Cognitive Impairment and Fatigue After Mild to Moderate COVID-19 - Relation to Biomarkers and Neuronal Network Functions
Overview
- Phase
- Not Applicable
- Intervention
- Not specified
- Conditions
- Post COVID-19 Condition
- Sponsor
- Danderyd Hospital
- Enrollment
- 100
- Locations
- 1
- Primary Endpoint
- Fatigability from Wechsler Adult Intelligence Scale (WAIS)-IV Coding Test
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Marika Moller
Associate Professor
Danderyd Hospital
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).
Outcomes
Primary Outcomes
Fatigability from Wechsler Adult Intelligence Scale (WAIS)-IV Coding Test
Time Frame: baseline
The subject must fill in the blank spaces with the symbol which is paired to the number for 120 seconds. Cognitive fatigue is assessed by subtracting the number of digits produced in the first 30 seconds from the number of digits produced in the last 30 seconds during the full 120-second period. A non-ascending score (\< 0) is considered an indicator of cognitive fatigue. Both the total value in the difference between the production between 0-30 seconds and 91-120 seconds are measured, and a dichotomized variable (non-ascending value) will be used.
Buschke selective reminding test (BSRT)
Time Frame: baseline
The BSRT measure verbal learning and long-term memory. The subject hears a list of 12 unrelated words and immediately after that have to recall as many of these 12 words as possible. On each subsequent trial, the subject only hears the words that the subject did not recall on the immediately preceding trial. The test proceed in this manner until the subject can correctly recall all 12 words on two consecutive trials, or until 12 trials have been completed. Through assessing the recall of items that are not presented on a given trial, this test is believed to distinguish between retrieval from long-term storage (LTS) and short-term recall (STR). Consistent recalled words (CLTS) are thought to represent executive aspects of the learning process. After the learning phase, the subject is asked to free recall the words after a 30-minute delay. A cued recall and a multiple-choice condition are also included in the test.
Task-based fMRI
Time Frame: baseline
Cerebral perfusion changes during reaction time paradigm.
Resting-state fMRI
Time Frame: baseline
Changes in functional connectivity after performance of a reaction time paradigm.
Visual Motion Sensitivity
Time Frame: baseline
Sensitivity to movement in the environment was assessed according to the Visual Motion Sensitivity Clinical Test Protocol. The subject is asked to stand and gaze straight ahead at a fixation mark on the wall at eye level at 4 m distance. An Opto Kinetic Nystagmus drum is held at 25 cm from the face. The drum is rotated at slow-medium velocity while the subject is asked to grade symptoms on a scale of 0-10, where zero means no bother at all and 10 a strong effect of nauseous or somatic or visual sensation.
Symptom questionnaire
Time Frame: baseline and 1 year and 2 years after the neuropsychological assessment
The subject rates 32 different cognitive, emotional and physical symptoms where 0 represents have not had this symptom at all, 1 = have had the symptom but is not a problem anymore, 2 = is still a small problem, 3 = is a moderate problem, and 4 = a severe problem. A maximum score is 128 points.
The Montreal Cognitive Assessment (MoCA)
Time Frame: baseline and 1 year and 2 years after the neuropsychological assessment
A rapid screening test consisting of seven different domains including 1) visuospatial/executive functions, 2) naming, 3) memory, 4) attention, 5) language, 6) abstraction, and 7) orientation. The total score is 30 points +1 point adjustment for low education); normal functioning is considered from score of 26 and above.
Ruff 2&7
Time Frame: baseline
Ruff 2 \& 7 measures sustained and selective attention as a continuous performance test during 5 minutes. The subject has to identify and cancel the target digits (2 and 7) among distractors; either letters (automatic sustained attention) or numbers (controlled selective attention), in random order. Both accuracy and speed are measured. Higher scores mean better performance. Performance is evaluated according to the test manual.
Fatigability on e-prime vigilance task in the fMRI scanner
Time Frame: baseline
The participants are instructed to push a button as quick as they can when a set of four zeroes appears in a red rectangle and do nothing if other numbers appear. After each response visual feedback of the reaction time is displayed. If the participant reacts at a false stimulus or if the response time of more than 1 sec. the feedback "false answer" or "no answer" is displayed respectively. The stimuli are presented at random intervals.
The Delis-Kaplan Executive Function System (D-KEFS) Color-Word Test
Time Frame: baseline
Inhibition of over-learned verbal responses. The test has four conditions: 1) naming colors (red, blue or green, 2) reading color words printed in black, 3) naming the color of the color words red, blue or green write in a different color than what is written, which means inhibition of an over-learned function of reading the word; 4) repeatedly switching between naming colors and reading out the printed words as quickly as possible, while at the same time the person needs to keep track of clues that indicate rule change. Contrast scores are used to examine the performance of the more complex tasks 3 and 4 and the basic tasks 1 and 2. The faster the time, the better
Biomarkers
Time Frame: baseline
S100B, Astrocyte-derived Extracellular Vesicles (EV) and High Mobility Group Box 1 (Hmbg1). Exploratory targeted analyses using panels of cytokines \& chemokines and neuroinflammation will also be used.
Developmental Eye Movement Test
Time Frame: baseline
Saccadic eye movements are assessed with the Developmental Eye Movement Test. In the first step, the subject read 40 one-digit numbers arranged in two columns. Time duration and reading errors are measured. This is repeated with a new set of numbers where the subject read 80 numbers distributed over 16 horizontal lines. There are 5 irregularly spaced numbers per line, intended to mimic the way the eyes make saccadic movements during reading. For at ratio the total time duration for reading numbers horizontally is divided by the total time for reading numbers vertically.
Multidimensional Fatigue Inventory-20
Time Frame: baseline and 1 year and 2 years after the neuropsychological assessment
The MFI-20 consists of five scales, based on different modes of expressing fatigue. Each scale contains four items for which the subject indicates on a seven-point scale to what extent the statement applies best. 'General fatigue' includes general statements concerning a person's functioning. 'Physical fatigue' refers to the physical sensation related to the feeling of tiredness. 'Reduced activities' measures reduction in activities and 'Reduced motivation' lack of motivation. 'Mental fatigue' measures cognitive symptoms related to fatigue. Some sentences are inverted and need to be rescored. On each scales the higher values the higher fatigue.
Secondary Outcomes
- Visual Analog Scale of Fatigue(baseline)
- D-KEFS Trail Making Test(baseline)
- Convergence Insufficiency Symptom Survey (CISS)(baseline)
- D-KEFS Word Fluency Test(baseline)
- WAIS-IV Digit Span(baseline)
- Brain Injury Vision Symptom Survey measuring general vision-related symptoms (BIVSS)(baseline)
- Rey-Complex Figure Test (RCFT)(baseline)
- Optical coherence tomography (OCT)(baseline)