The Diagnostic Value of a Short Memory Test: The TNI-93

Abstract

Background:

The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer’s disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients.

Objective:

In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status.

Methods:

We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 and November 2019. We compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria.

Results:

108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A + group (N= 80) were significantly more impaired than patients from the A- group (N= 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p ≤ 0.001), total recall (A+: 5.7±3.5; A-:7.8±2.8; p ≤ 0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). ROC curves revealed that the best scores to discriminate A + from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74).

Conclusion:

The TNI-93’s immediate, free, and total recalls are valuable tools for the 39 diagnosis of AD.

Keywords

Alzheimer’s disease AT(N)cerebrospinal fluid biomarkers illiteracy memory test neuropsychology

INTRODUCTION

Alzheimer’s disease (AD) affects more than one million patients in France and 35 million worldwide [1]. The diagnosis of AD relies on the association of clinical and biological arguments [2, 3]. Clinically, progressive episodic memory impairment, described as a hippocampal syndrome is considered as the usual presentation of AD [4, 5]. The patient typically shows a recall deficit that is not improved by cueing [6, 7].

A significant proportion of AD patients are illiterate or poorly educated. A person who is illiterate is defined as a person who cannot with understanding both read and write a short simple statement on his everyday life [8]. In a survey performed in France in 2011, 33%of people above 65 years old had strong difficulties in French writing. The proportion of patients having difficulties in writing and reading was a lot higher in people who went to school outside of France. This study estimated a total number of 2.5 million French people who are illiterate [9, 10]. Other countries from the OECD (Organisation for Economic Co-operation and Development), notably Spain and Italy showed similar illiteracy rate [11]. In patients who are illiterate, the hippocampal syndrome has to be searched for with memory tests adapted for this specific patient population. Only few validated and adapted clinical tests are available for low educated and/or non-western countries patients [12, 13]. Moreover, one study found that picture-based memory tests are more adapted to this specific patient population [14].

The TNI-93 developed at Avicenne hospital is a quick and easy test, based on 9 images with an encoding step followed by a delayed free and cued recall. It does not correlate with the level of education so it can be used in both literate and illiterate patients, and showed a good sensitivity and specificity as a screening tool for dementia, regardless of the etiology [15, 16].

AD diagnosis can also be supported by objective and specific biomarkers, such as amyloid PET or cerebrospinal fluid (CSF) analyses of amyloid-β peptide (Aβ₄₂), total tau, and phosphorylated tau [3 , 18]. Hippocampal volume on cerebral MRI [19] and cerebral metabolism on FDG PET scans [20] are altered in AD but these biomarkers are less specific for AD [17]. Based on biomarkers, diagnostic and research criteria have been developed by two main research groups, the International Working Group [2, 18] and the National Institute on Aging Alzheimer’s association (NIA-AA) [17, 21]. Following these criteria, CSF analysis is often proposed in the diagnosis process of cognitive disorders notably when the neuropsychological assessment is difficult to interpret. However, CSF analysis is not always possible in clinical practice, because the test is not available everywhere, because it sometimes costs too much for the patient, or because there is a medical contraindication to lumbar puncture (LP). It is therefore helpful to know whether there is a correlation between the cognitive presentation and the CSF status, especially in population that are difficult to evaluate and have less access to CSF analysis, such as patients who are illiterate. Indeed, less educated patients may have even less access to CSF analysis for economic reason, but also because they less consult the doctor due to a lack of health education [22].

The aim of the present study was to assess the diagnostic value of the TNI-93 to discriminate patients with CSF amyloid from those without. We aimed to assess the sensitivity and specificity of the test in the global population of patients with cognitive complaints. This group of patients seen at the memory clinic included patients with dementia (AD or non-AD), and patients with mild cognitive impairment (prodromal AD or other diagnosis). Additionally, we believe that a mixed visual-verbal memory test is informative in patients with memory complaints but is more difficult to interpret in patients with aphasia, notably because it requires the patient to be able to name the drawings. For this reason, in a practical aim to better determine in which clinical situation the test is most relevant, we assessed the diagnostic value of the TNI-93 according to the nature of the cognitive complaint (memory, language, or other complaint) reported by caregiver and/or the patient.

