Neurobehavior and Brain Connectivity in Post COVID-19 Patients (NAUTILUS)

Cognition, Emotion/Behavior, Functionality and Brain Connectivity in Recovered COVID-19 Patients

COVID-19 neurological effects can generate long-term neurobehavioral dysfunction. Our main objective is to examine the impact of COVID-19 on neurobehavior and its relationship with illness severity. Besides, we aim to study structural and functional brain connectivity in a subsample of middle-aged post-COVID-19 individuals. Finally, we aim to develop predictive models of neurobehavioural evolution in post-COVID-19 based on multimodal data.

Study Overview

• Status: Recruiting
• Conditions: Post-COVID Syndrome

Detailed Description

NAUTILUS is an observational, cross-sectional, and multicenter study. It will be performed at 22 public hospitals. Two groups of COVID-19 adults (Severe N=210, Moderate-mild N=210, WHO criteria) reporting cognitive complaints will compare to healthy controls (N=210). They will be assessed on neurobehavioral status. We will perform brain MRI in a subsample (N=120, 40 per group), and we will obtain potential biomarkers of neural damage (smell function, retinal blood plexuses integrity, and inflammation). Moreover, we will use machine learning-based algorithms based on demographics, previous pathologies, lifestyle, clinical data, and biomarkers to predict neurobehavioral models.

Expected results: Identify the neurobehavioral impact of post-COVID-19 individuals and the discriminative power of multimodal biomarkers in adverse outcomes. Our result would help develop clinically useful models to predict the neurobehavioral impact to develop future personalized and preventive intervention strategies.

• Study Type: Observational
• Enrollment (Estimated): 630

Contacts and Locations

• Study Contact: Name: Mar Ariza, PhD; Phone Number: +34 934 039 297; Email: mariza@ub.edu

Study Locations

• Spain
  • Barcelona
    • Terrassa, Barcelona, Spain, 08227
      • Recruiting
      • Consorci Sanitari de Terrassa
      • Contact: Maite Garolera, PhD; Phone Number: 1758 +34937310007; Email: mgarolera@cst.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

PCS from severe and mild COVID-19 group will be recruited in hospital and primary care services.

The control population will be searched in the general population through primary care centers, the media, social networks, and they will be offered to participate in the study without remuneration.

Description

PCS from SEVERE COVID-19 group

Inclusion Criteria:

• Confirmed diagnosis of COVID-19 according to WHO interim with signs and symptoms of the severe disease during the acute phase
• Presence of cognitive complaints after COVID-19 diagnosis
• Participants have to be discharged from the hospital at least three months before inclusion
• Accept to take part in the study and sign the informed consent according to the Declaration of Helsinki

Exclusion Criteria:

• Participants have symptoms of delirium according to Delirium Rating Scale-revised 98
• Established diagnosis before COVID-19 disease of psychiatric, neurological, neurodevelopmental disorder or systemic pathologies are known to cause cognitive deficits
• Motor or sensory alterations that impede the neuropsychological examination
• Participants with a metal prosthesis (for MRI studies)
• Subjects suffering from claustrophobia or requiring sedation due to high anxiety (for MRI studies)

PCS from MILD COVID-19 group

• Confirmed diagnosis of MILD COVID-19 according to WHO interim
• Presence of cognitive complaints after COVID-19 diagnosis
• Participants have to be diagnosed with COVID-19 at least three months before inclusion
• Accept to take part in the study and sign the informed consent according to the Declaration of Helsinki

Exclusion Criteria:

• Established diagnosis before COVID-19 disease of psychiatric, neurological, neurodevelopmental disorder or systemic pathologies are known to cause cognitive deficits
• Motor or sensory alterations that impede the neuropsychological examination
• Participants with a metal prosthesis (for MRI studies)
• Subjects suffering from claustrophobia or requiring sedation due to high anxiety (for MRI studies)

Healthy adult CONTROL group

Inclusion Criteria:

• Healthy people who have not had COVID-19
• Accept to take part in the study and sign the informed consent according to the Declaration of Helsinki

Exclusion Criteria:

• the same as COVID-19 groups

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Controls; Healthy adult controls
Post-COVID syndrome (PCS) Severe COVID-19; Severe COVID-19 with PCS with cognitive complains
Post-COVID syndrome (PCS) Mild COVID-19; Mild COVID-19 with PCS with cognitive complains

