Abstract
To investigate alterations in glymphatic system function and cerebral blood flow (CBF) in individuals with acute mountain sickness (AMS), and to determine the relationship between these imaging findings and clinical symptom severity using diffusion tensor imaging along the perivascular space (DTI-ALPS) and three-dimensional arterial spin labeling (3D-ASL).Forty-one participants who rapidly ascended to high altitude were prospectively enrolled and divided into an AMS group (n = 21) and a non-AMS group (n = 20). All underwent DTI and 3D-ASL MRI sequences. The ALPS index and CBF values were measured, compared between groups, and correlated with Lake Louise AMS Scores (LLS). No significant difference was found in the ALPS index between the AMS and non-AMS groups (P > 0.05). However, the mean ALPS index showed a significant negative correlation with LLS (r = − 0.523, P < 0.001). In contrast, CBF was significantly higher in the cerebral cortex and white matter of the AMS group compared to the non-AMS group (P < 0.05). A weak but significant positive correlation was found between CBF in the corpus callosum and LLS (r = 0.322, P = 0.046). While glymphatic function, as measured by the ALPS index, correlates with AMS severity, it does not significantly differ between AMS and non-AMS groups. Elevated CBF in white matter and cerebral cortex, particularly in the corpus callosum, may serve as a potential imaging biomarker of AMS, underscoring the value of 3D-ASL for non-invasive assessment of cerebral perfusion changes in high-altitude conditions.
Data availability
Data is provided within the manuscript.
References
Hackett, P. H. & Roach, R. C. High-altitude illness. N Engl. J. Med. 345, 107–114 (2001).
Roach, R. C. et al. The 2018 lake Louise acute mountain sickness score. High. Alt Med. Biol. 19, 4–6 (2018).
Luks, A. M. & Hackett, P. H. Medical conditions and High-Altitude travel. N Engl. J. Med. 386, 364–373 (2022).
Berger, M. M., Sareban, M. & Bärtsch, P. Acute mountain sickness: do different time courses point to different pathophysiological mechanisms? J. Appl. Physiol. 128, 952–959 (2020).
Storz, J. F., Scott, G. R. & Life Ascending Mechanism and process in physiological adaptation to High-Altitude hypoxia. Annu. Rev. Ecol. Evol. Syst. 50, 503–526 (2019).
Zhang, X. & Zhang, J. The human brain in a high altitude natural environment: A review. Front. Hum. Neurosci. 16, 915995 (2022).
Dhar, P. et al. Differential responses of autonomic function in sea level residents, acclimatized lowlanders at > 3500 m and Himalayan high altitude natives at > 3500 m: A cross-sectional study. Respir Physiol. Neurobiol. 254, 40–48 (2018).
Sander Mikael. Does the sympathetic nervous system adapt to chronic altitude exposure? Adv. Exp. Med. Biol. 903, 375–393 (2016).
Wilson, M. H. & Monro-Kellie 2.0: the dynamic vascular and venous pathophysiological components of intracranial pressure. J. Cereb. Blood Flow. Metab. 36, 1338–1350 (2016).
Wei, W., Wang, X., Gong, Q., Fan, M. & Zhang, J. Cortical thickness of native Tibetans in the Qinghai-Tibetan plateau. Am. J. Neuroradiol. 38, 553–560 (2017).
Iliff, J. J., Wang, M., Liao, Y. & Plogg, B. A. Weiguo Peng. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial Solutes, including amyloid beta. Sci. Transl Med. 4, 110–120 (2012).
Taoka et al. 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. Jpn J. Radiol. 35, 172–178 (2017).
Mestre Humberto, K. & Serhii, Mehta Rupal, I. Nedergaard Maiken. Perivascular spaces, glymphatic dysfunction, and small vessel disease. Clin. Sci. Lond. Engl. 1979. 131, 2257–2274 (2017).
Steward Christopher, E. et al. Assessment of the DTI-ALPS parameter along the perivascular space in older adults at risk of dementia. J. Neuroimaging. 31, 569–578 (2021).
Huili et al. Decreased AQP4 expression aggravates ɑ-Synuclein pathology in parkinson’s disease Mice, possibly via impaired glymphatic clearance. J. Mol. Neurosci. 71, 1–14 (2021).
Lee, D. A. et al. Glymphatic system dysfunction in Temporal lobe epilepsy patients with hippocampal sclerosis. Epilepsia Open. 7, 306–314 (2022).
