Sturchio Andrea, Espay Alberto J
James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States; Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, Stockholm, Sweden.
James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States.
Handb Clin Neurol. 2023;192:155-167. doi: 10.1016/B978-0-323-85538-9.00002-X.
The recognition of and approach to prodromal symptoms, those which manifest before a diagnosis can be ascertained at the bedside, are of increasing interest in neurodegenerative research. A prodrome is conceived of as an early window into a disease, a critical time when putative disease-modifying interventions may be best suited for examination. Several challenges affect research in this area. Prodromal symptoms are highly prevalent in the population, can be nonprogressive for years or decades, and exhibit limited specificity in predicting conversion versus nonconversion into a neurodegenerative category within a time window feasible for most longitudinal clinical studies. In addition, there is a large range of biological alterations subsumed within each prodromal syndrome, forced to converge into the unifying nosology of each neurodegenerative disorder. Initial prodromal subtyping efforts have been developed but given the scarcity of prodrome-to-disease longitudinal studies, it is not yet clear whether any prodromal subtype can be predicted to evolve into the corresponding subtype of manifesting disease - a form of construct validity. As current subtypes generated from one clinical population are not faithfully replicated to others, it is likely that, lacking biological or molecular anchors, prodromal subtypes may only be applicable to the cohorts within which they were developed. Furthermore, as clinical subtypes have not aligned with a consistent pattern of pathology or biology, such might also be the fate of prodromal subtypes. Finally, the threshold defining the change from prodrome to disease for most neurodegenerative disorders remains clinical (e.g., a motor change in gait becoming noticeable to a clinician or measurable with portable technologies), not biological. As such, a prodrome can be viewed as a disease state not yet overt to a clinician. Efforts into identifying biological subtypes of disease, regardless of clinical phenotype or disease stage, may best serve future disease-modifying therapeutic strategies deployed not for a prodromal symptom but for a defined biological derangement as soon as it can be determined to lead to clinical changes, prodromal or not.
前驱症状是指在床边能够确诊之前就出现的症状，对其的识别和处理在神经退行性疾病研究中越来越受到关注。前驱期被认为是疾病的早期窗口，是一个关键时期，此时假定的疾病修饰干预措施可能最适合进行研究。该领域的研究面临几个挑战。前驱症状在人群中非常普遍，可能在数年或数十年内无进展，并且在大多数纵向临床研究可行的时间窗口内，在预测是否会转变为神经退行性疾病类别方面表现出有限的特异性。此外，每个前驱综合征都包含大量的生物学改变，这些改变被迫汇聚到每种神经退行性疾病的统一分类学中。虽然已经开展了初步的前驱期亚型分类工作，但鉴于前驱期到疾病的纵向研究较少，目前尚不清楚是否可以预测任何前驱期亚型会演变成相应的显性疾病亚型——一种结构效度的形式。由于从一个临床群体产生的当前亚型不能忠实地复制到其他群体，缺乏生物学或分子锚定，前驱期亚型可能仅适用于其开发的队列。此外，由于临床亚型与病理或生物学的一致模式不一致，前驱期亚型可能也会如此。最后，大多数神经退行性疾病从前驱期转变为疾病的阈值仍然是临床标准（例如，临床医生注意到步态的运动变化或可用便携式技术测量），而非生物学标准。因此，前驱期可被视为临床医生尚未察觉的疾病状态。识别疾病的生物学亚型的努力，无论临床表型或疾病阶段如何，可能最有利于未来的疾病修饰治疗策略，这些策略不是针对前驱症状，而是针对一旦确定会导致临床变化（无论是否为前驱症状）的明确生物学紊乱。
