Mild Cognitive Impairment in Older People

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    Many recent studies report that a small proportion of older people perform in the abnormal or borderlinerange on neuropsychological tests [1,2], and that theseabnormalities occur predominantly in the domain of episodic memory [3]. While these people do not meetthe clinical criteria for any neurodegenerative disease,their performance indicates that their cognitive functions

    are not normal. Three accounts of the aetiology of suchmild cognitive impairment have been put forwardrecently. The first proposes that it represents the earlystages of Alzheimers disease (AD), while the secondproposes that it is a product of normal ageing [4]. Thethird, and most likely, account is that mild cognitiveimpairment is a heterogeneous disorder with multiplepossible outcomes [35]. These proposals have beeninvestigated recently through epidemiological, genetic,cognitive and neuroradiological studies of older peopleclassified as having mild cognitive impairment. Resultsfrom these studies have been varied, which has added tothe current confusion and contradiction occurring in theageing and dementia literature. We argue that the majorcause of this confusion is the inconsistency among the

    An analysis of systems of classifying mild

    cognitive impairment in older peopleAlexander Collie, Paul Maruff

    Objective: Over the past two decades, a number of systems have been developed for theclassification of cognitive and behavioural abnormalities in older people, in order that indi-viduals at high risk of developing neurodegenerative disease, particularly Alzheimersdisease, may be identified well before the disease manifests clinically. This article criticallyexamines the inclusion and exclusion criteria of a number of such classification systems,to determine the effect that variations in criterion may have on clinical, behavioural andneuroimaging outcomes reported from older people with mild cognitive impairment.Method: Qualitative review of the literature describing systems of classifying mild cognitiveimpairment, and outcomes from clinical, behavioural, neuroimaging and genetic studies ofolder people with mild cognitive impairment.Results: The exclusion and inclusion criteria for these classification systems varymarkedly, as do the design of studies upon which the validity of these systems has beenassessed. Minor changes to individual exclusion/inclusion criterion may result in substan-tial changes to estimates of the prevalence and clinical outcome of mild cognitive impair-ment, while inadequate experimental design may act to confound the interpretation ofresults.Conclusions: As a result of these factors, accurate and consistent estimates of the

    outcome of mild cognitive impairments in otherwise healthy older people are yet to beobtained. On the basis of this analysis of the literature, optimal criteria via which accurateclassifications of mild cognitive impairment can be made in future are proposed.Keywords: cognitive impairment, ageing, memory, diagnosis, neuropsychology.

    Australian and New Zealand Journal of Pschiatry 2002; 36:133140

    Alexander Collie, Centre for Neuroscience, The University of Melbourne(Correspondence); Paul Maruff, School of Psychology, Latrobe University

    Neuropsychology Laboratory, Mental Health Research Institute of Victoria, Locked Bag 11, Parkville, Victoria 3052, Australia.Email: [email protected]

    Received 11 October 2000; revised 24 August 2001; accepted 28 August2001.

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    CLASSIFYING MILD COGNITIVE IMPAIRMENT134

    many different systems that are currently used to clas-sify mild cognitive impairment (hereafter referred to asclassification systems).

    Identifying older people at high risk for AD is impor-tant for both the patient and their carers as it may allowtherapeutic intervention in the very earliest stages of thedisease, which in turn may delay or even prevent theonset of the disease process. In the worst case it allowsfor the planning of patient care. Such identification iscurrently hampered by the use of inadequate and incon-sistent diagnostic criteria for mild cognitive impairment.Nine such criteria have been developed, and a numberof other terms have been used to describe cognitivedysfunction in older individuals. Table 1 describes theseterms and provides an acronym for each. As well asbeing an individual classification system, the term mildcognitive impairment is used increasingly to describe

    cognitive dysfunction associated with ageing. Used inthis context, the term mild cognitive impairment impliesthat the different classification systems may be uniformand comparable, however, as discussed below this is notthe case. Because there are so many terms used for thisphenomenon (see Table 2), mild cognitive impairment will be used in this review to describe the concept of cog-nitive impairment associated with ageing that is notclearly dementia. The acronyms listed in Table 2 will beused when referring to individual classification systems.

