Reviews

Mild cognitive impairment: prevalence, prognosis, aetiology, and treatment

Charles DeCarli
Mild cognitive impairment (MCI) is a recently described syndrome that is currently thought of as a transition phase between healthy cognitive ageing and dementia. Although this notion seems to be reasonable, the general nature of the term MCIincluding its many definitionsmakes accurate accounting of the prevalence, prognosis, and potential benefit from treatment somewhat difficult. The differences in cognitive profile and clinical progression among individuals with MCI are generally recognised. However, recent evidence also suggests that the aetiological heterogeneity among individuals with MCI could be greater than previously reported. For example, cerebrovascular disease seems to be underestimated as a potential cause of MCI. In this review, I attempt to recognise workable definitions of MCI to discuss the prevalence, pathophysiology, prognosis, and possibilities for treatment of this disorder. Lancet Neurology 2003; 2: 1521

Dementia MCI

Normal

Time
Figure 1. Transition from healthy ageing to dementia. Clinical and pathological time course of AD dementia emphasising the long presymptomatic phase of the illness when pathology (red line) is accruing in the absence of clinical symptoms (green line).

Improvements in health care over the past 50 years have extended average life expectancy, which has resulted in a substantial increase in the numbers of individuals over 65 years of age.1 Many elderly people complain of impaired memory2 and do less well than the young in various cognitive tasks, particularly those that assess memory;3 these findings suggest that memory impairments are a common consequence of the ageing process. Careful cross-sectional examination of cognitive function among elderly people, however, reveals a range of cognitive impairment including deficits in various domains in the absence of clinically defined dementia.4,5 Gradual decline in cognitive ability is characteristic in longitudinal studies of elderly people. Although this is consistent with the hypothesis that normal ageing is accompanied by mental decline, differences between individual trajectories of change suggest that much of the age-related cognitive decline reflects the inclusion of individuals with incipient dementia.6 The notion that incipient dementia is common among elderly individuals is further supported by neuropathological studies that reveal evidence of Alzheimers disease (AD) years before clinical symptoms present.7,8 Extensive AD pathology can rarely be found in individuals with no detectable symptoms.7,9 AD pathology is, however, more common in individuals with memory impairment who are not demented.8 Clinical studies of elderly individuals with memory impairment also reveal a rapid rate of conversion to AD, reaching as high as 15% per year. This evidence suggests that significant memory impairment, short of dementia and often denoted as mild cognitive impairment (MCI), in elderly people may

be a transition phase between the normal ageing process and AD (figure 1).10,11 Although many individuals with MCI complain of memory loss, impairments in other cognitive domains also occur,12 and not all MCI patients go on to develop AD,10 particularly when MCI is studied in the general population.13 Recognition that MCI may represent a transition state between normal cognitive decline due to ageing and dementia offers possibilities for early diagnosis and potential treatment with the aim of delaying the onset or preventing dementia.14 Current definitions of MCI are, however, quite diverse,15,16 with variable prognosis10,13 and pathology5,17 leading to some confusion in the literature not directly addressed in recent reviews.11

Definitions of MCI
Several excellent reviews on the definition of MCI have recently been published15,16 and the interested reader is referred to these for a more detailed overview of the subject. The idea of ageing-effects versus disease is not new; in 1962, Kral18 introduced the notion of benign versus malignant senescent forgetfulness to recognise differences between
CD is at the Alzheimers Disease Center, Department of Neurology, University of California at Davis, Sacramento, California, USA. Correspondence: Dr Charles DeCarli, Department of Neurology, University of California at Davis, 4860 Y Street, Suite 3700, Sacramento, CA 95817, USA. Tel +1 916 734 6280; fax +1 916 734 6526; email cdecarli@ucdavis.edu

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

15

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Pathology

Review
Clinical definitions of cognitive-impairment syndromes
Term Initial description Benign senescent forgetfulness Kral18 Age-associated memory impairment Crook and co-workers19 Late-life forgetfulness Aging-associated cognitive decline Age-related cognitive decline Mild cognitive decline Mild neurocognitive decline Cognitive impairmentno dementia MCI Blackford, LaRue20 Levy21 DSM IV22 ICD-1023 DSM IV22 Graham and co-workers5 Petersen and co-workers10

