Rest Tremor Pattern Predicts DaTscan (123I-Ioflupane) Result in Tremulous Disorders,Movement Disorders

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Rest Tremor Pattern Predicts DaTscan (123I-Ioflupane) Result in Tremulous Disorders
Movement Disorders ( IF 7.4 ) Pub Date : 2021-09-28 , DOI: 10.1002/mds.28797
Andrea Quattrone ₁ , Rita Nisticò ₂ , Maurizio Morelli ₁ , Gennarina Arabia ₁ , Marianna Crasà ₃ , Basilio Vescio ₄ , Alessandro Mechelli ₁ , Giuseppe L Cascini ₅ , Aldo Quattrone _{2,

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Affiliation

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.^4-7 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**
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(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.

中文翻译：

静息震颤模式预测 DaTscan（123I-Ioflupane）导致震颤障碍

静息性震颤 (RT) 是帕金森病 (PD) 的典型特征，但也可发生在其他震颤疾病中，例如特发性震颤 (ET) 加张力障碍性震颤、药物性震颤、ET-PD 综合征以及没有多巴胺能缺乏证据的扫描。瑞典）。¹在临床上区分 RT 疾病可能具有挑战性，并且通常需要 DaTscan ( ¹²³ I-ioflupane)，^{2, 3}一种昂贵且耗时的程序，无法广泛使用，并且很少用于震颤疾病的常规诊断。因此，迫切需要新的可靠且具有成本效益的生物标志物，以在没有 DaTscan 的情况下揭示震颤患者的纹状体多巴胺能缺陷。

一些研究调查了 RT 的电生理特征，表明震颤模式可能有助于区分 PD 与其他震颤疾病。^4-7然而，这些研究是在小型患者系列中进行的，并侧重于疾病之间的区分，而不是震颤模式与 DaTscan 之间的关联。

在我们的研究中，我们连续招募了 205 名 RT 患者，并评估了震颤特征（模式、频率、幅度、突发持续时间、连贯性）在区分 DaTscan 异常 (DaT+) 和 DaTscan 正常 (DaT-) 患者时的表现（见支持信息中的方法附录 S1)。

共有 123 名 RT 患者有 DaT+，而 82 名患者有 DaT-。这些接受放疗的患者的临床特征见支持信息表 S1。该模式（交替或同步，图 1A）是 RT 特征，在区分纹状体多巴胺能缺陷患者与纹状体多巴胺能神经元完整性患者方面表现最佳（图 1B，C；支持信息表 S2）。与单独使用 RT 模式相比，随机森林特征选择和多变量逻辑回归模型并未显着改善 DaT+ 和 DaT- 患者的分类（图 1D），这表明这种平衡简单性和准确性的震颤特征可能代表最佳选择在临床实践中。RT 模式和 DaTscan 密切相关，支持模式对预测 DaTscan 结果的有用性（赔率模式 DaT-/同步，3.74；赔率模式 DaT+/交替，9.45；赔率比，34.3；置信区间，14.9-86.1）。在我们的队列中，绝大多数（104/115，90.4%）交替患者是 DaT+，而 71/90（78.9%）同步患者是 DaT-。104 名交替 DaT+ 患者中有 85 名 (81.7%) 患有帕金森病震颤，而所有 DaT-同步患者均受到非帕金森病 RT 障碍的影响（支持信息表 S3）。我们的研究有几个优势。首先，我们证明了 RT 模式在短期和长期内的稳定性（支持信息结果），这是使用该生物标志物诊断震颤综合征所必需的。其次，对患者进行2年的前瞻性随访以确认临床诊断。第三，使用 RT 模式预测 DaTscan 结果可以通过减少对正确震颤诊断的昂贵程序的需求转化为经济优势。这项研究的一个局限是它是在来自单个中心的大型队列中进行的，因此需要在独立的国际队列中进行进一步验证。