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Alzheimer 1
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  Alzheimer Disease Practice Essentials Alzheimer disease (AD) is a neurodegenerative disorder marked by cognitive and behavioral impairmentthat significantly interferes with social and occupational functioning. t is an incurable disease with a long preclinical period and progressive course. n AD! pla ues develop in the hippocampus! a structure deep in the brain that helps to encode memories! and in other areas of the cerebral corte# that are involved in thinking and making decisions. $hether pla ues themselves cause AD or whether they are a  by%product of the AD process remains unknown. &he following image depicts one of the cardinal neuroimaging findings in AD ' hippocampal atrophy. Signs and symptoms  Preclinical Alzheimer disease A patient with preclinical AD may appear completely normal on physical e#amination and mental status testing. pecific regions of the brain (eg! entorhinal corte#! hippocampus) are likely to be affected decades before any signs or symptoms appear.  Mild Alzheimer disease igns of mild AD can include the following  *emory loss  +onfusion about the location of familiar places  &aking longer to accomplish normal! daily tasks  &rouble handling money and paying bills  +ompromised ,udgment! often leading to bad decisions  -oss of spontaneity and sense of initiative  *ood and personality changes increased an#iety  Moderate Alzheimer disease &he symptoms of this stage can include the following  ncreasing memory loss and confusion  hortened attention span  Problems recognizing friends and family members  Difficulty with language problems with reading! writing! working with numbers  Difficulty organizing thoughts and thinking logically  nability to learn new things or to cope with new or une#pected situations  /estlessness! agitation! an#iety! tearfulness! wandering! especially in the late afternoon or atnight  /epetitive statements or movement occasional muscle twitches  0allucinations! delusions! suspiciousness or paranoia! irritability  -oss of impulse control hown through behavior such as undressing at inappropriate timesor places or vulgar language  Perceptual%motor problems uch as trouble getting out of a chair or setting the table Severe Alzheimer disease  Patients with severe AD cannot recognize family or loved ones and cannot communicate effectively. &hey are completely dependent on others for care! and all sense of self seems to vanish.1ther symptoms of severe AD can include the following  $eight loss  eizures! skin infections! difficulty swallowing  2roaning! moaning! or grunting  ncreased sleeping  -ack of bladder and bowel controln end%stage AD! patients may be in bed much or all of the time. Death is often the result of other illnesses! fre uently aspiration pneumonia.ee +linical Presentation for more detail. Diagnosis *eans of diagnosing AD include the following  +linical e#amination &he clinical diagnosis of AD is usually made during the mild stage of the disease! using the above%listed signs  -umbar puncture levels of tau and phosphorylated tau in the cerebrospinal fluid are often elevated in AD! whereas amyloid levels are usually low at present! however! routine measurement of +3 tau and amyloid is not recommended e#cept in research settings  maging studies maging studies are particularly important for ruling out potentially treatable causes of progressive cognitive decline! such as chronic subdural hematoma or normal%pressure hydrocephalus. 456  *oreover! volumetric studies of the hippocampus and 7%45836fluoro%7%Deo#y%D%glucose positron emission tomography (3D2%PE&) with or withoutamyloid imaging have been employed for early detection and differentiating dementia etiologies. 476 ee +linical Presentation and $orkup for more detail. Management All drugs approved by the 9 3ood and Drug Administration (3DA) for the treatment of AD are symptomatic therapies that modulate neurotransmitters! either acetylcholine or glutamate. &he standard medical treatment for AD includes cholinesterase inhibitors (+hEs) and a partial :%methyl%D%aspartate (:*DA) antagonist.  4;   ! <6 &hey do not treat the underlying cause of AD nor halt the rate of decline.&he following classes of psychotropic medications have been used to treat the secondary symptoms of AD! such as depression! agitation! aggression! hallucinations! delusions! and sleep disorders  4=6    Antidepressants  An#iolytics  Antiparkinsonian agents  >eta%blockers   Antiepileptic drugs   :euroleptics  Prevention &here are no proven modalities for preventing AD!  4;   6   but evidence! largely epidemiologic! suggests that healthy lifestyles can reduce the risk of developing the disease the following may be  protective  4?! @6    Physical activity  E#ercise  +ardiorespiratory fitness  Diet Although no definitive dietary recommendations can be made! in general! nutritional  patterns that appear beneficial for AD prevention fit the *editerranean diet ee &reatment and *edication for more detail. &he most common form of dementia! Alzheimer disease (AD) affects appro#imately =.< million  people in the 9nited tates alone! and that number is pro,ected to reach 5;.8 million by the year 7=  486  (see Epidemiology). t is the si#th leading cause of death in the 9nited tates! accounting for ;.?B of all deaths in 75<.  