METHODS

Patients

Patients’ data was retrospectively collected from all patients who consulted at the memory clinic of the Avicenne hospital (Bobigny) from January 2009 to November 2019 and underwent a LP. We included all patients who had a LP for the analysis of AD CSF biomarkers, a full neuropsychological assessment that included the TNI-93 test before or at the time of the LP (No later than one year after the LP) and an anatomical brain imaging (MRI or CT scan). Patients with an abrupt onset of cognitive disorders or a Mini-Mental State Examination (MMSE) score < 5 (out of 30) were excluded. There were no additional exclusion criteria notably no exclusion criteria regarding other cognitive comorbidities and non-French fluency if an interpreter was available. The confirmation of AD diagnosis relied on the study of the CSF, based on the latest published diagnostic criteria (classification ATN, 2018) [17].

Diagnostic criteria

We used the AT(N) criteria developed by the NIA-AA in 2018 [17] to classify patients in one of the following groups: 1) Patients with amyloid abnormalities secondary to a continuum of AD (A+) and 2) Patients with no amyloid abnormalities secondary to a continuum of AD (A-). Then, for subgroup analyses in patients with a biological profile of AD versus non-AD profile, we classified patients in one of the following groups: 1) Patients with AD (A + T+: amyloid and tau phosphorylated abnormalities) and 2) Patients with no AD (A-T-: no amyloid and no tau phosphorylate abnormalities).

Definition of illiteracy or low education

In the present study, patients with less than 5 years of schooling were considered illiterate or low educated. We included in the illiterate or low educated group patients who did not attend school at all.

CSF was collected by a LP sampled in a polypropylene tube, frozen, and sent to a storage container in the laboratory of the Lariboisière-Fernand Widal Hospital. The liquid was analyzed and peptide Aβ₄₂ and Aβ₄₀ as well as phosphorylated tau and total tau ratio were measured by Innotest^® ELISA method (Fujirebio) and then by the technology electrochemiluminescence Elecsys^® (Roche) after 2014. Between 2009 and 2019, techniques have changed as well as the interpretation thresholds (Supplementary Material).

Neuropsychological assessment

All patients had a neuropsychological assessment that was carried out by a certified neuropsychologist. Interviews took place with the patient alone or sometimes with a family member for translation needs. All patients underwent the TNI-93 and the MMSE. The rest of the neuropsychological assessment included assessment of language, executive functions, and memory with tests that varied according to patient’s and caregiver’s complaint, clinical severity, and level of education. The neuropsychological assessment’s objective was to draw up a cognitive profile in order to orient the diagnosis.

After the clinical evaluation and complementary exams, patients’ diagnosis was discussed and established in a weekly meeting of neurologists, neuropsychologists, and radiologists.

TNI-93

The TNI-93 was derived from the MIS (memory impairment screen) [23]. It consists of an A4 sheet with nine black and white drawings (Fig. 1). The instructions are simple, and the test lasts 5 to 10 min. There are two stages, encoding and then delayed recall. During the encoding stage, the drawings are placed in front of the patient. Participants first complete a naming task according to the semantic category given by the examiner by answering to the following question: “which one is an . . . ”. The semantic categories are as follows: animal, transportation, musical instrument, vegetable, part of the face, furniture, fruit, “something which is used to dress up”, kitchen utensil. If the patient does not understand the name of the category, the examiner may repeat it with a simpler description (for instance asking to show “an item used for eating” rather than “a kitchen utensil”). To finish the encoding, the examiner hides the images, and an immediate cued recall is undertaken by giving the semantic category as a cue (the same cue as previously used). If some items are not returned during the immediate recall, the images are placed in front of the patient a second time with the same encoding procedure as before (a third time is possible). After a 20-s interfering test (either to count backwards 3×3 from 40 during 20 s or to say the days of the week backwards for participants unable to count), a delayed free recall (without cues) test is performed (score ranging from 0 to 9, pathological < 6). Then a cued recall (score ranging from 0 to 9) is proposed for the forgotten images, performed by giving the semantic category of the missing items. Intrusions are reported for all steps. The sum of the delayed free and cued recall forms the total recall (score ranging from 0 to 9, pathological < 9) [15, 16].

