1. Introduction
Parkinson’s disease (PD) is characterized by both motor and non-motor symptoms that have a great impact on quality of life (QoL). Dysosmia is one of the non-motor symptoms of PD, and its prevalence ranges from 46 to 97% [
1,
2]. Normosmia is a marker of younger onset with a PD phenotype that has a less severe motor manifestation [
1]. Increasing evidence shows that dysosmia correlates with not only motor symptoms, but also various non-motor symptoms, including cognitive, psychiatric, sleep, and autonomic dysfunction [
3,
4,
5].
A plausible pathomechanism underlying the correlation of dysosmia with motor and non-motor manifestation is that α-synuclein (αSN) spreads in a prion-like fashion from the olfactory bulb to other structures. It primarily spreads to the anterior olfactory nucleus [
6], which connects to various locations, including the entorhinal cortices, olfactory tubercles, substantia nigra (SN), amygdala, dorsal motor nucleus of the vagus nerve, raphe nuclei, and locus coeruleus [
7]. However, there is conflicting evidence regarding the correlation between dysosmia in PD with motor dysfunction [
1,
2,
3,
4,
5,
8,
9,
10,
11,
12] and depression [
3,
4,
13], although there is a consistent correlation between dysosmia and cognitive dysfunction in PD [
3,
4,
5,
13,
14]. A cohort study showed that only 51–83% of autopsies of PD patients followed the Braak staging, while another cohort showed that 6.3% deviated from the Braak staging but showed prominent involvement of olfactory structures and amygdala [
15]. This reflects the need for more evidence exploring the role of dysosmia in the spreading of Lewy body pathology to the SN through the brainstem, limbic route, or cortical route [
16,
17].
Quality of life (QoL) reflects a patient’s holistic experiences of motor and non-motor symptoms. The 39-item Parkinson’s Disease Questionnaire (PDQ-39) is a thoroughly examined and widely utilized tool to assess QoL. It is used to measure severity levels in eight dimensions [
18]. Additionally, part I and II of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS UPDRS) measure motor and non-motor experiences of activities of daily living. The correlation of dysosmia with QoL in PD had rarely been studied [
19]. Therefore, in this cohort study, we aimed to evaluate the effect of dysosmia on QoL in PD. We hypothesized that αSN transmission through an olfactory route might cause more severe substantia-nigra symptoms, limbic symptoms, and cortical symptoms, and dysosmia might predict worse motor and non-motor QoL in patients with PD.
4. Discussion
In this study, we aimed to evaluate the effect of dysosmia on motor function and quality of life in patients with PD. We speculated that αSN transmission through an olfactory route might cause more severe motor, limbic, and cortical symptoms. Dysosmia may correlate worse motor and non-motor QoL in PD patients.
In the present study, 60% of PD patients had total anosmia (UPSIT score < 19), which is higher than the rate of 33–50% in other cohorts (using different translated versions of the UPSIT) [
4,
9,
19]. The mean UPSIT score was 16 ± 8. This score was lower than in a previous Taiwanese cohort (mean 21 ± 7), which recruited patients with disease duration ≤ 2 years. The Taiwanese population in that study also scored 2.5–5 points lower on the UPSIT than North American norms [
10], which might explain the relatively lower UPSIT score and frequent total anosmia in our cohort.
The total anosmia group had older age, higher AAO, higher disease severity, and more severe cognitive dysfunction than the non-anosmia group. The total anosmia group had a worse motor function according to the scores of MDS UPDRS part II and part III, and a worse QoL in the ADL and COG dimensions of PDQ-39. Meanwhile, non-motor scores of MDS UPDRS part I were comparable. The results of Spearman’s correlation showed the correlations of the UPSIT score with MDS UPDRS and PDQ-39 scores in the uniform dimensions. In the simple linear regression, dysosmia correlated with the MDS UPDRS part III score, ADL impairment, and DaTscan visual scale. In the multiple linear regression, dysosmia correlated the MDS UPDRS part III and DaTscan visual scale but not ADL impairment. Thus, the results showed that dysosmia correlated with motor dysfunction and worse QoL measurement of activities of daily living and cognition in PD patients and was indicative of a more severe phenotype. The results supported that dysosmia in PD is a marker of higher disease severity independent of disease duration [
1,
3] and supported the olfactory transmission of αSN to the SN and cortices.
