Diagnóstico de Demencia

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The DiagnosticEvaluation of a PatientWith Dementia

Douglas Galasko, MBBCh

ABSTRACTPurpose of Review: This review outlines a practical approach to the history, mentalstate, neurologic examination, and laboratory tests in the diagnosis of dementia.Recent Findings: Proposed new diagnostic criteria for Alzheimer disease recognizethat nonamnestic presentations with symptoms that predominantly affect language,

visuospatial abilities, or executive function mayoccur, particularly withonset before theage of 65. New criteria assign greater likelihood to diagnosis if progressive cognitivedecline is documented through serial assessment, or if biomarkers are supportive. Inpatients aged 80 or older, more than one cause of dementia is often present, forexample, Alzheimer disease plus vascular dementia. Clinical diagnostic criteria for non-Alzheimer dementias are evolving, particularly in areas such as frontotemporaldementia. Imaging and CSF biomarkers have been proposed in recent diagnosticcriteria for Alzheimer disease. Although biomarkers can provide a higher level ofcertainty that Alzheimer pathology may or may not be present, biomarkers for non-Alzheimer dementias are lacking.Summary: The availability of biomarkers does not replace or diminish the need for athorough clinical evaluation. A structured clinical approach helps to define the diag-nosis and collects information essential for establishing a comprehensive care plan for

patients with dementia and their families.Continuum (Minneap Minn) 2013;19(2):397410.

INTRODUCTIONDementia is defined as an acquireddecline of cognitive abilities sufficientto result in social or occupational im-pairment. The usual presentation is thegradual onset and progressive loss of memory and other cognitive abilities

occurring in elderly people; the preva-lence rises from about 1% to 2% at age65 to 10% to 15% at age 80, and may beas high as 40% by age 90. Whensomeone younger develops significantcognitive decline or behavioral changes,the diagnosis of dementia may often bedelayed because of a lower index of suspicion or a less typical clinical pre-sentation. Recently revised criteria for

the diagnosis of Alzheimer disease (AD)have improved the clinical descriptionof variants such as progressive aphasiaor posterior cortical atrophy, and al-though they indicate that biomarkersmay improve diagnostic accuracy, they also emphasize the importance of the

clinical evaluation.1

The key goals of a clinical evaluationare to establish whether dementia ispresent; to characterize the impairedareas of cognition, the severity of im-pairment, and functional consequences;and to determine the likely etiology.However, it is worth framing the evalu-ation more broadly. With the seriousimplications of dementia for the patient

Address correspondence toDr Douglas Galasko,Department of Neurosciences,UC San Diego, 9500 GilmanDrive 0948, La Jolla, CA 92093Relationship Disclosure:Dr Galasko serves as aconsultant for Elan Corporationand serves on the data andsafety monitoring boards of Elan Corporation and JanssenPharmaceuticals, Inc.Dr Galasko serves as aneditor-in-chief of Alzheimers Research and Therapy .Unlabeled Use of Products/Investigational Use Disclosure:Dr Galasko reports nodisclosure.* 2013, American Academy of Neurology.

397Continuum (Minneap Minn) 2013;19(2):397410 www.aan.com/continuum

Review Article

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


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and family, the evaluation must collectenough information to allow the clini-cian to discuss the diagnosis and itsimmediate and long-term implications,and formulate a comprehensive overallcare plan.

The evaluation of dementia is beststaged over two clinic visits. The first visit should allow enough time to obtaina detailed history and examination,interview family members (often sepa-rately from the patient), and order diagnostic tests. The second visit usu-ally consists of a conference with the

patient and family members, for whichthe goals are to present and discuss thediagnosis and etiologic factors; review medical treatment options; develop aplan for overall management, includingissues such as driving, financial matters,medications, and legal issues (eg, dura-ble power of attorney for health care);exchange information about social andcommunity resources; and, when relevant, discuss research options. Someclinicians who perform detailed cogni-tive or neuropsychological assessmentsthemselves may divide the evaluationinto three visits.

THE HISTORYInitiating the VisitMany patients with dementia lack in-sight into their deficits and tend to deny the existence of a problem. Patients with AD will often make excuses for their memory problems, for example,saying they do not do particular ac-tivities anymore or do not remember

things because that isnt important. Itis useful to determine the patientsdegree of insight into problems, be-cause this will influence his or her ac-ceptance of elements of a care plan.Early in the course of AD, patients may have striking preservation of social andinterpersonal skills, and a superficialconversation may show no obvioussigns of impairment other than the

shallow content of their speech. Pa-tients will often steer conversationtoward experiences that they are ableto recall in detail. On the other hand, when patients provide a rich and de-tailed account of their memory lapses,this usually indicates their awarenessof age-associated cognitive changes or may raise the possibility of anxiety or depression. The key to obtaining anaccurate history is to interview a knowl-edgeable informant. This is often bestdone when the patient is not present inorder to avoid arguments or distress

when the caregiver describes problems. A separate interview with one or morefamily members may be particularly important when the patient is referredagainst his or her will or is resistant tothe evaluation. Some patients may besensitive to or alarmed by the use of the words Alzheimer disease, and dis-cussing the problem as memory lossor in other general terms (eg, This isa checkup of how well youre doing)can smooth over the initial clinicalencounter.

