Cognitive impairment is a prevalent issue among aging populations and represents a significant concern for patients with Parkinson's disease (PD). While complete neuropsychological assessments (NPA) are considered the gold standard for diagnosis, 1 they are hindered by their labor‐intensive and time‐consuming procedures. In this study, we profiled plasma extracellular vesicle (EV) proteins to identify novel biomarkers robust for detecting cognitive decline in PD patients. We included 21 healthy controls (HC), 21 PD patients with normal cognition (PDNC; Mini‐Mental State Examination [MMSE] >26), 7 PD patients with mild cognitive impairment (PD‐MCI; MMSE 25–26 or Clinical Dementia Rating (CDR) = 0.5), and 20 PD dementia patients (PDD; MMSE <25 or CDR ≥1) 2 (Table S1).
In the discovery phase, we divided the subjects based on cognitive function, including HC, PDNC, PD‐MCI, and PDD. EV‐TAOK1 (Fig. 1A) is one of the leading biomarker candidates linked to cognitive impairment, showing significant elevation in patients with cognitive impairment (PD‐MCI and PDD; Fig. 1B). Additionally, levels of EV‐TAOK1 demonstrated a correlation with the MMSE score (Fig. 1C). The comprehensive NPA across various domains revealed that higher EV‐TAOK1 levels were associated with deficits in memory, execution, and attention (Table S2). TAOK1 kinase activity has been linked to pathological tau phosphorylation, 3 potentially leading to cognitive decline in Alzheimer's disease (AD). Therefore, we further evaluated plasma EV‐TAOK1 in a separate cohort (Table S3) and observed significantly higher levels of EV‐TAOK1 in 9 MCI and 5 AD patients compared with 22 HC individuals (Fig. 1D). 4 This indicates that EV‐TAOK1 may serve as a biomarker for cognitive impairment related to PD or AD.
FIG. 1.
Plasma EV‐TAOK1 as a potential biomarker for cognitive impairment. (A) Differential plasma extracellular vesicle (EV) protein levels between non‐cognitive impairment (healthy controls [HC] and Parkinson's disease with normal cognition [PDNC]) and cognitive impairment groups (PD with mild cognitive impairment [PD‐MCI] and PD dementia [PDD]) by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). (B) TAOK1 levels across disease groups. (C) Pearson correlation of TAOK1 levels with Mini‐Mental State Examination (MMSE) scores. (D) TAOK1 levels in HC, MCI, and Alzheimer's disease (AD). (E) Enzyme‐linked immunosorbent assay (ELISA) validation of TAOK1 concentration in HC, PDNC, PDD, and AD. (F) Area under the curve (AUC) for TAOK1 predicting cognitive impairment in the combined groups of PDD and AD versus HC and PDNC. *P < 0.05, **P < 0.01, ***P < 0.001. [Color figure can be viewed at wileyonlinelibrary.com]
To validate the abovementioned findings, we recruited an independent cohort of 32 HC, 16 PDNC, 16 PDD, and 16 AD patients (Table S4). We enriched CD9‐positive EVs from plasma and quantified EV‐TAOK1 by enzyme‐linked immunosorbent assay (ELISA). The results indicated that EV‐TAOK1 levels were significantly higher in PDD and AD compared with HC and PDNC patients (Fig. 1E). We utilized receiver operating curve (ROC) analysis to evaluate TAOK1 as a biomarker for cognitive impairment in PD and AD. Based on the cognitive function, using EV‐TAOK1 concentrations from ELISA, we allocated 80% of the data for training and 20% for testing with five‐fold cross‐validation in a reduced logistic regression model. The model indicated that TAOK1 levels predict cognitive impairment with an average area under the curve (AUC) of 0.889 (95% CI 0.667–1.000) (Fig. 1F). This highlights the significance of EV‐TAOK1 in differentiating cognitive impairment in neurocognitive conditions.