Bae Yun et al. Altered glymphatic system in idiopathic normal pressure hydrocephalus. Parkinsonism Relat. Disord. 82, 56–60 (2021).
Lawley, J. S. et al. Cerebral spinal fluid dynamics: effect of hypoxia and implications for high-altitude illness. J. Appl. Physiol. 120, 251–262 (2016).
Wu Bing, L. & Xin, W. X. Ma Lin. Intra- and interscanner reliability and reproducibility of 3D whole-brain pseudo-continuous arterial spin-labeling MR perfusion at 3T. J. Magn. Reson. Imaging JMRI. 39, 402–409 (2014).
Parkes Laura, M., Rashid Waqar, Chard Declan, T. & Tofts Paul, S. Normal cerebral perfusion measurements using arterial spin labeling: reproducibility, stability, and age and gender effects. Magn. Reson. Med. 51, 736–743 (2004).
Alsop, D. C. et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn Reson. Med 73, (2015).
Kellner, E., Dhital, B., Kiselev, V. G. & Reisert, M. Gibbs-ringing artifact removal based on local subvoxel‐shifts. Magn. Reson. Med. 76, 1574–1581 (2016).
Long, C. & Bao, H. Study of high-altitude cerebral edema using multimodal imaging. Front. Neurol. 13, 1041280 (2023).
Li, X. et al. Early detection of high-altitude hypoxic brain injury by in vivo electrochemistry. Angew Chem. Int. Ed. 64, e202416395 (2025).
Chi et al. Mechanism of Aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life Sci. 193, 270–281 (2018).
Fei et al. Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses. J. Neuroinflammation. 15, 1–13 (2018).
Turner Rachel, E. F. & Hannes, G. Falla Marika & Lawley Justin Stevan. High altitude cerebral edema - its own entity or end-stage acute mountain sickness? J Appl. Physiol. Bethesda Md 1985 131, (2021).
Kai et al. Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness. J. Cereb. Blood Flow. Metab. 27, 1064–1071 (2007).
Shi et al. Expression profile of cytokines and chemokines in a mouse high-altitude cerebral edema model. Int. J. Immunopathol. Pharmacol. 37, 3946320231177189–3946320231177189 (2023).
Pham et al. Inflammatory gene expression during acute high-altitude exposure. J. Physiol. 600, 4169–4186 (2022).
Yuyang, P., Huachun, Y. & Li, S. Yang Hui. Transcriptome of pituitary function changes in rat model of high altitude cerebral edema. Genomics 114, 110519–110519 (2022).
Wang et al. NRF1-mediated microglial activation triggers high-altitude cerebral edema. J Mol. Cell. Biol 14, (2022).
Simka & Marian Latacz Paweł & Czaja Joanna. Possible role of glymphatic system of the brain in the pathogenesis of High-Altitude cerebral edema. High. Alt Med. Biol. 19, 394–397 (2018).
Chen, H. L. et al. Associations among Cognitive Functions, Plasma DNA, and Diffusion Tensor Image along the Perivascular Space (DTI-ALPS) in Patients with Parkinson’s Disease. Oxid. Med. Cell. Longev. 4034509 (2021). (2021).
Hajime et al. Diagnostic Performance of Glymphatic System Evaluation Using Diffusion Tensor Imaging in Idiopathic Normal Pressure Hydrocephalus and Mimickers. Curr. Gerontol. Geriatr. Res. 5675014 (2019). (2019).
Carotenuto et al. Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability. Brain J. Neurol 145, (2021).
Mahdi, H. O. M., Rune, E., Hans-Arne, H. & Nagelhus Erlend, A. Eide per Kristian. Loss of perivascular aquaporin-4 in idiopathic normal pressure hydrocephalus. Glia 67, 91–100 (2019).
Iliff Jeffrey, J. et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J. Neurosci. Off J. Soc. Neurosci. 33, 18190–18199 (2013).
Lawley Justin, S. et al. Cerebral spinal fluid dynamics: effect of hypoxia and implications for high-altitude illness. J. Appl. Physiol. Bethesda Md. 1985 120, 251–262 (2016).
Jafarian Sirous, G. & Farzam, T. A. Lotfi Jamshid. High-altitude sleep disturbance: results of the Groningen sleep quality questionnaire survey. Sleep. Med. 9, 446–449 (2008).
Lee, H. J. & Ah, L. D. Shin Kyong Jin & park Kang Min. Glymphatic system dysfunction in obstructive sleep apnea evidenced by DTI-ALPS. Sleep. Med. 89, 176–181 (2022).
