Neurobiological Underpinnings of Neuropsychological Consequences in Long COVID

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.

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.

Eligibility Criteria:
Inclusion Criteria:

Inclusion criteria - patients:

* 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

Inclusion criteria - control a:

* 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).

Inclusion criteria - control b:

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

Exclusion Criteria:

* General 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.

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) (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