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Olfactory identification disorders due to Alzheimer’s disease: A new test from France to Quebec

['Magali Payne', 'Cobtek Lab', 'Cognition Behavior', 'Technology', 'Université Cote D Azur', 'Nice', 'Centre Hospitalier Universitaire De Nice', 'Service Clinique Gériatrique Du Cerveau Et Du Mouvement', 'Centre Mémoire Ressources Et Recherche', 'Université Côte D Azur']

Date: 2022-04

Abstract Olfactory identification disorder is regarded as an early marker of Alzheimer’s disease (AD) and of similar diagnostic significance of biological or cognitive markers. Premature damage of the entorhinal olfactory cortex, the hippocampus and the orbitofrontal cortex characterize AD and suggest a specific impairment of olfactory identification. The use of psychophysical olfactory identification tests in clinical diagnostic practice is therefore strongly recommended, but not required. As these widespread tests are rarely used, an innovative test, adapted to this target group has been developed. It has been used and validated in a routine care protocol at different Memory Centers in France and in Quebec, Canada. A total of 157 participants were recruited: including 63 Alzheimer’s patients and 94 healthy controls. The test was composed of 14 odorants diluted into 4 different concentrations. A computer interface generated randomization of 6 odors per participant and the automatic calculation of identification scores, of perceptual thresholds and of composite scores. All participants underwent a Mini Mental Scale Examination within the previous three months or on the same day of the olfactory test. The Alzheimer’s patients had a score between 20 and 30 and healthy controls participants had a score above 28 without any loss of points on recalled items. The results show that our olfactory identification test is able to significantly differentiate Alzheimer’s patients from healthy controls (p < 0.001), and to distinguish the French population tested from the Quebec population (p < 0.001). This study highlights an olfactory identification disorder as a target for early diagnosis of AD. Its cultural qualities make it a potential candidate for differentiated calibration between France and Quebec.

Citation: Payne M, Manera V, Robert P, Vandersteen C, Beauchet O, Galery K, et al. (2022) Olfactory identification disorders due to Alzheimer’s disease: A new test from France to Quebec. PLoS ONE 17(4): e0265764. https://doi.org/10.1371/journal.pone.0265764 Editor: Kensaku Kasuga, Niigata University, JAPAN Received: August 2, 2021; Accepted: March 7, 2022; Published: April 4, 2022 Copyright: © 2022 Payne et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: The author(s) received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist.