Hyperphosphorylation of tau is particularly noteworthy since TAOK1 is found with tau‐neurofibrillary tangles in the brains of AD patients. 3 , 5 TAOK1 would influence the interaction between tau and microtubules through phosphorylation. 3 Tau is crucial for microtubule stabilization and maintains neuronal structure, but abnormal phosphorylation leads to neurofibrillary tangles and contributes to the pathogenesis of neuronal death in AD and some cases of PDD. 6 , 7 Exploring TAOK1's roles in the underlying pathology of tau in AD and PDD could reveal insights into the early diagnosis of cognitive decline and guide therapeutic development.
Author Roles
(1) Research Project: A. Preparation and Design, B. Funding Acquisition; (2) Data: A. Acquisition, B. Analysis, C. Interpretation; (3) Manuscript Preparation: A. Writing of the First Draft, B. Revision for Important Intellectual Content; C. Final Editing.
P.‐J.K.: 1A, 1B, 2A, 2B, 2C, 3A, 3C.
Y.‐T.T.: 1A, 1B, 2A, 2B, 2C, 3A, 3C.
R.‐L. Y.: 2B, 2C, 3C.
H.‐H.L.‐W.: 2A, 2B, 3C.
M.‐C.K.: 1A, 2A, 3C.
C.‐C.W.: 1B, 3C.
C.‐T.H.: 1A, 2A, 3C.
K.U.: 2A, 2B, 2C, 3C.
S.‐P.L.: 1A, 1B, 2B, 2C, 3B, 3C.
R.‐M.W.: 1A, 1B, 2A, 2B, 2C, 3B, 3C.
Supporting information
Data S1. Supporting Information.
Table S1.
Table S2.
Table S3.
Table S4.
Figure S1.
Acknowledgments
The authors extend their sincere gratitude to the members of the Center for Parkinson and Movement Disorders at National Taiwan University Hospital for their valuable assistance in conducting cognitive assessment and collecting samples. Special thanks are also extended to Fu‐Ti Peng for her contributions to clinical data collection, and special appreciation to Teh‐Cheng Wang and Ya‐Fang Hsu for their exceptional support. Furthermore, the authors would like to express their appreciation to all participants who contributed to the success of this project.
Relevant conflicts of interest/financial disclosures: A USPTO provisional patent (63/455 953) applied on March 30, 2023 and a USPTO official patent (18/622 407) applied on March 29, 2024.
Funding agency: This work has been funded by the Ministry of Science and Technology, Taiwan, through grants MOST 109‐2314‐B‐002‐120‐MY3, 112‐2314‐B‐002‐163‐, 109‐2311‐B‐002‐024‐, 110‐2311‐B‐002‐032‐, and 111‐2311‐B‐002‐001‐ (from the National Science and Technology Council, Taiwan, to R.‐M.W. and S.‐P.L.). Additional support has been provided by grant 111‐UN0007 from the National Taiwan University Hospital to R.‐M.W. and S.‐P.L., as well as internal grants NTU‐108 L880304, NTU‐107 L880305, and NTU‐AS‐112 L104306 from the National Taiwan University to S.‐P.L. and R.‐M.W. This study was also supported by grant MS329 from the Center for Parkinson and Movement Disorders at National Taiwan University Hospital.
Contributor Information
Shau‐Ping Lin, Email: shaupinglin@ntu.edu.tw.
Ruey‐Meei Wu, Email: robinwu@ntu.edu.tw.
Data Availability Statement
The raw and processed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) data used in this study are available with accession number JPST003026 in the jPOST repository (https://repository.jpostdb.org/). For additional information contact the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1. Supporting Information.
Table S1.
Table S2.
Table S3.
Table S4.
Figure S1.
Data Availability Statement
The raw and processed liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) data used in this study are available with accession number JPST003026 in the jPOST repository (https://repository.jpostdb.org/). For additional information contact the corresponding author.