Mild Cognitive Impairment: ChallengingIssues

Mary Ganguli, M.B.B.S., Ronald C. Petersen, M.D., Ph.D.

The demographic imperative of global aging isnow ubiquitously discussed, and research on

cognition and dementia has burgeoned over the pastdecade. Ironically, the question of how to detect anddiagnose dementia in its clinical and preclinicalstages has become more, rather than less, complexover time, promoting endless debates, practiceguidelines, and competing sets of criteria. This issueof AJGP brings together a diverse and intriguinggroup of articles on the topic of aging-related cogni-tion and dementia. Three of the articles1–3 addressthe concepts and concomitants of cognitive function-ing and decline, examined from very different per-spectives. The fourth4 reports neuropathological val-idation of the current clinical criteria for Alzheimerdisease (AD). While at first glance these studies mayseem to resemble a collection of apples and oranges,or even bagels and oranges, there is in fact an im-portant theme that connects them conceptually andpotentially leads us forward.

From the well-known Kungsholmen Project inStockholm, Laukka et al.1 report prospective, popu-lation-level data on “terminal decline” in cognitionas older adults draw closer to the end of their lives.In this cohort of over 500 individuals aged 75 andolder, the key finding was that much of this acceler-ated decline proximal to death is in fact related topreclinical dementia. However, there were also somedistinct changes that predict hastened mortality inthose free of dementia.

From a different kind of sample, a group of 24normal-functioning older volunteers at the San Diego,CA, Veterans Administration Medical Center, Fine et

al.2 demonstrate the potential value of “cognitivediscrepancy” analysis. This approach essentially ex-amines the difference between an individual per-son’s standardized scores on two cognitive tasks.This intraindividual technique is contrasted to themore typical approach of comparing individual’sperformance on a given task with those of others onthe same task, e.g., comparing observed to expectedperformance based on group norms (as when classi-fying individuals’ scores based on the number ofstandard deviations below the mean of the appropri-ate peer group). The discrepancy between individu-al’s performances on higher and lower level condi-tions of the same executive function test was a strongpredictor of subsequent cognitive decline.

In a cross-sectional study of 77 adults, in an uni-versity medical setting, who were either cognitivelynormal or classified as having mild cognitive impair-ment (MCI), Jefferson et al.3 compared a novel in-strument. They measured subtle errors in selectedcomplex instrumental activities, such as cooking,with standard questionnaire-based scales on func-tional ability. Only the error-based scale distin-guished between the two groups, and only thisscale was associated with an independent cogni-tive measure (verbal learning). This study rein-forces the importance of developing appropriatelysensitive measures to detect the functional deficitsassociated with very mild MCI.

The above three studies shed light on differentpieces of the puzzle. Together they help addresscritical nuances involved in studying and interpret-ing cognitive function test performance. They are

Received January 21, 2008; accepted January 21, 2008. From the Departments of Psychiatry and Neurology, University of Pittsburgh School ofMedicine; University of Pittsburgh Graduate School of Public Health (MG); and Alzheimer’s Disease Research Center, Department of Neurology,Mayo Clinic College of Medicine (RCP). Send correspondence and reprint requests to Ronald C. Petersen, MD, PhD, 200 First Street SW,Rochester, MN 55905. e-mail: peter8@mayo.edu

© 2008 American Association for Geriatric Psychiatry

Am J Geriatr Psychiatry 16:5, May 2008 339

EDITORIAL

also part of broader efforts to tease out the relativecontributions to cognitive functioning of normal ag-ing, dementia, other disorders, and as yet unknownfactors. These efforts are necessary both to enhanceour understanding of how the brain works, and toprovide our patients with better diagnostic and prog-nostic information. Much current research on milderlevels of cognitive impairment is driven by the mo-tivation to detect AD in its earliest possible stages, inanticipation of the advent of disease-modifyingdrugs. The balance between sensitivity (missing notrue cases of disease) and specificity (labeling no-body falsely as having disease) has never been morecritical than it is today, given the substantial impli-cations of wrong diagnosis. Thus, all three studiespoint to the need for more accurate diagnostic crite-ria for early dementing disorders.

