INTRODUCTION
Alzheimer's disease (AD) is the most frequent cause of dementia (60-80%). Loss of
binding and difficulties in encoding new information are early signs of hippocampal
dysfunction and may facilitate an early AD diagnosis, a challenge for clinicians who
evaluate patients with memory complaints. To detect hippocampal dysfunction, we employ
screening and memory tests. As we live in a low-educated population area, verbal memory
tests have several limitations. In this context, we aimed to validate the "Associative
memory test of the Seine-Saint-Denis district" TMA-93, which examines "visual
relational binding." Through this doctoral work, we travel to TMA-93 validation and
normative studies.
METHODS AND RESULTS
In the preliminary TMA-93 validation (phase I), we compared its diagnostic accuracy
with FCSRT to differentiate patients with amnestic mild cognitive impairment (aMCI)
from Healthy Controls (HCs), including 41.7% low-educated participants. ROC curve
analysis determined an AUC of 0.97 (95% CI: 0.89 - 1.00, p <.001) to distinguish between
aMCI patients and HCs. The TMA-93 accuracy did not show significant differences with
the FCSRT.
Within the test reliability, the TMA-93 internal consistency between the related pictures
was "optimal" (Cronbach's alpha = 0.936). TMA-93 showed a “good” test-retest
reliability at 2-4 months for HCs [ICC = 0.802 (95% CI = 0.653 - 0.887)], suggesting
stability in the over-time performance. The inter-rater TMA-93 reliability was
“optimal” for the total score [ICC = 0.999, 95% CI 0.999 - 1], number of errors [ICC =
0.996, 95% CI 0.993 - 0.998], and number of intrusions [ ICC = 0.985, 95% CI 0.974-
0.992]. All participants completed the test, without significant differences in
administration time regarding educational level, with an average time of 6 minutes in
aMCI patients.
TMA-93 Spanish normative study provides normative percentiles data through a
systematized recruitment study on an 1131 participants' sample. We describe the healthy
population's reference scores with a broad representation of our region's community.
TMA-93 total score was influenced by age and educational level, but not by gender.
We finally validated the test’s diagnostic accuracy by comparing TMA-93 and FCSRT
variables’ predictive value with biomarkers’ result (CSF or Amyloid-PET), considered the
Gold-Standard. TMA-93 demonstrated "reasonable" diagnostic utility in discriminating
between "positive" and "negative" biomarker groups (AUC = 0.72; 95% CI: 0.62 - 0.82, p
<.001), higher than FCSRT variables. The sequential use of the TMA-93 after the
pictorial FCSRT increased the diagnostic sensitivity up to 95.3%.
DISCUSSION
TMA-93 uses ten semantically related pairs of drawings, assessing binding. Binding ability
decreases in prodromal AD so that it could facilitate an early diagnosis.
TMA-93 is a specific memory test suitable for elder and low-educated patients. It
is probably more accurate for diagnosing aMCI than others testing episodic memory, and
its short administration time turns the test suitable for Primary Care or General Neurology
outpatient clinics, in which there is limited time per patient.
We first validated TMA-93, comparing its diagnostic accuracy with FCSRT to differentiate
aMCI patients from HCs, finding a similar diagnostic accuracy. Afterwards, we studied
test’s reliability, finding an “optimal” internal consistency (Cronbach's alpha = 0.936),
“good” test-retest, and “optimal” inter-rater reliability. TMA-93 showed itself feasible
as all participants completed the test in an average time of 6 minutes in aMCI patients.
Through the normative study, we provide normative percentiles data through a
representative population. TMA-93 was influenced by age and educational level but not
by gender. This study showed wide variations of the 5th and 10th TMA-93 percentiles,
lower for the older and less educated groups, suggesting that the ability to learn by visual
association is lower and more sensitive to aging in the low-educated group.
We finally validated TMA-93 by comparing it and the FCSRT variables with biomarkers
(Gold Standard). The TMA-93 demonstrated "reasonable" diagnostic utility in
discriminating between biomarker groups (positive or negative). Memory impaired
patients with an MMSE ≥ 22 and TMA-93 total score ≤ 5th and 10th percentiles showed
75% and 86% sensitivity and 41% and 29% specificity, respectively, for AD biological
diagnosis. These high sensitivity values position the TMA-93 as a good memory
screening test, particularly for limited face-to-face time settings.
Therefore, we propose the patients' memory examination to start with the TMA-93 (as
screening), followed by the AD-pathology confirmation with the highest specific test at
present: biomarkers. The sequential use of the TMA-93 after the pictorial FCSRT
increased the diagnostic sensitivity up to 95.3%.
CONCLUSIONS
TMA-93 is highly discriminative to distinguish MCI patients without excluding loweducated
individuals. It has a high internal consistency and precision, with high
interobserver and good test-retest reliability. TMA-93 administration spends between 3-7
minutes, suitable for Primary Care. It seems as accurate as FCSRT to discriminate
between positive and negative AD biomarkers' results, improved by adding TMA-93 to
FCSRT variables. All together, position the test as a good screening tool in limit face-toface
consultations
