Introduction

Synucleinopathies result from the progressive accumulation of α-Synuclein inclusions in the brain, resulting in nerve cell death. The Braak Parkinson’s disease (PD) staging system suggests that many individuals with idiopathic and isolated REM Sleep Behavior Disorder (RBD) or olfactory dysfunction are actually exhibiting an early topography and temporal manifestation of synuclein pathology in the brainstem that evolves into neurodegenerative diseases [1,2,3]. Subsequently, various studies have confirmed the frequent occurrence of these premotor symptoms in connection with the prodromal development of synucleinopathies, including PD and dementia with Lewy bodies (DLB). They also pointed to the fact that the premotor signs were preceding the clinical onset by many years [4,5,6]. Along with RBD and hyposmia, patients with prodromal synucleinopathy experience depression and constipation [7] that are considered to be less specific because of their commonality in the general population.

Hyposmia prevalence can be up to 90% [8] making this sign one of the most common non-motor symptoms in parkinsonian syndromes. The prevalence of RBD in parkinsonian patients varies widely from 19 to 70% [9], which can be attributed largely to ethnic or methodological differences. Identifying such patients with prodromal RBD and/or hyposmia may be of great interest for future neuroprotective therapies to delay or prevent the development of synucleinopathies and in order to make a differential diagnosis—especially in excluding tauopathies that usually are not associated with olfactory dysfunction [10]. However, to our knowledge, no published data are currently available on the prevalence of RBD and hyposmia and the time scales over which they occur either in Morocco or in North African countries.

In the current study, we aim to specify the actual prevalence and the timeline of the development of RBD and hyposmia in a large cohort of Moroccan individuals with synucleinopathy compared with tauopathy patients and healthy control subjects.

Materials and methods

We studied 734 consecutive patients with synucleinopathy, including 697 patients with PD and 37 patients with DLB. The tauopathy group includes 40 patients with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Data were collected at the Specialized Consultations in Movement Disorder HEO (the first author) in the Neurology Department of Ibn Rochd University Hospital of Casablanca between 1 January 2018 and 30 June 2020 relying on expert consensus or validated diagnostic criteria [11,12,13,14]. We excluded all patients with the metabolic, iatrogenic, toxic or vascular origin, those who could not recall sufficiently detailed information and those who do not agree to be part of this study. As a control, we selected a healthy group of 100 participants among the hospital visitors with an equally balanced sex ratio and aged between 50 and 70 years. It should be mentioned, however, that the lockdown during the coronavirus disease pandemic has prompted us to stop data collection in order to respect precautionary measures and avoid interference with COVID-19 symptoms, particularly hyposmia. We confirm that this project received the approval of the local ethics committee.

The data collectors extracted the necessary data on patients’ demographic characteristics and clinical features. The criteria adopted for smell disorders diagnosis were purely clinical which involves a methodical line of questioning with a qualified health professional assistance. Hyposmia was retained each time the patient, or his spouse, mentioned a noticeable decrease in the sense of smell. This variable was hard to detect in patients with DLB due to problems associated with cognitive deterioration, which obliged us to rely on the spouse/companion responses. Regarding RBD diagnosis, we employed a validated screening questionnaire [15] translated and transculturally adapted into the Moroccan dialect.

For qualitative variables, we calculated absolute and relative frequencies. We used the Kolmogorov–Smirnov test in checking for normal distribution. The statistical differences between study groups involved the t-test and ANOVA test for quantitative variables when the data follows a normal distribution and Mann–Whitney and Kruskal–Wallis test when it does not. Chi-square tests were used to compare frequency distributions. The significance level was set at a p value less than 0.05. We used IBM SPSS Statistics 21 for statistical analysis.

Results

Our 774 patients with parkinsonian syndromes were predominantly PD cases. All groups have well-balanced sex ratios. Patients with PD have the youngest average age of all groups (57 years) and had widely dispersed ages at symptom onset that extend beyond 30 years in RBD and 40 years in hyposmia (Table 1). In addition, PD appears earlier compared to other groups with a significant statistical difference (p = 0.001).

