Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.
Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.
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DOI：
10.1016/s1474-4422(23)00109-6
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发表时间：
2023-05
期刊：
影响因子：
48
通讯作者：
Soto, Claudio
中科院分区：
文献类型：
--
作者：
Siderowf, Andrew;Concha-Marambio, Luis;Lafontant, David-Erick;Farris, Carly M.;Ma, Yihua;Urenia, Paula A.;Nguyen, Hieu;Alcalay, Roy N.;Chahine, Lana M.;Foroud, Tatiana;Galasko, Douglas;Kieburtz, Karl;Merchant, Kalpana;Mollenhauer, Brit;Poston, Kathleen L.;Seibyl, John;Simuni, Tanya;Tanner, Caroline M.;Weintraub, Daniel;Videnovic, Aleksandar;Choi, Seung Ho;Kurth, Ryan;Caspell-Garcia, Chelsea;Coffey, Christopher S.;Frasier, Mark;Oliveira, Luis M. A.;Hutten, Samantha J.;Sherer, Todd;Marek, Kenneth;Soto, Claudio
新出现的证据表明，α-突触核蛋白种子扩增试验（SAA）有可能区分帕金森病患者和健康对照者。我们使用了充分表征的多中心帕金森病进展标志物倡议（PPMI）队列，以进一步评估α-突触核蛋白SAA的诊断性能，并检查该测定是否能够识别患者之间的异质性，并能够早期识别高危人群。这种横断面分析是基于对PPMI参与者在登记时进行的评估（包括来自LRRK 2和GBA变异体的散发性帕金森病患者、健康对照者、患有快速眼动睡眠行为障碍（RBD）或嗅觉减退的前驱个体以及LRRK 2和GBA变异体的非明显携带者）（奥地利、加拿大、法国、德国、希腊、以色列、意大利、荷兰、挪威、西班牙、英国和美国）。使用先前描述的方法进行CSF的α-突触核蛋白SAA分析。我们评估了α-突触核蛋白SAA在帕金森病患者和健康对照者中的敏感性和特异性，包括基于遗传和临床特征的亚组。我们确定了前驱期参与者（RBD和嗅觉减退）和帕金森病相关遗传变异非显性携带者中α-突触核蛋白SAA结果阳性的频率，并将α-突触核蛋白SAA与临床测量和其他生物标志物进行了比较。我们使用比值比估计值和95%CI来衡量α-突触核蛋白SAA状态与分类指标之间的相关性，并使用来自research方法的双样本95%CI来评估α-突触核蛋白SAA阳性和阴性受试者之间连续指标的中位数差异。使用线性回归模型控制潜在混杂因素，如年龄和性别。该分析包括2010年7月7日至2019年7月4日期间入组的1123名参与者。其中，545人患有帕金森病，163人是健康对照，54人是没有多巴胺能缺陷证据的扫描参与者，51人是前驱参与者，310人是非表现携带者。帕金森病的敏感性为87.7%（95%CI 84.9 - 90.5），健康对照的特异性为96.3%（93.4 - 99.2）。α-synuclein SAA在散发性帕金森病伴典型嗅觉障碍患者中的敏感性为98.6%（96.4 ~ 99.4）。在包括LRRK 2帕金森病（67.5%[59.2 - 75.8]）和无嗅觉缺陷的散发性帕金森病参与者（78.3%[69.8 - 86.7]）在内的亚组中，α-突触核蛋白SAA阳性的比例低于这一数字。具有LRRK 2变异体和正常嗅觉的参与者的α-突触核蛋白SAA阳性率更低（34.7%[21.4 - 48.0]）。在前驱组和高危组中，51例RBD或嗅觉减退的参与者中有44例（86%）α-突触核蛋白SAA阳性（18例嗅觉减退中有16例，33例RBD中有28例）。310名非显性携带者中有25名（8%）为阳性（159名中有14名[9%] LRRK 2，151名中有11名[7%] GBA）。这项研究是迄今为止对α-突触核蛋白SAA用于帕金森病生化诊断的最大分析。我们的研究结果表明，该检测方法对帕金森病患者进行分类具有高灵敏度和特异性，提供了有关分子异质性的信息，并在诊断前检测前驱个体。这些发现表明α-突触核蛋白SAA在治疗开发中的关键作用，既可以识别帕金森病患者的病理定义亚组，也可以建立生物标志物定义的风险队列。PPMI由Michael J Fox Foundation for Parkinson's Research和资助合作伙伴资助，包括：Abbvie、AcureX、Aligning Science Across Parkinson's、Amathus Therapeutics、Avid Radiopharmaceuticals、Bial Biotech、Biohaven、Biogen、BioLegend、Bristol-Myers Squibb、Calico Labs、Celgene、Cerevel、Coave、DaCapo Brainscience、4D Pharma、Denali、Edmond J Safra Foundation、Eli Lilly、GE Healthcare、Genentech、GlaxoSmithKline、Golub Capital、Insitro、Janssen Neuroscience、Lundbeck、Merck、Meso Scale Discovery、Neurocrine Biosciences、Prevail Therapeutics、Roche、Sanofi Genzyme、Servier、Takeda、Teva、UCB、VanquaBio、Verily、Voyager Therapeutics和Yumanity。
Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson’s disease from healthy controls. We used the well characterised, multicentre Parkinson’s Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups. This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson’s disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) or hyposmia, and non-manifesting carriers of LRRK2 and GBA variants) from 33 participating academic neurology outpatient practices worldwide (in Austria, Canada, France, Germany, Greece, Israel, Italy, the Netherlands, Norway, Spain, the UK, and the USA). α-synuclein SAA analysis of CSF was