Mild cognitive impairment

Diagnostic criteria Memory complaints Subjective memory impairment with objective memory impairment compared with that of a young adult Age-associated memory impairment plus age-adjusted deficits in four or more specific cognitive tests Age-adjusted impairment on any cognitive task Objective decline in cognitive function not otherwise specified Impairments in cognitive tests of learning, memory, or concentration secondary to defined illness Impairments in memory, learning, perceptual-motor, linguistic, or executive functioning Impairments in memory, learning, perceptual-motor, linguistic or executive functioning in the absence of clinically defined dementia Subjective complaint of memory impairment with objective memory impairment adjusted for age and education in the absence of dementia

stable memory complaints of elderly people and those that potentially indicate early disease.18 Recognition that dementia can have a long prodromal phase has led to active investigation of individuals with cognitive impairment without dementia. Work in this area has created many definitions (table).5,10,1823 Review of these definitions reveals a general division into those that focus predominantly on memory impairment and those that include various degrees of impairment within all cognitive domains. Since the chosen definition of cognitive impairment can have a substantial effect on the apparent prevalence, aetiology, and prognosis of the disorder, this section reviews these two general categories in detail.
Memory dependent definitions

associated illnesses,5 which makes direct comparisons with other definitions, such as age-associated memory impairment and MCI, more difficult. Isolated memory impairment and cerebrovascular-related non-memory cognitive impairment, however, are two identifiable subtypes within the general category of CIND.31 The high prevalence of cerebrovascular disease among elderly people and the various ways in which this disorder can affect memory and cognition32,33 support the use of these more broadly defined terms of cognitive impairment in investigations of predictors of dementia among elderly people, particularly those assessesing the entire population.5
The importance of not demented

Crook and co-workers19 were the first to derive specific criteria and measurements for the definition of abnormal memory function among elderly people. These researchers used the term age-associated memory impairment for the decline in ability in older individuals with memory function one standard deviation or more below that in young people. This definition identifies a high prevalence of memory impairment among elderly people13,24 that does not reflect the presence of an underlying disorder.25 More recently, however, researchers have focused on definitions for memory impairment that is most likely to progress to dementia.10,11,2629 Petersen and colleagues10 have used the term MCI to define individuals with symptomatic and progressive memory impairment that shares many features with early AD.8 This definition has attracted much attention as a potential tool for the identification of individuals likely to have incipient AD8,29 and may have implications for clinical trials aimed at secondary prevention of the disorder.
More general definitions

Cognitive impairments of elderly people are not limited to memory, and a host of definitionsincluding ageingassociated cognitive decline,21 mild cognitive decline,30 and cognitive impairmentno dementia (CIND)5are based on more general impairments of cognition, including impairments in language, visuospatial awareness, and attention. As expected, these definitions are more broadly inclusive and encompass individuals with a host of

Crucial to all these definitions, however, is the notion that the individual does not have a dementia syndrome broadly defined by the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition.34 Unfortunately, various classification schemes also have been used to define the presence of dementia.13,35,36 Although many studies use functional scales such as the clinical dementia rating scale,37,38 others use clinical examination in conjunction with neuropsychological assessment35 or cut-off scores on the mini-mental-state examination.3942 Since the definition of dementia serves as the lower bound to the diagnostic criteria of cognitive impairment without dementia, differences in definitions of dementia may also affect the group of people described as being cognitively impaired, but not demented. Different diagnostic schemes may be sensitive to different diseases: on the one hand, the clinical dementia rating was designed primarily to track the progression of AD37,38 and is quite sensitive to even the earliest clinical changes;8 on the other hand, neuropsychological measures or mini-mental-state examination scores are more likely to be inclusive of a wider range of disease entities including cerebrovascular disease.5
Associated deficits within a defined set of criteria

This section focuses on the differences between two general classification schemes of cognitive impairment among elderly people. The limitations of this dichotomous approach must be recognised; for example, assessment of patients with MCI10 commonly reveals deficits in other

16

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Mild cognitive impairment

Review
population studied and the type of questions asked, but other factors such as sex and educational achievement appear important as well. For example, women and individuals with low educational achievement have a greater frequency of memory complaints.25 The high prevalence of complaints about memory problems from elderly people may reflect high rates of depressive symptoms,44 but even complaints of memory impairment may be a marker for future dementia. Estimates of the prevalence of cognitive impairment without dementia, however, are generally much lower and vary according to the definition used (figure 2). For example, age-associated memory impairment and CIND had the highest prevalence with average estimates of nearly 20%13, 24 and 168%5 respectively, whereas the prevalence of MCI was substantially lower.10,13 Strict statistical definitions of MCI based on age-specific population memory tests tend to give higher estimates of prevalence17 than do definitions based on screening examinations13 or associated memory complaints verified by carers at interview.10 The Petersen criterion10 is the most restrictive and generally gives a prevalence of about 3% of the population studied. This criterion also has the highest frequency of conversion to dementia11 and may be more specific to those individuals at the earliest stages of AD.8 Despite the influence these variable definitions may have on the exact prevalence of MCI among elderly people, all the definitions have two important features. First, the age-specific prevalence of MCI has universally been found to be greater than that of dementia (figure 3), and MCI is about four times more common than dementia when based on community assessment of non-institutionalised individuals.5 Second, despite the wide range of definitions used, older individuals with any cognitive impairment are at significantly increased risk of future conversion to dementia.24 However, the frequency of dementia in a group of individuals with cognitive impairment is the result of both the definition of the disorder and the underlying pathophysiology. Current evidence suggests that even within a carefully defined syndrome such as amnestic MCI, there may be both clinical and pathological heterogeneity.5,11,17,45
100 90 80 70 60 50 40 30 20 10 0 6574 7584 Age (years)
Normal CIND Mild dementia Moderate demenitia Severe dementia

