Developing disease-modifying interventions in idiopathic REM sleep behavior disorder and early synucleinopathy.

Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed solely through symptomatic treatment. Efforts to evaluate disease-modifying therapies during the established stage of the disease have not yielded positive outcomes in terms of clinical or imaging efficacy endpoints. However, alpha-synucleinopathies have a long prodromal phase that presents a promising opportunity for intervention with disease-modifying therapies. The presence of polysomnography-confirmed REM sleep behavior disorder (RBD) is the most reliable risk factor for identifying individuals in the prodromal stage of alpha-synucleinopathy. This paper discusses the rationale behind targeting idiopathic/isolated RBD in disease-modifying trials and outlines possible study designs, including strategies for patient stratification, selection of biomarkers to assess disease progression and patient eligibility, as well as the identification of suitable endpoints. Additionally, the potential targets for disease-modifying treatment in alpha-synucleinopathies are summarized.

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Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dario Arnaldi reports financial support was provided by Italian ministry of health. Dario Arnaldi reports financial support was provided by Italian ministry of university and research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.