It is helpful to characterize the natureof the onset and the early symptoms indetail. AD and other neurodegenerativecauses of dementia are characterized by a gradual onset of cognitive decline, whereas in vascular dementia the onsetmay be more abrupt. The course of ADis also gradual and relatively slow,measured over years. In early or mildstages, patients may have occasionallapses, but over time these becomemore frequent in AD and other neuro-

degenerative causes of dementia. Vas-cular dementia may show a stepwisedecline; a history of stroke or strokelikeepisodes increases the confidence of this diagnosis but is not essential. Someevents may accelerate the symptoms of dementia V for example, patients with AD may decline after undergoing major surgical procedures or become deliri-ous after a medical illness such as

KEY POINTh It is useful to determine

the patients degree ofinsight into problems,because this willinfluence his or heracceptance of elementsof a care plan.

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Diagnostic Evaluation



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pneumonia. This should not be taken asevidence of cerebrovascular pathology.Rapid cognitive decline with a subacutecourse over weeks or months raises adifferent set of diagnostic concerns.

Characterizing CognitionThe informant interview should charac-terize the patients cognition, behavior,and function to develop a detailedclinical picture and to help in diagnosisand staging. Although the cognitivehistory will generally focus on memory skills, some patients may present with

other areas of impairment, such aslanguage, executive function (ie, judg-ment, planning, and reasoning) or visuospatial abilit ies . Patien ts withfrontotemporal dementia (FTD) typi-cally have striking changes in behavior or personality, with relatively preservedmemory and visuospatial abilities. Sincehistory taking should be detailed andmay involve interviewing the informantseparately from the patient, it may behelpful to have the informant completea questionnaire or a series of ratingscales about these symptoms while thepatient is undergoing the examination.

Symptoms that point to a major memory problem include asking ques-tions repeatedly; forgetting details of conversations, appointments, andplans; not paying bills on time; and notrecalling the details of TV shows or movies. These types of problems needto be distinguished from complaintsthat are usually blamed on memory but reflect age-associated cognitive

changes. In particular, difficulty finding words or recalling peoples names isrelated to problems with retrieval rather than memory and is a hallmark of aging.It is often accompanied by the tip of the tongue phenomenon, in whichthe word or name comes back sometime later. Two other cognitive changesassociated with aging are slowing of cognitive processing and increased dif-

ficulty with multitasking, or susceptibil-ity to interference. Careful questioningcan reveal that the patient is able tocomplete a complex task, given enoughtime and the absence of distraction.This may not be the case for someone with early dementia.

Symptoms of other areas of cognitivedecline are shown in Table 6-1 . Lan-guage problems may include difficulty with names of people or objects,shorter sentences, circumlocution (ie,empty speech when describing thingsor answering a question), paraphasic

errors, or mispronunciation of words.Speech problems such as dysarthriamay be associated with decreased or slower language output. Patients withexecutive problems may have difficulty initiating activities, making plans, per-forming complicated tasks at work or in hobbies, or following multistep pro-cesses such as using a cell phone,computer, or remote control. Ques-tioning about executive abilities there-fore often overlaps with functionalabilities. Patients with visuospatial prob-lems may report unusual symptomssuch as difficulty using their hands for fine coordinated activities (eg, typingon a keyboard, using a screwdriver, or knitting) or misjudging where objectsare in space. They may have vaguedifficulty in reading or distinguishingobjects or peoples faces, and often re-ceive an ophthalmologic evaluationbefore the problem is attributed tothe brain rather than the eyes.

History of Functional Ability An assessment of functional abilities isbest obtained from a knowledgeableinformant. For clinical assessment, it ishelpful to divide activities of daily living(ADL) into two categories. Basic ADLinclude activities that are essential toself-maintenance: grooming, bathing,dressing, eating, and continence. Inmost patients with AD, independence

KEY POINTh Symptoms that point

to a major memoryproblem include askingquestions repeatedly;forgetting detailsof conversations,appointments, andplans; not paying billson time; and notrecalling the details of TVshows or movies. Thesetypes of problems needto be distinguished fromcomplaints that areusually blamed on

memory but reflectage-associated cognitivechanges.




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TABLE 6-1 Clinical Presentations of Alzheimer Disease and Other Degenerative Dementias

Clinical Presentations Symptoms Clinical Findings MRI/Imaging FindingsTypical amnesticAlzheimer disease (AD)

Forgets conversations,appointments, and plans

Impaired learning andmemory

Atrophy, especially inthe hippocampus andtemporal lobe, andventricular enlargement

Normal neurologicexamination

Posterior corticalatrophy

Difficulty recognizing faces orobjects, locating or manipulatingobjects that are in view,reading, and judging distances

Simultagnosia, Balintsyndrome

Occipital lobe atrophy

Difficulty reading ordrawing intersecting orvisually complex figures

AD withaphasia V logopenic

Difficulty withword-finding and

pauses during speech

Impaired single-wordretrieval in spontaneous

speech

Left posterior perisylvianor parietal atrophy, or

hypometabolismImpaired repetition ofphrases or longer sentences

Lewy body dementia Variable alertness andattention

Cognitive impairment,often with relativesparing of memory

Less atrophy than in AD

Visual hallucinationsImpaired visuospatial tests

Occipitalhypometabolismon fluorodeoxyglucose(FDG) positron emissiontomography (PET)

