Mild Cognitive Impairment and Mild Dementia: A Clinical Perspective

CONCISE REVIEW FOR CLINICIANS

From the DepartmentNeurology, Division ofBehavioral Neurology, MClinic, Rochester, MN.

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Mild Cognitive Impairment and Mild Dementia:A Clinical Perspective

of

ayo

David S. Knopman, MD, and Ronald C. Petersen, PhD, MD

CME Activity

Target Audience: The target audience for Mayo Clinic Proceedings is primar-ily internal medicine physicians and other clinicians who wish to advancetheir current knowledge of clinical medicine and who wish to stay abreastof advances in medical research.Statement of Need: General internists and primary care physicians mustmaintain an extensive knowledge base on a wide variety of topics coveringall body systems as well as common and uncommon disorders. Mayo ClinicProceedings aims to leverage the expertise of its authors to help physiciansunderstand best practices in diagnosis and management of conditionsencountered in the clinical setting.Accreditation: Mayo Clinic College of Medicine is accredited by the Accred-itation Council for Continuing Medical Education to provide continuing med-ical education for physicians.Credit Statement: Mayo Clinic College of Medicine designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s).�Physicians should claim only the credit commensurate with the extent oftheir participation in the activity.Learning Objectives: On completion of this article, you should be able to(1) describe the features that establish a diagnosis of mild cognitive impair-ment (MCI) vs mild dementia, (2) describe the prognosis of MCI and milddementia, and (3) describe the major management issues in MCI anddementia.Disclosures: As a provider accredited by ACCME, Mayo Clinic College ofMedicine (Mayo School of Continuous Professional Development) mustensure balance, independence, objectivity, and scientific rigor in its educa-tional activities. Course Director(s), Planning Committee members, Fac-ulty, and all others who are in a position to control the content of thiseducational activity are required to disclose all relevant financial relation-ships with any commercial interest related to the subject matter of theeducational activity. Safeguards against commercial bias have been put inplace. Faculty also will disclose any off-label and/or investigational use ofpharmaceuticals or instruments discussed in their presentation. Disclosureof this information will be published in course materials so that those

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Abstract

Mild cognitive impairment and mild dementia are common problems in the elderly. Primary care physiciansare the first point of contact for most patients with these disorders and should be familiar with their diagnosis,prognosis, and management. Both mild cognitive impairment and mild dementia are characterized byobjective evidence of cognitive impairment. The main distinctions between mild cognitive impairment andmild dementia are that in the latter, more than one cognitive domain is invariably involved and substantialinterference with daily life is evident. The diagnosis of mild cognitive impairment and mild dementia is basedmainly on the history and cognitive examination. The prognosis for mild cognitive impairment and milddementia is an important motivation for diagnosis because in both, there is a heightened risk for furthercognitive decline. The etiology of mild cognitive impairment and mild dementia can often be establishedthrough the clinical examination, although imaging and other laboratory tests may also contribute. AlthoughAlzheimer disease is the most common cause of both, cerebrovascular disease and Lewy body disease makeimportant contributions. Pharmacological treatments are of modest value in mild dementia due to Alzheimerdisease, and there are no approved pharmacological treatments for mild cognitive impairment of any etiology.Nonetheless, new-onset cognitive impairment is a worrisome symptom to patients and families that demandsanswers and advice. If a patient is having difficulties managing medications, finances, or transportationindependently, diagnosis and intervention are necessary to ensure the health and safety of the patient.

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MILD COGNITIVE IMPAIRMENT AND MILD DEMENTIA

ILLUSTRATIVE CASEMr Smith, a 73-year-old man, comes for hisyearly examination accompanied by his wife.After reviewing the conditions on his problemlist, his wife mentions that she has had con-cerns about his forgetfulness. Mr Smith isquick to point out that he doesn’t feel thatforgetfulness interferes with his activities. Afterasking Mr Smith if he would allow his wife tospeak, the patient’s wife elaborates, “Over thepast year, our children and I have noticedthat Mr Smith often asks the same questionover and over again. He didn’t used to dothis. He doesn’t seem to be paying attentionto what I am saying because he hardly ever re-members our conversations. If I ask him to gopick up some things in town, he usuallycomes back empty-handed or with only afew of the things I asked him to get. Hedoesn’t remember appointments. Yet, he hashad no difficulties with driving or with direc-tions, and he is still an excellent handyman.”

