Rate of progression of mild cognitive impairment to dementia meta-analysis of 41 robust inception cohort studies

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1 Acta Psychiatr Scand 2009: 119: All rights reserved DOI: /j x Ó 2009 John Wiley & Sons A/S ACTA PSYCHIATRICA SCANDINAVICA Review Rate of progression of mild cognitive impairment to dementia meta-analysis of 41 robust inception cohort studies Mitchell AJ, Shiri-Feshki M. Rate of progression of mild cognitive impairment to dementia meta-analysis of 41 robust inception cohort studies. Objective: To quantify the risk of developing dementia in those with mild cognitive impairment (MCI). Method: Meta-analysis of inception cohort studies. Results: Forty-one robust cohort studies were identified. To avoid heterogeneity clinical studies, population studies and clinical trials were analysed separately. Using Mayo defined MCI at baseline and adjusting for sample size, the cumulative proportion who progressed to dementia, to AlzheimerÕs disease () and to vascular dementia (VaD) was 39.2%, 33.6% and 6.2%, respectively in specialist settings and 21.9%, 28.9% and 5.2%, respectively in population studies. The adjusted annual conversion rate (ACR) from Mayo defined MCI to dementia,andvadwas9.6%,8.1%and1.9%,respectivelyin specialist clinical settings and 4.9%, 6.8% and 1.6% in community studies. Figures from non-mayo defined MCI and clinical trials are also reported. Conclusion: The ACR is approximately 5 10% and most people with MCI will not progress to dementia even after 10 years of follow-up. A. J. Mitchell 1, M. Shiri-Feshki 2 1 Liaison Psychiatry, Leicester Partnership Trust and University of Leicester, Leicester and 2 General Adult Psychiatry, Nottinghamshire Healthcare NHS Trust, Nottinghamshire, UK Key words: mild cognitive impairment; dementia; risk; AlzheimerÕs disease; meta-analysis Alex J Mitchell, Liaison Psychiatry, University Hospitals Leicester and University of Leicester, Leicester, UK. alex.mitchell@leicspart.nhs.uk Accepted for publication November 12, 2008 Summations In studies to date, typically less than half of individuals with mild cognitive impairment (MCI) progress to dementia. The annual conversion rate is about 7% to dementia and, and 2% for VaD. Risk of progress is influenced by the definition and subtype of MCI and the setting. Considerations Studies of less than 3 years duration were not analysed. Only placebo data from trial settings was included. The significance of subject memory complaints was difficult to study. Introduction From the time mild cognitive impairment (MCI) was first defined its definition and course have been subject to considerable debate (1). Petersen and colleagues at the Mayo clinic suggested diagnostic criteria for MCI, as well as introducing amnestic (amci), non-memory (nmmci) and multi-domain (mmci) subtypes although these concepts were not rigorously field tested (2, 3). Since then there has been further controversy about the optimal definition and utility of MCI (4 8). The Mayo clinic criteria are thought by some to be too restrictive, particularly in the requirement for subjective memory complaints (SMC) and objective memory performance deficits 1.5 standard deviations (SDs) below age-adjusted means. It has been suggested that these criteria might reduce the 252

2 Progression of MCI to dementia: meta-analysis proportion diagnosed with MCI too severely (9). Several large studies have recently reported on the community prevalence of strictly defined MCI. In a door-to-door survey of 1600 residents of Tuscany, Italy, the prevalence of amci was 4.9%, lower than the prevalence of dementia itself (6.2%) (10). In a study of 806 subjects (60 76 years of age) from eastern Finland, 5.3% met the Mayo MCI criteria (11). A cross-sectional community study incorporating neuropsychological testing found a 14.9% prevalence amongst 745 subjects in Kolkata, India (12). In the Canadian Study of Health and Aging (CSHA) a strict definition of MCI yielded a 1% prevalence of MCI whereas a modified definition increased the prevalence to 3% (13). In the latter study, cases with dementia were specifically excluded from the denominator when calculating prevalence rates. Recently, simplified criteria for MCI have been proposed by the Working Group of the European Consortium on AlzheimerÕs Disease and the MCI Working Group of the European Consortium on AlzheimerÕs Disease (see box 1) (14, 15). However, others have suggested their own criteria, most commonly omitting the requirement for subjective cognitive (memory) complaints (6, 16). The clinical value of MCI is thought to be its ability to predict later dementia. Bruscoli and Lovestone (2004) reviewed 19 longitudinal studies linking MCI with subsequent dementia