The fourth article in this issue, by Ranginwala etal.,4 reports on pathological validation of the currentclinical criteria for AD and concludes that the criteriaare doing pretty well after 25 years. Among 313autopsy cases from the Alzheimer’s Disease Centerat the University of Texas Southwestern, 88.6% ofcases diagnosed with probable AD met neuropatho-logic criteria for AD. The most common complicatingdiagnosis involved Lewy bodies, an entity whichwas challenging to diagnose clinically. This level ofclinical-pathological correlation is quite acceptableand typical of most AD research centers.

And yet, the diagnosis of AD at the clinical stage ofdementia remains a moving target, with several re-cent proposals5,6 for revising the current criteria.7,8 Aspecific recent appeal has been made to move theclinical diagnosis for AD to earlier points in theclinical spectrum, thus potentially including the pre-dementia stage in the disease process referred to bymany as MCI.9,10 This proposal is worthy of consid-eration, but poses significant challenges for us asresearchers and clinicians.

Three questions may capture the essence of theclinician’s dilemma: (i) how to make the most accu-rate diagnosis, (ii) when to make the diagnosis, and(iii) when and how to share the diagnosis with thepatient and family.

First, we should consider whether cognitive im-pairment has the same meaning in different settingsand populations. As Ranginwala et al.4 have demon-strated, patients who meet entry criteria for studiesin AD research centers receive diagnoses that turn

out to be highly accurate. Individuals with MCI whohave come to autopsy in specialty research centershave also been found to have neuropathology typicalof AD.11 However, in less selected populations, andat milder levels of impairment, clinico-pathologicalcorrelation is substantially less certain. Recent stud-ies on the neuropathology of MCI have indicatedthat there is more heterogeneity of outcome whenthe diagnosis is made earlier in the clinical spectrumand in community settings.12,13 In community-basedsamples, AD neuropathology has been found in thebrains of older persons without dementia or MCI,but with subtle changes in episodic memory.14 Dif-ferent individuals with the same test performancelevel may have different functional levels, dependingon available compensatory strategies and resources.Different individuals with the same amount of incip-ient brain disease can appear normal15 or manifestdifferent levels of symptoms or deficits, and takelonger or shorter times to cross the clinical thresholdfor the stage we define as dementia. Others may havethe same mild symptoms and deficits as a result ofsomething other than structural disease, e.g., depres-sion, anticholinergic drug effects, hypoxia, or hy-pothyroidism. Previous studies have emphasizedthe multifactorial nature of the pathological diag-noses when done in individuals from communitysettings.12

In Diagnostic and Statistical Manual of Mental Disor-ders, Fourth Edition (DSM-IV-TR), a diagnosis of De-mentia of the Alzheimer Type is listed on Axis I(with AD on Axis III), when the cognitive impair-ment is sufficient to impair social and occupationalfunctioning.6 Thus, American psychiatrists have nostraightforward way to list a diagnosis of AD beforethe patient has crossed the threshold into dementia,with impaired social and occupational functioning.We know the underlying disease pathology is presentlong before this threshold is crossed,16 and it mightbe argued that the most appropriate time to inter-vene with effective treatments is before the thresholdis crossed. (Imagine by analogy a situation in whichcancer could only be officially diagnosed and treatedafter it had started to interfere with functioning.)Further, the dementia threshold is arbitrary; at agiven level of cognitive impairment, whether or notan individual experiences social and occupationaldeficits is a function of the cognitive challengesposed by that individual’s life style and occupation.

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It can also be confounded by the subject’s and infor-mant’s perception of what is normal. It is thereforeimperative that we develop criteria with good pre-dictive validity for progression to clinical demen-tia. Several longitudinal studies currently under-way are expected to lead to a better understandingof the outcome, and predictors of outcome, of MCIand subtypes thereof.17

However, in efforts to increase sensitivity of diag-nosis and not miss any cases of early AD, we willlikely lose specificity and classify some individualsas AD who will not in fact progress to dementia.Alternatively if we wait till the impairment is moresevere and the diagnosis more certain, we will missmany early cases. One approach to enhancing spec-ificity at the early stage advocates the use of biomar-kers from neuroimaging, cerebrospinal fluid exami-nation, and genotyping.18 This approach deservesfurther study but will vary in applicability acrosscountries and clinical specialties.

