Dementia is a progressive global cognitive impairment syndrome. In 2009, more than 34 million people worldwide were estimated to be living with dementia—a number that will increase to more than 81 million by 2040 (Ferri 2005; Wimo 2010). Dementia encompasses a group of neurodegenerative disorders that are characterised by progressive loss of both cognitive function and the ability to perform daily living activities. It can be accompanied by neuropsychiatric symptoms and challenging behaviours of varying type and severity. Its underlying pathology is usually degenerative, and subtypes of dementia include Alzheimer’s disease dementia (ADD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia, among others. Considerable overlap may be noted in the clinical and pathological presentations of dementia (MRC CFAS 2001), and ADD and vascular dementia often coexist (Matthews 2009; Savva 2009).
Recently, a new type of predementia phase called mild cognitive impairment (MCI) was brought to light. MCI refers to a heterogeneous condition, and currently 16 different classifications are used to define it (Matthews 2008; Petersen 1999; Petersen 2004; Winblad 2004). Prevalence of MCI varies widely (between 0.1% and 42%) according to the criteria applied, with most systems including memory impairment and absence of cognitive decline as basic conditions for diagnosis (Stephan 2007). As part of ADAMS assessment, Plassman et al estimated the prevalence of cognitive impairment without dementia as 22% in people aged 71 years or older (Plassman 2008). MCI may be classified as amnestic or non-amnestic, according to the presence of clinically significant memory impairment that does not meet the criteria for dementia or a subtle decline in other functions not related to memory (Petersen 2011).
Over time, people with MCI may experience a gradually progressive cognitive decline and changes in personality and behaviour. When the cognitive impairment in memory, reasoning, language and visuospatial abilities interferes with daily function, individuals are diagnosed with dementia. Research studies indicate that an annual average of 10% to 15% of individuals with MCI may progress to dementia, in particular ADD, but with wide variation, depending upon the source of study participants, with self-selected clinic attendees having the highest conversion rates (Bruscoli 2004; Mitchell 2008). Information on long-term cohorts suggests that annual conversion rates range from 4.2% (95% confidence interval (CI) 3.9% to 4.6%) for any dementia to 5.8% (95% CI 5.5% to 6.5%) for ADD (Mitchell 2008).
Establishing a definitive diagnosis of MCI in the presence of subtle symptoms can be challenging. In these cases, it is necessary to document the cognitive decline from the patient's medical history and corroborate it by means of neuropsychological testing, among other suggested tools (Petersen 2001). The American Academy of Neurology recommended in 2001 that patients with MCI should be evaluated and monitored in accordance with their risk of progression to dementia by means of general or brief cognitive screening tools (Petersen 2001). Likewise, the National Institute on Aging and the Alzheimer's Association remarked in 2011 that longitudinal evidence of progressive decline in cognition could support the diagnosis of MCI due to AD and could allow assessment of the potential benefits of early treatment (Albert 2011).
Usually, recognition and assessment of people with suspected dementia in any setting (community, primary care or secondary care) requires a brief test of cognitive function and/or the use of informant questionnaires (Arevalo-Rodriguez 2013). The brief cognitive evaluations needed are usually paper-and-pencil tests that are easy to administer, take no longer than 10 minutes to complete, involve major executive functions and yield an objective score. This final score is useful in determining which individuals need a more comprehensive evaluation (usually identified by low scores) (Boustani 2003). One of these brief cognitive tests is the Mini-Mental State Examination (MMSE) (Folstein 1975), which has become the best-known and the most often used short cognitive screening test for dementia in clinical, research and community settings, although it is now the subject of copyright issues (Nieuwenhuis-Mark 2010).
Systematic assessments of the diagnostic accuracy of brief cognitive tests such as MMSE are scarce. In 1992, Tombaugh et al presented a narrative review of MMSE studies that emphasised psychometric properties such as reliability and construct validity without evaluating the quality of the included evidence (Tombaugh 1992). Later, Mitchell published a systematic review and meta-analysis of cross-sectional studies of MMSE and reported different estimations of sensitivity and specificity according to the setting and population (Mitchell 2009). Until now, the relationship between MMSE scores and conversion from MCI to ADD or other dementias has not been evaluated in a systematic fashion.
It is thus the aim of this DTA review for diagnostic test accuracy in dementia to evaluate the ability of the MMSE to identify those people with MCI who will progress to the full clinical syndrome of dementia in such settings as community residences, primary care facilities and memory clinics.
Target condition being diagnosed
In general, dementia as diagnosed is defined by a deficit in more than two cognitive domains 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 (McKhann 1984; McKhann 2011), vascular dementia (Roman 1993), fronto-temporal 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 will focus on conversion from MCI to Alzheimer's disease dementia, as well as conversion from MCI to other forms of dementia, respectively, which will be 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).
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).
Advantages of the MMSE include rapid administration, availability of multiple language translations and high level 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 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).
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 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 (e.g. 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.
Most tests (e.g. neuroimaging, CSF analysis) are usually performed after a cognitive deficit has been identified. However, it is conceivable that patients with abnormalities on brain imaging—performed for any number of reasons—are likely to be tested subsequently for cognitive deficits.
Role of index test(s)
Accurate diagnosis leads to opportunities for treatment. 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 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 also help to 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 dementia.
The Cochrane Dementia and Cognitive Improvement Group (CDCIG) is in the process of conducting a series of DTA reviews of biomarkers and other tests to determine their sensitivity and specificity for the diagnosis of Alzheimer’s disease dementia and other dementias. These include the following:
18F-FDG PET (positron emission tomography-fluorodeoxyglucose).
PET-PiB (positron emission tomography-Pittsburgh compound B).
sMRI (structural magnetic resonance imaging).
CSF (cerebrospinal fluid analysis of Abeta and tau).
APOE e4 (apolipoprotein E e4, a major genetic risk factor for cognitive decline).
FP-CIT SPECT (2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane single photon emission computed tomography).
Informant interviews (IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly); AD8 (a brief informant interview to detect dementia)).
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). At the population level, this event 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 (i.e. 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 also 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 (Davis 2013). Particularly, this review will be focused on evaluation of the MMSE and will include delayed-verification studies for assessment of conversion from MCI to dementia.