    In order to determine whether mild cognitive impair-ment represents the earliest stages of AD, recent studies

    have followed individuals classified as impaired accord-ing to one of the many available criteria over time(Table 2). Other recent studies have sought to determinewhether impaired older individuals show increased ratesof other risk factors for AD, including the apolipoproteinE (ApoE) epsilon 4 allele, hippocampal volume reduc-tion, and self-reported memory loss (Table 2). Bothtypes of investigation hypothesize that cognitivelyimpaired older individuals are at greater risk of devel-oping AD than non-impaired individuals. Despite manysuch studies being conducted recently, there is still dis-agreement about the clinical significance and outcomeof mild cognitive impairments in older people. In fact,there is still debate about the population prevalence of such impairment among older individuals [5]. Potentialreasons for these differences include inconsistent inclu-sion and exclusion criteria (Table 3), and variation in

    study design (e.g. sample size, baseline/follow-up inter-val), both of which may have considerable effects onstudy outcome. This review aims to compare and con-trast the inclusion and exclusion criteria of the publishedsystems for classifying mild cognitive impairment, andto determine the effects that changes to these criteriamay have on study outcome. The effect that differencesin experimental design may have on conclusions drawnfrom recent studies will also be considered. Based onthis analysis of the literature, optimal criteria for theaccurate identification of mild cognitive impairmentsare proposed.

    Table 1. Diagnostic and descriptive terminology for mild cognitive impairment in older people

    Acronym Title ReferenceAACD Ageing Associated Cognitive Decline Levy [34]AAMI Age-Associated Memory Impairment Crook et al . [35]ACMD Age Consistent Memory Decline Crook [24]ACMI Age Consistent Memory Impairment Blackford and La Rue [36]ARCD Age-Related Cognitive Decline DSM-IV [11]ARMD Age-Related Memory Decline Blesa et al . [37]BSF Benign Senescent Forgetfulness Kral [38]IMD Isolated Memory Decline Small et al . [12]IMI Isolated Memory Impairment Berent et al . [39]IML Isolated Memory Loss Bowen et al . [40]LCD Limited Cognitive Disturbance Gurland et al . [41]LLF Late Life Forgetfulness Blackford and La Rue [36]MCD Mild Cognitive Disorder Reisberg et al . [25]MCI Mild Cognitive Impairment Petersen et al . [2]MD Minimal Dementia Roth et al . [42]MND Mild Neurocognitive Disorder DSM-IV [11]QD Questionable Dementia Morris et al . [8]

    DSM-IV = Diagnostic and Statistical Manual of Mental Disorders Version 4, published by the American Psychiatric Association(1994).

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    A. COLLIE, P. MARUFF 135

    Inclusion and exclusion criteria

    Memory impairment

    All published classification systems propose as aninclusion criterion evidence of a memory deficit (Table 3).This arises from repeated findings that memory is thefirst cognitive domain affected by the AD process [2,3,6],and is also affected by the normal ageing process [7].However, the classification systems differ as to whetherthe memory impairment needs to be identified objec-tively. For example, the Age-Associated Memory Impair-ment (AAMI) and Mild Cognitive Impairment (MCI)criteria require that memory test performance be abnor-mal relative to a control group, whereas the Age-RelatedCognitive Decline (ARCD) criterion requires only a sub-

    jective report of problems recalling names and events. Of those classification systems that require objective evi-dence of a memory deficit, there are differences betweenthe composition of the group against which memory testperformance is compared. For example, the comparisongroup specified by the AAMI criterion is normal youngadults, whereas the MCI criterion requires an age-appropriate control group. Healthy young people gener-ally have superior memory test performance than healthy

    older people [7], and it is therefore likely that a greater

    proportion of older individuals will be classified asimpaired when the AAMI criterion is employed. Thecomposition of groups of impaired subjects classifiedaccording to AAMI and MCI criteria are also likely to bedifferent, and their relationships to outcome measures(e.g. prevalence, progression to AD) not comparable [4].