And yet, as clinicians, what level of certainty dowe need regarding a diagnosis of AD before wedisclose it to the patient and family? Given all itsconnotations, at what point should we first use theterm “Alzheimer disease,” (with or without qualifi-ers such as “probable” or “possible”)? Will thatthreshold change when we have a disease-modifyingtherapy to offer? Is there a way to share a probabi-listic statement, e.g., that the patient does not havedementia at this time but has clinical and laboratoryfeatures suggesting a 50% risk of progressing to de-mentia? Is it paternalistic to override patients’ “rightto know” or assume that they cannot handle theinformation or the uncertainty? On the one hand, alabel of AD is often viewed as a death sentence.Disclosing this diagnosis will have a profound im-pact on the patient and family’s subsequent deci-sions; thus, we may want to delay delivering the badnews until we were sure of it. On the other hand, tooffer effective treatment and counseling as early aspossible, we would want to make the diagnosis asearly as possible, allowing for the risk that the diag-nosis has a certain probability of being wrong. Aspsychiatrists, we may make the decision to disclosebased on assessment of what that individual patientand family seem to want to know, and seem ready tohear, at a given point in time.

Some authors contend that using a tentative diag-nostic term such as MCI is a more prudent approach

than prematurely labeling patients as having ADwhen the outcome is uncertain.19 Others might arguethat MCI is a useful broad descriptive term, just like“dementia,” but has no diagnostic or prognosticvalue unless subtyped on the basis of presumedetiology. However, terms such as “MCI of the ADtype” or “pre-AD MCI” will not solve the problem ofpatients’ and families’ potentially catastrophic re-sponses to the AD label, particularly when there isless than 100% certainty of the long-term outcome.An alternative approach might be to use the term“MCI” or one of its descriptive subtypes (e.g., am-nestic MCI)10 providing the patient and family withinformation about the uncertain nature of the out-come. Perhaps, even interventions at this stage canbe couched in the probabilistic terms regarding po-tential therapies and their outcomes.

The Karolinska Institutet study suggests that ac-celerated decline can be a marker not only fordementia but for impending death.1 The impor-tance of this finding is that mortality is increased inindividuals with amnestic MCI, particularly thosewith impairments in multiple domains.20 In theSan Diego, CA, VA study, intraindividual discrep-ancies in cognitive measures appeared more sen-sitive at detecting early decline than current nor-mative data-based approaches.2 The Boston Universitystudy suggests that subtle measures of impairmentin daily activities may be informative in identify-ing those who will decline cognitively in the fu-ture.3 Complementary work on this issue from theUniversity of Alabama in Birmingham documentsthe utility of higher order financial managementtasks as being sensitive at heralding future de-cline.21 As promising as these approaches are, theirspecificity for the outcome needs to be demon-strated before they can be said to have clinicalutility. The University of Texas Southwesternstudy,4 by demonstrating the validation by patho-logical confirmation of current AD diagnostic cri-teria, raises the question of whether preclinicaldiagnosis should be held to the same gold stan-dard. Thus, without addressing it directly, all fourarticles in this issue of AJGP have implications forthe challenges of early AD diagnosis. In differentways, they all have potential for further diagnosticrefinements which will one day help us serve ourpatients better.

Ganguli and Petersen

Am J Geriatr Psychiatry 16:5, May 2008 341

References

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3. Jefferson AL, Byerly LK, Vanderhill S, et al: Characterization ofactivities of daily living in individuals with mild cognitive impair-ment. Am J Geriatric Psychiatry 2008; 16:375–383

4. Ranginwala NA, Weiner MF, Hynan LS, et al: Clinical criteria forthe diagnosis of Alzheimer’s disease: still good after all theseyears. Am J Geriatric Psychiatry 2008; 16:384–388

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16. Price JL, Morris JC: Tangles and plaques in nondemented agingand “preclinical” Alzheimer’s disease Anna Neurol 1999; 45:358–368

17. Roberts RO, Knopman DS, Rocca WA, et al: Prevalence of mildcognitive impairment in Olmsted County, MN: a population-based study. Neurology 2006; 66 (suppl 2):A119

18. Shaw LM, Magdalena K, Clark CM, et al: Biomarkers of neurode-generation of diagnosis and monitoring therapeutics. Nat RevDrug Discov 2007; 6:295–303

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20. Leep Hunderford AN, Roberts RO, Slusser TC, et al: Mortality inamnestic mild cognitive impairment: a prospective communitystudy. Neurology 2006; 67:1764–1768

21. Okonkwo O, Griffith HR, Belue K, et al: Medical decision-makingcapacity in patients with mild cognitive impairment. Neurology2007; 69:1528–1535

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