Share：
Share this content in WeChat
X
[Chinese] [PDF] 32 1
• Clinical Article •
Elevated free water imaging metrics mediate white matter injury and cognitive decline in elderly patients with hypertension: An MRI study
WANG Mingliang  YANG Mingming  ZHANG Junjie  YU Mengmeng 

Cite this article as: WANG M L, YANG M M, ZHANG J J, et al. Elevated free water imaging metrics mediate white matter injury and cognitive decline in elderly patients with hypertension: An MRI study[J]. Chin J Magn Reson Imaging, 2026, 17(10): 21-27. DOI:10.12015/issn.1674-8034.2026.10.003.


[Abstract] Objective To investigate the correlations between brain glymphatic system functional MRI metrics including diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), free water (FW), and choroid plexus volume with cognitive function and Alzheimer's disease (AD) pathological biomarkers in elderly patients with hypertension, and to analyze the mediating role of glymphatic dysfunction in hypertension-related cognitive impairment.Materials and Methods This study was based on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and included 200 elderly participants (aged 60 to 90 years), comprising 94 hypertensive patients and 106 healthy controls. Hypertension was defined based on medical history and medication records [blood pressure ≥ 140/90 mmHg (1 mmHg = 0.133 kPa) or current use of antihypertensive medications]. All participants underwent 3.0 T MRI scanning, including structural imaging and diffusion tensor imaging. Clinical data, AD pathological biomarkers including β-amyloid (Aβ) and tau protein, as well as cognitive function assessments were collected. FW imaging was employed to calculate the whole-brain white matter free water index. Diffusion-related metrics were derived from diffusion tensor imaging data to calculate the DTI-ALPS index. Choroid plexus volume and white matter hyperintensity volume were obtained via segmentation of high-resolution structural images. Multiple linear regression was used to examine the relationship between hypertension and glymphatic metrics, and a mediation model was constructed to explore the mediating role of FW in the associations between hypertension and cognitive function as well as white matter injury.Results Compared with the control group, the hypertension group showed significantly higher FW fraction (P = 0.002), and hypertension was an independent predictor of elevated FW fraction (β = 0.010, P = 0.019). The hypertension group also exhibited significantly increased white matter hyperintensity volume and decreased executive function scores (P < 0.05). Mediation analysis revealed that FW fraction had a statistically significant mediating effect on the relationship between hypertension and white matter hyperintensities (β = 0.70, 95% CI: 0.22 to 1.68) and also significantly mediated the relationship between hypertension and executive function (β = -0.06, 95% CI: -0.14 to -0.01). However, no significant differences were observed between the two groups in the DTI-ALPS index, choroid plexus volume or AD pathological biomarkers (Aβ/tau).Conclusions FW fraction may serve as a potential imaging marker for cognitive impairment in elderly hypertensive patients, and improving glymphatic function may provide a new direction for intervention in hypertension-related cognitive impairment.
[Keywords] hypertension；vascular cognitive impairment；glymphatic system；free water imaging；diffusion tensor imaging；magnetic resonance imaging；white matter；cognitive function

WANG Mingliang1   YANG Mingming1   ZHANG Junjie1   YU Mengmeng2, 3*  

1 Department of Radiology, Shanghai Sixth People's Hospital, Shanghai 200233, China

2 Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China

3 Shanghai Institute of Medical Imaging, Shanghai 200032, China

Corresponding author: YU M M, E-mail: radiologistmoon@163.com

Conflicts of interest   None.

Received  2026-04-16
Accepted  2026-08-07
DOI: 10.12015/issn.1674-8034.2026.10.003
Cite this article as: WANG M L, YANG M M, ZHANG J J, et al. Elevated free water imaging metrics mediate white matter injury and cognitive decline in elderly patients with hypertension: An MRI study[J]. Chin J Magn Reson Imaging, 2026, 17(10): 21-27. DOI:10.12015/issn.1674-8034.2026.10.003.

