Mini‐Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI) (2024)

Monitoring Editor: Cochrane Dementia and Cognitive Improvement Group, Ingrid Arevalo-Rodriguez, Nadja Smailagic, Marta Roqué-Figuls, Agustín Ciapponi, Erick Sanchez-Perez, Antri Giannakou, Olga L Pedraza, Xavier Bonfill Cosp, and Sarah Cullum

Baseline scores of Mini‐Mental State examination (MMSE) for early prediction of developing dementia in people with mild cognitive impairments (MCI)

Patients with MCI should be evaluated and monitored due to their increased risk of progression to dementia. At present there are no agreements about what the best approach is to register the progression to dementia. Several cognitive function tests have been proposed for this task because most of them are easy to administer, take no longer than 10 minutes to complete, involve major executive functions, and yield an objective score. Our review assessed the current evidence related to one of those brief tests, the Mini‐Mental State Examination (MMSE), in the prediction of decline to dementia in people with cognitive impairments. After an extensive search and analysis of available information, we did not find evidence supporting a substantial role of MMSE as a stand‐alone single‐administration test in the identification of patients who will convert to dementia in the future.

Summary of findings 1

Summary of findings 2

Summary of findings 3

Target condition being diagnosed

In general, dementia as diagnosed is defined by a deficit in more than two cognitive domains that is of sufficient degree to impair functional activities. Symptoms are usually progressive over a period of at least several months and should not be attributable to any other brain disease (American Psychiatric Association 1994). Dementia develops over a trajectory of several years, and it is presumed that during some portion of this time people are asymptomatic and pathology is accumulating (Jack 2011). Individuals or their relatives may notice subtle impairments of recent memory during this time. Gradually, more cognitive domains become involved and difficulty planning complex tasks becomes increasingly apparent. Subtypes of dementia include Alzheimer's disease dementia (ADD) (McKhann 1984; McKhann 2011), vascular dementia (Roman 1993), frontotemporal dementia (Lund and Manchester Groups 1994) and Lewy body dementia (McKeith 1996), among others. Some dementia subtypes are related to other neurological diseases such as Parkinson's disease (Goetz 2008).

This review focused on conversion from MCI to all‐cause dementia, ADD, as well as conversion from MCI to other forms of dementia, which were assessed at follow‐up. As was previously noted, several studies have shown that most patients with MCI are at increased risk of developing dementia (Petersen 2011). Several medications have been evaluated for use in reducing or delaying the risk of progression, but none have been adopted for extended clinical use (Farina 2012; Russ 2012; Yue 2012).

Index test(s)

The Folstein Mini‐Mental State Examination (MMSE) is a 30‐question assessment of cognitive function that evaluates attention and orientation, memory, registration, recall, calculation, language and ability to draw a complex polygon (Folstein 1975). The MMSE has recently been subject to copyright restrictions (de Silva 2010). In its inception, the MMSE was not conceived to identify early stages of dementia, distinguish between different types of dementia or to predict the development of dementia in the long term.

Advantages of the MMSE include rapid administration, availability of multiple language translations and high levels of acceptance as a diagnostic instrument amongst health professionals and researchers (Nieuwenhuis‐Mark 2010). The presence of cognitive decline is determined by the total score. Traditionally, a 23/24 cut‐off has been used to select patients with suspected cognitive impairment or dementia (Tombaugh 1992). However, several studies have shown that sociocultural variables, age and education, among other factors, could affect individual scores (Bleecker 1988; Brayne 1990; Crum 1993); therefore local standards must be developed for each population and setting evaluated (Diniz 2007; Kulisevsky 2009; Shiroky 2007; Trenkle 2007).

