Patient self-report for evaluating mild cognitive impairment and prodromal Alzheimer's disease
© BioMed Central Ltd 2011
Published: 9 December 2011
Patient-reported outcome (PRO) measures are used to evaluate disease and treatments in many therapeutic areas, capturing relevant aspects of the disorder not obtainable through clinician or informant report, including those for which patients may have a greater level of awareness than those around them. Using PRO measures in mild cognitive impairment (MCI) and prodromal Alzheimer's disease (AD) presents challenges given the presence of cognitive impairment and loss of insight. This overview presents issues relevant to the value of patient report with emphasis on the role of insight. Complex activities of daily living functioning and executive functioning emerge as areas of particular promise for obtaining patient self-report. The full promise of patient self-report has yet to be realized in MCI and prodromal AD, however, in part because of lack of PRO measures developed specifically for mild disease, limited use of best practices in new measure development, and limited attention to psychometric evaluation. Resolving different diagnostic definitions and improving clinical understanding of MCI and prodromal AD will also be critical to the development and use of PRO measures.
Patient-reported outcome (PRO) measures are used to evaluate the impact of disease and treatment in many therapeutic areas. Among the advantages of patient report is the potential to capture aspects of the disease and treatment experience uniquely accessible to patients and, relatedly, to improve the measurement of therapeutic intervention effects . The clinician's specialized framework of knowledge makes the clinician the most accurate reporter for some aspects of the disease experience. For which is the patient the more accurate reporter?
The most recent recommendations for core clinical criteria for the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD)  note that despite 'preservation of independence in functional abilities' some impairment in complex functional tasks may be evident, such as higher error rate, taking longer, and/or being less efficient. The companion statement on research criteria for preclinical stages of AD  raises the possibility that biomarkers in combination with 'subjective assessment of subtle change will prove to be useful.' Subtle but potentially important features of the disease experience may be inaccessible to those other than the patient, raising the interesting possibility that the patient may have the most comprehensive and accurate knowledge of performance .
Although impairment in social or occupational functioning is part of AD diagnostic criteria , the place of functioning in diagnostic definitions of MCI is still evolving [2, 6–8]. Initial definitions of MCI were based on cognitive impairment and intact activities of daily living , but empirical data support the presence of functional deficits encompassing skills and activities beyond instrumental activities of daily living (ADLs), many of them subtle [10–15]. Functioning therefore emerges as an area of potential value for patient self-report. Two other areas with substantial prior research on patient self-report in AD and MCI are neuropsychiatric symptoms and health-related quality of life.
There are of course several important obstacles to use of patient self-report in cognitive impairment. Disease-related disruptions to memory and cognition may interfere with the ability to complete a questionnaire accurately, as might loss of insight with progressive disease , leading to reliance on informant and clinician report . However, accuracy of informants, especially family caregivers, can also be suboptimal for multiple reasons, including the distortions introduced by caregiver depression and lack of caregiver awareness of some symptoms (for example, ).
The focus of this overview is on the value of patient report for evaluating disease course and treatments in MCI and in prodromal, or 'early' AD . The emphasis is on early disease, corresponding to newer terminology referencing prodromal AD, as well as to the less specific 'mild cognitive impairment' referenced by Petersen and colleagues .
Methods and findings
Summary of select measures relevant to patient-reported outcomes in mild cognitive impairment
Mild through severe AD
23-item inventory of ADL, rated based on extent of assistance the patient requires (independently, with supervision, with physical help): 0 (total independence in performing an activity) to 4 (total inability to act independently). Each question varies in the number of options to chose. Total score range: 0 to 78; higher scores indicate less functional impairment. ADCS ADL-MCI: 18 item and 24 item versions
Item content developed by a subcommittee of the ADCS Initial item pool included ADL items from existing scales and novel items based on clinical experience Items refined following pre-testing
ADCS ADL-MCI: 24 item version demonstrated superior sensitivity and specificity for aMCI discrimination from controls
Widely used, including as endpoint in clinical trials. Developed based on substantial clinical experience; comprehensive item capture
Used in mild through severe AD
20-item measure of ADLs and physical functioning. Five difficulty-based response options from 'as well as usual/no difficulty' to 'a lot of difficulty'; with 'not at all' option. Total score ranges from 0 to 45; higher scores indicate less functional impairment.
Items selected based on discrimination between MCI and normal subjects Discriminated between CDR 0 and 0.5 Scores related to cognitive performance Moderate correlation of ADL-MCI patient rating with informant rating; although most scores near ceiling
Good psychometric performance; item content from established measures
Test-retest reliability acceptable to good (3-month interval)
Perceived Deficits Questionnaire (PDQ) 
Developed for multiple sclerosis; used in AD and MCI
The PDQ is a part of the Multiple Sclerosis Quality of Life Inventory that assesses self-perceived cognitive difficulties. It consists of 20 items that address cognitive difficulties in four dimensions (attention/concentration, planning/organization, retrospective memory and prospective memory). Items are rated on a five-point scale ranging from 1 (never) to 5 (almost always)
No psychometric data available for MCI/AD
Developed for multiple sclerosis population but content relevant to MCI/AD
Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS) 
Neurodegenerative disorders generally, early detection through more severe levels
Developed as a multidimensional measure permitting early detection and patient and informant comparison and applicable from mild severity onward. Developed to measure cognitive personality, functional, and motor symptoms. Items are rated on a five-point frequency scale from 0 (never) to 4 (routinely) with Once/occasionally/more than monthly as intermediate anchors
Four subscales supported by exploratory factor analysis Construct validity supported through moderate to high correlation with clinical measures
Multiple domains targeted to aid with differential diagnosis. Seeks to be gender-neutral, overcoming gender/activity confounds of other measures. Frequency scale may limit sensitivity
High internal consistency (alpha = 0.98) for both versions
Patient-Reported Outcomes in Cognitive Impairment (PROCOG)
MCI through moderate AD
55-item measure of cognitive impairment symptoms and their impact in patients with MCI and mild to moderate AD. There are seven subscales: affect, skill loss, semantic memory, short-term memory, cognitive functioning, social impact, and long-term memory. Items are rated on a five-point Likert scale. Total scores range from 0 to 220. Higher scores indicate greater impact of cognitive impairment
Developed based on clinician input and focus groups with patients and informants
Subscale and total scores were lowest for controls and highest for AD patients, with MCI patients intermediate Highest correlations with the PROCOG were observed for the QOL-AD (r = -0.53) and CES-D (0.60)
PROCOG Affect subscale was most highly correlated to the CES-D
Correlations with the neuropsychological measures were low to moderate
MCI and DAT scores differed significantly (P ≤ 0.05 for total and subscale scores with the exception of 'social impact')
'Long-term memory' item did not distinguish among the three groups
'Skill loss' and 'memory for recent events' subscales showed the most separation between MCI and DAT patients
Acceptable psychometric properties but no longitudinal data published. Broad content mixes domain assessment; however, subscales permit more focused domain selection
Internal consistency: Cronbach's alpha for all subscales was above 0.82
Test-retest: no statistically significant differences across 14 day retest
ICCs ranged from 0.49 (for the single-item 'long-term memory' subscale) to 0.90
Mail-In Cognitive Function Screening Instrument 
14-item brief screening instrument assessing cognitive and functional decline; prior year recall period.
Response options are 'yes' (1), 'no' (0), or 'maybe' (0.5).
Total scores range from 0 to 14; higher score indicate worse status.
