Preprint Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET, 2022, Visser et al

SNT Gatchaman

SNT Gatchaman

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Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET (Preprint)
Denise Visser, Sandeep S.V. Golla, Sander C.J. 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 N.M. van Berckel

A significant number of COVID-19 patients develop 'long COVID', a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown.

Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively.

This implicates profound neuroinflammation in the pathophysiology of long COVID.

Link | PDF
 
The radio tracer DPA-714 is a translator protein (TSPO). See here and related comments here. See also Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation (2012).

This study implicated neuroinflammation in persistent symptoms following COVID-19 infection and has several strengths. We were able to obtain spatial in-vivo information on neuroinflammation by using fully quantitative [18F]DPA-714 PET. We were able to compare the patients with three non-infected healthy control, with similar characteristics and scanned with the same methods on the same scanner, as well as blood data from a historical non-infected cohort. This permitted us to assess the severity of neuroinflammation.
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However, this study also has several limitations. First and foremost, we included only two patients with long COVID. These were the first two patients with long COVID included in this study, and we felt these data were too important not to publish at this stage. However, that does not negate that these remarkable findings will need to be replicated in a larger number of patients. Second, we had no comparable neuropsychological or questionnaire data available.
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In conclusion, we report widespread and large increases in [18F]DPA-714 binding throughout the brain in the first two long COVID patients included in our in-vivo study. Long COVID represents a worldwide problem that comes at great cost to both individuals and society. Although our findings are far from definitive, they are striking in extent and magnitude. They implicate profound neuroinflammation in the pathophysiology of long COVID, and raise the question of whether (individualized) anti-inflammatory treatment could be beneficial.
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Might have been interesting to know when the patient scans were made relative to their infections. The "first patient" became ill in December 2020, while the "second patient" became ill 9 months earlier in March. If the scans were done at the same time, the stronger intensity of patient 1's scan might reflect his more recent infection. Patient 2 was female, so a sex difference might also be a factor. Regardless, the scans of both patients are obviously dramatically different from the controls.
 
adambeyoncelowe said:
I'm cautious. Obviously, the Nakatomi paper used PET to find glial activation in ME, so this feels like a logical finding for LC, but this is still just two patients.
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The James lab also had preliminary findings as stated on the page I referenced above: “Our encouraging preliminary data shows increased [11C]DPA-713-PET signal in multiple brain regions of severe ME/CFS patients compared to healthy controls.”

it seems that this type of TSPO imaging agent finds abnormalities in a lot of CNS disorders. This paper reviewing types of radioligands describes some of the limitations of second gen agents. I don’t understand exactly if any TSPO agents are currently commercialized or if they are all used in research setting. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650818/
 
If these findings hold up in a larger cohort (or show up in ME patients), it seems like this could be pretty significant. It might also be really interesting to see if LDN or Abilify treatment would change the results in follow up scans on the same patients. Perhaps this could give us some idea if the theorized anti-inflammatory effects of these two drugs are real.

Forbin said:
Might have been interesting to know when the patient scans were made relative to their infections. The "first patient" became ill in December 2020, while the "second patient" became ill 9 months earlier in March. If the scans were done at the same time, the stronger intensity of patient 1's scan might reflect his more recent infection.
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They say in their trial registration that the actual start date was February of this year, so it seems they were at a minimum 14 and 23 months after infection. It looks like they plan to enrol 20 patients in the study, hopefully we'll see more results soon.
 
A related pre-print (it can have it's own thread if needed on acceptance).

SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling (Pre-print, Jun 2022)

Abstract said:
Neurological effects of COVID-19 and long-COVID-19 as well as neuroinvasion by SARS-CoV-2 still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro infection by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the Blood-Brain Barrier. Despite the low to non-productive viral replication, SARS-CoV-2-infected cultures displayed increased apoptotic cell death and tight junction protein expression and immunolocalization.

Transcriptomic profiling of infected cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression, and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.
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LarsSG said:
It might also be really interesting to see if LDN or Abilify treatment would change the results in follow up scans on the same patients. Perhaps this could give us some idea if the theorized anti-inflammatory effects of these two drugs are real
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Note that Hans 'CBT' Knoop is a co-author. He's trying to get the effect of CBT objectified by showing in decreased neuroinflammation.
 
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