Prevalence and Relationship of Rest Tremor and Action Tremor in Parkinson’s Disease

Background: Despite the significance of tremor in Parkinson’s disease (PD) diagnosis, classification, and patient’s quality of life, there is a relative lack of data on prevalence and relationship of different tremor types in PD. Methods: The presence of rest tremor (RT) and action tremor (AT; defined as combination of both postural and kinetic tremor) was determined and RT severity was defined using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) at baseline in the Progression Marker Initiative (PPMI, n = 423), the Fox Investigation for New Discovery of Biomarkers (BioFIND, n = 118) and the Parkinson’s Disease Biomarkers Program (PDBP, n = 873) cohorts. Results: Across baseline data of all three cohorts, RT prevalence (58.2%) was higher than AT prevalence (39.0%). Patients with RT had significantly higher (Chi-square test, p < 0.05) prevalence of AT compared to patients without RT in the PPMI (40.0% versus 30.1%), BioFIND (48.0% versus 40.0%) and PDBP (49.9% versus 21.0%) cohorts. Furthermore, patients with AT had significantly (Student t-test, p < 0.05) higher RT severity that those without AT in PPMI (5.7 ± 5.4 versus 3.9 ± 3.3), BioFIND, 6.4 ± 6.3 versus 3.8 ± 4.4) and PDBP (6.4 ± 6.6 versus 3.7 ± 4.4) cohorts. In the BioFIND cohort, the prevalence of all types of tremor and their combinations significantly decreased from the off-state to on-state. Discussion: The RT is the most frequent tremor type and present in more than half of the PD patients. However, AT is also present in nearly one-third of the PD patients. Our results also indicate that RT and AT may have cross-interactions in PD, and that dopaminergic treatment influences both RT and AT.

Within the category of clinical feature axis and its subcategory of tremor characteristics, 87 tremor is subclassified based on activation characteristics into rest tremor (RT) and action 88 tremor (AT) [2]. The RT has been defined as a tremor in a body part that is not voluntarily 89 activated, assessed when the patient is attempting to relax and is given adequate 90 opportunity to relax the affected body part. Whereas the MDS classification of RT is a 91 singular definition, AT is further sub-divided into postural tremor, kinetic tremor and 92 isometric tremor. AT has been defined as a tremor occurring in a body part while 93 voluntarily maintaining a position against gravity (postural tremor), during any voluntary 94 movement (kinetic tremor), or during muscle contraction against a rigid stationary object 95 (isometric tremor) [2]. 96 97 Although RT is one of the cardinal features of Parkinson's Disease (PD), PD patients are 98 also observed to have postural tremor, kinetic tremor or both [3,4]. In addition to being one 99 of the most visual symptoms of PD, tremor is also ranked as one of the most troubling 100 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ;https://doi.org/10.1101https://doi.org/10. /2020  biospecimen and other relevant data, such as imaging, by making the data available to 123 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10. 1101/2020 researchers in an open-access manner through their respective portals. The PPMI is an 124 international, longitudinal study of early stage PD patients (n= 423), recruited within 6 125 months from initial diagnosis and not on dopaminergic treatment, and healthy controls (n = 126 196). The BioFIND is a cross-sectional study of moderate to advanced stage PD patients 127 Baseline visit data of the PD patients (n = 423 for PPMI, n = 118 for BioFIND, n = 873 for 145 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint and Accelerating Medicine Partnership in Parkinson's Disease (AMP PD) databases 147 (https://amp-pd.org/). The For the BioFIND cohort, the MDS-UPDRS part III data from 148 baseline visit (on-state) were used by default for all calculations, while the follow-up visit 149 data (off-state; 14 days after the baseline visit) were used for comparison separately. tremor or kinetic tremor), any tremor (any of three basic tremor types) and all tremor (all 169 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint three basic tremor types), and distribution of perception of tremor across baseline data of 170 the three cohorts and in each individual cohort. We then tested the hypothesis that 171 prevalence RT and AT are not independent of each other, such that the severity of RT 172 would be higher in PD patients with AT versus without AT, in individual cohorts. Finally, we 173 also compared prevalence of RT, AT, postural tremor, kinetic tremor, any tremor and all 174 tremor in off-state and on-state in the BioFIND cohort. Statistical testing was performed 175 using SPSS version 26 with appropriate statistical tests at a significance level (p < 0.05). The average prevalence of RT and pure RT was 58.2% and 14.5 %, respectively. In 180 contrast, the average prevalence of AT and pure AT were 36.6% and 9.6%, respectively. 181 The average prevalence of postural tremor and pure postural tremor was 49.7% and 4.0 182 %, respectively. The average prevalence of kinetic tremor and pure kinetic tremor was 183 52.3% and 8.1 %, respectively. The average prevalence of patients with no tremor, any 184 tremor and all tremor were 19.9%, 79.9%, and 26.9%, respectively. Figure 1 provides a 185 summary of these results using a diagram. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. found that the severity of RT was significantly higher (Student's t-test) in patients with AT 201 than patients without AT in the PPMI (5.7 ± 5.4 versus 3.9 ± 3.3, p = 0.000), BioFIND (6.4 202 ± 6.3versus 3.8 ± 4.4, p = 0.000) and PDBP (6.4 ± 6.6 versus 3.7 ± 4.4, p = 0.000) 203 cohorts, respectively. 204