What should a health care professional doin this situation?

DEFINITION OF MILD COGNITIVEIMPAIRMENT AND MILD DEMENTIACognitive impairment in the elderly is a com-mon condition, and in most instances, primarycare physicians are the first point of contact fora patient and family. Among persons older than70 years, 14% have sufficient cognitive impair-ment to warrant a diagnosis of dementia,1 andan equal number have mild but unequivocalcognitive impairment short of dementia.2 Per-sons with moderate to severe dementia aregenerally brought to medical attention becausetheir care needs demand it.3 Milder forms of

TABLE 1. Diagnosis of Mild Cognitive Impairment and M

Mild cognitive impairment

Concern about a change in cognition, in comparison with thObjective evidence of low performance in one or more cognit

that is greater than expected for the patient’s age and edubackground

Does not substantially interfere with daily activities, althoughfunctional tasks performed previously, such as paying bills,meal, or shopping, may take more time or be performed leIndependence in daily life is preserved, with minimal aids o

Not explained by delirium or major psychiatric disorder

Adapted from Alzheimers Dement.5,6

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cognitive impairment, however, present formi-dable conceptual and practical challenges indetection by primary care physicians.

Mild cognitive impairment (MCI) is the termused to describe the condition of individualswhose cognition lies between the cognitivechanges of aging and early dementia4 (Table 1).They have objective evidence of cognitive impair-ment that represents a decline from the past, butthey function independently or nearly so in theirdaily lives in a manner that is indistinguishablefrom the past.4,5 Although most of the MCI liter-ature pertains to the earliestmanifestations of Alz-heimer disease (AD), MCI is a syndrome thatcould have many causes.4 Mild dementia is alsodefined by cognitive impairment and poor per-formance on objective cognitive assessmentsthat represent a decline from the past, but impor-tantly, dementia requires evidence of substantialdifficulties in daily life that interfere with inde-pendence.6 In mild dementia, patients retain in-dependence in simpler activities, in contrast tomore severe forms of dementia in which basic ac-tivities of daily living are compromised. Recentlyreleased criteria for the Diagnostic and StatisticalManual of Mental Disorders: DSM-57 includecriteria for a new diagnostic label, mild neurocog-nitive disorder, that closely resembles MCI.Although mild dementia represents a clinicallyrelevant step toward increasing impairment andworse prognosis, there are many similarities inthe diagnosis and recognition of MCI and milddementia. Hence, this review will explore the ba-ses for the diagnosis of MCI and mild dementia,the rationale for their timely recognition, the op-tions for management, and a glimpse at futuretrends. Recently, the topic of MCI has also beenreviewed elsewhere.8

ild Dementia

Mild dementia

e person’s previous levelive domainscational

Objective evidence of low performance in more than one cognitivedomain that is greater than expected for the patient’s age andeducational background

complexpreparing ass efficiently.r assistance

Substantial interference with the ability to function at work or at usualactivities but still able to carry out basic activities of daily living (bathing,dressing, personal hygiene) and participate in some pastimes, chores,and social functions

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Trajectory of a person destined to have development of dementiaTrajectory of a person destined to die nondemented

Time frame when daily functioning becomes impaired

Time frame when cognitiveimpairment certain

Mild cognitive impairment threshold

Dementia threshold

Wor

seni

ngde

men

tiaM

CI

Nor

mal

cogn

ition

FIGURE. Graphic demonstration of the differences in cognitive trajectoriesbetween a person destined to never become cognitively impaired during life(blue line) and a person destined to have development of dementia (orangeline). The x-axis represents age, and the y-axis represents cognitiveimpairment. Thresholds for mild cognitive impairment (MCI) and dementiaare indicated by horizontal orange bands. The continuous nature ofcognitive decline in persons destined to have dementia defies simple al-gorithms; clinical judgment is needed to weigh information from the historyand examination.