Fig. 1

Drawings of the TNI-93 test.

Details of the TNI-93 results have been carefully collected. However, in a few cases, the number of encoding attempts or the number of intrusions was not reported. In these cases, we left the result as a missing data.

Ethics

Our study was approved by the Local Ethics Committee for the Clinical Research of the Hôpitaux Universitaires de Paris Seine Saint-Denis (Number of protocol: CLEA-2019-93) and according to current French legislation for retrospective studies on file, patient consent was not required.

Statistics

Demographic, clinical, and cognitive measures were compared between A + and A- patients, as well as between A + T+ and A-T- patients. Fisher’s exact test was used for categorical variables and Welch’s t-test for continuous variables.

Generalized linear regressions (GLMs) were performed to study the impact of amyloid status on TNI-93 subscores adjusted for gender, age, education, MMSE, and tau status. Similar analyses were performed on A + T+ and A-T- patients to study the impact of AD pathology on TNI-93 subscores.

Additionally, the same models were performed in order to investigate differences in TNI-93 subscores between A + and A- patients in each cognitive complaint group (memory, language and other, as reported by the caregiver and/or the patient), looking at the interaction between amyloid status and cognitive complaint group. The group of patients with a mixt memory and language impairment was removed from this analysis due to small sample (n = 6).

GLMs with binomial family and logit link were used for TNI-93 naming, TNI-93 immediate recall (IR), TNI-93 free recall (FR), TNI-93 total recall (TR); and GLMs with Poisson family and logarithm link were used for TNI-93 number of encoding attempts, TNI-93 encoding intrusions and TNI-93 recall intrusions. Corrections for multiple comparisons were performed using Benjamini-Hochberg method. For all GLMs, type II F-tests were used. Cohen’s f2 were calculated to assess effect sizes. Normality of residuals as well as heteroskedasticity were checked visually. Cook’s distances and hat values were calculated to identify influential data. Analyses were run without subjects with Cook’s distances higher than 1.

Receiver Operating Characteristic (ROC) curves were performed on TNI-93 subscores to discriminate A + and A- patients. Optimal cutoffs were measured by maximizing sensitivity and specificity indicator.

Statistical analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/).

Results are expressed as mean±standard deviation (SD) and percentage.

RESULTS

A total of 108 patients were included (Table 1, Fig. 2). Among the 108 patients, 67 had a memory complaint, 19 had a language complaint, 6 had both memory and language complaint, and 16 had another complaint (behavioral disorder, hallucination, visual, mood disorder). Mean age of the population was 66.9 ± 8.5 years old and 51%were women. Mean education level was 8.9 ± 5.2 years and patients who are illiterate or low educated represented 27%of the population. French was the native language for 48%of patients, other native languages included Arabic in 22%, Portuguese in 10%, Vietnamese in 6%, and other language in 14%. Mean MMSE score was 17±5.5 (Table 1). All patients had brain imaging: 91 patients had a cerebral MRI, and 89 patients had an FDG-PET scan.

Table 1

Description and comparison of A + and A- patients

	all	A+N = 80	A- N = 28	p ‡
	N = 108	(74.07%)	(25.93%)
Age	66.93±8.49	67.86±7.53	64.28±10.50	0.054
Sex (Female)	55 (50.93%)	42 (52.50%)	13 (46.43%)	0.663
Education (y)	8.89±5.16	8.81±5.03	9.11±5.61	0.796
Native language (French)	52 (48%)	40(50%)	12 (43%)
Illiterate/low educated	29 (26.85%)	20 (25.00%)	9 (32.14%)	0.467
Disease duration (y)	2.38±2.86	2.27±2.11	2.71±4.39	0.489
MMSE (/30)	17.00 ± 5.48	16.20 ± 5.02	19.29 ± 6.17	0.010*
Complaint
memory	67 (62.04%)	52 (65.00%)	15 (53.57%)
language	19 (17.59%)	14 (17.50%)	5 (17.86%)
memory+language	6 (5.56%)	6 (7.50%)	0 (0.00%)
Other cognitive domain	16 (14.81%)	8 (10.00%)	8 (28.57%)	0.069
Tau	52 (48.15%)	50 (62.50%)	2 (7.14%)	< 0.001*
Naming	7.81±1.91	7.78±1.94	7.93±1.88	0.883
Immediate recall	6.25 ± 2.80	5.85 ± 2.77	7.39 ± 2.59	0.001*
Number of encoding^§	2.04±0.89	2.22±0.90	1.54±0.65	0.287
Encoding intrusion ^§	0.96±1.48	1.10±1.46	0.58±1.50	0.309
Free recall	4.14 ± 2.59	3.54 ± 2.67	5.86 ± 2.84	< 0.001*
Total recall	6.24 ± 3.43	5.68 ± 3.47	7.82 ± 2.82	< 0.001*
Recall intrusion^§	0.75 ± 0.61	1 ± 1.84	0.12 ± 0.33	0.002*

