Individuals With Long COVID Typically Suffer Massive Brain Neuroinflammation Including In The Thalamus Region

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A new study by researchers from Vrije Universiteit-Netherlands, University of Amsterdam-Netherlands and the University Medical Centre Utrecht-Netherlands has shockingly revealed that most Post-COVID individuals typically suffer continuous and massive brain neuroinflammation that contributes to various Long COVID manifestations.

The study involving the use of a new sensitive radiotracer ie the [18F] DPA714 for brain imaging via PET Scan, also found that the thalamus region of the brain also was subjected to inflammation. Considering that the thalamus is considered an important regulator, in relation to fatigue and cognitive functioning, this and may offer a clue towards the etiology of these symptoms in long COVID. 

The thalamus is an egg-shaped structure in the middle of the brain. It’s known as a relay station of all incoming motor (movement) and sensory information ie. hearing, taste, sight and touch (but not smell) from the body to the brain.

The radiotracer [18F] DPA714 is a pyrazolopyrimidine TSPO ligand with high affinity, which has a good stability in plasma and brain tissue and is only used when detailed imaging PET scan studies involving neuroinflammation is required.

It is already known that a significant number of COVID-19 patients develop ‘long COVID’, a condition defined by long-lasting debilitating, often neurological, symptoms.

However, the detailed pathophysiology of long COVID is unknown.

The study team in this research presented in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment via the DPA714 PET platform, in two long COVID patients.

The study team reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in 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.

The study findings were published on a preprint server and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1

Long COVID is a worldwide problem, with high individual and societal cost, but no known pathophysiology. In this study, we report widespread and large increases in [18F]DPA-714 binding throughout the brain in the first two patients included in our in-vivo study of neuroinflammation.

Although far from definitive, these findings are striking in extent and magnitude. As such, they implicate profound neuroinflammation in the pathophysiology of long COVID.

The extent of neuroinflammation in these patients with long COVID is remarkable. Whereas earlier post-mortem studies of acute COVID-19 patients have shown elevated neuroinflammation primarily in olfactory bulbs, medulla, brainstem and cerebellum, the current study suggests that the process of neuroinflammation may be more widespread in long COVID (5-7).

Furthermore, as can be visually appreciated, we found high binding in the thalamus for both patients. This has also been reported in MS, using similar (TSPO) PET ligands (12). The thalamus is considered an important regulator, in relation to fatigue and cognitive functioning (13, 14) and may offer a clue towards the etiology of these symptoms in long COVID.

In addition to hinting at the pathophysiology of long COVID, neuroinflammatory processes could also be informative in relation to the prognosis of patients with long COVID. A recent study described cortical thinning and gray matter volume loss over time, as well as cognitive decline, in patients with long COVID (15).

PET studies in MS have found that increased neuroinflammation is predictive of disease progression (16), suggesting a link between neuroinflammation and neurodegeneration on MRI.

This may be relevant equally to long COVID. Furthermore, this raises the very important question of the ‘need to treat’ in the context of long COVID. The patients with long COVID in this study had widespread increases in neuroinflammation and substantial functional impairment, with only minimal abnormalities on MRI.

Although these are preliminary findings and the exact relation between neuroinflammation, functional impairment and longer term structural brain changes is not yet established, taken together, these findings do raise the question whether treatment with anti-inflammatory drugs could be beneficial.

Given the millions of people worldwide affected by this condition, the tremendous cost associated with it (to individuals and society) and the current, limited status of our knowledge, this is perhaps worthy of clinical investigation. Especially given recent findings from a study showing that vaccination prior to infection only seems to confer partial protection in the post-acute phase of the disease (17).

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. 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.

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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