脑类淋巴系统磁共振成像在帕金森病认知障碍中的最新研究进展
Advances in Magnetic Resonance Imaging of the Glymphatic System in Parkinson’s Disease-Related Cognitive Impairment
摘要: 帕金森病(Parkinson’s disease, PD)是临床常见的神经退行性疾病，认知障碍是其高发且严重影响预后的非运动症状。脑类淋巴系统作为中枢神经系统代谢废物清除的重要通路，其功能异常与PD认知损害的发生发展密切相关。磁共振成像(magnetic resonance imaging, MRI)具有无创、可定量、可重复的优势，已成为活体评估类淋巴系统结构与功能的重要手段。本文围绕PD认知障碍的临床特点、脑类淋巴系统的结构功能及其主要影响因素、类淋巴系统损伤介导PD认知损害的病理机制进行阐述，重点综述对比增强MRI、沿血管周围间隙扩散张量成像分析(diffusion tensor image analysis along the perivascular space, DTI-ALPS)、脉络丛容积、血管周围间隙(perivascular space, PVS)、自由水成像以及全局血氧水平依赖性(global blood oxygen level dependent, gBOLD)信号与脑脊液(cerebrospinal fluid, CSF)耦合系数等影像学标志物在PD认知障碍中的最新研究进展，并对未来研究方向进行展望，旨在为PD认知障碍的早期识别、机制研究与临床评估提供神经影像学参考。
Abstract: Parkinson’s disease (PD) is a common neurodegenerative disorder in clinical practice. Cognitive impairment is a highly prevalent non-motor symptom that severely affects the prognosis of PD. As a critical pathway for metabolic waste clearance in the central nervous system, dysfunction of the brain glymphatic system is closely associated with the pathogenesis and progression of cognitive impairment in PD. Magnetic resonance imaging (MRI), with its advantages of being non-invasive, quantitative, and reproducible, has become an important tool for in vivo evaluation of the structure and function of the glymphatic system. This article reviews the clinical characteristics of cognitive impairment in PD, the structure and function of the brain glymphatic system and its major influencing factors, as well as the pathological mechanisms underlying glymphatic system dysfunction-mediated cognitive decline in PD. It focuses on the recent advances of multiple imaging biomarkers, including contrast-enhanced MRI, diffusion tensor image analysis along the perivascular space (DTI-ALPS), choroid plexus volume, perivascular space (PVS), free water imaging, and global blood oxygen level-dependent (gBOLD)-cerebrospinal fluid (CSF) coupling coefficient, in cognitive impairment in PD. Future research directions are also prospected. This review aims to provide neuroimaging references for the early identification, mechanistic investigation, and clinical evaluation of cognitive impairment in PD.
文章引用：田佳祺, 张维. 脑类淋巴系统磁共振成像在帕金森病认知障碍中的最新研究进展[J]. 临床医学进展, 2026, 16(5): 653-660. https://doi.org/10.12677/acm.2026.1651857

参考文献

[1] 中华医学会神经病学分会帕金森病及运动障碍学组. 中国帕金森病的诊断标准(2016版) [J]. 中华神经科杂志, 2016, 49(4): 268-271.
