Article Text
PDF
Abstract
Olfactory impairment and rapid eye movement sleep behaviour disorder (RBD) are prodromal symptoms of Parkinson’s disease (PD) that may be associated with each other. This review aims to investigate the significance of olfaction in the diagnosis and prognosis of patients with RBD and to assess moderating factors affecting olfactory performance. We searched articles on olfaction in RBD and PD in five electronic databases. We identified 32 studies for the systematic review and used 28 of those, including 2858 participants for meta-analysis. Results revealed significant deficits in odour identification (g=−1.80; 95% CI: −2.17 to −1.43), threshold (g=−1.29; 95% CI: −1.67 to −0.91), discrimination (g=−1.08; 95% CI: −1.28 to −0.87) and overall olfactory function (g=−1.64; 95% CI: −1.94 to −1.35) in patients with RBD. Except for the Unified Parkinson's Disease Rating Scale Part III scores, none of the known moderating variables (including age, sex, disease duration and years of education) accounted for the olfactory function heterogeneity in patients with RBD. We identified similar olfactory impairments in patients with RBD and patients with PD (either with or without underlying RBD). These findings suggest that olfactory impairment may be a sensitive and stable diagnostic biomarker of RBD and appears to be useful for identifying patients with idiopathic RBD at high risk for early conversion to PD.
- sleep disorders
- Parkinson's disease
- meta-analysis
Statistics from Altmetric.com
Introduction
Rapid eye movement (REM) sleep behaviour disorder (RBD) is a parasomnia and movement disorder described in humans by Schenck et al in 1986. RBD is characterised by the loss of normal muscle atonia during REM sleep and involves dream-enacting behaviours.1 The clinical implications of RBD range from unnoticed sleep disruption to severe self-injurious behaviours and/or injuries to bed partners. RBD has historically been classified as idiopathic or secondary to neurodegenerative diseases, and it frequently represents a prodromal phase of an α-synucleinopathy.2 Patients with RBD tend to be men, and the age of onset often ranges between 40 and 70 years.3 The prevalence of the disorder in the general population has been recently estimated at 1.06% with a video-polysomnographic (PSG) study.4 RBD has been considered an initial symptom of progressive neurodegeneration, and a recent meta-analysis of 51 longitudinal studies found that the risk of developing neurodegenerative diseases in patients with RBD was 34% after 5 years, 82% after 10.5 years and 97% after 14 years.5 Thus, early detection and diagnosis of RBD is important for potential intervention to modify the course of neurodegeneration.
The association between olfactory impairment and neurodegenerative disorders has been increasingly recognised.6 The high prevalence of olfactory impairment in patients with Parkinson’s disease (PD), along with the ease and low cost of assessment, has made olfaction an attractive biomarker for PD. Current evidence suggests hyposmia may help differentiate PD from other causes of parkinsonism and may also aid in the identification of ‘pre-motor’ PD, which manifests with early pathological involvement of olfactory pathways.7 Furthermore, olfactory function is also correlated with other non-motor features of PD and may serve as a predictor of cognitive decline in neurodegenerative diseases.8
RBD is a well-established clinical non-motor risk marker of PD.9 10 Olfactory impairment and RBD are prodromal symptoms of PD that may be associated with each other. Previous studies have reported substantial olfactory impairment in patients with RBD, including impairments in odour identification and discrimination, and an increment in odour threshold.11–14 For example, Stiasny-Kolster et al revealed that approximately 97% of patients with idiopathic RBD (iRBD) have a significantly increased odour threshold and that 63% had impaired odour discrimination and identification. Their study showed for the first time that patients with RBD can present with profound olfactory dysfunction.15
A few studies have focused on olfaction in patients with RBD, but a systematic understanding of this association is still lacking. The different olfactory assessment tools, inconsistent diagnostic RBD criteria and small study populations in these studies have led to inconclusive results. In addition, one of the significant current discussions is whether olfactory function in patients with RBD is affected by other independent factors. Fantini et al 16 and Miyamoto et al 17 found a significant negative correlation between age and the odour identification function in patients with RBD, and Postuma et al 11 revealed that measures of motor function, colour vision and cognition are highly correlated with the olfactory function in patients with RBD. In a study by Iranzo et al,18 the olfactory function of patients with RBD appeared to be unaffected by age. In yet another study, Miyamoto et al 19 found no significant correlation between RBD and variables such as age, motor function, cognition and odour identification function.