20 18 16 14 12 10 8 6 4 2 0 AAMI MCI CIND MCIa

Figure 2. Influence of various definitions of cognitive impairment on prevalence estimates. AAMI=age-associated memory impairment, MCIa=amnestic MCI.

associated cognitive domains, including verbal memory, object naming, verbal abstraction, and spatial localisation (Jagust WJ, personal communication). Impairments among other cognitive domains in the setting of MCI can blur the distinction between memory and non-memory cognitive impairments. Importantly, however, what predicts the likelihood of progression to dementia in many cases is the extent of these associated deficits,12 which reinforces the notion that multiple cognitive impairments are the inevitable consequence of evolving dementia.
The implications of a chosen definition

That the chosen definition of cognitive impairment will have an important effect on estimates of prevalence is clear. This effect could also extend to prognosis although these definitions describe syndromes and make no claim to causes. Memory predominant impairments (eg, ageassociated memory impairment and MCI) may well be part of the range of AD, and reasonable clinical guidelines have been established to detect individuals with such impairments;29 however, cerebrovascular disease is also strongly associated with MCI.17 Conversely, individuals with CIND are much more likely to have non-memorypredominant impairments resulting from cerebrovascular disease 5 and are less likely to have AD pathology.43 However, about 30% of patients with CIND do have isolated memory impairments that are clinically5 and pathologically43 consistent with early AD. Inadequate distinctions between syndrome and aetiology obviously serve to further confuse an already confusing subject. Throughout the remainder of this review, CIND is used to describe the more broad classification that includes isolated non-memory impairments, and MCI is used for syndromes in which only memory is affected; at various points I attempt to clarify presumed aetiologies by use of the descriptors amnestic (to indicate AD pathology) and vascular (to indicate cerebrovascular-disease pathology).

Prevalence (%)

Prevalence (%)

>84

Estimates of prevalence
Formal studies of the prevalence of memory complaints within the community vary greatly, from 22% to 56%. Much of the variation relates to the average age of the
Figure 3. Graphic representation of age-specific prevalence of normal cognition, CIND, and dementia from the Canadian Health and Aging Study.5

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

17

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review
Memory Vascular Depression Medication Psychiatric Delirium Mental retardation Unclassified

Mild cognitive impairment

Figure 4. Distribution of aetiological diagnoses for CIND among all participants in the Canadian Health and Aging Study.5 Memory impairment was the leading diagnosis followed by cerebrovascular disease. However, for over a third of the individuals, no aetiology was identified. Modified from the Canadian Health and Aging Study.5

Pathophysiology of MCI
Many diseases can lead to cognitive impairment in the absence of dementia, particularly when cognitive impairment is defined as CIND (figure 4).5 Even within more restrictive definitions such as amnestic MCI, however, there appears to be sufficient heterogeneity to cause potential confusion with regard to prognosis and treatment.17 A review of the available evidence supporting the presence of both AD and cerebrovascular disease among individuals classified as having MCI is, therefore, necessary.
MCI and AD

Study.43 Unlike Morris and Price,46 Riley and colleagues chose to define cognitive impairment in the domains of memory and non-memory impairments by defining nondemented individuals with cognitive impairment in a similar way to the CIND terminology used for this review. Three important conclusions can be drawn from this study. First, the relation between neurofibrillary-tangle pathology and clinical symptoms was strongest in the memoryimpaired group, with the proportion of individuals with non-memory cognitive impairments declining steadily as Braak and Braak staging increased. Second, no cognitively intact individual had a Braak and Braak score above 2, although some demented individuals had this pathological staging. Finally, cerebrovascular disease had a substantial influence on cognition within this group, even though individuals with macroscopic evidence of cerebral infarction were excluded from the analysis. These results further confirm the relation between AD pathology, defined primarily by the extent of neurofibrillary tangles outside the isocortex, and cognitive impairments that include impairments of memory without dementia (amnestic MCI).
MCI and cerebrovascular disease

The use of the term MCI for a transition state between normal ageing and disease has provoked intensive investigation of the pathological processes that could lead to this state of cognitive impairment. Even before MCI was strictly defined, however, there was much interest in the prodromal phases of AD,35 including pathological studies of normal elderly individuals.9 Studies of ageing populations suggest that age-related increases in the density of neurofibrillary tangles in the entorhinal cortex and hippocampus are a feature of normal ageing.7,46,47 Specific studies of neuropathological features across the range of cognitive impairment from normal ageing to AD, however, reveal that senile plaque density and neuron loss are the most important features that distinguish healthy ageing from dementia. In the study by Morris and Price,46 individuals with clinical dementia rating scores of 05 (similar to MCI, but called very mild AD by the investigators) had signs of pathology of a severity between those of normal elderly individuals and patients in the early stages of AD. These findings suggest that individuals with clinical features of the amnestic form of MCI10 have early AD pathology.8 These data, however, come from carefully selected groups of patients, in whom other medical illnesses, such as cerebrovascular disease, have been kept to a minimum. Further support for the relation between memory impairments and AD pathology, however, comes from the post-mortem analysis of neuropathology from the Nuns

