Edited by: Agustin Ibanez, Institute of Cognitive and Translational Neuroscience (INCYT), Argentina
Reviewed by: Alfredo Ardila, Florida International University, United States; Arun Bokde, Trinity College, Dublin, Ireland; Thais Helena Machado, Universidade Federal de Minas Gerais, Brazil
*Correspondence: Nilton Custodio
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Mild cognitive impairment (MCI) is a well recognized risk factor for Alzheimer’s disease (AD), and for the predemential phase of this and other dementias (Albert et al.,
Globally, there is a generalized low detection of dementia in the community. This is a real challenge in Latin America (LA; Lang et al.,
Various instruments have been developed to detect dementia (Folstein et al.,
In Peru, several short tests have been validated in urban samples from Lima, including the clock drawing test (CDT)—Mano’s version (Custodio et al.,
The M@T is a short cognitive test to detect dementia, able to discriminate between controls, patients with amnestic MCI (aMCI), and patients with early AD (Rami et al.,
Diagnostic test cross-sectional study to evaluate the performance of the M@T (study test), compared to the neuropsychological evaluation (gold standard test).
The M@T is a valid screening test that assess the temporal orientation and different types of memory (episodic, textual and semantic) and discriminates between healthy elderly subjects, patients with aMCI and patients with early AD. This is a cognitive test with high internal consistency and validity, short application (5–10 min), easy to perform and to interpret, developed in Spain (Rami et al.,
This test is totally oral and do not require reading or writing skills or the use of pencil and paper, allowing the evaluation of very low educated subjects. All the questions of M@T have a single correct answers, and covering five domains: temporal orientation (5), short term memory (10), semantic memory (15), free recall (10) and facilitated recall (10). Thus, the maximum score of this test is 50 points.
The neuropsychological assessment is the detailed evaluation of the cognitive functions, by means of a neuropsychological battery adapted to Peruvian population. The battery included the following tests: Rey Auditory Verbal Learning Test (RAVLT; Rey,
Following the order of the tests mentioned above, the neuropsychological battery has the main purpose to explore cognitive skills such as verbal memory and verbal learning through retention and evocation of verbal stimuli, immediate recall and delayed recall of stories, scanning and visuomotor tracking, divided attention, cognitive flexibility, visual memory and visuospatial construction skill. Also it appraises language skills like naming ability and word retrieval, executive functioning like forming concepts, conceptual flexibility as well attentional control, working memory and span of immediate verbal recall.
The decision criterion is two standard deviations below the mean in order to establish deficit in the cognitive domain assessed. These values were collected from the original articles for each selected test. Throughout the study, the neuropsychologists were blinded to results of M@T.
The study was carried out in elderly care home centers of two districts of Lima (four from “Carabayllo” and two from “Cercado de Lima”) between March and September of 2015. We included subjects older than 60 years, Spanish speakers with low educational level (<4 years of completed formal education), excluding those with any condition that might cause cognitive impairment non-related to neurodegenerative etiology (history of substances addiction or abuse, depression, hypothyroidism, vitamin B12 deficiency, chronic hepatopathy or nephropathy, neuroinfections by HIV or syphilis, severe brain injury, sub-dural hematoma, cerebrovascular illness, vascular dementia suggestion (Hachinski Ischemic Score >4), etc.) or that could affect their performance to realize the cognitive tests (auditory, visual or other physical deficits).
Additionally, we excluded to patients that consumed any of following drugs: opioid analgesics, decongestants, anti-spasmodics, anti-cholinergics, anti-depressants, antiarrhythmics, antipsychotics, anti-emetics, anxiolytics and valproate.
We requested the list of regular users (i.e., assistance frequency >3 times/week) of the elderly care home centers. By means of simple random sampling (table of random numbers), the potential participants were selected until completing a quota of half of available population (sample size = 0.5 N), consented to participate, and provided information necessary to assess compliance with eligibility criteria. The evaluation of cognitive impairment was performed in three successive stages: (1) screening (to detect cases with cognitive impairment); (2) nosological diagnosis (to determinate specific disease that is the cause of cognitive impairment); and (3) final classification (to differentiate disease subtypes).
