One critical question is whether the MMSE retains sufficient accuracy when looking for early dementia. People with early dementia are particularly at risk of being overlooked and undertreated [21]. Provisional evidence from three studies suggests a modest reduction in accuracy when attempting to diagnose those with mild dementia. For example, in specialist hospital or memory clinics, Heinik et al. found that the area under the ROC curve was 0.96 for all dementias but 0.89 for very mild dementia [22] and similarly Meulen and colleagues found that the area under the ROC for the MMSE was 0.95 for all dementias but 0.87 for mild dementia [23]. Also a cut-off threshold higher than ≤23 is recommended when looking for mild dementia. Yoshida et al. [24] found 95 % sensitivity and 83 % specificity looking for mild dementia in a Japanese memory clinic at a threshold of ≤28 which would give “good” clinical utility for screening (CUI + = 0.789) and case-finding (CUI− = 0.786). At a lower threshold of ≤25 sensitivity fell to 76 % but specificity increased to 97 % which would also have “good” clinical utility for screening (CUI + = 0.800) and case-finding (CUI− = 0.727). In a sub-analysis of 88 people with mild Alzheimer’s scoring >20 on the MMSE, Kalbe and colleagues [25] found that the MMSE had a sensitivity of 92 % and a specificity of 86 % (PPV = 85.2 %, NPV = 92.2 %) which again would imply “good” clinical utility for case-finding (CUI + = 0.781) and screening (CUI− = 0.796). Regarding diagnosis of mild dementia in primary care, Kilada and colleagues found adjustment of the MMSE cut-off to ≤27 was required [26]. Grober et al. [27] examined the value of MMSE in 317 primary care attendees with mild dementia (CDR of 1.0 and 0.5 but without MCI). In this study, at a cut-off of ≤23 sensitivity was 53 % and specificity 90 % (PPV = 52.7 %, NPV = 90.1 %), but at a cut-off of ≤26 sensitivity was 73 % and specificity 73 % (PPV = 36.0 %, NPV = 92.7 %) suggesting only “fair” clinical utility. Further information on the diagnosis of early dementia comes from studies in which the comparator sample is a combination of healthy controls and those with MCI as this is more likely to be the situation clinically (see Sect. 3.4).

There were only five studies published up to 2009 regarding MMSE for diagnosis of MCI [18] but by 2012 this had risen to 11 qualifying studies [19]. In 2015 a meta-analysis found 21 studies with a sensitivity estimate of 0.62 (95 % CI = 0.52–0.71) and specificity of 0.87 (95 % CI = 0.80–0.92) [20]. A new search for this chapter revealed 40 relevant studies (see Table 3.1 for summary findings). Most have used cross-sectional rather than longitudinal definitions of MCI and these criteria themselves remain somewhat controversial [28, 29]. These are essentially the combination of subjective memory complaints with objective impairment but no dementia and “minimal” functional decline. It is important to realise many patients with pre-dementia cognitive decline will not fulfil these rules largely because of measurable problems with activities of daily living or absence of recorded subjective memory complaints. Thus MCI should be considered as only one of several possible pre-dementia categories. Further, it is now recognised that many with MCI do not progress but remain stable or actually improve.

An overview of 40 studies shows that the majority used the Mayo Clinic diagnostic criteria suggested by Petersen and colleagues [28, 30] but some use revised Winblad criteria [29] and a minority use a Clinical Dementia Rating score of 0.5 (CDR) [31]. The vast majority were recruited from memory clinics or secondary care, only a handful claim to recruit directly from the community. Samples were not matched demographically but instead recruited from convenience samples, which is nevertheless similar to clinical practice. Thus across these 40 studies, the mean age of those with MCI was 73.2 years whilst in healthy controls it was 71.0 years. The proportion of females in MCI studies was 44 % and in controls 46.9 %. Regarding education, the mean number of educated years in those with MCI was 9.79 vs 9.64 in controls. Perhaps the major question regards cut-off threshold on the MMSE: 12 studies used <29; 9 studies used <28; 17 studies used <27; and 9 studies used <26.

Summary results are shown in Table 3.1. After weighting, the meta-analytic sensitivity was found to be 59.7 % (95 % CI = 58.6–60.7 %) and specificity was 80.2 % (95 % CI = 79.4–81.0 %). PPV was 72.1 % (95 % CI = 71.1–73.2 %) and NPV 69.9 % (95 % CI = 69.0–70.7 %). The positive clinical utility was 0.431 “poor” (95 % CI = 0.418–0.444) for case-finding and negative CUI was 0.561 (95 % CI = 0.553–0.568), that is qualitatively “fair”, for screening.

A related question is how the detection of dementia is influenced by the inclusion of patients with MCI in the comparator group alongside healthy controls. This is a clinically useful question as attendees in memory clinics usually are mixed in type and severity. One very large study (n = 6843) provides the answer [32]. In comparison to detection of dementia against healthy controls alone, specificity falls as does PPV when using MMSE to detect dementia vs healthy controls and/or people with MCI. For example, at a cut-off of ≤26 whilst sensitivity remains at 71.6 % (95 % CI = 69.8–73.4 %), specificity falls from 97.9 to 93.5 % (95 % CI = 92.8–94.2 %) and PPV falls from 96.3 to 85.1 % (95 % CI = 83.5–86.7 %). In this mixed comparison, overall the optimal threshold appears to be ≤26 as clinical utility is “fair” for case-finding (CUI + = 0.609) and “very good” for screening (CUI− = 0.808) at this cut-point.