Cerebrovascular disease is a common symptom of the ageing process,48 and several studies suggest that cerebrovascular risk factors are strongly associated with prevalent dementia including AD.4955 Given the high prevalence of cerebrovascular disease among elderly people and the evidence suggesting that it may contribute strongly to dementia, several studies have begun to explore the possible effects of cerebrovascular disease on cognitive impairment among elderly people.31,17,56 In one study,17 nondemented individuals from a community population were assessed. Average memory capacity was normal, and individuals with recall delayed 15 standard deviations below average were compared with the remaining individuals on various demographic and brain imaging features including vascular risk factors. Individuals identified as having MCI showed significantly increased frequencies of vascular risk factors and evidence of vascular brain injury;17 these results suggest that cerebrovascular disease is important to memory impairment. One investigation of a Hispanic community population with a range of cognitive ability had similar findings.49 The exact cause of memory impairment in the setting of cerebrovascular-related brain injury is uncertain, but current hypotheses suggest injury to frontal subcortical circuits involved in working memory.17,32 As these studies suggest, cerebrovascular disease is easily recognised through the presence of associated conditions and the use of brain imaging; however, pathological support for these clinical findings has been extremely limited. For example, Fein and co-workers57 had only five patients with ischaemic vascular disease, most of whom were demented. In this regard, the data from Riley and colleagues43 discussed in the previous section are helpfuleven in the absence of macroscopic infarctions, individuals with evidence of severe atherosclerotic disease in the circle of Willis were at substantially greater risk (relative risk >3) of memory-

18

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Mild cognitive impairment

Review
quantitative MRI studies suggests that hippocampal atrophy is present before dementia onset68,69,7173 and progresses with conversion to clinically apparent disease.74 In a large prospective study of amnestic MCI patients, Jack and coworkers69 found that the proportion of individuals converting to dementia within 5 years was four times the normal when hippocampal size was 25 standard deviations below norms defined for age and sex. These results have been confirmed in a separate double-blind, placebo-controlled treatment study of patients with amnestic MCI,75 and another investigation had similar findings, although memory scores were also significant predictors.68 A final study with qualitative estimates of hippocampal size also had similar results.76 This very brief review of clinical and imaging predictors of conversion from amnestic MCI to dementia suggests that the more closely individuals cognitive ability, brain imaging, and genetic susceptibility are to AD, the more likely they are to progress rapidly to dementia, particularly if the cognitive complaints are accompanied by carers reports of impaired daily function.77,78 These observations support the notion that this very specific form of MCI represents early AD.8 Predictors of conversion from vascular MCI to dementia have been less well studied. In a small study, Wolf and coworkers79 found increased rates of progression to dementia for those individuals with extensive abnormalities of cerebral white matter. More careful longitudinal study of the effect of vascular disease across the cognitive domains reveals that measures of brain and hippocampal atrophy are more strongly related to progressive cognitive decline than lacunar infarcts or abnormalities of cerebral white matter.80 These data suggest that evidence of features associated with AD in the vascular-MCI group may be a stronger predictor of conversion to dementia than associated measures of vascular disease. If confirmed, this finding would suggest different rates of progression for the two diseases81 or possible interactive effects where one disease works synergistically with the other, thus leading to dementia.49,82

related MCI. Because white-matter-hyperintensity volumes are associated with extracranial carotid-artery disease,5860 these findings strengthen the presumed pathophysiological relation between clinical and imaging evidence of cerebrovascular disease and the aetiology of the associated cognitive impairment. Although it is assumed that several diseases cause CIND in the general population (figure 4), pathological heterogeneity among cognitively impaired elderly people is even apparent within carefully identified subgroups of individuals (eg, those with amnestic MCI). These findings emphasise the importance of further study into the pathology of cognitive impairment. The effect that the different aetiologies could have on prognosis and treatment of these disorders highlights why this work is so important.

