Mild cognitive impairment (part 1): clinical characteristics and predictors of dementia

Orestes V. Forlenza1, Breno S. Diniz12, Florindo Stella13, Antonio L. Teixeira45, Wagner F. Gattaz1

Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil. 2 Department of Internal Medicine, School of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil. 3 Biosciences Institute, Universidade Estadual Paulista (UNESP), Rio Claro, SP, Brazil. 4 Neuroimmunology Group, Laboratory of Immunopharmacology, Institute of Biological Sciences, UFMG, Belo Horizonte, MG, Brazil. 5 Department of Mental Health, School of Medicine, UFMG, Belo Horizonte, MG, Brazil.

Objective: To critically review and evaluate existing knowledge on the conceptual limits and clinical usefulness of the diagnosis of mild cognitive impairment (MCI) and the neuropsychological assessment and short- and long-term prognosis thereof. Methods: We conducted a systematic search of the PubMed and Web of Science electronic databases, limited to articles published in English between 1999 and 2012. Based on the search terms mild cognitive impairment or MCI and epidemiology or diagnosis, we retrieved 1,698 articles, of which 248 were critically eligible (cross-sectional and longitudinal studies); the abstracts of the remaining 1,450 articles were also reviewed. Results: A critical review on the MCI construct is provided, including conceptual and diagnostic aspects; epidemiological relevance; clinical assessment; prognosis; and outcome. The distinct definitions of cognitive impairment, MCI included, yield clinically heterogeneous groups of individuals. Those who will eventually progress to dementia may present with symptoms consistent with the definition of MCI; conversely, individuals with MCI may remain stable or return to normal cognitive function. Conclusion: On clinical grounds, the cross-sectional diagnosis of MCI has limited prognostic relevance. The characterization of persistent and/or progressive cognitive deficits over time is a better approach for identification of cases at the pre-dementia stages, particularly if these cognitive abnormalities are consistent with the natural history of incipient Alzheimer's disease. Keywords: Mild cognitive impairment; dementia; Alzheimer's disease; biomarkers

limited to articles published in English between 1999 and 2012: mild cognitive impairment OR MCI AND epidemiology OR diagnosis.6 The current diagnostic framework for MCI was first used approximately 13 years ago by Mayo Clinic researchers.2 age-associated cognitive decline (AACD). particularly Alzheimer's disease (AD). we aim to review the conceptual and practical aspects of MCI diagnosis. Considering the insidious and progressive nature of most neurodegenerative disorders.698 articles. RESULTS Cognitive impairment in the elderly: the evolution of concepts A number of overlapping definitions have been proposed since the 1950s to describe the transition between normal cognitive aging and pathological cognitive decline. the reverse may not be true. we can assume that most patients who will progress to dementia will exhibit symptoms compatible with MCI at the earlier stages of the disease. Individuals diagnosed with MCI have an increased risk of progression to dementia.5 The latter has been the most widely employed definition both in clinical and research settings. along with their major limitations.1 age-associated memory impairment (AAMI). AD being the putative outcome. We reviewed the abstracts of the remaining 1. the experience accumulated in the last few years supports the notion that MCI is by no means a synonym of incipient dementia. these deficits should not impair global cognitive function nor the ability to perform activities of daily living (ADLs). and measurable by objective testing.8 In this article. such as benign forgetfulness of senescence (BFS). Several definitions have attempted to describe these changes. These definitions developed from the concept of benign and malignant senescent forgetfulness described by Kral1 more than 50 years ago and the age-related memory impairment described by Crook and Larrabee2 in the late 1980s. METHODS We carried out a systematic search of the PubMed and Web of Science electronic databases using the following broad MeSH terms in the title or abstract. However.3 cognitive impairment but no dementia (CIND). and the short and long-term prognosis associated with this condition.450 articles and critically summarized the most relevant publications in the following sections. of which 248 were reviews.4 and mild cognitive impairment (MCI).INTRODUCTION The characterization of the transition between normal cognitive aging and the earliest manifestations of dementing disorders. We retrieved 1. its clinical and neuropsychological assessment strategies.7 However. since many individuals who meet the diagnostic criteria for MCI in a given assessment may never progress to dementia.5MCI describes the cognitive state of non-demented individuals who report memory deficits. Table 1 Most common concepts used to define cognitive impairment/decline in the elderly . which should preferably be corroborated by an informant. Table 1 reviews the most commonly used terms and definitions. has been an area of major interest in the last decades.

