Blood extracellular vesicles carrying synaptic function- and brain-related proteins as potential biomarkers for Alzheimer's disease

Chen Tian; Tessandra Stewart; Zhen Hong; Zhen Guo; Patrick Aro; David Soltys; Catherine Pan; Elaine R Peskind; Cyrus P Zabetian; Leslie M Shaw; Douglas Galasko; Joseph F Quinn; Min Shi; Jing Zhang; Alzheimer's Disease Neuroimaging Initiative

doi:10.1002/alz.12723

Blood extracellular vesicles carrying synaptic function- and brain-related proteins as potential biomarkers for Alzheimer's disease

Alzheimers Dement. 2022 Jul 2:10.1002/alz.12723. doi: 10.1002/alz.12723. Online ahead of print.

Authors

Chen Tian^{1

2}, Tessandra Stewart², Zhen Hong^{2

3}, Zhen Guo¹, Patrick Aro², David Soltys², Catherine Pan^{1

2}, Elaine R Peskind^{4

5}, Cyrus P Zabetian^{6

7}, Leslie M Shaw^{8

9}, Douglas Galasko¹⁰, Joseph F Quinn^{11

12}, Min Shi², Jing Zhang^{1

13}; Alzheimer's Disease Neuroimaging Initiative

Affiliations

¹ Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
² Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.
³ Department of Neurology, West China Medical School, Sichuan University, Chengdu, China.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ Northwest (VISN-20) Mental Illness, Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
⁶ Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.
⁷ Department of Neurology, University of Washington School of Medicine, Seattle, Washington, USA.
⁸ Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Department of Neurology, University of California, San Diego, California, USA.
¹¹ Department of Neurology, Oregon Health & Science University, Portland, Oregon, USA.
¹² Department of Neurology and Parkinson's Disease Research Education and Clinical Care Center (PADRECC), VA Portland Healthcare System, Portland, Oregon, USA.
¹³ National Health and Disease Human Brain Tissue Resource Center, Zhejiang University, Zhejiang, China.

Abstract

Introduction: Objective and accessible markers for Alzheimer's disease (AD) and other dementias are critically needed.

Methods: We identified NMDAR2A, a protein related to synaptic function, as a novel marker of central nervous system (CNS)-derived plasma extracellular vesicles (EVs) and developed a flow cytometry-based technology for detecting such plasma EVs readily. The assay was initially tested in our local cross-sectional study to distinguish AD patients from healthy controls (HCs) or from Parkinson's disease (PD) patients, followed by a validation study using an independent cohort collected from multiple medical centers (the Alzheimer's Disease Neuroimaging Initiative). Cerebrospinal fluid AD molecular signature was used to confirm diagnoses of all AD participants.

Results: Likely CNS-derived EVs in plasma were significantly reduced in AD compared to HCs in both cohorts. Integrative models including CNS-derived EV markers and AD markers present on EVs reached area under the curve of 0.915 in discovery cohort and 0.810 in validation cohort.

Discussion: This study demonstrated that robust and rapid analysis of individual neuron-derived synaptic function-related EVs in peripheral blood may serve as a helpful marker of synaptic dysfunction in AD and dementia.

Keywords: Alzheimer's disease; biomarker; blood based; extracellular vesicles; flow cytometry; neuron specific biomarker.

Abstract

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