Introduction Alzheimer’s disease (AD) is a neurodegenerative disease where olfactory disorders appear prematurely [1] and act as a precursor that precede the clinical phase of the illness It has been shown that low olfactory scores, associated with a lack of awareness of the disorder, are prognostic factors of mild cognitive impairment [2]. According to the DSM V (Diagnostic and Statistical Manual of Mental Disorders), the cognitive deficit associated with AD can be mild (minor neurocognitive disorder) or patent (major neurocognitive disorder) [3]. The degenerative process underlying Alzheimer disease is characterized by the formation of amyloid plaques (Amyloïdopathy) and by the accumulation of neurofibrillary tangles (Tauopathy) [4]. These anatomical lesions are early observed in the transentorhinal and entorhinal regions of the temporal lobe [5] and progress to the limbic areas [6]. During the asymptomatic phase of AD, a gradual degeneration of the primary cortex occurs and then progresses to the hippocampus, the thalamus, the insula and the orbitofrontal cortex [7]. Olfactory disorders worsen as the disease progresses [2]. Early odour identification deficits have been identified [1] as a strong predictor of entry into AD. Among olfactory disorders, difficulties in olfactory identification are an early marker of vulnerability [8], while the detection threshold remains relatively preserved in early stages of the disease [9]. This is related to an early damage of the entorhinal cortex, hippocampus and orbitofrontal cortex [10–13], with high-level tasks being affected while olfactory information, and thus olfactory threshold is not damaged in the early phase [14,15]. The olfactory identification task involved presenting a set of odors and offering a choice of four to five names for each odor. Scores on olfactory identification tests significantly distinguish Alzheimer’s patients from healthy control [10,11] and could even have a better predictive value than an episodic memory test among adults at risk of cognitive decline [16]. There is a strong correlation between the results of the olfactory identification tests and the cognitive tests [17–20]. Thus, the use of an olfactory test (OT) is recommended [21,22] in daily clinical practice without an isolated use. It is, in fact, a very good candidate to be used as a marker of the disease in early detection tests [23]. This was demonstrated by Lafaille-Magnan et al. [24]. However, these scientific findings do not necessarily lead to a regular use of olfactory tests [25,26], which could be justified by their time-consuming nature and the lack of consensus on which tests should be used [27]. Many olfactory tests (OT) are available on the market. Some tests are taking into account the cultural dimensions of odors, which is an important aspect of olfactory identification [28], others are multicultural [27]. The best known are: the University of Pennsylvania Smell Identification Test (UPSIT) developed by Doty [29], including short versions [11] and culturally adapted to North American culture, the "Sniffin’ Sticks" test (Burghart Instruments, Wedel, Germany) [30] applicable to European study groups, and the ETOC (European Test of Olfactory Capabilities) which is cross-cultural [31]. All have been evaluated in populations with mild cognitive impairment [32]. They are very rarely used as an adjunct to the premature diagnosis of AD [33]. Olfactory testing in cognitive impairment is commonly performed by otorhinolaryngologists in daily clinical practice or by neurologists or psychiatrists in memory clinics [14,34]. A simple, accurate and inexpensive OT [35] that would minimize the cognitive load [17] is necessary and recommendations have been made to incorporate clinical, cultural and molecular aspects in a test, stipulating the use of odorants of a simple and reproducible molecular structure [27,36]. By taking into account these imperatives, we have created a new OT, the TODA (Computerized Olfactory Test for the Diagnosis of Alzheimer’s Disease), which offers an optimized test through fully automated and computerized processing. This automatization provides reliable and reproductible evaluation [37], as well as time saving, as recommended [25].The soft-touch feel and lightweight design make the touch tablet ergonomic. 14 high-quality fragrances have been manufactured by perfume chemists from the city of Grasse. They were formulated by the Institute of Chemistry of the University of Nice Cote d’Azur. We used the TODA during memory consultations in 5 different centers in France, and at the Centre of Excellence in Longevity of at RUISSS McGill in Quebec. The objective of this study was to validate the effectiveness of TODA in mild AD. Specifically, we aimed to: Evaluate the convergence validity of the TODA by comparing scores obtained from the control population and the AD’s population in France and in Quebec.

Compare results between the control group and the AD group in France and in Quebec.

Find correlations between the scores obtained in the Mini Mental State Examination (MMSE)(38) and the scores with the TODA.