Meghna, P., Mansukhani, B. P. & Kolla Bhanu Prakash Kolla & virend K. Somers. Hypertension and cognitive decline: implications of obstructive sleep apnea. Front. Cardiovasc. Med. 6, 96 (2019).
Baumgartner, R. W., Bärtsch, P., Maggiorini, M., Waber, U. & Oelz, O. Enhanced cerebral blood flow in acute mountain sickness. Aviat. Space Environ. Med. 65, 726–729 (1994).
Smith Zachary, M. et al. Sustained high-altitude hypoxia increases cerebral oxygen metabolism. J. Appl. Physiol. Bethesda Md. 1985 114, 11–18 (2013).
Liu et al. A longitudinal study of cerebral blood flow under hypoxia at high altitude using 3D pseudo-continuous arterial spin labeling. Sci. Rep. 7, 43246 (2017).
Ochsner, K. N., Silvers, J. A. & Buhle, J. T. Functional imaging studies of emotion regulation: A synthetic review and evolving model of the cognitive control of emotion. Ann N Y Acad. Sci 1251, (2012).
Sambuco, N. Cognition, emotion, and the default mode network. Brain Cogn. 182, 106229 (2024).
Hackett, P. H., Yarnell, P. R., Weiland, D. A. & Reynard, K. B. Acute and evolving MRI of High-Altitude cerebral edema: Microbleeds, Edema, and pathophysiology. Am J. Neuroradiol. ajnr;ajnr A5897. v1 (2019).
Lei et al. Glymphatic-System function is associated with addiction and relapse in heroin dependents undergoing methadone maintenance treatment. Brain Sci. 13, 1292 (2023).
Janelle & Felix Iorio Morin Christian, d’amour Sabrina & Fortin David. Superior longitudinal fasciculus: A review of the anatomical descriptions with functional correlates. Front. Neurol. 13, 794618–794618 (2022).
Taoka et al. Reproducibility of diffusion tensor image analysis along the perivascular space (DTI-ALPS) for evaluating interstitial fluid diffusivity and glymphatic function: changes in alps index on multiple condition acquisition eXperiment (CHAMONIX) study. Jpn J. Radiol. 40, 1–12 (2021).
Wang, X. et al. Neuroimaging advances regarding subjective cognitive decline in preclinical alzheimer’s disease. Mol. Neurodegener. 15, 55 (2020).
Lin, S. et al. Association of MRI indexes of the perivascular space network and cognitive impairment in patients with obstructive sleep apnea. Radiology 311, e232274 (2024).
Gumeler, E., Aygun, E., Tezer, F. I., Saritas, E. U. & Oguz, K. K. Assessment of glymphatic function in narcolepsy using DTI-ALPS index. Sleep. Med. 101, 522–527 (2023).
Shen, T. et al. Diffusion along perivascular spaces as marker for impairment of glymphatic system in parkinson’s disease. Npj Park Dis. 8, 174 (2022).
Stephen Thielke, C. G., Slatore & William, A. Banks. Association between alzheimer dementia mortality rate and altitude in California counties. JAMA Psychiatry. 72, 1–2 (2015).
Woods, J. G. et al. Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications. Magn. Reson. Med. 92, 469–495 (2024).
Acknowledgements
The authors would like to express their special thanks to all the volunteers who participated in this study. We also sincerely thank Dr. Shao Xin for the valuable support provided before and during data collection.
Funding
This study was supported by the National Clinical Key Specialty Construction Project (Office of Qinghai Provincial Health Commission [2024] No. 90).
Author information
Authors and Affiliations
Contributions
H.B and Y.G conceptualized the study.Y.G, S.W, and Y.H were responsible for the examination, diagnosis of the enrolled participants, and data collection.Y.G, S.W, T.T, and S.H performed the data analysis.H.B, Y.G, Y.T, and X.W played major roles in data curation.H.B obtained funding for the project.Y.G drafted the initial manuscript.All authors contributed to and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Conflicting interests
All other authors report no competing interests.
Ethics approval
This prospective study was approved by the Medical Ethics Committee of the Affiliated Hospital of Qinghai University, and an ethics approval letter was obtained (Ethics approval number: P-SL-2023-483). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All participants were fully informed about the study’s purpose, procedures, and precautions, and voluntarily signed written informed consent. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Guo, Y., Wen, S., Tao, T. et al. Evaluation of cerebral blood flow and glymphatic function in acute mountain sickness by MRI ASL and DTI ALPS. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39900-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41598-026-39900-x