[2] Postuma, R.B., Berg, D., Stern, M., Poewe, W., Olanow, C.W., Oertel, W., et al. (2015) MDS Clinical Diagnostic Criteria for Parkinson’s Disease. Movement Disorders, 30, 1591-1601. [Google Scholar] [CrossRef] [PubMed]
[3] Abbott, R.D., Ross, G.W., White, L.R., Tanner, C.M., Masaki, K.H., Nelson, J.S., et al. (2005) Excessive Daytime Sleepiness and Subsequent Development of Parkinson Disease. Neurology, 65, 1442-1446. [Google Scholar] [CrossRef] [PubMed]
[4] Aamodt, W.W., Waligorska, T., Shen, J., Tropea, T.F., Siderowf, A., Weintraub, D., et al. (2021) Neurofilament Light Chain as a Biomarker for Cognitive Decline in Parkinson Disease. Movement Disorders, 36, 2945-2950. [Google Scholar] [CrossRef] [PubMed]
[5] Braak, H., Tredici, K.D., Rüb, U., de Vos, R.A.I., Jansen Steur, E.N.H. and Braak, E. (2003) Staging of Brain Pathology Related to Sporadic Parkinson’s Disease. Neurobiology of Aging, 24, 197-211. [Google Scholar] [CrossRef] [PubMed]
[6] Neikrug, A.B., Avanzino, J.A., Liu, L., Maglione, J.E., Natarajan, L., Corey-Bloom, J., et al. (2014) Parkinson’s Disease and REM Sleep Behavior Disorder Result in Increased Non-Motor Symptoms. Sleep Medicine, 15, 959-966. [Google Scholar] [CrossRef] [PubMed]
[7] Iliff, J.J., Wang, M., Liao, Y., Plogg, B.A., Peng, W., Gundersen, G.A., et al. (2012) A Paravascular Pathway Facilitates CSF Flow through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid Β. Science Translational Medicine, 4, 147ra111. [Google Scholar] [CrossRef] [PubMed]
[8] Nedergaard, M. and Goldman, S.A. (2020) Glymphatic Failure as a Final Common Pathway to Dementia. Science, 370, 50-56. [Google Scholar] [CrossRef] [PubMed]
[9] Mestre, H., Mori, Y. and Nedergaard, M. (2020) The Brain’s Glymphatic System: Current Controversies. Trends in Neurosciences, 43, 458-466. [Google Scholar] [CrossRef] [PubMed]
[10] Holth, J.K., Fritschi, S.K., Wang, C., Pedersen, N.P., Cirrito, J.R., Mahan, T.E., et al. (2019) The Sleep-Wake Cycle Regulates Brain Interstitial Fluid Tau in Mice and CSF Tau in Humans. Science, 363, 880-884. [Google Scholar] [CrossRef] [PubMed]
[11] Nagelhus, E.A. and Ottersen, O.P. (2013) Physiological Roles of Aquaporin-4 in Brain. Physiological Reviews, 93, 1543-1562. [Google Scholar] [CrossRef] [PubMed]
[12] Gomolka, R.S., Hablitz, L.M., Mestre, H., Giannetto, M., Du, T., Hauglund, N.L., et al. (2023) Loss of Aquaporin-4 Results in Glymphatic System Dysfunction via Brain-Wide Interstitial Fluid Stagnation. eLife, 12, e82232. [Google Scholar] [CrossRef] [PubMed]
[13] Si, X., Dai, S., Fang, Y., Tang, J., Wang, Z., Li, Y., et al. (2024) Matrix Metalloproteinase-9 Inhibition Prevents Aquaporin-4 Depolarization-Mediated Glymphatic Dysfunction in Parkinson’s Disease. Journal of Advanced Research, 56, 125-136. [Google Scholar] [CrossRef] [PubMed]
[14] van Veluw, S.J., Hou, S.S., Calvo-Rodriguez, M., Arbel-Ornath, M., Snyder, A.C., Frosch, M.P., et al. (2020) Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain. Neuron, 105, 549-561.e5. [Google Scholar] [CrossRef] [PubMed]
[15] Lee, D., Lee, E., Park, S., Lee, J., Lee, M. and Oh, J. (2024) Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction. International Journal of Molecular Sciences, 25, Article 8752. [Google Scholar] [CrossRef] [PubMed]
[16] Shen, T., Yue, Y., Zhao, S., Xie, J., Chen, Y., Tian, J., et al. (2021) The Role of Brain Perivascular Space Burden in Early-Stage Parkinson’s Disease. npj Parkinson’s Disease, 7, Article No. 12. [Google Scholar] [CrossRef] [PubMed]