Discussion This study highlights the importance of using olfactory tests in clinical practice for early diagnosis of AD. For this reason, the psychophysical olfactory test TODA was developed. Our objectives were to compare the olfactory results obtained from the AD and HC groups in France and Quebec and to investigate correlations between cognitive scores on MMSE and TODA. Olfactory scores on TODA significantly differentiated AD patients from controls within French and Quebec population. This is consistent with previous studies [16,35] and highlights the olfactory identification task as a true biomarker of AD. In accordance with the literature [25,40,41], our results demonstrated that the olfactory test is a valid and reliable tool for the diagnosis of AD. As we know, the accuracy of such tests is comparable to measurements obtained by neuroimaging and cerebrospinal fluid biomarkers, which makes it a reliable biomarker [16]. The olfactory composite results with the TODA also differentiated the AD group from HC within each population, as highlighted for Quebec [20] and France [32]. The absence of correlation between the AD subjects and the HC subjects in France and Quebec can’t be assigned to MMSE or age. It can rather be attributed to the importance of cultural aspects in olfaction. The TODA allows to establish a cultural differentiation because of the choice of the odorants used in the test. Studies demonstrated the effect of culture on olfactory identification, and a variability in olfactory identification secondary to the culture of origin [28,42]. This highlights the need for specific calibration in France and Canada as it has been done for the UPSIT in different countries [40,41,43]. As in the TODA, the choice was to integrate cultural odors and consequently to identify the odors presenting the most significant differences in the two populations This study showed no connection between olfactory perception threshold and AD, which is expected in the early phase of the disease that is characterized by central damage [2,14]. Regarding the correlation of results between MMSE and olfactory scores, our findings indicated significance in AD patients and HC, which is the result of a strong correlation already established between MMSE scores and olfactory identification scores [9]. Olfactory identification performance diminishes as the MMSE score decreases [19,34,44] given to the association of olfactory identification and cognitive performance in AD. These results highlight also the relationship between olfactory dysfunction and cognitive condition in elderly people and the usefulness of TODA test as an additional marker of age- and pathology-related cognitive decline, or to detect persons at risk of cognitive decline. Indeed, it has been shown that olfactory changes could better predict cognitive decline compared to neuropsychological measures [45–47]. In addition, recent findings showed that, among other sensory markers (vision and audition), olfaction was identified as the most robust predictor of cognitive status and decline and, more specifically, the sensory modality with the greatest predictive power with respect to changes in episodic memory, digit symbol substitution, and vocabulary [48]. The MMSE scores of HC, is between 28 and 30 at the MMSE test and AD subjects is between 20 and 30. They do overlap in accordance with the international classifications, and this could explain the difficulty in distinguishing and finding specific correlations by population. The TODA test could be used as a follow-up for early AD because it is simple to use and quick to perform [9,43], and odors are randomized. That should minimize the re-test effects. Finally, the TODA test can also be useful for the early and differential diagnosis of dementia with Lewy bodies (DLB). Indeed, recent findings support the possible usefulness of hyposmia as a prodromal biomarker because it is present in some clinically normal GBA mutation carriers [45], is common in idiopathic REM sleep behavior disorder [46,47] and in older adults carrying the APOE ε4 allele, which is the most robust genetic risk allele for AD [49], DLB [50] and DLB spectrum [51] independently of AD pathology [52]. In addition, APOE-ε4 being linked to hippocampal atrophy and learning/memory phenotypes across the AD/DLB spectrum [53], it highlights once more the relationship between olfactory dysfunction and cognitive condition. Furthermore, studies suggest that olfactory function tests may be useful in differentiating DLB from AD [47,54–56]. Finally, TODA test in association with other markers (such as motor markers) may be employed to perform early, differential diagnosis and therapeutic strategies in AD and DLB. There are limitations in this study that should be addressed. First of all, the correlation was only made with a global cognitive measure (MMSE). This is the consequence of a choice based on the total duration of the evaluation that we wished short. Indeed, longer and more specific cognitive assessments will require a long waiting time in clinical practices. Also, it would have been interesting to allow the olfactory testing associated with the MMSE to be used as a quick screening to use as soon as possible while waiting for longer neuropsychological consultations. For the time being, it is necessary to combine this test with an in-depth examination of neuropsychological abilities [17], or with other cognitive variables which also influence olfactory scores [44] such as working memory, verbal fluency and executive functions [34] or naming and semantic memory [21]. The reference population came from hospital memory consultations to investigate mild cognitive impairments and probable AD. They are not exactly representative of the global early AD population and in a way that they had higher cognitive scores, which reduces the possibility of correlation by pathology and by country. The TODA needs to be calibrated for every country in order to distinguish the cultural specificity of each odor, and the retest effect to be evaluate.

Conclusion Our olfactory test has proven its validity to significantly differentiate AD patients from HC and can therefore be useful as a diagnostic aid. The significantly different scores in France and Quebec encourage country-specific calibration. Finally, because of its correlation with the MMSE, this olfactory test could also be useful as a measure for monitoring the evolution of AD at early stage.

Acknowledgments We thank the perfumer Payan Bertrand represented by Laure de Saint Lary and Aude Galouye for their help in the design of the odors; Xavier Fernandez and his students for their contribution to the formulation of the olfactory kit; Elise Faraut, Anne-Gaelle Corbille, Thomas Debourse, Geoffroy Hautecloque and Carole Blaye.

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