Hällqvist J, Bartl M, Dakna M, Schade S, Garagnani P, Bacalini MG, Pirazzini C, Bhatia K, Schreglmann S, Xylaki M, Weber S, Ernst M, Muntean ML, Sixel-Döring F, Franceschi C, Doykov I, Śpiewak J, Vinette H, Trenkwalder C, Heywood WE, Mills K, Mollenhauer B. Plasma proteomics identify biomarkers predicting Parkinson's disease up to 7 years before symptom onset. Nat Commun. 2024 Jun 18;15(1):4759. PubMed.
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The Amaranth Foundation
This study adds to growing evidence that protein biomarkers in biofluids can differentiate people with PD from healthy individuals, potentially before symptoms appear (Pereira et al., 2023; Virreira Winter et al., 2021; Rutledge et al., 2024). While the claim of 100 percent sensitivity and specificity is very likely a result of methodological limitations, this study nevertheless lends additional weight to the idea that small protein panels could be effective for PD screening and diagnosis (Rutledge et al., 2022; Del Campo et al., 2023), extending this further than previous work. Importantly, this is the first concrete demonstration that markers in blood can predict PD onset in presymptomatic patients at high risk.
A particularly interesting piece of the study is the use of a longitudinally sampled iRBD cohort with a decade of follow-up, providing rare and valuable data. Approximately 80 percent of these samples were identified as PD, aligning with expected progression rates, and importantly, presymptomatic PD detection was achieved in 16/16 cases that progressed to motor symptoms over the study period. While other biomarker studies have reported similar results in presymptomatic cases, they have lacked long enough follow-up to concretely show biomarkers predict progression. I expect this new evidence will have an important impact on clinical translation of these ideas.
The study also employs a targeted mass spectrometry approach for biomarker analysis, rather than affinity-based methods such as Olink and SomaScan used in other reports. The authors also demonstrate translation of findings from plasma to serum, something that would likely be difficult for affinity proteomics. This may highlight an advantage of mass spec in the screening use case.
Despite high reported sensitivity and specificity, real-world replication is doubtful. The authors did not use independent train and test datasets to arrive at these numbers. Indeed, using cross-validation they reported precision and recall of 87 percent, and a balanced accuracy of 82 percent. This puts the accuracy of the test in a similar range to that of the single protein marker DOPA decarboxylase, as recently reported by us and others (Pereira et al., 2023; Rutledge et al., 2024; Rutledge et al., 2022; Del Campo et al., 2023; Paslawski et al., 2023). Cross-validation is almost always an overestimate of the test performance compared to verification using independent data, so it is highly likely the real accuracy is lower than reported.
References:
Pereira JB, Kumar A, Hall S, Palmqvist S, Stomrud E, Bali D, Parchi P, Mattsson-Carlgren N, Janelidze S, Hansson O. DOPA decarboxylase is an emerging biomarker for Parkinsonian disorders including preclinical Lewy body disease. Nat Aging. 2023 Oct;3(10):1201-1209. Epub 2023 Sep 18 PubMed.
Virreira Winter S, Karayel O, Strauss MT, Padmanabhan S, Surface M, Merchant K, Alcalay RN, Mann M. Urinary proteome profiling for stratifying patients with familial Parkinson's disease. EMBO Mol Med. 2021 Mar 5;13(3):e13257. Epub 2021 Jan 22 PubMed.
Rutledge J, Lehallier B, Zarifkar P, Losada PM, Shahid-Besanti M, Western D, Gorijala P, Ryman S, Yutsis M, Deutsch GK, Mormino E, Trelle A, Wagner AD, Kerchner GA, Tian L, Cruchaga C, Henderson VW, Montine TJ, Borghammer P, Wyss-Coray T, Poston KL. Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson's disease. Acta Neuropathol. 2024 Mar 11;147(1):52. PubMed.
Rutledge J, Lehallier B, Zarifkar P, Losada PM, Ryman S, Yutsis M, Deutsch G, Mormino E, Trelle A, Wagner AD, Kerchner GA, Tian L, Henderson VW, Montine TJ, Borghammer P, Wyss-Coray T, Poston KL. Aromatic L-Amino Acid Decarboxylase is a novel fluid biomarker of Parkinson's disease. 2022 Nov 11 10.1101/2022.11.09.22282149 (version 1) medRxiv.
Del Campo M, Vermunt L, Peeters CF, Sieben A, Hok-A-Hin YS, Lleó A, Alcolea D, van Nee M, Engelborghs S, van Alphen JL, Arezoumandan S, Chen-Plotkin A, Irwin DJ, van der Flier WM, Lemstra AW, Teunissen CE. CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease. Nat Commun. 2023 Sep 13;14(1):5635. PubMed.
Paslawski W, Khosousi S, Hertz E, Markaki I, Boxer A, Svenningsson P. Large-scale proximity extension assay reveals CSF midkine and DOPA decarboxylase as supportive diagnostic biomarkers for Parkinson's disease. Transl Neurodegener. 2023 Sep 4;12(1):42. PubMed.
