Post COVID-19 ConditionNCT06042530
Cognitive Impairment and Fatigue After Mild to Moderate COVID-19
An observational study of Post COVID-19 Condition and Cognitive Impairment, run by Danderyd Hospital at 1 site in Sweden.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Post COVID-19 Condition, Cognitive Impairment, Fatigue, Mental
- What is being tested?
- Neuropsychological investigation, Optometric investigation and Magnetic Resonance Imaging
- How many people
- 100 participants
- Where
- 1 siteSweden
- Study dates
- 1 Apr 2021to 31 Dec 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Outpatients with long term (>3 months) cognitive symptoms and fatigue after a SARS-CoV-2 infection and present at the Department of Rehabilitation Medicine at Danderyd University Hospital
Who may be able to join
- 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.
Who cannot join
- 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
Show all 10Show fewer
- 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).
Trial locations and contacts
1 site in 1 country.
Sweden1 site, 1 recruiting
- Recruiting
Department of Rehabilitation Medicine, Danderyd Hospital
Stockholm, 18288
Marika C Möller, PhD, +46812358555, marika.moller@ki.se
Kristian Borg, Professor, +46704657065, kristian.borg@ki.se
About this study
Official title: Cognitive Impairment and Fatigue After Mild to Moderate COVID-19 - Relation to Biomarkers and Neuronal Network Functions
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.
Read the 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:
- Which cognitive problems (self-reported and test results/performance based?) are typical in patients with post-COVID syndrome compared to non-symptomatic controls?
- Which pre-existing factors affect cognitive functions and fatigue after a mild to moderate COVID-19 infection?
- 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?
- 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?
- 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?
- 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.
- Being tested
- Neuropsychological investigation, Optometric investigation, Magnetic Resonance Imaging, Immunological biomarkers
- Keywords
- cognition, fatigue, COVID-19, neuropsychology, biomarkers, vision, imaging
- Medical subject headings
- Cognitive Dysfunction, Mental Fatigue, Fatigue, COVID-19
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Neuropsychological investigationDiagnostic test
Comprehensive neuropsychological test battery covering logical reasoning, different attention functions, executive functions, visuospatial functions, different memory functions, psychomotor speed, motor functions, and smell identification
Optometric investigationDiagnostic test
Extended vision examination including symptom assessment, visual acuity, visual field (confrontation), eye movements, eye teaming and clinical assessment of hypersensitivity to visual stimuli.
Magnetic Resonance ImagingDiagnostic test
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.
Immunological biomarkersDiagnostic test
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.
| Study group | Role | What they receive |
|---|---|---|
| Post-COVID condition | Patients experiencing persisting cognitive dysfunction and fatigue after a SARS-CoV-2 infection, three months or more after the infections Receives: Diagnostic Test: Neuropsychological investigation; Diagnostic Test: Optometric investigation; Diagnostic Test: Magnetic Resonance Imaging; Diagnostic Test: Immunological biomarkers | |
| Non-symptomatic controls | Persons experiencing no symptoms after the SARS-CoV-2 infection or have not been subject for at SARS-CoV-2 infection Receives: Diagnostic Test: Neuropsychological investigation; Diagnostic Test: Optometric investigation; Diagnostic Test: Magnetic Resonance Imaging; Diagnostic Test: Immunological biomarkers |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fatigability from Wechsler Adult Intelligence Scale (WAIS)-IV Coding Test
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.
Measured: baseline
Buschke selective reminding test (BSRT)
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.
Measured: baseline
Ruff 2&7
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.
Measured: baseline
The Delis-Kaplan Executive Function System (D-KEFS) Color-Word Test
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
Measured: baseline
Fatigability on e-prime vigilance task in the fMRI scanner
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.
Measured: baseline
Task-based fMRI
Cerebral perfusion changes during reaction time paradigm.
Measured: baseline
Resting-state fMRI
Changes in functional connectivity after performance of a reaction time paradigm.
Measured: baseline
Developmental Eye Movement Test
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.