Patient scores associated with clinical measures
Patient/informant core difference associated with mMMSE, NYU Paragraph immediate and delayed recall; free and cued reminder test
Trend toward relationship to APOE genotype group (none, at least one) for patient but not informant score
Brief screening measure demonstrating sensitivity to subjective memory complaints. Brevity limits comprehensiveness but for intended purpose content is appropriate
75-item measure of executive functioning in adults composed of two index scores: the Behavioral Rating Index (BRI) and the Metacognitive Index (MI). The BRI has four subscales: inhibit, shift, emotional control, and self-monitor. The MI has five subscales: working memory, initiate, plan/organize, task monitor, and organization of materials. An overall score is obtained as a composite of two index scores. There are also three 'validity' scales used to screen for factors other than executive functioning that could explain scores on the main measure: negativity, infrequency, and inconsistency
No psychometric data reported
Item content targets accepted executive functioning skills
Multiple versions (original was 39-item self-report; 26-item version and 38-item version; family report version available). The 38-item self report version includes items related to difficulties in attention, concentration, orientation, memory, praxis, domestic activities and errands, facial recognition, task efficiency, and name finding. Items are rated on a five-point Likert scale on frequency of difficulty over prior month, from 0 (not at all) to 4 (very often)
Derived and adapted from existing measures Profile of Mood States, Inventory of Psychic and Somatic Complaints, and Minnesota Multiphasic Personality Inventory Item content also based on expert clinical opinion 38-item self-report version: moderate to high correlation with performance on neuropsychological measures of memory and attention
Developed from established measures. Provides measure of anosognosia
Test-retest reliability acceptable in original 39-item version as well as in 26-item version
Everyday Cognition (ECog) 
39-item measure of neuropsychological functioning related to cognitive impairment. Items are rated on a four-point scale: 1, better or no change compared to 10 years earlier; 2, questionable/occasionally worse; 3, consistently a little worse; 4, consistently much worse. Higher scores represent worse daily function
Developed through clinical input with reference to literature; designed to address key memory and cognition symptoms that can be linked to specific neuropsychological deficits Data support six domain factors and one global factor: everyday memory, everyday language (which includes everyday semantic knowledge), everyday visuospatial abilities, and the executive domains of everyday planning, organization, and divided attention
Psychometric performance acceptable, with discrimination by clinical severity level and discrimination by different MCI subtypes
Low correlation with age and educational level (r = 0.19 and -0.16, respectively), suggestive of minimal education level bias
Convergent validity supported based on magnitude of correlation to the clinical measures and relationship to diagnostic category
Developed to minimize confound with educational level
Test-retest reliability was good (r = 0.82) based on 2 day to 113 day interval
Multiple therapeutic areas
46-item behavior scale rates the frontal impairments of apathy, disinhibition, and executive dysfunction, on a five-point Likert scale ranging from almost never (1) to almost always (5) for a maximum score of 240. Higher scores indicate more abnormal behavior
High intrascale reliability (0.95) in normal and pathological populations, subscale reliabilities of 0.78 or higher, Adequate internal consistency reliability (Cronbach's alpha: 0.92), and construct and criterion-related validity in multiple Studies
Widely used across medical/psychiatric diseases. Captures cognitive-behavioral aspects of frontal symptoms
The initial literature search strategy targeted publications on AD and MCI (specifically 'AD, moderate to severe' and 'MCI or very early AD'), crossing this literature with specific domain terms (functioning, functional status, executive functioning, HRQL, affect/mood/behavior). The search was limited to English language publications from 2004 to 2009 in MedLine and Embase. To ensure that relevant measures used in clinical trials for currently marketed AD drugs were included, separate searches were conducted for MCI and AD in each domain of interest, limited to 1999 to 2009, with the main focus on 'Alzheimer's disease' OR 'mild cognitive impairment' OR 'cognitive impairment no dementia.' Since treatment efficacy was not the focus of this review, but rather measures used to assess efficacy and effectiveness from the perspective of patients and caregivers, this part of the search was limited to review articles. Searches were conducted in PubMed initially, followed by Medline, Cochrane Library of Systematic Reviews, PsychINFO, and Embase.
Full articles were retrieved if information on measure development, psychometric evaluation, and/or use were mentioned in the abstract. Information from retrieved articles was abstracted into tables addressing each of these elements. All relevant titles and abstracts were screened (level 1). Full papers were obtained for any studies considered potentially eligible or where uncertainty existed as to whether a paper should be included in the review. Full papers were formally assessed for relevance (level 2). Level 1 and 2 reviews for the literature review conformed to pre-determined inclusion and exclusion criteria, including focus on early AD/MCI patients, and caregiver- and patient-reported outcomes were included. Electronic data extraction forms were completed by reviewers trained in the critical assessment of evidence. A third reviewer independently examined any inconsistencies in extracted data elements between extractors and missing data fields. Any discrepancies in extracted data were resolved by consensus and any disagreements were resolved by consulting with a third investigator, as necessary. The consensus version of the extracted data was subsequently exported to the evidence tables. The extracted data elements from each accepted study included study design and measures, instruments, and domains and items of interest.
Patient-reported outcome measurement by domain
Everyday functioning: complex activities of daily living
Definitions of 'functioning' vary but generally include both basic activities of daily living (for example, bathing, dressing) and instrumental activities of daily living (for example, handling finances, cooking, phone use) [19–21], with the latter set widely used to assess MCI and prodromal AD [22–32]. The term 'everyday functioning' is used to indicate basic, instrumental, and complex or 'higher order' ADLs (for example, planning social functions; see, for example, ).
Consensus on the specific functional deficits that characterize MCI or prodromal AD has not been reached, especially since early definitions of MCI required the absence of functional deficits. The presence of MCI, as well as subtlety of functional deficits relative to AD, is now recognized .
Many AD functioning measures exist given the centrality of functioning to the expression of disease, but most are informant reported, including in: the Physical Self-Maintenance Scale [35–37]; the Blessed Dementia Scale [36–38]; the Dependence Scale in Alzheimer's Disease ; the Disability Assessment for Dementia Scale [40, 41]; the Interview for Deterioration in Daily Living Dementia [42, 43]; and the Progressive Deterioration Scale .
Like most measures of functioning used in AD, the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) was developed as an interview-based informant-reported measure of level of independence in specific tasks . Subsequently, a version for use with MCI, the ADCS ADL-MCI, was developed with both informant- and patient-completed versions; item content includes complex and instrumental ADLs, such as handling finances, shopping, travel, and remembering appointments . To meet the need for a brief in-home rated ADL measure, the Activities of Daily Living Prevention Instrument was developed by the Alzheimer's Disease Cooperative Study Prevention Instrument Project, and is based in part on items from the ACDS ADL-MCI, the Functional Activities Questionnaire , and the Disability Assessment for Dementia Scale [46, 48–52]. There are both patient- and informant-rated versions; item content overlaps substantially with the ADCS ADL-MCI.
The ADCS Prevention Instrument Project also developed the Mail-In Cognitive Function Screening Instrument, with patient-and informant-completed versions. Although intended as a screening tool, item content includes a range of everyday functioning, including social activities and work performance [41, 42, 51–54].
The Patient-Reported Outcomes in Cognitive Impairment (PROCOG)  measures the impact of MCI and early AD-associated cognitive impairment on multiple domains, including specific everyday functioning skills and social functioning. Similarly, the Perceived Deficits Questionnaire addresses a range of symptoms and functional impacts of memory loss based on patient self-report and has proven useful for signal detection in a treatment trial for MCI, although it was originally developed for use in multiple sclerosis . The Perceived Deficits Questionnaire is an example of a measure of 'subjective memory complaints', most of which include cognition symptom report along with functioning (for example, Questionnaire d'auto-évaluation de la mémoire (QAM)/Self-Evaluation Complaint Questionnaire ; Self-Rating Scale of Memory Functions ).
A summary of some relevant measures is provided in Table 1. As noted by others, few published reports on functioning measures include psychometric performance , although for the measures with patient-reported versions, available test-retest reliability data and con-current or predictive validity data generally indicate good psychometric performance, providing some evidence of accurate measurement. Of note is that despite content overlap in existing measures, some domains are relatively under-represented, such as social functioning or functioning related to language skills - both areas for which patient report may be particularly well-suited.