4C6  &he percentage of Alzheimers decedents who died in a medical facility (e.g.! hospital) declined from 5<.@B in 5CCC to ?.?B in 75<! whereas the percentage who died at home increased from 5;.CB in 5CCC to 7<.CB in 75<.  4C6 Economically! AD is a ma,or  public health problem. n the 9nited tates in 75?! the cost of health care! long%term care! and hospice services for people aged ?= years and older with AD and other dementias was e#pected to  be 7;? billion! and this figure does not include the contributions of unpaid caregivers. >y 7=! these costs could rise as high as 5.5 trillion.  486 +urrently! an autopsy or brain biopsy is the only way to make a definitive diagnosis of AD. n clinical practice! the diagnosis is usually made on the basis of the history and findings on *ental tatus E#amination (see Presentation).ymptomatic therapies are the only treatments available for AD. &he standard medical treatments include cholinesterase inhibitors and a partial  N   %methyl%D%aspartate (:*DA) antagonist. Psychotropic medications are often used to treat secondary symptoms of AD! such as depression! agitation! and sleep disorders. (ee &reatment.)3or additional information! see Alzheimers Disease lideshow. Anatomy0ealthy neurons have an internal support structure partly made up of structures called microtubules. &hese microtubules act like tracks! guiding nutrients and molecules from the body of the cell down to the ends of the a#on and back. A special kind of protein! tau! binds to the microtubules and stabilizes them. n AD! tau is changed chemically. t begins to pair with other threads of tau! which become tangled together. $hen this happens! the microtubules disintegrate! collapsing the neurons transport system (see the image below). &he formation of these neurofibrillary tangles (:3&s) may result first in malfunctions in communication between neurons and later in the death of the cells.n addition to :3&s! the anatomic pathology of AD includes senile pla ues (Ps also known as  beta%amyloid pla ues) at the microscopic level and cerebrocortical atrophy at the macroscopic  level (see the image below). &he hippocampus and medial temporal lobe are the initial sites of tangle deposition and atrophy.  4576  &his can be seen on brain magnetic resonance imaging early in AD and helps support a clinical diagnosis.Ps and :3&s were described by Alois Alzheimer in his srcinal report on the disorder in 5C@.  4556  &hey are now universally accepted as the pathological hallmark of the disease.PathophysiologyA continuum e#ists between the pathophysiology of normal aging and that of AD.  45;6 Pathologic hallmarks of AD have been identified however! these features also occur in the brains of cognitively intact persons. 3or e#ample! in a study in which neuropathologists were blinded to clinical data! they identified @?B of brains of cognitively intact elderly patients as demonstrating AD.  45<6  AD affects the ; processes that keep neurons healthy communication! metabolism! and repair. +ertain nerve cells in the brain stop working! lose connections with other nerve cells! and finally die. &he destruction and death of these nerve cells causes the memory failure! personality changes!  problems in carrying out daily activities! and other features of the disease.&he accumulation of Ps primarily precedes the clinical onset of AD. :3&s! loss of neurons! and loss of synapses accompany the progression of cognitive decline.  45;6 +onsiderable attention has been devoted to elucidating the composition of Ps and :3&s to find clues about the molecular pathogenesis and biochemistry of AD. &he main constituent of :3&s is the microtubule%associated protein tau (see Anatomy). n AD! hyperphosphorylated tau accumulates in the perikarya of large and medium pyramidal neurons. omewhat surprisingly! mutations of the tau gene result not in AD but in some familial cases of frontotemporal dementia.ince the time of Alois Alzheimer! Ps have been known to include a starchlike (or amyloid) substance! usually in the center of these lesions. &he amyloid substance is surrounded by a halo or layer of degenerating (dystrophic) neurites and reactive glia (both astrocytes and microglia).1ne of the most important advances in recent decades has been the chemical characterization of this amyloid protein! the se uencing of its amino acid chain! and the cloning of the gene encoding its precursor protein (on chromosome 75). &hese advances have provided a wealth of information about the mechanisms underlying amyloid deposition in the brain! including information about the familial forms of AD. (ee Amyloid 0ypothesis Fersus &au 0ypothesis! below.)Although the amyloid cascade hypothesis has gathered the most research financing! other interesting hypotheses have been proposed. Among these are the mitochondrial cascade hypothesis. 45=6 n addition to :3&s and Ps! many other lesions of AD have been recognized since Alzheimers srcinal papers were published. &hese include the granulovacuolar degeneration of himkowicz the neuropil threads of >raak et al  45=6  and neuronal loss and synaptic degeneration! which are thought to ultimately mediate the cognitive and behavioral manifestations of the disorder. Neurofibrillary tangles and senile plaques
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