persons with other APOEsubtypes. Mean age at onset is significantly lower in the presence of 2APOE E4 copies. A collaborative study has suggested that APOE E4

exerts its maximal effect before the age of 70.

Many APOE E4 carriers do not develop AD, and many patients with AD donot have this allele. Therefore, the presence of an APOE E4 allele does notsecure the diagnosis of AD, but instead, the APOE E4 allele acts as abiological risk factor for the disease, especially in those younger than70 years.

Epidemiology

United States statistics

Using 2000 US Census results, Hebert et al estimated that about 4.5million people in the United States had AD.These researchers calculated


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that by 2030, an estimated 7.7 million Americans aged 65 and older willhave AD and that by 2050, that number will rise to more than 13 million.

According to a 2010 report, AD affects approximately 5.3 million people inthe United States.A larger number of individuals have decreased cognitive

function (eg, mild cognitive impairment); this condition frequently evolveinto a full-blown dementia, thereby increasing the number of affectedpersons. The statistical projections cited in this report indicate that thenumber of persons affected by the disorder in the United States couldrange from 11 to 16 million by the year 2050.

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

International statistics

Prevalence rates of AD similar to those in the United States have beenreported in industrialized nations. The prevalence of dementia in subjects65 years and older in North America is approximately 6-10%, with ADaccounting for two-thirds of these cases. If milder cases are included, theprevalence rates double. Countries experiencing rapid increases in theelderly segments of their population have rates approaching those in theUnited States.

The World Health Organizations review in 2000 on the Global Burden ofDementiareported that an integrative analysis of 47 surveys across 17countries suggested that approximate rates for dementia from any causeare under 1% in persons aged 60-69 years, rising to about 39% in persons90-95 years old. The prevalence doubles with every 5 years of age withinthat range, with few differences taking into account secular changes, age,gender, or place of living.

AD has become nearly twice as prevalent as vascular dementia (VaD) inKorea, Japan, and China since transition in the early 1990s. American and

European studies consistently reported AD to be more prevalent than VaD.They found a dementia prevalence rate among Chinese aged 50 years andolder on the islet of Kinmen for this age group of 11.2 per 1,000. ADaccounted for 64.6% and VaD for 29.3%. These results, together withprevious studies in Chinese populations, suggest that the rates of AD in theChinese are low compared with those in whites.


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In Nigeria, the prevalence of dementia was low. Indian studies werecontradictory, with both AD and VaD being more prevalent in differentstudies.

Age distribution for Alzheimer disease

The prevalence of AD increases with age. AD is most prevalent inindividuals older than 60 years. Some forms of familial early-onset AD canappear as early as the third decade, but this represents a subgroup of theless than 10% of all familial cases of the disease.

More than 90% of cases of AD are sporadic and occur in individuals olderthan 60 years. However, of interest, results of some studies ofnonagenarians and centenarians suggest that the risk may decrease inindividuals older than 90 years. If so, age is not an unqualified risk factor for

the disease, but further study of this matter is needed.

Savva et al found that the association between dementia and thepathological features of AD (eg, neuritic plaques, diffuse plaques, tangles)is stronger in younger old persons (ie, age 75 years) than in older oldpersons (ie, 95 years). These results were achieved by assessing 456brains donated to the population-based Medical Research CouncilCognitive Function and Ageing Study from persons 69-103 years of age atdeath.

These results demonstrate that the relationship between cerebral atrophyand dementia persist into the oldest ages, but the strength of associationbetween pathological features of AD and clinical dementia diminished. It isimportant to take age into account when assessing the likely effect ofinterventions against dementia on the population.

Sex distribution for Alzheimer disease

AD affects both men and women; however, Plassman et al found the risk ofdeveloping AD to be significantly higher in women than in men, primarily

due to womens higher life expectancy.

Prevalence of Alzheimer disease by race

AD and other dementias are more common in African Americans than inwhites. According to the Alzheimers Association, in the population aged 71and older, African Americans are almost 2 times as likely to have AD and


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other dementias as whites (21.3% of African Americans vs 11.2% ofwhites). The number of Hispanic patients studied in this age group was toosmall to determine the prevalence of dementia in this population.

In individuals age 65 and older, 7.8% of whites, 18.8% of African-

Americans, and 20.8% of Hispanics have AD or other dementias, and theprevalence of AD and other dementias is higher in older versus youngerage groups

Prognosis

AD is initially associated with memory impairment that progressivelyworsens. Over time, patients with AD can display anxiety, depression,insomnia, agitation, and may become violent and paranoid. Eventually thepatient with AD loses all bodily function, including the ability to walk andswallow; feeding is possible only by gastrointestinal tube. Difficultyswallowing may lead to aspiration pneumonia.

The time from diagnosis to death varies from as little as 3 years if thepatient is older than 80 years when diagnosed to as long as 10 or moreyears if the patient is younger. The primary cause of death is intercurrent

illness, such as pneumonia.In the United States, AD is frequently considered a leading cause of death.In 2006, AD was the seventh leading cause of death ; however, AD as anunderlying cause of death is frequently underreported.

Patient Education

When counseling patients following a diagnosis of AD, it is essential to

involve the patients family and others who will play a supporting role in the

discussion. It is important to emphasize that not only the patient, but also

those who support him or her, will likely experience reactions of sadness


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and anger, and that these are normal reactions to such a catastrophic

diagnosis.