Progression of CIND
Longitudinal observation studies

Although individuals who complain of memory impairment may have variable rates of progression to dementia,25 any evidence of documented memory impairment, including age-associated memory impairment, increases the likelihood of future dementia.13,24 This link may, however, reflect inclusion of subgroups of people who are both cognitively and genetically more similar to individuals with amnestic MCI.61 Most studies have directly examined the progression of amnestic MCI to dementia within the confines of select clinical populations.10,12,6264 These studies generally show a yearly incidence of dementia of 1015%. Conversely, community-based studies tend to show lower rates of conversion (closer to 510% per year).13,40 Moreover, a substantial proportion of individuals in community studies actually improve their cognitive performance during the observation period.13,40 The differences in rates of conversion to dementia for individuals in the clinical populations are likely to reflect selection bias, because study groups are more likely to include individuals with early AD.8 Much less work has been done on longitudinal studies of non-demented individuals thought to have cerebrovasculardisease-related cognitive impairment.31,65 Preliminary evidence, however, suggests that of those individuals given the diagnosis of vascular CIND in the Canadian Study of Health and Aging,56 50% progressed to dementia within 5 years; this proportion is similar to that for individuals with amnestic MCI. Not all non-demented individuals with cognitive impairment progress to dementia. As noted above, some show cognitive improvement, but others die before dementia progression occurs.40,66 Both variable progression and increased mortality are further evidence for the heterogeneity of the MCI and CIND syndromes.41,42
Predictors of progression

Treatment
Recognition of MCI or CIND as transition phases between healthy ageing and dementia serves as an important tool for investigation of treatments aimed at secondary prevention of dementia.14 As emphasised earlier, however, treatment of the various forms of cognitive impairment among elderly people requires identification of the specific aetiology for the cognitive disorder to effect appropriate strategies. Current trials are focused on carefully selected populations at high risk of AD and cerebrovascular disease. Petersen and colleagues29 recognised the importance of early diagnosis and developed guidelines for the detection of MCI that emphasise the criteria that identify those individuals for whom progression to AD is highly likely. They stressed the need to identify and follow individuals with MCI, but they made no recommendations about treatment, because the clinical efficacy of treating MCI has yet to be fully tested. This is a topic of intense study given the possibility that individuals with mild clinical symptoms and possibly less severe pathology might benefit even more from currently available treatments for AD than those suffering

Several studies have examined clinical and imaging predictors that can improve the ability to detect individuals at the greatest risk of conversion to dementia within 13 years of diagnosis of amnestic MCI.10,12,36,6264,6770 Brain imaging may prove to be an important tool in this regard. Evidence from

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

19

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Review
Search strategy and selection criteria
Data for this review were identified by searches of PubMed and references from relevant articles published in English; additional articles were identified through searches of authors files. Search terms included mild cognitive impairment, memory impairment, and cognitive impairment, not demented.

Mild cognitive impairment

from a fully developed dementia. Moreover, drugs that have only modest effects on the amelioration of progression once dementia is established may prove to be more effective in lengthening the prodromal phase of MCI or preventing progression to dementia entirely. Therefore, large doubleblind, placebo-controlled, clinical trials are in pogress that include symptomatic treatments with cholinesterase inhibitors as well as those that have focused on secondary prevention with vitamin E, anti-inflammatory drugs, or other compounds with possible disease-modifying effects. Results of these studies are eagerly awaited. More complete information is available from the treatment of hypertension in elderly people.8385 In the SystEur trial,83 cognition was assessed mainly by the mini-mental state examination.39 Treatment with a calcium-channel blocking antihypertensive agent was associated with a reduction of nearly 50% in the frequency of dementia among about 2000 elderly individuals with isolated systolic hypertension.83 Given the high proportion of elderly people who have untreated hypertension,86 secondary prevention treatment trials such as Syst-Eur may have important implications for cognitive impairment among elderly people.

recognition that cognitive impairment syndromes may result from various causes that reflect both clinical and pathological heterogeneity as well as differences in prognosis and potential treatment. Definitions such as age-associated memory impairment, MCI, and CIND emphasise different clinical characteristics and potential pathologies that limit comparisons between studies that use these terms. Pathological and clinical heterogeneity exists, however, even within carefully defined categories such as amnestic MCI,17,45 and there is, therefore, a need for further study to define more accurately clinical syndromes specific to the transition states between normal ageing, AD, and other dementias. Despite these apparent limitations, recent definitions of amnestic MCI11 that emphasise specific clinical criteria to detect incipient AD8 have proven extremely useful in investigation of the prevalence and prognosis of this disorder as well as enabling the development of specific clinical trials aimed at secondary prevention of AD.14 Although vascular causes of MCI are less well studied, preliminary evidence suggests that vascular MCI may be common17,31 and treatable.8385 In an ageing population in which both AD and cerebrovascular disease are common and devastating illnesses, identification of transition phases between normal ageing and dementia is an important tool for the secondary prevention of these disorders.14,83 Current estimates suggest that many elderly people suffer from various cognitive impairments that will substantially increase their risk of developing dementia,5 hence the urgent need to identify and treat these disorders.
Conflict of interest

