Decoding Neurological Aftermath: Glymphatic Dysfunction in Post-COVID-19 Patients


The coronavirus disease 2019 (COVID-19) pandemic has left an indelible mark on global health, affecting millions of lives worldwide. While the majority of patients recover, an alarming number experience lingering symptoms, termed postsequelae, that span various domains of health. This article delves into the intricacies of post-COVID-19 sequelae, particularly focusing on neurological implications, and introduces a groundbreaking study investigating the role of the glymphatic system in the aftermath of the infection.

Postsequelae Diversity

Survivors of COVID-19 often grapple with a spectrum of symptoms, ranging from neurocognitive issues to respiratory and musculoskeletal challenges. Common complaints include headaches, fatigue, breathlessness, arthralgia, sleep disturbances, and chest pain. Notably, within the first year of recovery, neurological symptoms and psychological abnormalities emerge as the most prevalent complications.

Neurological Conundrum

Conventional magnetic resonance imaging (MRI) struggles to elucidate the nonspecific symptoms experienced by post-COVID-19 patients. Functional MRI studies exploring depression and fatigue have provided some insights, yet a more comprehensive understanding is required. Longitudinal studies reveal persistent brain atrophy and cognitive decline three years post-infection, indicating a potential neuroinvasive nature of the virus.

Olfactory Pathways and Neuroinvasion

COVID-19’s ability to invade the nervous system through respiratory pathways and olfactory receptors is a distinctive feature. Changes in the limbic system, including reduced grey matter thickness in critical areas, are observed, differentiating COVID-19 from other pneumonia-related degenerative changes.

Glymphatic System and COVID-19

Researchers postulate that the neurological syndrome may arise from damage to olfactory sensory neurons, leading to impaired cerebrospinal fluid outflow and subsequent glymphatic system congestion. While the link between COVID-19 and glymphatic function remains unclear, this novel perspective raises the possibility of targeting the glymphatic system to alleviate cognitive disorders in post-COVID-19 patients.

Assessing Glymphatic Function

Prior studies have assessed the glymphatic system using various techniques, such as dynamic contrast-enhanced MRI, intrathecal gadolinium administration, and dynamic PET imaging. The invasiveness of these methods prompted the exploration of diffusion-weighted MRI as a noninvasive tool, culminating in the development of the DTI-ALPS index. This index, proven to correlate with traditional glymphatic clearance detection methods, has been successfully applied in various neurological disorders.

The Hypothesis and Study Design:

The current study sets out to test the hypothesis that glymphatic system outflow is impaired in recovered COVID-19 patients. The DTI-ALPS index is employed to assess glymphatic function and is compared between healthy controls and post-COVID-19 individuals. Cluster analysis is conducted to identify behavioral ratings or nonspecific symptoms associated with the DTI-ALPS index.

DTI-ALPS Index Explained In-Depth

The DTI-ALPS index is a novel MRI-based biomarker used to assess the function of the glymphatic system, the brain’s waste removal pathway. It stands for “Diffusion Tensor Imaging – Along Perivascular Spaces.” Here’s a breakdown of its meaning and significance:

What it measures:

  • Diffusion: The movement of water molecules in brain tissue.
  • Tensor Imaging: A technique that measures the direction and magnitude of water diffusion.
  • Along Perivascular Spaces: The spaces surrounding blood vessels in the brain, where the glymphatic system operates.

How it works:

  • The DTI-ALPS index compares the diffusion of water molecules along and perpendicular to the perivascular spaces.
  • A lower index indicates restricted water diffusion, which suggests impaired glymphatic function.
  • A higher index suggests efficient glymphatic clearance and potentially healthy brain function.


  • Novel Biomarker: This is the first MRI-based biomarker specifically designed to assess the glymphatic system.
  • Potential Applications:
    • Early Diagnosis: It can potentially be used to diagnose neurodegenerative diseases like Alzheimer’s and Parkinson’s, which are associated with impaired glymphatic function, even before symptoms appear.
    • Monitoring Disease Progression: It can be used to monitor the progression of these diseases and evaluate the effectiveness of treatment.
    • Understanding Brain Function: It can contribute to our understanding of the role of the glymphatic system in brain health and disease.

Current Research:

  • Studies are ongoing to validate the DTI-ALPS index in larger patient populations and across various neurological conditions.
  • Researchers are exploring its potential use for developing glymphatic system-targeted therapies.