Measured: baseline
Visual Motion Sensitivity
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.
Measured: baseline
Biomarkers
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.
Measured: baseline
Symptom questionnaire
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.
Measured: baseline and 1 year and 2 years after the neuropsychological assessment
Multidimensional Fatigue Inventory-20
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.
Measured: baseline and 1 year and 2 years after the neuropsychological assessment
The Montreal Cognitive Assessment (MoCA)
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.
Measured: baseline and 1 year and 2 years after the neuropsychological assessment
Secondary outcomes (8)
Visual Analog Scale of Fatigue
Measurement of self-rated current fatigue level. Ranges from 0 (corresponding to no fatigue) to 10 (corresponding to the worst possible fatigue)
Measured: baseline
D-KEFS Word Fluency Test
The test measures expressive language skills, initiative and working memory and consists of three different conditions: verbal phonological flow (1) where the test person for 60 seconds produces as many unique words as possible that begins with a given letter., category flow (2) where the test person for 60 seconds per category produce as many unique words as possible in two given semantic categories and category change (3) where the test person in 60 seconds produce so many unique words and switch between two specified semantic categories every other time. The more words, the better the performance.
Measured: baseline
WAIS-IV Digit Span
The test person must repeat numbers that the test leader reads out the leader reads out. The number of digits is increased by one unit every two times). The test person repeats the numbers in the same order (forward repetition) or reverse order (backward repetition). Forward repetition measures auditory attention span and short-term memory, while backward repetition measures auditory working memory. Both the total number of digits, forward, backward, and the difference between forward and backward repetition will be measured
Measured: baseline
Convergence Insufficiency Symptom Survey (CISS)
Measures symptoms while reading and near activities and intended for symptom assessment in the presence of convergence insufficiency. It includes 15 questions on symptoms and the patient is asked to grade how frequently each symptom occurs: Never (0), Infrequently (1), Sometimes (2), Fairly often (3), or Always (4). A score of 21 is considered useful as a cut-off.
Measured: baseline
Brain Injury Vision Symptom Survey measuring general vision-related symptoms (BIVSS)
BIVSS is originally intended for visual symptom assessment in patients with mild to moderate brain injury. BIVSS includes 28 questions covering seven areas of symptoms: visual clarity/acuity, visual comfort, double vision, photosensitivity, dry eyes, depth perception, visual field, and reading. BIVSS is administered as an interview and for each question the patient is asked to grade how often the symptom occur: Never (0), Seldom (1), Occasionally (2), Frequently (3), or Always (4). A cut-off score of 31 is considered useful for symptom screening.
Measured: baseline
Rey-Complex Figure Test (RCFT)
The RCFT is a visual learning and memory test that also measures other cognitive dimensions, including visuospatial construction skills, fine motor coordination, and planning. The test consists of four subtests: 1) copying, when the subject without time pressure, the time is recorded, is allowed to watch the figure and at the same time depict it without rotating or turning the figure. Immediately afterwards the template is withdrawn, and the subject has to 2) draw the figure again from memory (immediate reproduction). 3) After about 30 minutes (in between, other tests are carried out), the subject must again draw the figure from memory (delayed reproduction), and finally the subject has to 4) select from a booklet possible components from the figure (recognition).
Measured: baseline
D-KEFS Trail Making Test
The TMT measure visual perceptual function, attention, cognitive flexibility, processing speed, and motor speed. The test distinguish whether any weaknesses are due to deficits in underlying skills measured with the subtests 1-3 and 5 (visual scanning, letter or number sequencing or motor speed) or in cognitive flexibility (subtest 4), which is the main measure of the test. The subject is tasked with drawing lines between circles with either letters or numbers or nothing inside. The test subject is asked to complete the tasks as quickly and correctly as possible. The time to perform is measured. The lower score the better the result.
Measured: baseline
Optical coherence tomography (OCT)
Detection of retinal hemorrhages or abnormal retinal layer thickness.