^‡Welch’s t-test was used to compare groups for continuous variables and Fisher’s exact test for qualitative variables. Data are given as mean±standard deviation for continuous variables and as count (percentages) for categorical variables. For TNI-93 subscores, p values were extracted from GLMs and thus, were adjusted for age, gender, education, MMSE and tau status. They were corrected from multiple testing using Benjamini-Hochberg correction. ^§GLMs with Poisson family and logarithm link and GLMs with binomial family and logit link otherwise. *Statistically significant. Tau, presence of phosphorylate tau.

Fig. 2

Flowchart of the population screening.

Patients were classified into two groups according to the AT(N) criteria: there were 80 patients in the A + group, corresponding to patients with amyloid abnormalities and 28 in the A- group, corresponding to patients without amyloid abnormalities. Patients in the A + group were clinically defined as having AD (n = 53 patients), Lewy body dementia (LBD) (n = 12 patients), both diseases (LBD and AD n = 2), vascular dementia (n = 4), mixed dementia (vascular and AD disease, n = 3), behavioral variant frontotemporal dementia (n = 2), semantic dementia (n = 2), Parkinson’s disease dementia (n = 1), or corticobasal dementia (n = 1). In the A- group, patients were clinically defined as having psychiatric disorders (n = 6 patients), behavioral variant frontotemporal dementia (n = 7), normal pressure hydrocephalus (n = 2), vascular dementia (n = 4), semantic dementia (n = 3), LBD (n = 2), sequelae of inflammatory pathology of the central nervous system (n = 1), vitamin deficiency (n = 1), and progressive supranuclear palsy (n = 2).

Comparison of A + and A- patients

Whole group of patients (Table 1)

Age, gender, and education did not significantly differ between A + and A- groups. MMSE score was significantly more altered in A + than in A- group (A+: 16.2±5.0; A-: 19.3±6.2; p = 0.010).

On TNI-93 scores, patients from the A + group (N = 80) were significantly more impaired than patients from the A- group (N = 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p < 0.001), and total recall (A+: 5.7±3.5; A-: 7.8±2.8; p < 0.001) (Table 2) and on the number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). We found no differences between both groups in naming, number of encoding attempts and number of intrusions during encoding.

Table 2

Comparison of TNI-93 scores between patients from A + T+group and A-T- group (all cognitive complaints included)

	A-T- N = 26	A+T+N = 50	p corrected
	(34.21%)	(65.79%)
Naming	7.85±1.93	7.54±2.05	0.941
Immediate recall	7.69 ± 2.22	5.42 ± 2.82	< 0.001*
Number of encoding ^§	1.52 ± 0.65	2.38 ± 0.86	0.049*
Encoding intrusion ^§	0.52 ± 1.50	1.25 ± 1.12	0.038*
Free recall	6.12 ± 2.69	3.44 ± 2.65	< 0.001*
Total recall	8.15 ± 2.44	5.51 ± 3.19	< 0.001*
Recall intrusion ^§	0.12 ± 0.34	1.24 ± 2.19	< 0.001*

Data are given as mean±standard deviation. p values were extracted from GLMs and thus, were adjusted for age, gender, education and MMSE. They were corrected from multiple testing using Benjamini-Hochberg correction. ^§GLMs with Poisson family and logarithm link and GLMs with binomial family and logit link otherwise. *statistically significant.