The domain of functional status in cognitive disorders is one with a long history of scale development and use, and AD research is currently well-served by existing informant-reported scales for assessing moderate to severe disease. However, most item content fails to capture subtle deficits, and few patient-reported measures have been developed to date.
Some performance-based assessments address areas that could be promising for adaptation as self-rated measures, including financial capacity [57, 58], facial emotion processing , and route navigation . Linking functioning to specific cognitive skills through these and other areas may expand clinical characterization of prodromal AD .
Because of limited use of qualitative data collection from patients in the measure development process, a step key to best practice in measure development , further refinement of 'functioning' measures may be warranted, including through identifying and measuring aspects of functioning most relevant to early disease, and establishing consensus on the definition of everyday functioning and complex ADL functioning.
Executive functioning represents the cognitive skills required for the planning, initiation, sequencing, and monitoring of complex goal-directed behavior, such as household chores [5, 62, 63]. Executive functioning impairment is a criterion for dementia diagnosis .
Executive functioning skills underlie the everyday functioning skills discussed above, but are considered separately here because measures of executive functioning focus on a specifically defined set of cognitive skills rather than on the tasks those skills enable. Data from Farias and colleagues [64, 65] support distinguishing between measurement of daily living skills and measurement of neuropsychological functioning, based on data showing a moderate correlation between measures of each in a sample with AD (see also ). More recently, data from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Cognitive Intervention Trial also support this distinction, as well as the relationship between cognitive skills and everyday functioning .
Executive functioning measures that have been used in MCI include the Behavior Rating Inventory of Executive Function - Adult version  (BRIEF-A ) and the Frontal Systems Behavior Scale [70, 71], with patient-and informant-reported versions for each. The BRIEF is a measure of everyday behavioral manifestations of executive control and is sensitive to subtle changes in MCI patients and those with cognitive complaints [68, 72]. Similar to findings from Farias and colleagues , BRIEF-A scores were only modestly correlated to neuropsychological measures of executive functioning, suggesting that self- and informant report provides unique information about executive functioning relative to performance-based measures. The Frontal Systems Behavior Scale is a rating scale of apathy, disinhibition, and executive function and has demonstrated sensitivity to impairment in an MCI sample .
Measures of executive functioning show promise for detection of subtle deficits in MCI [70, 71]. As noted above for everyday functioning measures, obtaining structured input from patients in accordance with best practice for measure development may usefully expand the set of relevant impacts to measure and/or aid with identifying differential importance of content from the patient perspective and by stage of disease.
Although neuropsychiatric symptoms are frequently an important part of the disease course of AD, their presence earlier in the disease is not as well-established. In recognition of the unique presentation and possible prognostic significance of major depressive disorder within AD, the National Institute of Mental Health developed a modified provisional set of criteria for depression in AD, distinct from the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria for major depressive disorder [73, 74]. Work with these criteria has indicated that the prevalence of major depressive disorder is significantly under-estimated in this population relative to DSM-IV-based prevalence estimates [74, 75].
Behavioral and psychological symptoms are evident among some MCI and mild AD patients , and at elevated rates relative to the normal aging population . Increased apathy and executive dysfunction have been documented in MCI [70, 77]. There is preliminary evidence for higher rates of neuropsychiatric symptoms such as depression, anxiety, agitation, disinhibition, irritability, and sleep problems among those with executive dysfunction type MCI relative to both amnestic and non-amnestic MCI  and presence of depression (based on caregiver report) has been found to be predictive of progression from amnestic MCI to AD .
Few measures of neuropsychiatric symptoms have self-report versions and few are validated for use in early disease. Further research is required to develop evidence for the validity of patient self-report for these symptoms.
Health-related quality of life
Health-related quality of life (HRQL) is the subjective assessment of an individual's psychological, physical and social functioning or well-being [78, 79] and is traditionally measured via self-report, although for AD, measures have both patient- and informant reported versions [80, 81]. No MCI-specific HRQL scale exists; instead, existing AD measures have been used in MCI (for example, the Alzheimer's Disease Related Quality of Life instrument ) as have generic measures (defined as measures intended for use with any population or therapeutic area; examples are the World Health Organization Quality of Life questionnaire, short version  and Short-Form (SF)-12 ). A systematic review of clinical trials in AD found very low use of HRQL measures (in <5% for trials conducted through part of 2006) . Data from a small sample suggest that reliability and validity of HRQL self-report in MCI and AD is correlated with insight level . While HRQL measures have been central to the rise of PRO assessment over the past two decades, the value of disease-specific HRQL assessment to treatment evaluation in MCI and prodromal AD is limited by lack of consensus on domains to include and lack of clarity about how to weight domains for scoring. The HRQL impact of MCI, distinct from that of later disease, remains to be defined. Further work exploring the relationship of HRQL to functioning, neuropsychological disease effects, and neuropsychiatric symptoms would enhance the quality of HRQL measurement and improve its usefulness for research applications.
Insight and patient self-report
Insight into illness is a critical issue for patient self-report in MCI and AD given that insight into disease effects declines as the disease progresses [87–91]. Lack of insight is defined as lack of the ability to elaborate on the experience of a disease, label the symptoms of the disease as pathological, or have knowledge of the deeper effects that the symptoms or disease will have on one's environment . Anosognosia is defined as unawareness of deficits, specific cognitive dysfunction, and lack of insight [16, 93–96]. The terms 'lack of insight' and 'anosognosia' are used largely interchangeably in the cognitive impairment literature.
The relationship of insight to progression in MCI is less clear than it is for AD. For a review of insight in MCI see . There is currently no consensus on the best method to measure insight. Most methods rely on informant report as a 'gold standard' with patient/informant concordance taken as an indirect measure of patient insight. When the informant is the caregiver, accuracy of report bears critical examination. Caregiver burden, level of depression and anxiety, and caregiver health, including cognitive health, may influence accuracy of caregiver report (for example, [97, 98]).
Within the AD literature, there has been examination of concordance along with caregiver factors in reporting [17, 86, 99, 100]. Data on patient/informant concordance and informant accuracy are limited for the milder levels of cognitive impairment. In general, data support an inverse correlation between insight and severity of cognitive impairment and an inverse correlation between patient and caregiver report and severity of cognitive impairment [88, 101, 102]. Dementia patients likely underestimate their deficits in comparison to caregiver informants , with concordance further reduced as disease progresses (for example, ).
Some empirical reports conclude MCI patients have preserved insight. For example, Farias and colleagues  found that MCI patient self-report was concordant with reports of others, suggesting that MCI patients do not under-report actual deficits in cognition and functioning. Other studies suggest lack of MCI patient insight (see  for a review). Conflicting findings about insight and ability of patients to self-report may be due to different definitions of insight, different definitions of MCI, and/or different methods of measuring insight. Most studies of insight focus on insight for memory functioning; few studies address insight for other cognitive skills, everyday functional abilities, behavior, or affect . The current literature on insight in MCI is limited by lack of specificity about domains affected, a critical point given evidence of differential insight by domain for MCI patients [91, 105–107]. Insight may be well-preserved in some domains across a range of disease severity, but may diminish more rapidly in others . For example, Clement and colleagues  found that some but not all domains assessed corresponded to performance deficits in global cognitive score and executive functioning for MCI patients, suggesting MCI patients may be aware of general cognitive deficits but not specific memory deficits. To date, the literature on MCI supports the conclusion that insight in MCI is not a single construct and that insight might be spared for some but impaired for other domains (see Roberts and colleagues  for a review).
Evidence suggests that MCI patients may have knowledge of deficits in advance of when deficits are clinically discernible [108–110]. Kalbe and colleagues  found that MCI patients overestimate cognitive deficits relative to informants on a 13-domain complaint interview; mild AD patients underestimate their deficits relative to an informant. The validity of the conclusion of 'overestimation' is worth challenging, however, as early cognitive loss may be apparent to the patient but no one else, in part because of the nature of the deficits and in part because MCI patients may actively hide symptoms from others.
