The glymphatic system is a brain-wide pathway involved in the movement of cerebrospinal fluid, exchange with interstitial fluid, and clearance of metabolic products from neural tissue. Although glymphatic research initially concentrated on adult sleep, ageing, and neurodegenerative diseases, researchers are increasingly examining how this system develops during fetal and early postnatal life.
The fetal and neonatal glymphatic system is particularly relevant because the developing brain undergoes rapid cellular proliferation, neuronal migration, synapse formation, vascular maturation, and myelination. These metabolically demanding processes require precise regulation of water, ions, extracellular molecules, and metabolic by-products. However, direct measurement of glymphatic transport in a human fetus is currently not possible with validated clinical methods. Most available evidence therefore comes from premature and term newborns, histological studies of developing brain tissue, animal models, and indirect magnetic resonance imaging biomarkers.
Recent studies published between 2023 and 2026 suggest that glymphatic-associated structures and imaging parameters change substantially during the perinatal period. They also indicate that premature birth, birth asphyxia, and hypoxic-ischemic injury may alter these developmental trajectories. Nevertheless, researchers must avoid equating an imaging proxy with actual fluid clearance. The current science supports the existence of developmental changes in perivascular physiology, but it has not yet established a complete functional model of the fetal and neonatal glymphatic system.
Biological Foundations of the Developing Glymphatic System
Cerebrospinal fluid and perivascular pathways
The adult glymphatic model proposes that cerebrospinal fluid enters or moves along periarterial and other perivascular spaces, exchanges with interstitial fluid within the brain, and contributes to the removal of solutes through perivenous, meningeal lymphatic, and other drainage routes. Astrocytes—the star-shaped glial cells surrounding neurons and blood vessels—are considered important regulators of this exchange.
Aquaporin-4 (AQP4), a water-channel protein highly expressed in astrocytic endfeet, has received particular attention. In the mature brain, AQP4 is concentrated at the interfaces between astrocytes and blood vessels. This spatial organization, called AQP4 polarization, may facilitate controlled water movement around the cerebral vasculature.
However, this organization is not present in its adult form throughout gestation. The fetal and neonatal brain contains immature astrocytes, evolving vascular networks, and changing extracellular spaces. Earlier histological research demonstrated that the coverage of cerebral vessels by astrocytic endfeet increases with maturation and differs between the germinal matrix, cerebral cortex, and white matter. The germinal matrix—a highly vascularized region that is prominent in premature infants—has relatively immature perivascular support, potentially contributing to its vulnerability to hemorrhage.
Consequently, the fetal and neonatal glymphatic system should not be understood simply as a smaller version of the adult system. Its cellular architecture is still being assembled.
A system developing alongside the neurovascular unit
Astrocytes, endothelial cells, pericytes, vascular smooth-muscle cells, basement membranes, and neurons collectively form the neurovascular unit. The maturation of these components influences blood–brain barrier integrity, cerebral blood-flow regulation, and perivascular fluid dynamics.
A 2025 review of perivascular astrocyte-process development emphasized that astrocytic coverage, molecular composition, and interaction with blood vessels continue to mature after birth. Proteins including AQP4, dystrophin-associated proteins, MLC1, and GlialCAM help organize the perivascular astrocytic membrane. Animal studies indicate that disrupting some of these proteins can impair cerebrospinal-fluid circulation and neurovascular coupling.
This evidence provides a plausible structural basis for a developing glymphatic system during late gestation. Nevertheless, the presence of astrocytic endfeet and perivascular channels does not, by itself, demonstrate the direction, volume, or clearance efficiency of fluid transport in the human fetus. Current science does not yet know precisely when a fully functional glymphatic pathway first emerges.
What Recent Neonatal MRI Studies Have Revealed
MRI-visible perivascular spaces
Perivascular spaces are fluid-containing compartments surrounding small cerebral blood vessels. Their appearance on MRI is frequently used as an indirect marker of perivascular development, although their size and visibility are not direct measurements of glymphatic flow.
A 2023 Radiology study analyzed MRI data from 244 newborns in the Developing Human Connectome Project. MRI-visible perivascular spaces were identified in the basal ganglia of 63% of the neonates, whereas 93% had no visible white-matter perivascular spaces. Basal-ganglia perivascular-space fraction decreased as postmenstrual age increased, and basal-ganglia perivascular-space volume was smaller in preterm than in term newborns. Biological sex was not significantly associated with volume. These findings indicate that perivascular-space appearance changes with maturation and premature birth, but they do not establish whether smaller spaces represent reduced clearance, developmental compaction, or another process.
