Methodological considerations for observational studies of treatment effectiveness in neurology: a clinician’s guide

神经病学治疗效果观察性研究的方法学考虑：临床医生指南

Data from cohorts, registries, randomised trials, electronic medical records and administrative claims databases have increasingly been used to inform the use of therapies for neurological diseases. While novel sophisticated methods are enabling us to use existing data to guide treatment decisions, the complexity of statistical methodology is making appraisal of clinical evidence increasingly demanding. In this narrative review, we provide a brief overview of the most commonly used methods for evaluation of treatment effectiveness in neurology. This primer discusses complementarity of randomised and non-randomised study designs, sources of observational data, different forms of bias and the appropriate mitigation strategies, statistical significance, Bayesian approaches and provides an overview of multivariable regression models, propensity score-based models, causal inference, mediation analysis and Mendelian randomisation.

来自队列、登记、随机试验、电子医疗记录和行政索赔数据库的数据越来越多地被用于为神经疾病的治疗提供信息。虽然新的尖端方法使我们能够使用现有的数据来指导治疗决策，但统计方法的复杂性使得对临床证据的评估越来越苛刻。在这篇叙述性综述中，我们简要概述了神经病学中最常用的治疗效果评估方法。这本入门读物讨论了随机和非随机研究设计的互补性、观察数据的来源、不同形式的偏差和适当的缓解策略、统计学意义、贝叶斯方法，并概述了多变量回归模型、基于倾向分数的模型、因果推断、中介分析和孟德尔随机化。

REF: Kalincik T, Roos I, Sharmin S, Malpas CB. Methodological considerations for observational studies of treatment effectiveness in neurology: a clinician's guide [published online ahead of print, 2023 Oct 27]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2022-330038. doi:10.1136/jnnp-2022-330038 PMID: 37890986

Proximity extension assay-based discovery of biomarkers for disease activity in chronic inflammatory demyelinating polyneuropathy

基于邻近延伸分析的慢性炎症性脱髓鞘多神经病疾病活动性生物标志物的发现

Objective disease activity biomarkers are lacking in chronic inflammatory demyelinating polyneuropathy (CIDP), impacting treatment decisions in clinical care and outcomes in clinical trials. Using a proximity extension assay, we aimed to identify candidate serum protein biomarkers for disease activity in CIDP. Our results indicate that IRAK4 and possibly SUGT1, DCTN1, NT5C3A and GLRX are candidate biomarkers for monitoring clinical disease activity in CIDP.

目的慢性炎症性脱髓鞘性多发性神经病(CIDP)缺乏疾病活动性生物标志物，影响临床治疗决策和临床试验结果。利用邻近延伸试验，我们的目标是确定CIDP疾病活动性的候选血清蛋白生物标志物。我们的结果表明，IRAK4以及可能的SUGT1、DCTN1、NT5C3A和GLRX是监测CIDP临床疾病活动性的候选生物标志物。

REF: Wieske L, Michael MR, In 't Veld SGJG, et al. Proximity extension assay-based discovery of biomarkers for disease activity in chronic inflammatory demyelinating polyneuropathy [published online ahead of print, 2023 Oct 25]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-332398. doi:10.1136/jnnp-2023-332398 PMID: 37879899

Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort

鉴别自身免疫性肾病与慢性阻塞性肺疾病的临床相关性：一项大型队列的纵向评估

The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

本研究的目的是确定自身免疫性神经病(AN)患者的治疗反应及其与抗体滴度变化的关系，并比较AN和CIDP的临床特点和治疗反应。区分CIDP和AN很重要，因为AN患者需要不同的治疗方法。病情改善和复发与抗体滴度的变化有关，支持这些抗体的致病性。

REF: Broers MC, Wieske L, Erdag E, et al. Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort [published online ahead of print, 2023 Oct 25]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-331378. doi:10.1136/jnnp-2023-331378 PMID: 37879898

Effect of long-term Tai Chi training on Parkinson’s disease: a 3.5-year follow-up cohort study

长期太极拳训练对帕金森病疗效的3.5年随访队列研究

Tai Chi has shown beneficial effects on the motor and non-motor symptoms of Parkinson's disease (PD), but no study has reported the effect of long-term Tai Chi training. This study is to examine whether long-term Tai Chi training can maintain improvement in patients with PD. Tai Chi training has a long-term beneficial effect on PD, with an improvement in motor and non-motor symptoms and reduced complications.