    Other cognitive impairment

    Some classification systems propose that memoryimpairment be accompanied by deficits in other cog-nitive domains, although this is not required universally(Table 3). For example, an individual can be classified ashaving Questionable Dementia (QD) when mild impair-ments are evident in a number of cognitive domains. Incontrast, the criteria for AAMI specifies that cognitiveprocesses other than memory remain unaffected. Deficitsin cognitive domains other than memory occur predom-inantly in more advanced stages of AD [8] or in otherneurodegenerative diseases (e.g. vascular dementia [9]),whereas the earliest stages of AD are characterized by anisolated memory impairment [3,10]. Therefore, classifi-cation systems which require impairment in multiplecognitive domains are likely to identify individuals in

    Table 2. Results from selected studies of older people classified as impaired according to different systems

    Study System of Outcome ResultClassification measure

    Smith et al . [5] AAMI Prevalence 796% depending on memory test usedBarker and Jones [22] AAMI Prevalence 1558% depending upon criteriaBarker et al . [43] AAMI Prevalence 5.815.8% depending on individual criteriaSoininen et al . [44] AAMI Brain volume Normal hippocampal volume; hippocampal asymmetryForstl et al . [29] AAMI Brain volume hippocampal volumeLaakso et al . [45] AAMI Brain volume Normal amygdala volumeKrasuski et al . [46] MCI Brain volume entorhinal, hippocampal, amygdale volumeJack et al . [47] MCI Brain volume hippicampal volumeTierney et al . [48] N/S Clinical outcome 24% develop AD 2 years after baselineBowen et al . [40] IML Clinical outcome 48% develop AD 31 months after baselineBerent et al . [39] IMI Clinical outcome 50% develop AD 3 years after baseline; 15% pseudodementiaPetersen et al . [2] MCI Clinical outcome 48% develop AD 2 years after baselineForstl et al . [29] AAMI ApoE genotype 58% carry e4 allele;Blesa et al . [37] ARMD ApoE genotype 56% carry e4 allele; 37% e3/3 homozygous; 4% carry e2 alleleBartres-Faz et al . [49] AAMI ApoE genotype 18% carry e4 allele; 64% e3/3 homozygous; 18% carry e2 alleleHanninen et al . [50] AAMI Cognitive function executive function performanceFowler et al . [28] QD Cognitive function 43% display episodic memory function over 12 month periodPetersen et al . [2] MCI Cognitive function episodic memory performance

    AAMI = Age-Associated Memory Impairment; MCI = Mild Cognitive Impairment; ARCD = Age-Related Cognitive Decline;IML = Isolated Memory Loss; IMI = Isolated Memory Impairment; QD = Questionable Dementia; = decreased; AD = Alzheimersdisease; ApoE = Apolipoprotein; N/S = system of classification system not specified. Results from studies of older people classifiedas having cognitive impairment can vary substantially according to the criteria used to classify impairment. This is true for a numberof different outcome variables, including estimated prevalence of impairment, brain volume measured with Magnetic ResonanceImaging, apolipoprotein E genotype, clinical outcome (the number of people subsequently meeting criteria for AD), andperformance on tests of cognitive function.

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    whom the AD process is already advanced. Despite this,it is important to obtain an overall picture of the individ-uals cognitive function prior to classification accordingto any system.

    Cognitive decline

    An issue yet to be addressed adequately is whetherpeople with mild cognitive impairment progress to developclinically identifiable dementia, or remain impaired with-out displaying evidence of deteriorating cognitive func-tion [10]. Diagnostic criteria for probable AD requiresobjective evidence of cognitive decline [11], however,many classification systems for mild cognitive impair-ment fail to specify whether decline should be evident(Table 3). These varied criteria reflect the different theo-retical basis of the individual classification systems.While some emphasize that mild cognitive impairmentsrepresent early AD, others propose that they are benignand unrelated to any disease process. This means that thesame mildly impaired individual could be rated as either

    normal or dementing depending on which classificationsystem is employed.