As the patients symptoms become more pronounced, a dialogue must beopened regarding the patients wishes for care when he or she is no longerable to make the necessary choices. Durable power of attorney should bediscussed, with particular attention to who will make decisions for bothmedical and financial issues. Medical advance directives should beconsidered while the patient is still able to participate in the decision-making process.

As the patient continues to decline, family members should be careful toselect qualified and trustworthy individuals to be involved in the day-to-daymanagement of the patient. Any suspicions of elder abuse should be

immediately addressed.Throughout the course of the illness, it is important that the family becounseled to continue to treat the patient as a competent adult as much aspossible, despite the patients decreasing ability to care for himself orherself.

Diagnostic Considerations

Clinical guidelines for the diagnosis of Alzheimer disease (AD) have beenformulated by the National Institutes of Health-Alzheimers Disease andRelated Disorders Association (NIH-ADRDA); the American PsychiatricAssociation, in the Diagnostic and Statistical Manual of Mental Disorders,Fourth Revision, Text Revision (DSM-IV-TR); and the Consortium to

Establish a Registry in Alzheimers Disease (CERAD). In 2011, theNational Institute on Aging (NIA) and the Alzheimers Association (AA)workgroup released new research and clinical diagnostic criteria for AD.

The NIH-ADRDA criteria for the diagnosis of AD require the finding of aslowly progressive memory loss of insidious onset in a fully consciouspatient. AD cannot be diagnosed in patients with clouded consciousness or


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delirium. Toxic metabolic conditions and brain neoplasms must also beexcluded as potential causes of the patients dementia.

The focus of the 2011 NIA-AA criteria is the need to create a more accuratediagnosis of preclinical disease so that treatment can begin before neurons

are significantly damaged, while they are more likely to respond. Thereforethe report includes criteria for identification of asymptomatic, preclinical AD(for purposes of research, not clinical diagnosis); for diagnosis of mildcognitive impairment (MCI), an early symptomatic but predementia phaseof AD; and for diagnosis of AD dementia.

The DSM-IV-TRlists 6 diagnostic criteria, labeled A-F, for dementia of theAlzheimer type:

A. The development of multiple cognitive deficits manifested by both of the

following:

Memory impairment (impaired ability to learn new information or to recallpreviously learned information)

One or more other cognitive disturbancesOther cognitive disturbances consist of the following:

Aphasia (language disturbance) Apraxia (impaired ability to carry out motor activities despite intact motor

function)

Agnosia (failure to recognize or identify objects despite intact sensoryfunction) Disturbance of executive functioning

B. The cognitive deficits must each cause significant impairment in social oroccupational function and represent a significant decline from a previouslevel of functioning.

C. The course of disease is characterized by gradual onset and continuingdecline.

D. The cognitive deficits are not due to any of the following:

Other central nervous system conditions that cause progressive deficits inmemory and cognition

Systemic conditions that are known to cause dementia Substance-induced conditions

E. The deficits do not occur exclusively during the course of a delirium.


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F. The disturbance is not better accounted for by another DSM-IV Axis Idisorder (ie, a clinical disorder).

These guidelines are widely believed to be 90-95% accurate (ashistopathologically verified) when followed carefully. They are important not

only for routine management but also for selecting and enrolling patients intherapeutic trials.

Depression and AD and other dementias have an association that is likelyto be complex and depression may be misdiagnosed in the realm ofdementia. Recent Framingham data have helped bolster theepidemiological association. The study showed a 50% increase in AD anddementia in those who were depressed at baseline.During a 17-yearfollow-up period, a total of 21.6% of participants who were depressed atbaseline developed dementia compared with 16.6% of those who were not

depressed.

In another related study, recurrent depression was noted to be particularlypernicious. One episode of depression conferred an 8792% increase indementia risk, while having 2 or more episodes nearly doubled the risk.

Other disorders to consider include the following:

Age-associated memory impairment Alcohol and drug abuse

Chronic obstructive pulmonary disease Depression Fecal impaction Hearing or visual problems Hypernatremia Hypoglycemia Hypothyroidism Polypharmacy Volume depletion


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Differentials

Aphasia

Carotid Artery, Stenosis

Cortical Basal Ganglionic Degeneration

Dementia in Motor Neuron Disease

Dementia With Lewy Bodies

Frontotemporal Lobe Dementia

Huntington Disease Dementia

Imaging in Normal Pressure Hydrocephalus

Neurosyphilis

Parkinson Disease

Parkinson-Plus Syndromes

Pediatric Lyme Disease

Prion-Related Diseases

Thyroid Disease

Vascular Dementia

Wilson Disease
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Approach Considerations

Clinical guidelines such as those described earlier are used. (SeeDiagnosis.) The main focus of these diagnostic guidelines consists ofverifying the initial finding of mild, slowly progressive memory loss,confirming that additional spheres of cognition are also compromised, andruling out other possible causes for dementia (eg, cerebrovascular disease,cobalamin [vitamin B-12] deficiency, syphilis, thyroid disease).