although only nine of these had duration of 3 years or longer (17). In this narrative review, the annual conversion rate (ACR) was approximately 10% but with large differences between studies that were unexplained. A 10 15% ACR has been very widely cited but rarely scrutinized using robust data (18). It is possible that a surplus of shortterm studies has given a misleading impression of the ACR. If a 10% ACR held true then within 10 years of diagnosis almost all surviving MCI suffers would have dementia. Peterson suggested that as many as 90% might develop dementia if followed for long enough (19). He was not alone in this assertion as other groups documented a 44 64% conversion rate within just 2 years of initial observation (1, 20, 21). This has led many to suggest that MCI is an inescapable intermediate Box 1. Simplified Consensus Criteria for MCI from Two Working Groups A. Moderate cognitive deficits, short of dementia B. Self-reported and or informant reported cognitive complaints C. Impairment on objective clinical cognitive tests D. Preserved basic activities of daily living and minimal impairment in complex instrumental functions Adapted from Winblad et al (14) and Portet et al (15). stage between normal ageing and dementia (18). Against this, it is well known that not all patients with MCI deteriorate. In fact some patients appear to improve over time (22, 23). For example, Wolf and colleagues (1998) were one of the first groups to show that over almost 3 years 19.5% of MCI sufferers had recovered and an additional 61% neither improved nor deteriorated (22). An alternate possibility therefore is that MCI may not be a homogenous condition but may comprise several disease groups united by propensity to cause modest cognitive impairment. If this hypothesis were true one might expect considerable variation in the long-term natural history and an adequate response to treatment in some but not all sufferers. Aims of the study Given this debate, the primary aim of this study was to systematically compile and analyse the rates of conversion from MCI to dementia but taking into account variations in sampling. Our hypothesis was that studies adhering to a strict MCI definition (particularly those requiring SMC) would show higher progression to dementia than other studies. Our secondary aim was to calculate the relative risk of progression when compared with elderly controls. Material and methods Inclusion criteria and definition of MCI Two minimum standards of sample size and study duration were set to ensure that only robust studies were added (see exclusions below for further details). Where authors adhered to the original 1997 Petersen et al. criteria (2) for MCI or the 2001 revised Petersen et al. criteria (the latter now called amci) (18) the study was denoted as following a Mayo clinic definition. Where authors deviated from this, typically by omitting the requirement for subjective cognitive complaints, then the study was denoted as using non-mayo clinic criteria. Regarding outcome measures, we allowed any operational (such as ICD10, DSMIIIR or DSMIV) or neuropsychologically based definition of dementia and further noted specific conditions of AlzheimerÕs Disease () or vascular dementia where defined by authors. Excluded studies Studies were excluded that defined cognitive impairment solely on the basis of Age-Associated 253

3 Mitchell and Shiri-Feshki Memory Impairment, Cognitive Impairment No Dementia (CIND) or Clinical Dementia Rating (CDR) definitions. We excluded studies that examined the progression of dementia alone (baseline CDR = 1.0) or those that examined risk in mixed samples comprised of both MCI individuals and healthy controls (CDR ) (24, 25). We excluded short-term follow-up studies of less than 3 years mean duration, as these were most likely to lead to inaccurate conclusions as a short follow-up period reduces the power of a cohort study. Equally, we excluded studies where the sample size of cases or controls was less than 20 subjects (26, 27). We excluded studies of cognitive impairment that were dependent upon specific aetiological factors such as alcohol (Wernicke Korsakoff dementia), vitamin or metabolic deficiencies or infections, unless other types of dementia were measured (28, 29). We excluded case control studies, which had no longitudinal period of observation (30, 31). We made every effort to only include analysis of unique patients and controls. Several groups reported findings in multiple publications, particularly those from large databases such as the CSHA. Where possible we excluded studies reporting subsamples and included only the main analysis (13, 32 35). We included data from randomized trials but only using placebo data as this was considered more representative of the natural history of MCI. We excluded studies that presented inadequate data for PsycINFO 1887 to October 2008 and Embase 1980 to October Five full-text collections, Science Direct, Ingenta Select, Ovid Full text, Blackwell Online and Wiley Interscience were searched. The abstract database Web of Knowledge (ISI) was searched, using the above terms as a text word search, and using key papers in a reverse citation search. The following search terms were used Ôprogress* or convert* or prognosis or deteriorate or develop or decline* or cohort or longitud* or prospective* [Abstract]Õ AND ÔDementia or Alzheimer* or mild cognitive [Abstract].