The primary aim of the project is to map fatigue, cognitive and visual dysfunctions andpossible underlying pathophysiological mechanisms in persons with long-term symptomsafter a mild to moderate COVID-19 infection. Secondary goals are to study whethercovarying factors such as depression and sleep disorders contribute to the results.
The primary aim of the project is to map neuropsychological and visual dysfunctions and
possible underlying pathophysiological mechanisms in patients suffering from Post-COVID
condition (PCC) after a mild to moderate COVID-19 infection. Secondary goals are to study
whether covarying factors such as depression and sleep disorders contribute to the
results.
The main objectives are:
1. Which cognitive problems (self-reported and test results/performance based?) are
typical in patients with post-COVID syndrome compared to non-symptomatic controls?
2. Which pre-existing factors affect cognitive functions and fatigue after a mild to
moderate COVID-19 infection?
3. Is there a relationship between self-perceived symptoms, cognitive and visual test
results, optical coherence tomography (OCT) examination, imaging results, and
biomarkers in patients who have undergone mild COVID-19 infection and does this
differ compared to non-symptomatic controls?
4. How are fatigue, cognitive fatigability and vision-related disorders related to
neuronal correlates and changes in the retina examined with OCT and biomarkers
(astocyte-derived extracellular vesicles (High Mobility Group Box 1 (Hmbg1) and
S100B) and inflammatory markers) in patients who have remaining symptoms after a
mild COVID-19 infection and do the results differ from what can be seen in
non-symptomatic controls?
5. Are specific cognitive dysfunctions and fatigue/cognitive fatigability correlated
with astocyte-derived extracellular vesicles in patients who have remaining symptoms
after a mild COVID-19 infection?
6. How do symptoms evolve over one and two years?
STUDY DESIGN The study is a controlled longitudinal cohort study that includes
cross-sectional sub-studies of imaging and biomarkers.
STUDY SETTING Outpatient rehabilitation clinic at the Department of Rehabilitation
Medicine at Danderyd University Hospital and Karolinska University Hospital, both located
in Stockholm, Sweden. At the Cognitive post-COVID clinic at Danderyd University Hospital,
patients with long-term cognitive problems and fatigue are investigated after a mild to
moderat (not ICU treated) COVID-19 infection. Clinical assessments are included for all
participants but in a sub-study we will consecutively invite participants to also
investigate vision and eye functions, brain connectivity and, biomarkers.
PARTICIPANTS PATIENTS All patients present at the Cognitive Post-COVID clinic att the
Department of Rehabilitation Medicine at Danderyd University Hospital will have a medical
examination. Those patients with cognitive dysfunctions related to a COVID-19 infection
will be offered a comprehensive neuropsychological investigation and asked if they are
interested in participating in the cohort study.
The first 100 patients are consecutively asked if they also are interested in taking
biomarkers. Of these, up to 30 patients, meeting the inclusion criteria for functional
Magnetic Resonance Imaging (fMRI) are asked for participation in the a sub-study
including an fMRI investigation as well as an optometric and OCT investigation.
NON-SYMPTOMATIC CONTROLS 50 healthy controls who do not suffer from long term symptoms
after a COVID-19 infection >3 months from the latest infections or have not had a
COVID-19 infection will be investigated for comparison. The same exclusion criteria as
for the patients are applied also for the controls. The non-symptomatic controls will
undergo neuropsychological examination, examination of visual functions, sampling of
biomarkers, as well as fMRI examination and an OCT examination. The controls will be
matched with the patients regarding age, gender and length of education.
The patients will be followed-up with questionnaires regarding current symptoms after 1
and 2 years after the neuropsychological investigation.
Diagnostic Test: Neuropsychological investigation
Comprehensive neuropsychological test battery covering logical reasoning, different
attention functions, executive functions, visuospatial functions, different memory
functions, psychomotor speed, motor functions, and smell identification
Diagnostic Test: Optometric investigation
Extended vision examination including symptom assessment, visual acuity, visual field
(confrontation), eye movements, eye teaming and clinical assessment of hypersensitivity
to visual stimuli.
Diagnostic Test: Magnetic Resonance Imaging
The MRI sequence protocol includes resting state fMRI before and after the participants
do an established 20 min long reaction time measurement paradigm (E-prime). During the
paradigm a pseudo-continious arterial spin labeling sequence (pCASL) is acquired for
continuous measurement of brain perfusion. Following the functional sequences the imaging
protocol also includes a high resolution 3D T1weighted sequence Magnetization Prepared
Rapid Gradient Echo (MPRAGE) for brain structure, a high resolution 3D T2-weighted
sequence Fluid-Attenuated Inversion Recovery (FLAIR) for pathology and a 3D
susceptibility weighted image (SWI) for microvascular abnormalities.
Diagnostic Test: Immunological biomarkers
Venous blood samples (10-20 ml) are taken from the elbow crease. They are drawn in the
morning, and the participants are asked to fast for 12 hours prior to sampling. They are
also asked to avoid physical activity prior to blood sampling. The samples are drawn into
citrated tubes.
Inclusion Criteria:
• Persons 18 years and older with a history of (> 3 months) verified COVID-19 (PCR /
rapid test / antibody) or an infection that is most likely a SARS-CoV-2 infection (e.g.,
a close relative had a verified infection that coincided in time with the patient's
illness) and who have persistent problems with cognitive impairment or fatigue affecting
the return to previous activities / employment.
Exclusion Criteria:
- Dominant recurrent and / or fluctuating symptoms of infection, circulatory,
respiratory or cardiac problems.
- Co-morbidities that may cause cognitive impairment such as neurodegenerative
disease, substance abuse, severe mental illness (eg. schizophrenia, mano depressive
disorder) or severe depression.
- Not fluent in Swedish, as test and self-reports rely on good mastering of the
Swedish language.
- Severe premorbid visual impairment.
Additionally for the fMRI study:
- Not verified SARS-CoV-2 infection with a Polymerase Chain Reaction (PCR) / rapid
test / antibody review
- Traumatic brain injury
- Neuropsychiatric disease such as diagnosed ADHD or autism
- Younger than 25 years or older than 55 years (to avoid the risk that the brain is
not fully developed or that there is a risk of age-related changes in the brain).
- MRI contraindications (such as metal objects in the body, fear of cramped spaces,
pregnancy, body weight over 130 kg), and left-handedness (to increase the likelihood
of uniform topological lateralization in the cohort).
Department of Rehabilitation Medicine, Danderyd Hospital
Stockholm, Sweden
Investigator: Marika C Möller, PhD
Contact: +46812358555
marika.moller@ki.se
Marika C Möller, PhD
+46812358555
marika.moller@regionstockholm.se
Kristian Borg, Professor
+46704657065
kristian.borg@ki.se