Rest tremor (RT) is typical of Parkinson's disease (PD) but can occur in other tremulous disorders, such as essential tremor (ET) plus dystonic tremor, drug‐induced tremor, ET‐PD syndrome, and scans without evidence of dopaminergic deficit (SWEDD). 1 Differentiating RT disorders clinically may be challenging and often requires DaTscan (123I‐ioflupane),2, 3 an expensive and time‐consuming procedure not widely available and rarely used in routine diagnosis of tremulous disorders. Thus, there is an urgent need for new reliable and cost‐effective biomarkers to reveal striatal dopaminergic deficit in tremulous patients in the absence of DaTscan.
A few studies investigated the electrophysiological features of RT, suggesting the possible usefulness of tremor pattern for differentiating PD from other tremulous disorders.4, 5, 6, 7 These studies, however, were conducted in small patient series and focused on differentiation between the diseases rather than on the association between tremor pattern and DaTscan.
In our study, we enrolled 205 consecutive patients with RT and assessed the performance of tremor features (pattern, frequency, amplitude, burst duration, coherence) in differentiating patients with abnormal DaTscan (DaT+) from those with normal DaTscan (DaT−) (see Methods in Supporting Information Appendix S1).
A total of 123 patients with RT had DaT+, while 82 patients had DaT−. Clinical characteristics of these patients with RT are shown in Supporting Information Table S1. The pattern (alternating or synchronous, Fig. 1A) was the RT feature that performed the best in distinguishing patients with striatal dopaminergic deficit from those with integrity of striatal dopaminergic neurons (Fig. 1B,C; Supporting Information Table S2). Random Forest feature selection and multivariate logistic regression model did not significantly improve the classification of DaT+ and DaT− patients compared with using RT pattern alone (Fig. 1D), suggesting that this tremor feature, which balances simplicity and accuracy, may represent the best option in clinical practice. RT pattern and DaTscan were strongly associated with each other, supporting the usefulness of pattern for predicting DaTscan result (odds pattern DaT−/synchronous, 3.74; odds pattern DaT+/alternating, 9.45; odds ratio, 34.3; confidence interval, 14.9–86.1). In our cohort, the large majority (104/115, 90.4%) of alternating patients were DaT+, while 71/90 (78.9%) synchronous patients were DaT−. Eighty‐five of 104 (81.7%) alternating DaT+ patients had parkinsonian tremor, while all DaT− synchronous patients were affected by non‐parkinsonian RT disorders (Supporting Information Table S3). Our study has several strengths. First, we demonstrated the stability of RT pattern both in the short‐ and long‐term periods (Supporting Information Results), which is necessary to use this biomarker in the diagnosis of tremulous syndromes. Second, patients were prospectively followed for 2 years to confirm clinical diagnosis. Third, the use of RT pattern for predicting DaTscan result can translate into economic advantages by reducing the need for expensive procedures for correct tremor diagnosis. A limitation to this study is that it was performed in a large cohort from a single center, and further validation in an independent international cohort is warranted.
FIG. 1.
(A) Electromyographic recordings from the extensor carpi radialis and flexor carpi ulnaris muscles of a patient with alternating pattern and a patient with synchronous pattern of rest tremor (RT). (B) Receiving operating characteristic (ROC) curves for assessing the classification performance of RT pattern (red) (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.81–0.91), amplitude (green) (AUC, 0.77; 95% CI, 0.69–0.84), frequency (blue) (AUC, 0.70; 95% CI, 0.62–0.78), burst duration (gray) (AUC, 0.54; 95% CI, 0.46–0.62), and coherence (black) (AUC, 0.49; 95% CI, 0.38–0.59) in differentiating patients with RT with abnormal DaTscan (DaT+) from those with normal DaTscan (DaT−). (C) ROC curves for assessing the classification performance of RT pattern (red) (AUC, 0.86; 95% CI, 0.81–0.91) and bradykinesia score (blue) (AUC, 0.68; 95% CI, 0.61–0.75) in differentiating patients with RT with DaT+ from those with DaT−. The bradykinesia score was calculated as the mean of the scores of the Unified Parkinsonʼs Disease Rating Scale motor, Part III items 23 (finger tapping), 24 (hand movements), and 25 (pronation‐supination movements) in the most affected upper limb with RT. (D) ROC curves for assessing the classification performance of RT pattern (red) (AUC, 0.86; 95% CI, 0.81–0.91) and multivariate logistic regression model with Random Forest feature selection (blue) (AUC, 0.90; 95% CI, 0.84–0.95) in differentiating patients with RT with DaT+ from those with DaT−. The performances of both classifiers are compared using DeLong's test (P = 0.27). The variables selected using Random Forest were pattern (importance = 5.61), amplitude (importance = 4.83), frequency (importance = 4.07), and burst duration (importance = 3.14). The cohort included 123 DaT+ and 82 DaT− patients. [Color figure can be viewed at wileyonlinelibrary.com]
The alternating pattern of RT is a powerful, low‐cost, and widely available biomarker of striatal dopaminergic deficit in tremulous patients. The evaluation of tremor pattern could help clinicians distinguish parkinsonian RT associated with dopaminergic deficit from non‐parkinsonian RT with intact dopaminergic neurons and guide the decision making in clinical practice.
Author Roles
1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique.
Andrea Quattrone: 1A, 1B, 1C, 3A, 3B
Rita Nisticò: 1B, 1C
Maurizio Morelli: 1B, 1C
Gennarina Arabia: 1B, 1C
Marianna Crasà: 1B, 1C
Basilio Vescio: 2A, 2B, 2C
Alessandro Mechelli: 1B, 1C
Giuseppe L. Cascini: 1B, 1C
Aldo Quattrone: 1A, 1B, 3B
Full Financial Disclosures for the Previous 12 Months
The authors received no funding from any institution, including personal relationships, interests, grants, employment, affiliations, patents, inventions, honoraria, consultancies, royalties, stock options/ownership, or expert testimony for the last 12 months.
Supporting information
Table S1. Demographic, clinical, electrophysiological and imaging data of patients with rest tremor
Table S2. Diagnostic performance of tremor electrophysiological features in distinguishing rest tremor patients with striatal dopaminergic deficit from those with normal DaTscan.
Table S3. Clinical diagnoses of patients with alternating or synchronous rest tremor pattern at the two‐year follow‐up.
Appendix S1. Supporting Information
Relevant conflicts of interest/financial disclosures: Nothing to report.
Full financial disclosures and author roles may be found in the online version of this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
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Supplementary Materials
Table S1. Demographic, clinical, electrophysiological and imaging data of patients with rest tremor
Table S2. Diagnostic performance of tremor electrophysiological features in distinguishing rest tremor patients with striatal dopaminergic deficit from those with normal DaTscan.
Table S3. Clinical diagnoses of patients with alternating or synchronous rest tremor pattern at the two‐year follow‐up.
Appendix S1. Supporting Information
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.