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PROGNOSISA diagnosis of MCI or mild dementia carriesimportant prognostic implications (Figure).Mild cognitive impairment and mild dementiarepresent markedly heightened risk for wors-ening over the ensuing several years.9 Forexample, in Olmsted County, Minnesota, therate of progression to dementia among personswith MCI was 7.1% per year in contrast to therate of progression among cognitively normalpersons of 0.2% per year.9 In typical clinical set-tings in whichMCI is likely to be diagnosed laterin the course, the rate of progression to dementiamay be even higher. These rates reflect averagesof all ages over 70 years; in fact, the risk of inci-dent dementia in persons with MCI increaseswith advancing age, so that a 90-year-old withMCI has a higher risk for progression to demen-tia than a 70-year-old who otherwise is similarlyimpaired. Because of the inherent variability inthe clinical diagnosis of MCI, some personsdiagnosed as having MCI may later appear tobe cognitively normal. Yet, even when MCI is

Mayo Clin Proc. n October 2014;89(

diagnosed and later rescinded because ofimprovement in cognition, individuals oncediagnosed as having MCI are at greater risk forfuture decline compared with persons whonever were considered to have MCI.9-11 Incontrast, persons with dementia almost invari-ably worsen over time.12,13

NATURE OF COGNITIVE IMPAIRMENTCognitive functioning is typically characterizedinto 1 of 5 domains: (1) learning and memory,(2) language, (3) visuospatial, (4) executive,and (5) psychomotor. These domains have arough correspondence with their cerebral local-ization. For a diagnosis of MCI, only one ofthese areas must be impaired, whereas a diag-nosis of dementia requires that more than onedomain must be impaired. Evidence forinvolvement of individual domains can be ob-tained from the history, a brief mental status ex-amination, or neuropsychological testing.

Forgetting is intrinsically human and in-creases with aging. It is part of normal experi-ence to forget a name temporarily or anappointment rarely. We may misplace a watchor keys occasionally. However, when suchevents become frequent, suspicion should behigh that there is more than just normal forget-ting. Similarly, frequent re-asking of questionsis much more likely to indicate substantialmemory impairment.14 The most commonearliest manifestation of pathologic cognitiveimpairment in the elderly is declining efficiencyof memory, often exemplified by re-asking ofquestions. The challenge to clinicians is to appre-ciate where the boundary between normal andabnormal is for a particular patient. In our illustra-tive case, the patientwas repeating himself in con-versation, and his wife had taken over refilling hisprescriptions because he was forgetting to do so.These symptoms strongly suggest an amnesticdisorder, in our patient’s case, amnestic MCI.

Nonamnestic cognitive impairments arenearly as common as the amnestic forms. Non-amnestic impairment can involve word findingand speech difficulties, impaired geographicorientation, visual perception problems, andimpaired mental agility. When there is dysfunc-tion in more than one cognitive domain in per-sons with MCI, referred to as multidomain MCI,the risk for decline to dementia is much higherthan when there are isolated memory problemsor word finding problems.9,15

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TABLE 2. Functional Activities Questionnaire

In the past 4 weeks, does the patient have any difficulty or need help with:1. Writing checks, paying bills, or balancing a checkbook2. Assembling tax records, business affairs, or other papers3. Shopping alone for clothes, household necessities, or groceries4. Playing a game of skill, working on a hobby5. Heating water, making a cup of coffee, turning off the stove6. Preparing a balanced meal7. Keeping track of current events8. Following a television show, book, or magazine and being able to discuss them

with acquaintances9. Remembering appointments or remembering to take medications, keeping track

of recent conversations, recent events, and the date10. Driving, traveling out of the neighborhood, or arranging to take public

transportationScoring guide: 0 ¼ can do this without help or never did the activity; 1 ¼ have some

difficulty but can do this without help; 2 ¼ need help with this; 3 ¼ can’t do this

Adapted from J Gerontol 17 and the United States Agency for Health Care Policy and Research.19