Most studies suggest that women have better olfactory performance than men for at least some odorants, but whether the olfactory function in patients with RBD differs among the sexes remains to be explored.20 Moreover, the association between olfactory impairment in patients with RBD and that in patients with PD remains inconsistent. Some studies have found a more severe olfactory impairment in patients with RBD than in patients with PD,19 21 22 while others have found more severe olfactory impairments in patients with PD than in patients with RBD.12 23 Systemic quantitative studies assessing the olfactory function in RBD and comparing the olfactory functions in RBD and PD are lacking.
Therefore, we conducted a systematic review and comprehensive meta-analysis of the existing studies to investigate the significance of olfactory function in the diagnosis and prognosis (the risk of conversion to PD) of patients with RBD, and to assess moderating factors affecting olfactory performance. We divided the main content and objectives of this study into three parts. First, we present a qualitative and quantitative synthesis of olfactory function in patients with RBD and compare the findings with those in healthy controls (HCs) to characterise the olfactory impairment in patients with RBD. Then, we present the results of an exploratory meta-regression to investigate the role of several potential independent factors such as sex, age, duration of illness, years of education and Unified Parkinson’s Disease Rating Scale Part III (UPDRS III) scores in the olfactory performance of patients with RBD. Last, we present a quantitative analysis performed to compare olfactory functions between patients with RBD and those with PD (with or without underlying RBD) to explore the potential role of olfaction in the prognosis of RBD.
Methods
Search strategies
Two researchers (ZL and SZ) independently performed a systematic search of the relevant literature in PubMed, Web of Science, Embase, PsycINFO and Scopus databases. The search terms selected were incorporated in the following Boolean expression: (rapid eye movement sleep behavior disorder OR REM sleep behavior disorder OR RBD OR Parkinson disease) AND (olfact* OR smell OR odor). The search was limited to English language articles that enrolled human subjects. The last date of search was 19 June 2020 and included both full-text articles and abstracts. Studies were selected and analysed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.24
Selection criteria and data extraction
We selected studies for the meta-analysis that fit the following criteria: (1) olfactory function in patients with RBD or PD had been assessed using standard psychophysical tasks; (2) case–control studies included an HC group; and (3) data or statistical information allowed for effect size calculation and use of meta-analytical procedures. Studies were excluded if: (1) the diagnosis criteria for RBD or PD were not specified or did not conform to the certified diagnostic criteria; (2) patients with RBD or PD comorbidities presented other neuropsychiatric disorders or lacked comorbidity information; (3) olfactory function had not been assessed in both patients and control groups; (4) analyses used the same sample as that in another study.
Two researchers (ZL and SZ) reviewed the literature and extracted data independently. All disagreements were resolved via discussion to reach consensus decisions. We designed a specific data extraction form for this meta-analysis that included: (1) the demographic data of the individuals included; (2) the olfactory outcomes of individuals; (3) the duration of disease in years and (4) the individual scores of relevant clinical scales (ie, UPDRS III and Mini-Mental State Examination (MMSE)). We chose the olfactory outcome means and SDs as the dependent variables, and the demographic data, disease duration, olfactory assessment tools, diagnostic criteria and scores of tested scales as the moderating variables. We merged data of individual subgroups of patients with RBD or PD based on age or illness severity.25 We categorised the olfactory scores in selected studies according to the different olfactory functions assessed (odour threshold, discrimination, identification and overall olfactory function), and extracted the relevant mean and SD data directly. We calculated means and SDs from the information in the articles that were missing those values or sent emails to the authors to acquire the data. We performed a cross-check after the data extraction, and any disagreements were resolved by discussion.
Statistical analysis
First, we performed a descriptive analysis to assess differences in the relevant characteristics between patients with RBD or PD and HCs in all included studies. The assessed variables included age, sex, publication year, sample size, diagnostic criteria, assessment tools, disease duration and others present in each study.