Our results showed that dysosmia correlated well with motor dysfunction, which was evident in the MDS UPDRS part II, part III, and PDQ-39 ADL dimension. In the multiple regression analysis, dysosmia was a stronger predictor for the MDS UPDRS part III than ADL impairment, which might be explained by applying the ADL quartile instead of original ADL measures as a dependent variable. Although the link between dysosmia and motor dysfunction is supported by the connection between the olfactory tract and the SN [
6,
29,
30], there have been contradictory results on the relationship between olfaction and motor function in PD patients. Studies have utilized different olfactory assessment tools, including odor threshold, detection, odor discrimination by the “Sniffin sticks” test [
2,
5,
11,
12], odor identification by different UPSIT versions [
3,
4,
8,
9,
10], the 12-item version of UPSIT including brief-smell identification (B-SIT) [
31], and the Cross-Cultural Smell Identification Test (CCSIT) [
1]. In some studies applying the “Sniffin stick” test, the motor severity scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) [
32] motor subscale (part III) or Hoehn and Yahr stage were not correlated with olfactory function [
2,
11,
12]. Meanwhile, in some of the studies using the UPSIT scores, the scores correlated with motor dysfunction assessed by the UPDRS part III [
3,
4,
9], while some studies failed to show the correlation [
8,
10,
19]. Different methodologies to assess general motor function [
8], study population [
19], and relatively mild disease severity [
10] might also account for the lack of correlation between dysosmia and motor dysfunction.
Our results demonstrated that dysosmia correlated with the activities of daily living (ADL) dimension but did not correlate with the mobility (MOB) dimension. To clarify the discrepant correlation of ADL and MOB dimensions with dysosmia, we explored the detailed items in each dimension in post hoc analysis Compared to the items in the ADL dimension, items in the MOB dimension were more closely related to gait and postural instability. Only the item of “carry shopping bags” in MOB dimension had the correlation with higher UPSIT score (
r = −0.1920,
p = 0.0037). The post hoc analysis on the MDS UPDRS items regarding gait and posture (i.e., part II 2.12–2.13; part III 3.10–3.12) showed no significant correlation with dysosmia, except for “2.13 freezing” in part II. The results may indicate that dysosmia had less correlation with gait and postural instability in PD patients, which might account for the lack of correlation between dysosmia with MOB. Our results showed a general lack of correlation of postural and gait aspects with dysosmia. The postural instability and gait difficulty (PIGD) phenotype did not display a strong association with dysosmia in previous studies [
31,
33,
34]. This might be explained by the involvement of postural and gait being relatively late in PD. Furthermore, the substantia nigra (SN) is closer to the olfactory route than the pedunculopontine nucleus (PPN), midbrain locomotor region (MLR), and other brainstem nuclei. Finally, Braak staging is best used in young-onset PD patients (age of onset: 55 ± 3 years) with long disease duration [
35] but is not valid for all types of PD, implying that diverse manifestations occur in PD. However, studies showed that freezing of gait (FOG) occurs more often in PD with dysosmia [
31,
36] and that Parkinsonian gait progresses in the dysosmic elderly [
37]. Therefore, further studies are required to explore the relationship between specific gait and postural disturbance with dysosmia in PD and other neurodegenerative diseases.
