Weintraub Daniel, Nair Anuprita R, Kurth Ryan, Brumm Michael C, Kohnen Christine, York Michele K, Dobkin Roseanne D, Marek Kenneth, Tanner Caroline, Simuni Tanya, Siderowf Andrew, Galasko Douglas, Chahine Lana M, Coffey Christopher, Merchant Kalpana, Poston Kathleen L, Foroud Tatiana, Mollenhauer Brit, Brown Ethan G, Kieburtz Karl, Frasier Mark, Chowdhury Sohini, Alcalay Roy N, Videnovic Aleksandar
Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA.
Department of Biostatistics, University of Iowa, Iowa City, IA.
Ann Neurol. 2025 Sep;98(3):482-491. doi: 10.1002/ana.27263. Epub 2025 Jul 11.
To determine the impact of dopamine deficiency and isolated rapid eye movement (REM) sleep behavior disorder (iRBD) on cognitive performance in early neuronal α-synuclein disease (NSD) with hyposmia but without motor disability.
Using Parkinson's Progression Markers Initiative baseline data, cognitive performance was assessed with a cognitive summary score (CSS) derived from robust healthy control (HC) norms. Performance was examined for participants with hyposmia in early NSD-Integrated Staging System (NSD-ISS), either stage 2A (cerebrospinal fluid α-synuclein seed amplification assay [SAA]+, dopamine transporter scan [DaTscan]-) or 2B (SAA+, DaTscan+).
Participants were stage 2A (n = 101), stage 2B (N = 227), and HCs (n = 158). Although stage 2 had intact Montreal Cognitive Assessment scores (mean [SD] = 27.0 [2.3]), stage 2A had a numerically worse CSS (z-score mean difference = 0.05, p = NS; effect size = 0.09) and stage 2B a statistically worse CSS (z-score mean difference = 0.23, p < 0.05; effect size = 0.40) compared with HCs. In stage 2A, hyposmia alone was associated with normal cognition, but those with comorbid iRBD had significantly worse cognition (z-score mean difference = 0.33, p < 0.05, effect size =0.50). In stage 2B, hyposmia alone had abnormal cognition (z-score mean difference = 0.18, p = 0.0078, effect size = 0.29), and superimposed iRBD had a statistically significant additive effect.
Using a novel CSS, we demonstrated that hyposmia is associated with cognitive deficits in prodromal NSD without motor disability, particularly when comorbid dopamine system impairment or comorbid iRBD is present. Therefore, it is critical to include and assess cognition at all stages when studying synuclein disease, even in the absence of motor disability. ANN NEUROL 2025;98:482-491.
确定多巴胺缺乏和孤立性快速眼动（REM）睡眠行为障碍（iRBD）对早期神经元α-突触核蛋白病（NSD）且伴有嗅觉减退但无运动功能障碍患者认知功能的影响。
利用帕金森病进展标志物计划的基线数据，通过源自健康对照（HC）稳健标准的认知综合评分（CSS）评估认知功能。对早期NSD综合分期系统（NSD-ISS）中2A期（脑脊液α-突触核蛋白种子扩增检测[SAA]+，多巴胺转运体扫描[DaTscan]-）或2B期（SAA+，DaTscan+）且伴有嗅觉减退的参与者的认知表现进行检查。
参与者分为2A期（n = 101）、2B期（n = 227）和健康对照组（n = 158）。虽然2期的蒙特利尔认知评估得分正常（均值[标准差]=27.0[2.3]），但与健康对照组相比，2A期的CSS在数值上较差（z评分均值差异=0.05，p=无统计学意义；效应量=0.09），2B期的CSS在统计学上较差（z评分均值差异=0.23，p<0.05；效应量=0.40）。在2A期，单纯嗅觉减退与认知正常相关，但合并iRBD的患者认知明显较差（z评分均值差异=0.33，p<0.05，效应量=0.50）。在2B期，单纯嗅觉减退认知异常（z评分均值差异=0.18，p = 0.0078，效应量=0.29），叠加iRBD有统计学意义的累加效应。
使用一种新的CSS，我们证明嗅觉减退与前驱期NSD且无运动功能障碍患者的认知缺陷相关，特别是当合并多巴胺系统损害或合并iRBD时。因此，在研究突触核蛋白病时，即使在无运动功能障碍的情况下，在所有阶段纳入并评估认知至关重要。《神经病学年鉴》2025年；98：482 - 491。
