Cognitive Impairment and Fatigue After Mild to Moderate COVID-19

The primary aim of the project is to map fatigue, cognitive and visual dysfunctions and possible underlying pathophysiological mechanisms in persons with long-term symptoms 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 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.

Eligibility Criteria:
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).