[17] Xie, L., Kang, H., Xu, Q., Chen, M.J., Liao, Y., Thiyagarajan, M., et al. (2013) Sleep Drives Metabolite Clearance from the Adult Brain. Science, 342, 373-377. [Google Scholar] [CrossRef] [PubMed]
[18] Massey, A., Boag, M., Magnier, A., Bispo, D., Khoo, T. and Pountney, D. (2022) Glymphatic System Dysfunction and Sleep Disturbance May Contribute to the Pathogenesis and Progression of Parkinson’s Disease. International Journal of Molecular Sciences, 23, Article 12928. [Google Scholar] [CrossRef] [PubMed]
[19] Saito, Y., Hayakawa, Y., Kamagata, K., Kikuta, J., Mita, T., Andica, C., et al. (2023) Glymphatic System Impairment in Sleep Disruption: Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS). Japanese Journal of Radiology, 41, 1335-1343. [Google Scholar] [CrossRef] [PubMed]
[20] Lopes, D.M., Llewellyn, S.K. and Harrison, I.F. (2022) Propagation of Tau and α-Synuclein in the Brain: Therapeutic Potential of the Glymphatic System. Translational Neurodegeneration, 11, Article No. 19. [Google Scholar] [CrossRef] [PubMed]
[21] Szlufik, S., Kopeć, K., Szleszkowski, S. and Koziorowski, D. (2024) Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration. Cells, 13, Article 286. [Google Scholar] [CrossRef] [PubMed]
[22] Zhao, Y., Xu, C., Chen, Y., Gong, T., Zhuo, M., Zhao, C., et al. (2025) Glymphatic Dysfunction Exacerbates Cognitive Decline by Triggering Cortical Degeneration in Parkinson’s Disease: Evidence from Diffusion-Tensor MRI. Brain Communications, 7, fcaf029. [Google Scholar] [CrossRef] [PubMed]
[23] Khan, A.U., Akram, M., Daniyal, M. and Zainab, R. (2018) Awareness and Current Knowledge of Parkinson’s Disease: A Neurodegenerative Disorder. International Journal of Neuroscience, 129, 55-93. [Google Scholar] [CrossRef] [PubMed]
[24] Ringstad, G., Vatnehol, S.A.S. and Eide, P.K. (2017) Glymphatic MRI in Idiopathic Normal Pressure Hydrocephalus. Brain, 140, 2691-2705. [Google Scholar] [CrossRef] [PubMed]
[25] Zhang, M., Tang, J., Xia, D., Xue, Y., Ren, X., Huang, Q., et al. (2023) Evaluation of Glymphatic-Meningeal Lymphatic System with Intravenous Gadolinium-Based Contrast-Enhancement in Cerebral Small-Vessel Disease. European Radiology, 33, 6096-6106. [Google Scholar] [CrossRef] [PubMed]
[26] Ding, X., Wang, X., Xia, D., Liu, H., Tian, H., Fu, Y., et al. (2021) Impaired Meningeal Lymphatic Drainage in Patients with Idiopathic Parkinson’s Disease. Nature Medicine, 27, 411-418. [Google Scholar] [CrossRef] [PubMed]
[27] He, P., Shi, L., Li, Y., Duan, Q., Qiu, Y., Feng, S., et al. (2023) The Association of the Glymphatic Function with Parkinson’s Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross‐Sectional Studies. Annals of Neurology, 94, 672-683. [Google Scholar] [CrossRef] [PubMed]
[28] Taoka, T., Masutani, Y., Kawai, H., Nakane, T., Matsuoka, K., Yasuno, F., et al. (2017) Evaluation of Glymphatic System Activity with the Diffusion MR Technique: Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) in Alzheimer’s Disease Cases. Japanese Journal of Radiology, 35, 172-178. [Google Scholar] [CrossRef] [PubMed]
[29] Taoka, T., Ito, R., Nakamichi, R., Nakane, T., Kawai, H. and Naganawa, S. (2024) Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS): Revisiting the Meaning and Significance of the Method. Magnetic Resonance in Medical Sciences, 23, 268-290. [Google Scholar] [CrossRef] [PubMed]
[30] Liu, X., Barisano, G., Shao, X., et al. (2024) Cross-Vendor Test-Retest Validation of Diffusion Tensor Image Analysis along the Peri-Vascular Space (DTI-ALPS) for Evaluating Glymphatic System Function. Aging and Disease, 15, 1885-1898.
