Fu YuHong, Halliday Glenda M
Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, New South Wales, Australia.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Nat Rev Neurol. 2025 May 12. doi: 10.1038/s41582-025-01090-x.
Biological definitions of neurological diseases are now becoming a reality, although still in the research phase. This development will recategorize neurological diseases, providing objective diagnostics and the promise of therapeutics that target biological mechanisms - similar to the strategy that has proven successful in tumours and other conditions. In this Perspective article, we discuss this development for dementias with dominant Lewy pathology, as the availability of biological assays for this pathology has sparked new interest in a single disease diagnosis for all individuals positive for α-synuclein. On the basis of current evidence, we argue that an α-synuclein assay alone is unlikely to be a specific criterion for a spectrum of clinical syndromes with Lewy pathology or a definitive diagnostic marker for Lewy body dementia. We advocate that one biological assay will not reflect the complex spatiotemporal features of brain pathology. Diverse sequential mechanisms underpin the highly heterogeneous phenotypes and clinicopathological processes of Lewy body dementias. Disease modification, if possible, will be most effective when it targets the early underlying mechanisms, especially those leading to aggressive phenotypes.
神经疾病的生物学定义如今正在成为现实，尽管仍处于研究阶段。这一进展将对神经疾病进行重新分类，提供客观的诊断方法，并有望开发出针对生物学机制的治疗方法，这与在肿瘤和其他疾病中已被证明成功的策略类似。在这篇观点文章中，我们讨论了伴有路易体病理改变的痴呆症的这一进展，因为针对这种病理改变的生物学检测方法的出现引发了人们对所有α-突触核蛋白阳性个体进行单一疾病诊断的新兴趣。基于目前的证据，我们认为仅α-突触核蛋白检测不太可能成为具有路易体病理改变的一系列临床综合征的特异性标准，也不太可能成为路易体痴呆的确切诊断标志物。我们主张单一的生物学检测无法反映脑病理的复杂时空特征。多种相继发生的机制构成了路易体痴呆高度异质性的表型和临床病理过程的基础。如果可能的话，疾病修饰在针对早期潜在机制，尤其是那些导致侵袭性表型的机制时将最为有效。