Õ Statistical pooled and meta-analysis All primary data were extracted as raw numbers and pooled to calculate raw cumulative conversion and then corrected for years of observation and sample size. Chi-squared test of significance was used for relative risks. We calculated rates of progression as a proportion of those recruited at baseline (inception cohort method) rather than those that survived to follow-up, as this most closely resembles clinical practice when attempting to give estimates of prognosis. Further most studies did not present clear completer data. We also calculated person years of observation in each type of study. Weighted proportion meta-analysis was used to adjust for study size using the DerSimonian Laird model to allow for heterogeneity. The inception cumulative conversion rate total number of progressive cases defined at follow-up and derived from the MCI cohort ¼ : number of MCI patients at recruitment The inception annual conversion rate mean number of progressive cases defined at follow-up and derived from the MCI cohort per year ¼ : number of MCI patients at recruitment inclusion in the analysis. For example, those in which no raw number was presented (or calculable), those that examined predictors of decline alone and those that looked at other aspects of prognosis such as functional decline, hospitalization and mortality. Search criteria A systematic literature search, critical appraisal of the collected studies and pooled analysis were conducted. The following abstract databases were searched: Medline Pubmed 1966 to October 2008, Results Search results Results of the initial search and exclusions are shown in Fig. 1. There were insufficient cases of mixed dementia, Lewy body dementia and frontotemporal dementia to analyse. We found 41 studies that met inclusion but not exclusion criteria (Tables 1 and 2). Twenty-five studies were conducted using strict Mayo clinic criteria, three of which were from randomized trials (36 38). Of the remaining 22, 14 were clinical studies conducted in specialist centres, largely memory 254

4 Progression of MCI to dementia: meta-analysis Pre-dementia prognostic studies (n = 157) CDR 0 or CDR 1.0 at baseline (n = 7) No primary data (n = 35) Cross-sectional (n = 3) Non-dementia as outcome (n = 5) CDR definition (n = 10) MCI Cohort cohort studies Studies with extractable data (n = 107) Inadequate duration (n = 35) CIND definition (n = 6) Inadequate sample size (n = 2) Robust MCI Cohort cohort studies Studies AAMI, AACD (n = 8) Duplicate data (n = 5) (n = 41) Type Observation period Outcome definition Criteria for MCI Comparator Cohort outcome of MCI alone (n = 30) 3 years (n = 8) Generic dementia (n = 25) Classical mayo type (n = 25) Cohort outcome of MCI vs. controls (n = 9) years (n = 17) Probable alzheimer s (n = 29) Modified (non-mayo) (n = 16) Subgroups Outcome of amci (n = 9) Outcome of amci (n = 9) 5 years (n = 9) Vascular dementia (n = 9) Outcome of mmci (n = 8) More than 5 years (n = 7) Outcome of nmmci (n = 5) Fig. 1. QUOROM flow diagram. clinics (39 52) and eight were population studies conducted in the community (53 60). Sixteen were conducted using modified (non-mayo) criteria. Of these four were conducted in specialist centres (61 64) and 12 in the community (65 76). Of 25 studies using a Mayo clinic definition the mean observation period was 4.57 years (SD 2.14) corresponding to person years of observation. In those conforming to a non-mayo definition the mean observation period was 4.59 years (SD 1.1) corresponding to person years of observation. Progression of mayo clinic defined MCI Cumulative risk of dementia and related conditions. Across 13 studies involving a total sample of 4301 individuals with Mayo defined MCI 32.3% (95% CI = %) converted to generic dementia over the natural observation period. Meta-analysis by settings revealed a 39.2% conversion in specialist settings (95% CI = %) and 21.9% (95% CI = %) in community studies. Only two groups documented a total conversion rate over 50% and these were both from specialist centres (40, 48). Eighteen studies