[1]
HAINSWORTH A H, MARKUS H S, SCHNEIDER J A. Cerebral Small Vessel Disease, Hypertension, and Vascular Contributions to Cognitive Impairment and Dementia[J]. Hypertension, 2024, 81(1): 75-86. DOI: 10.1161/hypertensionaha.123.19943.
[2]
MULLIGAN M D, MURPHY R, REDDIN C, et al. Population attributable fraction of hypertension for dementia: global, regional, and national estimates for 186 countries[J/OL]. eClinicalMedicine, 2023, 60: 102012 [2026-04-16]. https://dx.doi.org/10.1016/j.eclinm.2023.102012. DOI: 10.1016/j.eclinm.2023.102012.
[3]
GOTTESMAN R F, EGLE M, GROECHEL R C, et al. Blood pressure and the brain: the conundrum of hypertension and dementia[J]. Cardiovasc Res, 2025, 120(18): 2360-2372. DOI: 10.1093/cvr/cvaf010.
[4]
BASTRUP J A, FOLKE J, KAALUND S S, et al. Extracellular exosome signature links hypertension and Alzheimer's disease[J/OL]. Geroscience, 2026 [2026-04-16]. https://dx.doi.org/10.1007/s11357-026-02097-y. DOI: 10.1007/s11357-026-02097-y.
[5]
TRIPATHI S M, SHIELLS H, WAYMONT J, et al. Hypertension is the Main Vascular Risk Factor for Cognitive Impairment, Microvascular Pathology and Brain Atrophy in Alzheimer's Disease[J/OL]. Curr Alzheimer Res, 2026 [2026-04-16]. https://dx.doi.org/10.2174/0115672050399596251106033110. DOI: 10.2174/0115672050399596251106033110.
[6]
JIANG E, ULLAH S, WAHEED I, et al. Hypertension as a Major Risk Factor in Alzheimer's Disease: Mechanisms, Interactions and Therapeutic Perspectives[J]. Clin Interv Aging, 2026, 21: 585-864. DOI: 10.2147/cia.s585864.
[7]
RUTHIRAKUHAN M, SWARDFAGER W, XIONG L, et al. Investigating the impact of hypertension with and without diabetes on Alzheimer's disease risk: A clinico-pathological study[J]. Alzheimers Dement, 2024, 20(4): 2766-2778. DOI: 10.1002/alz.13717.
[8]
WANG Y, WANG D G. Research progress on hypertension and the occurrence and progression of Alzheimer's disease[J]. International Journal of Geriatrics, 2023, 44(6): 730-733. DOI: 10.3969/j.issn.1674-7593.2023.06.020.
[9]
UNGVARI Z, TOTH P, TARANTINI S, et al. Hypertension-induced cognitive impairment: from pathophysiology to public health[J]. Nat Rev Nephrol, 2021, 17(10): 639-654. DOI: 10.1038/s41581-021-00430-6.
[10]
GAO Y, DUAN X, LI W, et al. Elevated Homocysteine Levels and Hypertension Relate to Cognitive Impairment via Increased White Matter Hyperintensity Volume[J]. J Alzheimers Dis, 2023, 96(4): 1739-1746. DOI: 10.3233/jad-230687.
[11]
WEI W, MA D, LI L, et al. Cognitive impairment in cerebral small vessel disease induced by hypertension[J]. Neural Regen Res, 2024, 19(7): 1454-1462. DOI: 10.4103/1673-5374.385841.
[12]
KIM B, KANG Y T, MENDELSON F E, et al. Palmitate and glucose increase amyloid precursor protein in extracellular vesicles: Missing link between metabolic syndrome and Alzheimer's disease[J/OL]. J Extracell Vesicles, 2023, 12(11): e12340 [2026-04-16]. https://dx.doi.org/10.1002/jev2.12340. DOI: 10.1002/jev2.12340.
[13]
CAI W, NEITZEL J, GLODZIK L, et al. Effect Modifiers of the Association of Blood Pressure With Brain Amyloid and tau Pathology[J/OL]. Neurology, 2025, 104(6): e213441 [2026-04-16]. https://dx.doi.org/10.1212/wnl.0000000000213441. DOI: 10.1212/wnl.0000000000213441.
[14]
FATIMA G, ASHIQUZZAMAN A, KIM S S, et al. Vascular and glymphatic dysfunction as drivers of cognitive impairment in Alzheimer's disease: Insights from computational approaches[J/OL]. Neurobiol Dis, 2025, 208: 106877 [2026-04-16]. https://dx.doi.org/10.1016/j.nbd.2025.106877. DOI: 10.1016/j.nbd.2025.106877.
[15]
ILIFF J J, WANG M, LIAO Y, et al. A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β[J/OL]. Sci Transl Med, 2012, 4(147): 147ra111 [2026-04-16]. https://dx.doi.org/10.1126/scitranslmed.3003748. DOI: 10.1126/scitranslmed.3003748.
[16]
MORTENSEN K N, SANGGAARD S, MESTRE H, et al. Impaired Glymphatic Transport in Spontaneously Hypertensive Rats[J]. J Neurosci, 2019, 39(32): 6365-6377. DOI: 10.1523/jneurosci.1974-18.2019.
[17]
KIKUTA J, KAMAGATA K, TAKABAYASHI K, et al. An Investigation of Water Diffusivity Changes along the Perivascular Space in Elderly Subjects with Hypertension[J]. AJNR Am J Neuroradiol, 2022, 43(1): 48-55. DOI: 10.3174/ajnr.A7334.
[18]
TAOKA T, MASUTANI Y, KAWAI H, 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[J]. Jpn J Radiol, 2017, 35(4): 172-178. DOI: 10.1007/s11604-017-0617-z.
[19]
PASTERNAK O, SOCHEN N, GUR Y, et al. Free water elimination and mapping from diffusion MRI[J]. Magn Reson Med, 2009, 62(3): 717-730. DOI: 10.1002/mrm.22055.