TNI-93 scores in subgroups according to clinical presentation (Fig. 3, Supplementary Table 1)

In the subgroup of patients with memory complaints (N = 67), A + patients (N = 52) were significantly more affected than A- patients (N = 15) on immediate recall (mean difference (MD) between A + and A-±standard error (SE): –1.15±0.31, p < 0.001), free recall (MD±SE: –1.31±0.25, p < 0.001), and total recall (MD±SE: –2.80±0.39, p < 0.001) (Fig. 3). There was a tendency of more intrusions in A + patients during recall that did not reach significance (MD±SE: 2.13±1.09, p = 0.086). Naming, number of encoding attempts, and number of intrusions during encoding did not differ between both groups.

Fig. 3

Estimated marginal means of TNI-93 subscores, and their 95%confidences intervals, extracted from the interaction between amyloid group and main cognitive complaint in GLMs. *significant without correction for multiple testing on TNI-93 subscores; **significant after correction for multiple testing on TNI-93 subscores.

In the subgroup of patients with presentation other than memory complaint (i.e., language impairment or others presentation such as behavioral and hallucination), we observed no difference between A + and A- patients on the TNI-93 scores.

TNI-93 scores according to age, education, MMSE, and tau status (Supplementary Table 2)

Neither age, education, nor tau status were correlated with any of the TNI-93 scores. The MMSE score was correlated with all TNI-93 scores except number of intrusions at recall.

Comparison of TNI-93 scores in A + T+patients and A-T- patients (Table 2) – all cognitive complaints

A + T+patients (N = 50) were significantly more impaired than A-T- patients (N = 26) on immediate recall (p < 0.001), free recall (p < 0.001), and total recall (p < 0.001). A + T+patients also had significantly more intrusions during recall (p < 0.001), more encoding attempts (p = 0.049), and more intrusions during encoding (p = 0.038) than A-T- patients. There was no difference between A + T+ and A-T- patients in naming.

ROC curves (Fig. 4) – whole group of patients

Fig. 4

ROC curve analysis to discriminate A + and A- in the whole group of patients.

Analyses of the ROC curves revealed that the best scores of the TNI-93 test to discriminate A + patients from A- were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74) (Fig. 4). An immediate recall under 6 offered a sensitivity of 54%and specificity of 83%. A number of encoding trials under 3 offered a sensitivity of 44%and a specificity of 93%. A free recall under 4 and a total recall under 8 respectively offered a sensitivity of 63%and 72%and a specificity of 77%and 73%(Table 3).

Table 3

Results of the Receiver Operating Characteristics (ROC) curve analyses to discriminate patients with amyloid pathology (A+) from patients without amyloid pathology (A-)

	Optimal cutpoint	Accuracy	Sensitivity	Specificity	AUC
Naming	8	0.55	0.54	0.57	0.55
Immediate recall	6	0.62	0.54	0.83	0.7
Number of encoding trials	3	0.57	0.44	0.93	0.73
Encoding intrusion	1	0.61	0.54	0.79	0.66
Free recall	4	0.66	0.63	0.77	0.74
Total recall	8	0.72	0.72	0.73	0.74
Recall intrusion	1	0.52	0.37	0.89	0.64

DISCUSSION

In this study, we assessed the diagnostic value of the TNI-93 to discriminate A + and A- patients and we showed, in a group of patients presenting with cognitive complaint, that immediate recall, free recall, and cued recall were more impaired in A + patients that in A- patients. In subgroup analyses, this was significant only in patients presenting with memory complaints. ROC curves showed that immediate recall, free recall, and cued recall on the TNI-93 are sensitive and specific to distinguish patients with amyloid abnormalities.

Limitations

Our study has some limitations. First, we compared A + patients with A- patients in the main analysis. The presence of an amyloid peptide abnormality does not indicate definite AD, but it is evocative of an amyloid pathology. There is a continuum between amyloid disorder and AD, and amyloid peptide abnormality precedes tau pathology and neuronal loss AD [26]. To verify our results in patients with AD pathology and non-AD pathology, we compared a subgroup of patients with AD biological criteria (A + T+) with A-T- patients who did not have tau or amyloid pathology. These analyses showed similar results than the main analysis, with a slight increase in statistical significance. Hence, the alteration of immediate, free, and total recall on the TNI-93 might be an early sign of AD, specific to amyloid pathology rather than tau pathology.