Measured: baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Sep 2023
- Study start1 Apr 2021
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (36)Papers the sponsor has linked to this study.
- Other trials for Post COVID-19 ConditionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Danderyd Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Karolinska Institutet, Karolinska University Hospital, Uppsala University Hospital
- Responsible party
- Principal investigator, Marika Moller, Danderyd Hospital
- Investigators
- Kristian Borg, Professor, Study director, Karolinska InstitutetMarika C Möller, PhD, Principal investigator, Department of Rehabilitation Medicine, Danderyd University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06042530
- Sponsor's protocol ID
- 2021-03907_Cognition COVID-19
- Status last verified
- Sep 2023
- First submitted
- 7 Sep 2023
- Last updated
- 21 Sep 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Tsampasian V, Elghazaly H, Chattopadhyay R, Debski M, Naing TKP, Garg P, Clark A, Ntatsaki E, Vassiliou VS. Risk Factors Associated With Post-COVID-19 Condition: A Systematic Review and Meta-analysis. JAMA Intern Med. 2023 Jun 1;183(6):566-580. doi: 10.1001/jamainternmed.2023.0750.
PubMed 36951832Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. 2022 Jul;28(7):1461-1467. doi: 10.1038/s41591-022-01840-0. Epub 2022 May 25.
PubMed 35614233Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, DiBiase RM, Jia DT, Balabanov R, Ho SU, Batra A, Liotta EM, Koralnik IJ. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021 May;8(5):1073-1085. doi: 10.1002/acn3.51350. Epub 2021 Mar 30.
PubMed 33755344Premraj L, Kannapadi NV, Briggs J, Seal SM, Battaglini D, Fanning J, Suen J, Robba C, Fraser J, Cho SM. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci. 2022 Mar 15;434:120162. doi: 10.1016/j.jns.2022.120162. Epub 2022 Jan 29.
PubMed 35121209Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29.
PubMed 34973396Klironomos S, Tzortzakakis A, Kits A, Ohberg C, Kollia E, Ahoromazdae A, Almqvist H, Aspelin A, Martin H, Ouellette R, Al-Saadi J, Hasselberg M, Haghgou M, Pedersen M, Petersson S, Finnsson J, Lundberg J, Falk Delgado A, Granberg T. Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort. Radiology. 2020 Dec;297(3):E324-E334. doi: 10.1148/radiol.2020202791. Epub 2020 Jul 30.
PubMed 32729812Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Angles-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x. Epub 2020 May 4.
PubMed 32367170Heslin KP, Haruna A, George RA, Chen S, Nobel I, Anderson KB, Faraone SV, Zhang-James Y. Association Between ADHD and COVID-19 Infection and Clinical Outcomes: A Retrospective Cohort Study From Electronic Medical Records. J Atten Disord. 2023 Jan;27(2):169-181. doi: 10.1177/10870547221129305. Epub 2022 Oct 20.
PubMed 36264064Dobryakova E, DeLuca J, Genova HM, Wylie GR. Neural correlates of cognitive fatigue: cortico-striatal circuitry and effort-reward imbalance. J Int Neuropsychol Soc. 2013 Sep;19(8):849-53. doi: 10.1017/S1355617713000684. Epub 2013 Jul 10.
PubMed 23842042Nordin LE, Moller MC, Julin P, Bartfai A, Hashim F, Li TQ. Post mTBI fatigue is associated with abnormal brain functional connectivity. Sci Rep. 2016 Feb 16;6:21183. doi: 10.1038/srep21183.
PubMed 26878885Aceti A, Margarucci LM, Scaramucci E, Orsini M, Salerno G, Di Sante G, Gianfranceschi G, Di Liddo R, Valeriani F, Ria F, Simmaco M, Parnigotto PP, Vitali M, Romano Spica V, Michetti F. Serum S100B protein as a marker of severity in Covid-19 patients. Sci Rep. 2020 Oct 29;10(1):18665. doi: 10.1038/s41598-020-75618-0.