as measured by the CDR sum of boxes (SoB). Age-associated learning. which is confirmed by an informant. subjects may be classified into 5 major groups: CDR 0. Preserved ability to perform activities of daily living (ADLs).5. language. Table 2 Operational criteria for the diagnosis of MCI5. A higher .and education-matched norms) in memory. impairment Impairments (below age. CDR 0. with other memory cognitive functions unimpaired. Onset cognitive decline of decline is described as gradual and has been present for at least 6 months. When formal testing indicates no impairment.5 through 1) or dementia (CDR 1 through 3). an individual would be classified as worried well. attention. 2.10. Subjective complaint of cognitive impairment with objective cognitive Mild cognitive impairment adjusted for age. ranging from 0 to 18 points. subjects may be also classified according to the degree of overall functional impairment. 3. Normal general intellectual function. The term mild cognitive impairment itself was firstly used by researchers at New York University9 to refer to a specific stage of cognitive deterioration identified through the Global Deterioration Scale (GDS).11 After a careful clinical assessment. which ranges from 1 to 7. CDR 1. More inclusive than age-associated memory dementia impairment and age-related cognitive decline. Absence of dementia. or minimal impairment if considering instrumental ADLs. Inability to recall relatively unimportant data and parts of experience Benign senescent belonging to remote rather than the recent past. Age-associated Gradual decline in memory (below young healthy norms). CDR 2 and CDR 3. Consistent memory complaints which are preferentially corroborated by a close informant. with higher scores indicating more severe cognitive impairment (CDR 0.System Self-reported memory complaint Criteria Complaints of memory loss in the absence of formal testing. Intact impairment basic and instrumental activities of daily living. Objective characterization of specific deficits in memory and/or other cognitive domains. In addition to the CDR classification. A grade 3 in this scale. Cognitively impaired but no evidence of dementia according to DSM-IV Cognitive criteria. 5. or visuospatial functioning. as indicated by a poor performance on validated cognitive and/or neuropsychological assessment tests (scores bellow than expected according to norms adjusted for age and educational level). thinking. but performance of usual occupational duties and social activities is preserved. cognitive impairment can be in one or multiple domains and impairment no have a variety of etiologies. Adequate intellectual functioning. Normal global cognitive function. A research group at Washington University in the early 1980s developed a similar dementia staging system. the Clinical Dementia Rating Scale (CDR). 4. indicates that an individual has cognitive complaints and shows subtle cognitive decline. use of compensatory forgetfulness strategies.12 Mild cognitive impairment (MCI) 1.

structural and functional neuroimaging. In the late 1990s. one would be diagnosed in accordance to the number and type of functions affected: single-domain MCI.5 was used to include patients with incipient dementia. a CDR 0. and multipledomain MCI. In several studies. led by the U. this revision placed greater emphasis on the probable etiologic mechanisms leading to cognitive impairment and its degree of certainty.5 is also used interchangeably with MCI. as in dementia. Figure 1 illustrates the distinct MCI subtypes according to the number and type of cognitive deficits within the core construct. with a major focus on the early diagnosis of AD in contrast to dementias of other etiologies (e.12 proposed five operational criteria for the clinical diagnosis of MCI (Table 2).. the criteria for MCI were revised to encompass other patterns of cognitive impairment in addition to memory per se. its prevalence rates depend heavily on the age range of the cohort under study. 10% per year) as compared to elderly subjects with preserved cognitive function.e.S. Epidemiological characteristics of MCI in the elderly The global prevalence of MCI in the elderly is estimated to be 15-20%.g. molecular amyloid imaging). i.g.15 Yet. a group led by Ronald Petersen at the Mayo Clinic5. the presence of mild cognitive deficits that do not significantly interfere with the performance of ADLs.12.. These objectives would be achieved by a systematic evaluation of established disease biomarkers (e.14 Despite the similar clinical criteria for MCI diagnosis (known as the clinical core criteria).e. including or not memory.. In the original study. In the second part of this review. vascular dementia). nonetheless. we will address in detail the role of these biomarkers in the diagnosis and classification of AD. In subsequent years. Figure 1 Classification of patients with mild cognitive impairment (MCI) according to the type and number of affected cognitive domains12 A recent task force. proposed a revision of the MCI criteria and classification. if multiple cognitive domains were affected. cerebrospinal fluid.SoB score is indicative of more severe functional impairment. . increasing from 3% in individuals aged 60 years or over to 15% among those aged 75 years or older. However.13 Therefore. if only one cognitive domain was affected (memory or other cognitive domain). the core aspect of MCI has been preserved. Nonetheless. CDR 0.5patients classified as having amnestic MCI showed a significant increase in the risk of progression to dementia (largely AD) during follow-up (i. National Institute on Aging (NIA) and the Alzheimer's Association (AA)..