    The results of a recent functional neuroimaging studymay shed some light on this issue. Small and colleagues[12] used functional Magnetic Resonance Imaging(fMRI) to reveal two separate patterns of hippocampaldysfunction during facial encoding among 12 peopleclassified as having Isolated Memory Decline (IMD).The first pattern was observed in four IMD subjects,involved all hippocampal regions (entorhinal cortex, hip-pocampus proper and subiculum), and closely resembledthat observed in four patients with clinically recogniz-able AD. The second pattern of dysfunction was observedin eight IMD subjects and was restricted to the subicu-lum. Recent postmortem findings suggest that selectivesubicular damage may occur as a result of normal ageing[13,14]. These results suggest the existence of two sub-groups within the IMD group; one in the early or pre-clinical stages of AD, and another with memory declineassociated with normal ageing. An ideal system of clas-sifying mild cognitive impairment must therefore be able

    CLASSIFYING MILD COGNITIVE IMPAIRMENT136

    Table 3. Components of systems of classifying cognitive impairment in older people

    Other Subjective Associated Associated ImpairedSystem of Memory cognitive Cognitive memory Recommended Neurological mood dailyClassification Impairment impairment decline loss cognitive tests disturbance disturbance livingAge Associated Yes No Yes Yes Yes No No N/S

    Memory Objective SubjectiveImpairment

    Age Related Yes N/S N/S N/S No N/S N/S N/SCognitive SubjectiveDecline

    Benign Senescent Yes No No No No N/S N/S N/SForgetfulness Subjective

    Questionable Yes* Yes* Yes N/S No N/S N/S Yes*Dementia Objective Objective Objective(CDR 0.5)

    Mild Neurocognitive Yes Yes Yes No No Yes N/S Yes

    Disorder Objective Objective ObjectiveMild Cognitive Yes N/S N/S Yes Yes N/S Yes Yes

    Decline (GDS 3) Objective

    Mild Cognitive Yes No N/S No No No No NoImpairment Objective

    Limited Cognitive Yes No Yes Yes No N/S N/S NoDisturbance Objective Subjective

    Minimal Dementia Yes Yes No No Yes N/S N/S YesObjective Objective

    Note: N/S = Not specified; Yes = required to meet criteria; No = not required to meet criteria; Objective = objectively identified;Subjective = subjectively identified. *A Clinical Dementia Rating (CDR) of 0.5 may be reached in a number of ways, and memoryimpairment may not necessarily be accompanied by deficits in other cognitive domains for CDR 0.5 to be obtained. Similarly, aCDR of 0.5 may be reached in the absence of memory impairment, provided that impairment is observed in a number of other

    domains of function.

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    For example, in many studies, the proportion of individ-uals meeting criteria for cognitive impairment is deter-mined from within a small sample (often N < 100). Theincreased variability in test scores associated with smallsample sizes means that the degree to which that esti-mate is an accurate representation of the expression of cognitive impairment in the population is questionable.Small sample sizes may also operate to increase the vari-ability in the reported rates of progression to AD in thesestudies. The specificity of inclusion and exclusion crite-ria may also affect reported outcomes. For example, esti-mates of prevalence for the more strict and explicitclassification systems are generally found to be lowerthan for the less strict and poorly defined systems [21].A recent study by Barker and Jones [22] found that18.5% of people aged between 50 and 94 years met thecriterion for AAMI described by Crook et al . [23]. A

    modified AAMI criterion has also been described, inwhich the memory test cut-scores below which perfor-mance is said to be impaired were relaxed [24]. Whenthis modified criterion was applied to the same cohort,estimated prevalence for people aged between 50 and94 years was recorded at 25.5%, an increase of 40% onthe previous estimate. The rigor of the exclusion andinclusion criteria adopted may also affect the observedrate of progression to AD among these studies, whichhave range from five per cent [25] to 69% [26]. Investi-gations which classify subjects as impaired according tomore strict and well-defined criteria observe higher rates

