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Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism.
J Neurol Neurosurg Psychiatry. 2020 07; 91(7):720-729.JN

Abstract

OBJECTIVE

Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies.

METHODS

We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.

RESULTS

Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression.

CONCLUSIONS

Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism.

Authors+Show Affiliations

Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. Department of Neurology, Christian-Albrechts-University, Kiel, Germany.Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, United Kingdom.Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, United Kingdom.Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. Oxford Parkinson's Disease Centre, Oxford, United Kingdom.Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.Department of Neurology, Christian-Albrechts-University, Kiel, Germany.Department of Neurology, Christian-Albrechts-University, Kiel, Germany.Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.Department of Neurology, Christian-Albrechts-University, Kiel, Germany.Department of Clinical and Experimental Sciences, Neurology Unit, University of Brescia, Brescia, Italy.Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. Oxford Parkinson's Disease Centre, Oxford, United Kingdom.Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, United Kingdom.Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK george.tofaris@ndcn.ox.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32273329

Citation

Jiang, Cheng, et al. "Serum Neuronal Exosomes Predict and Differentiate Parkinson's Disease From Atypical Parkinsonism." Journal of Neurology, Neurosurgery, and Psychiatry, vol. 91, no. 7, 2020, pp. 720-729.
Jiang C, Hopfner F, Katsikoudi A, et al. Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism. J Neurol Neurosurg Psychiatry. 2020;91(7):720-729.
Jiang, C., Hopfner, F., Katsikoudi, A., Hein, R., Catli, C., Evetts, S., Huang, Y., Wang, H., Ryder, J. W., Kuhlenbaeumer, G., Deuschl, G., Padovani, A., Berg, D., Borroni, B., Hu, M. T., Davis, J. J., & Tofaris, G. K. (2020). Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism. Journal of Neurology, Neurosurgery, and Psychiatry, 91(7), 720-729. https://doi.org/10.1136/jnnp-2019-322588
Jiang C, et al. Serum Neuronal Exosomes Predict and Differentiate Parkinson's Disease From Atypical Parkinsonism. J Neurol Neurosurg Psychiatry. 2020;91(7):720-729. PubMed PMID: 32273329.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Serum neuronal exosomes predict and differentiate Parkinson's disease from atypical parkinsonism. AU - Jiang,Cheng, AU - Hopfner,Franziska, AU - Katsikoudi,Antigoni, AU - Hein,Robert, AU - Catli,Candan, AU - Evetts,Samuel, AU - Huang,Yongzhi, AU - Wang,Hong, AU - Ryder,John W, AU - Kuhlenbaeumer,Gregor, AU - Deuschl,Guenther, AU - Padovani,Alessandro, AU - Berg,Daniela, AU - Borroni,Barbara, AU - Hu,Michele T, AU - Davis,Jason J, AU - Tofaris,George K, Y1 - 2020/04/09/ PY - 2019/12/06/received PY - 2020/02/10/revised PY - 2020/03/23/accepted PY - 2020/4/11/pubmed PY - 2020/11/12/medline PY - 2020/4/11/entrez SP - 720 EP - 729 JF - Journal of neurology, neurosurgery, and psychiatry JO - J Neurol Neurosurg Psychiatry VL - 91 IS - 7 N2 - OBJECTIVE: Parkinson's disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson's from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson's disease, multiple system atrophy and other proteinopathies. METHODS: We performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson's and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins. RESULTS: Mean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson's disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson's disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson's disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson's disease progression. CONCLUSIONS: Increased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson's disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson's disease from atypical parkinsonism. SN - 1468-330X UR - https://www.unboundmedicine.com/medline/citation/32273329/Serum_neuronal_exosomes_predict_and_differentiate_Parkinson's_disease_from_atypical_parkinsonism_ L2 - https://jnnp.bmj.com/lookup/pmidlookup?view=long&pmid=32273329 DB - PRIME DP - Unbound Medicine ER -