the incidence of amnestic MCI subtypes.000 person-years.prevalence rates of MCI show considerable variation in different studies.22 Thus. low educational attainment.21 In a community-based study conducted in Southern Brazil. prevalence estimates can vary between 0. whether the study was conducted within the community or in specialized clinics.23 The authors showed that the classification of individuals as cognitively normal or cognitively impaired is highly dependent on how the inclusion criteria are defined. apathy or sleep disorders. In this scenario. is time-consuming and expensive.5% in this study. cerebral and cognitive reserve. it is important to ascertain which is more suitable to illustrate the clinical framework of prodromal dementia. The prevalence of amnestic MCI as defined by the Mayo Clinic was 2.000 person-years. In a clinical study.000 person-years. Given the different definitions and conceptualizations that describe the cognitive dysfunction observed in the elderly. the coverage and sensitivity of batteries for cognitive testing.. from 28 to 36.20 The authors found that advanced age.6 per 1. 1. around one-third of elderly subjects assessed at a university memory center met the criteria for MCI. formal neuropsychological testing may not be widely available.9 to 40. and the magnitude of cognitive impairment that delimits caseness (e. a comprehensive neuropsychological evaluation may be considered a gold standard for the identification of patients with MCI. Despite a wealth of data on the epidemiology of dementia. cognitive deficits are very mild. As a consequence. easy to administer and that generate results that are easy to interpret. in many instances. and hypertension were the most significant risk factors for incident MCI. based on data from a large-scale multicenter study conducted in the United Kingdom. Such wide variance could be explained by fundamental differences in the operationalization of the MCI diagnosis. among other demographic features. whether the patients applied voluntarily or were summoned by advertisements). requiring highly trained and skilled professionals to be carried out. there is an urgent need for more epidemiological studies on the prevalence and incidence of MCI in the Brazilian elderly population. while . heterogeneity in methodological approaches may be the reason for the large variance in prevalence estimates. little information is available regarding its prodromal stages in the Brazilian population. from 9.000 individuals aged 65 or older.1 (adopting the most restrictive criteria) and 42% (when the definition was based only on the existence of subjective complaints). including the requirement of objective measurement of cognitive decline (as opposed to self-reported complaints).000 person-years. the inclusion of cognitive functions other than episodic memory in the diagnostic workup. there is a need for development of assessment strategies that are cost-effective. 60% of these subjects were classified as having multiple-domain MCI. anxiety. and that of non-amnestic MCI subtypes.8 per 1. such as the definition of cognitive decline and diagnosis criterion employed. and the presence of psychiatric comorbidities such as depression. the incidence of all MCI subtypes ranged from 51 to 76..3 per 1. the incidence of MCI was 13 cases per 1. from 3 to 53%. average age and educational level.g.5 SD below the mean).24 However. requiring more sophisticated cognitive assessments. 30% as amnestic MCI and 10% as nonamnestic MCI. Thus.e. A notable analysis on how varied definitions work to detect early cognition changes in the general population was published in 2007. with a cohort of over 13. Diagnosis of MCI: is there a gold standard for clinical evaluation? The clinical procedures for the diagnosis of MCI are complex and. procedures for patients recruitment and the research setting (i. Hence.16-19 In a recent systematic review.

