Abstract：
The neurodegenerative synucleinopathies, including Parkinson\'s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson\'s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson\'s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson\'s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.
摘要：
神经退行性突触核蛋白病，包括帕金森病和路易体痴呆,其特征在于进行性亚临床运动和非运动表现的典型漫长的前驱期。其中,特发性REM睡眠行为障碍（iRBD）是一个强有力的早期预测最终的表型转换，因此代表了干预神经保护疗法的关键机会。为随机试验的设计提供信息，为了建立最佳的临床终点,研究疾病前驱阶段临床标志物的自然进展至关重要.在这项研究中,我们结合了来自12个国家的国际REM睡眠行为障碍研究组28个中心的前瞻性随访数据.使用运动障碍协会标准评估多导睡眠图证实的REM睡眠行为障碍受试者的前驱帕金森病，并进行周期性结构化睡眠，电机,认知，自主和嗅觉测试。我们使用线性混合效应模型来估计按疾病亚型分层的年度临床标志物进展率，包括前驱帕金森病和路易体前驱痴呆。此外,我们计算了样本量要求,以证明在不同的预期治疗效果下进展缓慢.总的来说,1160名受试者平均随访3.3±2.2年。在连续评估的临床变量中，电机变量往往进展更快，需要最低的样本量，每组151-560不等（50％药物疗效和2年随访）。相比之下,认知，嗅觉,自主神经变量显示出适度的进展，变异性更高，导致高样本量。最有效的设计是使用运动和认知衰退的综合里程碑进行事件时间分析，在50％的药物疗效和2年的试验持续时间下，估计每组117.最后,虽然酚转换器在电机方面显示出比非转换器更大的整体进展，嗅觉,认知，和某些自主标记，帕金森病和痴呆伴路易体表型转化者之间唯一显著的进展差异是认知测试.这项大型多中心研究证明了前驱突触核蛋白病中运动和非运动表现的演变。这些发现提供了优化的临床终点和样本量估计，以告知未来的神经保护试验。
