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Reliability and Feasibility of the Memory Associative Test TMA-93

Background: Memory tests focused on binding may be more sensitive to diagnose Alzheimer’s disease (AD) at an early phase. TMA-93 examines relational binding by images. Objective: Evaluate the reliability (internal consistency and inter-rater and test-retest reliability) and feasibility of the TMA-93 in a clinic setting with low-educated individuals and limited face-to-face time per patient. Methods: The study was undertaken in a neurology outpatient clinic of a hospital in Southern Spain. The internal consistency of the TMA-93 was estimated in 35 patients with amnestic mild cognitive impairment (aMCI) and 40 healthy controls (HCs). The inter-rater reliability (by two raters) and feasibility (by recording the percentage of participants who completed the test, and by timing the administration time) were evaluated in HCs (n = 16), aMCI patients (n = 18), and mild dementia patients (n = 15). The test-retest reliability for the TMA-93 total score was studied in 51 HCs tested by the same examiner 2–4 months apart. The internal consistency was estimated by Cronbach’s alpha. The inter-rater and test-retest reliability was quantified by the intraclass correlation coefficient (ICC). The administration time was compared by diagnosis. Results: The internal consistency was “optimal” (Cronbach’s alpha = 0.936). The test-retest reliability was “good” [ICC = 0.802 (CI 95%  = 0.653–0.887)]. The inter-rater reliability was “optimal” [ICC = 0.999, (CI 95%  = 0.999–1)]. All participants completed the test. The administration time ranged from less than 3 min in HCs to 6 min in aMCI patients, and 7 min in mild dementia patients. Conclusion: Good feasibility and reliability support using the TMA-93 for examining visual relational binding, particularly in the context of low-educational attainment and limited time per patient.


INTRODUCTION
In cognition, binding is the function that supports the integration of multiple elements together [1][2][3]. Errors in conjunctive binding (the integration of features within an object) and also in relational binding or associative memory (the ability to remember novel 432 E. Franco-Macías et al. / Reliability and Feasibility of the  associations between words or pictures) have been reported in Alzheimer's disease (AD) at an early phase [4]. Conjunctive binding is supported by the entorhinal and perirhinal cortex and seems more sensitive than the relational one to early AD [5,6]. The "Short-Term Memory Binding Test" is the most used tool for examining conjunctive binding. This test, one of the most promising neuropsychological tools, has been incorporated into trials to predict who among those with mild cognitive impairment will go on to develop AD [7]. There is also evidence that relational binding, that relies on the hippocampus, parahippocampal cortex, and default mode network regions (posterior cingulate cortex/precuneus/lateral parietal and medial frontal cortex) [5], declines in the prodromal stages of late-onset sporadic AD [8][9][10]. Even more, asymptomatic individuals with greater amyloid-␤ burden on amyloid imaging have shown abnormal scores on relational binding tests when the performance on other standardized episodic memory test is still preserved [11]. In neuropsychology, the relational binding ability can be examined by different tests. The "Wechsler Memory Scale" (WMS) assesses binding through learning and recall of paired associated words [12]. This WMS subtest discerns between easy (i.e., North/South) and complex associations (i.e., School/Cellar) [12]. The "Memory Binding Test" (MBT) examines associative memory through the recall of pairs of items that belong to the same semantic category (i.e., flea/ant = insects) but presented in two different lists of words [13]. The "Face Name Associative Memory Exam" is a crossmodal associative test based on a functional magnetic resonance imaging (fMRI) task that pairs pictures of unfamiliar faces with common first names [14].
Testing relational binding only by images rather than words could be more feasible for low educated individuals. The "Memory Associative Test of the district of Seine-Saint-Denis" (TMA-93) was recently developed in France for the early diagnosis of AD among low educated immigrants [15]. Briefly, during the encoding phase, the patient is shown ten pairs of drawings of common and easy to recognize objects from daily life that are semantically related (Fig. 1A). Only one of the two items is shown in the recall phase, and the patient is asked to recall the missing item (Fig. 1B) [15]. In the original paper, the test demonstrated high diagnostic accuracy for discriminating AD patients from healthy controls in a sample of immigrant residents from a district in Paris (France) [15]. In that study, the cutoff of 24 of 30 showed a sensitivity of 88% and a specificity A B Fig. 1. Pairs of semantically-related drawings of the TMA-93. In the codification phase, the semantically-related drawings are presented in pairs (A). In the recall phase, the subject has to recall the missing object (B).
of 97% for distinguishing AD patients from healthy controls [15]. A posterior validation study in older educationally-diverse Spanish people demonstrated that the test is so sensitive as the picture version of the Free and Cued Selective Reminding Test (FCSRT) in discriminating between amnestic mild cognitive impairment (aMCI) patients and healthy controls (HCs) [16]. In that study, the receiver operating characteristic (ROC) curve analysis determined an optimal area under the ROC curve (AUC) of 0.97 (95% CI, 0.89-1.00, p < 0.001) to distinguish between aMCI patients and HCs [16].
On the other hand, the most used memory tests are based on learning and recalling two paragraphs or a list of words and often include a final step of facilitation with verbal cues or recognition among distractors that have to be administered 15-30 min later [17,18]. These tests take too long time to be used in busy primary care and general neurology outpatient settings with limited face-to-face time per patient. On the contrary, the TMA-93 is a relatively short test that may be more suitable in that context.
These potential uses and advantages of the TMA-93 encourage the completion of the development of the test. There are no previous studies focused on the reliability or feasibility of the TMA-93. There is a need to validate the test-retest reliability of binding tasks to detect and monitor AD-related populations [4]. Tests providing such reliability will be appropriate for use in longitudinal research. On the other hand, feasibility has been considered a crucial prerequisite by a consensus document on neuropsychological assessment [19]. The aim here was to study the reliability (the internal consistency and the inter-rater and test-retest reliability) of the TMA-93 and its feasibility (by recording the percentage of participants who completed the test, and by timing the administration time).