[31] Wood, K.H., Nenert, R., Miften, A.M., Kent, G.W., Sleyster, M., Memon, R.A., et al. (2024) Diffusion Tensor Imaging‐along the Perivascular‐Space Index Is Associated with Disease Progression in Parkinson’s Disease. Movement Disorders, 39, 1504-1513. [Google Scholar] [CrossRef] [PubMed]
[32] Mao, C.J., Yang, Y.P., Chen, J.P., Wang, F., Chen, J., Zhang, J.R. et al. (2018) Poor Nighttime Sleep Is Positively Associated with Dyskinesia in Parkinson's Disease Patients. Parkinsonism & Related Disorders, 48, 68-73. [Google Scholar] [CrossRef] [PubMed]
[33] Tian, Y., Cai, X., Zhou, Y., Jin, A., Wang, S., Yang, Y., et al. (2023) Impaired Glymphatic System as Evidenced by Low Diffusivity along Perivascular Spaces Is Associated with Cerebral Small Vessel Disease: A Population-Based Study. Stroke and Vascular Neurology, 8, e002191. [Google Scholar] [CrossRef] [PubMed]
[34] Bae, Y.J., Kim, J., Choi, B.S., Choi, J., Ryoo, N., Song, Y.S., et al. (2023) Glymphatic Function Assessment in Parkinson’s Disease Using Diffusion Tensor Image Analysis along the Perivascular Space. Parkinsonism & Related Disorders, 114, Article ID: 105767. [Google Scholar] [CrossRef] [PubMed]
[35] Lun, M.P., Monuki, E.S. and Lehtinen, M.K. (2015) Development and Functions of the Choroid Plexus-Cerebrospinal Fluid System. Nature Reviews Neuroscience, 16, 445-457. [Google Scholar] [CrossRef] [PubMed]
[36] Kolahi, S., Zarei, D., Issaiy, M., Shakiba, M., Azizi, N. and Firouznia, K. (2024) Choroid Plexus Volume Changes in Multiple Sclerosis: Insights from a Systematic Review and Meta-Analysis of Magnetic Resonance Imaging Studies. Neuroradiology, 66, 1869-1886. [Google Scholar] [CrossRef] [PubMed]
[37] Wang, Z., Song, Z., Zhou, C., Fang, Y., Gu, L., Yang, W., et al. (2023) Reduced Coupling of Global Brain Function and Cerebrospinal Fluid Dynamics in Parkinson’s Disease. Journal of Cerebral Blood Flow & Metabolism, 43, 1328-1339. [Google Scholar] [CrossRef] [PubMed]
[38] Li, Y., Zhou, Y., Zhong, W., Zhu, X., Chen, Y., Zhang, K., et al. (2023) Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment. Annals of Neurology, 94, 182-195. [Google Scholar] [CrossRef] [PubMed]
[39] Tu, Y., Li, Z., Xiong, F. and Gao, F. (2023) Decreased DTI-ALPS and Choroid Plexus Enlargement in Fibromyalgia: A Preliminary Multimodal MRI Study. Neuroradiology, 65, 1749-1755. [Google Scholar] [CrossRef] [PubMed]
[40] Wardlaw, J.M., Benveniste, H., Nedergaard, M., Zlokovic, B.V., Mestre, H., Lee, H., et al. (2020) Perivascular Spaces in the Brain: Anatomy, Physiology and Pathology. Nature Reviews Neurology, 16, 137-153. [Google Scholar] [CrossRef] [PubMed]
[41] Barisano, G., Lynch, K.M., Sibilia, F., Lan, H., Shih, N., Sepehrband, F., et al. (2022) Imaging Perivascular Space Structure and Function Using Brain MRI. NeuroImage, 257, Article ID: 119329. [Google Scholar] [CrossRef] [PubMed]