A combination of clinical examination and ancillary imaging studies (eg,computed tomography [CT], magnetic resonance imaging [MRI], and, in

selected cases, single-photon emission CT [SPECT] or positron emissiontomography [PET]) and laboratory tests may be used. At the AlzheimersAssociation International Conference on Alzheimers Disease (AAICAD) inJuly 2010, operational research criteria were presented to define preclinicalAD, mild cognitive impairment due to AD, probable AD, and possible AD,involving PET imaging, cerebrospinal fluid (CSF) A42 and tau levels, andgenetic analysis in order to facilitate future studies. These criteria were notintended to serve as diagnostic criteria for clinical purposes. However, thefinal version of the NIA-AA criteria, published in April (online) and May2011, also includes core clinical criteria for diagnosis of mild cognitive

impairment by health care providers without access to CSF testing oradvanced imaging. TheNIA-AA criteria for diagnosis of dementia due to ADare clinical, with biomarkers in an assisting, nonessential role.

Lab Studies

Laboratory workup can be performed to rule out other conditions that maycause cognitive impairment. Current recommendations from the AmericanAcademy of Neurology (AAN) include measurement of the cobalamin(vitamin B-12) level and a thyroid function screening test. Additionalinvestigations are left to the physician, to be tailored to the particular needsof each patient. Initial test results that require further investigation includethe following:


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Abnormalities in complete blood cell count and cobalamin (vitamin B-12)levels require further workup to rule out hematologic disease

Abnormalities found in screening of liver enzyme levels require furtherworkup to rule out hepatic disease

Abnormalities in thyroid-stimulating hormone (TSH) levels require furtherworkup to rule out thyroid disease

Abnormalities in rapid plasma reagent (RPR) require further workup torule out syphilis

There is a possible link between vitamin D deficiency and cognitiveimpairment.However, vitamin D deficiency has not been identified as areversible cause of dementia.

Brain MRI or CT Scanning

AAN recommendations indicate that structural neuroimaging with either anoncontrast CT or MRI scan is appropriate in the initial evaluation ofpatients with dementia, in order to detect lesions that may result incognitive impairment (eg, stroke, small vessel disease, tumor).In patientswith Alzheimer disease (AD), brain MRIs or CT scans can show diffusecortical and/or cerebral atrophy, but these findings are not diagnostic of AD.

In clinical research studies, atrophy of the hippocampi (structures important

in mediating memory processes) on coronal MRI is considered a validbiomarker of AD neuropathology. Nonetheless, measurement ofhippocampal volume is not used in routine clinical care in the diagnosis ofAD.

SPECT or PET scanning

Brain scanning with SPECT or PET is not recommended for the routineworkup of patients with typical presentations of AD. These modalities maybe useful in atypical cases or when some form of frontotemporal dementia

is a more likely diagnosis.

Electroencephalography

Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob diseaseor other prion-related disease is a likely diagnosis . Periodic high-amplitude
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sharp waves can eventually be detected in most cases of Creutzfeldt-Jakobdisease.

EEG is also useful if pseudodementia is a realistic consideration when anormal EEG in a patient who appears profoundly demented would support

that diagnosis. Multiple unwitnessed seizures rarely can present asdementia and an EEG would be valuable for evaluating that possibility.

Lumbar Puncture

Perform lumbar puncture in select cases to rule out conditions such as

normal-pressure hydrocephalus, neurosyphilis, neuroborreliosis, and

cryptococcosis.

Cerebrospinal fluid (CSF) levels of tau and phosphorylated tau are often

elevated in AD, whereas amyloid levels are usually low. The reason for this

is not known, but perhaps amyloid levels are low because the amyloid is

deposited in the brain rather than the CSF. By measuring both proteins,

sensitivity and specificity of at least 80% and more often 90% can be

achieved.

At present, however, routine measurement of CSF tau and amyloid is not

recommended except in research settings. Lumbar puncture for

measurement of tau and amyloid may become part of the diagnosticworkup when effective therapies that slow the rate of progression of AD are

developed, particularly if the therapies are specific for AD and carry

significant morbidity.

Genotyping

Genotyping for apolipoprotein E (APOE) alleles is a research tool that ishelpful in determining the risk of AD in populations, but it is of little, if any,value in making a clinical diagnosis and developing a management plan inindividual patients.

In a prospective, randomized, controlled trial of the effect of disclosingAPOE genotyping results to 162 asymptomatic adults who had a parentwith AD, Green et al found that follow-up testing over the course of a yearshowed no significant differences with disclosure versus nondisclosure ontime-averaged measures of anxiety, depression, or test-related distress.
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Test-related distress was reduced among those who learned that they didnot carry the APOE epsilon 4 (APOE E4) allele. Persons who had highlevels of emotional distress before undergoing genetic testing were morelikely to have emotional difficulties after disclosure.

Genetic Testing for APP and Presenilin Mutations

After appropriate counseling, genetic testing for APP and presenilin

mutations is appropriate in early-onset cases.

Approach Considerations

Therapeutic approaches to Alzheimer disease (AD) will someday includeboth symptomatic therapy and disease-modifying therapies. To date, onlysymptomatic therapies are available. All drugs approved by the US Foodand Drug Administration (FDA) for the treatment of AD modulateneurotransmitters, either acetylcholine or glutamate. The standard medicaltreatment for AD includes cholinesterase inhibitors (ChEIs) and partial N-methyl-D-aspartate (NMDA) antagonists.