Then, we performed a meta-analysis to obtain a quantitative evaluation of the olfactory function in patients with RBD and patients with PD. In addition, we conducted a meta-regression with data from patients with RBD. All statistical analyses were performed using the Stata V.12.0 software. We computed standardised mean differences (SMDs) and 95% CIs to estimate Hedges’ g for the meta-analysis to deal with the different tools to measure olfactory function in the studies included.26 We considered the g effect sizes as small (0.2), medium (0.5) or large (0.8) as published.27 Owing to the heterogeneity among studies, we applied a random-effects model to reduce statistical heterogeneity in the extracted data and to get the mean of a distribution of true effects.28 Sensitivity analyses were applied to evaluate the influence of each individual study on the stability of the overall pooled estimate by removing one study at a time.29
Heterogeneity across study effects was examined applying Χ2, Tau2 and I2 statistics. I2, which is independent from the number of studies included, indicates a high heterogeneity when it is 75% or higher.30 The publication biases of six meta-analyses were examined by applying Egger’s regression test.31 We represented the results with funnel and Egger’s publication bias plots. The SE was used when generating the funnel plot. We considered severe and significant asymmetries of the funnel plot as indicative of the likely presence of bias.31 32 We also performed subgroup analyses and exploratory meta-regressions to investigate the potentially independent effects of several predictors, including sex, age, disease duration, years of education and UPDRS III scores.
Results
Study selection
We applied the inclusion and exclusion criteria defined above and removed 2873 duplications. Following review of the title and abstract of 3104 articles, we examined the full text of 394 articles in detail. Finally, we selected 32 studies fitting criteria for the systemic review, and 28 of those for the meta-analysis. Figure 1 shows the flow chart for selection of studies. All the selected studies had an HC group. We found 14 studies that had patients with both RBD and PD, 18 studies that had patients with RBD only. However, one of the studies that had patients with both RBD and PD provided olfactory function data in patients with RBD only. We categorised the olfactory outcomes in this study into four types: odour identification (assessed in 24 studies), threshold (assessed in 9 studies), discrimination (assessed in 7 studies) and overall olfactory function (assessed in 9 studies by summing scores of the other three functions).
Flowchart of study selection. PD, Parkinson’s disease; RBD, rapid eye movement sleep behaviour disorder.
Study characteristics
In all, 32 studies involving a total of 3342 participants (1366 patients with RBD, 555 patients with PD without RBD, 138 patients with PD and RBD, and 1283 HCs) were included in our systematic review. The studies were published during the last 15 years, from 2005 to 2020, and included papers published in peer-reviewed journals (28/32) and conference abstracts (4/32) to minimise the file drawer effect (publication bias). The studies for the systematic review were conducted in 13 different countries: 6 in Japan; 5 in Korea; 4 in Spain; 2 in Germany, Canada, China, France, Italy and the Czech Republic; and 1 in each of the following countries: the Netherlands, Australia, Chile, Sweden, and both Italy and Canada. Table 1 describes the sample characteristics.
Characteristic of all included studies that assessed olfactory function in patients with RBD and patients with PD
Participants’ characteristics
The sample sizes ranged from 11 to 202 for the participants with RBD, from 11 to 151 for the participants with PD without RBD, from 8 to 42 for participants with PD and RBD, and from 12 to 336 for the HC. The mean ages of the RBD participants ranged from 48.20 to 71.80 years, those for the patients with PD without RBD ranged from 60.60 to 70.00 years, those for the patients with PD and RBD ranged from 68.80 to 70.70 years, and those for the HCs ranged from 48.20 to 71.00 years. Men seemed more likely to be included in these studies than women, and although the proportions varied from study to study, men accounted for 50%–100% in RBD groups, from 47% to 100% in PD without RBD groups, from 57% to 82% in PD and RBD groups, and from 23% to 100% in HC groups. According to the available data in 25 included studies, the mean disease duration for RBD ranged from 0.8 years to 11.3 years, and from 0.8 years to 6.2 years for PD. Also, 21 studies reported UPDRS III scores to evaluate the severity of motor symptoms in RBD (range, 0.40–6.40), 8 studies reported them in participants with PD without RBD (range, 8.40–31.30), and 4 studies reported them in participants with PD and RBD (19.50 and 25.60). Many studies also assessed years of education and cognitive function.