our group addressed whether the combination of cognitive screening tests would improve the identification of MCI. even when higher than usual cutoff scores were evaluated. These results are similar to previous studies with elderly populations. CDT and VF tests. misidentifying most of these subjects as having normal cognitive function.35 evaluated several possible combinations of the MMSE. Subjects with multiple-domain MCI had a worse performance on the drawing task and on the late-recall subtest of the MMSE.26 However. this yields better sensitivity and specificity to distinguish dementia from normal aging.31 showed that scores on 4 out 8 sub-items (language.28 its administration is timeconsuming (usually taking 20 to 30 minutes) and specific training is necessary for correct administration and interpretation of scores.32. Many different approaches have been developed. careful and qualitative analysis of performance on individual MMSE items and scores on relevant domains may yield more relevant information on mild cognitive disturbances rather than consideration of the total MMSE score alone. memory. Ladeira et al. Abreu et al. Therefore. despite having a similar total test score. In a recent study by our group. they still have important limitations. its commonly used cutoff scores do not show good accuracy for discrimination of MCI.36. such as the clock drawing test (CDT) and the semantic verbal fluency (VF). and calculation) retain the psychometric properties of the whole test and similar accuracy to identify subjects with MCI (above 80%). they did not show good accuracy for the diagnosis of MCI. with . healthy elderly controls beyond that found for the MMSE alone. In a previous study.IQCODE) and an objective cognitive test (MMSE) would increase accuracy for identification of MCI. Other screening tests.34 assessed whether the combination of an informant-based dementia screening test (Informant Questionnaire of Cognitive Decline in the Elderly . while non-amnestic MCI patients had a worse performance on the three-stage command subtest. mainly because they were designed for the diagnosis of established dementia. Aprahamian et al. The mini-mental state examination (MMSE) is the most widely used cognitive screening test in clinical and research settings. developed to provide the diagnosis of neuropsychiatric disorders . The combination of scores on two or more tests is a common strategy for increasing the accuracy of dementia diagnosis in clinical practice.29 The Cambridge Cognitive test (CAMCOG) is a comprehensive cognitive assessment tool. Ultimately. This combination did not significantly improve the sensitivity and specificity of each test alone in recognizing MCI cases as compared with healthy elderly subjects. these strategies should be widely available to all clinical the elderly. part of the Cambridge Mental Disorders of the Elderly Examination (CAMDEX). These issues may limit its broad applicability in primary and secondary clinical settings. None of the chosen strategies were able to significantly improve the accuracy to differentiate MCI vs. In another study. according to their neuropsychological classification.27 Individuals with amnestic MCI had worse performance only on the late recall subtest. As with other tests. have also been tested for identification of MCI. more specific tools to tackle the challenge of identifying.30 Despite good sensitivity and specificity to identify subjects with MCI (above 80%). it is important to develop new.maintaining good sensitivity and specificity to identify MCI cases. not of its prodromal and milder manifestations. In general. praxis.33 In a series of studies.37 Although some of the currently used cognitive screening tests yield good results for recognizing subjects with MCI. with promising results. we showed that subjects with MCI had worse performance in specific MMSE subtests.particularly dementia .25 Despite good sensitivity and specificity for diagnosis of dementia.

