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000257678 1001_ $$aSiderowf, Andrew$$b0
000257678 245__ $$aAssessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study.
000257678 260__ $$aLondon$$bLancet Publ. Group$$c2023
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000257678 520__ $$aEmerging 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.
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000257678 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000257678 650_7 $$2NLM Chemicals$$aBiomarkers
000257678 650_2 $$2MeSH$$aHumans
000257678 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000257678 650_2 $$2MeSH$$aParkinson Disease: diagnosis
000257678 650_2 $$2MeSH$$aParkinson Disease: genetics
000257678 650_2 $$2MeSH$$aCross-Sectional Studies
000257678 650_2 $$2MeSH$$aAnosmia
000257678 650_2 $$2MeSH$$aREM Sleep Behavior Disorder
000257678 650_2 $$2MeSH$$aBiomarkers
000257678 7001_ $$aConcha-Marambio, Luis$$b1
000257678 7001_ $$aLafontant, David-Erick$$b2
000257678 7001_ $$aFarris, Carly M$$b3
000257678 7001_ $$aMa, Yihua$$b4
000257678 7001_ $$aUrenia, Paula A$$b5
000257678 7001_ $$aNguyen, Hieu$$b6
000257678 7001_ $$aAlcalay, Roy N$$b7
000257678 7001_ $$aChahine, Lana M$$b8
000257678 7001_ $$aForoud, Tatiana$$b9
000257678 7001_ $$aGalasko, Douglas$$b10
000257678 7001_ $$aKieburtz, Karl$$b11
000257678 7001_ $$aMerchant, Kalpana$$b12
000257678 7001_ $$0P:(DE-2719)9001340$$aMollenhauer, Brit$$b13$$udzne
000257678 7001_ $$aPoston, Kathleen L$$b14
000257678 7001_ $$aSeibyl, John$$b15
000257678 7001_ $$aSimuni, Tanya$$b16
000257678 7001_ $$aTanner, Caroline M$$b17
000257678 7001_ $$aWeintraub, Daniel$$b18
000257678 7001_ $$aVidenovic, Aleksandar$$b19
000257678 7001_ $$aChoi, Seung Ho$$b20
000257678 7001_ $$aKurth, Ryan$$b21
000257678 7001_ $$aCaspell-Garcia, Chelsea$$b22
000257678 7001_ $$aCoffey, Christopher S$$b23
000257678 7001_ $$aFrasier, Mark$$b24
000257678 7001_ $$aOliveira, Luis M A$$b25
000257678 7001_ $$aHutten, Samantha J$$b26
000257678 7001_ $$aSherer, Todd$$b27
000257678 7001_ $$0P:(DE-2719)9000201$$aMarek, Kenneth$$b28$$udzne
000257678 7001_ $$aSoto, Claudio$$b29
000257678 7001_ $$aInitiative, Parkinson's Progression Markers$$b30$$eCollaboration Author
000257678 773__ $$0PERI:(DE-600)2079704-7$$a10.1016/S1474-4422(23)00109-6$$gVol. 22, no. 5, p. 407 - 417$$n5$$p407 - 417$$tThe lancet <London> / Neurology$$v22$$x1474-4422$$y2023
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