Psychotropic medications are often used to treat secondary symptoms ofAD, such as depression, agitation, and sleep disorders. These includeantidepressants, anxiolytics, antiparkinsonian agents, beta-blockers,antiepileptic drugs used for their effects on behavior, and neuroleptics.Several studies have examined the efficacy of psychotropic drugs; mosthave demonstrated no or limited efficacy, but many issues makeinterpretation of data from these studies difficult.

Other medications that have been used to treat AD include antioxidants(vitamin E [-tocopherol]), hormones (conjugated estrogens), nonsteroidal

anti-inflammatory drugs (NSAIDs), and Ginkgo biloba.

Hospitalization should be considered for any unstable medical conditionthat may complicate the patients treatment. If a patient becomes a dangerto him/herself or others, admission to a long-term care facility due to gravedisability should be considered for everyones safety.


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Treatment of Mild to Moderate Disease

ChEIs and mental exercises are used in an attempt to prevent or delay thedeterioration of cognition in patients with AD.

Cholinesterase inhibition

Numerous lines of evidence suggest that cholinergic systems that modulateinformation processing in the hippocampus and neocortex are impairedearly in the course of AD. These observations have suggested that some ofthe clinical manifestations of AD are due to loss of cholinergic innervationto the cerebral cortex.

Centrally acting ChEIs prevent the breakdown of acetylcholine. Four suchagents have been approved by the FDA for the treatment of AD: tacrine(Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine(Razadyne, formerly Reminyl).

All ChEIs have shown modest benefit compared with placebo on measuresof cognitive function and activities of daily living. Patients on ChEIs declinemore slowly on cognitive and functional measures than patients onplacebo. In general, the benefits are temporary because ChEIs do not

address the underlying cause of the degeneration of cholinergic neurons,which continues during the disease. The ChEIs may also alleviate thenoncognitive manifestations of AD, such as agitation, wandering, andsocially inappropriate behavior.

Although the ChEIs were originally expected to be efficacious in only theearly and intermediate stages of AD (because the cholinergic deficitbecomes more severe later in disease and fewer intact cholinergicsynapses are present), they are also helpful in advanced disease.

ChEIs are also helpful in patients with AD with concomitant infarcts and inpatients with dementia with Lewy bodies. (Frequently, AD and dementiawith Lewy bodies occur in the same patient; this is sometimes called theLewy body variant of AD.)

The ChEIs share a common profile of adverse effects, the most frequent ofwhich are nausea, vomiting, diarrhea, and dizziness. These are typicallydose related and can be mitigated with slow up-titration to the desired


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maintenance dose. As antimuscarinic drugs are used for the treatment ofincontinence, logically, ChEIs might exacerbate incontinence. One briefreport has supported this hypothesis.

ChEIs prescribed to treat dementia can provoke symptomatic bradycardia

and syncope and precipitate fall-related injuries, including hip fracture. Apopulation-based cohort study that identified community-dwelling olderadults with dementia who were taking cholinesterase inhibitors (n=19,803)and controls who were not (n=61,499) found hospital visits for syncopewere more frequent in people receiving ChEIs than in controls (31.5 vs 18.6events per 1000 person-years).

Other syncope-related events, including hospital visits for bradycardia,permanent pacemaker insertion, and hip fracture, were also more commonamong people receiving cholinesterase inhibitors compared with controls.

ChEI use in older adults with dementia is associated with increased risk ofsyncope-related events; these risks must be weighed against the benefitsof taking ChEIs.

Anecdotal reports exist of acute cognitive and behavioral declineassociated with the abrupt termination of ChEIs. In several of these cases,restarting the ChEI was not associated with substantial improvement.These reports have implications concerning the best practice whenswitching a patient from one ChEI to another in this class.

Reasons for switching might include undesirable side effects or seeminglack of efficacy. Nonetheless, no published data help clinicians know whenswitching to another ChEI would be helpful. The common practice oftapering a patient off one central nervous system (CNS)-active medicationbefore starting a new one should not be followed when changing ChEIs.For example, a patient who had been taking 10 mg of donepezil should bestarted the next day on galantamine, at least 8 mg/d and possibly 16 mg/d.

No current evidence supports the use of more than 1 ChEI at a time.

Of note, tacrine has potential liver toxicity, requires frequent bloodmonitoring, and has been rarely prescribed since the other agents havebecome available.

Centrally acting anticholinergic medications should be avoided. Patients notuncommonly receive both ChEIs and anticholinergic agents, whichcounteract each other. Medications with anticholinergic effects, such as


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diphenhydramine (Benadryl) and tricyclic antidepressants (eg, amitriptyline,nortriptyline) can cause cognitive dysfunction. Therefore, a careful listing ofthe patients medications is important so that the physician can reduce thedoses of, or ideally eliminate, all centrally acting anticholinergic agents.

Mental activity to support cognition

Many patients with normal cognition or those with mild impairment areconcerned that they may develop AD. Many experts believe that mentallychallenging activities, such as doing crossword puzzles and brainteasers,may reduce the risk in such patients. Whether such activities might slowthe rate of disease progression in patients who already have AD is notknown. Clinical trials are underway to determine the effect these cognitiveactivities have on AD progression.

The mental activities should be kept within a reasonable level of difficultyfor the patient. They should preferably be interactive, and they should bedesigned to allow the patient to recognize and correct mistakes. Mostimportant, these activities should be administered in a manner that doesnot cause excessive frustration and that ideally motivates the patient toengage in them frequently. Unfortunately, little standardization or rigoroustesting has been done to validate this treatment modality.