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In the BioFIND cohort (in which patients were examined in on-state on baseline visit and 206 off-state in second visit), we found that the prevalence of RT, AT, postural tremor, kinetic 207 tremor, any tremor and all tremor were significantly (p < 0.05, Chi-square test) higher in 208 off-state, compared to on-state (figure 2). The RT severity was also higher in off-state 209 (5.87 ± 8.94) compared to on-state (4.04 ± 6.76), however, this difference did not reach 210 statistical significance (p=0.051). 211 212 Discussion: 213 214 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint Our study results indicate that across the PPMI, BioFIND and PDBP cohorts, although RT 215 has the highest prevalence (58.2%) in PD, AT can also be present in a sizable number 216 (36.2%) of PD patients, which is in line with similar literature [11,12,17]. In comparison, a 217 large majority (79.5%) of the patients self-report having tremor. Our study results also 218 indicate all tremor types are reduced by dopaminergic treatment, which is consistent with 219 the traditionally held view on the influence of levodopa and dopamine agonist on tremor in 220 PD [18,19]. 221

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We also found that the PD patients with RT had significantly higher prevalence of AT in all 223 three cohorts. Moreover, we found that the patients with AT, compared to patients without 224 AT, had more severe RT in all three cohorts, similar to findings reported in previous 225 studies [11,12]. These findings together demonstrate that AT could be a part of broader One of the limitations of our study was that the data used for defining prevalence of 236 different types of tremor were collected by multiple investigators in the PPMI, BioFIND and 237 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint PDBP cohorts. However, these data are considered valid as the clinical examination for 238 recording presence of tremor were done as part of the standardized MDS-UPDRS by 239 trained movement disorders specialists in all three of these studies conducted at 240 internationally recognized movement disorders centers. Another limitation was that we 241 could not include isometric tremor in defining AT, which was unavoidable since the MDS-242 UPDRS scale does not capture isometric tremor. It is also worth noting that MDS-UPDRS have been shown to improve differential diagnosis of PD from essential tremor [22]. All 253 together, these results provide further evidence that PD tremor is highly heterogenous and 254 its correct phenotypic classification in PD will be essential in optimizing diagnostic, 255 therapeutic and prognostic approaches. 256 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  [1977][1978][1979][1980][1981][1982][1983][1984][1985][1986]. 319 320 321 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ;https://doi.org/10.1101https://doi.org/10. /2020  All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this this version posted November 12, 2020. ;https://doi.org/10.1101https://doi.org/10. /2020  All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20227850 doi: medRxiv preprint Gupta 21 preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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