Multimodal imaging maps spinal glymphatic transport in health and its disruption after injury
- 1Center for Translational Neuromedicine, University of Copenhagen, Blegdamsvej 3, Copenhagen N, 2200 DENMARK, Center for Translational Neuromedicine, University
Abstract
Spinal cord injury (SCI) is an incurable neurological condition in which post-traumatic edema contributes to secondary ischemic damage because the spinal cord is confined within the rigid vertebral canal. However, glymphatic transport in the healthy and injured spinal cord remains poorly characterized. We hypothesized that spinal cerebrospinal (CSF) and glymphatic transport is shaped by anatomy, administration route, and molecular size of the tracer; is disrupted after SCI; and is further impaired by loss of aquaporin-4 (AQP4). CSF tracers were administered by cisterna magna or lumbar intrathecal injection to anesthetized adult C57BL/6 mice. Dynamic contrast-enhanced MRI, ex vivo fluorescence imaging, and histology were used to characterize tracer distribution, influx, and clearance. Constrictions of the spinal subarachnoid space at C3-C7, T6-T12 and L5-S1 spinal segments accelerated contrast-agent dispersion, demonstrating that local anatomy regulates spinal CSF transport. Tracer influx into the cord itself occurred primarily along periarterial pathways.Tracer distribution depended on the administration route: cisterna magna injection preferentially labeled white matter in the upper spinal cord, whereas lumbar injection preferentially labeled grey matter in the lower spinal cord. Gadobutrol and ovalbumin penetrated and dispersed throughout the parenchyma, whereas fibrinogen remained confined to the meninges. Under physiological conditions, intraparenchymal tracers cleared within 24 h. SCI was modeled using a minimally invasive NMDA-induced lesion at T11 that produced focal necrosis while preserving the dura and vertebral structures. Glymphatic transport, lesion volume, and motor recovery were compared between wild-type and AQP4-knockout mice using imaging, the Basso Mouse Scale, and voluntary wheel running. After SCI, intrathecal contrast propagated more rapidly, especially at T7-T8 segments and at the S1 segment, but tissue clearance was profoundly impaired, with tracer retention persisting for up to seven days. AQP4-knockout mice showed greater clearance impairment, larger lesions, and poorer motor recovery than wild-type controls compared at 24 h. These findings define major determinants of spinal glymphatic transport and show that accelerated tracer propagation after SCI does not indicate effective clearance. Instead, SCI produces glymphatic dysfunction that is exacerbated by loss of AQP4 and associated with greater tissue damage and functional impairment. The results extend the glymphatic framework to the spinal cord and identify fluid-clearance pathways as potential therapeutic targets for limiting edema and secondary injury. Future studies should determine whether restoring glymphatic function improves neurological recovery after SCI.
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BibTeX
@misc{kaur2026multimodal,
title = {{Multimodal imaging maps spinal glymphatic transport in health and its disruption after injury}},
author = {J. Kaur and M. J. Giannetto and D. T. Wong and D. H. Kelley and P. Weikop and M. Nedergaard},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.16.752122},
url = {https://www.biorxiv.org/content/10.64898/2026.09.16.752122v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Multimodal imaging maps spinal glymphatic transport in health and its disruption after injury
AU - J. Kaur
AU - M. J. Giannetto
AU - D. T. Wong
AU - D. H. Kelley
AU - P. Weikop
AU - M. Nedergaard
PY - 2026
DA - 2026/09/16
PB - bioRxiv
DO - 10.64898/2026.09.16.752122
UR - https://www.biorxiv.org/content/10.64898/2026.09.16.752122v1
AB - Spinal cord injury (SCI) is an incurable neurological condition in which post-traumatic edema contributes to secondary ischemic damage because the spinal cord is confined within the rigid vertebral canal. However, glymphatic transport in the healthy and injured spinal cord remains poorly characterized. We hypothesized that spinal cerebrospinal (CSF) and glymphatic transport is shaped by anatomy, administration route, and molecular size of the tracer; is disrupted after SCI; and is further impaired by loss of aquaporin-4 (AQP4). CSF tracers were administered by cisterna magna or lumbar intrathecal injection to anesthetized adult C57BL/6 mice. Dynamic contrast-enhanced MRI, ex vivo fluorescence imaging, and histology were used to characterize tracer distribution, influx, and clearance. Constrictions of the spinal subarachnoid space at C3-C7, T6-T12 and L5-S1 spinal segments accelerated contrast-agent dispersion, demonstrating that local anatomy regulates spinal CSF transport. Tracer influx into the cord itself occurred primarily along periarterial pathways.Tracer distribution depended on the administration route: cisterna magna injection preferentially labeled white matter in the upper spinal cord, whereas lumbar injection preferentially labeled grey matter in the lower spinal cord. Gadobutrol and ovalbumin penetrated and dispersed throughout the parenchyma, whereas fibrinogen remained confined to the meninges. Under physiological conditions, intraparenchymal tracers cleared within 24 h. SCI was modeled using a minimally invasive NMDA-induced lesion at T11 that produced focal necrosis while preserving the dura and vertebral structures. Glymphatic transport, lesion volume, and motor recovery were compared between wild-type and AQP4-knockout mice using imaging, the Basso Mouse Scale, and voluntary wheel running. After SCI, intrathecal contrast propagated more rapidly, especially at T7-T8 segments and at the S1 segment, but tissue clearance was profoundly impaired, with tracer retention persisting for up to seven days. AQP4-knockout mice showed greater clearance impairment, larger lesions, and poorer motor recovery than wild-type controls compared at 24 h. These findings define major determinants of spinal glymphatic transport and show that accelerated tracer propagation after SCI does not indicate effective clearance. Instead, SCI produces glymphatic dysfunction that is exacerbated by loss of AQP4 and associated with greater tissue damage and functional impairment. The results extend the glymphatic framework to the spinal cord and identify fluid-clearance pathways as potential therapeutic targets for limiting edema and secondary injury. Future studies should determine whether restoring glymphatic function improves neurological recovery after SCI.
ER -