A 2026 review of imaging biomarkers in the developing brain concluded that perivascular-space volume generally decreases from the neonatal period through later development. However, the authors cautioned that available studies use heterogeneous methods and relatively small populations. Therefore, a universally accepted normal trajectory for the fetal and neonatal glymphatic system has not yet been established.
DTI-ALPS and choroid plexus measurements
Diffusion tensor imaging along the perivascular space, commonly abbreviated as DTI-ALPS, estimates the directional diffusion of water in brain regions where perivascular spaces run approximately perpendicular to major white-matter fibres. A higher DTI-ALPS index is often interpreted as indicating more extensive water diffusivity along perivascular pathways.
In a prospective study of preterm newborns, investigators found that DTI-ALPS values increased between approximately 25 and 34 weeks of postmenstrual age and then appeared to plateau. This pattern was also observed in an independent dataset from the Developing Human Connectome Project. The finding suggests a nonlinear period of rapid perivascular maturation during late gestation or its extrauterine equivalent. Importantly, the participants had already been born; the study did not directly image glymphatic function in fetuses remaining in utero.
A separate 2025 study assessed 117 newborns using DTI-ALPS and choroid plexus volume. Preterm newborns had a lower total DTI-ALPS index than term newborns—1.01 compared with 1.05—and the difference remained significant after covariate adjustment. Choroid plexus volume increased in association with postmenstrual age, whereas differences between preterm and term groups became non-significant after adjustment. No significant sex effect was found for either metric.
Because the choroid plexus produces most cerebrospinal fluid, its development may influence glymphatic-associated physiology. Yet choroid plexus volume is not equivalent to cerebrospinal-fluid production, and DTI-ALPS does not directly measure solute clearance. The researchers consequently described these variables as potential developmental biomarkers rather than validated diagnostic tests.
Development continues after the neonatal period
Evidence published in 2026 suggests that glymphatic-associated MRI parameters continue to change well beyond birth. Researchers analyzing Baby Connectome Project data from 60 children aged two months to five years found that DTI-ALPS values increased with age, particularly in the right cerebral hemisphere. Sex and head motion were not significant predictors in their models.
These observations support the concept that the fetal and neonatal glymphatic system is the beginning of a longer developmental trajectory. They also raise the possibility of cerebral asymmetry in perivascular water diffusion. However, the study was cross-sectional and relatively small, so it could not establish how individual children’s glymphatic-associated measurements changed over time.
Prematurity, Asphyxia, and Hypoxic-Ischemic Injury
Premature birth may interrupt normal maturation
Premature birth transfers the developing brain from the intrauterine environment to neonatal intensive care during a period of rapid vascular, glial, and white-matter maturation. Oxygen exposure, inflammation, hemodynamic instability, medication, nutrition, sleep disruption, and mechanical ventilation could potentially affect perivascular development.
Recent neonatal imaging studies consistently report differences between preterm and term groups, including lower DTI-ALPS indices and altered perivascular-space measurements. These associations suggest delayed or modified maturation of the fetal and neonatal glymphatic system. They do not prove that premature birth directly causes glymphatic dysfunction, because gestational age, birth weight, neonatal illness, postmenstrual age at scanning, and treatment exposures are difficult to separate statistically.
Longitudinal imaging beginning shortly after birth and continuing through infancy will be required to determine whether these differences persist, normalize, or predict later neurodevelopmental outcomes.
Birth asphyxia and neonatal brain injury
In the prospective preterm study, infants with birth asphyxia had a substantially lower mean DTI-ALPS index than those without birth asphyxia—0.98 versus 1.08. Germinal matrix–intraventricular hemorrhage was not significantly associated with this index. The authors therefore identified birth asphyxia as a potentially important modifier of glymphatic-system development in premature newborns.
Another 2025 investigation examined 127 neonates, including 30 with MRI-visible hypoxic-ischemic injury. Newborns with injury had smaller basal-ganglia perivascular-space volumes and fractions than those without injury. In contrast, DTI-ALPS values did not differ significantly between the groups. Moreover, the perivascular-space measurements and DTI-ALPS indices were not significantly correlated with each other.
This lack of agreement is scientifically important. It indicates that different MRI biomarkers may represent different anatomical or physiological components rather than a single unified measure of glymphatic function.