Additionally, we used the AT(N) criteria developed by the [17] NIA-AA in 2018 to classify patients with abnormalities secondary to a continuum of AD (A+) and patients with or without pathological modification but not secondary to AD (A-). Other diagnostic criteria could have been selected such as the IWG criteria [2] or the 2011 NIA-AA criteria [21]. However, both are based on the cognitive and clinical assessment of patients. They seemed less relevant to our approach and difficult to use in a retrospective study without being a source of bias due to the difficulty of collecting and transcribing clinical data. We chose the NIA-AA 2018 criteria [17] since they are objective and independent from the clinical evaluation. Hence, the diagnosis of AD in this study does not rely on neuropsychological tests, notably on the TNI-93. This would have led to a circular reasoning which is also a source of bias.

The diagnoses performed with the AT(N) criteria were sometimes different from the clinical diagnoses retained during the weekly meetings of neurologists, neuropsychologists, and radiologists at Avicenne hospital. In the A + group (n = 80), 70 patients had a concordant clinical and ATN diagnosis of AD (n = 53) or associated pathology (n = 17, LBD and mixed AD+other pathology). In the A- group (n = 28), only one patient had a clinical diagnosis of AD but with a normal CSF profile (no amyloid, tau, or phospho-tau disorder). Objective criteria based on biomarkers limit bias and are easily reproducible, but they do not consider the patient’s semiology as a whole and they lack nuances. Additionally, some patients had associated comorbidities (vascular or neurodegenerative) that participated to cognitive symptoms. TNI-93 scores might be impacted by the additional disease and reflect both AD and comorbidity.

Finally, our patient population was not entirely representative of patients with AD. The female predominance was less obvious than in other AD studies [24 –26] and our patients were younger (mean age 66.9 years; literature mean age > 75 years), less educated (mean: 8.9 years; literature: 12 years) [16], and had a lower MMSE score (17; literature: > 23) [26]. This may indicate a selection bias that could be explained by the inclusion criteria of our study. Indeed, we only included patients who underwent a LP, which is mainly prescribed in patients under 65 years old and/or patients presenting with complex semiology. Moreover, compared to the FCSRT, the TNI-93 was preferably proposed to illiterate or low educated patients and to patients who had a significant cognitive impairment. Additionally, these characteristics may be explained by the multicultural background of our patient population. Our population pool belonged to the “Seine Saint Denis” French department which is one of the poorest and most multicultural department in France with a high rate of population who immigrated to France and who did not attend school or dropped out at a young age [10].

TNI-93 and education or cultural background

The specificities of our patient population demonstrate that the TNI-93 test is suitable for most patients, including patients who are illiterate because the test does not involve reading or writing. In the GLMs, the TNI-93 scores did not correlate with the level of education as it has already been demonstrated by Maillet et al. [16], on a different patient population. It suggests that the test is not impacted by education and can be used in high or low educated patients. The test can also be proposed to multicultural patients because drawings were selected to be recognized by multicultural patients [15], and the test can easily be performed with a translator. However, the use of family members as interpreter for some patients may have affected the results from cognitive assessments, notably from the TNI-93 scores, since family members may not be objective and tend to help the patient. Moreover, the cultural background of patients may have an impact on performance due to lack of familiarity with some images. Finally, the TNI-93 is shorter and more appropriate to patients suffering from severe dementia in comparison to the Enhanced Cued Recall test included in the 7-minute screen, that relies on 16 pictures, and has also been shown to be unaffected by illiteracy and cultural background [27].

Alteration of recall in A + patients

According to ROC curves, the best subscores of the TNI-93 to discriminate A + patients from A- were the immediate recall (AUC: 0.70), free recall (AUC: 0.74), total recall (AUC: 0.74), and number of encoding trials (AUC: 0.73). All four scores had an AUC > 0.7. Lowering the previously defined thresholds for the diagnosis of dementia [16] from 6 to 4 for the immediate recall, and from 9 to 8 for the total recall seems to add more specificity for the diagnosis of AD. A threshold at 6 for immediate recall also offered a good specificity. More than 2 encoding trials seem to reflect the AD-related slowing of learning.