Olfactory assessment tests
Different olfactory assessments were carried out across these studies to test olfactory function. The Sniffin’ Sticks Tests (SST), a worldwide-used olfactory function assessment tool, was the most commonly applied (in 14 studies).12 14 15 17 33–42 The SST can objectively assess odour identification, threshold and discrimination, and an overall olfactory function can be calculated.43 Other tests used in different studies included the University of Pennsylvania Smell Identification Test (UPSIT), the Sniffin’ Sticks Screening 12 Test (SS-12), the Odour Stick Identification Test for Japanese (OSIT-J) and the Brief Smell Identification Test (B-SIT), also called Cross-Cultural Smell Identification Test (CC-SIT). The UPSIT, one of the most frequently used odour identification tests, was administered in eight studies.18 22 35 44–48 Both the SST and UPSIT have a brief version with 12 odorants for odour identification assessment (the SS-12 and the B-SIT/CC-SIT, respectively). In this systematic review, SS-12 was used in two studies13 49 and B-SIT/CC-SIT in seven studies.11 16 21 50–53 Also, four studies conducted in Japan used the OSIT-J.17 19 47 54 Three of the studies selected employed two tools to evaluate odour identification: one used the OSIT-J and SST,17 one used the OSIT-J and UPSIT,47 and the other one used SST and UPSIT.35 In addition, Yoon et al 53 and Shin et al 21 also applied the n-Butanol Threshold Test to assess the odour threshold, and Iranzo et al 18 estimated the detection sensitivity to the odorant phenyl ethyl alcohol to assess the odour threshold.
Diagnostic criteria
We only included studies with clear diagnostic criteria for RBD and/or patients with PD in the analysis of the systematic review and meta-analysis: 19 studies used the diagnostic criteria of the International Classification of Sleep Disorders (ICSD) (including ICSD, ICSD-2 and ICSD-3) and 11 used PSG for RBD demonstration. One study used the diagnostic criteria of the Principles and Practice of Sleep Medicine, fourth edition (PPSM-4) and the other one study used PSG or PPSM or ICSD for RBD demonstration. All patients with PD in the studies included met the UK PD Society Brain Bank criteria55 except in one study, which used the European Federation of Neurological Societies recommendations for the diagnosis of PD.56
Synthesis of results
Ultimately, we had to exclude four studies from the systemic review due to the lack of useful statistical data for the quantitative analysis and were left with only 28. Among them, 24 studies assessed odour identification (14 studies for patients with RBD only, 10 studies for both patients with RBD and patients with PD), 9 studies assessed odour threshold (6 studies for patients with RBD only, 3 studies for both patients with RBD and patients with PD), 7 studies assessed odour discrimination (5 studies for patients with RBD only, 2 studies for both patients with RBD and patients with PD), and 9 studies assessed the overall olfactory function (7 studies for patients with RBD only, 2 studies for both patients with RBD and patients with PD). We conducted separate meta-analyses for studies assessing the three olfactory domains and the overall olfactory function as described below. Less than five studies assessed odour threshold, discrimination or overall olfactory function in patients with PD; therefore, we compared only odour identification between patients with PD and patients with RBD. We were able to compare olfactory function data between patients with RBD and patients with PD from the included studies directly; thus, we did not compare olfactory function scores between patients with PD and HCs.
Meta-analysis results between patients with RBD and HCs
Odour identification
We analysed data from 24 studies to compare odour identification scores between 901 patients with RBD and 1033 HCs.11–19 21 22 35–37 39 44 45 47–50 52–54 As shown in figure 2, the pooled SMD (Hedges’ g) was −1.80 (Z=9.53, p<0.001; 95% CI: −2.17 to −1.43), and indicates that the odour identification ability in patients with RBD was significantly reduced compared with that in HCs. We found high heterogeneity across studies (Q=226.65, df=23, p<0.001, I2=89.90%, Tau2=0.75). Egger’s test results (p<0.001) showed publication bias for odour identification. Our leave-one-out model sensitivity analysis showed no significant changes in the pooled SMDs and 95% CIs after single study exclusions (g ranged from −1.85 to −1.55; all p<0.001), which indicates that the overall pooled estimates were stable.
Forest plot of odour identification in patients with RBD and healthy controls. Overall effect size was significant difference between the RBD and healthy control groups. Diamond represents overall effect size. B-SIT, Brief Smell Identification Test; OSIT-J, Odour Stick Identification Test for Japanese; RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference; SS-12, Sniffin’ Sticks Screening 12 Test; SST, Sniffin’ Sticks Tests; UPSIT, University of Pennsylvania Smell Identification Test.
Odour threshold
We used data from nine studies to compare odour threshold between 312 patients with RBD and 271 controls.12 15 17 18 21 35–37 53 As shown in figure 3, overall, the patients with RBD had a significantly reduced odour threshold capacity than the HCs (Hedges’ g=−1.29, Z=6.72, p<0.001; 95% CI: −1.67 to −0.91). We found moderate heterogeneity across studies (Q=30.86, df=8, p<0.001, I2=74.10%, Tau2=0.24). The p value of Egger’s test was 0.385, indicating an absence of publication bias for the odour threshold. After performing the sensitivity analysis with a leave-one-out model, we found no significant changes in the pooled SMDs and 95% CIs on the exclusion of single studies (g ranged from −1.39 to −1.18; all p<0.001), which indicates that the overall pooled estimates were stable.