In The Vienna Trans-Danube Aging Study. Another interesting assessment strategy is the use of computer-based cognitive tests. the amnestic MCI and multiple-domain MCI subtype was as a predictor of both AD and VD. not progressing to dementia even on long-term follow-up.39 It has been translated to and validated in European Portuguese40 and Brazilian Portuguese. since impairment of episodic memory is considered the most common prodromal clinical symptom of AD. primary progressive aphasia.high accuracy. the findings of several clinical and epidemiological studies did not corroborate the association between specific MCI subtypes and distinct outcomes.g.44 In some studies. subjects with mild cognitive deficits. As the conceptual framework for MCI and its subtypes evolved.48which adopted broader and more inclusive criteria to define cognitive loss in a large cohort of elderly without dementia (Cognitive Impairment No Dementia. CIND).52. the Canadian Study of Health and Aging. the diagnosis of nonamnestic MCI was not predictive of other neurodegenerative dementias. 26. or other nondementia outcomes. would indicate higher risk of progression to frontotemporal dementia (FTD). it was hypothesized that specific MCI subtypes would be associated with distinct outcomes. 1-2%/year).38. Validation of the CANS-MCI in Brazilian older adults. Longitudinal studies and MCI prognosis In the seminal work of Petersen et al.7%. Non-amnestic MCI. submitted).49 Despite this reasonable hypothetical foundation.. vascular dementia (VD) or Lewy body dementia (LBD). The MoCA (Montreal Cognitive Assessment) is a brief cognitive test specifically developed to screen for mild cognitive deficits and has been regarded as a suitable test for initial workup of subjects with suspected MCI.5 subjects with amnestic MCI showed a significantly higher risk of progression to AD as compared with cognitively preserved agematched individuals (10-12%/year vs. this outcome was not subtype-specific. This technology seeks to provide accurate and timely identification of MCI cases. Pure amnestic MCI would be associated with higher risk of progression to AD. showed that this population was at a higher risk of developing dementia than those with unimpaired cognition (47 versus 15%). some promising strategies have been developed are being tested in several populations. Multiple-domain MCI (amnestic and non-amnestic) would be associated with higher risk of progression to AD.51 A large proportion of subjects classified as having MCI can resume normal cognitive function (backconversion or diagnostic instability) or maintain stable cognitive deficits. at the Mayo Clinic. e. with rates ranging from 10 to 40% per year. we found that 22% of patients initially diagnosed as MCI resumed normal cognitive function after 1 year of .8% in those with non-amnestic MCI.50 In a clinical study.13 Several studies have confirmed the higher risk of progression to dementia in subjects with MCI.44-47 Also. particularly among less educated samples. however.43 which has recently been culturally adapted and validated into Brazilian Portuguese (Memória et al.41 but further studies are still needed to assess its potential as a screening tool for MCI in our population. vs.53 In a longitudinal study carried out by our group. major depression. e.g. the diagnosis of MCI was associated with higher rates of progression to AD on follow-up. the Cambridge Neuropsychological Test Automated Battery (CANTAB)42 and the ComputerAdministered Neuropsychological Screen for Mild Cognitive Impairment(CANS-MCI). which is manifested by the involvement of one or more cognitive functions other than memory. as the rate of conversion to AD of subjects presenting amnestic MCI was around 48. the rate of backconversion reached up to 40% of patients with MCI.. such as LBD and FTD. Several computer-based batteries have been developed.50 Furthermore.. with no significant differences between these outcome. Indeed.

Therefore. such as handling financial matters.58 In this study. in particular when facing more complex tasks. is also an important predictor of conversion.61 Where lies the threshold between MCI and incipient dementia? The importance of functional assessment The progression from MCI to dementia requires cognitive decline to be severe enough to impair one's ability to perform ADLs. apathy and anxiety.55 Another key point when assessing individuals with MCI is to ascertain the predictors of conversion to dementia and AD. as opposed to 12% of subjects with multiple-domain MCI and 14% of those with non-amnestic MCI. Similar results were also found in large community-based epidemiological studies. unlike those with dementia.14 Despite the importance of characterizing the cognitive profile of MCI subjects and understanding the predictors of conversion to dementia.66 This decision usually relies on the clinician's judgment. characterizing the dementia syndrome.60. the progression to more widespread cognitive and functional decline. and cognitive . supported by relatively crude measures of functional ability. we found that the most common pathway from cognitive aging and incipient AD was the emergence of single amnestic deficits (amnestic MCI) with the subsequent impairment of other cognitive domains (multiple-domain MCI. when comes the time to decide whether a patient with MCI meets the diagnostic criteria for dementia on follow-up assessment (i.follow-up. due to impairments in memory and executive functions) and. being an APOE ε4 carrier. worse global cognitive performance at baseline assessment and being an APOE ε4 allele carrier.56 In a recent study in Brazilian older adults. this provides little (or no) information on the trajectories from normal cognitive aging to MCI and.67 The objective assessment of functional status is not a routine procedure when evaluating subjects with suspected cognitive impairment.62-65 However. characterizing the actual conversion from MCI to AD). recent studies have demonstrated that MCI subjects do have minimal functional deficits. including the informant's personality.54 When the specific MCI subtype was taken into account. with no or minimal functional impairment. This finding highlights the importance of careful assessment of other cognitive domains beyond memory in these individuals. finally. According to the most recent criteria.57 It is interesting to note that worsening of memory impairment was not shown to be a major predictor of MCI conversion in a large longitudinal study. we sought to determine the most common paths from normal cognition to AD. the most significant predictors of dementia in amnestic MCI subjects were older age.12 However.. 37. MCI patients. rather. and worse performance on memory tests. or even on the patient's self-judgment.6 The presence of psychiatric symptoms. one must demonstrate that cognitive deficits do affect functioning. and shopping. paying bills.59 In this work. mood.5% of amnestic MCI subjects resumed normal cognitive function. In this study. These results were also observed in other studies.e. Most studies found that the main predictors of conversion from MCI to AD are older age. the emergence of executive dysfunction during follow-up was the most important determinant of conversion from MCI to AD. must have preserved global cognitive function. finally. it usually relies on the subjective appraisal of a relative or caregiver. to dementia. rendering this information inaccurate and subject to several sources of bias. such as depression. enabling them to perform ADLs independently. the best predictors of diagnostic instability were younger age and better global cognitive performance at baseline.

