Gender-Related Differences in the Correlation between Odor Threshold, Discrimination, Identification, and Cognitive Reserve Index in Healthy Subjects

Simple Summary Many studies indicated significant associations between olfactory function and cognitive abilities in healthy controls. However, the gender-related association between olfactory function and each specific cognitive domain of the Cognitive Reserve Index (CRI) questionnaire has so far not been evaluated. The aim of this study was to evaluate gender-related differences in the relationship between olfactory function and each specific cognitive domain of the CRI questionnaire, such as education, working activity, and leisure time in healthy subjects. Our data indicated significant gender-related associations between olfactory function and CRI score. In women, odor threshold, odor discrimination, and identification were associated with CRI-Leisure Time, while in men, only a significant association between odor threshold and CRI-Education was observed. Abstract Background: Many studies suggested that olfactory function could be associated with semantic memory, executive function, and verbal fluency. However, the gender-related association between olfactory function and the cognitive domain is not well investigated. The aim of this study was to estimate gender-related differences in the relationship between olfactory function and each specific cognitive domain of the Cognitive Reserve Index (CRI) questionnaire, such as education, working activity, and leisure time in healthy subjects. Methods: Two hundred and sixty-nine participants were recruited (158 women and 111 men), with a mean age of 48.1 ± 18.6 years. The CRI questionnaire and Sniffin’ Sticks test were used to evaluate the cognitive reserve and the olfactory function, respectively. Results: In all subjects, significant associations between the odor threshold versus CRI-Education, between the odor discrimina-tion and identification versus CRI-Working activity and CRI-Leisure Time, were found. In women, odor threshold, discrimination, and identification were associated with CRI-Leisure Time, while in men, only a significant association between odor threshold and CRI-Education was observed. Conclusions: Our data, showing significant gender-related associations between olfactory function and CRI scores, suggested the use of olfactory evaluation and cognitive reserve as an important screening tool for the early detection of mild cognitive impairment.


Discussion
This study focused on the evaluation of gender-related differences in the association between olfactory function and cognitive reserve index. The brain cognitive reserve is closely related to cortical plasticity and is considered the potential capability of the brain to cope with neuronal damage in relation to individual differences such as brain size and synapse count. Cognitive reserve is important in order to recover brain damage affected by aging or neurodegenerative diseases through the recruitment of pre-existing brain networks [27]. Robertson indicated that the right hemisphere plays an important role in cognitive reserve using a noradrenergic pathway [28].
Our results showed statistical differences between men and women for the OT, global olfactory function (TDI score), and CRI-Working Activity. According to previous studies, in women, higher mean values in OT and TDI scores were found compared to men [29,30]. Moreover, in our study, women showed significantly decreased scores in CRI-Working Activity compared to men, while no significant differences were observed