Forest plot of odour threshold in patients with RBD and healthy controls. Overall effect size was significant difference between the RBD and healthy control groups. Diamond represents overall effect size. RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference.
Odour discrimination
We used data from seven studies to compare odour discrimination between 265 patients with RBD and 213 HCs.12 15 17 35–38 As shown in figure 4, the pooled SMD (Hedges’ g) was −1.08 (Z=10.38, p<0.001; 95% CI: −1.28 to −0.87), indicating that patients with RBD had a significantly reduced odour discrimination ability compared with that in HCs. We found a low heterogeneity on the odour discrimination results among studies (Q=4.11, df=6, p=0.662, I2 <0.01%, Tau2 <0.01). Egger’s test results (p=0.891) showed a lack of potential publication bias for odour discrimination. The sensitivity analysis with a leave-one-out model showed the absence of significant changes in the pooled SMDs and 95% CIs on exclusion of single studies (g ranged from −1.13 to −1.03, all p<0.001), which indicates that the overall pooled estimates were stable.
Forest plot of odour discrimination in patients with RBD and healthy controls. Overall effect size was significant difference between the RBD and healthy control groups. Diamond represents overall effect size. RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference.
Overall olfactory function
We used data from nine studies to compare overall olfactory function between 514 patients with RBD and 326 HCs.12 15 17 33 35–37 40 42 As shown in figure 5, the pooled SMD (Hedges’ g) was −1.64 (Z=10.93, p<0.001; 95% CI: −1.94 to −1.35), indicating that patients with RBD had a significantly reduced overall olfactory function than HCs. We found moderate heterogeneity among the overall olfactory function results among studies (Q=22.25, df=8, p=0.004, I2=64.10%, Tau2=0.13). The Egger’s test result (p=0.259) indicates the absence of publication bias for overall olfactory function. The overall pooled estimates of overall olfactory function were stable after the leave-one-out sensitivity analysis (g ranged from −1.72 to −1.56, all p<0.001).
Forest plot of overall olfactory function in patients with RBD and healthy controls. Overall effect size was significant difference between the RBD and healthy control groups. Diamond represents overall effect size. RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference.
Meta-analysis results between patients with RBD and patients with RBD and PD
Four studies compared olfactory function scores between patients with RBD and patients with PD and RBD. Only two studies compared odour identification scores between 29 patients (with RBD and PD) and 61 patients (with RBD).50 53 As shown in figure 6, the pooled SMD (Hedges’ g) was −0.36 (Z=1.55, p=0.121; 95% CI: −0.82 to 0.10), indicating that patients with RBD had similar odour identification scores than patients with RBD and PD. We found low heterogeneity across studies (Q=0.90, df=1, p=0.344, I2 <0.01%, Tau2 <0.01).
Forest plot of odour identification in patients with RBD and PD with RBD. Overall effect size was non-significant difference between the RBD and PD groups. Diamond represents overall effect size. PD, Parkinson’s disease; RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference.
Meta-analysis results between patients with RBD and patients with PD without RBD
We analysed data from seven studies to compare the odour identification scores between 218 patients with RBD and 473 patients with PD.12 13 19 21 22 39 54 As shown in figure 7, the pooled SMD (Hedges’ g) was −0.40 (Z=1.77, p=0.076; 95% CI: −0.83 to 0.04), indicating that patients with RBD had similar odour identification scores than patients with PD. We found high heterogeneity across studies (Q=35.70, df=6, p<0.001, I2=83.20%, Tau2=0.29). The p value of the Egger’s test was 0.852, indicating a lack of publication bias for these studies. After performing a sensitivity analysis using the leave-one-out model, we found significant changes in the pooled SMDs and 95% CIs on the exclusion of either the Shin et al 21 (g=−0.49, p=0.042) or the Pereira et al 22 (g=−0.58, p<0.001) studies, but we found no significant differences in those statistics on exclusion of other single studies (g ranged from −0.41 to −0.30, p value ranged from 0.117 to 0.211).
