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A panel of eight blood biomarkers may be able to identify which patients will go on to develop Parkinson’s disease (PD) up to 7 years before the development of motor symptoms or dementia with Lewy bodies, results of a new study suggest.
The search for a test to diagnose PD reached a milestone recently with the arrival of alpha-synuclein seed amplification assays, hailed as potential game-changer because of their high performance as a diagnostic biomarker.
However, these assays rely on cerebrospinal fluid, cannot track changes longitudinally, and haven’t been sufficiently linked to the underlying pathophysiology, said first author Michael Bartl, MD, Department of Neurology, University Medical Center Goettingen, Germany.
“This is a big step because for the first time we are working with peripheral fluids and have a test that can predict something in an objective way,” he told Medscape Medical News. “Our panel of proteins is also more dynamic and involves the pathophysiology.”
The study was published online June 18 in Nature Communications.
Discovery and Validation Phases
For the study, the researchers performed a proteomics analysis of plasma using mass spectrometry that identified 1238 proteins in 10 randomly selected drug-naive patients with PD and 10 matched healthy controls from the de novo PD cohort.
They then constructed a targeted, mass spectrometry proteomic assay with 121 proteins and applied it to plasma samples from 99 patients with de novo PD and 36 healthy controls, and then validated the assay in 41 patients with other neurologic diseases and in 18 patients with premotor isolated REM sleep behavior disorder (iREM).
The assay identified 23 distinct proteins involved in inflammatory pathways, Wnt-signaling, and coagulation cascade that were consistently dysregulated in patients with PD compared with healthy controls. Six of these proteins were also shown to be dysregulated in patients with iREM, reported Bartl, co–first author Jenny Hällqvist, PhD, Great Ormond Street Hospital, London, United Kingdom, and colleagues.
Finally, after refining the assay, the researchers applied a machine-learning model and analyzed an additional set of 146 longitudinal blood samples from an independent cohort of 54 persons with iRBD and follow-up sampling of up to 7 years.
The model included eight proteins: GRN, MASP2, HSPA5, PTGDS, ICAM1, complement C3, DKK3, and SERPING1.
The model was able to identify 100% of the patients with PD based on the expression of the eight proteins and predict with 79% accuracy which patients with iREM would convert to PD up to 7 years before the onset of motor symptoms.
“We know that isolated REM sleep disorder is a strong predictor of the disease and we wanted to see if maybe there is something in common,” Bartl said. “And to our surprise, they had a lot in common with the patients with Parkinson’s. It’s not just that they are at risk, but they already have blood that indicates the pathological processes in Parkinson’s disease have already taken place.”
Of note, most of the markers also robustly correlated with clinical scores on the Unified Parkinson’s Disease Rating Scale and Mini-Mental State Examination.
‘Amazing Study’
Reached for comment, Chan-Hyun Na, PhD, Department of Neurology, Institute for Cell Engineering, Johns Hopkins University, Baltimore, Maryland, said that “this is quite an amazing study because diagnosis of Parkinson’s disease using biomarkers is actually quite challenging, especially compared to other diseases.”
“My lab and my collaborators have been working on discovering Parkinson’s biomarkers using cerebral spinal fluid, but we found it is quite challenging,” he said. “But what [these researchers] found is they could discover some biomarkers from serum. This is much easier to get samples from patients and less invasive. Then, they could even predict Parkinson’s up to 7 years before the motor symptom onset. So, I think it is a quite an impressive study.”
“Blood tests for Parkinson’s for diagnosis and prediction remain a massive unmet need,” Ray Chaudhuri, MBBS, MD, professor of neurology/movement disorders at King’s College Hospital and King’s College London and medical director of the Parkinson Foundation International Centre of Excellence at King’s College London, United Kingdom, said in a statement.
“If replicated in larger studies, these tests or panel may prove to be invaluable in supporting the diagnosis of Parkinson, which work from our Centre and others have shown is a syndrome and not a single disease,” he added. “Questions, however, remain about the ethics of predictive diagnosis in relation to proper counseling as well as absence, currently, of any disease-modifying treatment.”
Bartl said that his team hopes to validate the findings in a larger cohort of at least 100 patients and also noted that the ability to identify patients with early PD could lead to greater recruitment in preventative clinical trials and potentially improve treatment options. For example, drugs can modify Wnt-signaling pathways in oncology thus may be of interest to the PD field.
The study was funded by the Michael J. Fox Foundation, PDUK, The Peto Foundation, The TMSRG (UCL), The BRC at Great Ormond Street Hospital, and the Horizon 2020 Framework Programme. Bartl has received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation). Hällqvist reports no competing financial interests. Other co-author disclosures are listed in the paper. Na and Chaudhuri report having no conflicts to declare.
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