involving a total sample of 4454 individuals with Mayo defined MCI found that 624 (unadjusted crude rate of 14.0%) converted to Ôprobable Õ over the natural observation period. Of these only two groups documented a total conversion rate over 50% (44, 56). Meta-analysis stratified by settings showed a 33.6% conversion in specialist settings (95% CI = %) and 28.9% (95% CI = %) in community studies. Seven studies involving 3659 individuals with Mayo defined MCI at baseline found that 74 progressed to VaD (unadjusted crude rate of 2.0%). There were insufficient studies to examine other types of dementia. Using random effects proportion meta-analysis this was adjusted to 6.2% (95% CI = %) in specialist settings and 5.2% (95% CI = %) in community studies. 255

5 Mitchell and Shiri-Feshki Table 1. Methodological summary of rates of progression from MCI to Observation period Study period (years, mean) Setting MCI definition Outcome Mayo clinic definition of MCI Visser et al. (2006) (39) 10 Memory clinic MCI diagnostic criteria in memory clinic Amnestic MCI was defined as a score 1.5 SD below age-, sex-, and education-corrected means on the learning measure or delayed recall measure of the RAVLT or a 10-word list Ganguli et al. (2004) (53) 10 Pennsylvania Community sample: MoVIES-study Retrospective application of The Petersen amnestic MCI criteria were operationalized as i) impaired memory: Word List Delayed Recall score of <1 SD below mean; ii) normal mental status: Mini-Mental State Examination score of 25+; iii) normal daily functioning: no instrumental impairments; iv) memory complaint: subjective response to standardized question; v) not demented: CDR Scale score of <1 Annerbo et al. (2006) (49) 6 Specialist centre Revised Petersen crtieria Subjective memory complaints, objective memory impairment (by neuropsychological tests), not demented not normal, and no impairment in activity in daily living Busse et al. (2006) (54) 6 Community MCI original criteria Sample 75 years or older Dementia (CER) Dementia by DSMIV and ICD10 Dementia (DSMIV) Hansson et al. (2007) (40) 5.2 Specialist centre Original Petersen crtieria Conversion to DSMIIIR Dementia and NINCDS- RDA Larrieu et al. (2002) (60) 5 Personnes Ages QUID study (PAQUID) followed a community-based cohort of healthy elderly for 5 years MCI was defined as memory complaints with objective memory impairment according to Peterson et al. Gabryelewicz et al. (2008) (51) 5 Specialist centre Petersen crtieria Conversion to DSMIIIR dementia, Dickerson et al. (2007) (58) 5 Community volunteers MCI defined by a. informant based complaints b. MMSE above 23 c. objective deficits d. no functional decline e. no dementia NINCDS_RDA criteria Visser & Verhey (2008) (42) 5 Maastricht memory clinic Amnestic MCI (Petersen et al. 1999) was defined as a score 1.5 SD below the mean of a reference population after correction for age, gender and education and with no functional impairment (a score below 4 on the GDS). Single-domain and multidomain MCI considered together under amci Artero et al. (2008) (59) 4 Community (three cities in France) Classical criteria (a) presence of a cognitive complaint from either the subject or a family member, (b) absence of dementia, (c) change from normal cognitive functioning, (d) decline in any area of cognitive functioning, and (e) preserved overall general functioning but maybe increasing difficulty in the performance of activities of daily living. NINCDS_RDA criteria dementia (DSMIV), and VaD Petersen et al. (1999) (41) 4 Mayo clinic CDR 0.5 plus Mayo clinic criteria Outcome Tabert et al. (2006) (42) 3.88 Memory clinic Peterson criteria Conversion to (not generic dementia) Bombois et al. (2008) (52) 3.8 Lille memory clinic Classical criteria Dementia,, VaD, LBD Jack et al. (2004) (44) 3.6 Mayo clinic (community and specialist referral patients) Criteria for the diagnosis of MCI were as follows: i) memory complaint documented by the patient and collateral source, ii) normal general cognition, iii) normal activities of daily living, iv) no dementia v) memory impairment for age and education 256