Loss of insight into one’s own cognitive dif-ficulties is a common, although not invariant,part of both MCI and mild dementia. Contraryto older clinical lore, persons who otherwiseappear cognitively intact but report cognitivedifficulties have a slightly greater likelihood ofexperiencing cognitive decline in the future.14,16

However, clinicians should be cautious in usingsubjective cognitive complaints as a prognosticfactor because secondary gain, depression, orlifelong personality traits can also producecognitive complaints. In our patient, loss ofinsight was the issue: it was his wife and notthe patient who mentioned the cognitive con-cerns to the physician. The loss of insight inour patient might suggest that his illness issomewhat more advanced; patients in the earlierstages of MCI often have some preservation ofinsight into their cognitive decline.

CLINICAL DIAGNOSIS OF MCI AND MILDDEMENTIAA medical history and a mental status examina-tion are the principal tools for diagnosing MCIor mild dementia. The medical history is the pri-mary means by which the clinician establisheswhether the patient has impairment in dailyfunctioning. The mental status examination isthe means by which the clinician establisheswhether there is objective evidence of cognitiveimpairment. Clinical judgment is required tointegrate information from the 2 sources. A gen-eral neurologic examination should also be per-formed, but its role in the diagnostic process islargely in contributing to an understanding ofthe etiology of the cognitive disorder.

A thoroughhistory fromboth thepatient andsomeonewho knows the patientwell is essential.In the early stages of MCI, patients are aware oftheir cognitive difficulties and may themselvesraise the concernwith their physician. Generally,however, an informant who knows the patientwell is necessary to corroborate the patient’sown observations. Finding such an individualand finding the time to interview an informantis one of the greatest challenges to diagnosis inthe primary care setting. Several inventories ofactivities of daily living are available; for routineclinical use, the 10-item Functional ActivitiesQuestionnaire17,18 is a valid tool for character-izing daily functioning (Table 2). Even if thequestionnaire is not administered verbatim, thecontent of the 10 items is a useful guide for


surveying a person’s strengths and weaknessesin daily life. Understanding the patient’s othermedical conditions, if any, is highly relevant toplacing cognitive symptoms in perspective. Forexample, a patient with severe congestive heartfailure or emphysema could have hypoxemia,hypercapnia, or markedly elevated hematocrit,all of which could affect cognitive functioning.All of the patient’s medications should also bereviewedwhen the diagnosis of cognitive impair-ment is being considered. Many widely usedmedications have the potential to impair cogni-tion. Sedatives, narcotic pain medications, andmedications with anticholinergic profiles are ofgreatest concern. In addition, anxiety or depres-sion can contribute to cognitive difficulties.

The second tool for the diagnosis of cogni-tive impairment is the mental status examina-tion. There are several instruments designedfor use in primary care settings, but such exam-inations may take 10 minutes to complete. TheMontreal Cognitive Assessment20,21 and theShort Test of Mental Status22,23 are 2 instru-ments we use. Mental status examinations arenot perfect tools, but they are far more sensitivethan casual conversations or ad hoc questions.In our patient, abnormalities on a mental statusexamination would provide important confir-mation of the wife’s observations. A “normal”score would also be informative. Indeed,bedside examinations are known to be insen-sitive. Thus, if the patient, family, or physi-cian suspect cognitive impairment, referral for

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neuropsychological testing24da far more sen-sitive methoddshould be considered.

More detailed evaluation of cognition woulddepend in part on the wishes of the patient andfamily, the experience of the health care profes-sional, and the accessibility of consultationswith a neurologist, psychiatrist, geriatrician, orneuropsychologist to obtain further expertise indiagnosis. The decision also depends on theseverity of the cognitive impairment and the con-sequences of the diagnosis. When symptoms aremild or uncertain or when major life decisionsare at stake, neuropsychological testing can beinvaluable.