Clinical pathway

Dementia develops over a trajectory of several years. It is presumed that during some portion of this time people are asymptomatic and pathology is accumulating. Individuals or their relatives may notice subtle impairments of recent memory during this time. Gradually, more cognitive domains become involved and difficulty planning complex tasks becomes increasingly apparent. People with memory complaints usually present to their general practitioner (primary care), who may administer one or more brief cognitive tests and potentially refer the individual to a memory clinic (secondary care). However, many people with dementia do not present until much later in the course of the disease and follow a different pathway to diagnosis. In community settings, screening tests are usually administered to estimate the epidemiological figures of dementia, identify cases to be included in clinical trials or even establish a follow‐up to detect incident cases or changes in cognitive performance (Brayne 2011). In all cases, a follow‐up period is mandatory to detect cognitive changes in populations and conversion of mild cases to dementia (delayed verification).

Standard assessment of dementia includes a history and clinical examination (including neurological, mental state and cognitive examinations); laboratory tests such as thyroid‐stimulating hormone, serum folic acid, serum vitamin B₁₂ and blood count; an interview with a relative or other informant; and neuroradiological evaluation (Feldman 2008; Hort 2010). Before dementia is diagnosed, other physical and mental disorders (for example hypothyroidism, depression) that might be contributing to cognitive impairment should be excluded or treated. Neuropsychological examination includes full assessment of major cognitive domains, including memory, executive functions, language, attention and visuospatial skills. A neuroradiological examination (computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain) is also recommended in most recent consensus guidelines (McKhann 2011), although the use of cerebrospinal fluid (CSF) biomarkers is controversial (Dubois 2010). Sometimes the diagnosis is made on the basis of history and presentation alone.

Rationale

The public health burden of cognitive and functional impairment due to dementia is of growing concern. With the changing age structure of populations in both high‐ and low‐income countries, the prevalence of dementia is increasing (Ferri 2005; Prince 2013). At the population level, this has major implications for service provision and planning given that the condition leads to progressive functional dependence over several years. Accurate diagnosis leads to opportunities for treatment and appropriate care, but it is also crucial to identify participants for clinical trials of sufficient power to demonstrate the effectiveness of potential treatments.

At the present time, no 'cure' for dementia is known, but some treatments can slow cognitive and functional decline or reduce associated behavioural and psychiatric symptoms of dementia (Birks 2006; Clare 2003; McShane 2006). Furthermore, diagnosis of ADD (and other dementias) at an early stage (that is MCI) will help people with dementia, their families and potential carers in making timely plans for the future. Coupled with appropriate contingency planning, proper recognition of the disease may help prevent inappropriate and potentially harmful admissions to hospital or institutional care. In addition, accurate early identification of dementia may increase opportunities for the use of newly evolving interventions designed to delay or prevent progression to more debilitating stages of disease.

The Cochrane Dementia and Cognitive Improvement Group is undertaking a series of DTA systematic reviews, including three on the accuracy of the MMSE for diagnosing dementia. This review will be focused on evaluation of the MMSE and delayed‐verification studies for assessment of conversion from MCI to dementia.

Secondary objectives

To assess the heterogeneity of test accuracy by population (for example memory clinics, community settings) and MMSE thresholds, amongst other factors.

Criteria for considering studies for this review

Search methods for identification of studies

Data collection and analysis

Results of the search

Our search resulted in 24,357 citations (47 identified in congress reports), of which 17,513 references that were not related to MMSE information were excluded (Figure 1). After that, 6844 records were screened by the authors; excluding 6611 citations. Then 233 records were assessed in more depth in order to apply the inclusion criteria; 186 studies were excluded as they did not include participants with MCI at baseline, and did not assess the conversion from MCI to dementia. Finally, 47 references were retrieved in full text. The review team excluded 35 of them, mainly because they did not provide data about the accuracy of MMSE for conversion to dementia from MCI (see Characteristics of excluded studies). We contacted nine authors to request useable data, of which six responded. Two studies with insufficient data were therefore excluded (Li 2011; Mauri 2012). One study retrieved in abstract form was classified as an 'ongoing study' because the authors presented a protocol in progress but without information about the accuracy of MMSE scores (Hall 2012). The review included 12 references representing 11 datasets with a total of 1569 participants (Table 2).

