Soto Claudio, Mollenhauer Brit, Hansson Oskar, Kang Un Jung, Alcalay Roy N, Standaert David, Trenkwalder Claudia, Marek Kenneth, Galasko Douglas, Poston Kathleen
Department of Neurology, Mitchell Center for Alzheimer's disease and related brain disorders, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, USA.
University Medical Center Göttingen, Department of Neurology, Göttingen, Germany.
Nat Med. 2025 Feb;31(2):396-408. doi: 10.1038/s41591-024-03469-7. Epub 2025 Jan 30.
Cerebral accumulation of alpha-synuclein (αSyn) aggregates is the hallmark event in a group of neurodegenerative diseases-collectively called synucleinopathies-which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Currently, these are diagnosed by their clinical symptoms and definitively confirmed postmortem by the presence of αSyn deposits in the brain. Here, we summarize the drawbacks of the current clinical definition of synucleinopathies and outline the rationale for moving toward an earlier, biology-anchored definition of these disorders, with or without the presence of clinical symptoms. We underscore the utility of the αSyn seed amplification assay to detect aggregated αSyn in living patients and to differentiate between neuronal or glial αSyn pathology. We anticipate that a biological definition of synucleinopathies, if well-integrated with the current clinical classifications, will enable further understanding of the disease pathogenesis and contribute to the development of effective, disease-modifying therapies.
α-突触核蛋白（αSyn）聚集体在大脑中的蓄积是一组神经退行性疾病（统称为突触核蛋白病）的标志性事件，这些疾病包括帕金森病、路易体痴呆和多系统萎缩。目前，这些疾病通过临床症状进行诊断，并在死后通过大脑中存在αSyn沉积物得到明确证实。在此，我们总结了当前突触核蛋白病临床定义的缺点，并概述了朝着基于生物学的、更早的这些疾病定义发展的基本原理，无论是否存在临床症状。我们强调αSyn种子扩增检测在检测活体患者中聚集的αSyn以及区分神经元或胶质细胞αSyn病理学方面的实用性。我们预计，如果突触核蛋白病的生物学定义能与当前临床分类很好地整合，将有助于进一步了解疾病发病机制，并促进有效疾病修饰疗法的开发。