6 Progression of MCI to dementia: meta-analysis Table 1. (Continued) Observation period Study period (years, mean) Setting MCI definition Outcome Yaffe et al. (2006) (48) 3.1 Mayo clinic (community and specialist referral patients) MCI defined as cognitive impairment but did not meet criteria for dementia MCI subtypes also studied Gabryelewicz et al. (2006) (45) 3.02 Specialist centre The diagnosis of MCI according to Mayo Clinic PetersenÕs Criteria was conducted by a panel of specialists (NINCDS-RDA criteria), vascular (State of California criteria) outcome not clearly reported DSMIII dementia Marcos et al. (2006) (46) 3 Specialist centre Petersen et al. criteria for MCI (all had SMC) Progression to Herukka et al. (2005) (47) 3 Specialist centre Petersen et al. criteria for MCI including subjective (method not stated) memory complaints. Palmer et al. (2007) (56) 3 Community Kungsholmen Project, a longitudinal populationbased study of those aged 75 years living in the Kungsholmen area of Stockholm, Sweden. Mayo clinic Petersen Criteria for baseline MCI. amci and mmci combined in data by criteria similar to NINCDS_RDA criteria Ravaglia et al. (2006) (50) 3 Specialist Participants were recruited among the outpatients seeking medical advice for cognitive complaints at the Center for Physiopathology of Aging, University of Bologna. Ritchie et al. (2001) (57) 3 Community (recruited from GP research network) MCI subtypes diagnosed according to standardized Petersen criteria (amnestic; impairment of memory plus other cognitive domains; non-amnestic) Original Petersen criteria) Dementia VaD Zanetti et al. (2006) (55) 3 Community Mayo clinic Petersen Criteria for MCI Dementia VaD Non-Mayo clinic definition of MCI Tyas et al. (2007) (65) 8 Community Analyses were based on seven annual examinations ( ) of 470 Nun Study participants living in the United States MCI had at least one specific area of impaired cognitive function, such as memory or naming, but had intact global cognitive ability and activities of daily living Aggarwal et al. (2005) (66) 5.1 Community Clinical diagnoses were performed using a three-stage process, including neuropsychological tests Devanand et al. (2007) (61) 5 Specialist clinical Broadly defined MCI MRI MMSE Selective Reminding Test (SRT) WAIS Bozoki et al. (2001) (62) 5 Specialist centre Michigan AlzheimerÕs disease research centre Hogan & Ebly (2000) (68) 5 Community and institution Canadian Study of Health and Aging (CSHA) randomly selected community- and institution-dwelling respondents, aged 65 years and older Grober et al. (2000) (67) 5 Community Elderly volunteers from the Einstein Aging Study Definition consisted of neuropsychological deficits plus MMSE over 23 plus not depressed They assessed cognitive function and divided them into two groups of M) (=amci) and M+ MCI ICD10 type 2 (short or long-term memory impairment with intellectual decline but no functional impairment) Blessed score without dementia Dementia (clinical criteria) NINCDS_RDA Criteria NINCDS_RDA Criteria NINCDS_RDA Criteria 257

7 Mitchell and Shiri-Feshki Table 1. (Continued) Observation period Study period (years, mean) Setting MCI definition Outcome Ishikawa & Ikeda (2007) (69) 5 Community MCI without SMC i) normal general cognitive function, with MMSE 24; ii) objective memory impairment, assessed by three-words recall in MMSE (delayed recall 0 3or1 3); iii) neuropsychiatric examination: absence of dementia or depression, diagnosed by geriatric neuropsychiatrists according to the DSM-III R and iv) no L impairment Dementia VaD Heun et al. (2006) (70) 4.7 Community Peterson (1999) Mayo criteria [interviewed using the Structured Interview for Diagnosis of Dementia of the Alzheimer Type, Multi-infarct Dementia, and Dementia of other Aetiology (SIDAM)] Bennett et al. (2002) (71) 4.5 Special community All subjects were older Catholic nuns, priests, and brothers Storandt et al. (2002) (63) 4.4 Alzheimer Disease Research Center Lopez et al. (2007) (72) 4.3 Community (Cardiovascular Health Study) Cognitive Impairment short of dementia Fifty-nine people in the CDR 0.5 group received a global CDR of 0.5 but had impairments in fewer than four areas and thus did not meet our strict diagnostic criteria for Group similar to MCI, as they had memory complaints, poor memory performance, CDR of 0.5, and preserved general cognitive abilities as defined by MMSE scores of _24 and do not meet criteria for CHS Cognition Study diagnostic criteria for MCI MCI-AT included subjects with impairments (defined as performance <1.5 SD from controls) and possible mild defects of IL MCI-MCDT, required impairments in at least one cognitive domain (other than memory), or one abnormal test in at least two domains (defined as performance <1.5 SD) from controls, without severe impairment, in activities of daily living Di Carlo et al. (2007) (76) 3.9 Community From the ILSA MCI using neuropsychological tests Subjects not scoring 1 SD only on the BSRT and preserved attention were defined as MCI Solfrizzi et al. (2004) (74) 3.5 Community From the ILSA Clinical criteria of MCI using neuropsychological tests including the BSRT and MMSE Solfrizzi et al. (2007) (75) 3.5 Community From the ILSA Clinical criteria of MCI using neuropsychological tests including the BSRT and MMSE Alexopoulos et al. (2006) (64) 3.49 Specialist Outpatients register for cognitive disorders Impaired cognition