Forest plot of odour identification in patients with RBD and PD without RBD. Overall effect size was non-significant difference between the RBD and PD groups. Diamond represents overall effect size. PD, Parkinson’s disease; RBD, rapid eye movement sleep behaviour disorder; SMD, standardised mean difference.
Moderator analysis
Subgroup analyses
Given the variations in assessment tests for odour identification across studies, we carried out a subgroup analysis to explore whether the different tests affected the olfactory performance of patients with RBD. We classified the assessment tests into five subgroups: SST (eight studies), UPSIT (six studies), B-SIT (six studies), OSIT-J (two studies) and SS-12 (two studies). As shown in figure 2, the results in all five subgroups indicated that patients with RBD had significant reductions in odour identification scores compared with those in HCs. Also, we found high heterogeneity in the SST (Q=36.17, df=7, p<0.001, I2=80.60%, Tau2=0.33), UPSIT (Q=38.89, df=5, p<0.001, I2=87.10%, Tau2=0.57), B-SIT (Q=146.09, df=5, p<0.001, I2=96.60%, Tau2=2.99) and OSIT-J (Q=2.48, df=1, p=0.116, I2=59.60%, Tau2=0.16) subgroups; but not in the SS-12 subgroup (Q=0.12, df=1, p=0.730, I2 <0.01%, Tau2 <0.01).
Meta-regression
We applied meta-regression to explore the sources of heterogeneity. We used demographic data from quantifiable variables present in more than three studies: age, disease duration, male to female ratio and years of education. The score of MMSE was lacking in most studies of odour discrimination or overall olfactory function scores, thus it was not appropriate for meta-regression. Therefore, we only explored the effects of the available demographic data and UPDRS III scores to assess the heterogeneities on odour identification, threshold, discrimination and overall olfactory function.
Table 2 shows a summary of the statistical results of the exploratory meta-regression analyses for patients with RBD. In general, we found a significant association between overall olfactory function scores and the UPDRS III scores (p=0.032), while no significant association was found between the UPDRS III scores and odour identification (p=0.410), threshold (p=0.516) or discrimination scores (p=0.889). In addition, none of the other between-study variables (mean age, male to female ratio, years of education or mean disease duration) revealed associations with odour identification, threshold, discrimination or overall olfactory function scores.
Statistical results of the meta-regression analysis with patients with RBD
Discussion
To our knowledge, this is the first systematic review and meta-analysis comparing olfactory functions among patients with RBD, patients with PD and HCs. We qualitatively and quantitatively synthesised data on different olfactory functions in patients with RBD and HCs; and we compared the odour identification impairment characteristics between patients with RBD and patients with PD. Our results confirmed research findings from the extant literature that patients with RBD suffered from significant olfactory impairment than healthy controls. In addition, we identified potential moderating factors affecting the psychophysical olfactory performance in patients with RBD using an exploratory meta-regression analysis.
The results of the systematic review and meta-analysis indicate that patients with RBD present robust olfactory deficits different from HCs. Thus, patients with RBD had significantly lower scores than HCs with large effect sizes for odour identification (g=−1.80, p<0.001), threshold (g=−1.29, p<0.001), discrimination (g=−1.08, p<0.001) and overall function (g=−1.64, p<0.001). Moreover, the overall pooled estimates for each olfactory function were stable after performing sensitivity analyses using the leave-one-out model. Our results suggest that olfactory deficit may be a sensitive and stable marker for diagnosing RBD.
