Understanding the Cognitive Impairments in Post-Acute SARS-CoV-2 Infection Through Advanced Neuroimaging


Cognitive impairment (CI) emerges as a prevalent and perplexing symptom of post-acute sequelae of SARS-CoV-2 infection (PASC), colloquially known as long COVID. The intricate pathogenesis behind these neurological complications remains enigmatic, with theories pointing towards immune dysregulation, autoimmunity, formation of microthrombi, and disruptions to the blood-brain barrier (BBB). Despite numerous studies, a definitive understanding, especially utilizing longitudinal brain imaging techniques, remains elusive, with only one prior study utilizing magnetic resonance imaging (MRI) to explore BBB disruptions without a longitudinal framework.

The Role of Brain Imaging in Understanding Post-COVID Cognitive Impairment

Brain imaging has been instrumental yet limited in shedding light on the neuropathogenesis of cognitive impairment following a COVID-19 infection. Early studies primarily focused on severely affected individuals during the acute phase of the infection, identifying critical issues like ischemia, hemorrhage, and venous sinus thromboses. However, there is a conspicuous scarcity of literature employing advanced neuroimaging techniques during the post-acute phase of COVID-19.

Recent investigations employing structural and diffusion MRI have indicated notable changes in grey matter volumes, particularly in regions like the hippocampus, and alterations in white matter across several brain regions. For instance, a volumetric MRI study tracking 401 patients from the onset of their infection and subsequently four months post-acute phase revealed diminished brain volume in critical areas associated with olfactory and gustatory functions. Furthermore, studies utilizing dynamic contrast-enhanced (DCE) perfusion imaging have linked BBB impairment with neuroinflammatory markers, suggesting a potential pathway to chronic neuropathological changes in PASC patients.

Longitudinal Study Design and Methodology

The study adopted a longitudinal design to delve deeper into the mechanistic pathways potentially leading to cognitive impairment in PASC patients. We aimed to test a ‘triple-hit hypothesis’, suggesting that the convergence of BBB changes, altered brain neurochemicals, and disrupted white matter microstructure could collectively precipitate cognitive decline. This was investigated using serial imaging alongside correlation analyses with cognitive scores in participants.

Participant Recruitment and Data Collection

The researchers recruited fourteen participants who had been experiencing persistent symptoms such as anosmia, ageusia, fatigue, and cognitive impairment following COVID-19. These participants underwent extensive neurological assessments and MRI scans at defined intervals—initially early in the post-acute phase and subsequently at a one-year follow-up. Advanced MR imaging techniques were employed to ascertain changes in BBB permeability, brain metabolites, and white matter microstructure.

Findings and Observations Our findings highlighted several critical aspects:

  • Blood-Brain Barrier Permeability: Initial data indicated a significant increase in BBB permeability in PASC patients compared to controls, a finding consistent with theories suggesting BBB disruption as a cornerstone in PASC pathogenesis.
  • Brain Metabolites: Metabolic analysis revealed alterations in key brain chemicals like Glx and NAA, which are indicative of neurochemical imbalances possibly driven by excitotoxicity—a condition where neuron damage is caused by excessive neurotransmitter release.
  • White Matter Microstructure: Diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) showed increased fractional anisotropy (FA) and decreased mean diffusivity (MD) in white matter tracts, suggesting ongoing inflammatory or degenerative changes in brain tissue.

Discussion and Interpretation of Results

The study corroborates the hypothesis that BBB impairment, alongside shifts in neurochemical and structural parameters, plays a pivotal role in the development of cognitive impairment in PASC. The observed changes in white matter microstructure and brain metabolites underscore a complex interplay of neuroinflammatory processes that could perpetuate cognitive deficits.

Limitations and Directions for Future Research

Despite the insightful findings, our study is not without limitations. The small sample size and the absence of control data at the 12-month mark may limit the generalizability and depth of our conclusions. Moreover, the narrow scope of cognitive impairments assessed and the specific participant criteria could further restrict the applicability of our results.


While the study does not claim conclusive evidence on the pathogenesis of PASC-induced cognitive impairment, it significantly enhances our understanding by linking BBB integrity disruptions with ongoing neuroinflammatory processes. These insights pave the way for future research, which should aim to expand on these findings through larger, more diverse cohort studies that could eventually inform targeted therapeutic interventions designed to mitigate long-term cognitive effects post-COVID-19.


Let’s break down and explain the findings and observations from the study on cognitive impairment in post-acute SARS CoV-2 infection (PASC), also known as long COVID. This explanation will focus on three main areas detailed in the study: Blood-Brain Barrier Permeability, Brain Metabolites, and White Matter Microstructure.

Blood-Brain Barrier Permeability (BBB)

What is the Blood-Brain Barrier? The BBB is a selective barrier that separates the circulating blood from the brain and extracellular fluid in the central nervous system (CNS). It is crucial for protecting the brain from pathogens, toxins, and regulating the transport of nutrients and neurotransmitters necessary for brain function.

Findings: The study found a significant increase in BBB permeability in PASC patients compared to healthy controls. This means that the BBB in patients suffering from long COVID became more permeable or “leaky.”

Implications: This increased permeability can allow harmful substances, which are normally blocked, to enter the brain and potentially cause damage. The finding supports the hypothesis that BBB disruption is a critical factor in the development of cognitive impairments seen in PASC. The disruption could be due to inflammation, immune system dysregulation, or direct viral effects.

Methodology Highlight: The assessment of BBB integrity was likely performed using advanced imaging techniques, possibly involving contrast agents that help visualize the degree of permeability in brain scans.

Brain Metabolites

What are Brain Metabolites? Brain metabolites are various chemicals present in the brain that are crucial for its function. They can include neurotransmitters, amino acids, and other biochemicals that play roles in neuron function and communication.

Key Metabolites Mentioned: Glx and NAA

  • Glx (Glutamate + Glutamine): Glx is a measure that combines glutamate, the most abundant excitatory neurotransmitter, with glutamine. It plays a key role in synaptic transmission.
  • NAA (N-Acetylaspartate): NAA is considered a marker of neuronal health and function. It is found in neurons and is used in brain imaging to assess neuronal integrity.

Findings: The study noted alterations in these metabolites, indicating neurochemical imbalances. Specifically, changes in Glx and NAA levels suggest neuronal distress or damage.

Implications: The observed changes are thought to be linked to excitotoxicity, a harmful process triggered by excessive release of glutamate and other excitatory neurotransmitters, which leads to neuronal damage and death. This process is detrimental to brain health and could contribute to the cognitive symptoms experienced by PASC patients.

Methodology Highlight: Magnetic Resonance Spectroscopy (MRS) might have been used to measure these metabolites, providing insights into the chemical environment of the brain.

White Matter Microstructure

What is White Matter Microstructure? White matter in the brain consists of nerve fibers (axons) that connect different brain regions. The microstructure of white matter refers to the organization and integrity of these nerve fibers.

Techniques Used: DTI and TBSS

  • Diffusion Tensor Imaging (DTI): DTI is an MRI technique that maps the diffusion process of molecules, mainly water, in biological tissues. In brain imaging, it’s used to visualize and characterize the white matter tract integrity.
  • Tract-Based Spatial Statistics (TBSS): TBSS is a method used with DTI data to enhance the objectivity and sensitivity of analysis of diffusion measures across subjects in a study.

Findings: The study observed increased fractional anisotropy (FA) and decreased mean diffusivity (MD) in the white matter tracts of PASC patients. FA measures the degree of directional water diffusion and is often used as an indicator of fiber density, axonal diameter, and myelination in white matter. An increase in FA and a decrease in MD suggest changes in the white matter’s structural integrity.

Implications: These changes could indicate ongoing inflammatory or degenerative processes affecting the brain’s white matter. This could be due to a direct viral effect, immune-mediated damage, or a secondary consequence of other changes in the brain, such as the disruption of the BBB.

Methodology Highlight: The use of DTI and TBSS allows for a detailed assessment of the microstructural integrity of white matter, providing a way to visualize and quantify changes that are not detectable with standard MRI.

In summary, these findings from the study provide critical insights into the neurological impacts of long COVID, highlighting the complex interplay of BBB integrity, neurochemical balance, and white matter structure in the brain. These insights are crucial for developing targeted therapies to mitigate the neurological consequences of PASC.

reference link : https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1350848/full


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