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. 2025 Apr 28;25(1):187.
doi: 10.1186/s12883-025-04198-1.

Neurologic symptoms as a hallmark of glymphatic alteration in recovered patients with COVID-19

Minhoe Kim #  1 , Kyung Hoon Lee #  2 , Ji Su Ko  2 , Myung Sub Kim  2 , Kyu Sung Choi  3 , Jiwon Seo  4 , Minchul Kim  5
Affiliations

Neurologic symptoms as a hallmark of glymphatic alteration in recovered patients with COVID-19

Minhoe Kim et al. BMC Neurol. .

Abstract

Background: The glymphatic system is a glial-based perivascular network that facilitates the clearance of metabolic waste from the brain. Dysfunction of the glymphatic system, along with neurological symptoms such as cognitive deficits and olfactory dysfunction, has been reported in patients with coronavirus disease (COVID-19). However, the link between these neurological symptoms and alterations in the glymphatic system remains unclear. In this study, we aimed to evaluate magnetic resonance imaging (MRI)-based measures of the glymphatic system in patients recovered from COVID-19 with and without neurological symptoms.

Methods: This study included 89 patients who recovered from respiratory infections, of whom 71 had confirmed COVID-19 (20 experienced anosmia and 41 had cognitive symptoms). Three MRI-based measures were quantified and compared: the dilated perivascular spaces (dPVS), free water (FW) fraction, and diffusion tensor image analysis along the perivascular spaces (DTI-ALPS). A partial correlation network was used to assess the relationships between COVID-19 infection, neurological symptoms, and glymphatic measures.

Results: COVID-19 patients with anosmia had increased FW in the left orbitofrontal area compared to those without anosmia (mean difference: 0.01, p = 0.48), while patients with cognitive symptoms showed decreased left-sided DTI-ALPS (mean difference: 0.06, p = 0.40). Neurological symptoms mediate the relationship between COVID-19 and glymphatic system measures.

Conclusions: Our findings imply that neurological symptoms accompanied by COVID-19 are linked to distinct alterations in the glymphatic system, suggesting a potential association between neuroinvasion and neuroinflammatory processes related to COVID-19.

Keywords: Anosmia; COVID-19; DTI-ALPS; Glymphatic alteration.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All participants gave their informed consent, and the Ethics Committee of Clínica Alemana—Universidad del Desarrollo approved all experimental procedures. The consent process and all experimental methods adhered to Chilean national laws, institutional policies, and the Declaration of Helsinki, and have any necessary ethics permissions to share the data publicly under a Creative Commons CC0 license ( https://docs.openneuro.org/faq.html ). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic of the glymphatic system (upper row) and MRI-based noninvasive methods (Bottom row). Briefly, from arteries, cerebrospinal fluid (CSF) crosses the perivascular space entering the interstitium through the AQP-4 channel and moving toward perivenous spaces (zigzag arrow). Although formal validation studies are still lacking, we hypothesized that PVS may serve as a proxy for periarterial flow; deterioration in the exchange of CSF and interstitial fluid would increase the extracellular fractional volume of free water (FW); DTI-ALPS measures the diffusivity capacity of the perivenous space surrounding the deep medullary vein at the lateral ventricle body level, enabling the assessment of the CSF outflow channel within this system. Abbreviation: PVS, perivascular space; AQP-4, aquaporin-4; DTI-ALPS, Diffusivity Along the Perivascular Spaces
Fig. 2
Fig. 2
Between-group differences in MRI-based measures of the glymphatic system. Panel (A) shows the free water increase in COVID-19 with anosmia, while panel (B) shows the left side diffusion along the perivascular space (DTI-ALPS) index decrease in COVID-19 with cognitive symptoms than those without. Panel (C) shows the network of the COVID-19 infection (COVID), cognitive symptoms (Cog Sx), Anosmia, and MRI-based measures the glymphatic system. Note that COVID is linked to glymphatic system measures via Cog Sx and anosmia. Blue lines represent positive associations, and red lines represent negative associations. Abbreviation: s̅: without, c̅: with, pvs: perivascular space, alps_L: left Diffusivity Along the Perivascular Spaces, FW: extracellular fractional volume of free water. * p < 0.05
Fig. 3
Fig. 3
TBSS result. Red-yellow voxels represent regions in which free water was increased significantly in COVID-19 with anosmia relative to those without. The recognized tracts encompass left uncinate fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, and forceps minor
See this image and copyright information in PMC

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