To optimize patient self-report, further research is warranted to determine the relationship of insight to level of disease severity, attending to potential differences in insight by domain rather than treating insight as a single global construct. It will be particularly interesting to identify those domains for which patients, especially MCI patients, may have the most accurate view of performance relative to other informants, including clinicians.
Some patient-reported insight scales are presented in Table 1.
The increasing interest in MCI due to AD , preclinical AD , and prodromal AD  presents an opportunity to advance outcomes measurement in cognitive disorders by addressing ceiling effects of existing measures and by expanding the range of measurement targets beyond neuropsychological assessments into the realm of patient-reported outcomes. Patient self-report also offers a means of expressing, and perhaps quantifying, the clinical significance of specific clinical changes.
Progress in identification of treatments for cognitive impairment depends on accurate measurement. Among the concepts for which patient self-report could be valuable, and for which measurement appears feasible based on available psychometric data, are aspects of everyday functioning and complex activities of daily living and some aspects of executive functioning. Few measures currently address these concepts. Further, domains included in existing measures vary and no measure is comprehensive; consensus on specific functioning domains relevant to early disease would improve measurement. The extent to which under-studied areas, such as social functioning and language skills, are useful to assess is uncertain given lack of data.
Subtle changes in mood and affect specific to MCI may be usefully captured by self-report but to date there are limited data on validity of patient self-report of neuropsychiatric symptoms in early disease. Measurement of the health-related quality of life impact of MCI has proceeded largely on the basis of measures developed for AD; relevance to the MCI experience remains to be established. Understanding the MCI experience in greater depth can improve conceptualization of HRQL. Currently, HRQL assessments in MCI and mild AD are based largely on existing AD measures with little psychometric performance data on suitability for measurement of milder levels of impairment.
Other domains may prove useful to explore for self-report. For example, cognitive impairment is often associated with somatic changes, including changes in eating behavior, such as dysphagia, along with weight loss, changes in olfaction, sleep quality, balance, and increased fall risk [112–119].
The impact of fluctuating or declining insight in mild cognitive impairment on patient report is unclear. At what point does loss of insight make patient self-report no longer reliable and valid? Current research suggests that this point may vary by domain, with patients demonstrating sufficient insight to reliably and validly self-report about disease-related impairment in some areas well into mild to moderate AD.
Consideration of strategies for quantifying the impact of other variables on the accuracy of measurement should be part of measure validation. Cultural differences in symptom expression and interpretation are one example. Item response theory methods will likely be of value to identifying differential item functioning and quantifying cultural confounds [120–122]. In addition to the possibilities of new measure development, such as is being undertaken by the Cognition Working Group of the Critical Path Institute's PRO Consortium, existing AD measures could be tested in the MCI population and converted to self-report if feasible.
The increasing emphasis of research on symptoms, correlates, and impact of cognitive impairment at mild levels suggests that the time is right for development of new patient-reported measures for MCI. Although measurement from the perspective of patients with MCI and prodromal AD is still at an early stage, the development of new measures and psychometric evaluation of existing AD measures for use in early disease should be pursued to increase the tools available and to expand our understanding of mild levels of cognitive impairment.
Alzheimer's Disease Cooperative Study Activities of Daily Living
activities of daily living
Behavior Rating Inventory of Executive Function - Adult version
Diagnostic and Statistical Manual of Mental Disorders: Fourth Edition
health-related quality of life
mild cognitive impairment
Funding for this review was provided by the Cognition Working Group of Critical Path Institute's PRO Consortium. The pharmaceutical firms participating in the Cognition Working Group are: Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Critical Path Institute's PRO Consortium is supported by grant number U01FD003865 from the United States Food and Drug Administration and by Science Foundation Arizona under grant number SRG 0335-08. The authors gratefully acknowledge the comments and feedback from the Cognition Working Group members on earlier drafts of this manuscript. The authors also thank Leah Kleinman, Jill Bell, and Anne Brooks for their assistance and review. The views expressed in this article are those of Dr Frank and do not necessarily reflect those of PCORI.
- U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health: Guidance for Industry on Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. Health Qual Life Outcomes. 2006, 4: 79-PubMed CentralGoogle Scholar
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH: The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011, 7: 270-279. 10.1016/j.jalz.2011.03.008.PubMed CentralPubMedGoogle Scholar
- Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, Iwatsubo T, Jack CR, Kaye J, Montine TJ, Park DC, Reiman EM, Rowe CC, Siemers E, Stern Y, Yaffe K, Carrillo MC, Thies B, Morrison-Bogorad M, Wagster MV, Phelps CH: Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement. 2011, 7: 280-292. 10.1016/j.jalz.2011.03.003.PubMed CentralPubMedGoogle Scholar
- Doody RS, Ferris SH, Salloway S, Sun Y, Goldman R, Watkins WE, Xu Y, Murthy AK: Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial. Neurology. 2009, 72: 1555-1561. 10.1212/01.wnl.0000344650.95823.03.PubMedGoogle Scholar
- American Psychiatric Association. Task Force on DSM-IV: Diagnostic and Statistical Manual of Mental Disorders: DSM-IV. International Version with ICD-10 Codes. 1995, Washington, DC: American Psychiatric Association, 4Google Scholar
- Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P: Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007, 6: 734-746. 10.1016/S1474-4422(07)70178-3.PubMedGoogle Scholar
- Hachinski V: Shifts in thinking about dementia. JAMA. 2008, 300: 2172-2173. 10.1001/jama.2008.525.PubMedGoogle Scholar
- Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC: Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004, 256: 240-246. 10.1111/j.1365-2796.2004.01380.x.PubMedGoogle Scholar