performed using previously described methods. We assessed the sensitivity and specificity of the α-synuclein SAA in participants with Parkinson’s disease and healthy controls, including subgroups based on genetic and clinical features. We established the frequency of positive α-synuclein SAA results in prodromal participants (RBD and hyposmia) and non-manifesting carriers of genetic variants associated with Parkinson’s disease, and compared α-synuclein SAA to clinical measures and other biomarkers. We used odds ratio estimates with 95% CIs to measure the association between α-synuclein SAA status and categorical measures, and two-sample 95% CIs from the resampling method to assess differences in medians between α-synuclein SAA positive and negative participants for continuous measures. A linear regression model was used to control for potential confounders such as age and sex. This analysis included 1123 participants who were enrolled between July 7, 2010, and July 4, 2019. Of these, 545 had Parkinson’s disease, 163 were healthy controls, 54 were participants with scans without evidence of dopaminergic deficit, 51 were prodromal participants, and 310 were non-manifesting carriers. Sensitivity for Parkinson’s disease was 87·7% (95% CI 84·9–90·5), and specificity for healthy controls was 96·3% (93·4–99·2). The sensitivity of the α-synuclein SAA in sporadic Parkinson’s disease with the typical olfactory deficit was 98·6% (96·4–99·4). The proportion of positive α-synuclein SAA was lower than this figure in subgroups including LRRK2 Parkinson’s disease (67·5% [59·2–75·8]) and participants with sporadic Parkinson’s disease without olfactory deficit (78·3% [69·8–86·7]). Participants with LRRK2 variant and normal olfaction had an even lower α-synuclein SAA positivity rate (34·7% [21·4–48·0]). Among prodromal and at-risk groups, 44 (86%) of 51 of participants with RBD or hyposmia had positive α-synuclein SAA (16 of 18 with hyposmia, and 28 of 33 with RBD). 25 (8%) of 310 non-manifesting carriers (14 of 159 [9%] LRRK2 and 11 of 151 [7%] GBA) were positive. This study represents the largest analysis so far of the α-synuclein SAA for the biochemical diagnosis of Parkinson’s disease. Our results show that the assay classifies people with Parkinson’s disease with high sensitivity and specificity, provides information about molecular heterogeneity, and detects prodromal individuals before diagnosis. These findings suggest a crucial role for the α-synuclein SAA in therapeutic development, both to identify pathologically defined subgroups of people with Parkinson’s disease and to establish biomarker-defined at-risk cohorts. PPMI is funded by the Michael J Fox Foundation for Parkinson’s Research and funding partners, including: Abbvie, AcureX, Aligning Science Across Parkinson’s, Amathus Therapeutics, Avid Radiopharmaceuticals, Bial Biotech, Biohaven, Biogen, BioLegend, Bristol-Myers Squibb, Calico Labs, Celgene, Cerevel, Coave, DaCapo Brainscience, 4D Pharma, Denali, Edmond J Safra Foundation, Eli Lilly, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Insitro, Janssen Neuroscience, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Prevail Therapeutics, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, VanquaBio, Verily, Voyager Therapeutics, and Yumanity.