Kiel University in Germany develops blood test method for early diagnosis of Parkinson's disease

Parkinson's disease is a neurodegenerative disease. When patients show obvious clinical symptoms of movement disorders, at least half of the neurons have died. Due to the non-regenerative nature of neurons, it is currently difficult to replenish dead neurons through effective means. Therefore, it is particularly important to detect preclinical patients through early diagnosis and take effective preventive measures to prevent the death of dopaminergic neurons to block the occurrence of the disease. Non-motor symptoms such as gene mutations, sleep disorders or hyposmia may exist several years before the onset of motor symptoms and may be prompts or biomarkers for the early diagnosis of Parkinson's disease. In fact, many studies have spent a lot of effort on exploring the early diagnosis of Parkinson's disease. However, whether using imaging technology (such as MRI, PET or EMG) or detecting biomarkers in peripheral body fluids (such as Aβ42, α-syn, p-tau or HVA in cerebrospinal fluid), they have failed to improve the accuracy of early Parkinson's diagnosis [1].

Recently, Daniela Berg's research team at the University of Kiel in Germany published a research paper titled Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson's Disease in the journal Movement disorders. The research team completed the conceptual verification of the feasibility of early diagnosis of Parkinson's disease based on the blood-based α-syn seed amplification assay (α-syn SAA), indicating that this peripheral blood-based α-syn SAA method has the potential to serve as a biomarker for early diagnosis of Parkinson's disease.

The seed amplification assay (SAA) is essentially a method of amplifying proteins or promoting protein misfolding so that extremely small amounts of proteins in the original tissue can be detected by instruments. The effectiveness of using α-syn SAA to diagnose diseases with α-syn pathological characteristics (such as Parkinson's disease, Lewy body dementia, and multiple system atrophy) using patients' brain tissue, cerebrospinal fluid, skin, and olfactory mucosa has been verified. For example, in 2023, the largest analysis of α-syn SAA in the biochemical diagnosis of Parkinson's disease to date (a total of 1,123 participants) found that the sensitivity of using α-syn SAA in cerebrospinal fluid to diagnose Parkinson's disease can reach 87.7% and the specificity can reach 96.3%. In addition, the sensitivity of α-syn SAA for detecting sporadic Parkinson's disease patients with olfactory impairment is as high as 98.6% [2].

In the early diagnosis of Parkinson's disease, α-syn SAA is often used in combination with idiopathic rapid-eye-movement (REM) sleep behavior disorder (iRBD) and pure autonomic failure (PAF). These two symptoms are considered to be early symptoms of Parkinson's disease. Early diagnosis of iRBD and PAF can also help predict the onset of Parkinson's disease. Cerebrospinal fluid testing has found that α-syn SAA has a sensitivity of 90.4% and a specificity of 90% for iRBD patients. Among these iRBD patients, 62% will develop Parkinson's disease or Lewy body dementia within an average of 3.4 years in the future [1]. Considering the difficulty of obtaining cerebrospinal fluid, people prefer to use body fluids such as blood and saliva for live testing.

In 2022, the research team of this article detected α-syn in neuron-derived extracellular vesicles in the blood and found that the α-syn SAA based on this was clinically compatible with the diagnosis of Parkinson's disease [3]. In order to further explore whether this method can be used for the early diagnosis of Parkinson's disease, the research team used patient samples provided by the TREND study initiated by the University of Tübingen for conceptual verification [4]. The TREND study covered a total of 1,201 participants aged 50-80 years, none of whom were diagnosed with Parkinson's disease at the time of recruitment. Starting in 2009, blood samples were collected every 2 years, and by the end of the study in 2022, a total of 20 participants were diagnosed with Parkinson's disease. This article used α-syn SAA to analyze serum samples from 12 of these patients and 13 healthy people. In addition, this article also collected serum plasma samples from 20 confirmed iRBD patients for comparative studies.
The research team found that after the formal diagnosis of 12 patients, the α-syn SAA signal was significantly increased compared to healthy people. Looking back in time, all patients had a time point before the formal diagnosis when the α-syn SAA signal began to increase. The time point of the first increase in the signal was 1-10 years before the formal diagnosis. If the time point of the first increase in the α-syn SAA signal is used to predict whether Parkinson's disease will occur, 5 participants (41.7%) are likely (possible) and 1 participant (8.3%) is very likely (probable) to have early Parkinson's disease. If the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS-III) score and the α-syn SAA signal are combined, the research team found that there was a significant positive correlation between the score and the α-syn SAA signal before and after the formal diagnosis (rho = 0.719, P < 0.001), which means that the α-syn SAA signal can also reflect the movement of the subject (Figure 1). Analysis of samples from iRBD patients found that only 6 patients (30%) had elevated α-syn SAA signals.

Figure 1 Changes in α-syn SAA signals before and after diagnosis and their relationship with the patient's movement disorder score

At present, whether for the early diagnosis or clinical diagnosis of Parkinson's disease, a diagnostic method based on blood testing has not yet been fully established. Although some studies have diagnosed Parkinson's disease by detecting the total α-syn content in the blood, the diagnostic method of the total α-syn content is not very accurate because it is impossible to distinguish the specific content of physiological and pathological α-syn in the total content. This study combined the extracellular vesicle extraction technology and SAA technology to make it possible to directly detect pathological α-syn. In addition, this study has expanded the detection range of this technology to the early stage of Parkinson's disease . Compared with the cerebrospinal fluid or solid tissue used in other early diagnosis methods of Parkinson's disease, this study can complete the detection through easily obtained blood. On the contrary, the prediction probability of iR BD patients through blood biomarkers is only 30%, which is much less than the prediction probability based on skin or cerebrospinal fluid biomarkers. This is also a problem worthy of more researchers to think about in the future.

References:

[1] Srivastava A, Alam P, Caughey B. RT-QuIC and Related Assays for Detecting and Quantifying Prion-like Pathological Seeds of α-Synuclein. Biomolecules. 2022 Apr 14;12(4):576. doi: 10.3390/biom12040576. PMID: 35454165; PMCID: PMC9030929.

[2] 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 LMA, 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. doi: 10.1016/S1474-4422(23)00109-6. PMID: 37059509; PMCID: PMC10627170.

[3] Kluge A, Bunk J, Schaeffer E, Drobny A, Xiang W, Knacke H, Bub S, Lückstädt W, Arnold P, Lucius R, Berg D, Zunke F. Detection of neuron-derived pathological α-synuclein in blood. Brain. 2022 Sep 14;145(9):3058-3071. doi: 10.1093/brain/awac115. Erratum in: Brain. 2023 Jan 5;146(1):e6. PMID: 35722765.

[4] Kluge A, Schaeffer E, Bunk J, Sommerauer M, Röttgen S, Schulte C, Roeben B, von Thaler AK, Welzel J, Lucius R, Heinzel S, Xiang W, Eschweiler GW, Maetzler W, Suenkel U, Berg D. Detecting Misfolded α-Synuclein in Blood Years before the Diagnosis of Parkinson's Disease. Mov Disord. 2024 Apr 23. doi: 10.1002/mds.29766. Epub ahead of print. PMID: 38651526.