Some investigators have attempted various forms of cognitive retraining,also known as cognitive rehabilitation. The results of this approach remain

controversial, and a substantial experimental study must still be performedto determine if it is useful in Alzheimer disease.

Treatment of Moderate to Severe Disease

The partial NMDA antagonist memantine (Namenda) is believed to work by

improving the signal-to-noise ratio of glutamatergic transmission at theNMDA receptor. This agent is approved by the FDA for treating moderateand severe AD. Several studies have demonstrated that memantine can besafely used in combination with ChEIs. Studies suggest that the use ofmemantine with donepezil affects cognition in moderate to severe AD butnot in mild to moderate AD.


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Treatment of Secondary Symptoms

A variety of behavioral and pharmacologic interventions can temporarilyalleviate clinical manifestations of AD, such as anxiety, agitation,depression, and psychotic behavior. The effectiveness of suchinterventions is often modest and temporary, and they do not prevent theeventual deterioration of the patients condition.

No specific agent or dose of individual agents is unanimously accepted forthe wide array of clinical manifestations. At present, the FDA has notapproved any psychotropic agent for the treatment of AD.

Behavioral interventions

Behavioral interventions range from patient-centered approaches tocaregiver training to help manage cognitive and behavioral manifestationsof AD. These interventions are often combined with the more widely usedpharmacologic interventions, such as anxiolytics for anxiety and agitation,neuroleptics for aberrant and/or socially disruptive behavior, andantidepressants or mood stabilizers for mood disorders and specificmanifestations (eg, episodes of anger or rage).

Neuroleptic agents

In 2005, the FDA added a black box warning on the use of atypicalneuroleptics in the treatment of secondary symptoms of AD such asagitation.Analyses suggested that patients on atypical neuroleptics hadincreased risk of death or stroke compared with patients on placebo. In2008, a black box warning was included on haloperidol, prochlorperazine,thioridazine, and chlorpromazine for the same reason.

The general recommendation is to use such agents as infrequently as

possible and at the lowest doses possible to minimize adverse effects,particularly in frail, elderly patients. Particular concern has been raisedabout the potential for dopamine-depleting agents to aggravate the motormanifestations of dementia with Lewy bodies (DLB), because patients withDLB may be extremely sensitive to these agents.
http://emedicine.medscape.com/article/1135041-overviewhttp://emedicine.medscape.com/article/1135041-overview


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Antidepressants and mood modulators

Antidepressants have an important role in the treatment of mood disordersin patients with AD. Depression is observed in more than 30% of patientswith AD, and it frequently begins before AD is clinically diagnosed.Therefore, palliation of this frequent comorbid condition may improvecognitive and noncognitive performance.

Nyth found citalopram to be beneficial in mood and other neuropsychiatricsymptoms in patients in the moderate stage of AD.However, Weintraub etaland Petraccafound sertraline and fluoxetine to have no short- or long-term benefit in mood over placebo.

Other mood modulators, such as valproic acid, can be helpful for thetreatment of disruptive behaviors and outbursts of anger, which patients

with moderately advanced or advanced stages of AD may have.

Results of several studies indicate that anticonvulsants (eg, gabapentin,valproic acid) may have a role in the treatment of behavioral problems inpatients with Alzheimer disease.

Suppression of Brain Inflammation

Many studies have suggested that intense inflammation occurs in thebrains of patients with AD. Epidemiologic studies suggest that some

patients on long-term anti-inflammatory therapy have a decreased risk ofdeveloping AD. Nonetheless, no randomized clinical trial of greater than 6-months duration has demonstrated efficacy of anti-inflammatory drugs inslowing the rate of progression of AD.

Although previous reports reflect delayed onset of AD in individuals whoused nonsteroidal anti-inflammatory drugs (NSAIDs), a study by Breitner etal showed that NSAIDs do not protect against AD, at least in very oldpeople. Relying on computerized pharmacy dispensing records andbiennial dementia screening, investigators found AD incidence was

increased in heavy NSAID users. These findings may represent deferral ofAD symptoms from earlier to later old age.

Experimental Therapies

A variety of experimental therapies have been proposed for AD. Theseinclude antiamyloid therapy, reversal of excess tau phosphorylation,


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estrogen therapy, and vitamin E therapy free-radical scavenger therapy.Studies of these therapies have yielded mostly disappointing results.

Antiamyloid therapy

In the past 10 years, numerous studies have been conducted, and manyare still ongoing, that test therapies designed to decrease toxic amyloidfragments in the brain. A wide variety of approaches have been tried,including the following:

Vaccination with amyloid species Administration of monoclonal antiamyloid antibodies Administration of intravenous immune globulin that may contain amyloid-

binding antibodies Selective amyloid-lowering agents Chelating agents to prevent amyloid polymerization Brain shunting to improve removal of amyloid Beta-secretase inhibitors to prevent generation of the A-beta amyloid

fragmentTo date, no phase III study of these approaches has shown an acceptablecombination of efficacy and acceptable side effects.

Tau-directed therapies

Studies are also ongoing with agents that may prevent or reverse excesstau phosphorylation and thereby diminish formation of neurofibrillarytangles.

Free-radical scavenger therapy

Excess levels of free radicals in the brain are neurotoxic. Nonetheless, nostudy has demonstrated efficacy of free-radical scavengers in the treatmentof the cognitive symptoms of AD.