Study population
The studies were undertaken in a general neurology outpatient clinic at the University Hospital Virgen del Rocio, a tertiary referral academic center in Seville, in the Southern Spanish region of Andalusia. Many older people of this region had limited access to primary school and are not skilled in reading or writing. In the region, time availability for examining patients with memory complaints is limited: from 5 min in busy primary care to 20 min in a general neurology outpatient setting.
The internal consistency was studied in an extension of the phase I validation study for the TMA-93 [16]. Here, the sample was increased to 75 individuals (35 patients with aMCI and 40 HCs) to meet the required sample size for studying the internal consistency of a test composed of 10 items. Procedures for this cross-sectional study has been previously described [16] and included Phototest, a brief cognitive test developed in Spain with high diagnostic accuracy for diagnosing cognitive impairment and dementia [20], and the "Delayed Matching-to-Sample Task 48" (DMS-48), a visual recognition memory task on which the diagnosis of aMCI was based [21]. The diagnosis of aMCI had been made according to the National Institute on Aging and Alzheimer's Association (NIA-AA) recommendations [22] and operationally put into practice as follows: 1) memory complaint corroborated by a reliable informant; 2) objective memory impairment measured by a score equal to or below the 10 percentile on set 2 of DMS-48 (this score being lower than that on set 1); and 3) no significant functional decline for activities of daily living [score up to 39 on "Interview for Deterioration in Daily Living Activities in Dementia" (IDDD) (23)]. We recruited HCs among the caregivers and relatives of patients attending the center. They met the following inclusion criteria: 1) absence of memory complaints; 2) absence of objective memory impairment (DMS-48 set 2 score equal to or above the 25-percentile); and 3) intact level of independence in activities of daily living (score between 33 and 36 on IDDD).
For the test-retest reliability, HCs were recruited among the participants in the Spanish normative study for the TMA-93 [24]. The inclusion criteria for this study were: 1) age equal to or above 50; 2) no cognitive complaints; 3) score equal or above 10-percentile according to normative data for the Phototest in Spain [25]; and 4) independent level of functioning. 51 randomly selected HCs were invited to repeat the TMA-93 conducted by the same examiner (SRH) between 2 and 4 months after the initial examination.
For studying the inter-rater reliability and feasibility, an ad-hoc sample composed of 16 HCs, 18 patients with aMCI, and 15 patients with mild dementia due to probable AD (n = 15) was recruited. Both groups of patients had been diagnosed according to NIA-AA recommendations [22,26]. The diagnosis of mild dementia due to probable AD was based on core clinical criteria for AD [26]. Amnestic presentation and classification at stage 4 according to the Global Deterioration Scale were required [27]. All available information had been used for this diagnostic process including history, blood tests, brain imaging (head CT or brain MRI), and the following battery of neuropsychological tests: the Spanish version of the Informant Questionnaire AD8 [28], the Phototest [20], the picture version of the FCSRT [29], the Stroop Color and Word Test [30], the ADAS-Cog subtest of constructive praxis [31], the 12-item Boston Naming Test [32], the VOSP subtests of Dot Counting and Number Location [33], the IDDD [23], and the 15-item Geriatric Depression Scale [34]. The TMA-93 was conducted by two examiners (1 = EGC and 2 = SRH), who followed an alternating order for its administration and timing on the same subjects, and were blinded to both the subject's diagnosis and the score obtained by the other examiner.