Experimental research provides complementary—but not directly transferable—evidence. A 2025 mouse study using dynamic contrast-enhanced MRI and fluorescent cerebrospinal-fluid tracers found delayed transport and abnormal tracer retention following neonatal hypoxic-ischemic encephalopathy. The affected animals also exhibited loss of normal AQP4 polarization. These results support a mechanistic relationship between hypoxic injury, astrocytic organization, and impaired glymphatic transport. However, results from neonatal mice cannot establish the same mechanisms in human infants without further clinical validation.
Methodological Limits and Future Research
Imaging biomarkers remain indirect
Direct glymphatic imaging often requires administration of a contrast agent into cerebrospinal fluid, an invasive procedure that is generally inappropriate for healthy fetuses and newborns. Researchers therefore rely on non-invasive proxies, including:
- MRI-visible perivascular-space volume or fraction;
- DTI-ALPS indices;
- choroid plexus volume;
- cerebrospinal-fluid movement detected with specialized MRI sequences;
- diffusion and perfusion measurements.
Each biomarker captures a different property. DTI-ALPS is influenced by white-matter fibre orientation, crossing fibres, head motion, region-of-interest placement, brain size, and scanner parameters. Perivascular-space visibility depends on image resolution and tissue water content. Choroid plexus volume may reflect growth or pathology but does not directly quantify cerebrospinal-fluid secretion.
Consequently, expressions such as “glymphatic function” should be used cautiously when a study has measured only one indirect MRI parameter.
Priorities for fetal and neonatal research
Future studies of the fetal and neonatal glymphatic system should combine multiple imaging measurements rather than treating one index as definitive. Large, longitudinal cohorts should include gestational age, maternal health, placental function, birth conditions, inflammation, oxygen exposure, neonatal treatments, sleep state, and long-term cognitive and motor outcomes.
Motion-tolerant fetal MRI may eventually provide information about cerebrospinal-fluid pulsation and perivascular water movement in utero. Before such measurements can be described as fetal glymphatic biomarkers, researchers will need reproducible acquisition protocols, developmental reference ranges, and validation against experimental or physiological evidence.
Artificial intelligence may assist with neonatal brain segmentation, but automated measurements must be verified across hospitals, scanner manufacturers, and diverse populations. The latest research supports continued investigation; it does not yet support using glymphatic MRI biomarkers to guide routine fetal or neonatal treatment.
Conclusion
Research into the fetal and neonatal glymphatic system is moving from anatomical hypotheses toward measurable developmental imaging. Current evidence suggests that perivascular spaces, water diffusivity along vascular pathways, choroid plexus characteristics, and astrocytic organization change rapidly during late gestation and early childhood.
Premature birth, birth asphyxia, and hypoxic-ischemic injury are associated with differences in several glymphatic-related MRI parameters. Nevertheless, these findings are associations based mainly on neonatal measurements. Direct human fetal glymphatic transport has not been conclusively demonstrated, and no single MRI marker has been validated as a complete measure of brain clearance.
The most defensible scientific conclusion is therefore that the fetal and neonatal glymphatic system is an emerging research field with promising biomarkers but substantial methodological uncertainty. Multimodal longitudinal studies will be essential to determine whether early glymphatic development influences neurodevelopmental outcomes and whether it can eventually provide clinically useful information.
Selected Scientific Sources
- Choi A. et al. (2026). Imaging Biomarkers of the Glymphatic System in the Developing Brain. Korean Journal of Radiology.
- Cortes-Albornoz M.C. et al. (2026). Developmental changes in diffusion MRI metrics along the perivascular space in children during the first 5 years of life. Pediatric Radiology.
- Peng T. et al. (2025). Assessing neonatal brain glymphatic system development using DTI-ALPS and choroid plexus volume. BMC Medical Imaging.
- Choi A. et al. (2025). Association of Hypoxic-Ischemic Injury With MRI-Derived Glymphatic Parameters in Neonates. Korean Journal of Radiology.
- Lin S. et al. (2025). Glymphatic System in Preterm Neonates: Developmental Insights Following Birth Asphyxia. Journal of Magnetic Resonance Imaging.
- Wen J. et al. (2025). Impaired glymphatic transport in hypoxic-ischemic encephalopathy. NeuroImage.
- Kim H.G. et al. (2023). MRI-visible Perivascular Spaces in the Neonatal Brain. Radiology.
- El-Khoury N. et al. (2006). Astrocyte End-Feet in Germinal Matrix, Cerebral Cortex, and White Matter in Developing Infants. Pediatric Research.
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