太极已经显示出对帕金森氏病(PD)的运动和非运动症状的有益影响，但还没有研究报告长期太极训练的效果。本研究旨在探讨长期太极训练能否维持帕金森病患者的改善。太极拳训练对帕金森病有长期的有益作用，可以改善运动和非运动症状，减少并发症。

REF: Li G, Huang P, Cui S, He Y, Tan Y, Chen S. Effect of long-term Tai Chi training on Parkinson's disease: a 3.5-year follow-up cohort study [published online ahead of print, 2023 Oct 24]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2022-330967. doi:10.1136/jnnp-2022-330967 PMID: 37875337

Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers

详细的临床，生理和病理表型可以影响ATTR携带者获得疾病修饰治疗

Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

遗传性甲状腺素运载蛋白淀粉样变性是一种由致病性TTR变异体（ATTRv）引起的危及生命的常染色体显性全身性疾病，主要累及外周神经和心脏。该疾病的特征是症状、器官受累和组织学淀粉样蛋白沉积的组合。如果早期开始，现有的疾病修饰ATTRv治疗（DMT）更有效。病理性神经传导研究（NCS）结果是大纤维多发性神经病诊断的基石，但这种异常发生在疾病的晚期。我们研究了多模式神经和心脏评估在检测ATTRv携带者早期疾病发作中的效用。对TTRv携带者进行多模式神经和心脏检查对于早期发现ATTRv淀粉样变性和开始DMT至关重要。

REF: Beauvais D, Labeyrie C, Cauquil C, et al. Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers [published online ahead of print, 2023 Oct 24]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-332180. doi:10.1136/jnnp-2023-332180 PMID: 37875336

Alzheimer’s disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI

阿尔茨海默病标记物磷酸化tau181在中至重度脑损伤后第一年不升高

Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.

创伤性脑损伤与各种脑病、阿尔茨海默病和慢性创伤性脑病有关。高级免疫分析显示，脑损伤后早期血浆总tau(t-tau)显著升高，但随后浓度迅速恢复正常。在丝氨酸181处磷酸化的tau(p-tau181)是一种经过充分验证的阿尔茨海默病标记物，可能会导致进行性神经退化。我们测试了创伤后p-tau181浓度是否升高，并与进行性脑萎缩有关。血浆p-tau181在中到重度颅脑损伤后的第一年内并没有明显升高，而且水平与神经变性的神经影像指标无关。

REF: Graham N, Zimmerman K, Heslegrave AJ, et al. Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI [published online ahead of print, 2023 Oct 13]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-331854. doi:10.1136/jnnp-2023-331854 PMID: 37833041

Temporal course of cognitive and behavioural changes in motor neuron diseases

运动神经元疾病认知和行为改变的时间进程

Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.

运动神经元疾病(MND)患者可能会出现认知和行为功能障碍，一些研究表明与C9ORF72重复扩增有关。然而，它们的发生和发展却鲜为人知。我们探索了认知和行为是如何随着时间的推移而变化的，以及人口、临床和遗传因素是否会影响这些变化。在这项研究中，认知功能障碍并不像以前报道的那样常见，而且在大多数情况下随着时间的推移保持稳定。然而，认知在一个小的子集中纵向下降，这并不完全与C9ORF72状态有关。我们的发现提出了一个问题，即MND患者认知障碍的发生时间，以及它是否出现在早期临床明显的疾病期间，甚至是在运动表现之前。

REF: McHutchison CA, Wuu J, McMillan CT, et al. Temporal course of cognitive and behavioural changes in motor neuron diseases [published online ahead of print, 2023 Oct 12]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-331697. doi:10.1136/jnnp-2023-331697 PMID: 37827570

Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease

超敏检测技术和流体生物标志物在周围神经疾病评估中的应用

The field of biomarker discovery is rapidly expanding. The introduction of ultrasensitive immunoassays and the growing precision of genetic technologies are poised to revolutionise the assessment and monitoring of many diseases. Given the difficulties in imaging and tissue diagnosis, there is mounting interest in serum and cerebrospinal fluid biomarkers of peripheral neuropathy. Realised and potential fluid biomarkers of peripheral nerve disease include neuronal biomarkers of axonal degeneration, glial biomarkers for peripheral demyelinating disorders, immunopathogenic biomarkers (such as the presence and titre of antibodies or the levels of cytokines) and genetic biomarkers. Several are already starting to inform clinical practice, whereas others remain under evaluation as potential indicators of disease activity and treatment response. As more biomarkers become available for clinical use, it has become increasingly difficult for clinicians and researchers to keep up-to-date with the most recent discovery and interpretation. In this review, we aim to inform practising neurologists, neuroscientists and other clinicians about recent advances in fluid biomarker technology, with a focus on single molecule arrays (Simoa), chemiluminescent enzyme immunoassays (CLEIA), electrochemiluminescence (ECL), proximity extension assays (PEA), and microfluidic technology. We discuss established and emerging fluid biomarkers of peripheral neuropathy, their clinical applications, limitations and potential future developments.

生物标志物发现的领域正在迅速扩大。随着超灵敏免疫分析技术的引入和基因技术日益精确，许多疾病的评估和监测都将发生革命性的变化。鉴于影像和组织诊断的困难，周围神经病的血清和脑脊液生物标记物越来越受到人们的关注。已知的和潜在的周围神经疾病的流体生物标记物包括轴突变性的神经元生物标记物，周围脱髓鞘疾病的神经胶质生物标记物，免疫致病生物标记物(如抗体的存在和滴度或细胞因子的水平)和遗传生物标记物。其中一些已经开始为临床实践提供信息，而另一些仍在评估中，作为疾病活动和治疗反应的潜在指标。随着越来越多的生物标志物可用于临床，临床医生和研究人员越来越难及时了解最新的发现和解释。在这篇综述中，我们旨在向执业神经学家、神经学家和其他临床医生介绍流体生物标志物技术的最新进展，重点是单分子阵列(SIMOA)、化学发光酶免疫分析(CLEIA)、电化学发光(ECL)、邻近延伸分析(PEA)和微流控技术。我们讨论了已建立的和正在出现的周围神经病的液体生物标记物，它们的临床应用，局限性和潜在的未来发展。

REF: Bellanti R, Keddie S, Lunn MP, Rinaldi S. Ultrasensitive assay technology and fluid biomarkers for the evaluation of peripheral nerve disease [published online ahead of print, 2023 Oct 11]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-332031. doi:10.1136/jnnp-2023-332031 PMID: 37821222

Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage

针对裂解的、潜伏的和可能的交叉反应的EBV抗原的血清反应性平均在MS引起临床前神经轴突损害的10年前出现

Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.

多发性硬化症（MS）和症状前轴突损伤似乎只有在EB病毒（EBV）感染后才会发生。这种关联仍有待在广泛的临床前时间范围内，裂解和潜伏EBV血清反应性，并为潜在的交叉反应抗原证实。针对潜伏性和溶解性EBV抗原的血清反应性，以及在亚组ANO2中，在临床MS发病前的最后十年中发生的逐渐增加的轴突损伤的出现之前平均十年可检测到。这些发现加强了潜伏性EBV参与MS发病机制的假设。

REF: Jons D, Grut V, Bergström T, et al. Seroreactivity against lytic, latent and possible cross-reactive EBV antigens appears on average 10 years before MS induced preclinical neuroaxonal damage [published online ahead of print, 2023 Oct 6]. J Neurol Neurosurg Psychiatry. 2023;jnnp-2023-331868. doi:10.1136/jnnp-2023-331868 PMID: 37802637