[42] Donahue, E.K., Murdos, A., Jakowec, M.W., Sheikh‐Bahaei, N., Toga, A.W., Petzinger, G.M., et al. (2021) Global and Regional Changes in Perivascular Space in Idiopathic and Familial Parkinson’s Disease. Movement Disorders, 36, 1126-1136. [Google Scholar] [CrossRef] [PubMed]
[43] Park, Y.W., Shin, N., Chung, S.J., Kim, J., Lim, S.M., Lee, P.H., et al. (2019) Magnetic Resonance Imaging-Visible Perivascular Spaces in Basal Ganglia Predict Cognitive Decline in Parkinson’s Disease. Movement Disorders, 34, 1672-1679. [Google Scholar] [CrossRef] [PubMed]
[44] Foreman, R.P., Donahue, E.K., Duran, J.J., Schiehser, D.M., Petkus, A., O’Neill, J., et al. (2024) High Baseline Perivascular Space Volume in Basal Ganglia Is Associated with Attention and Executive Function Decline in Parkinson’s Disease. Brain and Behavior, 14, e3607. [Google Scholar] [CrossRef] [PubMed]
[45] Chen, H., Wan, H., Zhang, M., Wardlaw, J.M., Feng, T. and Wang, Y. (2022) Perivascular Space in Parkinson’s Disease: Association with CSF Amyloid/tau and Cognitive Decline. Parkinsonism & Related Disorders, 95, 70-76. [Google Scholar] [CrossRef] [PubMed]
[46] Sun, X., Zhao, C., Chen, S., Chang, Y., Han, Y., Li, K., et al. (2024) Free Water MR Imaging of White Matter Microstructural Changes Is a Sensitive Marker of Amyloid Positivity in Alzheimer’s Disease. Journal of Magnetic Resonance Imaging, 60, 1458-1469. [Google Scholar] [CrossRef] [PubMed]
[47] 孙璇, 王兵兵, 白岩, 等. 自由水扩散张量成像在神经退行性疾病中的研究进展[J]. 磁共振成像, 2024, 15(12): 171-175.
[48] Liguori, C., De Franco, V., Cerroni, R., Spanetta, M., Mercuri, N.B., Stefani, A., et al. (2021) Sleep Problems Affect Quality of Life in Parkinson’s Disease along Disease Progression. Sleep Medicine, 81, 307-311. [Google Scholar] [CrossRef] [PubMed]
[49] Lin, S., Lin, X., Chen, S., Liang, Q., Li, Y., Wei, F., et al. (2024) Association of MRI Indexes of the Perivascular Space Network and Cognitive Impairment in Patients with Obstructive Sleep Apnea. Radiology, 311, Article ID: 232274. [Google Scholar] [CrossRef] [PubMed]
[50] Wang, X., Huang, P., Haacke, E.M., Wu, P., Zhang, X., Zhang, H., et al. (2024) MRI Index of Glymphatic System Mediates the Influence of Locus Coeruleus on Cognition in Parkinson’s Disease. Parkinsonism & Related Disorders, 123, Article ID: 106558. [Google Scholar] [CrossRef] [PubMed]
[51] Han, F., Brown, G.L., Zhu, Y., Belkin‐Rosen, A.E., Lewis, M.M., Du, G., et al. (2021) Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson’s Disease Cognitive Decline. Movement Disorders, 36, 2066-2076. [Google Scholar] [CrossRef] [PubMed]
[52] Zhang, Y., Zhang, C., He, X., Li, Z., Meng, J., Mao, R., et al. (2023) Interaction between the Glymphatic System and Α-Synuclein in Parkinson’s Disease. Molecular Neurobiology, 60, 2209-2222. [Google Scholar] [CrossRef] [PubMed]
[53] Zeng, X., Hua, L., Ma, G., Zhao, Z. and Yuan, Z. (2024) Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia. NeuroImage, 303, Article ID: 120924. [Google Scholar] [CrossRef] [PubMed]