Table 1 Demographic characteristics of the study population and the prevalence of RBD and hyposmia and their timing of occurrence
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The prevalence rate of patients with RBD, was 52% in PD, 100% in DLB, 0% in tauopathies (PSP/CBD) and 12% among healthy controls. Hyposmia has been diagnosed among 47% of patients with PD, 68% in patients with DLB, 0% in tauopathy patients (PSP/CBD) and among 10% of healthy controls. The prevalence of RBD and hyposmia differs significantly between the synucleinopathy groups (Table 2) and, more often than not, these symptoms occur in the prodromal phase preceding the diagnosis (Table 1). Hyposmia and RBD were less widespread in the healthy control group, while patients with CBD and PSP, conversely, did not show any above-mentioned signs. Furthermore, four individuals from control subjects presented both RBD and hyposmia at the same time and only two symptom-free control subjects reported a family history of PD.

Table 2 Comparison of REM Sleep Behavior Disorder and Hyposmia prevalences and onset timing medians between the synucleinopathies (PD and DLB)
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Irrespective of the timing of occurrence, the RBD prevalence was higher than hyposmia in all groups, including healthy controls. These findings change, however, if one considers only the prodromal phase (or the timing before diagnosis); it appears that, in this period specifically, the prevalence of hyposmia evolved to become higher than RBD for almost all study subjects. Nevertheless, the difference between the timing medians of premotor signs over the synucleinopathies did not reach statistical significance (Table 2).

Discussion

The epidemiology of premotor symptoms in patients with synucleinopathy and tracing their time of occurrence has become a salient topic of study due to their importance in developing neuroprotective therapies and in improving differential and early diagnosis. In general, our data are consistent with the literature and show that RBD and hyposmia are prevalent in the Moroccan population, especially during the prodromal phase.

During the study period, the incidence of patients with PD was higher than those with DLB in our population, which is consistent with the scientific literature [16]. In fact, RBD prevalence changes significantly between PD and DLB. It was 52% of our participants with PD, which is similar to previous published studies [17,18,19,20], and this symptom occurs with a median of 9 years before the motor signs, which remains relatively a short period compared with another published study [21]. In the group of patients with DLB, the RBD symptom was present among the entirety of participants and it was developed during the prodromal phase in 75% of cases with an average age of onset of 6 years prior to diagnosis. In a previous study, Oertel et al. [22] report a prevalence of up to 80% of RBD among patients with DLB and other synucleinopathies, combined with a longer onset time that goes back nearly two decades before diagnosis.

Hyposmia tends to be common in patients with both synucleinopathies (PD and DLB) compared to the tauopathy group and healthy controls (0 and 10% respectively). When patients and their spouses were interviewed in the present study, hyposmia was perceived in 68% of patients with DLB and in 47% of PD patients; other study reported similar rates for DLB [23] but a cohort study reported that more than 90% of PD patients had developed hyposmia [8]. In our series, PD patients’ hyposmia appeared essentially during the prodromal phase in 67% of cases with an average age of onset of 11 years, which extends up to 40 years before the diagnosis. Some researchers found similar results [24], while others have reported a shorter time of onset ranging from 2 to 5 years [25]. The subjective assessment of data collectors and/or the use of different data collection tools as well as the possibility of recall bias can partly explain this disparity. We must mention that some patients with synucleinopathy among our study population reported having congenital hyposmia or anosmia in their families.

Broadly speaking, our data show that patients with tauopathy (CBD and PSP) did not exhibit any evidence of probable RBD and have a tendency to preserve normal olfactory function. Similarly, other separate studies did not find any presence of hyposmia in PSP and CBD patients compared to controls [26, 27]. As well, the prevalence of RBD symptoms among patients with tauopathy is reported to be very rare [28].

The main result of our study is that RBD and hyposmia are prevalent among Moroccan patients with synucleinopathy, specifically those with PD and DLB. However, our main aim was to compare the prevalence of the study variables between the Moroccan and foreign populations with parkinsonian syndromes, which has been clearly shown in the present study. Nevertheless, the validity of our results should be considered alongside the limitations of our methodology. Despite our large sample and the novelty of sample origin, we conducted a single-center study, which may eventually affect representativeness. In addition, the use of clinical assessment scales to diagnose RBD without resorting to polysomnography and using a hyposmia questionnaire that has not been validated in the population of interest may alter the reliability of the measure. As well, premotor symptom onset was assessed retrospectively, increasing the possibility of recall bias.

Conclusion

Our results confirm that RBD and hyposmia are frequent among Moroccan synucleinopathy patients. Premotor symptoms screening may have benefit in early and differential diagnosis and in selecting eligible candidates for clinical trials of proposed neuroprotective therapies.