Instrument: TMA-93
The TMA-93 was administered following the instructions given by its authors [15]. During the encoding phase, subjects were shown and asked to name 10 pairs of real-life semantically-related objects presented as drawings in cards (tree/bird, bed/bedside lamp, boat/fish, dog/sheep, foot/trousers, knife/apple, glasses/book, hand/watch, car/car keys, flower/sun). The examiner specifically asked the participants to memorize the pairs of drawings (Fig. 1A). Next, the first associative memory trial was administered: examinees were shown only one of each pair's drawings and asked to recall the missing one (Fig. 1B). After each subject's response (regardless accuracy) or a period of up to 5 s, we displayed the pair again. This protocol was repeated for the 9 remaining pairs.
The maximum score of 30 points was granted only when the participant produced 10 out of 10 correct responses in this first trial, in which case, the second and the third trials were omitted. Otherwise, the participants were scored from 0 to 9 based on their number of correct answers in this first trial and were administered a second similar trial with the same 10 pairs of drawings. If a subject correctly recalled the 10 missing objects in this second trial, s/he was given 20 points: 10 points corresponding to the second trial, and 10 more corresponding to the third trial, which was cancelled. The score of each of the 10 items of the TMA-93 ranged from 0 to 3 and these scores were used for estimating the test's internal consistency.
Three types of incorrect answers were recorded: 1) error, when the subject recalls an object that belongs to a different pair; 2) intrusion, when the subject recalls an object that was never shown to him/her; and 3) perseveration, when the subject repeated the same error [15].

Ethics
The studies were approved by the ethics committee of the Hospital Virgen del Rocio (Seville, Spain) and conducted according to the World Medical Association Declaration of Helsinki. All participants accepted the study procedures by signing informed consent.

Statistical analyses
Descriptive results are shown as frequency (percent) for dichotomous and categorical variables, mean (±SD, range) for normally-distributed continuous variables, and median [interquartile range (IQR), range] for non-normally distributed continuous variables. Between-group comparisons of continuous variables were performed with Student's t-test or one-way ANOVA (or their non-parametric alternatives Mann-Whitney U test and Kruskal-Wallis ANOVA, respectively). Between-group comparisons of categorical variables were performed with the Chi square test.
Internal consistency was estimated by Cronbach's alpha. Values of Cronbach's alpha above 0.70 were considered acceptable, between 0.90 and 0.95 were considered "optimal", and above 0.95 were interpreted as indicative of "item redundancy" [35,36]. In addition, "split-half reliability" was analyzed considering the first five pairs of drawings of the TMA-93 as a half and the last five ones as the other half and estimating the correlation between each other by the Spearman-Brown coefficient. "Corrected item-total correlations" were calculated, and a value below 0.40 was considered indicative of item redundancy [35]. Item redundancy was also evaluated by "Cronbach's alpha if item deleted", considering an item as redundant if the Cronbach's alpha increased at deleting it [37].
Test-retest reliability for the TMA-93 total score was estimated by the intra-class correlation coefficient (ICC). In addition, we also created the variable "total score time 2 minus total score time 1" and analyzed its distribution.
Inter-rater reliability for the TMA-93 total score and number of errors, intrusions, and perseverations were estimated by the ICC.
The feasibility was analyzed by recording the number of participants who completed the test, and comparing the administration time according to diagnosis, and educational attainment.
Statistical significance was set at a p < 0.05, and all estimates were obtained with a 95% confidence interval (CI 95%).
All statistical analyses were run in SPSS version 25 (IBM, USA).