REM sleep behavior disorderParkinsonism

Behavioral-variantfrontotemporaldementia

Disinhibition: change inpersonal decorum, inappropriateinterpersonal behavior, andrash/impulsive behavior

Executive impairment,relatively preserved memory,and visuospatial skills

Frontal or anteriortemporal lobe atrophy(CT or MRI) orhypometabolism

(FDG PET)Apathy or inertiaNormal neurologicexamination; somepatients may have ALSor mild parkinsonism

Loss of empathy

Repetitive, ritualistic behavior

Hyperorality and diet changes

Primary progressiveaphasia V semanticvariant

Difficulty thinking of words(eg, names of objects)

Impaired confrontationnaming

Anterior temporallobe atrophy orhypometabolism onFDG PET

Fluent language output Impaired single-wordcomprehension

Loss of object knowledge

Surface dyslexia (misreadingof irregularly pronounced

words)Primary progressiveaphasia V nonfluent

Slow, halting speech Agrammatism Left posteriorfrontoinsular atrophyor hypometabolism

Halting speech, sometimesspeech sound distortionsor errorsSpared wordknowledge/comprehension

Continued on next page





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in basic ADL is preserved until late inthe course; early problems with basic ADL may be due to physical problemssuch as a gait disorder or urologicalproblem. Identifying impairments inmore complex tasks, referred to asinstrumental activities of daily living(IADL), is a critical part of the history.Structured questionnaires such as the AD8 (which combines cognition andfunction) 2 or functional activities ques-tionnaire 3 can be useful tools. Alterna-tively, tailoring functional inquiries tothe patients activities and lifestyle canalso provide useful information. Theclinician should always inquire aboutactivities that could pose significantsafety risks in the setting of dementia;for example, even though the potentialloss of driving privileges is a highly sensitive issue, the clinician must ask

whether the patient has had problemssuch as getting lost while driving,having accidents (even minor ones),or being unable to locate the car in alarge parking lot. The clinician must beaware of local legal reporting require-ments for dementia V in many states, areport does not automatically lead to asuspension of driving privileges butmay result in the Department of Motor

Vehicles performing a driving evalua-tion through a written or observeddriving test. Handling medications ac-curately, managing small sums of mon-ey, balancing a checkbook or creditcard statement, paying bills, and com-pleting income tax returns are other examples of IADL that could posesubstantial risks.

Other IADL matters worth probinginclude trouble using gadgets such asa remote control, cell phone, or com-puter; difficulty with pastimes or hobbies, particularly when they arecognitively complex; and declining abil-ities to prepare food or perform house-hold maintenance activities. Patients with dementia may have problemsremembering appointments and planseven when they use a calendar, diary, or electronic device as a reminder. When

there are changes in functional abilities,a physical health factor (eg, severe ar-thritis, impaired mobility, or poor visionor hearing) may need to be taken intoaccount.

Assessing Changes in BehaviorBehavioral symptoms are commonin patients with dementia, may provide diagnostic clues, and should be

KEY POINTh The clinician should

always inquire aboutactivities that could posesignificant safety risks inthe setting of dementia.

TABLE 6-1 Continued

Clinical Presentations Symptoms Clinical Findings MRI/Imaging FindingsCorticobasal syndrome Variable: eg, difficulty with

movement, clumsiness, stiffnessof affected limb; visual orlanguage symptoms

Rigidity, apraxia, corticalsensory loss, alien limb,limb dystonia, reflex focalmyoclonus V often startsin one limb

Asymmetrical corticalatrophy, often parietal

Progressive supranuclearpalsy

Slow speech, dysarthria,and dysphagia

Impaired eye movements,especially vertical gaze

Atrophy of midbrain,hummingbird sign

Slow gait, falls Postural instability

Apathy Akinesia, rigidity,retrocollis

Slowed cognition,

dysexecutive syndrome




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considered when formulating a treat-ment plan. Patients with behavioral- va ri an t fron to te mp or al dem en ti a(bvFTD) characteristically have early symptoms reflecting a deterioration of personality, social conduct, and inter-personal relations; loss of interest; withdrawal; and difficulty with plan-ning. 4 Although apathy, inertia, andpoor planning may also occur in AD,the manifestation of these distinctivesymptoms of social and personality changes in a patient with preservedmemory abilities points to bvFTD.

Symptoms such as depression, delu-sions, and hallucinations (particularly visual) can provide clues to specifictypes of dementia. In addition, thesebehavioral changes are often distressingto family members and make care moredifficult. Although the treatment of behavioral problems can be challeng-ing, it is important to inquire about andtreat them whenever possible.

Changes in sleep are important be-havioral symptoms that also provideclues to specific types of dementia. For example, REM sleep behavior disorder occurs in Parkinson disease and Lewy body dementia and can be assessed by asking whether patients appear to actout their dreams during sleep. 5 Insom-nia or sleep apnea may affect memory consolidation and daytime cognitiveabilities. Excessive daytime sleepinessusually occurs in moderate to severedementia, although it can be a prom-inent and early feature of Lewy body dementia.

Points to Emphasize in the Restof the HistoryOther components of the medical his-tory color the background of evolvingcognitive problems. A patients hand-edness and educational and work his-tory are relevant to the interpretation of cognitive testing and may influence thehealth literacy of the patient and family.