- 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). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001, 56: 1133-1142.PubMedGoogle Scholar
- Lu YF, Haase JE: Experience and perspectives of caregivers of spouse with mild cognitive impairment. Curr Alzheimer Res. 2009, 6: 384-391. 10.2174/156720509788929309.PubMed CentralPubMedGoogle Scholar
- Robert P, Onyike CU, Leentjens AF, Dujardin K, Aalten P, Starkstein S, Verhey FR, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, Gauthier S, Grossberg G, Vellas B, Byrne J: Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry. 2009, 24: 98-104. 10.1016/j.eurpsy.2008.09.001.PubMedGoogle Scholar
- Clare L, Rowlands J, Bruce E, Surr C, Downs M: 'I don't do like I used to do': a grounded theory approach to conceptualising awareness in people with moderate to severe dementia living in long-term care. Soc Sci Med. 2008, 66: 2366-2377. 10.1016/j.socscimed.2008.01.045.PubMedGoogle Scholar
- Bennett HP, Piguet O, Grayson DA, Creasey H, Waite LM, Lye T, Corbett AJ, Hayes M, Broe GA, Halliday GM: Cognitive, extrapyramidal, and magnetic resonance imaging predictors of functional impairment in nondemented older community dwellers: the Sydney Older Person Study. J Am Geriatr Soc. 2006, 54: 3-10. 10.1111/j.1532-5415.2005.00532.x.PubMedGoogle Scholar
- Frank L, Flynn JA, Kleinman L, Margolis MK, Matza LS, Beck C, Bowman L: Validation of a new symptom impact questionnaire for mild to moderate cognitive impairment. Int Psychogeriatr. 2006, 18: 135-149. 10.1017/S1041610205002887.PubMedGoogle Scholar
- Farias ST, Mungas D, Jagust W: Degree of discrepancy between self and other-reported everyday functioning by cognitive status: dementia, mild cognitive impairment, and healthy elders. Int J Geriatr Psychiatry. 2005, 20: 827-834. 10.1002/gps.1367.PubMed CentralPubMedGoogle Scholar
- Vogel A, Stokholm J, Gade A, Andersen BB, Hejl AM, Waldemar G: Awareness of deficits in mild cognitive impairment and Alzheimer's disease: do MCI patients have impaired insight?. Dement Geriatr Cogn Disord. 2004, 17: 181-187. 10.1159/000076354.PubMedGoogle Scholar
- Arguelles S, Loewenstein DA, Eisdorfer C, Arguelles T: Caregivers' judgments of the functional abilities of the Alzheimer's disease patient: impact of caregivers' depression and perceived burden. J Geriatr Psychiatry Neurol. 2001, 14: 91-98. 10.1177/089198870101400209.PubMedGoogle Scholar
- Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O'Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P: Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010, 9: 1118-1127. 10.1016/S1474-4422(10)70223-4.PubMedGoogle Scholar
- Benjamin Rose Hospital Staff: MULTIDISCIPLINARY studies of illness in aged persons; a new classification of functional status in activities of daily living. J Chronic Dis. 1959, 9 (1): 55-62. 10.1016/0021-9681(59)90137-7.Google Scholar
- Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW: Studies of Illness in the Aged. The Index of Adl: A Standardized Measure of Biological and Psychosocial Function. JAMA. 1963, 185: 914-919. 10.1001/jama.1963.03060120024016.PubMedGoogle Scholar
- Lawton MP, Brody EM: Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969, 9: 179-186. 10.1093/geront/9.3_Part_1.179.PubMedGoogle Scholar
- Leidy NK: Using functional status to assess treatment outcomes. Chest. 1994, 106: 1645-1646. 10.1378/chest.106.6.1645.PubMedGoogle Scholar
- Arlt S, Lindner R, Rosler A, von Renteln-Kruse W: Adherence to medication in patients with dementia: predictors and strategies for improvement. Drugs Aging. 2008, 25: 1033-1047. 10.2165/0002512-200825120-00005.PubMedGoogle Scholar
- Aalten P, van Valen E, Clare L, Kenny G, Verhey F: Awareness in dementia: a review of clinical correlates. Aging Ment Health. 2005, 9: 414-422. 10.1080/13607860500143075.PubMedGoogle Scholar
- Aupperle PM: Navigating patients and caregivers through the course of Alzheimer's disease. J Clin Psychiatry. 2006, 67 (Suppl 3): 8-14. quiz 23PubMedGoogle Scholar
- Birks J, Flicker L: Donepezil for mild cognitive impairment. Cochrane Database Syst Rev. 2006, 3: CD006104-PubMedGoogle Scholar
- Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, Clegg A: The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease. Health Technol Assess. 2006, 10: iii-iv. ix-xi, 1-160PubMedGoogle Scholar
- Martinon-Torres G, Fioravanti M, Grimley EJ: Trazodone for agitation in dementia. Cochrane Database Syst Rev. 2004, CD004990-4Google Scholar
- Moniz-Cook E, Vernooij-Dassen M, Woods R, Verhey F, Chattat R, De Vugt M, Mountain G, O'Connell M, Harrison J, Vasse E, Dröes RM, Orrell M, INTERDEM group: A European consensus on outcome measures for psychosocial intervention research in dementia care. Aging Ment Health. 2008, 12: 14-29. 10.1080/13607860801919850.PubMedGoogle Scholar
- Rabheru K: Disease staging and milestones. Can J Neurol Sci. 2007, 34 (Suppl 1): S62-66.PubMedGoogle Scholar
- Scherder E, Dekker W, Eggermont L: Higher-level hand motor function in aging and (preclinical) dementia: its relationship with (instrumental) activities of daily life--a mini-review. Gerontology. 2008, 54: 333-341. 10.1159/000168203.PubMedGoogle Scholar
- Sikkes SA, de Lange-de Klerk ES, Pijnenburg YA, Scheltens P, Uitdehaag BM: A systematic review of Instrumental Activities of Daily Living scales in dementia: room for improvement. J Neurol Neurosurg Psychiatry. 2009, 80: 7-12. 10.1136/jnnp.2008.155838.PubMedGoogle Scholar
- Ball K, Berch DB, Helmers KF, Jobe JB, Leveck MD, Marsiske M, Morris JN, Rebok GW, Smith DM, Tennstedt SL, Unverzagt FW, Willis SL, Advanced Cognitive Training for Independent and Vital Elderly Study Group: Effects of cognitive training interventions with older adults: a randomized controlled trial. JAMA. 2002, 288: 2271-2281. 10.1001/jama.288.18.2271.PubMed CentralPubMedGoogle Scholar
- Burton CL, Strauss E, Bunce D, Hunter MA, Hultsch DF: Functional abilities in older adults with mild cognitive impairment. Gerontology. 2009, 55: 570-581. 10.1159/000228918.PubMedGoogle Scholar
- Cidboy EL: Significance of behavioral pathology on functional performance in individuals with Alzheimer's disease and related dementias. Am J Alzheimers Dis Other Demen. 2004, 19: 279-289. 10.1177/153331750401900505.PubMedGoogle Scholar
- Demers L, Oremus M, Perrault A, Champoux N, Wolfson C: Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of functional and quality of life scales. J Geriatr Psychiatry Neurol. 2000, 13: 170-180. 10.1177/089198870001300402.PubMedGoogle Scholar
- Blessed G, Tomlinson BE, Roth M: The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry. 1968, 114: 797-811. 10.1192/bjp.114.512.797.PubMedGoogle Scholar
- Erkinjuntti T, Hokkanen L, Sulkava R, Palo J: The blessed dementia scale as a screening test for dementia. Int J Geratr Psychiatry. 1988, 3: 267-273. 10.1002/gps.930030406.Google Scholar
- Stern Y, Albert SM, Sano M, Richards M, Miller L, Folstein M, Albert M, Bylsma FW, Lafleche G: Assessing patient dependence in Alzheimer's disease. J Gerontol. 1994, 49: M216-222.PubMedGoogle Scholar