[54] Feng, S., Wu, C., Zou, P., Deng, Q., Chen, Z., Li, M., et al. (2023) High-Intensity Interval Training Ameliorates Alzheimer’s Disease-Like Pathology by Regulating Astrocyte Phenotype-Associated AQP4 Polarization. Theranostics, 13, 3434-3450. [Google Scholar] [CrossRef] [PubMed]
[55] Hablitz, L.M., Vinitsky, H.S., Sun, Q., Stæger, F.F., Sigurdsson, B., Mortensen, K.N., et al. (2019) Increased Glymphatic Influx Is Correlated with High EEG Delta Power and Low Heart Rate in Mice under Anesthesia. Science Advances, 5, eaav5447. [Google Scholar] [CrossRef] [PubMed]
[56] Chen, B., Meseguer, D., Lenck, S., Thomas, J. and Schneeberger, M. (2025) Rewiring of the Glymphatic Landscape in Metabolic Disorders. Trends in Endocrinology & Metabolism, 36, 710-720. [Google Scholar] [CrossRef] [PubMed]
[57] Salman, M.M., Kitchen, P., Yool, A.J. and Bill, R.M. (2022) Recent Breakthroughs and Future Directions in Drugging Aquaporins. Trends in Pharmacological Sciences, 43, 30-42. [Google Scholar] [CrossRef] [PubMed]
[58] Alghanimy, A., Martin, C., Gallagher, L. and Holmes, W.M. (2023) The Effect of a Novel AQP4 Facilitator, TGN-073, on Glymphatic Transport Captured by Diffusion MRI and DCE-MRI. PLOS ONE, 18, e0282955. [Google Scholar] [CrossRef] [PubMed]
[59] Huang, H., Lin, L., Wu, T., Wu, C., Zhou, L., Li, G., et al. (2024) Phosphorylation of AQP4 by LRRK2 R1441G Impairs Glymphatic Clearance of IFNγ and Aggravates Dopaminergic Neurodegeneration. npj Parkinson’s Disease, 10, Article No. 31. [Google Scholar] [CrossRef] [PubMed]
[60] Salehpour, F., Khademi, M., Bragin, D.E. and DiDuro, J.O. (2022) Photobiomodulation Therapy and the Glymphatic System: Promising Applications for Augmenting the Brain Lymphatic Drainage System. International Journal of Molecular Sciences, 23, Article 2975. [Google Scholar] [CrossRef] [PubMed]
[61] Verghese, J.P., Terry, A., de Natale, E.R. and Politis, M. (2022) Research Evidence of the Role of the Glymphatic System and Its Potential Pharmacological Modulation in Neurodegenerative Diseases. Journal of Clinical Medicine, 11, Article 6964. [Google Scholar] [CrossRef] [PubMed]
[62] Gao, Y., Liu, K. and Zhu, J. (2023) Glymphatic System: An Emerging Therapeutic Approach for Neurological Disorders. Frontiers in Molecular Neuroscience, 16, Article 1138769. [Google Scholar] [CrossRef] [PubMed]
[63] Pang, H., Wang, J., Yu, Z., Yu, H., Li, X., Bu, S., et al. (2024) Glymphatic Function from Diffusion-Tensor MRI to Predict Conversion from Mild Cognitive Impairment to Dementia in Parkinson’s Disease. Journal of Neurology, 271, 5598-5609. [Google Scholar] [CrossRef] [PubMed]
[64] Deike, K., Decker, A., Scheyhing, P., Harten, J., Zimmermann, N., Paech, D., et al. (2024) Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease. Investigative Radiology, 59, 667-676. [Google Scholar] [CrossRef] [PubMed]

为你推荐