Vitamin E therapy

A report by Sano et al in 1997 suggested that high-dose vitamin E (2000units per day of alpha-tocopherol) might decrease the risk of death or therate of conversion to severe dementia. This benefit presumably resultedfrom the antioxidant effects of vitamin E. Nonetheless, subsequent studies


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suggested that vitamin E supplementation may increase risk of adversecardiovascular outcomes. Therefore, use of these agents is not currentlyrecommended, and most practitioners have abandoned their use.

Estrogen therapy

No data show that women with AD who are placed on estrogentherapy (ET) have fewer symptoms or progress more slowly than womentreated with a placebo. Furthermore, a randomized clinical trial of estrogenin cognitively normal women aged 65 years and older with a first-degreerelative with AD showed that ET might actually increase the risk of strokeand dementia. Whether ET might decrease risk if started well before age65 years is not known.

Presymptomatic disease-modifying therapy

Disease-modifying therapies would delay the onset of AD and/or slow therate of progression. Since brain changes associated with AD probably startdecades before dementia becomes clinically apparent, many investigatorsbelieve that disease-modifying therapies are much more likely to beeffective if they are started in a presymptomatic stage.

Studies are identifying patients at increased risk with neuropsychological,neuroimaging, and genetic methods. Although phase III trials for severalpotential disease-modifying therapies have been completed, to date none

of these agents have shown clear efficacy and hence none have beenapproved by the FDA.

Surgical Treatment

No accepted surgical treatments exist for AD. Potential surgical treatmentsin the future may include the use of devices to infuse neurotrophic factors,such as growth factors, to palliate AD.

Dietary Measures

No special dietary considerations exist for Alzheimer disease.

Caprylidene is a prescription medical food that is metabolized into ketonebodies. The brain can use these ketone bodies for energy when its ability toprocess glucose is impaired. Brain-imaging scans of older adults andpersons with AD reveal dramatically decreased uptake of glucose.
http://emedicine.medscape.com/article/276107-overviewhttp://emedicine.medscape.com/article/276107-overviewhttp://emedicine.medscape.com/article/276107-overviewhttp://emedicine.medscape.com/article/276107-overview


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The approval of caprylidene was based on a double-blind, randomized,placebo-controlled, 90-day study that enrolled 152 patients with mild-to-moderate AD.At day 45, Alzheimers Disease Assessment Scalecognitivesubscale (ADAS-Cog) scores stabilized in the caprylidene group, whereasthese scores declined in the placebo group.

The ADAS-Cog change from baseline score was also analyzed based onAPOE E4 genotype. The APOE E4(-) patients receiving caprylideneshowed improved cognitive function when compared with APOE E4(-)patients receiving placebo. In APOE E4(+) patients, the mean change inADAS-Cog total scores for the 2 groups was essentially identical at all timepoints, with more patients showing decline rather than improvement at days45 and 90.

Physical Activity

Routine physical activity and exercise may have an impact on ADprogression, and perhaps has a protective effect on brain health.Increasedcardiorespiratory fitness levels are associated with higher hippocampalvolumes in patients with mild AD, suggesting that cardiorespiratory fitnessmay modify AD-related brain atrophy.

The activity of each patient should be individualized. The patientssurroundings should be safe and familiar. If the patients activity isoptimized too much, it can cause agitation, but too little can cause thepatient to withdraw and maybe become depressed.

The patient needs contact with the outside environment. Television can behelpful for this task. Maintaining structured routines may be helpful todecrease patient stress in regard to meals, medication, and othertherapeutic activities aimed at maintaining cognitive functioning.

Long Term Monitoring

Patients should receive regular follow-up care by their outpatient physician

to closely monitor the illness and maximize the patients functioning as longas possible.


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Medication Summary

The mainstay of therapy for patients with Alzheimer disease (AD) is the useof centrally acting cholinesterase inhibitors to attempt to compensate for

the depletion of acetylcholine (ACh) in the cerebral cortex andhippocampus. A partial N-methyl-D-aspartate (NMDA) antagonist isapproved for treatment of moderate and severe AD.

Various medications are used for treatment of secondary symptoms of AD,including antidepressants, anti-anxiety agents, and antipsychotic agents.

Cholinesterase Inhibitors

Class Summary

Cholinesterase inhibitors (ChEIs) are used to palliate cholinergic deficiency.All 4 currently approved ChEIs (ie, tacrine, donepezil, rivastigmine,galantamine) inhibit acetylcholinesterase (AChE) at the synapse (specificcholinesterase).

Tacrine and rivastigmine also inhibit butyrylcholinesterase (BuChE).Although BuChE levels may be increased in AD, it is not clear thatrivastigmine or tacrine have greater clinical efficacy than donepezil andgalantamine.

Galantamine has a different second mechanism of action; it is also apresynpatic nicotinic modulator. No data exist that this second mechanismis of clinical importance.

Donepezil (Aricept, Aricept ODT)

Donepezil is a centrally acting AChE inhibitor, but it does not inhibit BuChE.