Social history should focus on maritalstatus, the existence of a social supportnetwork of family and friends, and ex-posure to alcohol and drugs. Physicalactivity, including walking or other forms of exercise, should be document-ed.Medical history should highlight risk factors that could contribute to demen-tia. Vascular risk factors such as heartdisease, diabetes, hypertension, tran-sient ischemic attack, and stroke shouldbe recorded in detail. Traumatic braininjury, particularly with loss of con-sciousness, and coexisting neurologic

problems such as seizures, Parkinsondisease, multiple sclerosis, or other disorders that could affect cognitionshould be noted. Problems with visionand hearing can contribute, and a his-tory of major psychiatric disorders may be relevant.

Medications may also be relevant tothe assessment and management of de-mentia. Drugs with strong anticholiner-gic actions 6 or sedating side effects canplay a role in worsening cognitiveimpairment, although it is unusual for them to be the sole cause. If cardio- vascular risk factors are present, theadequacy of their medical treatmentshould be assessed.

Hints of a family history of dementiashould be systematically reviewed. It isoften helpful to record a detailed pedi-gree, particularly for patients with cog-nitive or behavioral symptoms beforethe age of 65. The family history shouldinquire broadly about different symp-toms or phenotypes among relatives;

for example, some inherited disordersmay produce a picture of progressivedementia in one relative and ALS or acombination of cognitive and motor dysfunction in another.

THE NEUROCOGNITIVE (ORMENTAL STATE) EXAMINATIONThe neurocognitive examination is of prime importance in the diagnosis of

KEY POINTh Behavioral symptoms

are common in patientswith dementia, mayprovide diagnostic clues,and should be consideredwhen formulating atreatment plan.





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dementia. During a clinical office visit,cognitive testing needs to strike a bal-ance between comprehensiveness andpracticality. The goals are to documentperformance of memory and other key cognitive domains, to define areas of strength and weakness that may supporta diagnosis, and to help stage the severity of dementia. There are two mainapproaches: overall cognitive tests anddetailed batteries that cover specificcognitive domains.

Overall Cognitive Tests

Overall cognitive tests provide a brief,structured approach and are widely used for screening in general neurolog-ic and medical practices. 7 The Mini-Mental State Examination (MMSE) isone of the best known of these tests. Itprobes memory (through the task of learning and recalling three words),orientation (predominantly through amemory test) , working memory (through the task of serial 7 subtrac-tion or spelling world backward), lan-guage (through tasks of naming,repetition, reading, writing, and follow-ing a three-step command), and visuo-spatial abilities (through the task of copying interlocking pentagons). Ad- vantages of the MMSE are its ease of use, familiarity to physicians and fami-lies of patients with AD, and moderatesensitivity for the diagnosis of demen-tia. It is also helpful in staging andtracking progression over time. How-ever, there are many problems withthe MMSE, including insensitivity for

mild dementia, test-retest variability of a patients scores, and a lack of readily available translations and alternative versions (some patients rehearse thedate and words typically used to testrecall in the MMSE while en route tothe clinic). In addition, the MMSE is notavailable for use free of charge; a fee of $1.20 for each administration is sup-posed to be paid to Psychology As-

sessment Resources, Inc, which holds apublishing copyright to the MMSE.There may also be problems in applyingthe MMSE to criteria for the diagnosisof AD or other forms of dementia. Although a cutoff score of 24 or below may support the diagnosis, it is difficultto use the MMSE to formally documentimpairment of memory and an addi-tional area of cognition. Recall of three words is an insensitive and inaccuratetest of memory, although combining it with orientation may improve the as-sessment. Moreover, language is super-

ficially assessed, and visuospatial abilitiesand executive function are minimally, if at all, assessed by the MMSE.

Slightly longer overall tests su ch asthe Montreal Cognitive Assessment(MoCA) ( www.mocatest.org )8 and theSaint Louis University Mental Status(SLUMS) examination 9 offer greater sensitivity than the MMSE, as well asthe ability to sample cognitive domainsmore widely. The MoCA and SLUMSexamination both take about 7 to 10minutes to administer and yield scoresthat range from 0 to 30. The MoCA isavailable in three alternative versions inEnglish, and translations of the original version are available in many languages.Diagnostic cutoffs for AD and for mildcognitive impairment have been sug-gested based on several studies. TheMoCA screens attention and compo-nents of executive function and probeslanguage and memory in more detailthan the MMSE. However, one needsto be cautious about using a cutoff

score as a diagnostic test. The five-item word list on the MoCA is a moredifficult learning and recall task thanthe three-word test on the MMSE. TheMoCA uses only two encoding trials(compared to formal psychometric word list tasks, which typically use four to five trials of longer word lists), andsome subjects with no dementia may show a falsely positive apparent memory

KEY POINTh The goals of cognitive

testing are to documentperformance of memoryand other key cognitivedomains, to defineareas of strength andweakness that maysupport a diagnosis, andto help stage theseverity of dementia.


http://www.mocatest.org/http://www.mocatest.org/


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deficit if they do not attend adequately to the learning trials. Repetition of complex sentences on the MoCA canbe nonspecifically affected by problemssuch as decreased hearing. The MoCA adjusts for people with fewer than 12 years of formal education by rec-ommending adding one point to thetotal score, but cutoffs and test perfor-mance among less well-educated in-dividuals have not been widely studied. A test like the MoCA can form thefoundation of a detailed cognitive eval-uation in clinic ( Case 6-1 ). Besides

considering the total score for theMoCA, the domains that are affectedshould be examined. Additional cogni-tive testing may be carried out to help

to confirm impairment in suspecteddomains. If uncertainty remains, formalneuropsychological testing will providea clearer picture of cognitive strengthsand weaknesses.