- Gelinas I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther. 1999, 53: 471-481.PubMedGoogle Scholar
- Gelinas I, Gauthier L, McIntyre M, Gauthier S: Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther. 1999, 53 (5): 471-481.PubMedGoogle Scholar
- Teunisse S, Derix MM: The interview for deterioration in daily living activities in dementia: agreement between primary and secondary caregivers. Int Psychogeriatr. 1997, 9 (Suppl 1): 155-162.PubMedGoogle Scholar
- Teunisse S, Derix MM, van Crevel H: Assessing the severity of dementia. Patient and caregiver. Arch Neurol. 1991, 48: 274-277. 10.1001/archneur.1991.00530150042015.PubMedGoogle Scholar
- DeJong R, Osterlund OW, Roy GW: Measurement of quality-of-life changes in patients with Alzheimer's disease. Clin Ther. 1989, 11: 545-554.PubMedGoogle Scholar
- Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S: An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997, 11 (Suppl 2): S33-39.PubMedGoogle Scholar
- Galasko D, Bennett DA, Sano M, Marson D, Kaye J, Edland SD: ADCS Prevention Instrument Project: assessment of instrumental activities of daily living for community-dwelling elderly individuals in dementia prevention clinical trials. Alzheimer Dis Assoc Disord. 2006, 20: S152-169. 10.1097/01.wad.0000213873.25053.2b.PubMedGoogle Scholar
- Pfeffer RI, Kurosaki TT, Harrah CH, Chance JM, Filos S: Measurement of functional activities in older adults in the community. J Gerontol. 1982, 37: 323-329.PubMedGoogle Scholar
- Cummings JL, Raman R, Ernstrom K, Salmon D, Ferris SH: ADCS Prevention Instrument Project: behavioral measures in primary prevention trials. Alzheimer Dis Assoc Disord. 2006, 20: S147-151. 10.1097/01.wad.0000213872.17429.0f.PubMedGoogle Scholar
- Ferris SH, Aisen PS, Cummings J, Galasko D, Salmon DP, Schneider L, Sano M, Whitehouse PJ, Edland S, Thal LJ: ADCS Prevention Instrument Project: overview and initial results. Alzheimer Dis Assoc Disord. 2006, 20: S109-123. 10.1097/01.wad.0000213870.40300.21.PubMedGoogle Scholar
- Patterson MB, Whitehouse PJ, Edland SD, Sami SA, Sano M, Smyth K, Weiner MF: ADCS Prevention Instrument Project: quality of life assessment (QOL). Alzheimer Dis Assoc Disord. 2006, 20: S179-190. 10.1097/01.wad.0000213874.25053.e5.PubMedGoogle Scholar
- Feldman H, Sauter A, Donald A, Gelinas I, Gauthier S, Torfs K, Parys W, Mehnert A: The disability assessment for dementia scale: a 12-month study of functional ability in mild to moderate severity Alzheimer disease. Alzheimer Dis Assoc Disord. 2001, 15: 89-95. 10.1097/00002093-200104000-00008.PubMedGoogle Scholar
- Gelinas I, Gauthier S, Cyrus PA: Metrifonate enhances the ability of Alzheimer's disease patients to initiate, organize, and execute instrumental and basic activities of daily living. J Geriatr Psychiatry Neurol. 2000, 13: 9-16. 10.1177/089198870001300102.PubMedGoogle Scholar
- Behl P, Lanctot KL, Streiner DL, Guimont I, Black SE: Cholinesterase inhibitors slow decline in executive functions, rather than memory, in Alzheimer's disease: a 1-year observational study in the Sunnybrook dementia cohort. Curr Alzheiner Res. 2006, 3 (2): 147-156. 10.2174/156720506776383031.Google Scholar
- Walsh SP, Raman R, Jones KB, Aisen PS: ADCS Prevention Instrument Project: the Mail-In Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc Disord. 2006, 20: S170-178. 10.1097/01.wad.0000213879.55547.57.PubMedGoogle Scholar
- Perrotin A, Belleville S, Isingrini M: Metamemory monitoring in mild cognitive impairment: Evidence of a less accurate episodic feeling-of-knowing. Neuropsychologia. 2007, 45: 2811-2826. 10.1016/j.neuropsychologia.2007.05.003.PubMedGoogle Scholar
- Michon A, Deweer B, Pillon B, Agid Y, Dubois B: Relation of anosognosia to frontal lobe dysfunction in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1994, 57: 805-809. 10.1136/jnnp.57.7.805.PubMed CentralPubMedGoogle Scholar
- Griffith HR, Belue K, Sicola A, Krzywanski S, Zamrini E, Harrell L, Marson DC: Impaired financial abilities in mild cognitive impairment: a direct assessment approach. Neurology. 2003, 60: 449-457.PubMedGoogle Scholar
- Marson DC, Sawrie SM, Snyder S, McInturff B, Stalvey T, Boothe A, Aldridge T, Chatterjee A, Harrell LE: Assessing financial capacity in patients with Alzheimer disease: A conceptual model and prototype instrument. Arch Neurol. 2000, 57: 877-884. 10.1001/archneur.57.6.877.PubMedGoogle Scholar
- Teng E, Lu PH, Cummings JL: Deficits in facial emotion processing in mild cognitive impairment. Dement Geriatr Cogn Disord. 2007, 23: 271-279. 10.1159/000100829.PubMedGoogle Scholar
- DeIpolyi AR, Rankin KP, Mucke L, Miller BL, Gorno-Tempini ML: Spatial cognition and the human navigation network in AD and MCI. Neurology. 2007, 69: 986-997. 10.1212/01.wnl.0000271376.19515.c6.PubMedGoogle Scholar
- Okonkwo OC, Wadley VG, Griffith HR, Ball K, Marson DC: Cognitive correlates of financial abilities in mild cognitive impairment. J Am Geriatr Soc. 2006, 54: 1745-1750. 10.1111/j.1532-5415.2006.00916.x.PubMedGoogle Scholar
- Duke LM, Kaszniak AW: Executive control functions in degenerative dementias: a comparative review. Neuropsychol Rev. 2000, 10: 75-99. 10.1023/A:1009096603879.PubMedGoogle Scholar
- Royall DR, Palmer R, Chiodo LK, Polk MJ: Declining executive control in normal aging predicts change in functional status: the Freedom House Study. J Am Geriatr Soc. 2004, 52: 346-352. 10.1111/j.1532-5415.2004.52104.x.PubMedGoogle Scholar
- Farias ST, Mungas D, Reed BR, Cahn-Weiner D, Jagust W, Baynes K, Decarli C: The measurement of everyday cognition (ECog): scale development and psychometric properties. Neuropsychology. 2008, 22: 531-544.PubMed CentralPubMedGoogle Scholar
- Farias ST, Harrell E, Neumann C, Houtz A: The relationship between neuropsychological performance and daily functioning in individuals with Alzheimer's disease: ecological validity of neuropsychological tests. Arch Clin Neuropsychol. 2003, 18: 655-672.PubMedGoogle Scholar
- Cahn-Weiner DA, Ready RE, Malloy PF: Neuropsychological predictors of everyday memory and everyday functioning in patients with mild Alzheimer's disease. J Geriatr Psychiatry Neurol. 2003, 16: 84-89. 10.1177/0891988703016002004.PubMedGoogle Scholar
- Gross AL, Rebok GW, Unverzagt FW, Willis SL, Brandt J: Cognitive predictors of everyday functioning in older adults: results from the ACTIVE Cognitive Intervention trial. J Gerontol B Psychol Sci Soc Sci. 2011, 66: 557-566.PubMedGoogle Scholar
- Gioia GA, Isquith PK, Guy SC, Kenworthy L: Behavior rating inventory of executive function. Child Neuropsychol. 2000, 6: 235-238. 10.1076/chin.188.8.131.5252.PubMedGoogle Scholar
- Roth RM, Isquith PK, Gioia GA: Behavioral Rating Inventory of Executive Function - Adult Version. 2005, Lutz, FL: Psychological Assessment Resources, IncGoogle Scholar
- Ready RE, Ott BR, Grace J, Cahn-Weiner DA: Apathy and executive dysfunction in mild cognitive impairment and Alzheimer disease. Am J Geriatr Psychiatry. 2003, 11: 222-228.PubMedGoogle Scholar