Rivastigmine (Exelon)

Rivastigmine is a centrally acting inhibitor of both AChE and BuChE.
http://reference.medscape.com/drug/aricept-donepezil-343057http://reference.medscape.com/drug/exelon-oral-solution-rivastigmine-343069http://reference.medscape.com/drug/exelon-oral-solution-rivastigmine-343069http://reference.medscape.com/drug/aricept-donepezil-343057


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Rivastigmine transdermal patch (Exelon patch)

The rivastigmine transdermal patch is a competitive and reversible AChE

inhibitor. While its mechanism of action is unknown, it may reversibly inhibitcholinesterase, which may, in turn, increase concentrations of AChavailable for synaptic transmission in the central nervous system (CNS)and thereby enhance cholinergic function. The effect may lessen as thedisease process advances and fewer cholinergic neurons remainfunctionally intact.

It is available as a 5-cm2 patch containing 9 mg (releases 4.6 mg/24 h) and10-cm2 patch containing 18 mg (releases 9.5 mg/24 h). It is indicated forthe treatment of dementia associated with Alzheimer disease and for

dementia associated with Parkinson disease.

Galantamine (Razadyne, Razadyne ER)

Galantamine is indicated for the treatment of mild-to-moderate dementia ofthe Alzheimer type. It enhances central cholinergic function and likely

inhibits AChE.

N-Methyl-D-Aspartate (NMDA) Antagonists

Class Summary

NMDA antagonists are the newest class of agents indicated for the

treatment of AD. The only FDA-approved drug in this class is memantine.This agent may be used alone or in combination with AChE inhibitors.
http://reference.medscape.com/drug/razadyne-er-galantamine-343059http://reference.medscape.com/drug/razadyne-er-galantamine-343059


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Memantine (Namenda, Axura)

Memantine is an NMDA antagonist indicated for all stages of AD. NMDA-

receptor overstimulation in the CNS by glutamate (excitatory amino acid)may contribute to symptoms; no evidence confirms a glutamatergic deficitin AD.

Nutritional Supplement

Class Summary

Caprylidene is a prescription medical food that is metabolized into ketonebodies. The brain can use these ketone bodies for energy when its ability toprocess glucose is impaired, which brain-imaging scans suggest is thecase in AD. Vitamin E has antioxidant properties.

Caprylidene (Axona)

Caprylidene is indicated for clinical dietary management of metabolic

processes associated with mild-to-moderate AD. It is available in oralpowder form (40 g/packet; contains 20 g medium-chain triglycerides).

Vitamin E (Aquasol E, Natural Vitamin E)

Vitamin E is a nutritional supplement with antioxidant properties. It is used

to palliate postulated oxidative damage as a cause or contributing factor ofAD.
http://reference.medscape.com/drug/namenda-xr-memantine-343063http://reference.medscape.com/drug/axona-caprylic-triglyceride-caprylidene-999480http://reference.medscape.com/drug/aquasol-e-alpha-tocopherol-vitamine-344429http://reference.medscape.com/drug/aquasol-e-alpha-tocopherol-vitamine-344429http://reference.medscape.com/drug/axona-caprylic-triglyceride-caprylidene-999480http://reference.medscape.com/drug/namenda-xr-memantine-343063


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Anticonvulsants

Class Summary

The activity of anticonvulsants may be related to increased brain levels ofgamma-aminobutyric acid (GABA) or enhanced GABA action. Results fromseveral studies indicate that anticonvulsants (eg, gabapentin, valproic acid)may have a role in the treatment of behavioral problems in patients withAlzheimer disease (AD).

Carbamazepine (Carbatrol, Epitol, Equetro, Tegretol,

Tegretol XR)

The anticonvulsant action of carbamazepine may involve depressingactivity in the nucleus ventralis anterior of the thalamus, resulting inreduction of polysynaptic responses and blocking posttetanic potentiation.It reduces sustained high-frequency repetitive neural firing. Carbamazepineis a potent enzyme inducer that can induce its own metabolism.

Due to potentially serious blood dyscrasias, undertake benefit-to-risk

evaluation before carbamazepine is instituted. Therapeutic plasma levelsare between 4-12 mcg/mL for analgesic and antiseizure response. Peakserum levels occur in 4-5 h. Half-life (serum) occurs in 12-17 h withrepeated doses. It is metabolized in liver to active metabolite (ie, epoxidederivative) with half-life of 5-8 h. Metabolites are excreted through fecesand urine.

Carbamazepine is effective in patients who have not responded to lithiumtherapy. It has been effective in treating patients who have rapid-cyclingbipolar disorder or those who have not been responsive to lithium therapy.

Valproic acid (Depacon, Depakene, Depakote, Depakote ER,

Depakote Sprinkles)
http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/depakote-depakene-valproic-acid-343024http://reference.medscape.com/drug/depakote-depakene-valproic-acid-343024http://reference.medscape.com/drug/depakote-depakene-valproic-acid-343024http://reference.medscape.com/drug/depakote-depakene-valproic-acid-343024http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005http://reference.medscape.com/drug/tegretol-xr-equetro-carbamazepine-343005


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Although the mechanism of action of valproic acid is not established, itsactivity may be related to increased brain levels of GABA or enhancedGABA action. Valproate may also potentiate postsynaptic GABAresponses, affect potassium channel, or have a direct membrane-stabilizing effect.

Valproic acid has proven effectiveness in treating and preventing mania. Itis classified as a mood stabilizer and can be used alone or in combinationwith lithium. It is useful in treating patients with rapid-cycling bipolardisorders and has been used to treat aggressive or behavioral disorders.