Evaluating Cognitive DomainsSome dementia specialists with appro-priate expertise may perform and billfor detailed cognitive evaluations. Al-though many formal psychometric tests with norms for age and education areavailable,10 it is often beyond the re-sources or time availability of a general

neurologist to perform such testing.Computerized batteries have beenused in research settings, but few have been validated in clinical practice.

Case 6-1A 77-year-old retired college professor was brought to the clinic by hiswife. He denied any problems, although she stated that he sometimesasked questions repeatedly, forgot details of conversation, had troubleremembering computer passwords, and struggled to recall details or theplots of novels. He could write emails and letters, drive, and manage acredit card without difficulty. His wife thought that he sometimes forgot

to take his medications. His problems had been present for about12 months. Medical history was notable for hypertension and increasedcholesterol; family history was negative for cognitive or neurologicproblems. Medications included antihypertensives, a statin, and aspirin. Hesometimes slept poorly, and his general health was notable for slowingof gait. He showed less interest in attending social functions but did nothave symptoms of depression. A primary care physician noted that hescored 29/30 on the Mini-Mental State Examination.

On mental state examination, he scored 26/30 on the MontrealCognitive Assessment, losing three points for recall and one for executivefunction. Results of the remainder of the neurologic examination and oflaboratory blood tests were normal. Brain MRI showed cortical atrophyconsistent with age and a few hyperintensities in the periventricular whitematter. Neuropsychological testing revealed impairment of learning andmemory on both a list-learning test and a task of copying and recalling acomplex figure. He had impairment on category fluency, the Trail-MakingTest Part B, and the Stroop Color-Word Association Test. The diagnosisof Alzheimer disease was made and discussed in detail with the patientand his family at a follow-up visit.

Comment. This case illustrates the importance of detailed history takingfrom a knowledgeable informant, the exclusion of other contributory factorsin the evaluation, the insensitivity of screening cognitive tests in patientswith high levels of education, and the value of neuropsychological testing.





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Suggestions for testing a variety of cognitive domains in a clinical settingare outlined below. An important con-sideration in interpreting tests is thatrelatively few of them probe a singlecognitive domain exclusively. For ex-ample, drawing a clock and setting thetime depends on judgment and plan-ning (executive function) as well as visuospatial abilities. Patients with im-pairment in a key domain such aslanguage may show impairment acrosstests with verbal instructions and re-sponses, and patients with markedly

impaired attention may show difficulty with learning and memory due tofailure to encode material.

The term memory impairment isoften used loosely in relation to AD.The major feature of memory impair-ment in AD is episodic memory, whichdepends on the structural integrity of the hippocampus and allows us toencode and remember where or whensomething happened. Semantic mem-ory (the knowledge of what objects, words, or ideas are) may be impairedlater in the course of AD and is a de-fining feature of a form of progressiveaphasia called semantic dementia. Pro-cedural memory (the memory of skilledor sequential motor tasks) is preservedin AD. Among the most widely usedtests of memory is list-learning, in which10 to 16 words are read to the patient, who is asked to repeat as many as he or she can remember. A series of trials isgiven and an index of immediate recallor learning across these trials is calcu-

lated. After a typically 15-minute or longer delay filled with distractor tests,the patient is asked to recall as many of the words as possible. Impaired recall,in particular rapid forgetting (defined asrecalling less than 50% of the words that were learned), is suggestive of a major memory disorder such as AD. Another psychometric approach to memory testing is story recall, in which brief

narratives are read to the patient, whois asked to repeat as many details aspossible and then to recall as much of the story as possible after a delay. Thelogical memory test (part of the Wechsler Adult Intelligence Scale) in- volves recall of two stories, each of which consists of 25 embedded factoids.Nonverbal memory and learning can betested through copying a complex draw-ing (eg, the Rey-Osterreith figure) anddrawing it after a delay. Without re-course to the time or structured testingenvironment needed for these proce-

dures, testing memory and learning canbe difficult for a clinician. Some sugges-tions for additional office-based tests of memory include having the patient learnand recall a five-item name and address,asking the patient to describe what sheor he ate for each meal the day before,and asking about an outing or event thepatient attended in the past month or two, if there is an informant who can verify the details. Asking the patient todescribe details of major recent newsevents can also be informative, providedthat they have heard about these events(eg, through reading a newspaper or watching TV); recen t bad-weather events, earthquakes, accidents, sportsevents, or news involving celebrities or politicians are examples.

Attention includes the important ca-pacity of working memory: the ability tomaintain a short piece of information,such as a telephone number, in memory storage for a short interval. It is impor-tant to test in its own right, early in a

cognitive examination, because inability to attend can markedly affect other cognitive domains. Digit span is a typicalapproach.Most people can remember atleast six digits forward and four backward (the MoCA is more lenient, usingfour digits forward and three backward).

Language testing begins by listeningto the patients spontaneous output.Naming objects or their parts, including

KEY POINTh The term memory

impairment is oftenused loosely in relationto Alzheimer disease.The major feature ofmemory impairment inAlzheimer disease isepisodic memory, whichdepends on thestructural integrity ofthe hippocampus andallows us to encode andremember where orwhen somethinghappened.




