Restricted accessResearch articleFirst published online 2026-2
Feasibility of relaxation-exchange magnetic resonance imaging (REXI) for measuring water exchange across the blood–CSF barrier in the human choroid plexus
The choroid plexus (CP) is important for cerebrospinal fluid (CSF) secretion and forms the blood–CSF barrier (BCSFB), which is essential for brain homeostasis. However, noninvasive methods for evaluating BCSFB function remain limited. Previously, we introduced a novel magnetic resonance imaging (MRI) technique, relaxation-exchange MRI (REXI), to quantify water exchange between CP and CSF in rats by leveraging the substantial difference in transverse relaxation times between CP tissue and CSF. Here, we adapted REXI to human applications by implementing segmented echo-planar imaging readout for enhanced acquisition speed, optimizing key parameters based on the Cramér–Rao lower bound, and refining the analysis methodology. We conducted simulations and phantom experiments for methodological validation. Subsequently, we performed a scan–rescan experiment in healthy volunteers (n = 6, mean-age ∼22 years), revealing relatively good repeatability in measurements of the apparent water exchange rate kBCSFB (intraclass correlation coefficient = 0.84). REXI detected a 34% decrease in kBCSFB among middle-aged healthy adults (n = 6, mean-age ∼55 years) compared with young healthy adults (n = 9, mean-age ∼23 years, p = 0.0048). These results demonstrate the feasibility of REXI in quantifying water exchange in human CP in vivo, providing a promising tool for future investigations of BCSFB function.
RedzicZBPrestonJEDuncanJA, et al.
The choroid plexus‐cerebrospinal fluid system: from development to aging. Curr Top Dev Biol2005;
71: 1–52.
2.
LiuGLadrón-de-GuevaraAIzhimanY, et al.
Measurements of cerebrospinal fluid production: a review of the limitations and advantages of current methodologies. Fluids Barriers CNS2022;
19: 101.
3.
BitanihirweBKYLizanoPWooT-UW.Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders. Mol Psychiatry2022;
27: 3573–3582.
4.
SaundersNRDziegielewskaKMFameRM, et al.
The choroid plexus: a missing link in our understanding of brain development and function. Physiol Rev2023;
103: 919–956.
5.
SolárPZamaniAKubíčkováL, et al.
Choroid plexus and the blood–cerebrospinal fluid barrier in disease. Fluids Barriers CNS2020;
17: 35.
6.
CousinsOHodgesASchubertJ, et al.
The blood–CSF–brain route of neurological disease: the indirect pathway into the brain. Neuropathol Appl Neurobiol2022;
48: e12789.
7.
MayCKayeJAAtackJR, et al.
Cerebrospinal fluid production is reduced in healthy aging. Neurology1990;
40: 500–503.
8.
LiuGMestreHSweeneyAM, et al.
Direct measurement of cerebrospinal fluid production in mice. Cell Rep2020;
33: 108524.
9.
JohansonCEDuncanJAKlingePM, et al.
Multiplicity of cerebrospinal fluid functions: new challenges in health and disease. Cerebrospinal Fluid Res2008;
5: 10.
10.
SilverbergGDHeitGHuhnS, et al.
The cerebrospinal fluid production rate is reduced in dementia of the Alzheimer’s type. Neurology2001;
57: 1763–1766.
11.
MassermanJH.Cerebrospinal hydrodynamics: IV. CLINICAL experimental studies. Arch NeurPsych1934;
32: 523.
12.
RubinRCHendersonESOmmayaAK, et al.
The production of cerebrospinal fluid in man and its modification by acetazolamide. J Neurosurg1966;
25: 430–436.
13.
EvansPGSokolskaMAlvesA, et al.
Non-invasive MRI of blood–cerebrospinal fluid barrier function. Nat Commun2020;
11: 2081.
14.
ZhaoLTasoMDaiW, et al.
Non-invasive measurement of choroid plexus apparent blood flow with arterial spin labeling. Fluids Barriers CNS2020;
17: 58.
15.
PetitclercLHirschlerLWellsJA, et al.
Ultra-long-TE arterial spin labeling reveals rapid and brain-wide blood-to-CSF water transport in humans. NeuroImage2021;
245: 118755.
16.
AndersonVCTaggeIJDoudA, et al.
DCE-MRI of brain fluid barriers: In vivo water cycling at the human choroid plexus. Tissue Barriers2022;
10: 1963143.
17.
WuXHeQYinY, et al.
Relaxation-exchange magnetic resonance imaging (REXI): a non-invasive imaging method for evaluating trans-barrier water exchange in the choroid plexus. Fluids Barriers Cns2024;
21: 94.
18.
UludağKMüller-BierlBUğurbilK.An integrative model for neuronal activity-induced signal changes for gradient and spin echo functional imaging. NeuroImage2009;
48: 150–165.
19.
SpijkermanJMPetersenETHendrikseJ, et al.
T 2 mapping of cerebrospinal fluid: 3T versus 7T. Magn Reson Mater Phy2018;
31: 415–424.
20.
AlexanderDC.A general framework for experiment design in diffusion MRI and its application in measuring direct tissue-microstructure features. Magn Reson Med2008;
60: 439–448.
21.
LampinenBSzczepankiewiczFvan WestenD, et al.
Optimal experimental design for filter exchange imaging: apparent exchange rate measurements in the healthy brain and in intracranial tumors. Magn Reson Med2017;
77: 1104–1114.
22.
Van LandeghemMHaberAD’espinose De LacaillerieJ, et al.
Analysis of multisite 2D relaxation exchange NMR. Concepts Magnetic Resonance2010;
36A: 153–169.
23.
BaiRBenjaminiDChengJ, et al.