Gabapentin (Neurontin)

Gabapentin is a membrane stabilizer and structural analogue of inhibitoryneurotransmitter GABA, which paradoxically is thought not to exert effecton GABA receptors. It appears to exert action via the alpha(2)delta1 andalpha(2)delta2 auxiliary subunits of voltage-gaited calcium channels

Antidepressants, Selective Serotonin Reuptake Inhibitors

Class Summary

This class of drug enhances serotonin activity due to selectivereuptake inhibition at neuronal membrane. Antidepressants havean important role in the treatment of mood disorders in patientswith Alzheimer disease (AD).

Sertraline (Zoloft)

Sertraline selectively inhibits presynaptic serotonin reuptake.
http://reference.medscape.com/drug/neurontin-gralise-gabapentin-343011http://reference.medscape.com/drug/zoloft-sertraline-342962http://reference.medscape.com/drug/zoloft-sertraline-342962http://reference.medscape.com/drug/neurontin-gralise-gabapentin-343011


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Citalopram (Celexa)

Citalopram enhances serotonin activity by selective reuptakeinhibition at the neuronal membrane. It may be beneficial in moodand other neuropsychiatric symptoms in patients in the moderatestage of AD.

Antiparkinson Agents

Class Summary

Antiparkinson agents with activity against major depressive

disorder may improve the behavioral aspects of AD.

Selegiline (Emsam, Eldepryl, Zelapar)

Selegiline is an irreversible monoamine oxidase inhibitor (MAOI).It has greater affinity for monoamine oxidase (MAO)-B than for

MAO-A; however, at antidepressant doses, it inhibits bothisoenzymes. MAO-A and MAO-B catabolize neurotransmitteramines in the CNS (eg, norepinephrine, dopamine, serotonin). Itis indicated for treating major depressive disorder. At its loweststrength (ie, 6 mg delivered over 24 h), it may be used without thedietary restrictions required for oral MAOIs used to treatdepression.

Antianxiety Agents

Class Summary

Anxiolytics can temporarily alleviate clinical manifestations of ADsuch as anxiety. Agents in this category may have effects inserotonergic neurotransmission and some dopaminergic effects inthe CNS.
http://reference.medscape.com/drug/celexa-citalopram-342958http://reference.medscape.com/drug/eldepryl-zelapar-selegiline-343052http://reference.medscape.com/drug/eldepryl-zelapar-selegiline-343052http://reference.medscape.com/drug/celexa-citalopram-342958


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Lorazepam (Ativan)

Lorazepam is a benzodiazepine and sedative hypnotic with ashort onset of effects and relatively long half-life. By increasingthe action of GABA, which is a major inhibitory neurotransmitter inthe brain, it may depress all levels of the CNS, including limbicand reticular formation. When the patient needs to be sedated forlonger than a 24-hour period, this medication is excellent.

Buspirone (BuSpar)

Buspirone is an antianxiety agent that is not chemically orpharmacologically related to the benzodiazepines, barbiturates, orother sedative or anxiolytic drugs. It is a 5-HT1 agonist withserotonergic neurotransmission and some dopaminergic effects in

the CNS. It has anxiolytic effects but may take up to 2-3 wk for fullefficacy.

Antipsychotic Agents

Class Summary

The US Food and Drug Administration (FDA) has issued blackbox warnings regarding increased mortality with the use of bothtypical (first-generation) and all 3 classes of atypical (second-generation) antipsychotics as treatment for behavioraldisturbances in elderly patients with dementia. The generalrecommendation is to use such agents as infrequently as possibleand at the lowest doses possible to minimize adverse effects,particularly in frail, elderly patients.
http://reference.medscape.com/drug/ativan-loraz-lorazepam-342906http://reference.medscape.com/drug/buspar-buspirone-342913http://reference.medscape.com/drug/buspar-buspirone-342913http://reference.medscape.com/drug/ativan-loraz-lorazepam-342906


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Haloperidol (Haldol, Haldol Decanoate)

Haloperidol is the drug of choice for patients with acute psychosis when nocontraindications exist. Haloperidol is a dopamine (D2) antagonist. It is aderivative of butyrophenone, which is noted for its high potency and lowpotential for causing orthostasis. The drawback is the high potential forextrapyramidal symptoms/dystonia. The parenteral dosage form may bemixed in same syringe with 2 mg of lorazepam for better anxiolytic effects.

Quetiapine (Seroquel, Seroquel XR)

Quetiapine may act by antagonizing dopamine and serotonin effects. It is anewer antipsychotic used for long-term management. Improvements overearlier antipsychotics include fewer anticholinergic effects and lessdystonia, parkinsonism, and tardive dyskinesia. Immediate- and extended-release formulations are available.

Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)

Risperidone has both D2 and serotonin 5-HT2 antagonism. It improvesnegative symptoms of psychoses and reduces the incidence ofextrapyramidal adverse effects.
http://reference.medscape.com/drug/haldol-decanoate-haloperidol-342974http://reference.medscape.com/drug/seroquel-xr-quetiapine-342984http://reference.medscape.com/drug/risperdal-consta-risperidone-342986http://reference.medscape.com/drug/risperdal-consta-risperidone-342986http://reference.medscape.com/drug/seroquel-xr-quetiapine-342984http://reference.medscape.com/drug/haldol-decanoate-haloperidol-342974

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