Year: 2024
Type: preprint
Study design: Observational Study
Abstract: α-Synuclein (α-syn) strains can serve as discriminators between Parkinson’s disease (PD) and related α-synucleinopathies. The relationship between α-syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of α-syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct α-syn strains in PD patients correlating to their level of cognitive impairment. Machine learning (ML) was employed to achieve high classification accuracy. The combination of thioflavin T (ThT) maximal fluorescence intensity (mfi), max slope of rise curve (forming rate), lag time (t lag ), 20% time (t 20 ), and half-time (t 50 ), dynamic light scattering (DLS) (peak number, ½ peak size, ½ peak intensity) and neurotoxicity together with demographic variables for model training yielded superior performance (89∼99% accuracy in the 4- and 2- classification schema) compared to individual features alone in classifying cognitive status. For the longitudinal study, DLS peak number emerged as the strongest predictor of cognitive transition (HR = 0.12, P = 0.002), with the optimal predictive model combining DLS peak number, sex, education, DLS peak 1 size, and DLS peak 2 polydispersity achieving high accuracy (C-index of ∼93%). This study presents evidence that individuals with PD have different α-syn strains correlating to their cognitive status and highlights the potential of α-syn strain dynamics to guide future diagnosis, management, and stratification of PD patients. One Sentence Summary Distinct features of α-syn strains change with cognitive decline in Parkinson’s disease and AI-based analysis incorporating these combined characteristics serves as a powerful tool for PD clinical stratification.
Authors: Kundlik Gadhave, Ning Wang, Kyungdo Kim, Enquan Xu, Xiaodi Zhang, Hanyu Li, Jacob Deyell, Jun Yang, Anthony Wang, Youngjae Cha, Ramhari Kumbhar, Haiqing Liu, Lili Niu, Rong Chen, Shu Zhang, Catherine C. Bakker, Lingtao Jin, Yajie Liang, Mingyao Ying, Brenna Cholerton, Vadim Zipunnikov, Nikolay Bliznyuk, Joseph F. Quinn, Kathryn A. Chung, Amie L. Hiller, Kimmy Su, Shu-Ching Hu, Thomas J. Montine, Shizhong Han, Cyrus P. Zabetian, Chan Hyun Na, Valina L. Dawson, Ted M. Dawson, Liana S. Rosenthal, Xiaobo Mao
Institutions: Johns Hopkins University, Johns Hopkins Medicine, The University of Texas at San Antonio Health Science Center, University of Maryland, Baltimore, Kennedy Krieger Institute, VA Puget Sound Health Care System, Stanford Medicine, Stanford University, University of Florida, Oregon Health & Science University, VA Portland Health Care System, University of Washington, Lieber Institute for Brain Development
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Michael J. Fox Foundation for Parkinson's Research, Johns Hopkins University, CurePSP, Parkinson's Foundation, National Institutes of Health, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, Common Fund
Awards: Determine the role of microglial LAG3 in Parkinson's disease, G2024185938, Understanding the Mechanism of Pathological alpha-Synuclein Transmission, G3374888835, Shedding light on functional heterogeneity of dementia-related alpha-synuclein strains, Johns Hopkins Medicine Biomarker Discovery in Parkinson's Disease, JHU Center for Neuroscience Research, Biomarkers of Cognitive Decline Among Normal Individuals: The Biocard Cohort, α-Synuclein strain properties are associated with diagnosis of and progression to Parkinson's disease with dementia, Influence of Aging on Pathogenic Alpha-Synuclein Strains and Transmission Mechanism, Chemical Fingerprints of Cognitive Impairment-related alpha-Synuclein Strains using 3D Small Molecule Microarray and Related Therapeutic Application, G5861938336, Determine the role of atmospheric particulate matter pollutants in contributing to Lewy Body Dementia, G6574781593, Johns Hopkins Alzheimer's Disease Research Center, Johns Hopkins Institute for Clinical and Translational Research, G8121226415, G8644530734, G8694191853, G9000061500, G9000073538, G9000121389, G9000130253, G9000284371, Heterochronic Blood Exchange Inhibits α?Synucleinopathy through Modulating Plasma Protein's Mediation on Pathological α?Synuclein Spreading, Mechanism of Pathologic Tau Fibrils Neuron-to-Neuron Transmission and Neuroinflammation in Alzheimer's Disease, Johns Hopkins Alzheimer's Disease Research Center, α-Synuclein strain properties are associated with diagnosis of and progression to Parkinson's disease with dementia, G906873184
OpenAlex ID: W4403735719