plus preserved basic L plus CDR = 0.5 without dementia Tschanz et al. (2006) (73) 3 Community Baseline cognitive disorder as indicated by mild difficulty in daily functioning (based on informant report) or objective impairment on neuropsychological testing using 3MS and IQCODE In addition those with those with early memory involvement and or neuropsychological testing consisting of a predominance of memory impairment (1.5 or more SD below age-corrected means or percentile equivalent) with no or lesser impairment of other cognitive domains were sub-classified as prodromal whereas others were called other cognitive syndromes NINCDS_RDA Criteria Dementia and by expert evaluation with some postmortem confirmation Dementia and Dementia (ICD10) NINCDS-RDA also examined 258

8 Progression of MCI to dementia: meta-analysis Table 1. (Continued) Observation period Study period (years, mean) Setting MCI definition Outcome Randomized trial settings Thal et al. (2005) (36) 4 RCT in specialist centres Criteria: patient reports memory problem, or informant reports that patient has memory problem; informant reports that patientõs memory has declined in the past year; MMSE score over24 plus neuropsychological criteria Feldman et al. (2007) (38) 4 RCT in specialist centres All patients were identified at entry to have MCI operationally defined by having cognitive symptoms, a global CDR stage of 0.5 and a score of less than 9 on the New York University delayed paragraph recall test Petersen et al. (2005) (37) 3 RCT in specialist centres Amnestic mild cognitive impairment of a degenerative nature (insidious onset and gradual progression), seven impaired memory, a Logical Memory delayed-recall score approximately SD below an educationadjusted norm, a CDR of 0.5, a score of 24 to 30 on MMSE, and an age of years NINCDS_RDA Criteria NINCDS_RDA Criteria NINCDS_RDA Criteria 3MS, Modified Mini-Mental State Examination; MCI, mild cognitive impairment; amci, amnestic variant of mild cognitive impairment; mmci, multi-domain variant of mild cognitive impairment; nmci, non-memory variant of mild cognitive impairment; HR, hazard ratio; RR, relative risk; MMSE, Mini-mental state examination; BSRT, Babcock Story Recall Test; ILSA, Italian Longitudinal Study on Aging; CDR, clinical dementia rating; SD, standard deviation. Annual risk of dementia and specific dementias. In studies adhering to the Mayo clinic definition, correcting for sample size, and dementia type the ACR in specialist settings was 9.6% (95% CI = %) to dementia, 8.1% (95% CI = %) to and 1.9% (95% CI = %) to VaD. The adjusted ACR in community settings was 4.9% (95% CI = %) to dementia, 6.8% (95% CI = %) to and 1.6% (95% CI = %) to VaD. Progression of MCI in studies using non-mayo definition of MCI Cumulative risk of dementia and related conditions. Twelve studies involving a total sample of 4456 individuals with non-mayo defined MCI found that 520 (unadjusted crude rate of 16.3%; adjusted 24.1%, 95% CI %) converted to broadly defined dementia. Of those conducted in community settings, the corrected meta-analytic proportion was 22.7% (95% CI = %). Three studies conducted in specialist settings, found that 33.1% (95% CI = %) progressed to compared with 17.1% (95% CI = %) for population studies in the community. Only two studies involving 731 non- Mayo MCI defined patients documented VaD as an outcome, both in the community. The metaanalytic cumulative proportion was 2.9% (95% CI = %). Annual risk of generic dementia and specific dementias. There was only one study for generic dementia in specialist settings using non-mayo definition with an 11.7% ACR. For community studies there equivalent corrected ACR was 5.2% (95% CI = %). For the corrected ACR was 6.9% (95% CI = %) for clinical studies and 3.6% for community (population) studies (95% CI = %). There were no VaD specialist studies of this type but in the community the ACR was VaD 0.6% (corrected 0.54%, 95% CI = %) Table 3. Comparative risk of dementia in healthy controls Eight studies (three using Mayo definition and five not using Mayo definition) examined the risk of dementia or in healthy age comparable controls head-to-head with the risk in individuals with MCI, a total pooled sample of 6713 individuals (39, 44, 56, 65, 67, 71, 73). One addition study was excluded because of an unrealistically small sample of just 18 individuals (26). Across all but one study (71) there were no significant demographic differences with the comparator MCI population. In five head-to-head studies where dementia was the outcome, the ACR (mean follow-up 6.0 years) was 3.6% to dementia vs. 0.43% for healthy subjects a relative risk of Correcting for sample size, meta-analysis showed a pooled relative risk of 13.8 (95% CI = ) which was statistically significant (P < 0.01). In six headto-head studies for, the ACR (mean follow-up 6.0 years) was 3.5% to vs. 0.78% for healthy subjects, a relative risk of This was adjusted 259

