Neuroinflammation can be an important regulator of long COVID, specifically fatigue andcognitive complaints. There is evidence that peripheral inflammation andneuro-inflammation are involved in fatigue and cognitive complaints, but precisepathophysiological mechanisms and causal relationship with viral infections are stillunknown. The primary aim of this study is to quantify neuroinflammation with [18F]DPA-714(TSPO-binding) PET scans in post-COVID-19 patients with and without post-infectiousfatigue and cognitive complaints and relate it to cognitive, psychiatric andpost-infectious fatigue symptoms.
In this study we will include 20 post-COVID-19 patients (>3 months after diagnosis or
discharge from hospital) (50% with post-infectious fatigue and/or cognitive complaints)
and 50% without post-infectious fatigue/cognitive complaints; matched for disease
severity). We will also include 10 age/sex-matched healthy controls without history of
COVID-19 or severe fatigue/cognitive complaints. RS6971 polymorphism of the TSPO receptor
will be determined and low affinity binders will be excluded from this study.
The main study parameter is the measurement of in vivo neuroinflammation with a
[18F]DPA-714 90 minutes PET scan, alternately capturing brain (60 minutes) and body (30
minutes) with both continuous on-line and manual arterial blood sampling for full
quantification ([18F]DPA-714 volume of distribution). The 30-minutes body scan will be
performed to examine whole-body inflammation. Brain MRI will be performed for functional
and anatomical information. We will use questionnaires and neuropsychological evaluation
to assess chronic fatigue, depressive, anxiety and cognitive symptoms, partially for
descriptive purposes.
Radiation: [18F]DPA-714 positron emission tomography (PET) scan
60 minute dynamic brain [18F]DPA-714 positron emission tomography (PET) scan followed by
a 30 minute static whole body positron emission tomography (PET) scan
Inclusion Criteria for post-COVID-19 individuals:
- The individual was diagnosed with symptomatic COVID-19, confirmed by a positive PCR
for SARS-CoV-2, positive SARS-CoV-2 serology or CO-RADS (COVID-19 Reporting and Data
System) 4 or 5 on CT-scan, or antigen quicktest, or had typical symptoms and was
part of a household in which another person was tested positive by PCR 2 weeks
before or after the first day of illness;
- The individual is 3 months after being diagnosed with COVID-19 or after hospital
discharge in case the patient was admitted.
- The individual is in the range 40-60 years of age (to ensure radiation safety)
- The individual has sufficient command of the Dutch language
- Genotyping of rs6971 must show that the individual is a mixed or high affinity
binder
Additional Inclusion criteria for patients with post-COVID-19 complaints:
- The patient experiences severe levels of fatigue (≥ 40) on the fatigue subscale of
the Checklist Individual Strength [CIS-fatigue]) and/or cognitive complaints (≥ 15)
on the concentration subscale of the Checklist Individual Strength
[CIS-concentration].The severe fatigue or cognitive complaints started with or
increased substantially directly after the onset of symptoms of COVID-19;
- The patient reports physical/social disability (≤ 65 on the Rand36 physical
functioning subscale or a score of ≥ 10 on the Work and Social Adjustment Scale
[WSAS];
Additional Inclusion criteria for individuals without post-COVID-19 complaints:
- The individual experiences no significant levels of fatigue (< 35 on the fatigue
subscale of the Checklist Individual Strength [CIS-fatigue]) or cognitive complaints
(<15 on the concentration subscale of the Checklist Individual Strength
[CIS-concentration]) and does not subjectively major symptoms of fatigue or
cognitive complaints. Based upon average of normal population +1SD.
- The individual reports no physical/social disability (> 65 on the Rand36 physical
functioning subscale or a score of < 10 on the Work and Social Adjustment Scale
[WSAS]
Inclusion Criteria for Healthy Controls:
- Should be negatively tested for COVID-19 trough PCR, serology, antibodies, or via
antigen quicktest
- No evidence for substantial fatigue or cognitive complaints as evidenced by the CIS
subscale fatigue (<35) and CIS subscale concentration (<15) and does not
subjectively major symptoms of fatigue or cognitive complaints. Based upon average
of normal population +1SD
- The individual is in the range 40-60 years of age (to ensure radiation safety)
- The individual has sufficient command of the Dutch language
- Genotyping of rs6971 must show that the individual is a mixed or high affinity
binder
Exclusion Criteria:
- Rs6971 shows low affinity binding
- Individuals who are unable to lay still for scanning due to claustrophobia or severe
back pain or trypanophobia (fear of needles)
- Gross neurological pathology (strategic or lobar infarcts or stroke or neurotrauma)
on MRI or CT that may interfere with the interpretation of the PET scan.
- Have a hemoglobin test (Hb) result of < to 8 in males and < to 7 in females;
- Are females of childbearing potential who are not surgically sterile, not refraining
from sexual activity or not using reliable methods of contraception. Females of
childbearing potential must not be pregnant (negative serum β-HCG at the time of
screening and negative urine β-HCG within 24 hours prior to injection) or
breastfeeding at screening.
- Have donated blood within 6 months prior to the [18F]DPA-714 PET scan day;
- The individual has an already known psychiatric or somatic condition that can
explain his/her fatigue or major psychiatric disorder other than somatic-symptom
disorder (chronic fatigue) as a main diagnosis. We will also screen for the presence
of Post-Traumatic Stress Disorder PTSD as a main diagnosis] (PCL-5) which prevalence
may be high in this patient group because of traumatic experiences during the acute
phase of COVID-19. We will also screen for the presence of depressive disorder as a
main diagnosis. To screen for PTSD and depressive disorder we will use the
Diagnostic and Statistical Manual of Mental Disorders version 5 and verbally check
if (any) symptoms do not meet the requirements for a PTSS or depression
diagnostic/classification;
- Current use of benzodiazepines11brg
VU University Medical Center
Amsterdam, Netherlands
Bart NM van Berckel, Prof., Principal Investigator
Radiology & Nuclear Medicine, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC