COVID-19, caused by the novel coronavirus, is a severe emerging respiratory viral infectious disease (Haider et al., 2020). Beyond the acute infection symptoms, long-term symptoms associated with COVID-19 have become a notable global public health issue (Soriano et al., 2022; Chow et al., 2023). While the novel coronavirus primarily affects the pulmonary respiratory system, leading to severe pneumonia, it also exhibits neurotropic properties that can cause damage to the brain (Xu et al., 2024; Reis et al., 2022). Many patients who experienced acute COVID-19 continue to exhibit significant fatigue and cognitive impairment long after recovery (Greene et al., 2024). Approximately 80% of hospitalized patients display sequelae post-recovery (Drouin et al., 2024).

The brain glymphatic system, consisting of perivascular spaces formed by astrocyte endfeet and vascular walls, functions similarly to the lymphatic system in clearing cellular metabolic waste (Mestre et al., 2020; Hablitz and Nedergaard, 2021). Recent studies indicate that 50% of COVID-19 patients exhibit blood–brain barrier disruption and elevated inflammatory cytokines in cerebrospinal fluid (Jarius et al., 2022). Patients with COVID-19-related neurological manifestations present with different cerebrospinal fluid characteristics (Jarius et al., 2022). Some studies suggest that neurological syndromes may result from SARS-CoV-2 infection leading to a reduction in olfactory sensory neurons and decreased cerebrospinal fluid outflow, subsequently causing glymphatic circulation disturbances (Wostyn, 2021; Kempuraj et al., 2023). Over time, this can lead to the accumulation of toxic substances in the central nervous system (Kempuraj et al., 2023).However, these studies primarily focus on the chemical environment of cerebrospinal fluid and have not extensively examined the relationship between cognitive function changes and glymphatic function post-COVID-19 infection. If confirmed, glymphatic system function could potentially become a target for addressing the sequelae of COVID-19.

As early as 2012, Iliff et al. discovered, using fluorescence labeling techniques with two-photon microscopy, that perivascular spaces formed between astrocyte endfeet and vascular walls in the mouse brain have a function in clearing cellular metabolic waste (Iliff et al., 2012). They named this system the brain glymphatic system, demonstrating the existence of a lymphatic-like structure in the central nervous system. Subsequently, neuroimaging techniques such as dynamic contrast-enhanced MRI, PET and intrathecal gadolinium injection, were developed to assess the lymphatic system in vivo (Ding et al., 2021; Zhang et al., 2021; Schubert et al., 2019). However, these methods are invasive and can cause significant ionizing radiation exposure (Pei et al., 2024).In contrast, Diffusion Tensor Imaging-Analysis Along the Perivascular Space (DTI-ALPS) allows for non-invasive assessment of the glymphatic system using diffusion tensor imaging (Wang et al., 2023). Currently, studies using DTI-ALPS technology to investigate changes in brain glymphatic function in post-recovery COVID-19 patients are limited.

Therefore, we hypothesize that DTI-ALPS could be used to evaluate glymphatic changes post Covid-19, and that these changes gradually improve over time following recovery. To test this hypothesis, we employed DTI-ALPS technology to quantitatively assess brain glymphatic function in recovered COVID-19 patients, comparing glymphatic function at different time points, and analyzing the correlation between glymphatic function and cognitive performance.

we conducted a prospective investigation to explore the longitudinal and cross-sectional changes in the brain lymphatic circulation of COVID-19 patients within 1 year after viral clearance. Our key findings are as follows: (1) Overall cognitive function gradually recovered over time, but showed a significant decline at 3 months after COVID-19 recovery, and mental fatigue persisted even at 1 year; (2) The brain lymphatic circulation in both hemispheres exhibited dynamic changes, gradually increasing at 1 month after COVID-19 clearance and then gradually recovering; (3) The brain lymphatic function was highly active at 3 months after COVID-19 clearance; and (4) The brain lymphatic circulation was associated with overall cognitive function and mental fatigue.

SARS-CoV-2 infection can lead to a variety of neurological features, and fatigue and cognitive impairment are among the most common neurological symptoms of long COVID (Hampshire et al., 2024; Yu et al., 2022). Both our cross-sectional and longitudinal studies revealed abnormal changes in cognitive function and fatigue in COVID-19 convalescent patients. Specifically, the overall cognitive function (assessed by the Montreal Cognitive Assessment, MoCA) showed a significant decline at the 3-month follow-up compared to healthy controls and the 1-month follow-up, but recovered to baseline levels by the 12-month follow-up. Fatigue assessment using the Fatigue Assessment Scale (FAS) indicated that while physical fatigue did not differ significantly from healthy controls across follow-up time points, mental fatigue persisted and remained significantly higher than healthy levels throughout the study period. Previous studies have shown that 40.5% of participants had mild cognitive impairment based on the MoCA score, with declines in auditory-verbal learning and delayed recall (Peskar et al., 2023; Ariza et al., 2024). Moreover, fatigue, cognitive dysfunction (brain fog, memory problems, attention deficits), and sleep disturbances are major features of post-acute COVID-19 syndrome, and neuropsychiatric symptoms may improve over time, but can persist for more than a year (Premraj et al., 2022; Liu et al., 2023). There are also studies that although the overall cognitive impairment in COVID-19 recovered to normal levels within 6 months, some aspects were more severely and persistently impaired, such as attention, concentration, short-term memory, and executive function (Almeria et al., 2024). Within 12 weeks or longer after COVID-19 diagnosis, about one-third of individuals experienced persistent fatigue, and more than one-fifth exhibited cognitive impairment (Alkodaymi et al., 2022).

However, most studies have focused on brain-related symptoms and have not objectively and visually reported on brain lymphatic function, and the potential pathophysiological mechanisms underlying the neurological symptoms in COVID-19 convalescent patients remain to be further explored (Colizzi et al., 2024; Patil et al., 2024). The DTI-ALPS index can provide a non-invasive tool for measuring this in COVID-19 convalescent patients. Some studies using functional MRI (fMRI) or positron emission tomography (PET) have found that recovered COVID-19 patients exhibit alterations in brain functional connectivity and metabolic abnormalities after the acute phase (Guo et al., 2024; Morbelli et al., 2020). Compared to these studies, our findings further suggest that dynamic changes in the brain’s glymphatic system may underlie these functional and metabolic alterations.

The role of lymphatic function in COVID-19 cannot be ignored (Witte and Daley, 2020). SARS-CoV-2 has a certain neuroinvasive ability and can also affect the outcome and function of the brain lymphatic system (Miyasaka, 2022). In the early stage, SARS-CoV-2 may continuously enter the brain parenchyma through the retrograde lymphatic channels within the nasopharyngeal epithelium. The blood–brain barrier function of COVID-19 patients with neurological symptoms may be disrupted without intraparenchymal inflammation (Bhaskar et al., 2020; Mao and Jin, 2020). However, the majority of patients did not show pathological results in cerebrospinal fluid analysis.

Our study found that in the cross-sectional analysis, the DTI-ALPS index of recovered COVID-19 patients was higher in Bilateral cerebral hemispheres at 3 months after viral clearance compared to uninfected participants. In the longitudinal analysis, the DTI-ALPS index at 3 months of follow-up was higher than at 1 month and 12 months of follow-up, with no significant difference between 1 month and 12 months, indicating that the virus’ impact on brain lymphatic circulation was most evident at 3 months, and the brain’s glymphatic system returns to normal after 12 months.Additionally, we observed that some patients exhibited a more pronounced increase in the DTI-ALPS index at the 3-month mark and demonstrated faster recovery by 12 months. In contrast, a few patients showed incomplete recovery of the DTI-ALPS index at 12 months, which may be associated with long-term COVID-19 symptoms, such as brain fog.A subset of patients with long COVID-19 exhibit elevated levels of inflammatory markers (e.g., IL-6) in the blood at 3 months post-infection (Kang et al., 2022), while the activity of lymphatic function is closely associated with inflammatory factors. The brain’s glymphatic function may exhibit a compensatory response to these inflammatory changes. Additionally, SARS-CoV-2 may increase resistance to cerebrospinal fluid (CSF) outflow through the cribriform plate, and patients with post-COVID-19 fatigue syndrome might enhance waste clearance by upregulating glymphatic transport, leading to heightened brain glymphatic activity (Wostyn, 2021). This may be related to the observed increase in the DTI-ALPS index among recovered COVID-19 patients at 3 months post-infection. However, the underlying mechanisms remain unclear and require validation through larger cohort studies and more comprehensive data analysis.

A study of 273,618 COVID-19 patients also showed that 36.55% of individuals developed various clinical symptoms such as fatigue, cognitive impairment, and anxiety between 3 and 6 months after COVID-19 infection, with fatigue (18.82% in 1–180 days; 5.87% in 90–180 days) and cognitive symptoms (7.88% in 1–180 days; 3.95% in 1–180 days) occurring, but not immediately after infection (Taquet et al., 2021). This is consistent with our findings.

Under normal circumstances, the brain parenchyma receives cerebrospinal fluid that flows along the perivascular spaces of arteries, and the interstitial fluid flows out along the perivascular spaces of veins. These two pathways of influx and clearance mainly rely on the communication between the end feet of astrocytes and the gaps between the vessel walls, where the water channel protein AQP4 facilitates the exchange of cerebrospinal fluid and interstitial fluid. The increased DTI-ALPS index suggests enhanced clearance of cerebrospinal fluid through the perivascular spaces of veins (Liu et al., 2021).The lymphatic system’s ability to clear metabolic waste from the brain is widely accepted. During sleep or anesthesia, the interstitial space increases by 60%, leading to a significant increase in the convective exchange of cerebrospinal fluid and interstitial fluid, and the increased convective flow also accelerates the clearance of β-amyloid during sleep (Xie et al., 2013). Brain inflammation and changes in the brain microenvironment can also lead to increased cerebrospinal fluid production (Gumeler et al., 2023; Yu et al., 2022).Certain immune molecules can have neuromodulatory effects on the brain, and the activity of the meningeal lymphatic vessels can alter the accessibility of these neuroimmune modulators in the cerebrospinal fluid to the brain parenchyma, thereby changing their influence on the brain (Xie et al., 2013; Da et al., 2018). This further supports the enhanced cerebrospinal fluid clearance function in COVID-19 convalescent patients. The causes of delayed neurological sequelae might be confirmed by objective brain evidence provided by these MRI scans (Mohammadi and Ghaderi, 2024).

Our study also identified associations between the MOCA score, mental fatigue, and brain lymphatic circulation. The occurrence of cognitive impairment and mental fatigue may be attributed to various factors, such as the accumulation of central toxic metabolites, disruption of the brain microenvironment, and neuronal injury, which can collectively contribute to a series of related neurological diseases and cognitive dysfunction. The lymphatic system plays a crucial role in clearing metabolic waste from the brain and regulating the accessibility of neuroimmune modulators in the cerebrospinal fluid to the brain parenchyma. These functions are essential for alleviating mental fatigue and supporting higher cognitive functions, including learning and memory (Xie et al., 2013; Yu et al., 2024). However, it is important to note that this study design does not establish a causal relationship between these variables. Although our results suggest that impaired glymphatic function is associated with cognitive decline, correlation does not imply causation.

This study has several limitations: 1. Lack of pre-infection and during-infection cognitive, lymphatic, and MRI data: Due to the unanticipated transmissibility of COVID-19 and concerns about nosocomial transmission, the researchers were unable to collect cognitive, lymphatic, and MRI data from the participants prior to and during their SARS-CoV-2 infection. This limits the ability to analyze the complete trajectory from baseline to recovery. Future studies should aim to obtain baseline data on the participants prior to their COVID-19 infection to enable a more comprehensive comparison. 2. Lack of longitudinal comparison with healthy controls: The study only examined the longitudinal changes within the COVID-19 patient group, without a parallel longitudinal comparison with a healthy control group. 3. Larger-scale studies are needed to confirm and expand upon the current results. 4. Lengthy intervals between follow-up assessments: The extended time intervals between the follow-up assessments may have failed to fully capture the long-term temporal evolution of the ALPS index. Despite these limitations, this study provides a novel perspective on the neurobiological underpinnings of cognitive impairment and mental fatigue in COVID-19 convalescent patients, emphasizing the potential role of the brain lymphatic circulation in cognitive recovery. The identified limitations suggest the need for improvements in future research to more comprehensively and accurately unravel this complex issue.

In summary, this prospective study systematically investigated the longitudinal changes in the brain lymphatic circulation of COVID-19 patients within 1 year after viral clearance, and its association with cognitive function and mental fatigue. The results showed that: The overall cognitive function of COVID-19 convalescent patients gradually recovered, but exhibited a significant decline at 3 months post-recovery. However, mental fatigue persisted even at 1 year post-recovery. The brain lymphatic circulation in both cerebral hemispheres exhibited dynamic changes, with the highest level of lymphatic activity observed at 3 months post-recovery. The changes in the brain lymphatic circulation were significantly correlated with the overall cognitive function and mental fatigue, suggesting it may be a potential underlying mechanism for the cognitive impairment and persistent mental fatigue observed in COVID-19 convalescent patients. These findings suggest that enhancing brain glymphatic function, potentially through targeted interventions, may offer a novel therapeutic approach for mitigating long COVID-19 symptoms, including cognitive impairment and mental fatigue, by improving waste clearance and reducing neuroinflammation.