Erskine Daniel, Taylor John-Paul
Translational and Clinical Research Institute, Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, NE4 5PL, UK.
Mol Neurodegener. 2025 Jul 1;20(1):78. doi: 10.1186/s13024-025-00856-7.
Dementia with Lewy bodies (DLB) is thought to be the second most common form of dementia after Alzheimer’s disease, and is characterised by a combination of cognitive, neuropsychiatric and motor symptoms. The present review seeks to discuss current strategies for the management of DLB, and future directions for novel disease-modifying therapies. Current best practice for the clinical management of DLB is based upon therapies that target specific symptom domains due to the lack of disease-modifying therapies. Cholinesterase inhibitors are the frontline treatment for treating cognitive decline in DLB, whereas the treatment of motor symptoms remains challenging due to poor response to dopaminergic therapies and the potential for exacerbation of neuropsychiatric features. There is emerging evidence suggesting a range of further pharmacological and non-pharmacological therapies may be effective in treating specific symptom domains of DLB, but further evidence is warranted to demonstrate their efficacy. A key challenge in the treatment of DLB is incomplete understanding of disease pathophysiology, which has limited attempts to develop disease-modifying therapies. In the present article, we discuss the multi-faceted nature of DLB neuropathology, from Lewy body pathology to mitochondrial dysfunction, and discuss therapies in development that target particular aspects of DLB neuropathology. In particular, we highlight antibody-based therapies to attenuate protein aggregation, compounds that enhance the generation of cellular energy and autophagy-enhancing agents as particular areas of promise. Furthermore, we discuss how optimal strategies for disease modification will be centred on agents that treat DLB neuropathology more holistically, and will be underpinned by a more complete understanding of the pathogenic events that underlie the full spectrum of pathological changes observed in the DLB brain.
路易体痴呆（DLB）被认为是仅次于阿尔茨海默病的第二常见的痴呆形式，其特征是认知、神经精神和运动症状的综合表现。本综述旨在讨论DLB的当前管理策略以及新型疾病修饰疗法的未来发展方向。由于缺乏疾病修饰疗法，DLB临床管理的当前最佳实践基于针对特定症状领域的疗法。胆碱酯酶抑制剂是治疗DLB认知功能下降的一线治疗方法，而运动症状的治疗仍然具有挑战性，因为对多巴胺能疗法反应不佳且可能会加重神经精神症状。越来越多的证据表明，一系列进一步的药物和非药物疗法可能对治疗DLB的特定症状领域有效，但仍需进一步证据来证明其疗效。DLB治疗中的一个关键挑战是对疾病病理生理学的理解不完整，这限制了开发疾病修饰疗法的尝试。在本文中，我们讨论了DLB神经病理学的多方面性质，从路易体病理学到线粒体功能障碍，并讨论了针对DLB神经病理学特定方面的正在开发的疗法。特别是，我们强调基于抗体的疗法以减轻蛋白质聚集、增强细胞能量生成的化合物和自噬增强剂是特别有前景的领域。此外，我们讨论了疾病修饰的最佳策略将如何以更全面治疗DLB神经病理学的药物为中心，并将基于对DLB大脑中观察到的全谱病理变化背后的致病事件的更完整理解。