DISCUSSION
To our knowledge, this is the first study focused on the reliability and feasibility of the TMA-93, the French visual relational binding test [15]. The test has already demonstrated high diagnostic accuracy in validation studies [15,16] and has normative studies from French and Spanish populations [24,38].
Internal consistency among the 10 pairs of semantically-related drawings of real-life objects that compose the TMA-93 was "optimal" (Cronbach's alpha = 0.936). This result means the 10 items of the test are highly correlated each other and measure the construct of interest, visual relational binding, in a similar way [39]. By comparison, an "acceptable" internal consistency has been reported for the FCSRT, a standard memory test (Cronbach's alpha = 0.810) [40].
"Corrected Item-Total Correlation" is the correlation of the item designed with the summated score for all other items. A rule-of-thumb states that this value should be at least 0.40 to rule out item redundancy [35]. Every item of the TMA-93 fulfilled the rule. In the same way, the Cronbach's alpha did not increase at deleting any of the ten pairs, so, again, redundancy of any item could not be demonstrated.
Split-half testing is another measure of internal consistency. This method measures the extent to which all parts of the test contribute equally to what is being measured. We found a strong correlation between the two virtual halves of the TMA-93, indicating that HCs and aMCI patients performed equally well (or as poorly) on both halves of the test.
The TMA-93 showed a "good" test-retest reliability [ICC = 0.802 (CI 95% = 0.653-0.887)]. By comparison, this reliability is similar to that reported for the "Mini-Mental State Examination" (MMSE) (0.80) [41] and suggests stability in performance over time. The test-retest reliability studies' design varies by the time considered between test 1 and test 2, and by the selection of participants (only HCs or mixed sample of HCs and patients). Here, we considered 2-4 months for administering the retest and only HCs. The time interval seems to be short enough to pre-  vent the effect of an eventual cognitive impairment on the sample, particularly from participants with lower scores, and long enough to prevent a practice effect. With a similar design, the MBT demonstrated ICC values ranged from 0.64 to 0.76 [42]. Analyzing the distribution of the "total score time 2 minus total score time 1" variable, there were four atypical observations that probably precluded this reliability could be upgraded to "optimal". Two of them scored 3 points more at the retest. On the opposite side, two outliers scored 2 and 3 points less, respectively. The former could be explained by practice effect and the latter by cognitive decline, but a more global explanation could be that binding is somewhat changeable and dynamic, making it difficult for a test to achieve an "optimal" test-retest reliability [43]. The variability in the measure were greater for scores below 28 at time 1. The test-retest reliability could be supported by scores above 28 at time 1 and, thus, overestimated due to ceiling effect. To clarify this issue, future test-retest reliability TMA-93 studies should recruit enough HCs scoring below 28 at time 1 and consider participants' AD biomarker status to understand eventual score changes over time.
Inter-rater reliability of the TMA-93 was "optimal" for the total score and the number of errors and intrusions, and "good" for the number of perseverations. We noted that the administration and scoring are relatively simple, but that classifying the incorrect responses in errors, intrusions or perseverations can lead to disagreements between examiners and requires some training. Individually, perseverations-scored as the number of times that an error (a response that corresponds to a different drawing pair) is repeated-were the main source of disagreement between examiners.
Regarding TMA-93 feasibility, all participants, including mild AD dementia patients, were able to complete the test. Participants' task-tolerability was good, including that of those who scored the minimum (4 out of 30) or whose administration time was the longest (17.2 min). There were significant differences in administration time by diagnosis: cognitively impaired patients spent more time on recalling the missing drawing, made more mistakes, and usually needed the maximum of three memory trials.
The average time required to complete the test was 2-3 min for HCs, 6 min for aMCI patients, and 7 min for mild AD dementia patients, so this test is relatively short despite being a specific memory test and not a brief cognitive screening test as MMSE or MoCA. By comparison, the time of passing the MMSE in cognitively impaired patients is, on average, 4 min 51 s [44]. Busy primary care and general neurology outpatient settings with limited face-toface time per patient need a short but specific memory test. The TMA-93 could fill the gap. The test runs with a ceiling effect in HCs and is highly discriminative for diagnosing patients with aMCI or mild dementia [16]. However, a floor effect should be expected in patients with moderate dementia and may could be already present in some patients with mild dementia, here represented by the outliers for whom the administration of the test took longer than 15 min. The target of the TMA-93 are mainly patients with memory complaints and no functional impairment when total scores on MMSE or MoCA are around the cutoffs and are not conclusive [24]. Studies comparing the diagnostic accuracy and feasibility of the TMA-93 against screeners, as MMSE or MoCA, in settings with limited face-to-face time per patient are needed.
The samples here tested were composed of a relatively high percentage of low-educated participants. Lack of education remains a limitation in many elderly Spanish people since they had limited primary school access in the aftermath of the Spanish Civil War (1936)(1937)(1938)(1939). Although the situation has significantly improved in recent years, 59% of the population over 65 years of age in Spain did not complete primary studies [45]. Low-education is also a limitation for people in many developing countries in the world. In most developed countries, multicultural individuals with a different primary language, not proficient in the host country one, also have this limitation. The neuropsychological examination must comply with this handicap. Here, the TMA-93 was again demonstrated feasible to be administered to low-educated individuals. In fact, there were no significant differences in administration time by educational attainment. Despite this feasibility, the TMA-93 total score should be expected lower in low-educated individuals. Feasibility does not mean that the test is free of educational bias. Associative learning is also trained and acquired at school and, accordingly, normative studies show lower TMA-93 total score in less educated groups [24,38].
In addition to optimal diagnostic accuracy previously reported for the TMA-93, the good reliability and feasibility here demonstrated encourages the completion of the test´s development. The next steps will be phase II and III validation studies, including AD biomarkers and comparing the diagnostic accuracy of the test with that of the standard mem-ory instruments on samples organized by educational attainment.

Conclusion
In summary, our findings of good reliability (internal consistency and inter-rater and test-retest reliability) and feasibility (task-tolerability, short administration time, and simplicity of administration and scoring after some training) make the TMA-93 a brief relational binding memory test suitable to be administered to patients with memory complaints, particularly in settings with limited face-to-face time per patient and low-educated population.