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences between groups in auditory attention	Auditory attention is measured with Digit Span Forward. Participants are asked to repeat numbers in the same order as read aloud by the examiner. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in working memory	Working memory is measured with Digit Span Backward. Participants are asked to repeat the numbers in the reverse order of that presented by the examiner. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in language	Language is measured with the Boston Naming Test. It consists of 60 line drawings of objects of graded difficulty, ranging from very common things to less familiar objects. The total score is the sum of correct answers. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in verbal memory	Verbal memory is measured with the Auditory Verbal Learning Test (AVLT). It is a word-learning test where five presentations of a 15-word list are given, each followed by an attempted recall. This is followed by a second 15-word interference list (list B), followed by recall of list A. Delayed recall and recognition are also tested. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in visual memory	Visual memory is measured with the Rey-Osterrieth Complex Figure (ROCF) test. The participants are asked to copy complex geometric shapes and then reproduce them from memory. A delayed recall is also tested. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in psychomotor speed	Processing speed is measured with Coding subtest of WAIS. Participants are asked to use a key to put in the appropriate symbols for a list of numbers. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in perceptual reasoning	Perceptual reasoning is measured with Matrix reasoning subtest of WAIS. Participants are asked to choose which of some possible options the missing picture is from matrix of abstract pictures. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in executive function	A composite score is made with the z-scores of phonemic (sum of the three letters) and semantic fluency, Trail Making Test B (time) and STROOP test (color-word interference total items in 120 seconds).	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in social cognition	Social cognition is measured with the Reading the Mind in the Eyes Test. Participants are asked to choose the emotional state that best describes the eyes, choosing between one of four possible emotions in the 36 photographs of male and female eyes depicting emotional states. Higher scores mean a better outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in anxiety	Anxiety is measured with the 7-item Generalized Anxiety Disorder Scale (GAD-7), a Likert-type scale with questions ranging from "not at all" (0 points) to "nearly every day" (3 points). The maximum score is 24. Higher scores mean a worse outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in depression	Depression is measured with the Patient Health Questionnaire-9 (PHQ-9) which scores each of the 9 DSM-IV criteria as "not at all" (0 points) to "nearly every day" (3 points). Higher scores mean a worse outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in Post-traumatic Stress Disorder	Post-Traumatic Stress Disorder is measured with The Post-Traumatic Stress Disorder Checklist (PCL-5), a 20-item questionnaire corresponding to the DSM-5 symptom criteria for PTSD, which scores each criterion as "not at all" (0 points) to "extremely" (4 points). The ratings of items are added together to calculate the total score (range=0-80). Higher scores mean a worse outcome.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Differences between groups in Fatigue	Fatigue is measured with the Chalder Fatigue Scale, an 11-item questionnaire measuring the severity of physical and mental fatigue on two separate subscales. Seven items represent physical fatigue (items 1-7) and 4 represent mental fatigue (items 8-11). Each item " less than usual" (0) to " much more than usual" (3). The ratings of items are added together to calculate the total score (range=0-33). High scores represent high levels of fatigue.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in White Matter integrity	White matter integrity: tractography measured by MRI	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in brain Volumetry	Grey and white matter volume measured by MRI	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in Resting-state connectivity	Resting state brain activity using fMRI	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic Interleukin- 6 (IL-6)	The plasma levels of IL-6 are measured with enzyme-linked immunosorbent assay (ELISA) Kit	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic Nerve Growth Factor (NGF)	The plasma levels of NGF are measured with ELISA Kit	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic Glial Fibrillary Acidic Protein (GFAp)	The plasma levels of GFAp are measured with ELISA Kit	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic lipid peroxidation products	The plasma levels of malondialdehyde are measured with TBARS assay method	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic Ferritin	The plasma levels of Ferritin are measured with biochemical assay	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in plasmatic C-Reactive Protein (CRP)	The plasma levels of CRP are measured with high sensitivity c-reactive protein ELISA Kit	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in Quality of Life	Quality of life is measured with a 12-item World Health Organization Disability Assessment Schedule-II (WHODAS-II). Patients are asked to state the level of difficulty experienced, considering how they usually do the activity. The scale scores each item as "none" (1) to "cannot do" (5). The total score is calculated with an SPSS syntax, and the range varies from 0 to 100, with higher scores reflecting more significant disability.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups in smell function	Smell function is evaluated with the University of Pennsylvania Smell Identification Test (UPSIT), which measures the individual's ability to detect odors at a suprathreshold level. The UPSIT comprises four booklets, each of which contains ten pages. An odorized "scratch & sniff" label is present on each booklet page. The subject scratches the label and then indicates which of the four response alternatives best matches the perceived smell. A score ranging from 6-18 means anosmia, 19-25 means severe microsmia, 26-30 in women and 26-29 in men means moderate microsmia, 31-34 in women and 30-33 in men means mild microsmia and a score of more than 34 in women and 33 in men means normosmia.	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19
Differences between groups retinal plexuses integrity	Retinal plexuses integrity is measured with Optical Coherence Tomography Angiography (OCTA)	At the time of inclusion of the participant, between 3 and 12 months from the start of COVID-19

Collaborators and Investigators

• Sponsor: Consorci Sanitari de Terrassa
• Collaborators: University of Barcelona; Universitat Politècnica de Catalunya
• Investigators: Principal Investigator: Maite Garolera, PhD, Consorci Sanitari de Terrassa

Publications and helpful links

General Publications

• Ariza M, Cano N, Segura B, Adan A, Bargallo N, Caldu X, Campabadal A, Jurado MA, Mataro M, Pueyo R, Sala-Llonch R, Barrue C, Bejar J, Cortes CU; NAUTILUS-Project Collaborative Group; Junque C, Garolera M. Neuropsychological impairment in post-COVID condition individuals with and without cognitive complaints. Front Aging Neurosci. 2022 Oct 20;14:1029842. doi: 10.3389/fnagi.2022.1029842. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2021
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): September 1, 2024

Study Registration Dates

• First Submitted: March 31, 2022
• First Submitted That Met QC Criteria: March 31, 2022
• First Posted (Actual): April 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 30, 2023
• Last Update Submitted That Met QC Criteria: May 26, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Mental Health; Cognition; Machine Learning; Neuroimage; COVID-10
• Other Study ID Numbers: 202111-30-31-32 Fundació La Ma

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No