In this study, we comprehensively examined clinical and kinematic features of rest tremor and bradykinesia in a relatively large sample of ET patients. Our focus was on their relationship with action tremor, as well as on the side distribution, i.e., asymmetry and side concordance, of these symptoms. Correlation analysis revealed a relation between the severity of rest and postural tremor, while no relationship was present between rest or postural tremor and bradykinesia. Although clinical evaluation showed an asymmetric distribution of rest tremor and bradykinesia in a large proportion of patients, no side concordance was observed between the two parkinsonian soft signs in both clinical and kinematic assessments. These results suggest that the two soft signs in ET may originate from distinct pathophysiological mechanisms.

Our results are consistent with the relatively high prevalence of rest tremor and bradykinesia in ET (Bologna et al. 2020; Erro et al. 2022a, b, c), emphasizing their clinical significance. Notably, in our sample bradykinesia was more frequent when compared with other studies with similar populations (Bologna et al. 2020; Erro et al. 2022b) because it was among the inclusion criteria for ET-plus subjects, and also because of the lower diagnostic threshold (i.e., at least 1 point in the relevant MDS-UPDRS item) we choose to identify slight motor abnormalities. Accordingly, the comparison with the HC group confirmed a lower velocity during finger tapping in patients. A similar finding in ET has been clearly demonstrated in previous neurophysiological studies (Paparella et al. 2021b), including studies on repetitive finger movements (Farkas et al. 2006; Jiménez-Jiménez et al. 2010; Costa et al. 2010; Bologna et al. 2020). A novel aspect in the present study is the comprehensive analysis of the clinical correlates of rest tremor and bradykinesia in ET. Our data revealed that patients with rest tremor showed more severe and widespread action tremor. These data may suggest a more severe involvement of the cerebello-thalamo-cortical circuit (van den Berg and Helmich 2021) in this subgroup. This finding is consistent with our recent observation in patients with valproate-induced tremor, where underlying cerebellar dysfunction resulted in a more extensive distribution of tremor throughout the body and a higher occurrence of rest tremor (Paparella et al. 2021a; De Biase et al. 2022). This is also in line with what has been observed as the disease progresses over time, (Louis 2020; Angelini et al. 2023). Consistent with this hypothesis, the correlation analysis demonstrated a positive relationship between the amplitude of rest and postural tremor in kinematic assessment. Common pathophysiological bases, with oscillations in the same cerebral network, may underlie these two symptoms.

In patients with ET and bradykinesia, higher MDS-UPDRS scores were observed in repetitive movement tasks, as expected. However, no differences were found in action tremor compared to other subgroups. Correlation analysis indicated no significant association between bradykinesia and action tremor, suggesting that bradykinesia represents a distinct characteristic of ET. It is indeed present at different degrees in all subgroups compared to healthy subjects, and is independent of other main motor manifestations. These findings suggest the involvement of separate pathophysiological mechanisms for bradykinesia and rest tremor in ET, as it is also considered to occur in PD (Chen et al. 2022). In the present paper, we considered bradykinesia as movement slowness, as it is a common movement alteration in ET patients (Bologna et al. 2020; Paparella et al. 2023). There is evidence, however, that the combination of components of the bradykinesia complex (Bologna et al. 2023) may differ in ET from other movement disorders (Bologna et al. 2020; Paparella et al. 2023). Further studies on the characterization of bradykinesia in ET, and analyses on the role of its different components and their relationship to other motor symptoms are needed.

The cognitive results confirmed the high risk and prevalence of MCI in ET patients (Louis et al. 2019; Bologna et al. 2019; Angelini et al. 2023) without differences in prevalence in ET-plus subgroups with parkinsonian signs. However, correlation analysis allowed us to exclude a direct influence of cognitive disturbances on motor signs in our sample. Similarly, no differences were observed in the prevalence of ITG in the various subgroups. The relationships between voluntary movement alterations and cognitive disturbances in ET need to be further investigated in specifically designed studies. 

Further insights into the pathophysiology of parkinsonian soft signs in ET can be gained from analyzing these signs’ asymmetry and side concordance. Consistent with previous findings (Cohen et al. 2003; Louis et al. 2011, 2015; Delgado et al. 2022), our data provide evidence of asymmetric rest tremor in a high proportion of patients. Bradykinesia was also frequently asymmetric, as well as, to a lesser extent, the action tremor. These findings suggest mechanisms of lateralization similar to those hypothesized in other neurodegenerative diseases (Lubben et al. 2021). Data on the relationship between the asymmetry of action tremor amplitude and handedness are conflicting (Hornabrook and Nagurney 1976; Louis et al. 1998; Machowska-Majchrzak et al. 2011; Biary and Koller 1985; Putzke et al. 2006), and the role of handedness in parkinsonian soft signs in ET has never been addressed. Our results do not show a clear side prevalence of these motor features as some evidence has shown in PD (van der Hoorn et al. 2012). Regarding the side concordance of motor manifestations in ET, only studies on rest and action tremor are available, and some of them showed side concordance of the two motor signs (Louis et al. 2011, 2015; Delgado et al. 2022), but opposite evidence exists (Cohen et al. 2003). In a recent study, Delgado and colleagues demonstrated that concordant pairings of asymmetrical rest tremor and action tremor are more common than discordant (Delgado et al. 2022). Our results do not suggest side concordance between action tremor and parkinsonian soft signs in ET and do not reveal co-occurrence of rest tremor and bradykinesia on the same side, from both a clinical and kinematic perspective. These findings strengthen the hypothesis that different mechanisms with a different distribution in the central nervous system may underly the heterogeneous motor symptoms in ET.