9 Mitchell and Shiri-Feshki Table 2. Statistical summary of rates of progression from MCI to Study Duration (years, mean) Setting MCI sample size Proportion developing dementia Proportion developing Proportion developing VaD ACR dementia ACR ACR VaD Mayo clinic definition of MCI Visser et al. (2006) (39) 10 Specialist centre Annerbo et al. (2006) (49) 6 Specialist centre Hansson et al. (2007) (40) 5.2 Specialist centre Visser & Verhey (2008) (42) 5 Specialist centre Gabryelewicz et al. (2008) (51) 5 Specialist centre Petersen et al. (1999) (41) 4 Specialist centre Tabert et al. (2006) (42) 3.88 Specialist centre Bombois et al. (2008) (52) 3.8 Specialist centre Jack et al. (2004) (44) 3.6 Specialist centre Gabryelewicz et al. (2006) (45) 3.02 Specialist centre Yaffe et al. (2006) (48) 3.1 Specialist centre Herukka et al. (2005) (47) 3 Specialist centre Marcos et al. (2006) (46) 3 Specialist centre Ravaglia et al. (2006) (50) 3 Specialist centre Ganguli et al. (2004) (53) 10 Community Busse et al. (2006) (54) 6 Community Dickerson et al. (2007) (58) 5 Community Artero et al. (2008) (59) 4 Community Palmer et al. (2007) (56) 3 Community Zanetti et al. (2006) (55) 3 Community Larrieu et al. (2002) (60) 5 Community Ritchie et al. (2001) (57) 3 Community Non-Mayo clinic Definition of MCI Devanand et al. (2007) (61) 5 Specialist centre Bozoki et al. (2001) (62) 5 Specialist centre Storandt et al. (2002) (63) 4.4 Specialist centre Alexopoulos et al. (2006) (64) 3.49 Specialist centre Tyas et al. (2007) (65) 8 Community Aggarwal et al. (2005) (66) 5.1 Community Grober et al. (2000) (67) 5 Community Hogan & Ebly (2000) (68) 5 Community Ishikawa & Ikeda (2007) (69) 5 Community Heun et al. (2006) (70) 4.7 Community Bennett et al. (2002) (71) 4.5 Community Lopez et al. (2007) (72) 4.3 Community Di Carlo et al. (2007) (76) 3.9 Community Solfrizzi et al. (2004) (74) 3.5 Community Solfrizzi et al. (2007) (75) 3.5 Community Tschanz et al. (2006) (73) 3 Community Randomized trial settings Thal et al. (2005) (36) 4 Specialist centre Petersen et al. (2005) (37) 3 Specialist centre Feldman et al. (2007) (38) 4 Specialist centre MCI, mild cognitive impairment;, AlzheimerÕs disease; VaD, vascular dementia; ACR, annual conversion rate. to 8.93 (95% CI = , P < 0.01) on random effects meta-analysis Fig. 2. Progression of dementia and or in MCI subgroups Nine studies examined the trajectories of subtypes of MCI, specifically amci and or mmci and or nmmci (42, 44, 48, 50, 55, 62, 64, 76, 77). The corrected ACR for amci was 11.7% (nine studies sample size = 646), mmci 12.2% (eight studies, sample size = 446) and nmmci 4.1% (five studies, sample size = 354). There was a significant difference in outcomes (amci vs. nmmci v 2 = 35.1, P = ; mmci vs. nmmci v 2 = 35.0, P = ). Progression of MCI in long-term clinical trials Cumulative risk of dementia. No studies were identified that defined generic dementia. Cumulative risk of specific dementias. Three studies involving placebo treatment of 1501 individuals with Mayo defined MCI found that 264 (18.4%) 260

10 Progression of MCI to dementia: meta-analysis Table 3. Summary of rates of annual progression from MCI to dementia and related conditions Mayo defined MCI (N = 24) Non-Mayo defined MCI (N = 17) Progression to dementia (any type) Progression to Progression to VaD Progression to VaD Progression to Progression to Dementia (any type) Setting 9.6% (N = 8) (95% CI = %) 8.1% (N = 12) (95% CI = %) 1.9% (N = 5) (95% CI = %) 11.7% (N = 1) (95% CI = %) 6.9% (N = 3) (95% CI = %) No data Specialist (clinical) 4.9% (N = 5) (95% CI = %) 6.8% (N = 6) (95% CI = %) 1.6% (N = 2) (95% CI = %) 5.2% (N = 11) (95% CI = %) 3.6% (N = 5) (95% CI = %). 0.54% (N = 2) (95% CI = %) Community (population) No data 5.5% (N = 3) (95% CI = %) No data No data No data No data Randomized trial setting converted to over a mean observation period of 3.6 years. No studies examined outcomes of other dementias. Annual risk of dementia and specific dementias. The uncorrected ACR to was 4.1%, corrected to 5.5% (95% CI = %). Discussion Across 41 robust cohort studies the overall ACR was 6.7% (95% CI = %) for progression to dementia, 6.5% (95% CI = %) for, and 1.6% (95% CI = %) for VaD all substantially less than previously thought. Nevertheless the relative risk of progression was 15.9 (MCI Mayo type) and 6.2 (MCI non-mayo type) for dementia and 9.5 (MCI Mayo type) and 4.7 (MCI non-mayo type) for when compared with healthy elderly individuals. The cumulative proportion that progressed to dementia rarely exceeded 50% even