The exact temporal relation between onset of RBD and onset of olfactory impairment remains unknown, but both conditions are believed to be associated with the functions of the olfactory bulb and of other central olfactory regions. According to the Braak staging, an olfactory bulb pathology is prevalent in the early stages of PD.57Studies have demonstrated that the dopaminergic interneurons in the olfactory bulb participate in olfactory processing, determine olfactory abilities and modulate functions of the olfactory pathway.58 59 The pathogenesis of PD is similar to that of RBD at least in the dopaminergic impairment known to play a major role in both conditions.60 Neuroimaging studies of patients with iRBD have found an association between abnormal dopamine transporter binding and the presence of olfactory impairment, reflecting the probable simultaneous development of underlying pathologies in the substantia nigra, the susceptible brainstem and the olfactory nuclei in individuals with prodromal synucleinopathy.44 Also, olfactory impairment has been correlated with an abnormal metabolic brain network in patients with iRBD53 and with abnormal white matter in olfactory regions.61
It is worth mentioning that our results show that the absolute value of Hedges’ g in odour identification (1.80) is higher than those in odour threshold (1.29) and discrimination (1.08). This may be due to the fact that the evidence for the presence of an odour identification deficit in patients with RBD is stronger than the evidence for odour threshold or discrimination deficits in the same patients. Odour identification may play a special role in the examination of RBD. We found that researchers have been more interested in the odour identification function than in other olfactory functions, as explained in the above section on olfactory assessment tools. More tests exist for odour identification assessment than for any other olfactory function, and several studies have compared the characteristics between different odour identification assessment tools. For example, Campabadal et al 35 studied the accuracy and neuroanatomical correlates of the SST and the UPSIT in patients with RBD, and they showed that odour identification was the best olfactory function discriminator for patients with RBD. These facts suggest that odour identification may be more frequently or severely impaired in patients with RBD than other olfactory functions. Still, part of the emphasis on odour identification testing in patients with RBD is probably due to odour identification being a very convenient and most readily available tool to obtain an olfactory function parameter. Based on all of the above, we believe that odour identification may be used as a representative function for olfactory impairment in patients with RBD.
Based on our exploratory meta-regression, a significant negative association between overall olfactory function scores and the UPDRS III scores was found in patient with RBD, while there was no significant association between the UPDRS III scores and different olfactory domains (including odour identification, threshold and discrimination). Moreover, none of the other moderating variables studied accounted for the olfactory function heterogeneity in patients with RBD. These mean that none of the olfactory functions (odour identification, threshold, discrimination or overall olfactory function) in patients with RBD were influenced by any of the four potential moderating variables (sex, age, disease duration and years of education), but the overall olfactory function may be influenced by the UPDRS III scores. Since the UPDRS III score is a well-known indicator used to assess the severity of motor symptoms in PD, the special association between the overall olfactory function and the UPDRS III scores in patients with RBD implies that olfactory impairment may be a marker of the conversion from RBD to PD. Though striking difference has been found in the rate of RBD occurrence among men and women, we found similar olfactory function scores among the sexes and similar measures of other commonly altered variables in RBD, such as autonomic, visual and cognitive functions.11 Thus, the pathogenesis of RBD may be largely similar in both sexes. While previous studies show the prevalence and severity of olfactory dysfunction increases with age in healthy individuals,6 we found no effects of age on the olfactory function of the patients with RBD in our review. In addition, neither disease duration nor years of education have been associated with olfactory impairment in patients with RBD.18 19 35 These results suggest that olfactory impairment develops early and remains relatively stable as the disease progresses in patients with RBD, and it may be a marker of the conversion from RBD to PD.
Given the close associations among olfaction, RBD and PD, we also compared the olfactory function among patients with RBD, those with PD and RBD, and those with PD without RBD. Given the limited number of studies available, we only quantitatively analysed studies on odour identification. The results of forest plots overlapped with zero, suggesting similar olfactory impairments among all the groups of patients. However, the odour identification scores of patients with PD without RBD in the study of Shin et al 21 and the study of Pereira et al 22 were higher than patients with RBD, but lower or very similar in all other studies. It probably explains why excluding these two studies from the leave-out-one model analysis results in significantly different findings. As mentioned above, previous studies have indicated that olfactory impairment develops early and remains relatively stable as the disease progresses in patients with either RBD or PD.11 16 18 19 A longitudinal study suggested that the olfactory function in patients with RBD does not get worse during the process of developing clinical PD, while dopamine transporter imaging data showed a decline in the striatal tracer uptake after 3 years of follow-up.62 These findings may be explained by a floor effect in olfactory loss reached before RBD is diagnosed. On the other hand, a progressive nigrostriatal denervation is detectable before the appearance of parkinsonism. This possible disease progression agrees with the Braak staging for PD pathology in which olfactory impairment (stage 1) precedes the onset of sleep disorders including iRBD (stage 2).57 At the same time, these findings also help us understand the theoretical foundations for the difficulty in using odour identification tests to distinguish patients with iRBD from patients with PD.