Imaging studies and blood tests are a neces-sary part of the evaluation of suspected cognitiveimpairment. Laboratory tests cannot answer thequestion of whether the patient has cognitiveimpairment, but they can aid in establishing anetiology of the cognitive disorder. The AmericanAcademy of Neurology recommended a simplebattery of laboratory tests and a brain imagingstudy as part of the initial evaluation of someonewith suspected dementia25 or MCI.26 Noncon-trast brain magnetic resonance imaging (MRI)or brain computed tomography (CT) will pro-vide sufficient evidence to rule out brain tumors,subdural hematoma, and other structural brainlesions. Routine MRI or CT may also show evi-dence of cerebrovascular disease, with MRI be-ing much more sensitive than CT. Thesesimple scanning techniques cannot be used todiagnose AD itself, however. Our patient shouldundergo laboratory studies such as measure-ment of his vitamin B12 and thyrotropin levelsand a brain imaging study.

ETIOLOGYIn persons older than 65 years, AD is the mostcommon etiology of MCI and mild demen-tia.27-29 Amnestic impairment is most typicalfor AD whether in the MCI or mild dementiastage. However, other diseases may also causeMCI and mild dementia, and comorbiditiesare often seen with AD. Cerebrovascular dis-ease that causes brain infarctions becomesmore common with advancing age as well. Es-timates vary widely as to the exact contribu-tion of cerebrovascular disease to MCI andmild dementia, but it is likely clinically impor-tant.29 Brain MRI may reveal silent infarcts orextensive white matter changes thought to beischemic in nature. Patients with imaging


evidence of these lesions who also havevascular risk factors might be treated differ-ently than patients without these imagingfindings. Both amnestic and nonamnestic im-pairments occur with cerebrovascular disease.Parkinson disease with concomitant cognitiveimpairment, now referred to as Lewy body dis-ease, also becomes more common withadvancing age. In its typical presentation,Lewy body disease may cause cognitiveimpairment and parkinsonism, prominentchanges in personality, and alterations in sleepand wakefulness. Its typical mildest cognitiveprofile is that of a nonamnestic MCI.30 Thefrontotemporal degenerations are the leastcommon of the degenerative dementias, butthey too can produce an MCI syndrome.Depression, multiple medical comorbidities,and adverse effects of drugs can sometimesproduce cognitive impairment; in principle,prognosis in these etiologies is more favorablethan for neurodegenerative disease. In general,AD and other neurodegenerative diseases andcerebrovascular disease are inevitably progres-sive; hence, when they are the cause of MCIand mild dementia, worsening cognitive func-tion can be anticipated.

TREATMENTTreatment of patients with MCI and mild de-mentia should include strong encouragementto remain physically, socially, and mentallyactive. One study of persons with subjectivememory impairment showed clear, althoughmodest, benefits of physical exercise.31 Al-though a review of nonpharmacological inter-ventions in MCI or dementia asserted that theevidence was weak,32 we believe that mentaland physical stimulation should be encouraged.There are also no prospective studies of theimpact of more aggressive treatment of vascularrisk factors,32 but management of vascular riskfactors is a part of good general care.

Pharmacological treatment ofMCI presumedto be due to AD is quite limited, and treatmentof MCI due to other neurodegenerative diseasesis not available. There have been several trialsof cholinesterase inhibitors in persons withamnestic-type MCI, the type most likely to bedue to underlying AD. The results have beendisappointing.33,34 Although a hint of treatmentbenefit in the form of delay of progression to de-mentia was documented in one study33 that





found a positive effect of donepezil for 12monthsand up to 24 months in apolipoprotein ε4carriers, the benefit did not persist over the36-month duration of the study. Three cholines-terase inhibitorsddonepezil, rivastigmine, andgalantaminedare approved for the treatment ofmild dementia due to AD. Treatment of patientswith mild dementia due to AD has tangible butmodest benefits.35,36 Our decision to treat ourpatient with a cholinesterase inhibitor woulddepend on the results of our clinical assessmentand formal neuropsychological testing as wellas our impression of the likelihood that AD wasthe underlying etiology. No treatments havebeen approved by the US Food andDrug Admin-istration for MCI.