Methodological quality of included studies

We assessed the risk of bias using the QUADAS‐2 tool (Appendix 3; Appendix 4). The main results are summarized below (Figure 2; Figure 3).

In the patient selection domain we judged three studies (Conde-Sala 2012; Meguro 2007a; Meguro 2007b) to be at high risk of bias due to poor reporting of both the sampling procedure and exclusion criteria. We considered four studies (Buchhave 2008; Chopard 2009; Modrego 2005; Palmqvist 2012) to be at unclear risk of bias because they did not report whether the participants were systematically enrolled. We considered the remaining four studies (Devanand 2008; Modrego 2013; Pozueta 2011; Xu 2002) to be at low risk of bias. We stated that all included studies avoided a case‐control design because we only considered data on the performance of the index test to discriminate between patients with MCI who converted to dementia and those who remained stable (that is delayed verification cohort studies).

In the index test domain we considered eight studies (Buchhave 2008; Chopard 2009; Devanand 2008; Modrego 2005; Modrego 2013; Palmqvist 2012; Pozueta 2011; Xu 2002) to be at high risk of bias because the threshold used was not pre‐specified and the optimal cut‐off level was determined from ROC analyses; therefore, the accuracy of the MMSE reported in these studies appeared to be overestimated. Some studies reported poorly which MMSE version was used and who administered and interpreted the test. We judged the remaining three studies (Conde‐Sala 2012; Meguro 2007a; Meguro 2007b) to be at low risk of bias.

In the references´ standard domain we considered four studies (Buchhave 2008; Conde‐Sala 2012; Modrego 2013; Xu 2002) to be at 'unclear' risk of bias and two more at high risk (Modrego 2005; Pozueta 2011) because they did not provide enough information about independence and blinding between baseline MMSE scores and the final diagnosis of dementia. These last studies also did not provide enough information about the criteria to establish the conversion from MCI to dementia at follow‐up.

In the flow and timing domain we considered the majority of studies (eight) to be at low risk of bias. We judged two (Devanand 2008; Pozueta 2011) to be at high risk of bias and one (Modrego 2005) to be at unclear risk of bias due to loss to follow‐up (5% to 15% of losses at follow‐up) or poor reporting, or both.

For assessment of applicability concerns, for the majority of the studies (seven) there was no concern that the included patients and setting, the conduct and interpretation of the index test, and the target condition (as defined by the reference standard) did not match the review question. We judged that there was unclear concern about applicability for Modrego 2005 regarding all three domains and for Buchhave 2008, Modrego 2013 and Pozueta 2011 regarding the reference standard domain. It should be noted that the lack of concern about applicability of the three domains mentioned above was based on the inclusion criteria set in the review.

Findings

Included studies are detailed in Characteristics of included studies and Table 2 and Table 3. The total number of participants across all included studies was 1569 (median = 109; inter‐quartile range (IQR) = 105 to 140). The maximum percentage of losses to follow‐up was 15% (Devanand 2008).

One of the references (Meguro 2007a; Meguro 2007b) contained two independent datasets with different follow‐ups and we included these as separate entries. Another reference had a single population followed in two different time frames and thresholds (Modrego 2005). We included the information from the longest follow‐up (three years) in general analysis. Finally, one of the studies showed information about the accuracy of the Orientation and Recall MMSE subscales (Palmqvist 2012) but this information was not included in our analysis.

More than half of the studies were developed with patients from memory clinics (Buchhave 2008; Chopard 2009; Conde‐Sala 2012; Devanand 2008; Palmqvist 2012; Pozueta 2011) with average ages greater than 60 years. In all studies, between 36.3% and 70% of participants were women. Few studies provided descriptive information about social class, years of education, MMSE version used, comorbidities or APOE‐ε4 status. No study provided information about pharmacological or non‐pharmacological interventions for MCI during the follow‐up.