The potential significance of olfactory function results for the prognosis of patients with RBD is also of concern. Previous evidences suggested that the estimated risk for patients with RBD to develop a neurodegenerative disease (including PD, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)) over a long-term follow-up is more than 90%, and the majority of patients with RBD converted to PD (43%), followed by DLB (25%).5 As far as we know, several studies discussed the relationship among olfactory deficits, RBD and DLB or MSA, suggested that the presence of olfactory dysfunction in iRBD is associated with an increased risk of early conversion to DLB,12 63 but lack of enough evidence. Given the purpose of this review, we focused on the question some researchers have wondered that whether the presence of olfactory impairment in iRBD is associated with an increased risk of early conversion to PD.12 21 38 Evidence of numerous potential predictive markers of PD has been found in patients with iRBD, including impairments of olfaction, colour vision and motor function.11 The similar olfactory deficits in patients with iRBD and patients with PD (with or without underlying RBD) suggest the presence of an underlying Lewy body disease, at least in a proportion of patients with RBD (even if the olfactory deficits are less prominent in these patients than in patients with PD), and support the notion of a continuum between RBD and PD.16 The significant negative association between overall olfactory function scores and the UPDRS III scores we found in patient with RBD by our exploratory meta-regression suggested that the overall olfactory function may be associated with the UPDRS III scores. Since the UPDRS III score is a well-known indicator used to assess the severity of motor symptoms in PD, the association between the overall olfactory function and the UPDRS III scores in patients with RBD implies that olfactory impairment may play a special role in the conversion of RBD to PD. According to the research criteria of the International Parkinson and Movement Disorder Society Task Force,64 both olfactory loss and PSG-proven RBD have a relatively high positive likelihood ratio for diagnosing prodromal PD, which means persons with positive scores in both of these areas meet the criteria for prodromal PD, if there are no other major markers to influence the diagnosis.13 Recently, a study on genotypic characteristics indicated that patients with hyposmia and RBD had the minor G allele of rs894278 that is present in a specific subtype of PD.65 Moreover, in a 5-year prospective follow-up study of patients with iRBD, those with impaired olfaction at baseline had a 65% 5-year risk of developing a defined neurodegenerative disease (including parkinsonism, dementia, or a combination of parkinsonism and dementia), compared with a 14% risk in those with normal olfaction.63 Therefore, we believe that olfactory impairment may be useful for identifying patients with iRBD who are at high risk of early conversion to PD.
Limitations and future directions
Several limitations of this study need to be considered when examining our findings. First, the included number of studies was relatively small. Although we used 24 studies to analyse the odour identification function, we only analysed data from 7 to 9 studies in our analyses of odour threshold, discrimination and overall olfactory function. The small number of studies may weaken the usefulness of our meta-analyses. Studies with a more rigorous experimental design on this topic and updating the systematic and meta-analyses are needed to better understand the nature of olfaction impairments in RBD. Also, due to these limitations in the available data, we failed to conduct an exploratory meta-regression between cognition and olfactory function in patients with RBD, even though cognition is closely associated with both RBD and olfaction.52 For the same reason, we were unable to examine the effects of other clinical and demographic independent factors such as smoking history, emotional status and usage of medications. These variables need to be addressed in future studies. In addition, we only included two studies for the comparison of olfactory function between patients with RBD and patients with PD and RBD; however, the characteristics of olfaction function in RBD with underlying PD are of great value to help us understand the pathogenesis of olfactory impairment in RBD. Longitudinal investigations will need to focus on the comparison and combination of olfactory functions and other potential biomarkers in patients with RBD.
Conclusions
In conclusion, our findings suggest the presence of robust olfactory impairments in patients with RBD, including deficits in odour identification, threshold, discrimination and overall olfactory function. These deficits are independent from age, sex, disease duration or years of education but associated with the UPDRS III scores. Specifically, we found similar odour identification impairments in patients with RBD and in patients with PD (regardless of the presence of underlying RBD). Overall, our findings suggest that olfactory impairment may be a sensitive and stable diagnostic biomarker of RBD and that it appears to be useful for identifying patients with iRBD who are at high risk of early conversion to PD.
References
Footnotes
ZL and SZ contributed equally.
Contributors ZL and LZ conceived the study. ZL and SZ selected reports and extracted the data. ZL, SZ and YM analysed and interpreted the data. ZL, XZ and LZ wrote the first draft of the manuscript. All authors critically revised the manuscript for intellectual content and approved the final version.
Funding This work was supported by the National Natural Science Foundation of China (grant number: 31 700 963), the Natural Science Foundation of Guangdong Province, China (grant number: 2019A1515012135), and the Medical Science and Technology Foundation of Guangdong Province, China (grant number A2019192)
Disclaimer These funding agents had no further role in any aspect of the study or the writing of this paper.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.