- Grace J, Malloy P: Frontal Systems Behavior Scale (FrSBe): Professional Manual. 2001, Lutz, FL: Psychological Assessment ResourcesGoogle Scholar
- Rabin LA, Roth RM, Isquith PK, Wishart HA, Nutter-Upham KE, Pare N, Flashman LA, Saykin AJ: Self-and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints. Arch Clin Neuropsychol. 2006, 21: 721-732. 10.1016/j.acn.2006.08.004.PubMedGoogle Scholar
- Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD: Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002, 10: 125-128.PubMedGoogle Scholar
- Teng E, Ringman JM, Ross LK, Mulnard RA, Dick MB, Bartzokis G, Davies HD, Galasko D, Hewett L, Mungas D, Reed BR, Schneider LS, Segal-Gidan F, Yaffe K, Cummings JL, Alzheimer's Disease Research Centers of California-Depression in Alzheimer's Disease Investigators: Diagnosing depression in Alzheimer disease with the national institute of mental health provisional criteria. Am J Geriatr Psychiatry. 2008, 16: 469-477. 10.1097/JGP.0b013e318165dbae.PubMed CentralPubMedGoogle Scholar
- Lu PH, Edland SD, Teng E, Tingus K, Petersen RC, Cummings JL: Donepezil delays progression to AD in MCI subjects with depressive symptoms. Neurology. 2009, 72: 2115-2121. 10.1212/WNL.0b013e3181aa52d3.PubMed CentralPubMedGoogle Scholar
- van der Linde R, Stephan BC, Matthews FE, Brayne C, Savva GM: Behavioural and psychological symptoms in the older population without dementia--relationship with socio-demographics, health and cognition. BMC Geriatr. 2010, 10: 87-10.1186/1471-2318-10-87.PubMed CentralPubMedGoogle Scholar
- Apostolova LG, Cummings JL: Neuropsychiatric manifestations in mild cognitive impairment: a systematic review of the literature. Dement Geriatr Cogn Disord. 2008, 25: 115-126. 10.1159/000112509.PubMedGoogle Scholar
- Schipper H, Clinch JJ, Olweny CL: Quality of Life Studies: Definitions and Conceptual Issues. 1996, Philadelphia: Lippincott-Raven, 2Google Scholar
- Ware JE: Methodological Considerations in the Selection of Health Status Assessment Procedures. 1984, Greenwich, CT: La JacqGoogle Scholar
- Ettema TP, Droes RM, de Lange J, Mellenbergh GJ, Ribbe MW: A review of quality of life instruments used in dementia. Qual Life Res. 2005, 14: 675-686. 10.1007/s11136-004-1258-0.PubMedGoogle Scholar
- Logsdon RG, Gibbons LE, McCurry SM, Teri L: Quality of life in Alzheimer's disease: patient and caregiver reports. J Mental Health Aging. 1999, 5: 21-32.Google Scholar
- Missotten P, Squelard G, Ylieff M, Di Notte D, Paquay L, De Lepeleire J, Fontaine O: Quality of life in older Belgian people: comparison between people with dementia, mild cognitive impairment, and controls. Int J Geriatr Psychiatry. 2008, 23: 1103-1109. 10.1002/gps.1981.PubMedGoogle Scholar
- Muangpaisan W, Assantachai P, Intalapaporn S, Pisansalakij D: Quality of life of the community-based patients with mild cognitive impairment. Geriatr Gerontol Int. 2008, 8: 80-85. 10.1111/j.1447-0594.2008.00452.x.PubMedGoogle Scholar
- Arlt S, Hornung J, Eichenlaub M, Jahn H, Bullinger M, Petersen C: The patient with dementia, the caregiver and the doctor: cognition, depression and quality of life from three perspectives. Int J Geriatr Psychiatry. 2008, 23: 604-610. 10.1002/gps.1946.PubMedGoogle Scholar
- Scholzel-Dorenbos CJ, van der Steen MJ, Engels LK, Olde Rikkert MG: Assessment of quality of life as outcome in dementia and MCI intervention trials: a systematic review. Alzheimer Dis Assoc Disord. 2007, 21: 172-178. 10.1097/WAD.0b013e318047df4c.PubMedGoogle Scholar
- Berwig M, Leicht H, Gertz HJ: Critical evaluation of self-rated quality of life in mild cognitive impairment and Alzheimer's disease--further evidence for the impact of anosognosia and global cognitive impairment. J Nutr Health Aging. 2009, 13: 226-230. 10.1007/s12603-009-0063-4.PubMedGoogle Scholar
- Mangone CA, Hier DB, Gorelick PB, Ganellen RJ, Langenberg P, Boarman R, Dollear WC: Impaired insight in Alzheimer's disease. J Geriatr Psychiatry Neurol. 1991, 4: 189-193. 10.1177/089198879100400402.PubMedGoogle Scholar
- McDaniel KD, Edland SD, Heyman A: Relationship between level of insight and severity of dementia in Alzheimer disease. CERAD Clinical Investigators. Consortium to Establish a Registry for Alzheimer's Disease. Alzheimer Dis Assoc Disord. 1995, 9: 101-104. 10.1097/00002093-199509020-00007.PubMedGoogle Scholar
- Starkstein SE, Sabe L, Chemerinski E, Jason L, Leiguarda R: Two domains of anosognosia in Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1996, 61: 485-490. 10.1136/jnnp.61.5.485.PubMed CentralPubMedGoogle Scholar
- Arkin S, Mahendra N: Insight in Alzheimer's patients: results of a longitudinal study using three assessment methods. Am J Alzheimers Dis Other Demen. 2001, 16: 211-224. 10.1177/153331750101600401.PubMedGoogle Scholar
- Clement F, Belleville S, Gauthier S: Cognitive complaint in mild cognitive impairment and Alzheimer's disease. J Int Neuropsychol Soc. 2008, 14: 222-232.PubMedGoogle Scholar
- Markova IS, Berrios GE: Insight into memory deficits. Memory Disorders in Psychiatric Practice. Edited by: Berrios GE, Hodges JR. 2000, New York: Cambridge University Press, 204-233.Google Scholar
- Kalbe E, Salmon E, Perani D, Holthoff V, Sorbi S, Elsner A, Weisenbach S, Brand M, Lenz O, Kessler J, Luedecke S, Ortelli P, Herholz K: Anosognosia in very mild Alzheimer's disease but not in mild cognitive impairment. Dement Geriatr Cogn Disord. 2005, 19: 349-356. 10.1159/000084704.PubMedGoogle Scholar
- Ries ML, Jabbar BM, Schmitz TW, Trivedi MA, Gleason CE, Carlsson CM, Rowley HA, Asthana S, Johnson SC: Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in selfappraisal. J Int Neuropsychol Soc. 2007, 13: 450-461.PubMed CentralPubMedGoogle Scholar
- Roberts JL, Clare L, Woods RT: Subjective memory complaints and awareness of memory functioning in mild cognitive impairment: a systematic review. Dement Geriatr Cogn Disord. 2009, 28: 95-109. 10.1159/000234911.PubMedGoogle Scholar
- Cosentino S, Metcalfe J, Butterfield B, Stern Y: Objective metamemory testing captures awareness of deficit in Alzheimer's disease. Cortex. 2007, 43: 1004-1019. 10.1016/S0010-9452(08)70697-X.PubMed CentralPubMedGoogle Scholar
- Dassel KB, Schmitt FA: The impact of caregiver executive skills on reports of patient functioning. Gerontologist. 2008, 48: 781-792. 10.1093/geront/48.6.781.PubMedGoogle Scholar
- Mitchell M, Miller LS: Executive functioning and observed versus self reported measures of functional ability. Clin Neuropsychol. 2008, 22: 471-479. 10.1080/13854040701336436.PubMedGoogle Scholar
- Wlodarczyk JH, Brodaty H, Hawthorne G: The relationship between quality of life, MMSE, and the IADL in patients with Alzheimer' s disease. Arch Gerontol Geriatr. 2004, 39: 25-33. 10.1016/j.archger.2003.12.004.PubMedGoogle Scholar
- Greenop KR, Xiao J, Almeida OP, Flicker L, Beer C, Foster JK, van Bockxmeer FM, Lautenschlager NT: Awareness of cognitive deficits in older adults with cognitive-impairment-no-dementia (CIND): comparison with informant report. Alzheimer Dis Assoc Disord. 2011, 25: 24-33. 10.1097/WAD.0b013e3181f81094.PubMedGoogle Scholar