Conclusions
This review began by defining cognitive impairment syndromes among elderly people into two useful classificationsthose that emphasise memory impairment and probably represent incipient AD, and those that are more broadly inclusive and encompass definitions that include non-memory cognitive impairments. The importance of making such distinctions stems from the
References
1 Hebert LE, Beckett LA, Scherr PA, Evans DA. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050. Alzheimer Dis Assoc Disord 2001; 15: 16973. Cutler SJ, Grams AE. Correlates of self-reported everyday memory problems. J Gerontol 1988; 43: S8290. La Rue A. Aging and neuropsychological assessment. New York: Plenum Press, 1992. Robertson D, Rockwood K, Stolee P. The prevalence of cognitive impairment in an elderly Canadian population. Acta Psychiatr Scand 1989; 80: 30309. Graham JE, Rockwood K, Beattie BL, et al. Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 1997; 349: 179396. Wilson RS, Beckett LA, Bennett DA, Albert MS, Evans DA. Change in cognitive function in older persons from a community population: relation to age and Alzheimer disease. Arch Neurol 1999; 56: 127479. Price JL, Morris JC. Tangles and plaques in nondemented aging and preclinical Alzheimers disease. Ann Neurol 1999; 45: 35868. Morris JC, Storandt M, Miller JP, et al. Mild 9

The author has no conflict of interest.

Role of the funding source

The writing of this review was partly funded by NIH grants: P30AG10129, 1R01 AG16495-01, and 2R01 AG111101-06 from the National Institute on Aging; 5R01 NS17050 from the National Institute on Neurological Disorders and Stroke; 2RO1 HL51429-04 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, and by Contract DHS 9814970 of the California Department of Health Services Alzheimers Disease Program, Sacramento, CA, USA.
conceptual basis and current nosological status. Lancet 2000; 355: 22528. Collie A, Maruff P. The neuropsychology of preclinical Alzheimers disease and mild cognitive impairment. Neurosci Biobehav Rev 2000; 24: 36574. DeCarli C, Miller BL, Swan GE, Reed T, Wolf PA, Carmelli D. Cerebrovascular and brain morphologic correlates of mild cognitive impairment in the National Heart, Lung, and Blood Institute Twin Study. Arch Neurol 2001; 58: 64347. Kral VA. Senescent forgetfulness: benign and malignant. Can Med Assoc J 1962; 86: 25760. Crook T, Bartus RT, Ferris SH, et al. Age associated memory impairment: proposed diagnostic criteria and measures of clinical change: report of a National Institute of Mental Health Work Group. Dev Neuropsychol 1986; 2: 26176. Blackford RC, La Rue A. Criteria for diagnosing age associated memory impairment: proposed improvements in the field. Dev Neuropsychol 1989; 5: 295306. Levy R. Aging-associated cognitive decline. Working Party of the International Psychogeriatric Association in collaboration with the World Health Organization. Int Psychogeriatr 1994; 6: 6368.

2 3 4 5

10

11 12

13

14

7 8

15

cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001; 58: 397405. Morris JC. Is Alzheimers disease inevitable with age? Lessons from clinicopathologic studies of healthy aging and very mild Alzheimers disease. J Clin Invest 1999; 104: 117173. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 30308. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. Arch Neurol 2001; 58: 198592. Bozoki A, Giordani B, Heidebrink JL, Berent S, Foster NL. Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss. Arch Neurol 2001; 58: 41116. Ritchie K, Artero S, Touchon J. Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 2001; 56: 3742. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimers disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88: 133742. Ritchie K, Touchon J. Mild cognitive impairment:

16

17

18 19

20

21

20

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

For personal use. Only reproduce with permission from The Lancet Publishing Group.