[20]
LI Y, ZHOU Y, ZHONG W, et al. Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment[J]. Ann Neurol, 2023, 94(1): 182-195. DOI: 10.1002/ana.26648.
[21]
YU J, LAM A K F, KONG S D, et al. Exploring the combined effect of hypertension and hypoxic burden index on cognition and underlying sex differences[J/OL]. Alzheimers Dement, 2025, 21(Suppl 2): e100148 [2026-04-16]. https://dx.doi.org/10.1002/alz70856_100148. DOI: 10.1002/alz70856_100148.
[22]
KIM J, WOO S Y, KIM S, et al. Differential effects of risk factors on the cognitive trajectory of early- and late-onset Alzheimer's disease[J/OL]. Alzheimers Res Ther, 2021, 13(1): 113 [2026-04-16]. https://dx.doi.org/10.1186/s13195-021-00857-w. DOI: 10.1186/s13195-021-00857-w.
[23]
GEORGE K M, MAILLARD P, GILSANZ P, et al. Association of Early Adulthood Hypertension and Blood Pressure Change With Late-Life Neuroimaging Biomarkers[J/OL]. JAMA Netw Open, 2023, 6(4): e236431 [2026-04-16]. https://dx.doi.org/10.1001/jamanetworkopen.2023.6431. DOI: 10.1001/jamanetworkopen.2023.6431.
[24]
KIM J S, LEE S, SUH S W, et al. Association of Low Blood Pressure with White Matter Hyperintensities in Elderly Individuals with Controlled Hypertension[J]. J Stroke, 2020, 22(1): 99-107. DOI: 10.5853/jos.2019.01844.
[25]
LI Z, SANG F, ZHANG Z, et al. Effect of the duration of hypertension on white matter structure and its link with cognition[J]. J Cereb Blood Flow Metab, 2024, 44(4): 580-594. DOI: 10.1177/0271678x231214073.
[26]
LESPINASSE J, CHÊNE G, MANGIN J F, et al. Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort[J]. Alzheimers Dement, 2023, 19(6): 2332-2342. DOI: 10.1002/alz.12866.
[27]
PETREA R E, PINHEIRO A, DEMISSIE S, et al. Hypertension Trends and White Matter Brain Injury in the Offspring Framingham Heart Study Cohort[J]. Hypertension, 2024, 81(1): 87-95. DOI: 10.1161/hypertensionaha.123.21264.
[28]
KERN K C, ZAGZOUG M S, GOTTESMAN R F, et al. Blood-brain barrier disruption and increased free water are associated with worse cognitive performance in patients with chronic cerebrovascular disease[J/OL]. Neuroimage Clin, 2024, 44: 103706 [2026-04-16]. https://dx.doi.org/10.1016/j.nicl.2024.103706. DOI: 10.1016/j.nicl.2024.103706.
[29]
ZHANG C, SONG C, SHENG S, et al. Reduced DTI-ALPS in H-type hypertension: insights into perivascular space function[J/OL]. Front Neurol, 2025, 16: 1536001 [2026-04-16]. https://dx.doi.org/10.3389/fneur.2025.1536001. DOI: 10.3389/fneur.2025.1536001.
[30]
ZENG B, ZENG P, XIANG Y, et al. Expansion of white matter hyperintensities is associated with the glymphatic system dysfunction in cerebral small vessel disease[J/OL]. Brain Res Bull, 2025, 227: 111391 [2026-04-16]. https://dx.doi.org/ DOI: 10.1016/j.brainresbull.2025.111391.
[31]
LEI X, QIU W, XU Z, et al. Increased extracellular free water is related to white matter hyperintensity burden[J]. Acta Radiol, 2024, 65(10): 1265-1271. DOI: 10.1177/02841851241282085.
[32]
HUANG P, ZHANG R, JIAERKEN Y, et al. White Matter Free Water is a Composite Marker of Cerebral Small Vessel Degeneration[J]. Transl Stroke Res, 2022, 13(1): 56-64. DOI: 10.1007/s12975-021-00899-0.
[33]
PATIENCE J, LAI K S P, RUSSELL E, et al. Relationship Between Mood, Thinking, and Walking: A Systematic Review Examining Depressive Symptoms, Executive Function, and Gait[J]. Am J Geriatr Psychiatry, 2019, 27(12): 1375-1383. DOI: 10.1016/j.jagp.2019.07.007.
[34]
JI F, PASTERNAK O, LIU S, et al. Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer's disease with and without cerebrovascular disease[J/OL]. Alzheimers Res Ther, 2017, 9(1): 63 [2026-04-16]. https://dx.doi.org/10.1186/s13195-017-0292-4. DOI: 10.1186/s13195-017-0292-4.
[35]
GULLETT J M, O'SHEA A, LAMB D G, et al. The association of white matter free water with cognition in older adults[J/OL]. Neuroimage, 2020, 219: 117040 [2026-04-16]. https://dx.doi.org/10.1016/j.neuroimage.2020.117040. DOI: 10.1016/j.neuroimage.2020.117040.

PREV Identification of brain structural alterations and key molecular pathways in Alzheimer<sup><sup>,</sup></sup>s disease using voxel-based morphometry and the Allen Human Brain Atlas
NEXT Application value of artificial intelligence-based automatic brain region segmentation technology in the study of the correlation between the volumes of hippocampal and amygdalar subfields and cerebral small vessel disease-related cognitive impairment
  


LINK


Tel & Fax: +8610-67113815    E-mail: editor@cjmri.cn