In the screening phase, an integral clinical evaluation was performed, including measurement of anthropometry and blood pressure, application of Pfeffer Functional Activities Questionnaire (PFAQ) and cognitive screening tests (MMSE and CDT). If any cognitive test was positive for impairment, it was repeated by a different evaluator. The confirmed cases were considered as patients with cognitive impairment (PCI). According to educational level, the cutoff score used was 23 for subjects with 4 years of education, 21 for subjects with 1–3 years of education, and 18 for subjects with less than 1 year of education (Custodio and Lira,
In the second stage, the PCIs were assessed using blood tests (hemogram, glucose, electrolytes, transaminases, rapid plasma reagin (RPR), urea, creatinine, vitamin B12, folic acid, free T3 and T4, and ultra-sensitive TSH), images studies (brain tomography and/or magnetic resonance imaging), and Beck Depression Inventory II (BDI-II) for discarding non-neurodegenerative causes of cognitive impairment. We applied the DSM-IV (American Psychiatric Association,
Finally, in the third stage, we performed the neuropsychological evaluation of patients with MCI or dementia to typify its subtype. We applied the criteria of Petersen (Petersen et al.,
The subjects with negative results in all tests for cognitive assessment were considered as cognitively normal (controls). The M@T was applied to study subjects in first stage and the evaluators were blinded to the results of this psychometric. The results of M@T were not used as part of the neuropsychological battery for diagnosis. The team of evaluators of the second and third phases (expert neurologists and neuropsichologists) was different from the team of the first phase (students of medicine and psychology supervised by expert neurologists).
The corresponding descriptive statistics were performed. The analysis was performed comparing the cognitive groups (controls, aMCI and AD) by pairs. For this purpose we applied
We performed a logistic regression (logit) for each pair of study groups (early AD/aMCI, aMCI/control, and early AD/control), using a model of two variables: final diagnosis as dependent variable and test as independent variable. We applied postestimation analysis to compute area under receiver operating characteristics (ROC) curve and graph ROC curve, and calculate validity measures (sensitivity, specificity and positive and negative predictive values).
Additionally, we calculated the diagnostic accuracy (percentage of correctly classified individuals) for M@T, MMSE and CDT. The maximum values of this measure were the standard for the cut-off scores selection of sensitivity, specificity and predictive values. Finally, we compared the AUC of this tests using the method of Hanley and McNeil. The tests were performed at 95% confidence using the STATA software (version 12.0).
This study was carried out in accordance with the recommendations of the Council for International Organizations and Medical Sciences (CIOMS). A written informed consent was obtained from all participants or their carers in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the
The first stage started with 346 participants, but 41 were missed (14 due to withdrawal of informed consent, 21 due to difficulty in attending scheduled appointments and six due to caregiver or evaluator illness). In the second stage, 22 of 305 participants were missed (seven due to difficulty in attending scheduled appointments, four for lack of blood tests results and 11 for lack of brain tomography).
Finally, 283 participants completed the third stage. However, 36 participants were not included in the present analysis because they were classified as non-amnesic MCI (16), vascular dementia (6), Frontotemporal dementia (4), dementia associated with Parkinson’s disease (2) and other unspecified dementias (8).
Statistical analysis of the sociodemographic data, MMSE scores and M@T scores were performed according to the comparison groups. In patients with AD, compared to those with aMCI, age was significantly higher and test scores (MMSE, CDT and M@T) were significantly lower. On the other hand, in the patients with aMCI the age was significantly higher and the M@T and CDT scores were significantly lower, compared to control subjects (Table
Demographic characteristics and cognitive test scores in 247 low-level education individuals from Lima-Peru, according to definitive diagnosis.