the reverse may not be true. Nonetheless. Revised (DAFS-R). Neuropsychiatric symptoms and risk of cognitive decline Although patients with dementia commonly exhibit neuropsychiatric symptoms such as depression.76-78 In the second part of this review. the best approach is to perform longitudinal reassessment of individuals diagnosed with MCI. anxiety. However. given the insidious progressive nature of most neurodegenerative diseases. but those who actually convert to AD show greater difficulties in performing specific tasks such as shopping and handling financial matters.68 Therefore.70 In addition. Given the foregoing.74. the objective assessment of functional status not only helps to establish the threshold at which cognitive decline significantly impact ADL performance. Characterization of the cognitive signs and symptoms that pertain to the natural history of the disease is undoubtedly an important aid to the early diagnosis of AD and other dementias. at the earliest stages. Despite wide acceptance by researchers and clinicians of the MCI construct as an important step toward understanding of the prodromal stages of dementia. the use of biomarkers has been included in the most recent revisions of the diagnostic criteria for AD and MCI. Indeed.70 Independent investigators have reported similar findings in a different population. neuropsychiatric symptoms now tend to be incorporated into any comprehensive clinical examination of individuals with MCI. including AD. but enables the investigation of which functional abilities are more sensitive to such alterations. of the limitation of informant-based scales. sleep disorders. we found that functional impairment correlates significantly with executive dysfunction71 and with biological parameters intrinsic to the pathogenic process of AD.75 These symptoms could confer a higher risk for dementia even among cognitively preserved persons. In the future. irritability. if not most. we validated the Brazilian Version of the Direct Assessment of Functional State. . Massive efforts have been dedicated to increasing the accuracy of crosssectional diagnosis of pre-dementia AD. Also. Considering the need for more objective functional assessment strategies.73 Accordingly. disinhibition. and apathy. symptoms consistent with MCI. we will address recent developments regarding biological markers of AD and how they can help improve the predictive accuracy of the clinical diagnosis of MCI. agitation. it is reasonable to assume that most of the patients who tend to develop dementia will exhibit. the association of clinical and biological markers may help increase the specificity of MCI criteria. the objective assessment of functional status may overcome some. the careful assessment of functional status may help the clinician to determine those MCI subjects most likely to progress to dementia.69 We have demonstrated that all MCI patients show mild objective functional impairments. thus enabling identification of patients at actual risk of progression.72 Hence. others have harshly criticized the validity of this concept in light of the heterogeneity of its clinical setting and prognosis. and definite progress has been achieved in the development of biomarkers which reflect the core changes observed in the disease.state. is there an urgent need for improvement of the predictive accuracy of clinically defined MCI to aid the selection of subjects at risk of progressing to dementia? On clinical grounds.73-75 There is a growing tendency to admit that neuropsychiatric symptoms may accelerate the transitional state from MCI to dementia. since many individuals who do meet the criteria for MCI in a given assessment resume normal cognitive function or do not progress to dementia at all. these occurrences have been consistently associated with faster cognitive decline and with increased risk of progressing to dementia across individuals with MCI.

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