Alteration of immediate recall in A + patients

Impairment of immediate recall refers to a deficit in encoding, in spite of the help of semantic indices. This forgetfulness reflects the anterograde memory disorder that appears early and is a source of disability in patients with AD [28]. Similar results were observed in studies assessing the diagnostic value of verbal memory cognitive tests based on word reading, such as the Free and Cued Selective Reminding Test (FCSRT): Immediate recall was decreased in patients with AD, although it was not the most specific subscore of the FCSRT for AD diagnosis [29, 30].

Although not significant, the number of encoding trials tended to be higher in A + patients compared to A- patients. The increased number of encoding attempts reflects a slowdown in overall information and cognitive processing leading to a slowdown in encoding. This appears to be discriminative with a good positive predictive value especially when there are more than two encoding attempts (Table 3). It could reflect description of patients with AD in real life situations, where slowing down and hesitation are observed in the performance of known or unknown tasks [31]. Additionally, slow learning could be an early sign of hippocampal-type cognitive impairment, before the onset of forgetfulness.

Alteration of free and total recall in A + patients

The deficit in free and total recall reflects a lack of consolidation with an alteration in storage and retrieval not improved by semantic indices (delayed free and total recall). This pattern, and notably the alteration of total recall, characterized by the absence of response to semantic indexes, corresponds to the so-called hippocampal syndrome, which has been described in patients with AD [4 , 28]. Similar results were observed in studies assessing the diagnostic value of other verbal memory cognitive tests such as the FCSRT or the 5-word test in AD [30, 32]. These tests, as the TNI-93, use reinforced encoding followed by immediate, free, and then cued recall. Studies assessing verbal memory tests showed more specificity of the total recall in the diagnosis of AD but suggest that free recall is more sensitive [30, 32].

Interestingly, we showed here that although the alteration of total recall was specific to amyloid pathology (Specificity of 73%with a cut off score of 8), the alteration of free recall was at least as specific to amyloid pathology (specificity of 77%with a cut off score of 4). Our results regarding free recall might be due to the design of the test, to the specificities of our patient population, that is less educated, but also to the short delay between encoding and recall (20 s). Because of this short delay, free and total recall may partly reflect encoding processes rather than storage and retrieval. For this reason, it might be interesting to assess the diagnostic value of a delayed recall of the TNI-93 items 20 min after encoding.

There were significantly more intrusions during the free and total recalls in the A + group. Similarly, more intrusions were observed during recall of other verbal memory tests in patients with AD compared to patients with no AD [29 , 34]. A study comparing the TNI-93 to the gold standard FCSRT [30] would be interesting to verify that both tests assess the same component of episodic memory.

However, compared to the FCSRT, the TNI-93 is a quick and easy to explain test. It is therefore easy to use during medical consultation. Moreover, it does not necessitate any specific material because it relies on a black and white A4 sheet, and instructions are easy to understand, so it can be performed without specific training or funding by any medical practitioner or psychologist. The TNI-93 test is also compatible with illiteracy and it can be used in a larger patient population than other verbal memory tests.

Results according to population specificities

The TNI-93 test was not informative in patients with language or other complaints than memory complaint, notably because naming difficulties impact all other scores of the tests and lead to interpretation difficulties. Alternatively, the absence of difference in the language subgroup might be due to a lack of power, due to the small sample of this subgroup (n = 19). Indeed, in the language group, there was a tendency toward a difference between A + and A- patients in immediate recall, free recall, and total recall.

Finally, our results on TNI-93 subscores were significant regardless of level of education, tau status and MMSE score. The TNI-93 subscores did not correlate with the tau status but they did correlate with amyloid status. This suggests it is a specific test of amyloid pathology.

CONCLUSION

We showed that the TNI-93 is suitable regardless of education level, with good value of immediate recall, free and total recall for the diagnosis of AD pathology.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0546r2).

Footnotes

The supplementary material is available in the electronic version of this article: .

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