View all comments by Jarod RutledgeBanner Sun Health Research Institute
As usual for biomarker studies “validated” by the clinical diagnosis of PD, the “true” diagnostic accuracy cannot be claimed to be higher than the known clinical diagnostic accuracy against the postmortem diagnosis of PD. As these are all “de novo” PD cases and most of the cases, at least in the supplemental table 1, are of less than three years disease duration, and as the diagnostic accuracy against the postmortem neuropathological diagnosis of PD for such early PD cases that we and others have published is only between 60-70 percent at most (Beach et al., 2023; Adler et al., 2021; Beach and Adler, 2018; Adler et al., 2014), then this new diagnostic test’s true accuracy for PD cannot be any greater than that. Additionally, there did not seem to be third-party blinding (triple-blinding) so there is a potential for conscious or subconscious bias.
References:
Beach TG, Adler CH, Shill HA, Zhang N, Driver-Dunckley ED, Mehta SH, Serrano GE. Accuracy of the Early Diagnosis of Parkinson's Disease. Mov Disord. 2023 Aug;38(8):1573-1574. PubMed.
Adler CH, Beach TG, Zhang N, Shill HA, Driver-Dunckley E, Mehta SH, Atri A, Caviness JN, Serrano G, Shprecher DR, Sue LI, Belden CM. Clinical Diagnostic Accuracy of Early/Advanced Parkinson Disease: An Updated Clinicopathologic Study. Neurol Clin Pract. 2021 Aug;11(4):e414-e421. PubMed.
Beach TG, Adler CH. Importance of low diagnostic Accuracy for early Parkinson's disease. Mov Disord. 2018 Oct;33(10):1551-1554. Epub 2018 Oct 4 PubMed.
Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN. Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study. Neurology. 2014 Jul 29;83(5):406-12. Epub 2014 Jun 27 PubMed.
View all comments by Thomas BeachUniversity of Pennsylvania, Veterans Affairs Medical Center
This biomarker study establishes a novel, mass-spectrometry-based paradigm to identify, in an unbiased manner, biomarker proteins in blood that differentiate healthy individuals from those with Parkinson’s disease. Within this study, a panel of eight proteins shows perfect identification of individuals with Parkinson’s disease relative to healthy controls with strong cross-validation metrics. As with all biomarker studies, replication of these protein markers in an independent cohort, as well as comparison with other established biomarkers for Lewy body diseases, including skin biopsy immunofluorescence (Gibbons et al., 2024) and cerebrospinal fluid seed aggregation assay (Siderowf et al., 2023), will determine the real-world clinical and diagnostic utility of the identified proteins.
Moreover, the findings are exciting because they implicate a biochemical signature in individuals with REM-behavior disorder (RBD) that is not directly tied to α-synuclein pathology or dopamine metabolism, yet is present before phenoconversion. Despite less than 80 percent of individuals with RBD in this study having this signature, it was longitudinally stable in those who did. While this biomarker signature did not reliably predict, or correlate with, phenoconversion to neurodegeneration, understanding its mechanistic relevance in individuals with RBD, and its presence before onset of PD, will be very important to the field. Notably, this biochemical signature reinforces the idea of a dysregulated inflammatory state in individuals with, and at risk for, Lewy body diseases.
References:
Gibbons CH, Levine T, Adler C, Bellaire B, Wang N, Stohl J, Agarwal P, Aldridge GM, Barboi A, Evidente VG, Galasko D, Geschwind MD, Gonzalez-Duarte A, Gil R, Gudesblatt M, Isaacson SH, Kaufmann H, Khemani P, Kumar R, Lamotte G, Liu AJ, McFarland NR, Miglis M, Reynolds A, Sahagian GA, Saint-Hillaire MH, Schwartzbard JB, Singer W, Soileau MJ, Vernino S, Yerstein O, Freeman R. Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies. JAMA. 2024 Apr 16;331(15):1298-1306. PubMed.
Siderowf A, Concha-Marambio L, Lafontant DE, Farris CM, Ma Y, Urenia PA, Nguyen H, Alcalay RN, Chahine LM, Foroud T, Galasko D, Kieburtz K, Merchant K, Mollenhauer B, Poston KL, Seibyl J, Simuni T, Tanner CM, Weintraub D, Videnovic A, Choi SH, Kurth R, Caspell-Garcia C, Coffey CS, Frasier M, Oliveira LM, Hutten SJ, Sherer T, Marek K, Soto C, Parkinson's Progression Markers Initiative. Assessment of heterogeneity among participants in the Parkinson's Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023 May;22(5):407-417. PubMed.
View all comments by George KannarkatUniversity of Cambridge
The best treatment for Parkinson’s Disease (PD) would be to prevent the loss of existing dopaminergic neurons, but it is challenging to identify individuals who would benefit from such an intervention. This study from Hällqvist and colleagues is an important step in this direction, since they can distinguish people who are undergoing neurodegeneration, but have not yet developed PD-associated motor symptoms.
One potential criticism of the study is that there are many different types of neurodegenerative diseases, and they only compare samples from PD patients to a few other cohorts, so it’s unclear how specific their panel of biomarkers is for PD. However, if these biomarkers are also altered in other neurodegenerative conditions, and there are neuroprotective treatments that target shared mechanisms between those diseases, then the potential impact of their findings extends beyond just PD.
View all comments by Florian MerkleMake a Comment
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