Study group | |||||
---|---|---|---|---|---|
Early Alzheimer’s dementia ( |
amnestic mild cognitive impairment ( |
Control ( |
|||
Sex: female | 52 (64.20%) | 30 (66.67%) | 68 (56.20%) | 0.781 | 0.223 |
Age, years§ | 74.18 (3.81) | 71.09 (4.20) | 69.53 (4.11) | 0.000** | 0.032* |
Education, years§ | 2.65 (1.28) | 2.53 (1.46) | 2.57 (1.45) | 0.629 | 0.885 |
MMSE, score§ | 18.32 (2.78) | 21.36 (0.98) | 22.02 (1.26) | 0.000** | 0.056 |
CDT, score§ | 2.42 (1.69) | 8.02 (1.06) | 8.75 (0.91) | 0.000** | 0.000** |
M@T, score§ | 17.54 (4.67) | 30.53 (2.54) | 41.97 (2.68) | 0.000** | 0.000** |
Score in Memory Alteration Test (M@T) in 247 low-level education individuals from Lima-Peru, according to definitive diagnosis. AD, Alzheimer’s dementia; aMCI, amnestic mild cognitive impairment.
Results of the neuropsychological assessment in 247 low-level education individuals from Lima-Peru, according to definitive diagnosis.
Test | Sub-test | Study group Test | ||
---|---|---|---|---|
Early Alzheimer’s dementia ( |
amnestic mild cognitive impairment ( |
Control ( |
||
RAVLT | Free-recall | 3.22 (0.72) | 5.33 (0.67) | 6.17 (0.90) |
Recognition | 5.84 (1.01) | 9.93 (0.98) | 13.02 (1.05) | |
Logical memory | Immediate recall | 1.89 (1.07) | 6.51 (0.94) | 12.00 (1.38) |
Delayed recall | 1.42 (0.91) | 6.18 (0.74) | 11.83 (1.24) | |
Trail making test | Test A (s) | 80.93 (8.30) | 67.96 (7.80) | 54.00 (8.74) |
Test B (s) | 188.98 (21.37) | 115.09 (12.39) | 99.31 (14.92) | |
ROCF | Copy | 16.62 (2.29) | 24.93 (2.23) | 28.35 (1.93) |
Recall | 6.30 (1.65) | 9.67 (1.72) | 13.97 (2.81) | |
Test of denomination of Boston | 13.85 (3.70) | 28.67 (5.44) | 51.59 (3.37) | |
WCST | Categories | 2.73 (0.63) | 4.16 (0.64) | 4.97 (0.53) |
Perseverations | 13.07 (2.76) | 6.13 (1.79) | 1.86 (0.73) | |
Letter—Number | 4.83 (0.75) | 7.13 (0.94) | 10.10 (1.66) | |
Digit span | 2.40 (0.72) | 4.24 (0.43) | 4.90 (0.55) |
Internal consistency (Cronbach’s alpha coefficient: 0.79) and concurrent validity (
Cut-off points and diagnostic performance of M@T and MMSE to discriminate between AD, aMCI.
Discrimination between early AD and aMCI | Discrimination between aMCI and controls | Discrimination between early AD and controls | |||||||
---|---|---|---|---|---|---|---|---|---|
M@T | MMSE | CDT | M@T | MMSE | CDT | M@T | MMSE | CDT | |
Optimal cut-off § | 26 | 21 | 5 | 35 | 21 | 8 | 29 | 21 | 5 |
Sensitivity | 100.00 | 86.67 | 100.00 | 99.17 | 90.91 | 95.04 | 100.00 | 90.91 | 100.00 |
Specificity | 97.53 | 75.31 | 87.65 | 91.11 | 13.33 | 31.11 | 98.77 | 75.31 | 87.65 |
Correctly classified (%) | 98.41 | 79.37 | 92.06 | 96.99 | 69.88 | 77.71 | 99.50 | 84.65 | 95.05 |
Likelihood ratio + | 40.500 | 3.51 | 8.10 | 11.16 | 1.05 | 1.38 | 81.00 | 3.68 | 8.10 |
Likelihood ratio − | 0.000 | 2.07 | 0.00 | 0.009 | 0.68 | 0.16 | 0.000 | 0.12 | 0.00 |
Area under | 0.9960† | 0.8278 | 1.0000 | 0.9956†‡ | 0.6536 | 0.6869 | 1.0000† | 0.8820 | 1.0000 |
curve [95% CI] | [0.99–1.00] | [0.76–0.90] | [1.00–1.00] | [0.99–1.00] | [0.57–0.74] | [0.60–0.78] | [1.00–1.00] | [0.83–0.93] | [1.00–1.00] |
The performance of the M@T to discriminate between early AD and aMCI was 0.9960 (Figure
Receiver operating characteristics (ROC) curve of M@T, MMSE and CDT to discriminate between patients with aMCI and controls in 166 low-level education individuals from Lima-Peru. MMSE, Mini Mental State of Examination; CDT, Clock Drawing Test—Mano’s version; M@T, Memory Alteration Test.