  • DTI-ALPS is a relatively new technique, and further research is needed to fully understand its clinical implications.
  • It requires specialized expertise to interpret the results correctly.
  • The glymphatic system itself is not fully understood, and more research is needed to elucidate its exact functions and dysfunction mechanisms.

Overall, the DTI-ALPS index is a promising tool for assessing glymphatic function and holds potential for furthering our understanding of brain health and disease.

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This groundbreaking study represents the first attempt to unravel the intricate relationship between the glymphatic system and COVID-19 infection in vivo. The investigation unveils a spectrum of findings that shed light on the impact of the virus on glymphatic function and its potential implications for neurological sequelae. The following detailed discussion elaborates on the key findings and their implications for our understanding of post-COVID-19 neurological complications.

Decline in DTI-ALPS Indices:

The study reveals a significant reduction in both left and right DTI-ALPS indices in recovered COVID-19 patients compared to healthy controls, irrespective of the presence of postsequelae symptoms. This decline within the first four months postinfection suggests a swift impairment of glymphatic function, indicating a potential avenue for understanding the lingering effects of COVID-19.

Age-Related Variation:

A noteworthy observation is the greater decline in glymphatic function among older individuals infected with COVID-19. This aligns with existing literature that emphasizes the severity of the disease in the elderly population. The association between age and glymphatic dysfunction hints at a susceptibility of older individuals to more pronounced impairments, raising concerns about the long-term neurological consequences in this demographic.

Asynchronous Hemispheric Decline:

Hierarchical subgroup analysis unveils asynchronous declines in the left and right DTI-ALPS indices, introducing a nuanced perspective on the lateralization of glymphatic dysfunction. Subgroup 1, characterized by a lower right DTI-ALPS index, exhibits a higher proportion of cognitive abnormalities. This lateralized decline suggests that distinct brain injuries may manifest in different stages of COVID-19, emphasizing the complexity of the neurological impact.

Implications for Cognitive Impairment:

The study provides a novel link between glymphatic dysfunction and cognitive impairment in post-COVID-19 patients. The reduced DTI-ALPS indices correlate with cognitive decline, reinforcing the idea that glymphatic failure may be a key contributor to cognitive sequelae. The findings underscore the importance of considering neurological consequences in the aftermath of COVID-19, especially in older adults.

Neurological Pathways of COVID-19:

The discussion delves into the potential mechanisms through which COVID-19 may induce glymphatic dysfunction. The virus’s ability to directly infect the brain, coupled with systemic inflammation and ischemia-hypoxia, may collectively contribute to alterations in the glymphatic system’s structure and function. The study proposes a disrupted drainage efflux of interstitial fluid, leading to a disturbance in the glymphatic pathway, ultimately contributing to cognitive impairment.

Limitations and Considerations:

Acknowledging the limitations of the study, the discussion addresses the lack of pre-infection assessments of glymphatic function in COVID-19 patients. The absence of direct tests, such as high-resolution MRI for glymphatic vessel structure evaluation, poses a challenge in conclusively establishing the causality between COVID-19 and glymphatic dysfunction. The exclusion of severe and critically ill patients due to the study’s focus on community recruitment is acknowledged, emphasizing the need for future investigations with a broader participant pool.

Advantages of DTI-ALPS:

The study emphasizes the advantages of employing the DTI-ALPS index as a noninvasive tool for assessing glymphatic function. Its applicability in larger populations, without the need for contrast agents or multiple invasive procedures, positions it as a practical tool for clinical use. The high repeatability and reliability of DTI-ALPS, unaffected by the shape of the region of interest (ROI), further validate its robustness.


In conclusion, this study pioneers the exploration of glymphatic dysfunction in the context of COVID-19, uncovering significant declines in DTI-ALPS indices within four months postinfection. The age-related variation, asynchronous hemispheric decline, and association with cognitive impairment provide critical insights into the nuanced impact of COVID-19 on the glymphatic system.

While acknowledging study limitations, the findings highlight the potential of DTI-ALPS as a valuable tool in assessing glymphatic function and understanding the neurological aftermath of COVID-19. Further research is warranted to unravel the complexities of COVID-19-induced glymphatic dysfunction and its implications for long-term neurological health.

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