In the current study, the PDQ-39 cognition (COG) dimension showed correlations with dysosmia. The individual items within the COG dimension include the patient’s subjective experience of daytime sleepiness, concentration, poor memory, and distressing dreams and hallucinations. The four items correlated with dysosmia and MoCA except for “dreams and hallucinations”. The PDQ-39 COG dimension has been shown to correlate with individual neuropsychological tests [
38], individual cognitive domains [
39], and depression [
39]. Our previous studies suggested there is a close relationship between dysosmia and impaired cognition according to neuropsychological testing [
13,
14], but there seemed to be a lack of correlation between dysosmia and depression [
13,
40]. The findings in our study revealed similar results. Dysosmia seemed to be correlated with the COG dimension of PDQ-39, but it lacked the association with the emotional well-being (EMO) dimension. “Daytime sleepiness” could represent various sleep disorders, such as sleep onset and maintenance insomnia, nocturnal restlessness, nocturnal motor symptoms, nocturia [
41], or the effect of dopaminergic medication [
42]. Excessive daytime sleepiness may also be exacerbated or caused by other secondary mechanisms such as obstructive sleep apnea or REM-sleep behavior disorder (RBD) [
42]. It has been shown that daytime sleepiness correlates with PD dementia and more advanced disease [
43]. Previous studies also showed a correlation between dysosmia and sleep disturbance [
3,
4], particularly daytime sleepiness [
4]. However, in our study, there was no significant correlation between the UPSIT and MoCA scores with “dreams and hallucinations”, which indicated RBD or psychosis. The lack of link between dysosmia and distressing dreams and hallucinations could imply a brain-first PD process in patients with olfactory dysfunction, instead of a body-first PD process presenting RBD as a premotor symptom [
17]. Jacob Horsager et al. [
17] speculated that Parkinson’s disease comprises two subtypes: a brain-first type and a body-first type. In the “brain-first” type, the αSN pathology may enter via the olfactory bulb and spread to the brainstem and cortex. It results in marked involvement of the SN, moderate involvement of the pons, but little involvement of the medulla and autonomic nervous system (ANS). In contrast to a brain-first type, a body-first type is caused by the pathology originating in the enteric or peripheral ANS and then spreading to the brain. Due to less involvement of locus coeruleus from the olfactory route, RBD is less present in a brain-first (top-down) type than a body-first (bottom-up) type. It may explain why there was no significant correlation between dysosmia and the item of “dreams and hallucinations” in our results. However, this hypothesis requires more comprehensive studies to support it.
Although COG and ADL dimensions could have a prominent impact on a patient’s overall QoL, the summary index (SI) of PDQ-39 and the MDS UPDRS part I score failed to show a significant correlation with dysosmia. The PDQ-39 SI has identical weights of the eight dimensions, so outstanding dimensions could not be highlighted. MDS UPDRS part I encompasses a variety of non-motor symptoms but is non-specific. These non-motor symptoms include cognition, psychiatric, sleep, autonomic disturbance, and pain symptoms. Although anxiety, apathy, sleep, and autonomic disturbance have been correlated with dysomia [
3,
4,
44], depression is still a matter of debate [
3,
4,
13,
40]. Furthermore, there is no pathophysiological basis for the relationship between pain and dysosmia at present.
To the best of our knowledge, there were very few studies discussing the relationship between olfactory dysfunction and QoL by using detailed dimensions of PDQ-39 in PD patients. We also correlated olfactory function with the items of the PDQ-39 regarding the mobility, activity of daily living, and cognition dimensions and tried to find the relationship. Besides, part I and II of MDS UPDRS, which also measure non-motor and motor experiences of activities of daily living, have not been correlated with dysosmia in previous studies. We applied these two assessment tools and analyzed the correlation between dysosmia and QoL in PD patients. In addition, we utilized DaTscan to indicate nigral dopaminergic dysfunction in the study.
This is an analytical cross-sectional study, and we collected data from a single medical center. There were several limitations. First, we did not use other assessment tools for nonmotor symptoms of PD, such as BDI-II for depression, PDSS-2 for sleep [
41]. However, our primary aim was to study QoL in PD. PDQ-39 was recommended by the MDS task force to evaluate QoL in PD [
18]. Additionally, PDQ-39 could serve as an indirect indicator of non-motor symptoms in PD [
45]. Second, sleep and sexual dysfunction could have a significant impact on a patient’s QoL, but PDQ-39 is deficient in measurements in these dimensions. Third, DaTscans visual scale were only available in a subgroup of patients due to retrospective data collection. Hence, we performed a comparison between DaTscan visual rating-missing and available group (
Table A1). Fourth, we were concerned about type I error when executing the post hoc analysis. However, the Bonferroni method was not utilized. We acknowledged that the questions within the same dimension were not independent, and its use was at the price of loss of power [
46]. Fifth, we did not evaluate the type of hallucination along with the PDQ-39 item. Of note, olfactory hallucinations can occur in 11.3% of PD patients [
47]. Finally, our study recruited patients from a single tertiary center with a median disease duration of 30 months, which might limit its generalizability.