Four different diagnostic thresholds were used to define a positive MMSE (≤ 21, ≤ 26, ≤ 28, ≤ 29). Two additional datasets (Meguro 2007a and Meguro 2007b) considered cut‐offs according to individual years of education (≤ 17 for less or equal to 6 years of education, ≤ 20 for 7 to 8 years of education, and ≤ 23 for 10 or more years of education). One additional study provided accuracy for a predicted risk of 0.5 derived from a univariate logistic regression model, instead of a MMSE threshold (Devanand 2008).

Average follow‐up times ranged from 15 months to seven years. Median incidence of all‐cause dementia in general was 36.5% (4 datasets; IQR = 32.9 to 37.8), while the median incidence of ADD was 39.4% (8 datasets; IQR = 13.3 to 54.2). Only one study provided data for vascular dementia (VaD) incidence (Xu 2002, 6.26%). The scope of the studies included data from five different countries: four studies from Spain; two from Japan, Switzerland and USA; and one from France. In general, sensitivity and specificity figures ranged between 23% and 88% and 32% and 94%, respectively (Table 3).

Summary of main results

In this review we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of MMSE in conversion from MCI to all‐cause dementia (defined by the authors of each study) and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia (ADD). Only one study provided information about MMSE and conversion from MCI to vascular dementia (VaD). Other dementias, such as frontotemporal dementia or Lewy body dementia, were not assessed by any study. Due to the high heterogeneity and the scarcity of data we could not formally evaluate the influence of factors such as the threshold, the follow‐up times, or even the incidence of dementia in the accuracy of this test.

For conversion from MCI to all‐cause dementia, we included information from 792 patients (Chopard 2009; Meguro 2007a; Modrego 2005; Xu 2002), 255 of whom developed dementia. Two out of four included studies used CDR scores of 0.5 as the definition of cognitive impairment without dementia. The follow‐up time frames were wider in comparison with the rest of studies included in this review (from 14 months to 7 years). Only two studies shared a common cut‐off to define dementia (scores ≤ 26) and showed higher specificities and lower sensitivities in comparison with the rest of studies in this group. The accuracy of baseline MMSE scores ranged from sensitivities of 23% (Meguro 2007b) to 76% (Chopard 2009) and specificities from 40% (Chopard 2009) to 94% (Meguro 2007a). We obtained a summary sensitivity of 40% from the SROC curve at the median specificity of 88%. According to this information, MMSE scores appear to have a modest specificity but without the capacity to detect more than half of the MCI converters.

Related to conversion from MCI to ADD, we included information from 1128 patients (Buchhave 2008; Conde‐Sala 2012; Devanand 2008; Modrego 2005; Modrego 2013; Palmqvist 2012; Pozueta 2011; Xu 2002) 374 of whom developed ADD. Five out of eight included studies used the Petersen diagnostic criteria (Petersen 1999; Petersen 2004) for defining MCI. The follow‐up times in this group of studies were between two and six years. Only three studies (Modrego 2005; Pozueta 2011; Xu 2002) shared a common threshold (scores ≤ 26). The accuracy of baseline MMSE scores ranged from sensitivities of 27% (Devanand 2008) to 89% (Buchhave 2008) and specificities from 32% (Buchhave 2008) to 90% (Devanand 2008). We obtained a summary sensitivity of 54% from the SROC curve at the median specificity of 80%. Again, MMSE scores appear to have a modest specificity but without the capacity to detect near to half of MCI‐converters.

Strengths and weaknesses of the review

Our review is part of a series of diagnostic test accuracy (DTA) reviews related to neuropsychological tests on dementia, for which a generic protocol was developed. This protocol identified a priori the best methodology in order to assess the accuracy of cognitive tests in the identification or conversion to any type of dementia (Davis 2013).