Discussion
This study focused on the evaluation of gender-related differences in the association between olfactory function and cognitive reserve index. The brain cognitive reserve is closely related to cortical plasticity and is considered the potential capability of the brain to cope with neuronal damage in relation to individual differences such as brain size and synapse count. Cognitive reserve is important in order to recover brain damage affected by aging or neurodegenerative diseases through the recruitment of pre-existing brain networks [27]. Robertson indicated that the right hemisphere plays an important role in cognitive reserve using a noradrenergic pathway [28].
Our results showed statistical differences between men and women for the OT, global olfactory function (TDI score), and CRI-Working Activity. According to previous studies, in women, higher mean values in OT and TDI scores were found compared to men [29,30]. Moreover, in our study, women showed significantly decreased scores in CRI-Working Activity compared to men, while no significant differences were observed for CRI-Education and CRI-Leisure Time. This result may be explained as a difference in the employment and retirement age between the two sexes, as reported by Boots and Colleagues [31]. In fact, some studies reported that women with healthy working conditions (e.g., crafts worker, shopkeeper, and farmer) may reduce the risk of mild cognitive impairment and dementia [18,32].
Considering all subjects, our data showed a noteworthy association between olfactory function and CRI. In particular, we found significant associations between the OT and CRI-Education and between the OD and OI and CRI-Working Activity and CRI-Leisure Time. These data suggested and highlighted the close association between olfactory function and cognitive abilities. Subjects with lower scores in olfactory function usually exhibit weaker cognitive performance [2]. In addition, higher olfactory scores are usually associated with better semantic memory and verbal abilities [33]. Craick and colleagues [34] showed that, both in women and men, Alzheimer's disease symptoms appeared five years later in bilinguals than in monolinguals. Another study indicated that cognitive ability and vocabulary were associated with OI [35]. A possible explanation of these data is due to partial overlapping in the brain areas involved in cognitive abilities and those involved in olfactory function such as the orbitofrontal cortex and amygdala. Our data also suggested a significant positive correlation between OD and OI scores and CRI-Leisure Time and are similar to those obtained in a previous study [36], suggesting a relationship between OI and social life. On the other hand, the relationship between OI and OD and CRI-Leisure Time is not clearly understood. In the multivariate linear regression analyses, we found that there was a positive significant association between OI and OD and CRI-Leisure Time only in women, but not in men. These data support the hypothesis that CRI-Leisure Time is closely correlated to OI and OD performance only in women. Generally, women showed better olfactory performance compared to men [10,37] and also had more social connections. It is likely that women perform differently in social relationships and there could possibly be an association between leisure time, social networks, and health measures. In fact, Codina and Pestana showed that men had more leisure time, but women had a higher positive leisure experience than men [38]; women enjoyed themselves more with less leisure time and were more positive about time orientations. Moreover, Larsson and colleagues observed that women identified more odors than men due to gonadal hormones, fluctuations of the menstrual cycle, and neuroendocrine influences on brain regions involved in olfactory function, but sex differences disappeared in older age [35]. Although the potential cause of the difference between men and women remains unclear, the higher identification in women may be due to sex differences in verbal abilities, prior experience, and odor memory [39]. However, social factors may also contribute as women generally experience greater olfactory pleasantness, odor familiarity, and greater exposure to odors in their social environment. A better performance in OD and OI is considered a measure of general good health in the population. Indeed, good health is often connected with social lives and the number of social contacts that the individuals have in their life.
The association between OT and CRI-Education was observed only in men and not in women. Our data suggested that the CRI-Education sub-score may have a minor contribution in women, as indicated in a previous study [17]. Instead, Heian and colleagues showed that men with low education had lower olfactory function scores after a comparison between self-reported tests and Sniffin' sticks data analysis [40].
Our data suggested that in men, CRI-Education and not CRI-Working activity was associated with the odor threshold. Moreover, both in men and in women, working activity had no relation with the total olfactory function. Education probably has a protective role in mild cognitive decline, as previously indicated by Meng and D'Arcy [41]. In fact, people with a high level of education correctly identified more odors, as indicated by Larsson and colleagues [35].
Considering these results, our data suggested a potential role of biomarkers for olfactory function in the early diagnosis of mild cognitive impairment. Similarly, other previous studies indicated that olfactory impairment represents a peculiar biomarker in neurodegenerative disorders [6][7][8][42][43][44][45][46]. Recently, there has been an increased interest in the evaluation of olfactory dysfunction in the early stage of neurodegenerative disorders such as Parkinson's disease. In our previous study on Parkinson's disease, patients' significant correlations were observed between OT and language, between OD and visuospatial domain, and between OI and executive index scores and attention [6], suggesting that the OT, OD, and OI are differently related to the cognitive abilities of the subjects.
One limitation of our study is the cross-sectional design, thereby it did not allow us to evaluate these associations over time.

Conclusions
Our data indicated gender-related associations between olfactory function and Cognitive Reserve Index. In women, odor threshold, odor discrimination, and identification were associated with CRI-Leisure Time, while in men, only a significant association between odor threshold and CRI-Education was observed. The gender differences observed in our study could play a key role in order to predict the risk of mild cognitive impairment and to develop a precision medicine approach. In fact, this study could help in the development of new and appropriate intervention strategies differentiated by sex regarding the prevention of cognitive impairment. Our study confirmed that olfactory dysfunction and cognitive impairment had a severe negative impact on subjects' daily life. Finally, this study highlighted the use of olfactory evaluation and cognitive reserve assessment as important screening tools for the early detection of mild cognitive impairment.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki and approved by the "Azienda Ospedaliero Universitaria" AOU Cagliari Ethical Committee (Prot. PG/2018/10157).