Deep neuroinflammation associated with long COVID

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In a recent study published on medRxiv* pre-print server, the researchers used a new quantitative assessment, [18F]DPA-714 positron emission tomography (PET), to collect live evidence of generalized neuroinflammation in two patients with post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC).

Study: Long COVID is associated with extensive in vivo neuroinflammation on [18F]DPA-714 PET. Image Credit: DOERS/Shutterstock

Background

About 36-53% of patients with coronavirus disease 2019 (COVID-19) develop persistent chronic symptoms, often referred to as long COVID or PASC. These symptoms are mainly neurological and manifest as fatigue, dysgeusia, anosmia and cognitive impairment.

Although for a long time, COVID has affected millions of people around the world; however, relatively little is known about its pathophysiology. Studies have shown microglial activation and neuroinflammation in the brains of patients with long COVID. Therefore, more live studies examining neuroinflammation in COVID-19 patients are needed. This would help elucidate the pathophysiological cascade underlying the neurological symptoms of long COVID and aid in finding potential corrective therapies.

About the study

In the current study, researchers asked both study patients to provide informed consent for further screening. Subsequently, they provided their medical records and participated in standardized neuropsychological assessment tests.

The first patient was a Dutch woman in her fifties who worked full time. She first contracted COVID-19 in December 2020, confirmed by a positive reverse transcription-polymerase chain reaction (RT-PCR). She did not need hospitalization or treatment during her acute phase of infection. However, she developed persistent fatigue, parosmia, anosmia, and some visual and concentration deficits later. Prior to SARS-CoV-2 infection, she suffered from high cholesterol and fibromyalgia, but her condition was stable and did not interfere with her work. Following the infection, her fatigue worsened and persisted (along with other symptoms) for 15 months.

The second patient was a Dutchman in his sixties who worked full time. A positive RT-PCR indicated that he acquired SARS-CoV-2 infection in March 2020. During 15 days of hospitalization during the acute phase of SARS-CoV-2 infection, he remained one night in the intensive care unit (ICU) due to certain respiratory problems. He encountered difficulty concentrating and suffered from severe post-COVID-19 fatigue. His symptoms having persisted 24 months after the infection, he was declared partially unfit for work. Both patients were unvaccinated at the time of infection but received their vaccination after one year of SARS-CoV-2 infection. They received their respective primary vaccination one year and 21 months after infection.

The researchers determined the genotype of the RS6971 polymorphism in the gene encoding the translocator protein (TSPO). The three healthy control subjects in the current study matched the study subjects in having high affinity for TSPO. Notably, the first control subject was female, while subjects two and three were male.

The researchers also included data from eight patients with multiple sclerosis (MS) for a (quantitative) comparison of the [ 18F]Metabolism of DPA-714. They subjected all study participants to magnetic resonance imaging (MRI) and also obtained their [18F]DPA-714 PET scans with arterial blood sampling.

Additionally, the researchers compared the [18F]Metabolites of DPA-714 in the blood of the two long COVID patients. Similarly, they compared brain gray matter BPn/a values ​​between two long COVID patients and three matched healthy control subjects using 2T4k_VB approach. Finally, they generated distribution volume (VJ) images using Logan plot analysis. Using t*=10 minutes, they divided these images by the k1/k2 ratio of whole-brain gray matter, after subtracting one to correct for Logan VJ images for the resulting non-displaceable volume of distribution in BPn/a (=k3/k4) pictures.

Neuroinflammation in two long-term COVID patients.  Quantify [18F]DPA-714 binding in whole-brain gray matter (GM), we used a dual plasma input tissue compartment model with blood volume parameter (2T4k_VB).  All quantitative whole brain gray matter binding potential (BPND (=k3/k4)) values ​​reported are estimated using 2T4k_VB.  For visualization purposes, we generated volume of distribution (VT) images using Logan plot analysis (11), using t* = 10 min, and divided these images by the ratio k1/ k2 of whole brain gray matter obtained by the 2T4k_VB plasma input model, after subtracting 1. In doing so, Logan VT images were corrected for non-displaceable volume of distribution resulting in BPND images (=k3/k4 ) for illustrative purposes.  (A) T1-weighted MRI and parametric images of [18F]DPA-714 binding in the brains of two long COVID patients.  Higher binding potential (BPND) values ​​indicate more tracer binding and therefore higher levels of neuroinflammation.  The long COVID 1 patient showed severely elevated binding in all brain regions compared to healthy control subjects.  The long COVID 2 patient also showed high binding, with higher BPND values ​​than healthy control subjects.  (B) T1-weighted MRI and parametric images of [18F]Binding of DPA-714 in the brain of three healthy control subjects.

Neuroinflammation in two long-term COVID patients. Quantify [18F]DPA-714 binding in whole-brain gray matter (GM), we used a dual plasma input tissue compartment model with blood volume parameter (2T4k_VB). All quantitative whole brain gray matter binding potential (BPND (=k3/k4)) values ​​reported are estimated using 2T4k_VB. For visualization purposes, we generated volume of distribution (VT) images using Logan plot analysis (11), using t* = 10 min, and divided these images by the ratio k1/ k2 of whole brain gray matter obtained by the 2T4k_VB plasma input model, after subtracting 1. In doing so, Logan VT images were corrected for non-displaceable volume of distribution resulting in BPND images (=k3/k4 ) for illustrative purposes. (A) T1-weighted MRI and parametric images of [18F]DPA-714 binding in the brains of two long COVID patients. Higher binding potential (BPND) values ​​indicate more tracer binding and therefore higher levels of neuroinflammation. The long COVID 1 patient showed severely elevated binding in all brain regions compared to healthy control subjects. The long COVID 2 patient also showed high binding, with higher BPND values ​​than healthy control subjects. (B) T1-weighted MRI and parametric images of [18F]Binding of DPA-714 in the brain of three healthy control subjects.

Study results

According to the results of neuropsychological tests, the two patients with long-term COVID suffered from fatigue, severe functional impairment and problems concentrating. The first patient had mild disturbances of sustained attention and verbal memory, while the second had fluctuating disturbances of sustained attention and visuo-constructive deficits.

Compared to a [18F]In the DPA-714 cohort of healthy control subjects and MS patients, the relative tracer fraction and corrected whole blood activity concentration for both study patients were within range. Thus, differences in tracer metabolism cannot reasonably explain differences in [18F]DPA-714 link.

MRI of healthy control subjects and the first long COVID patient was consistent with age; however, the second patient’s MRI showed mild atrophy of the parietal region. In addition, the first patient showed severe elevation [18F]DPA-714 binding in all regions of the brain. Compared to healthy controls, BPn/a (=k3/k4) values ​​obtained from 2T4k_VB model in the first patient increased by an average of 121%, while the same values ​​for the second patient increased by an average of 79%.

conclusion

Study data indicated widespread increases in [18F]DPA-714 binding throughout the brain in the two long COVID patients. The breadth and depth of the study’s findings may not have been definitive, but they were striking; thus, there is an urgent need for further research to understand whether anti-inflammatory therapy might benefit long COVID patients.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.

Journal reference:

  • Long COVID is associated with extensive in vivo neuroinflammation on [18F]DPA-714 PET, Denise Visser, Sandeep SV Golla, Sander CJ Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn , Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart NM van Berckel, medRxiv pre-print 2022, DOI : https://doi.org/10.1101/2022.06.02.22275916, https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1
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