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some lower-frequency words, can be agood screen for anomia, a commonfinding in many types of aphasia. Askingthe patient to repeat or read consonantsounds (eg, P-T-K) and single words of increasing length can screen for dysar-thria. Fluency tests, such as naming asmany words as possible in 1 minutebelonging to a specific category or witha specific first letter, probe language as well as executive function. Assessmentprocedures and criteria for diagnosingsubtypesof primary progressive aphasia were recently proposed. 11

There are many aspects of executivefunction, and testing for it often placesdemands on other cognitive abilities as well. Clock drawing, for example, de-pends on judgment, planning, and visuospatial abilities. Explaining similar-ities between word pairs is a better testof reasoning than explaining proverbs,because the meanings of proverbs aretypically learned at school rather thansolved on the spot. Attention tasks suchas reciting the months backward (or,more difficult, letters of the alphabetbackward) also depend on executivefunction. Calculation tasks, such as se-rial 7 subtraction or making change,depend on attention, right parietalabilities, and frontal lobe function.

As visuospatial tests, clock drawingand copying complex intersecting fig-ures can extend a screening examina-tion. If the examiner suspects posterior cortical atrophy, then asking the patientto describe a visually rich and complex drawing or photograph can help to

screen for simultagnosia.

THE REMAINDER OF THENEUROLOGIC EXAMINATIONBeyond mental status testing, the re-mainder of the neurologic examinationcan yield important clues about etiol-ogy, particularly for less common disor-ders. The clinician should be preparedto apply extra diligence in testing visual

fields, examining eye movements, as-sessing praxis, or looking for signs of motor neuron disease when evaluatinga patient who does not have a typical AD presentation.

In a patient with AD, normal neuro-logic examination results are expected.During the neurologic examination of an elderly patient, the examiner willoften identify findings associated withnormal aging, such as decreased large-fiber sensation in the toes, decreased or absent ankle reflexes, a mildly stoopedposture, and marked difficulty with

tandem gait. Frontal release signs or primitive reflexes (such as the glabellar tap, snout, suck, palmar-mental reflex,and grasp reflex) are of dubious diag-nostic value because they occur in many normal elderly people as well as inpatients with AD or frontotemporaldementia. Procedures to elicit them(eg, the number of glabellar taps thatcontinue to produce a blink beyond what is thought of as normal) are notagreed upon, and many specialists inneurodegenerative or cognitive disor-ders do not assign any special signifi-cance to these signs.

The neurologic examination is some-times revealing. Focal findings consis-tent with stroke, or a gait disorder not explained by other factors, may support a cerebrovascular contributionto dementia. The gait in vascular de-mentia due to multiple lacunes is oftendescribed as marche a petits pas , re-ferring to a slow gait with short stepsand an upright posture. Normal pres-

sure hydrocephalus classically results ina magnetic gait, in which the patientsfeet appear stuck to the ground; how-ever, nonspecific gait slowing with poor balance may be a more common pic-ture. Signs of parkinsonism may pointto Lewy body dementia. These can besubtle; a common pattern is slowing of movement, slightly increased tone, par-kinsonian gait and postural instability

KEY POINTh Focal findings consistent

with stroke, or a gaitdisorder not explainedby other factors, maysupport a cerebrovascularcontribution to dementia.





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(demonstrated on a backward pull),and the absence of rest tremor. Par-kinsonian findings are less specificin patients with moderate to severedementia.

In posterior cortical atrophy, ele-ments of Balint syndrome may bepresent, namely difficulty perceivingthe entire visual field, fixating the eyes,and moving a hand to a precise locationor specific object by using vision. 12

These features can be identified by careful testing of visual fields, havingthe patient reach into space to a de-

fined location and move his or her eyes to selected areas of gaze. Askingthe patient to describe a photographor painting of a complex scene andlooking for elements of Gerstmannsyndrome or apraxia can help withthe clinical characterization ( Case 6-2 ).

Progressive supranuclear palsy may have several clinical variants. 13 It iseasiest to diagnose when the charac-teristic eye-movement abnormalitiesappear, including slow saccades andimpaired vertical then horizontal gaze, which are correctable with the dollshead maneuver. In some patients,these findings may appear late. Other features are dysarthria, increased tone(especially axial rigidity), and slowingof gait with retropulsion. Corticobasalsyndrome may be difficult to diag-nose, especially early in the course. 14

The typical motor features such asakinesia, rigidity, dystonia, focal myoc-lonus, ideomotor apraxia, and alien-limb phenomenon, affecting one limbor one side of the body predominant-ly, are not always present. Presenta-tions with dysarthria, aphasia (usually

Case 6-2A 61-year-old journalist had difficulty typing on a keyboard and troublereading for 18 months. He had a car accident 6 months ago in which hehad difficulty judging how close a traffic barrier was when he changed

lanes. He saw an ophthalmologist and received new glasses, but problemspersisted. He reduced his workload and stopped driving on freewaysbecause of his symptoms. There were no visual hallucinations. He had nosignificant medical history.

