Introduction
Hyposmia is one of the most common non-motor symptoms in Parkinson’s disease (PD), with a reported prevalence of up to 90% (Doty et al.
1988; Haehner et al.
2009; Hawkes et al.
1997), that may precede the first motor symptoms by several years (Ponsen et al.
2004; Ross et al.
2008). Given the increasing load of Lewy body pathology in the olfactory system with advancing neuropathological stages of PD (Braak et al.
2003; Del Tredici et al.
2002), one would expect a progressive decline in olfactory function that correlates with other clinical markers of disease progression. However, previous clinical studies have yielded conflicting data. Although some studies showed a correlation between disease duration and olfactory function (Deeb et al.
2010; Ramjit et al.
2010), most studies have failed to find this correlation (Cavaco et al.
2015; Haehner et al.
2009; Hawkes et al.
1997; Herting et al.
2008; Lee et al.
2015; Masala et al.
2018). In the only longitudinal study, olfactory loss in PD remained stable over time (Doty et al.
1988). Similarly, while in some studies hyposmia was associated with disease severity as measured with the Unified PD Rating Scale motor subscale (UPDRS III) (Cavaco et al.
2015; Deeb et al.
2010; Lee et al.
2015; Masala et al.
2018; Tissingh et al.
2001), others found no association between the degree of hyposmia and disease stage or severity (Boesveldt et al.
2008; Doty et al.
1988; Haehner et al.
2009; Herting et al.
2008; Ramjit et al.
2010; Siderowf et al.
2005).
So far, only few studies have focused on the relationship between olfactory function and non-motor symptoms in PD. Correlations have been reported between hyposmia and apathy (Cramer et al.
2010; Hong et al.
2015), cognitive dysfunction (Domellof et al.
2017; Fullard et al.
2016), and autonomic failure (Chen et al.
2015; Fullard et al.
2016; Goldstein et al.
2010). In a few studies in which striatal dopamine transporter (DaT) binding was used as a marker of the nigrostriatal dopaminergic deficit, hyposmia was associated with lower striatal DaT binding (Bohnen et al.
2007; Siderowf et al.
2005).
The aim of this study was to examine the association between olfactory function and various motor and non-motor symptoms and striatal DaT binding in a large cohort of PD patients.
Discussion
The present cross-sectional study demonstrates that olfactory function, as measured by the UPSIT, correlates with various motor and non-motor measures of disease severity in PD patients. Especially, the relationship with sleep, depression and anxiety has not been reported previously. This observation emphasizes the profound involvement of the olfactory system in the PD process. In addition, greater olfactory dysfunction was associated with more pronounced loss of nigrostriatal dopamine neurons, as measured by DaT-SPECT, in both the putamen and caudate nucleus. Finally, the data confirm the previously reported high prevalence of olfactory loss in PD patients as measured by the UPSIT (Berendse et al.
2011; Deeb et al.
2010; Doty et al.
1988; Hawkes and Shephard
1998; Hawkes et al.
1997).
It is important to note that the poorest olfactory function was associated with a higher UPDRS III score, corresponding to more severe motor symptoms, even when correcting for sex and age. Only when using a conservative adjustment for multiple testing (Bonferroni), the correlation lost statistical significance. Also previous studies have noted an association between UPDRS III scores and scores on the UPSIT (Berendse et al.
2011; Deeb et al.
2010) and various other olfactory tests (Cavaco et al.
2015; Lee et al.
2015; Masala et al.
2018; Tissingh et al.
2001). The reason why previous studies failed to find an association between olfactory dysfunction and disease severity may reflect differences in study populations, sample sizes, or the types of olfactory tests that were employed (Boesveldt et al.
2008; Doty et al.
1988; Haehner et al.
2009; Herting et al.
2008; Ramjit et al.
2010). A contributory factor is the relative weakness of the association, making it more difficult to detect in studies with insufficient power.
Our finding that disease duration is not independently associated with the degree of olfactory dysfunction is in accord with the findings of earlier studies (Cavaco et al.
2015; Doty et al.
1988; Haehner et al.
2009; Hawkes and Shephard
1998; Herting et al.
2008; Lee et al.
2015; Masala et al.
2018). Thus, olfactory function in PD is largely impacted by disease severity and clinical phenotype, but not by disease duration.
Lower olfactory test scores were correlated in our study with decreased global cognitive function, as measured by the MMSE. This is in line with the results of a previous study in which lower UPSIT scores were associated with more cognitive impairment, as measured by the Montreal Cognitive Assessment (MoCA) test (Fullard et al.
2016). In this study, baseline olfactory test scores were associated with a decline in verbal memory and executive function at follow-up and predicted, in combination with lower Aβ
1–42 levels, the development of mild cognitive impairment (MCI) within three years. In another study, lower baseline scores on the Brief Smell Identification Test (B-SIT; a test made up of 12 UPSIT items) increased the risk of dementia up to 10 years after PD diagnosis, independent of baseline cognitive performance (Domellof et al.
