Clinical Memory Research Unit, Department of Clinical Sciences, Malmö, Lund University, Lund, Sweden.
Memory Clinic, Skåne University Hospital, Malmö, Sweden.
Nat Med. 2023 Aug;29(8):1971-1978. doi: 10.1038/s41591-023-02450-0. Epub 2023 Jul 18.
α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about the effects of LB pathology in preclinical (presymptomatic) individuals, either as isolated pathology or coexisting with Alzheimer's disease (AD) pathology (β-amyloid (Aβ) and tau). We examined the effects of LB pathology using a cerebrospinal fluid α-synuclein-seed amplification assay in 1,182 cognitively and neurologically unimpaired participants from the BioFINDER study: 8% were LB positive, 26% Aβ positive (13% of those were LB positive) and 16% tau positive. LB positivity occurred more often in the presence of Aβ positivity but not tau positivity. LB pathology had independently negative effects on cross-sectional and longitudinal global cognition and memory and on longitudinal attention/executive function. Tau had cognitive effects of a similar magnitude, but these were less pronounced for Aβ. Participants with both LB and AD (Aβ and tau) pathology exhibited faster cognitive decline than those with only LB or AD pathology. LB, but not AD, pathology was associated with reduced sense of smell. Only LB-positive participants progressed to clinical LB disease over 10 years. These results are important for individualized prognosis, recruitment and choice of outcome measures in preclinical LB disease trials, but also for the design of early AD trials because >10% of individuals with preclinical AD have coexisting LB pathology.
α-突触核蛋白聚集构成路易体（LB）疾病的病理学基础。目前对于 LB 病理学在临床前期（无症状期）个体中的影响知之甚少，无论是作为孤立的病理学还是与阿尔茨海默病（AD）病理学（β-淀粉样蛋白（Aβ）和 tau）共存的情况。我们使用脑脊液 α-突触核蛋白种子扩增检测法，在来自 BioFINDER 研究的 1182 名认知和神经功能正常的参与者中检查了 LB 病理学的影响：8%为 LB 阳性，26% Aβ 阳性（其中 13%为 LB 阳性），16% tau 阳性。LB 阳性的发生频率在 Aβ 阳性的情况下更高，但在 tau 阳性的情况下则不然。LB 病理学对横断面和纵向整体认知和记忆以及纵向注意力/执行功能具有独立的负面影响。tau 具有相似程度的认知效应，但 Aβ 的效应则不那么明显。同时具有 LB 和 AD（Aβ 和 tau）病理学的参与者比仅有 LB 或 AD 病理学的参与者表现出更快的认知下降。LB 但不是 AD 病理学与嗅觉减退有关。仅 LB 阳性的参与者在 10 年内进展为临床 LB 疾病。这些结果对于临床前期 LB 疾病试验中的个体化预后、招募和结果测量选择很重要，但对于早期 AD 试验的设计也很重要，因为 >10%的临床前期 AD 患者存在共存的 LB 病理学。