On the Montreal Cognitive Assessment he lost two points for recall, onefor copying a cube, and one for poor layout of numbers on a clock, with afinal score of 26/30. Visual fields were grossly intact. He had difficultydescribing details of a painting, with some slowing and a need to directhis gaze carefully. When reading, he sometimes omitted words at theends of lines. The remainder of his neurologic examination was otherwiseunremarkable. Neuropsychological testing revealed impairment onvisuospatial tasks, borderline performance on recall of a word list, andslowing on the Trail-Making Test Part B.

A brain MRI showed slight atrophy of the left parieto-occipital area.CSF biomarkers showed a decreased level of amyloid- " 42, increased totaltau, and borderline phosphorylated tau. An amyloid imaging positronemission tomography (PET) scan was positive, with widespread binding oftracer throughout the brain. A diagnosis of posterior cortical atrophydue to Alzheimer disease was made; the patient was started on acholinesterase inhibitor and reported mild improvement of reading ability.

Comment. This patient has typical symptoms and findings of posteriorcortical atrophy. Biomarkers enable the underlying diagnosis of Alzheimerdisease to be made with greater confidence.




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nonfluent), or executive dysfunctionmay make the specific diagnosis diffi-cult. Underlying pathology is variable, with corticobasal degeneration and AD the most common.

Suspicion for prion disorders shouldarise when patients have subacute or rapidly progressing dementia. 15 Confu-sion or a deliriumlike picture may dom-inate, or focal cognitive deficits may bepresent. Myoclonus, while often pres-ent, tends to occur later in the course.Other presentations include ataxia andextrapyramidal signs.

NEUROPSYCHOLOGICAL TESTING Although not mandatory to diagnosedementia, neuropsychological testingis valuable in a number of situations. When dealing with an unusual presen-tation of dementia, a comprehensiveneuropsychological evaluation can de-fine areas of impairment and preservedabilities. In cases in which a decisionabout dementia could substantially alter the patients life (eg, a patient who isstill working) or in which there are legalquestions (eg, competency to manageassets), detailed neuropsychologicalevaluation can strengthen the clinicaldiagnosis and provide sensitive indicesof the degree of impairment relative tonormal performance. For details of neuropsychological testing and inter-pretation in dementia, see reference 10in the list below.

LABORATORY WORKUPAND IMAGING

The American Academy of Neurology (AAN) guidelines for laboratory eval-uation in suspected AD recommendroutinely measuring B12 and thyroid-stimulating hormone levels. 16 Other tests that provide information aboutfactors that contribute to or worsencognitive function include completeblood count (anemia) and creatinine(renal failure). Tests such as rapid

plasma reagin, HIV testing, or workupfor unusual CNS inflammatory disordersare not part of a standard evaluation butshould be used when clinical suspicionarises. Lumbar puncture is not recom-mended as a routine test but may behelpful to rule out meningitis or enceph-alitis, confirm suggested neurosyphilis,or measure CSF pressure in suspectednormal-pressure hydrocephalus. An EEGdoes not have a place in the routineevaluation of dementia.

A structural brain imaging study V e ithe r MRI o r h ead C T V i s rec-

ommended in the AAN guidelines for AD. MRI has higher resolution and isstrongly preferred. In addition to atro-phy, stroke (including lacunes), and white matter changes, MRI can alsodetect microhemorrhages, which may indicate amyloid angiopathy, and prob-lems such as subdural hematoma. Theability to obtain volumetric readout onMRI is not widely available.

It is extremely helpful to review neu-roimaging tests and not merely to reada report. Findings such as hippocampalatrophy, focal atrophy affecting thecortex, and an appreciation of the ext-ent and location of subcortical whitematter changes are three areas wherecareful examination of the images canclarify the diagnosis.

The Workup for RapidlyProgressive DementiaBrain imaging and CSFevaluation shouldbe obtained in patients with rapidly progressive dementia. MRI may show

evidence of unusual problems such asencephalitis, vasculitis, carcinomatousmeningitis, primary or metastatic braincancer, or other brain mass lesions.Diffusion-weighted MRI is the mostsensitive way to detect findings consis-tent with prion disease. 17 Findings suchas a cortical ribbon appearance or al-tered appearance of basal ganglia struc-tures should be carefully examined.

KEY POINTh In cases in which a

decision about dementiacould substantially alterthe patients life (eg, apatient who is stillworking) or in whichthere are legal questions(eg, competency tomanage assets), detailedneuropsychologicalevaluation can strengthenthe clinical diagnosis andprovide sensitive indices ofthe degree ofimpairment.





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The CSF biomarkers of tau, P-tau, and14-3-3 protein are often increased inprion disorders, but they have sub-stantially lower sensitivity than abnor-malities on diffusion-weighted MRI. Autoantibodies against a variety of brain proteins have been reported inpatients with rapidly progressive or unusual dementia syndromes. These were reviewed comprehensively in

2010;16:31 Y 56.