This review is the first Cochrane DTA review to assess the role of a well‐known paper‐and‐pencil test (MMSE) in the evaluation of people in the early dementia stage, an entity recently recognized as an important frontier for successful management of this condition. We were challenged in the selection of studies for the research question because we shared a search strategy designed to cover all the DTA reviews related to MMSE and its accuracy in different settings (that is in people over 65 years within a secondary healthcare setting, and asymptomatic and previously clinically unevaluated people aged over 65 years in community and primary care populations). At the same time, with the use of such an exhaustive search strategy we could be sure we included all possible studies, even those with smaller sample sizes, to determine the accuracy of MMSE in predicting conversion from MCI to full dementia.

Although the MMSE is a cognitive test with more than 40 years of use, we only identified studies published since 2002 to answer our research question, possibly due to our specific baseline population (MCI). Also, the review only included studies with a delayed verification of the diagnosis, in contrast to the classic cross‐sectional assessment of test accuracy. Such a combination of inclusion criteria had a direct influence on the number of retrieved and included studies in our review. For instance, a considerable number of studies with potential information were excluded because MMSE scores were evaluated as a part of prediction models without providing information about the accuracy of a specified threshold. We hope that in the future we can update our review with information provided by the contacted authors of excluded studies as well as ongoing studies.

We noticed that most of the included studies did not have the assessment of baseline MMSE scores as a main purpose. In most studies the MMSE was included as part of the usual diagnostic pathway for MCI patients and a common comparator for the principal test assessed. This directly affected the reporting quality and, most importantly, the methodological evaluation of included studies. Our results showed that the index test domain had the greater risk of bias, in most of the cases due to lack of reporting related to administration of MMSE as well as the absence of pre‐specified thresholds. We think that the lack of pre‐specified thresholds partially explained the high level of heterogeneity among the included studies. The scarcity of information did not allow us to formally assess the influence of this factor in the accuracy of MMSE, but the differences are easily noticed in the analysis of SROC curves. Additional factors that could affect the operative characteristics of MMSE, such as APOE status, the duration of MCI stage at the beginning of the study or even the administration of pharmacological or non‐pharmacological interventions were not reported in a consistent way to be considered in our analyses.

Applicability of findings to the review question

Although the MMSE is a test with quick and easy administration, needs few resources and covers multiple cognitive domains at once, it is necessary to remark that this test was not developed to identify the early stages of dementia or even to predict the development of dementia in the long term. In our review, although it was not possible to estimate in a valid way the pooled operating characteristics, the descriptive data provided by the studies showed that neither the sensitivity nor specificity exceeded 80% at the same time. Only one study (Modrego 2005) shows a balance between accuracy figures, estimating a sensitivity of 76% and a specificity of 67% for the conversion of MCI to ADD, but derived from information with a high risk of bias. Our results suggest that MMSE may be of value to decrease the post‐test probability of progression to dementia in the presence of normal test scores that confirm the possible conversion. These results may show that the items of the MMSE are insufficient to detect the change from mild to advanced cognitive decline, or even that some factors such as age, education and literacy must be taken into account to determine its true value in MCI patients. Likewise, this brief cognitive test may be more useful to document cognitive changes over time rather than to predict future progression with a single measurement. The verification of this hypothesis requires the assessment of evidence not presented in this review.

Implications for practice

Implications for research

Ingrid Arévalo‐Rodríguez is a PhD student at the Department of Pediatrics, Obstetrics and Gynecology and Preventive Medicine of the Universitat Autònoma de Barcelona.

The authors would like to thank Anna Noel‐Storr, Trials Search Co‐ordinator of the Cochrane Dementia and Cognitive Improvement Group, for her assistance with writing the search strategy, searching and initial screening of search results.

Tests

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

Internal sources

• Fundación Universitaria de Ciencias de la Salud, Hospital San José/Hospital Infantil de San José, Bogotá D.C., Colombia

• Institute for Clinical Effectiveness and Health Policy IECS, Buenos Aires, Argentina

• Iberoamerican Cochrane Centre, Barcelona, Spain

External sources

• Agencia de Calidad del Sistema Nacional de Salud, Ministry of Health, Madrid, Spain

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Palmqvist 2012 {published data only}

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