in long-term studies and averaged 32.3% for those with Mayo clinic defined MCI and 24.1% for those with non- Mayo criteria (30.2%, 22.9% for respectively). Even in six studies with an observation period of 5 years or more the cumulative conversion rate was only 38.2%. This suggests that many, perhaps most people with MCI do not deteriorate to dementia in the medium term (78, 79). A significant proportion improve and others do not survive long enough to allow dementia to develop. For those individuals with SMC fulfilling full criteria for MCI presenting to memory clinics then the risk of dementia is about 10% per year. Even then, in this high risk group the risk of progression appears to diminish with time (56, 71, 80, 81). For individuals who do not meet Mayo criteria for MCI (typically those without SMC) and for those seen in the community and annual risk of progression is usually about 5% with about one in five deteriorating to dementia over the next 5 years. Even in clinical trials from specialist centres the ACR is about 8%, demonstrating why large samples are needed to examine therapeutic effects. Related to this, the large Antiinflammatory Prevention Trial of 2528 individuals recently showed that of those who developed incident dementia over 3 years only 63% (66% for ) had a prodromal phase of CIND, MCI or a related condition (82). Taken together this suggests that MCI is neither necessary nor sufficient for later dementia. Certain types of cognitive impairment do not warrant a label of well-defined MCI, such as those with impaired global cognition but persevered memory, language, and visuospa- 261

11 Mitchell and Shiri-Feshki (a) Relative risk meta-analysis plot (random effects) Visser et al (2006) (13.61, 32.51) Jack et al (2004) (5.02, 64.21) Dickerson et al (2007) (8.47, infinity) Palmer et al (2007) 6.25 (3.74, 10.41) Ishikawa & Ikeda (2007) 2.77 (0.87, 9.02) Bennett et al (2002) 4.73 (3.39, 6.56) Combined [random] 8.93 (4.18, 19.07) Relative risk (95% confidence interval) (b) Relative risk meta-analysis plot (random effects) Visser et al (2006) (13.61, 32.51) Tyas et al (2007) 8.33 (3.73, 18.67) Grober et al (2000) (10.09, ) Ishikawa & Ikeda (2007) 5.54 (1.87, 17.00) Tschanz et al (2006) (10.49, 18.04) Combined [random] (8.44, 22.60) Relative risk (95% confidence interval) Fig. 2. Relative risk meta-analysis of annual progression in mild cognitive impairment (MCI) vs. healthy subjects. (a) Relative risk of AlzheimerÕs disease. (b) Relative risk of dementia. Axis indicates the relative risk of conversion to dementia in those with MCI vs. those without. The size of the boxes represent the size of the sample in the study. tial functioning but these individuals still carry a high risk of decline (58, 77). From our data several key factors moderated rates of deterioration namely, the classification of MCI, the subtype of MCI and the setting. The relative risk of progression was approximately twofold in those defined using strict criteria and in those recruited from specialist settings, but only about 1 3rd in those with nmmci. The finding that risk was significantly higher in patients diagnosed using the Mayo clinic criteria may be partly because of the difference in requirement for SMC. It is to be expected that when omitting SMC, people with baseline cognitive deficits progress more slowly as SMC are a known risk factor for dementia (83). It is also likely that most of those presenting to specialist centres would have SMC whether SMC have been documented or not. There has been considerable interest in the proposed subtypes of MCI. We identified nine studies that examined differential rates of progression. There was a significantly higher ACR for mmci and amci than nmmci. Further studies are required before clear conclusions can be drawn about the 262

12 Progression of MCI to dementia: meta-analysis validity of these MCI subtypes. Alternate classifications based on aetiology may be more successful. This analysis has a number of limitations. Notably we were reliant on the quality and nonrepetition of primary publications. We sought to ensure data integrity by excluding small studies of less than 3 years duration. However, long-term studies are subject to greater attrition and there is likely to be difference in risk when compared using an inception vs. completer cohort method [see Mitchell and Shiri-Feshki (84) for further discussion]. There is a possibility of double counting some individuals especially where several related publication arise from one group. We attempted to deal duplicate data from the same authors by excluding studies where the population characteristics were nearly identical to those already entered (see table). 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