Neurobiological Underpinnings of Neuropsychological Consequences in Long COVID

NCT ID: NCT06279936

Last Updated: 2024-02-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 130 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-11-01
• Study Completion Date: 2024-12-31

Brief Summary

Objectives:

To describe the standardized evaluation of the psychological and cognitive function of long COVID patients and their evolution, to compare immunological and HPA-axis related biomarkers between long COVID patients and healthy controls, to explore cross-sectional and longitudinal associations between immunological measures and long COVID symptoms.

Study design:

Cov-N-Psy is a longitudinal observational study. Three groups will be included from 2021 until 2023: long COVID patients with neuropsychological complaints (P), COVID-survivors without persistent complaints (Ca) and healthy volunteers without a history of COVID-19 (Cb). The total sample size is estimated on 130. Four visits are organized: at baseline, three, six and twelve months.

The study is organized in three work packages (WP). WP1 includes a blood withdrawal and psychometric questionnaires and is part of every visit. WP2 includes cortisol measurement in saliva and takes place on the baseline visit for every participant and on the third visit for patients. Finally, WP3 includes a neurocognitive assessment at baseline for patients and Ca controls and on the third visit for patients.

Detailed Description

Research Objectives

Describe the standardized evaluation of the psychopathological and neurocognitive function of long COVID NP patients and their evolution over time; Compare the immunological profile and the cortisol awakening response (CAR) of long COVID NP patients to those of COVID-19 survivors without persistent complaints and healthy uninfected controls; Explore the cross-sectional and longitudinal association between long COVID NP symptoms and immunological and cortisol measures.

Methodology

Recruitment and study population

Inclusion criteria - patients:

All patients 18-70 years referred to the University Psychiatric Hospital (Campus UZA and Campus Duffel) for psychological and/or cognitive complaints at least >4 weeks following a confirmed diagnosis of COVID-19 infection with a positive PCR test or an antibodies test will be invited to participate in the study. The sample size of the patients is estimated on 50 participants. The patients have to be examined by their treating physician before enrollment to make sure other medical causes for their complaints are excluded. A positive score on at least two domains (psychological /cognitive) is necessary during the screening phase.

Inclusion criteria - controls:

Two control groups, one of 30 healthy uninfected controls (Cb), another of 50 COVID-19 survivors without persistent complaints (Ca), matched on age, sex and education with the patient group will be included. The participants for Ca will be recruited in UZA and by advertising. The healthy controls (Cb) will be recruited by mailing within the hospital and by advertising. A positive score on maximum one domain (psychological / cognitive) is allowed in the absence of a psychiatric diagnosis (confirmed by the MINI) and when the complaint causes significant distress (which is investigated during the screening phase).

Exclusion criteria for each subgroup:

• HPA subgroup: Participant is pregnant or breastfeeding / Participant receives hormonal replacement therapy (contraception is allowed) /Participant is treated with cortisol <4 weeks ago
• Neurocognitive assessment: IQ < 90 (screened with Raven Standard Progressive Matrices (Short Form) (RSPM-SF) / Participant takes sedative medication: benzodiazepines (Larger than the equivalent of diazepam 10mg per day, Last administration <8 hours prior to the neurocognitive test), new sedative antipsychotics/antidepressants (<4 weeks), other medication from DRUID class III (<4 weeks), last administration <8 hours prior to the neurocognitive tests, or causing significant sedation / Severe substance abuse (alcohol + drugs) / Pre-existing neurological diseases causing cognitive problems.

Study design This is a longitudinal study, which will be organized into three work packages (WP1, WP2 and WP3). Enrollment will continue for an estimated period of 24 months, depending on the time course of the epidemic curve. Last-patient-in is expected no later than November 1st, 2023. Patients will be referred mainly by the University Hospital of Antwerp (UZA) and enrolled at first visit to the University Psychiatric Hospital (UPCD), where follow-up will also take place at 3, 6 and 12 months. Patients can also be referred by the Flemish long COVID patient support group.

WP1 includes a blood withdrawal and psychometric questionnaires and is part of every visit. WP2 includes cortisol measurement in saliva and takes place on the baseline visit for every participant and on the third visit for patients. Finally, WP3 includes a neurocognitive assessment at baseline for patients and Ca controls and on the third visit for patients.