PubMed 33122776Cantor F. Central and peripheral fatigue: exemplified by multiple sclerosis and myasthenia gravis. PM R. 2010 May;2(5):399-405. doi: 10.1016/j.pmrj.2010.04.012.
PubMed 20656621Tahyra ASC, Calado RT, Almeida F. The Role of Extracellular Vesicles in COVID-19 Pathology. Cells. 2022 Aug 11;11(16):2496. doi: 10.3390/cells11162496.
PubMed 36010572Wallensten J, Nager A, Asberg M, Borg K, Beser A, Wilczek A, Mobarrez F. Leakage of astrocyte-derived extracellular vesicles in stress-induced exhaustion disorder: a cross-sectional study. Sci Rep. 2021 Jan 21;11(1):2009. doi: 10.1038/s41598-021-81453-8.
PubMed 33479350Kanberg N, Ashton NJ, Andersson LM, Yilmaz A, Lindh M, Nilsson S, Price RW, Blennow K, Zetterberg H, Gisslen M. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology. 2020 Sep 22;95(12):e1754-e1759. doi: 10.1212/WNL.0000000000010111. Epub 2020 Jun 16.
PubMed 32546655
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cognitive Impairment and Fatigue After Mild to Moderate COVID-19 - Relation to Biomarkers and Neuronal Network Functions
- ClinicalTrials.gov ID
- NCT06042530
- Acronym / sponsor ID
- 2021-03907_Cognition COVID-19
- Keywords
- cognition, fatigue, COVID-19, neuropsychology, biomarkers, vision, imaging
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Danderyd HospitalUniversity, hospital or other
- Collaborators
- Karolinska Institutet, Karolinska University Hospital, Uppsala University Hospital
- Study start
- 1 Apr 2021 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 18 Sep 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Which cognitive problems (self-reported and test results/performance based?) are typical in patients with post-COVID syndrome compared to non-symptomatic controls?
- Which pre-existing factors affect cognitive functions and fatigue after a mild to moderate COVID-19 infection?
- 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?
- 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?
- 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?
- 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.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Post-COVID condition | – | Diagnostic Test: Neuropsychological investigation, Diagnostic Test: Optometric investigation, Diagnostic Test: Magnetic Resonance Imaging, Diagnostic Test: Immunological biomarkersPatients experiencing persisting cognitive dysfunction and fatigue after a SARS-CoV-2 infection, three months or more after the infections |
| Non-symptomatic controls | – | Diagnostic Test: Neuropsychological investigation, Diagnostic Test: Optometric investigation, Diagnostic Test: Magnetic Resonance Imaging, Diagnostic Test: Immunological biomarkersPersons experiencing no symptoms after the SARS-CoV-2 infection or have not been subject for at SARS-CoV-2 infection |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Outpatients with long term (>3 months) cognitive symptoms and fatigue after a SARS-CoV-2 infection and present at the Department of Rehabilitation Medicine at Danderyd University Hospital
Key inclusion criteria (1 listed)
- 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.
Key exclusion criteria (10 listed)
- 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.
- Not verified SARS-CoV-2 infection with a Polymerase Chain Reaction (PCR) / rapid test / antibody review
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Neuropsychological investigationComprehensive 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 | Non-symptomatic controls, Post-COVID condition |
| Optometric investigationExtended vision examination including symptom assessment, visual acuity, visual field (confrontation), eye movements, eye teaming and clinical assessment of hypersensitivity to visual stimuli. | Diagnostic test | Non-symptomatic controls, Post-COVID condition |
| Magnetic Resonance ImagingThe 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 | Non-symptomatic controls, Post-COVID condition |
| Immunological biomarkersVenous 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. | Diagnostic test | Non-symptomatic controls, Post-COVID condition |
Primary outcome
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
8 secondary outcomes
Visual Analog Scale of Fatigue
Time frame: baseline
D-KEFS Word Fluency Test
Time frame: baseline
WAIS-IV Digit Span
Time frame: baseline
Convergence Insufficiency Symptom Survey (CISS)
Time frame: baseline
Brain Injury Vision Symptom Survey measuring general vision-related symptoms (BIVSS)
Time frame: baseline
Rey-Complex Figure Test (RCFT)
Time frame: baseline
D-KEFS Trail Making Test
Time frame: baseline
Optical coherence tomography (OCT)
Time frame: baseline
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2023.