Concerning the possible pathophysiology of parkinsonian soft signs in ET, some neurotransmitter neuroimaging studies (Lee et al. 1999; Ceravolo et al. 2008; de Verdal et al. 2013) showed nigrostriatal dopaminergic denervation in ET patients with rest tremor. Structural and functional neuroimaging studies in these patients also showed an involvement of basal ganglia, mainly globus pallidus (Nicoletti et al. 2015; Caligiuri et al. 2017). In addition, the cerebellum also seems to play a role in ET with rest tremor (Novellino et al. 2016; Prasad et al. 2018), in the context of the involvement of the cerebello-thalamo-cortical circuit in tremor genesis (van den Berg and Helmich 2021). Considering that dopamine influences the cerebellum in the ET (Kosmowska and Wardas 2021), and that the cerebellum itself may modulate dopamine levels in the basal ganglia (Washburn et al. 2024), it is plausible that an abnormality in the interplay between the basal ganglia and cerebellum, potentially mediated by the same neurotransmitter, could account for the rest tremor observed in ET. In relation to bradykinesia in ET, it has been suggested that similar to PD it may arise from a network dysfunction involving the cerebellum, basal ganglia, and sensorimotor cortical areas (Paparella et al. 2021b). Recent evidence also showed that subtle changes in dopaminergic tone in the striatum can play a role in movement slowness in ET (Colella et al. 2023). In ET patients with bradykinesia, the underlying changes may both originate in the cerebellum, disrupting its functions related to velocity coding, or in the basal ganglia component of this network. Differences in the proportion of involvement of these two circuits in ET patients with parkinsonian soft signs may explain the different clinical-neurophysiological correlates in patients with rest tremor and bradykinesia.

Based on our findings, we make some considerations on the concept of ET-plus. The data concerning rest tremor may suggest that it is a feature that manifests in the later stages of the disease, with the tremor intensifying in terms of severity, spreading throughout the body and appearing under different activation conditions (Louis 2020; Angelini et al. 2023). This seems to be confirmed by the trend observed in our data. On the other hand, ET patients with bradykinesia only seem to form a distinct subgroup characterized by less severe tremor and no correlation between bradykinesia and other motor symptoms. The ET-plus category is highly heterogeneous and may encompass different subgroups that display varying relationships to ET, representing distinct entities. These two parkinsonian soft signs should be considered separately in this contest as they appear to have different significance in indicating the state of disease severity, and it is necessary in view of a precise phenotypic characterization of ET manifestations.

It can be argued that patients with both rest tremor and bradykinesia may fall into the diagnostic category of parkinsonism, also in view of the trend of older age in patients with both soft signs that may suggest conversion to a different clinical picture. However, as these signs were of a questionable nature, mild in intensity, and only the speed component of movement was taken into account, there was insufficient evidence to formulate alternative diagnoses. Furthermore, the patients included in this study have been followed in the outpatient clinic for an extended period, and we have confidence in the ET diagnosis, also because of the lack of other typical signs of PD and the slow evolution of symptoms over time. Only in cases where a diagnostic doubt might persist (n. 10), a DAT scan was performed, and all results showed no significant nigrostriatal dopaminergic dysfunction, supporting the absence of alternative conditions. It cannot be ruled out that ET patients with parkinsonian signs represent a subgroup that will develop PD, due to the occurrence of ongoing processes that will manifest over time. Currently, the relationship between ET and PD is debated (Algarni and Fasano 2018; Tarakad and Jankovic 2019). However, this being a cross-sectional study, it cannot provide information on the evolution of symptoms over time. Longitudinal studies are necessary to clarify the relationship between ET and PD.

It is important to acknowledge the possible confounding and limitations of this study. All patients were right-handed, and further studies are needed to explore the relationship between soft signs asymmetry and handedness. Furthermore, we focused here on rest tremor and questionable bradykinesia in ET, whereas the characterization of other mild motor signs was beyond the scope of the study. Some of these motor symptoms, such as questionable dystonia, although minimal and of unclear significance (Becktepe et al. 2021; Pandey et al. 2020) could still have some influence on voluntary movement, so it is necessary for these to be deepened with targeted studies. In addition, only the upper limbs were assessed as they most frequently show the symptoms investigated. The low level of severity we have considered for bradykinesia may include alterations also observed in healthy subjects (Williams et al. 2023; Paparella et al. 2023), and further studies on the role of factors such as ageing in the healthy population will be helpful in clarifying this aspect. Finally, the sample size, though not small, may have some impact on the results, particularly when analyzing smaller subgroups, and larger-scale studies are needed to strengthen our findings.

Our study has some important strengths. First of all, a comprehensive analysis and detailed phenotyping were conducted studying parkinsonian soft signs together with action tremor under different activation conditions. In addition, the clinical data were supported by an objective neurophysiological measurement of tremor and movement speed, which takes into account small alterations invisible to clinical assessment.

In conclusion, by characterizing the parkinsonian soft signs in ET we uncovered clues about the underlying pathophysiology of these symptoms. Our findings suggest that rest tremor and bradykinesia are likely mediated by distinct mechanisms, and contribute differently to the heterogeneity of ET-plus. Future studies should better characterize parkinsonian soft signs in ET to unravel their clinical significance and their pathophysiology.