RATIONALE FOR DIAGNOSISNew-onset cognitive impairment is commonand is a worrisome symptom to patients andfamilies. If a patient is having difficulties in man-aging medications, finances, or transportationindependently, diagnosis and intervention arenecessary to ensure the health and safety of thepatient. Acknowledging that we lack therapiesthat block the progression of AD or other degen-erative dementias, there are nonetheless impor-tant reasons to make a diagnosis. First, iffamily members sense that the patient is havingcognitive difficulties, affirming the diagnosisthrough a rational evaluation enables them tocome to grips with how thememory or cognitivedifficulties interfere with daily life and what ac-commodations are needed. Second, the diag-nosis of MCI enables families to plan for thefuture. Some patients and families may chooseto discount future risk, but others might desireas much information as possible.

There are those who argue against making adiagnosis ofMCI. Recent critical reviewshighlightthebenefits andchallenges.37Thecritics point outthe stigma associatedwith a diagnosis of cognitiveimpairment, the modest interventional opportu-nities, and the occasional reversal ofMCI to cogni-tive normality. In our patient, the first 2 criticismsare effectively refuted by the need for the patientandhis family toknowwhat is goingon.The thirdpoint, the variable prognosis, can be conveyed tothe patient and family through discussion andeducation. We acknowledge that cognitivescreening of the elderly in the absence of a clinicalconcern has not been found to be of clearbenefit.38 However, cognitive assessments pay


off in the long run. Almost all clinicians wouldappreciate the added certainty for making a diag-nosis when prior documentation exists that ver-ifies a genuine change in condition. Ourpatient’s situation should not be viewed as anexample of screening for cognitive impairment;in our patient, the spouse asked the physicianfor help with the problem.

FUTURE TRENDSResearch on imaging and cerebrospinal fluidbiomarkers is intense and accelerating, butmost of the progress has not yet affected routineclinical practice. The introduction of positronemission tomographic imaging of brain b-amy-loid39 hasmade it possible in the research settingand in clinical practice (for a very high cost, notcovered by insurance) to establish whether aperson is harboring abnormal levels of brainb-amyloid. Positron emission tomography fordetection of tau protein is also being studied inthe research setting.40 A combination of imagingor cerebrospinal fluid studies has been intro-duced for research purposes into the diagnosticcriteria forMCI (and dementia).41,42 Future clin-ical trials are likely to benefit from the enhancedantemortem diagnostic accuracy offered by thenew imaging and fluid biomarker studies. Asof 2014, however, the clinical value ofbiomarker characterization of patients withMCI or mild dementia has not been established.

CONCLUSIONMild cognitive impairment and mild dementiaare common problems in our aging society.Proper and timely diagnosis can minimize thedysfunction that accompanies cognitive loss.

Abbreviations and Acronyms: AD = Alzheimer disease;CT = computed tomography; MCI = mild cognitiveimpairment; MRI = magnetic resonance imaging

Grant Support: This work was supported in part by grantsU01 AG06786 (Mayo Clinic Study of Aging) and P50AG016574 (Mayo Alzheimer Center) and by funds fromthe Robert H. and Clarice Smith and Abigail Van BurenAlzheimer’s Disease Research Program.

Potential Competing Interests: Dr Knopman serves asDeputy Editor for Neurology; serves on data safety moni-toring boards for Lundbeck Pharmaceuticals and for theDominantly Inherited Alzheimer’s Disease Treatment Unit;has served on a data safety monitoring board for Eli Lillyand Company; served as a consultant to Tau Rx TherapeuticLtd; in the past 2 years; and receives research support fromthe National Institutes of Health. Dr Petersen serves on data

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monitoring committees for Pfizer, Inc, and Janssen Alz-heimer Immunotherapy; is a consultant for Elan Pharmaceu-ticals, Inc, Roche Inc, and Merck & Co, Inc; receivespublishing royalties from Oxford University Press; and re-ceives research support from the National Institutes ofHealth/National Institute on Aging.

Correspondence: Address to David S. Knopman, MD,Department of Neurology, Mayo Clinic, 200 First St SW,Rochester, MN 55905 ([email protected]).

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Mild Cognitive Impairment and Mild Dementia: A Clinical Perspective