Delirium is a mental disorder usually characterized by acute or sub-acute onset, impaired attention, an altered level of consciousness and a fluctuating course. Frequently there are widespread cognitive deficits in orientation, memory, attention, thinking, perception and insight. It occurs in approximately 10–30 % of vulnerable patients admitted to hospital. If unresolved, delirium is strongly associated with poor outcomes such as disability and death [33–35]. Randomized trials have shown multi-component preventive strategies to be effective in preventing and treating delirium [36]. However it remains under-recognized leaving a possible role for screening instruments [37]. A recent review of the accuracy of 11 instruments used in 25 studies highlighted potential value of the Global Attentiveness Rating (GAR), Memorial Delirium Assessment Scale (MDAS), Delirium Rating Scale Revised-98 (DRS-R-98), Clinical Assessment of Confusion (CAC), Delirium Observation Screening Scale (DOSS) and Nursing Delirium Screening Scale (Nu-DESC) [37]. The Confusion Assessment Method (CAM) was the most thoroughly studied but the Mini-Mental State Examination (MMSE) was omitted from this review [37].

The MMSE may not seem the ideal choice for delirium but nevertheless has the potential to be useful because of its broad cognitive remit. Indeed the accuracy of the MMSE in detecting delirium has been reported in a recent meta-analysis [38]. No more recent primary studies have been published to date. Thirteen studies were included in this meta-analysis representing 2017 patients in medical settings of whom 29.4 % had delirium. The meta-analysis revealed the MMSE had an overall sensitivity and specificity estimate of 84.1 and 73.0 %, but this was 81.1 and 82.8 % in a subgroup analysis involving robust high quality studies. Sensitivity was unchanged but specificity was 68.4 % (95 % CI = 50.9–83.5 %) in studies using a predefined cut-off of <24 to signify a case. Clinical utility was poor for confirmation (case-finding) of delirium but good for initial screening (minimizing false negatives).

This chapter brings up to date the latest evidence concerning the application of the MMSE as a diagnostic test for dementia, MCI and delirium. It is worth acknowledging that the MMSE has a number of obvious limitations [4]. It has a floor effect (imprecise measurement in the very severe range) [39, 40] which is notable in advanced dementia, in those with little formal education, and in those with severe language problems. There is also a ceiling effect, meaning it may not perform well in people with very mild dementia or indeed MCI [41]. This is thought to relate to its relatively crude testing of recall based solely on three objects. This problem is likely to be amplified when testing highly educated individuals. That said, this current analysis reveals that the MMSE is only marginally impaired in the detection of mild dementia as compared to the detection of moderate to severe dementia.

Most cognitive tests are influenced by age, education, and ethnicity and the MMSE is no exception [40]. Twelve percent of the variance in MMSE scores can be attributed to age and education alone [42]. Tables of adjustment by age and education have been published but are often overlooked by busy clinicians [43]. However a useful rule of thumb when screening for dementia is to choose a cut-off threshold of <21 for those with a basic school education, <23 for those with a high school education, and <24 for those with graduate/university education. Another important limitation is its length, particularly when its intended use is in primary care [44, 45]. Whilst it can be completed and scored in 5–8 min in unimpaired healthy individuals, it often takes 15 min or more in patients with dementia [23].

The focus of this chapter has been on the accuracy of the MMSE when used to help in the diagnosis of a cognitive disorder. A cognitive test can be used as a screening tool to reassure those without cognitive impairment, or as a case-finding tool to confirm those that do have cognitive impairment. The MMSE performs differently for each purpose and does not perform well as a single tool used for all types of patient in all settings. Overall results from 108 studies suggest it performs best when separating dementia from healthy cognitively unimpaired individuals. Here clinical utility was qualitatively “fair” (CUI + = 0.608) for case-finding and “excellent” (CUI− = 0.822) for screening. Performance was slightly weaker in early dementia vs healthy unimpaired individuals but the MMSE still achieved a “good” clinical utility. For MCI, however, the MMSE had a poor positive clinical utility (0.431) for case-finding and the negative CUI was only “fair” (0.561) for screening, illustrating limited performance for MCI. In most memory clinics people are not simply divided into dementia or healthy, therefore the comparison of dementia vs healthy combined with MCI is of note. In the detection of dementia vs healthy controls or MCI the clinical utility is no longer “poor” but “fair” for case-finding (CUI + = 0.609) but a “good” rating is preserved for screening (CUI− = 0.808). However an adjustment of cut-off threshold to ≤26 is necessary. Thus in specialist settings the MMSE is likely to be useful for initial reassurance in those who score 27 or above. Regarding delirium the latest evidence shows clinical utility of the MMSE was fair for confirmation (case-finding) of delirium but again “good” for initial screening (minimizing false negatives).