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| Name | Class |
|---|---|
| University of Barcelona | OTHER |
| Universitat Politècnica de Catalunya | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 | ||
| Controls | Healthy adult controls |
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| 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. |
| 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. |
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PCS from SEVERE COVID-19 group
Inclusion Criteria:
Exclusion Criteria:
PCS from MILD COVID-19 group
Exclusion Criteria:
Healthy adult CONTROL group
Inclusion Criteria:
Exclusion Criteria:
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Maite Garolera, PhD | Consorci Sanitari de Terrassa | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Consorci Sanitari de Terrassa | Terrassa | Barcelona | 08227 | Spain |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41851162 | Derived | Goset J, Ariza M, Mestre C, Vinuela-Navarro V, Perez-Mana L, Vilaseca M, Cano N, Delas B, Garolera M, Aldaba M. Eye tracking and machine learning to assess cognitive impairment in post-COVID-19 patients. Sci Rep. 2026 Mar 18;16(1):9637. doi: 10.1038/s41598-025-34664-2. | |
| 40595626 | Derived | Carreras-Vidal L, Pacheco-Jaime L, Ariza M, Cano N, Garolera M, Garcia-Vicente C, Roura I, Capdevila-Lacasa C, Oltra J, Pardo J, Martin-Barcelo C, Campabadal A, Sala-Llonch R, Bargallo N, Barrue C, Bejar J, Cortes CU, Junque C; NAUTILUS-Project Collaborative Group; Segura B. Functional brain abnormalities in post COVID-19 condition and their relationship with cognition. Sci Rep. 2025 Jul 1;15(1):22259. doi: 10.1038/s41598-025-00739-3. |
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| ID | Term |
|---|---|
| D000092862 | Psychological Well-Being |
| ID | Term |
|---|---|
| D010549 | Personal Satisfaction |
| D001519 | Behavior |
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| 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 |
| 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 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 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 |
| 40008326 | Derived | Pacheco-Jaime L, Garcia-Vicente C, Ariza M, Cano N, Garolera M, Carreras-Vidal L, Roura I, Capdevila-Lacasa C, Oltra J, Pardo J, Martin-Barcelo C, Campabadal A, Sala-Llonch R, Bargallo N, Barrue C, Bejar J, Cortes CU, Junque C, Segura B; NAUTILUS-Project Collaborative Group. Structural brain changes in post-COVID condition and its relationship with cognitive impairment. Brain Commun. 2025 Feb 12;7(1):fcaf070. doi: 10.1093/braincomms/fcaf070. eCollection 2025. |
| 38285245 | Derived | Ariza M, Bejar J, Barrue C, Cano N, Segura B; NAUTILUS Project Collaborative Group; Cortes CU, Junque C, Garolera M. Cognitive reserve, depressive symptoms, obesity, and change in employment status predict mental processing speed and executive function after COVID-19. Eur Arch Psychiatry Clin Neurosci. 2025 Jun;275(4):973-989. doi: 10.1007/s00406-023-01748-x. Epub 2024 Jan 29. |
| 36939932 | Derived | 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; Garolera M, Junque C. COVID-19 severity is related to poor executive function in people with post-COVID conditions. J Neurol. 2023 May;270(5):2392-2408. doi: 10.1007/s00415-023-11587-4. Epub 2023 Mar 20. |
| 36337708 | Derived | 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. |