Abstract
This study explored free-water diffusion tensor imaging (FW-DTI) in the basal ganglia as a biomarker for mild cognitive impairment (MCI) in Parkinson’s disease (PD). One hundred and fourteen drug-naïve PD patients (without MCI at baseline) and 102 healthy controls (HC) from Parkinson’s Progression Markers Initiative (PPMI) were included, and FW-DTI metrics were extracted from the bilateral putamen, caudate, external globus pallidus (GPe), and internal globus pallidus (GPi). The result showed that PD-MCI convertors had significantly higher FW in GPe and GPi. Cox regression identified that GPe FW, MDS-UPDRS Part I score, and CSF Aβ42/pTau were significantly associated with MCI conversion in PD during 5-year follow-up. GPe FW > 0.328 predicted a 4.698-fold increased MCI risk (95% CI: 1.974–11.179) in PD in 5 years, after adjusting for CSF Aβ42/pTau value and MDS-UPDRS part I score. Furthermore, higher GPe FW correlated with executive dysfunction (symbol digit modalities: R = -0.272, P = 0.004; letter number sequencing: R = -0.199, P = 0.035) and elevated serum neurofilament light chain (R = 0.322, P < 0.001) in PD, but not HC. In conclusion, GPe FW may serve as a sensitive imaging biomarker reflecting neuronal injury and MCI conversion risk in PD.
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Data availability
PPMI data was publicly available on PPMI website (https://www.ppmi-info.org/).
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Acknowledgements
Wen Su and Huimin Chen are funded by National High-Level Hospital Clinical Research Funding (BJ-2023-067, BJ-2024-183). PPMI—a public–private partnership—is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including 4D Pharma, Abbvie, AcureX, Allergan, Amathus Therapeutics, Aligning Science Across Parkinson's, AskBio, Avid Radiopharmaceuticals, BIAL, BioArctic, Biogen, Biohaven, BioLegend, BlueRock Therapeutics, Bristol-Myers Squibb, Calico Labs, Capsida Biotherapeutics, Celgene, Cerevel Therapeutics, Coave Therapeutics, DaCapo Brainscience, Denali, Edmond J. Safra Foundation, Eli Lilly, Gain Therapeutics, GE HealthCare, Genentech, GSK, Golub Capital, Handl Therapeutics, Insitro, Jazz Pharmaceuticals, Johnson & Johnson Innovative Medicine, Lundbeck, Merck, Meso Scale Discovery, Mission Therapeutics, Neurocrine Biosciences, Neuron23, Neuropore, Pfizer, Piramal, Prevail Therapeutics, Roche, Sanofi, Servier, Sun Pharma Advanced Research Company, Takeda, Teva, UCB, Vanqua Bio, Verily, Voyager Therapeutics, the Weston Family Foundation and Yumanity Therapeutics. The authors wish to acknowledge the helpful input and advice from Professors Tao Wu (Beijing Tiantan Hospital).
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Study concept and design: W.S., Hb.C., and Hm.C. Data analysis and interpretation: Hm.C. Drafting of the manuscript: Hm.C. Critical revision of the manuscript for important intellectual content: all authors. Study supervision: W.S. and Hb.C. W.S. is the senior author and took responsibility for the integrity of the data and the accuracy of the data analysis.
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Chen, H., Liu, H., Kou, W. et al. Free water in the external globus pallidus predicts mild cognitive impairment in Parkinson’s disease and is associated with serum neurofilament light chain levels. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01291-1
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DOI: https://doi.org/10.1038/s41531-026-01291-1