- Zanetti O, Vallotti B, Frisoni GB, Geroldi C, Bianchetti A, Pasqualetti P, Trabucchi M: Insight in dementia: when does it occur? Evidence for a nonlinear relationship between insight and cognitive status. J Gerontol B Psychol Sci Soc Sci. 1999, 54: P100-106.PubMedGoogle Scholar
- Tremont G, Alosco ML: Relationship between cognition and awareness of deficit in mild cognitive impairment. Int J Geriatr Psychiatry. 2011, 26: 299-306. 10.1002/gps.2529.PubMedGoogle Scholar
- Ott BR, Lafleche G, Whelihan WM, Buongiorno GW, Albert MS, Fogel BS: Impaired awareness of deficits in Alzheimer disease. Alzheimer Dis Assoc Disord. 1996, 10: 68-76. 10.1097/00002093-199601020-00003.PubMedGoogle Scholar
- Kleinman L, Frank L, Flynn JA, Matza L, Bowman L: Comparison of Informant and Neuropsychological Ratings of Cognitive Impairment. 2004, New York, NY: American Psychiatric AssociationGoogle Scholar
- Okonkwo OC, Griffith HR, Vance DE, Marson DC, Ball KK, Wadley VG: Awareness of functional difficulties in mild cognitive impairment: a multidomain assessment approach. J Am Geriatr Soc. 2009, 57: 978-984. 10.1111/j.1532-5415.2009.02261.x.PubMed CentralPubMedGoogle Scholar
- Rankin KP, Baldwin E, Pace-Savitsky C, Kramer JH, Miller BL: Self awareness and personality change in dementia. J Neurol Neurosurg Psychiatry. 2005, 76: 632-639. 10.1136/jnnp.2004.042879.PubMed CentralPubMedGoogle Scholar
- Banks S, Weintraub S: Self-awareness and self-monitoring of cognitive and behavioral deficits in behavioral variant frontotemporal dementia, primary progressive aphasia and probable Alzheimer's disease. Brain Cogn. 2008, 67: 58-68. 10.1016/j.bandc.2007.11.004.PubMed CentralPubMedGoogle Scholar
- Cook S, Marsiske M: Subjective memory beliefs and cognitive performance in normal and mildly impaired older adults. Aging Ment Health. 2006, 10: 413-423. 10.1080/13607860600638487.PubMed CentralPubMedGoogle Scholar
- Reisberg B, Prichep L, Mosconi L, John ER, Glodzik-Sobanska L, Boksay I, Monteiro I, Torossian C, Vedvyas A, Ashraf N, Jamil IA, de Leon MJ: The premild cognitive impairment, subjective cognitive impairment stage of Alzheimer's disease. Alzheimers Dement. 2008, 4: S98-S108. 10.1016/j.jalz.2007.11.017.PubMedGoogle Scholar
- Reisberg B, Gauthier S: Current evidence for subjective cognitive impairment (SCI) as the pre-mild cognitive impairment (MCI) stage of subsequently manifest Alzheimer's disease. Int Psychogeriatr. 2008, 20: 1-16.PubMedGoogle Scholar
- Jack CR, Albert M, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH: Introduction to revised criteria for the diagnosis of Alzheimer's disease: National Institute on Aging and the Alzheimer's Association workgroup. Alzheimers Dement. 2011, 7: 257-262. 10.1016/j.jalz.2011.03.004.PubMed CentralPubMedGoogle Scholar
- Cummings JL: Changes in neuropsychiatric symptoms as outcome measures in clinical trials with cholinergic therapies for Alzheimer disease. Alzheimer Dis Assoc Disord. 1997, 11 (Suppl 4): S1-9.PubMedGoogle Scholar
- Nourhashemi F, Vellas B: Weight loss as a predictor of dementia and Alzheimer's disease?. Expert Rev Neurother. 2008, 8: 691-693. 10.1586/14737184.108.40.2061.PubMedGoogle Scholar
- Gillette Guyonnet S, Abellan Van Kan G, Alix E, Andrieu S, Belmin J, Berrut G, Bonnefoy M, Brocker P, Constans T, Ferry M, Ghisolfi-Marque A, Girard L, Gonthier R, Guerin O, Hervy MP, Jouanny P, Laurain MC, Lechowski L, Nourhashemi F, Raynaud-Simon A, Ritz P, Roche J, Rolland Y, Salva T, Vellas B, International Academy on Nutrition and Aging Expert Group: IANA (International Academy on Nutrition and Aging) Expert Group: weight loss and Alzheimer's disease. J Nutr Health Aging. 2007, 11: 38-48.PubMedGoogle Scholar
- Vellas B, Lauque S, Gillette-Guyonnet S, Andrieu S, Cortes F, Nourhashemi F, Cantet C, Ousset PJ, Grandjean H: Impact of nutritional status on the evolution of Alzheimer's disease and on response to acetylcholinesterase inhibitor treatment. J Nutr Health Aging. 2005, 9: 75-80.PubMedGoogle Scholar
- Gillette-Guyonnet S, Nourhashemi F, Andrieu S, de Glisezinski I, Ousset PJ, Riviere D, Albarede JL, Vellas B: Weight loss in Alzheimer disease. Am J Clin Nutr. 2000, 71: 637S-642S.PubMedGoogle Scholar
- Chouinard J: Dysphagia in Alzheimer disease: a review. J Nutr Health Aging. 2000, 4: 214-217.PubMedGoogle Scholar
- Priefer BA, Robbins J: Eating changes in mild-stage Alzheimer's disease: a pilot study. Dysphagia. 1997, 12: 212-221. 10.1007/PL00009539.PubMedGoogle Scholar
- Djordjevic J, Jones-Gotman M, De Sousa K, Chertkow H: Olfaction in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2008, 29: 693-706. 10.1016/j.neurobiolaging.2006.11.014.PubMedGoogle Scholar
- Fuh JL, Mega MS, Binetti G, Wang SJ, Magni E, Cummings JL: A transcultural study of agitation in dementia. J Geriatr Psychiatry Neurol. 2002, 15: 171-174.PubMedGoogle Scholar
- Chow TW, Liu CK, Fuh JL, Leung VP, Tai CT, Chen LW, Wang SJ, Chiu HF, Lam LC, Chen QL, Cummings JL: Neuropsychiatric symptoms of Alzheimer's disease differ in Chinese and American patients. Int J Geriatr Psychiatry. 2002, 17: 22-28. 10.1002/gps.509.PubMedGoogle Scholar
- Reynish E, Cortes F, Andrieu S, Cantet C, Olde Rikkert M, Melis R, Froelich L, Frisoni GB, Jönsson L, Visser PJ, Ousset PJ, Vellas B, ICTUS Study Group: The ICTUS Study: A Prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort. Neuroepidemiology. 2007, 29: 29-38. 10.1159/000108915.PubMedGoogle Scholar
- Pedrosa H, De Sa A, Guerreiro M, Maroco J, Simoes MR, Galasko D, de Mendonca A: Functional evaluation distinguishes MCI patients from healthy elderly people--the ADCS/MCI/ADL scale. J Nutr Health Aging. 2010, 14: 703-709. 10.1007/s12603-010-0102-1.PubMedGoogle Scholar
- Sullivan MJL, Edgley K, Dehoux E: A survey of Multiple Sclerosis. Part I: Perceived cognitive problems and compensory stratey use. Can J Rehab. 1990, 4: 99-105.Google Scholar
- Locke DE, Dassel KB, Hall G, Baxter LC, Woodruff BK, Hoffman Snyder C, Miller BL, Caselli RJ: Assessment of patient and caregiver experiences of dementia-related symptoms: development of the Multidimensional Assessment of Neurodegenerative Symptoms questionnaire. Dement Geriatr Cogn Disord. 2009, 27: 260-272. 10.1159/000203890.PubMed CentralPubMedGoogle Scholar
- McNair D, Kahn R: Self assessment of cognitive deficits. Assessment in Geriatric Psychopharmacology. Edited by: Crook T, Ferris A, Baltus R. 1983, New Canaan, CT: Mark Powley, 137-143.Google Scholar
- Spitznagel MB, Tremont G: Cognitive reserve and anosognosia in questionable and mild dementia. Arch Clin Neuropsychol. 2005, 20: 505-515. 10.1016/j.acn.2004.11.003.PubMedGoogle Scholar
- Hathaway SR, McKinley JC: A multiphasic personality schedule (Minnesota): I. Construction of the schedule. J Psychology. 1940, 10: 249-254. 10.1080/00223980.1940.9917000.Google Scholar
- Stout JC, Wyman MF, Johnson SA, Peavy GM, Salmon DP: Frontal behavioral syndromes and functional status in probable Alzheimer disease. Am J Geriatr Psychiatry. 2003, 11: 683-686.PubMedGoogle Scholar