Mild cognitive impairment

Review
Arch Gen Psychiatry 1990; 47: 22427. 45 Lautenschlager NT, Riemenschneider M, Drzezga A, Kurz AF. Primary degenerative mild cognitive impairment: study population, clinical, brain imaging and biochemical findings. Dement Geriatr Cogn Disord 2001; 12: 37986. 46 Morris JC, Price AL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimers disease. J Mol Neurosci 2001; 17: 10118. 47 Bouras C, Hof PR, Morrison JH. Neurofibrillary tangle densities in the hippocampal formation in a non-demented population define subgroups of patients with differential early pathologic changes. Neurosci Lett 1993; 153: 13135. 48 DAgostino RB, Belanger AJ, Kannel WB. Probability of stroke: a risk profile from the Framingham Study. Stroke 1991; 22: 31218. 49 Wu CC, Mungas D, Petkov CI, et al. Structural brain changes and cognitive impairment in a community sample: the SALSA Study. Neurology 2002; 59: 38391. 50 Slooter AJ, van Duijn CM, Bots ML, et al. Apolipoprotein E genotype, atherosclerosis, and cognitive decline: the Rotterdam Study. J Neural Transm Suppl 1998; 53: 1729. 51 Launer LJ, Ross PW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging 2000; 21: 4955. 52 Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet 1996; 347: 114145. 53 Kivipelto M, Helkala EL, Hanninen T, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 2001; 56: 168389. 54 Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors and Alzheimers disease in later life: longitudinal, population based study. BMJ 2001; 322: 144751. 55 Kivipelto M, Laakso MP, Tuomilhelto J, et al. Hypertension and hypercholesterolaemia as risk factors for Alzheimers disease: potential for pharmacological intervention. CNS Drugs 2002; 16: 43544. 56 Rockwood K, Howard K, MacKnight C, Darvesh S, et al. Spectrum of disease in vascular cognitive impairment. Neuroepidemiology 1999; 18: 24854. 57 Fein G, Di Sclafani V, Tanabe J, et al. Hippocampal and cortical atrophy predict dementia in subcortical ischemic vascular disease. Neurology 2000; 55: 162635. 58 de Leeuw FE, de Groot JC, Bots ML, et al. Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 2000; 247: 29196. 59 Manolio TA, Kronmal RA, Gurke GL, et al. Magnetic resonance abnormalities and cardiovascular disease in older adults: the Cardiovascular Health Study. Stroke 1994; 25: 31827. 60 Longstreth WT Jr, Manolio TA, Arnold A, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people: the Cardiovascular Health Study. Stroke 1996; 27: 127482. 61 Bartres-Faz D, Junque C, Lopez-Alomar A, et al. Neuropsychological and genetic differences between age-associated memory impairment and mild cognitive impairment entities. J Am Geriatr Soc 2001; 49: 98590. 62 Tierney MC. Cognitive tests that best discriminate between presymptomatic AD and those who remain nondemented. Neurology 2001; 57: 16364. 63 Tierney MC, Szalai JP, Dunn E, Geslani D, McDowell I. Prediction of probable Alzheimer disease in patients with symptoms suggestive of memory impairment: value of the Mini-Mental State Examination. Arch Fam Med 2000; 9: 52732. 64 Tierney MC, Szalai JP, Snow WG, et al. A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment. Neurology 1996; 46: 14954. 65 Wentzel C, Rockwood K, MacKnight C, et al. Progression of impairment in patients with vascular cognitive impairment without dementia. Neurology 2001; 57: 71416. 66 Bennett DA, Wilson RS, Schneider JA, et al. Natural history of mild cognitive impairment in older persons. Neurology 2002; 59: 198205. 67 Marquis S, Moore MM, Howieson DB, et al. Independent predictors of cognitive decline in healthy elderly persons. Arch Neurol 2002; 59: 60106. 68 Visser PJ, Sheltens P, Verhey FER, et al. Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment. J Neurol 1999; 246: 47785. 69 Jack CR Jr, Petersen RC, Xu YC, et al. Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology 1999; 52: 1397403. 70 Petersen RC, Waring SC, Smith GE, Tangalos EG, Thibodeau SN. Predictive value of APOE genotyping in incipient Alzheimers disease. Ann N Y Acad Sci 1996; 802: 5869. 71 Jack CR Jr, Petersen RC, Xu YC, et al. Medial temporal atrophy on MRI in normal aging and very mild Alzheimers disease. Neurology 1997; 49: 78694. 72 Kaye JA, Swihart T, Howieson D, et al. Volume loss of the hippocampus and temporal lobe in healthy elderly persons destined to develop dementia. Neurology 1997; 48: 1297304. 73 Fox NC, Warrington EK, Freeborough PA, et al. Presymptomatic hippocampal atrophy in Alzheimers disease: a longitudinal MRI study. Brain 1996; 119: 200107. 74 Fox NC, Warrington EK, Stevens JM, et al. Atrophy of the hippocampal formation in early familial Alzheimers disease: a longitudinal MRI study of atrisk members of a family with an amyloid precursor protein 717Val-Gly mutation. Ann N Y Acad Sci 1996; 777: 22632. 75 Grundman M, Sencakova D, Jack CR Jr, et al. Brain MRI hippocampal volume and prediction of clinical status in a mild cognitive impairment trial. J Mol Neurosci 2002; 19: 2327. 76 de Leon M, Golomb J, George AE, et al. The radiologic prediction of Alzheimer disease: the atrophic hippocampal formation. AJNR Am J Neuroradiol 1993; 14: 897906. 77 Tabert MH, Albert SM, Burokhova-Milov L, et al. Functional deficits in patients with mild cognitive impairment: prediction of AD. Neurology 2002; 58: 75864. 78 Albert SM, Tabert MH, Dienstag A, Pelton G, Devanand D. The impact of mild cognitive impairment on functional abilities in the elderly. Curr Psychiatry Rep 2002; 4: 6468. 79 Wolf H, Ecke GM, Bettin S, Dietrich J, Gertz HJ. Do white matter changes contribute to the subsequent development of dementia in patients with mild cognitive impairment? A longitudinal study. Int J Geriatr Psychiatry 2000; 15: 80312. 80 Mungas D, Jagust WJ, Reed BR, et al. MRI predictors of cognition in subcortical ischemic vascular disease and Alzheimers disease. Neurology 2001; 57: 222935. 81 Mungas D, Reed BR, Ellis WG, Jagust WJ. The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease. Arch Neurol 2001; 58: 124347. 82 Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease: the Nun Study. JAMA 1997; 277: 81317. 83 Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebocontrolled Systolic Hypertension in Europe (SystEur) trial. Lancet 1998; 352: 134751. 84 Hansson L. Antihypertensive treatment and the prevention of dementia: further insights from the Syst-Eur trial. J Hypertens 1999; 17: 30708. 85 Birkenhager WH, Forette F, Seux ML, Wang JG, Staessen JA. Blood pressure, cognitive functions, and prevention of dementias in older patients with hypertension. Arch Intern Med 2001; 161: 15256. 86 Barker WH, Mullooly JP, Linton KL. Trends in hypertension prevalence, treatment, and control: in a well-defined older population. Hypertension 1998; 31: 55259.