Conditions

Long COVID

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Long Covid patients

Long Covid patients with (neuro)psychological complaints

Neuropsychological battery

Intervention Type: OTHER

COVID-19 patients with persistent complaints of cognitive disabilities (more than 4 weeks post-infection) in daily life are examined with an extensive neuropsychological test battery (see below) at the outpatient clinic of the University Psychiatric Centre in Duffel and at the University Hospital Antwerp. This battery covers a broad range of reliable and valid tests divided into six cognitive domains: attention, memory, visuospatial functions, language, executive functions and psychomotor speed/coordination. The neuropsychological examination lasts an average of 2 hours per participant. The tests are carried out by the same experienced neuropsychologist and also follow a standardized sequence. In addition to the neuropsychological assessment, two self-report scales are filled out by each patient. These scales are used to detect possible complaints of fatigue and possible cognitive problems which are experienced by the patient during daily life activities.

Surveys and symptom severity questionnaires

Intervention Type: OTHER

Both self-rated surveys and clinician administered questionnaires

Blood withdrawal

Intervention Type: OTHER

Blood samples will be collected in a standardized manner by venipuncture. Two blood vials will be collected and processed to perform the following analyses:

• serum collection tube(s) allowing for HERV-W ENV and serological assays
• plasma collection tubes for the assessment of other immune-related biomarkers (including but not limited to CRP, IL-6, IL-1b, TNF-a, IFN-g, tryptophan, kynurenine, 3-OH-kynurenine, quinolinic acid, kynurenic acid, enzymes of the kynurenine pathway).

Saliva swabs

Intervention Type: OTHER

Salivary cortisol measures will be used as functional measure of the HPA axis activity, as the unbound cortisol fraction in saliva is highly correlated to plasma cortisol. Baseline diurnal cortisol and CAR levels will be measured using saliva, collected at home with Salivette® (Sarstedt) synthetic swabs. The rationale behind the choice of home sampling, is to maximize normal circumstances and to minimize stress related to the measuring procedure.

Covid controls (Ca)

COVID-19 survivors without persistent complaints

Neuropsychological battery

Intervention Type: OTHER

COVID-19 patients with persistent complaints of cognitive disabilities (more than 4 weeks post-infection) in daily life are examined with an extensive neuropsychological test battery (see below) at the outpatient clinic of the University Psychiatric Centre in Duffel and at the University Hospital Antwerp. This battery covers a broad range of reliable and valid tests divided into six cognitive domains: attention, memory, visuospatial functions, language, executive functions and psychomotor speed/coordination. The neuropsychological examination lasts an average of 2 hours per participant. The tests are carried out by the same experienced neuropsychologist and also follow a standardized sequence. In addition to the neuropsychological assessment, two self-report scales are filled out by each patient. These scales are used to detect possible complaints of fatigue and possible cognitive problems which are experienced by the patient during daily life activities.

Surveys and symptom severity questionnaires

Intervention Type: OTHER

Both self-rated surveys and clinician administered questionnaires

Blood withdrawal

Intervention Type: OTHER

Blood samples will be collected in a standardized manner by venipuncture. Two blood vials will be collected and processed to perform the following analyses:

• serum collection tube(s) allowing for HERV-W ENV and serological assays
• plasma collection tubes for the assessment of other immune-related biomarkers (including but not limited to CRP, IL-6, IL-1b, TNF-a, IFN-g, tryptophan, kynurenine, 3-OH-kynurenine, quinolinic acid, kynurenic acid, enzymes of the kynurenine pathway).

Saliva swabs

Intervention Type: OTHER

Salivary cortisol measures will be used as functional measure of the HPA axis activity, as the unbound cortisol fraction in saliva is highly correlated to plasma cortisol. Baseline diurnal cortisol and CAR levels will be measured using saliva, collected at home with Salivette® (Sarstedt) synthetic swabs. The rationale behind the choice of home sampling, is to maximize normal circumstances and to minimize stress related to the measuring procedure.

Non-Covid controls (Cb)

healthy uninfected controls

Surveys and symptom severity questionnaires

Intervention Type: OTHER

Both self-rated surveys and clinician administered questionnaires

Blood withdrawal

Intervention Type: OTHER

Blood samples will be collected in a standardized manner by venipuncture. Two blood vials will be collected and processed to perform the following analyses:

• serum collection tube(s) allowing for HERV-W ENV and serological assays
• plasma collection tubes for the assessment of other immune-related biomarkers (including but not limited to CRP, IL-6, IL-1b, TNF-a, IFN-g, tryptophan, kynurenine, 3-OH-kynurenine, quinolinic acid, kynurenic acid, enzymes of the kynurenine pathway).