2017).
The present observation that the severity of the olfactory deficit in PD is associated with the degree of autonomic failure confirms the results of two previous clinical studies in which the olfactory deficit correlated with a higher score on the SCOPA-AUT (Chen et al.
2015; Fullard et al.
2016). In addition, Goldstein et al. reported an association between olfactory test scores and physiological, neurochemical, and neuroimaging markers of autonomic failure in PD (Goldstein et al.
2010). In the present study a higher score on the SCOPA-SLEEP, corresponding to more severe sleeping problems, was associated with a lower UPSIT score. As far as we know, this is the first study to investigate the direct relation between UPSIT scores and sleeping disturbances in PD. However, REM-sleep behaviour disorder has been related to a decline in such scores (Miyamoto et al.
2009; Postuma et al.
2009; Shin et al.
2013; Stiasny-Kolster et al.
2005).
Neuropsychiatric symptoms are highly prevalent in PD (Weintraub and Burn
2011). In a large cross-sectional study by Morley et al., PD patients with lower UPSIT scores exhibited more psychotic symptoms than those with higher UPSIT scores (Morley et al.
2011). Furthermore, measures of apathy reportedly correlate with lower scores on a number of different types of olfactory tests (Cramer et al.
2010; Hong et al.
2015; Masala et al.
2018). However, our study is the first to report a correlation between odor identification test scores and measures of depression and anxiety in PD. A few previous studies have addressed this issue but failed to observe such an association (Rossi et al.
2015; Verbaan et al.
2008), possibly because they employed an olfactory test comprised of only 16 odorants (vs. the 40 of the UPSIT), which may have limited their statistical power.
Our finding of a correlation between olfactory decline and lower striatal DaT binding is in accord with earlier findings (Bohnen et al.
2007; Siderowf et al.
2005). In both studies, this association was demonstrated in PD patients whose disease duration was approximately 2–2.5 years. In our study, the average duration of disease was longer, almost 4 years, implying that the association between smell loss and decreased DaT binding in PD continues over a considerable period of time. Our observation does not necessarily imply that a causal relationship exists between dopaminergic losses and olfactory dysfunction, since numerous other neurotransmitter and neuromodulator systems, including the cholinergic system, are altered in PD (Doty
2017). Moreover, olfactory dysfunction and most other non-motor symptoms do not seem to be influenced by dopaminergic medication (Doty et al.
1988). In addition, despite the largely ipsilateral olfactory afferent projections from the olfactory bulb to the cerebral cortex, there is no association between the side of major motor dysfunction and the side of the nose with greater olfactory dysfunction when, on rare occasion, asymmetry is present (Doty et al.
1992). Lastly, in a PET study of patients with moderately severe PD, cholinergic denervation of the limbic archicortex was more strongly related to poor UPSIT scores than nigrostriatal dopaminergic denervation (Bohnen et al.
2010).
The present study clearly demonstrates that the severity of the olfactory deficit in PD is associated with various motor and non-motor symptoms, as well as with an imaging marker of the integrity of the nigrostriatal dopaminergic system, but not with disease duration. Whether these observations reflect the presence of a group of patients with a more rapid disease progression or suggest that there are PD subtype(s) with more extensive extranigral pathology needs to be further examined in a longitudinal study. Studying olfactory function at baseline and follow-up, in parallel with measuring various motor, non-motor, and imaging markers, may well provide an answer to this longstanding question, as well as confirm the present cross-sectional observations. Olfactory function would have a number of distinct advantages as a clinical marker of disease progression. Not only because of its early-stage presence, but also since olfactory function correlates with both motor and non-motor function and is not influenced by dopaminergic therapy. Moreover, olfactory testing with the UPSIT is non-invasive. Because of its low cost and ability to be self-administered, this test has been found to be very useful in clinical practice.
The strengths of this study include its large sample size, the use of a well-validated and reliable 40-item smell test, and its assessment of the relationship of olfactory test scores of PD patients with a wide range of both motor and non-motor functions, as well as with measures of central dopaminergic function. A potential weakness of the study is that the dosage of dopamine replacement therapy was not taken into account. However, since olfactory function and other non-motor symptoms do not seem to be influenced by dopaminergic medication (Doty et al.
1988), it is unlikely that we have introduced a major bias. Although UPDRS III scores might have been higher in patients examined while not using dopamine replacement therapy, this would likely have increased, not decreased, the observed associations. Another potential weakness is that individuals with other causes of olfactory loss, including trauma or infection, were not specifically excluded from our population. However, any effect would have led to an underestimate of the actual strength of the correlations.
In conclusion, the severity of the olfactory deficit in PD is associated with both clinical (motor and non-motor) and brain imaging measures of disease severity, not with disease duration, per se. Olfactory dysfunction, therefore, merits further longitudinal assessment as a potential clinical marker of disease progression in patients with PD.
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