22 American Psychiatric Association. Diagnostic and statistical manual, 4th edn. Washington: American Psychiatric Association, 1994. 23 WHO. The ICD-10 classification of mental and behavioural disorders: diagnostic criteria for research. Geneva: WHO, 1993. 24 Goldman WP, Morris JC. Evidence that ageassociated memory impairment is not a normal variant of aging. Alzheimer Dis Assoc Disord 2001; 15: 7279. 25 Jonker C, Geerlings MI, Schmand B. Are memory complaints predictive for dementia? A review of clinical and population-based studies. Int J Geriatr Psychiatry 2000; 15: 98391. 26 Shah S, Tangalos EG, Petersen RC. Mild cognitive impairment: when is it a precursor to Alzheimers disease? Geriatrics 2000; 55: 6568. 27 Petersen RC. Mild cognitive impairment: transition between aging and Alzheimers disease. Neurologia 2000; 15: 93101. 28 Petersen RC. Aging, mild cognitive impairment, and Alzheimers disease. Neurol Clin 2000; 18: 789806. 29 Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST. Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology 2001; 56: 113342. 30 Christensen H, Henderson AS, Jorm AF, Mackinnon AJ, Scott R, Korten AE. ICD-10 mild cognitive disorder: epidemiological evidence on its validity. Psychol Med 1995; 25: 10520. 31 Rockwood K, Wentzel C, Hachinski V, et al. Prevalence and outcomes of vascular cognitive impairment. Neurology 2000; 54: 44751. 32 Reed BR, Eberling JL, Mungas D, Weiner MW, Jagust WJ. Memory failure has different mechanisms in subcortical stroke and Alzheimers disease. Ann Neurol 2000; 48: 27584. 33 Swan GE, DeCarli C, Miller BL, Reed T, Wolf PA, Carmelli D. Biobehavioral characteristics of nondemented older adults with subclinical brain atrophy. Neurology 2000; 54: 210814. 34 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn. Washington, DC: American Psychiatric Association, 1987. 35 Graham JE, Rockwood K, Beattie BL, McDowell I, Eastwood R, Gauthier S. Standardization of the diagnosis of dementia in the Canadian Study of Health and Aging. Neuroepidemiology 1996; 15: 24656. 36 Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG. Aging, memory, and mild cognitive impairment. Int Psychogeriatr 1997; 9 (suppl 1): 6569. 37 Berg L, Hughes CP, Coben LA, Danziger WL, Martin RL, Knesevich J. Mild senile dementia of Alzheimer type: research diagnostic criteria, recruitment, and description of a study population. J Neurol Neurosurg Psychiatry 1982; 45: 96268. 38 Morris JC, McKeel DW Jr, Fulling K, Torack RM, Berg L. Validation of clinical diagnostic criteria for Alzheimers disease. Ann Neurol 1988; 24: 1722. 39 Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 18998. 40 Palmer K, Wang HX, Backman L, Winblad B, Fratiglioni L. Differential evolution of cognitive impairment in nondemented older persons: results from the Kungsholmen Project. Am J Psychiatry 2002; 159: 43642. 41 Frisoni GB, Fratiglioni L, Fastbom J, Guo Z, Viitanen M, Winblad B. Mild cognitive impairment in the population and physical health: data on 1,435 individuals aged 75 to 95. J Gerontol A Biol Sci Med Sci 2000; 55: M32228. 42 Frisoni GB, Fratiglioni L, Fastbom J, Viitanen M, Winblad B. Mortality in nondemented subjects with cognitive impairment: the influence of health-related factors. Am J Epidemiol 1999; 150: 103144. 43 Riley KP, Snowdon DA, Markesbery WR. Alzheimers neurofibrillary pathology and the spectrum of cognitive function: findings from the Nun Study. Ann Neurol 2002; 51: 56777. 44 OConnor DW. Memory complaints and impairment in normal, depressed and demented elderly persons identified in a community survey.

THE LANCET Neurology Vol 2 January 2003

http://neurology.thelancet.com

21

For personal use. Only reproduce with permission from The Lancet Publishing Group.