Saliva swabs

Intervention Type: OTHER

Salivary cortisol measures will be used as functional measure of the HPA axis activity, as the unbound cortisol fraction in saliva is highly correlated to plasma cortisol. Baseline diurnal cortisol and CAR levels will be measured using saliva, collected at home with Salivette® (Sarstedt) synthetic swabs. The rationale behind the choice of home sampling, is to maximize normal circumstances and to minimize stress related to the measuring procedure.

Interventions

Neuropsychological battery

COVID-19 patients with persistent complaints of cognitive disabilities (more than 4 weeks post-infection) in daily life are examined with an extensive neuropsychological test battery (see below) at the outpatient clinic of the University Psychiatric Centre in Duffel and at the University Hospital Antwerp. This battery covers a broad range of reliable and valid tests divided into six cognitive domains: attention, memory, visuospatial functions, language, executive functions and psychomotor speed/coordination. The neuropsychological examination lasts an average of 2 hours per participant. The tests are carried out by the same experienced neuropsychologist and also follow a standardized sequence. In addition to the neuropsychological assessment, two self-report scales are filled out by each patient. These scales are used to detect possible complaints of fatigue and possible cognitive problems which are experienced by the patient during daily life activities.

Intervention Type: OTHER

Surveys and symptom severity questionnaires

Both self-rated surveys and clinician administered questionnaires

Intervention Type: OTHER

Blood withdrawal

Blood samples will be collected in a standardized manner by venipuncture. Two blood vials will be collected and processed to perform the following analyses:

• serum collection tube(s) allowing for HERV-W ENV and serological assays
• plasma collection tubes for the assessment of other immune-related biomarkers (including but not limited to CRP, IL-6, IL-1b, TNF-a, IFN-g, tryptophan, kynurenine, 3-OH-kynurenine, quinolinic acid, kynurenic acid, enzymes of the kynurenine pathway).

Intervention Type: OTHER

Saliva swabs

Salivary cortisol measures will be used as functional measure of the HPA axis activity, as the unbound cortisol fraction in saliva is highly correlated to plasma cortisol. Baseline diurnal cortisol and CAR levels will be measured using saliva, collected at home with Salivette® (Sarstedt) synthetic swabs. The rationale behind the choice of home sampling, is to maximize normal circumstances and to minimize stress related to the measuring procedure.

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• 18-70 years
• Diagnosis of long COVID
• (Neuro)psychological symptoms >4 weeks after infection
• Infection with SARS-Cov-2 was detected with PCR (or antigen test)
• Other causes for their complaints are excluded by their GP or specialist
• Positive score on at least 2 NP domains during the screening phase

• 18-70 years
• No prolonged symptoms due to SARS-CoV-2 infection within 4 weeks after infection
• No current (Neuro)psychological symptoms
• Infection with SARS-Cov-2 was detected with PCR (or antigen test)
• A positive score on maximum one domain (psychological / cognitive) is allowed in the absence of a psychiatric diagnosis (confirmed by the MINI) and when the complaint causes significant distress (which is investigated during the screening phase).

• 18-70 years
• No (known) infection with SARS-CoV-2
• No current or previous (neuro)psychological symptoms

Exclusion Criteria

Participant is unable to read and understand the consent form and patient-reported outcomes, complete study-related procedures, or communicate with the study staff and informed consent cannot realistically be obtained in retrospect or with the help of a competent family member or legal representative.

• HPA subgroup

• Participant is pregnant or breastfeeding
• Participant receives hormonal replacement therapy (contraception is allowed).
• Participant is treated with cortisol <4 weeks ago
• Neurocognitive assessment:

• IQ < 90 (screened with Raven Standard Progressive Matrices (Short Form) (RSPM-SF) (39)
• Participant takes sedative medication
• Benzodiazepines: Larger than the equivalent of diazepam 10mg per day. Last administration <8 hours prior to the neurocognitive tests.
• New sedative antipsychotics/antidepressants (<4 weeks)
• Other medication from DRUID class III (<4 weeks), last administration <8 hours prior to the neurocognitive tests, or causing significant sedation.

• Severe substance abuse (alcohol + drugs)
• Pre-existing neurological diseases that influence cognitive functioning

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

UZA Foundation

UNKNOWN

Sponsor Role: collaborator

Universiteit Antwerpen

OTHER

Sponsor Role: lead

Responsible Party

Dr Livia De Picker

Clinical Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

SINAPS

Duffel, Antwerp, Belgium

Countries

Belgium

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

https://www.sinapsduffel.com/longcovid

Related Info

Other Identifiers

B3002021000171

Identifier Type: -

Identifier Source: org_study_id