ROC curve of M@T, MMSE and CDT to discriminate between patients with aMCI and early AD in 126 low-level education individuals from Lima-Peru. MMSE, Mini Mental State of Examination; CDT, Clock Drawing Test—Mano’s version; M@T, Memory Alteration Test.
This study shows a good performance of M@T to discriminate between early AD and aMCI in subjects with less than 4 years of education. These results are similar to those previously obtained with a sample of 6.5 years of average education (AUC: 0.9986; Custodio et al.,
Similarly, we found a good performance to discriminate between patients with aMCI and controls (AUC: 0.9956), which was slightly lower than that reported previously (AUC: 0.9986; Custodio et al.,
Additionally, we found that the performance of M@T is higher than MMSE and CDT for discriminating both AD vs. aMCI and aMCI vs. controls. This findings can be explained because M@T evaluates episodic and semantic memory, which have their biological substrate in the hippocampus, the medial temporal lobe and temporal neocortex, areas that are early affected in AD (Rami et al.,
According to recent UNESCO data, 16% of adults have emerged from education systems without basic literacy skills, which is a major problem in the regions of Sub-Saharan Africa and South Asia, where more than 1/3 of adults are illiterate. Around the world, at least 20 countries have adult literacy rates less than 60% and 43 countries have adult literacy rates less than 75% (UNESCO Institute for Statistics,
There are evidence about the demographic influences (e.g., age, gender, education, and residence rural/urban) on the performance of several cognitive tests (Freitas et al.,
Additionally, previous studies have shown that non-specialist physicians have difficulties in effectively identifying aMCI and early AD. Thus, it is necessary to develop clinically useful, non-invasive and/or cost-effective, screening tools (Connolly et al.,
In addition to age, another important sociodemographic variable is the sex. Several population-based studies have shown nearly two-thirds of individuals diagnosed with AD are females (Dal Forno et al.,
In our sample, MMSE and CDT showed a suboptimal performance for discriminating between aMCI and healthy controls. This findings contrasts with previous studies, which found an AUC values higher than 0.80 and 0.70 with the use of MMSE and CDT, respectively (Cacho et al.,
We have not included rural populations or with native language other than Spanish. Consequently, the results of this study may not be applicable to these population subgroups. The comparison groups were statistically different for the age, a potential confounding variable. However, we performed a secondary sub-analysis for checking that the performance of the logistic regression model is not affected by the age.
The psychometric properties of M@T allow its application in subjects with less than 4 years of primary education in urban settings. Cut-off points should be corrected for educational level and, according our data, values of 35 and 26 are useful for distinguishing patients with aMCI and early AD, respectively, in patients with low level of education. However, M@T should not be used in isolation to define dementia, since it measures memory impairment (episodic and semantic) and orientation well, but no other types of cognitive impairment nor functionality. Therefore, the simultaneous use of brief functional tests to compensate for this deficiency is required.
Recent studies in European populations have evaluated the ability of M@T to discriminate between aMCI and subjective memory complaints (SMC), showing an optimal performance in subjects with medium (Rami et al.,
Additionally, the future studies should include population with a broad variability of educational level and higher sample size. Thus, multivariate models could be applied to assess the factors that is statistically associated with clinical diagnosis, which includes the years of education.
The M@T constitutes a brief, non-invasive and reliable cognitive test, which could be applicable for non-specialist physicians to support the discrimination between aMCI and early AD in primary care centers.
NC performed the conception of the study. NC, DL, RM and EH-P designed the study. NC, DL, RM, SC-S, JC-A and LV-L collected the data. NC and EH-P analyzed and interpreted the data of the work. EH-P and NC drafted the first draft of the article. All authors critically revised the manuscript and approved the version to be published.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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