    of conversion to AD than investigations which utilize lessstrict and poorly defined classification systems [21,27].The amount of time between the classification of mild

    cognitive impairment and the follow-up assessment atwhich clinical outcome is determined may also affectthese estimates. Some studies report outcome five yearsafter initial classification [2], while others have left aslittle as 2 years between classification and follow-up[28,29]. There is evidence to suggest that the biochemi-cal and neuropsychological changes that precede AD canbe detected up to 20 years before the disease manifestsclinically [3032]. An accurate determination of the rateof conversion to AD would therefore require longerperiods of observation than have been reported recently.

    Summary and conclusions

    While all available classification systems for mild cog-nitive impairment require that the individual display evi-dence of a memory deficit, other inclusion and exclusioncriteria are much less uniform (Table 3). These incon-sistencies have led to discrepant reports regarding theprevalence, clinical outcome and genetic correlates of mild cognitive impairment (Table 2). The ultimate aim

    of identifying older people with cognitive impairment isto allow intervention into the preclinical stages of theneurodegenerative process. However, before the utilityof any such intervention can be determined, preciseestimates of the outcome of such impairment need tobe obtained. The acquisition of these estimates in turnrequires the development and implementation of an accu-rate classification system for mild cognitive impairment.

    Given the considerable differences between the inclu-sion and exclusion criteria of published classificationsystems, there is surprising consensus regarding the cog-nitive, genetic and cortical correlates of mild cognitiveimpairment. Episodic memory impairment, hippocampalatrophy, and the ApoE e4 allele are all consistentlyshown to be associated with cognitive impairment inolder people (Table 2). Although there is substantial vari-ability, the rate of expression of these outcome measures

    in older people with mild cognitive impairment is broadlysimilar to that observed in patients with clinically diag-nosed AD. Other consistent results become evident uponanalysis of the literature. For example, criteria that requirethe individual to display moderate deficits report a higherrate of progression to AD, and a lower estimated rate of prevalence, than classification systems that require onlymild impairment [21]. A large proportion of older indi-viduals with mild cognitive impairment do not progressto develop clinically recognizable AD, regardless of the severity of their deficit [3]. There are two potentialreasons for this common finding. First, the period of time

    between classification of impairment and determinationof clinical outcome in many studies may not have beensufficient for all incipient cases of AD to be expressedclinically. Second, the systems for classifying cognitiveimpairment may not be specific to the preclinical stagesof AD.

    Conclusions regarding the optimal criteria for identify-ing older individuals at high risk for AD can be drawnfrom analysis of studies that have employed the existingsystems of classification. First, it seems evident that atleast a moderate episodic memory impairment shouldbe requisite, and that this memory impairment neednot occur concurrently with deficits in other cognitivedomains. Second, the determination of impairment shouldbe made against the performance of an age-appropriategroup of normal controls. Third, objective evidence of cognitive decline from a baseline (or previous) levelof performance should be obtained prior to classificationof impairment. Fourth, the neuropsychological mea-sures on which such comparisons are made should havesufficient sensitivity to allow the identification of subtlechanges in cognitive function. Fifth, individuals exhibit-ing depressive and anxiety symptomatology should beassessed more thoroughly and excluded if the observed

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    impairment is thought to be a consequence of that symp-tomatology. This final criterion should be exercised withcaution, given that AD and depression often co-occurearly in the course of AD [33].

    Analysis of the literature also suggests that a numberof methodological and conceptual issues must beaddressed before accurate estimates of the prevalenceand clinical outcome of mild cognitive impairments maybe gained. Methodological issues include that the periodof time between identification of cognitive impairmentand determination of clinical outcome must appropri-ately reflect the expected length of time between theonset of the AD process and the clinical diagnosis of thedisease. Also, sample sizes should be large enough thatsuch findings may be generalized to the population.Conceptually, we propose that before the value of self-reported cognitive impairment in predicting clinical out-

    come is determined, subjective ratings should not beconsidered as inclusion criteria for mild cognitiveimpairment.

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