BIOMARKERSBiomarkers for AD are beginning to

transition from research to practice,and the evidence for their use is cov-ered by Drs Sperling and Johnson( , this issue). New re-search criteria for AD proposed by theNational Insti tu te on Aging and Alzheimers Association workgroup 1

and similar efforts by an international working group have divided biomarkersinto categories according to the type of brain processes they measure. For example, MRI volumetric analysis or fluorodeoxyglucose positron emissiontomography (PET) scans can measureregional atrophy or hypometabolism,and thus the topography of neurode-generative changes in AD. Finding anincreased level of CSF tau or P-tauproteins provides an index of neuro-degeneration. Amyloid imaging usingPET (which recently came a step closer to clinical use when the US Food andDrug Administration approved the li-gand florbetapir) or CSF amyloid- " 42levels provide a readout reflecting am-

yloid deposition in the brain.Guidelines for the clinical use of biomarkers in the diagnosis of dementiahave not yet emerged. The new re-search criteria proposed for AD 1 provide some suggestions and caveats. Inparticular, efforts to standardize bio-marker measurement and interpreta-tion are still in progress, and these testsdo not always provide a quantitative

readout or a definite positive or nega-tive interpretation regarding suspected AD. Insurance coverage for biomarker tests is under negotiation. One of thefew currently approved procedures,namely fluorodeoxyglucose PET brainscan to distinguish between AD andfrontotemporal dementia, may need tobe reappraised once amyloid PET im-aging, which may address this question with greater accuracy, 18 is available.

As mentioned above, a brain imagingtest, typically MRI, is recommended aspart of the dementia workup to rule out

a structural (surgical) cause of dementiaand estimate the extent of vascular changes. Volumetric measurements of the whole brain, hippocampus, and ventricles can help support the diagno-sis of AD. At present these are availableprimarily through research, althoughcomputerized (automated) volumetricprograms have been developed. Care-ful examination of a brain MRI canreveal whether there is focal atrophy affecting brain areas implicated in spe-cific diagnoses.

REFERENCES1. McKhann GM, Knopman DS, Chertkow H,

et al. The diagnosis of dementia due toAlzheimers Disease: recommendations fromthe National Institute on Aging-AlzheimersAssociation workgroups on diagnosticguidelines for Alzheimers disease.Alzheimers Dement 2011;7(3):263 Y 269.

2. Galvin JE, Roe CM, Xiong C, Morris JC.Validity and reliability of the AD8 informantinterview in dementia. Neurology 2006;67(11):1942 Y 1948.

3. Brown PJ, Devanand DP, Liu X, et al.Functional impairment in elderly patientswith mild cognitive impairment and mildAlzheimer disease. Arch Gen Psychiatry2011;68(6):617 Y 626.

4. Rascovsky K, Hodges JR, Knopman D, et al.Sensitivity of revised diagnostic criteria forthe behavioural variant of frontotemporaldementia. Brain 2011;134(pt 9):2456 Y 2477.

5. Ferman TJ, Boeve BF, Smith GE, et al.Inclusion of RBD improves the diagnosticclassification of dementia with Lewy bodies.Neurology 2011;77(9):875 Y 882.




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6. Holsinger T, Deveau J, Boustani M, WilliamsJW Jr. Does this patient have dementia?JAMA 2007;297(21):2391 Y 2404.

7. Appels BA, Scherder E. The diagnosticaccuracy of dementia-screening instrumentswith an administration time of 10 to 45minutes for use in secondary care: a systematicreview. Am J Alzheimers Dis Other Demen2010;25(4):301 Y 316.

8. Markwick A, Zamboni G, de Jager CA.Profiles of cognitive subtest impairment onthe Montreal Cognitive Assessment (MoCA)in a research cohort with normal Mini-MentalState Examination (MMSE) scores. J Clin ExpNeuropsychol 2012;34(7):750 Y 757.

9. Tariq SH, Tumosa N, Chibnall JT, et al.Comparison of the Saint Louis University

mental status examination and themini-mental state examination for detectingdementia and mild neurocognitivedisorder V a pilot study. Am J GeriatrPsychiatry 2006;14(11):900 Y 910.

10. Salmon DP, Bondi MW. Neuropsychologicalassessment of dementia. Annu Rev Psychol2009;60:257 Y 282.

11. Gorno-Tempini ML, Hillis AE, Weintraub S,et al. Classification of primary progressiveaphasia and its variants. Neurology 2011;76(11):1006 Y 1014.

12. Crutch SJ, Lehmann M, Schott JM, et al.

Posterior cortical atrophy. Lancet Neurol2012;11(2):170 Y 178.

13. Schofield EC, Hodges JR, Macdonald V, et al.Cortical atrophy differentiates Richardsonssyndrome from the parkinsonian form ofprogressive supranuclear palsy. Mov Disord2011;26(2):256 Y 263.

14. Lee SE, Rabinovici GD, Mayo MC, et al.Clinicopathological correlations incorticobasal degeneration. Ann Neurol2011;70(2):327 Y 340.

15. Geschwind MD, Shu H, Haman A, et al.Rapidly progressive dementia. Ann Neurol2008;64(1):97 Y 108.

16. Knopman DS, DeKosky ST, Cummings JL,et al. Practice parameter: diagnosis ofdementia (an evidence-based review).Report of the Quality StandardsSubcommittee of the American Academyof Neurology. Neurology 2001;56(9):1143 Y 1153.

17. Vitali P, Maccagnano E, Caverzasi E, et al.Diffusion-weighted MRI hyperintensitypatterns differentiate CJD from otherrapid dementias. Neurology 2011;76(20):1711 Y 1719.

18. Rabinovici GD, Rosen HJ, Alkalay A, et al.Amyloid vs FDG-PET in the differentialdiagnosis of AD and FTLD. Neurology 2011;77(23):2034 Y 2042.



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Diagnóstico de Demencia

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