- Background: PubMed 36951832Tsampasian V, Elghazaly H, Chattopadhyay R, Debski M, Naing TKP, Garg P, Clark A, Ntatsaki E, Vassiliou VS. Risk Factors Associated With Post-COVID-19 Condition: A Systematic Review and Meta-analysis. JAMA Intern Med. 2023 Jun 1;183(6):566-580. doi: 10.1001/jamainternmed.2023.0750.
- Background: PubMed 35614233Al-Aly Z, Bowe B, Xie Y. Long COVID after breakthrough SARS-CoV-2 infection. Nat Med. 2022 Jul;28(7):1461-1467. doi: 10.1038/s41591-022-01840-0. Epub 2022 May 25.
- Background: PubMed 33755344Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, DiBiase RM, Jia DT, Balabanov R, Ho SU, Batra A, Liotta EM, Koralnik IJ. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 "long haulers". Ann Clin Transl Neurol. 2021 May;8(5):1073-1085. doi: 10.1002/acn3.51350. Epub 2021 Mar 30.
- Background: PubMed 35121209Premraj L, Kannapadi NV, Briggs J, Seal SM, Battaglini D, Fanning J, Suen J, Robba C, Fraser J, Cho SM. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci. 2022 Mar 15;434:120162. doi: 10.1016/j.jns.2022.120162. Epub 2022 Jan 29.
- Background: PubMed 34973396Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Epub 2021 Dec 29.
- Background: PubMed 32729812Klironomos S, Tzortzakakis A, Kits A, Ohberg C, Kollia E, Ahoromazdae A, Almqvist H, Aspelin A, Martin H, Ouellette R, Al-Saadi J, Hasselberg M, Haghgou M, Pedersen M, Petersson S, Finnsson J, Lundberg J, Falk Delgado A, Granberg T. Nervous System Involvement in Coronavirus Disease 2019: Results from a Retrospective Consecutive Neuroimaging Cohort. Radiology. 2020 Dec;297(3):E324-E334. doi: 10.1148/radiol.2020202791. Epub 2020 Jul 30.
- Background: PubMed 32367170Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Angles-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x. Epub 2020 May 4.
- Background: PubMed 36264064Heslin KP, Haruna A, George RA, Chen S, Nobel I, Anderson KB, Faraone SV, Zhang-James Y. Association Between ADHD and COVID-19 Infection and Clinical Outcomes: A Retrospective Cohort Study From Electronic Medical Records. J Atten Disord. 2023 Jan;27(2):169-181. doi: 10.1177/10870547221129305. Epub 2022 Oct 20.
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- Background: PubMed 33122776Aceti A, Margarucci LM, Scaramucci E, Orsini M, Salerno G, Di Sante G, Gianfranceschi G, Di Liddo R, Valeriani F, Ria F, Simmaco M, Parnigotto PP, Vitali M, Romano Spica V, Michetti F. Serum S100B protein as a marker of severity in Covid-19 patients. Sci Rep. 2020 Oct 29;10(1):18665. doi: 10.1038/s41598-020-75618-0.
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- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kristian Borg, Professor study director
Karolinska Institutet
Marika C Möller, PhD principal investigator
Department of Rehabilitation Medicine, Danderyd University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Post COVID-19 Condition and Cognitive Impairment, run by Danderyd Hospital at 1 site in Sweden.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 21 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Marika C Möller, PhD (+46812358555, marika.moller@regionstockholm.se), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fatigability from Wechsler Adult Intelligence Scale (WAIS)-IV Coding Test (time frame: baseline). The study lists 13 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06042530, which also lists 36 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2023.