Fast, accurate 2D-MR relaxation exchange spectroscopy (REXSY): beyond compressed sensing. J Chem Phys2016;
145: 154202.
24.
LeeJHLabadieCSpringerCS, et al.
Two-dimensional inverse Laplace transform NMR: altered relaxation times allow detection of exchange correlation. J Am Chem Soc1993;
115: 7761–7764.
25.
ÅslundINowackaANilssonM, et al.
Filter-exchange PGSE NMR determination of cell membrane permeability. J Magnetic Resonance2009;
200: 291–295.
26.
LasičSNilssonMLättJ, et al.
Apparent exchange rate mapping with diffusion MRI. Magn Reson Med2011;
66: 356–365.
27.
NilssonMLättJVan WestenD, et al.
Noninvasive mapping of water diffusional exchange in the human brain using filter-exchange imaging. Magn Reson Med2013;
69: 1573–1581.
28.
BaiRLiZSunC, et al.
Feasibility of filter-exchange imaging (FEXI) in measuring different exchange processes in human brain. NeuroImage2020;
219: 117039.
29.
SchillingFRosSHuD-E, et al.
MRI measurements of reporter-mediated increases in transmembrane water exchange enable detection of a gene reporter. Nat Biotechnol2017;
35: 75–80.
30.
LiCFieremansENovikovDS, et al.
Measuring water exchange on a preclinical MRI system using filter exchange and diffusion time dependent kurtosis imaging. Magn Reson Med2023;
89: 1441–1455.
31.
StaniszGJOdrobinaEEPunJ, et al.
T1, T2 relaxation and magnetization transfer in tissue at 3T. Magn Reson Med2005;
54: 507–512.
32.
LuHNagae‐PoetscherLMGolayX, et al.
Routine clinical brain MRI sequences for use at 3.0 tesla. J Magn Reson Imaging2005;
22: 13–22.
33.
SteffensenABEdelboBLBarbuskaiteD, et al.
Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure. Fluids Barriers CNS2023;
20: 49.
34.
YushkevichPAPivenJHazlettHC, et al.
User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. NeuroImage2006;
31: 1116–1128.
35.
BaiRKoayCGHutchinsonE, et al.
A framework for accurate determination of the T2 distribution from multiple echo magnitude MRI images. J Magn Reson2014;
244: 53–63.
36.
LiAMXuJ.Cerebrospinal fluid‐tissue exchange revealed by phase alternate labeling with null recovery MRI. Magn Reson Med2022;
87: 1207–1217.
37.
VoldRLDanielESChanSO.Magnetic resonance measurements of proton exchange in aqueous urea. J Am Chem Soc1970;
92: 6771–6776.
38.
DortchRDHorchRADoesMD.Development, simulation, and validation of NMR relaxation-based exchange measurements. J Chem Phys2009;
131: 164502.
39.
BaiRWangBJiaY, et al.
Shutter‐speed DCE‐MRI analyses of human glioblastoma multiforme (GBM) data. J Magn Reson Imaging2020;
52: 850–863.
40.
KarimyJKKahleKTKurlandDB, et al.
A novel method to study cerebrospinal fluid dynamics in rats. J Neurosci Methods2015;
241: 78–84.
41.
QuayWB.Regional and quantitative differences in the postweaning development of choroid plexuses in the rat brain. Brain Res1972;
36: 37–45.
42.
ZhengW.Toxicology of choroid plexus: Special reference to metal-induced neurotoxicities. Microsc Res Tech2001;
52: 89–103.
43.
ChiuCMillerMCCaralopoulosIN, et al.
Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months. Fluids Barriers CNS2012;
9: 3.
44.
BouzerarRChaaraniBGondry-JouetC, et al.
Measurement of choroid plexus perfusion using dynamic susceptibility MR imaging: capillary permeability and age-related changes. Neuroradiology2013;
55: 1447–1454.
45.
EismaJJMcKnightCDHettK, et al.
Choroid plexus perfusion and bulk cerebrospinal fluid flow across the adult lifespan. J Cereb Blood Flow Metab2023;
43: 269–280.
46.
ZhangYChenHLiR, et al.
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther2023;
8: 248.
47.
ČarnaMOnyangoIGKatinaS, et al.
Pathogenesis of Alzheimer’s disease: involvement of the choroid plexus. Alzheimers Dement2023;
19: 3537–3554.
48.
SilverbergGDMayoMSaulT, et al.
Alzheimer’s disease, normal‐pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol2003;
2: 506–511.
49.
ChoiJDMoonYKimH-J, et al.
Choroid plexus volume and permeability at brain MRI within the Alzheimer disease clinical spectrum. Radiology2022;
304: 635–645.
50.
MacAulayN.Molecular mechanisms of brain water transport. Nat Rev Neurosci2021;
22: 326–344.
51.
WelchK.Secretion of cerebrospinal fluid by choroid plexus of the rabbit. Am J Physiol-Legacy Content1963;
205: 617–624.
52.
DavsonHSegalMB.The effects of some inhibitors and accelerators of sodium transport on the turnover of 22 Na in the cerebrospinal fluid and the brain. J Physiol1970;
209: 131–153.
53.
ZeuthenT.Molecular water pumps. In R. Greger (Ed.),Reviews of physiology biochemistry and pharmacology.
Berlin, Heidelberg:
Springer, pp. 97–151.
54.
BaiRSpringerCSPlenzD, et al.
Fast, Na +/K + pump driven, steady‐state transcytolemmal water exchange in neuronal tissue: a study of rat brain cortical cultures. Magn Reson Med2018;
79: 3207–3217.
55.
SpringerCS.Using 1H2O MR to measure and map sodium pump activity in vivo. J Magn Reson2018;
291: 110–126.
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