Received: 11 August 2021 Revised: 27 December 2021 Accepted: 5 January 2022 DOI: 10.1002/brb3.2508 ORIGINAL ARTICLE Neuropsychological deficits in patients with cognitive complaints after COVID-19 Carmen García-Sánchez1 Marco Calabria2 Nicholas Grunden3 Catalina Pons4 Juan Antonio Arroyo5 Beatriz Gómez-Anson6 Alberto Lleó7 Daniel Alcolea7 Roberto Belvís8 Noemí Morollón8 Isabel Mur9 Virginia Pomar9 Pere Domingo9 1 Neuropsychology Unit, Neurology Department, Hospital de la Santa Creu i Sant Abstract Pau, Barcelona, Spain Background: While much of the scientific focus thus far has been on cognitive sequelae 2 Faculty of Health Sciences, Universitat Oberta de Catalunya, Barcelona, Spain in patients with severe COVID-19, subjective cognitive complaints are being reported 3 Department of Psychology, Concordia across the spectrum of disease severity, with recent studies beginning to corrob- University, Montreal, Canada orate patients’ perceived deficits. In response to this, the aims of this study were 4 Facultat de Psicologia, Ciències de l’Educació to (1) explore the frequency of impaired performance across cognitive domains in i l’EsportBlanquernaUniversitat Ramon Llull, Barcelona, Spain post-COVID patients with subjective complaints and (2) uncover whether impairment 5 Internal Medicine Department, Hospital de la existed within a single domain or across multiple. Santa Creu i Sant Pau, Barcelona, Spain Methods: Sixty-three patients with subjective cognitive complaints post-COVID were 6 Neurodiagnostic Department, Hospital de la assessed with a comprehensive protocol consisting of various neuropsychological tests Santa Creu i Sant Pau, Barcelona, Spain 7 Memory Unit, Neurology Department, and mood measures. Cognitive test performance was transformed into T scores and Hospital de la Santa Creu i Sant Pau, classified based on recommended guidelines. After performing a principal component Barcelona, Spain analysis to define cognitive domain factors, distributions of test scores within and 8 Headache Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, across domains were analyzed. Barcelona, Spain Results: Results revealed pervasive impact on attention abilities, both as the singularly 9 Infectious Disease Unit, Hospital de la Santa affected domain (19% of single-domain impairment) as well as coupled with decreased Creu i Sant Pau, Barcelona, Spain performance in executive functions, learning, and long-term memory. These salient Correspondence attentional and associated executive deficits were largely unrelated to clinical factors Carmen García-Sánchez, Neuropsychology Unit, Neurology Department, Hospital de la such as hospitalization, disease duration, biomarkers, or affective measures. Santa Creu i Sant Pau, Mas de Casanova 90, Discussion: These findings stress the importance of comprehensive evaluation and Barcelona, Spain. Email: cgarcias@santpau.cat intervention to address cognitive sequelae in post-COVID patients of varying disease courses, not just those who were hospitalized or experienced severe symptoms. Future studies should investigate to what extent these cognitive abilities are recuperated over time as well as employ neuroimaging techniques to uncover underlying mechanisms of neural damage. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC Brain Behav. 2022;12:e2508. wileyonlinelibrary.com/journal/brb3 1 of 11 https://doi.org/10.1002/brb3.2508 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 2 of 11 GARCÍA-SÁNCHEZ ET AL . KEYWORDS cognition, cognitive complaints, neuropsychology, post-COVID-19 1 INTRODUCTION weeks and months following infection and/or hospital discharge. Short- term deficits were found in attention (Almeria et al., 2020; Zhou et al., After more than 1 year since the beginning of the pandemic, we have 2020), in long-term memory, attention and executive functions (Alme- consistent evidence that the disease caused by SARS-CoV-2 infection, ria et al., 2020), and in inhibitory control (Ortelli et al., 2021). Consider- COVID-19, is a multisystemic syndrome (Jiang et al., 2020). This coron- ing more long-term effects, Ferrucci et al. (2021) reported evidence of avirus has been shown to cause multi-organ dysfunction, affecting not long-term memory deficits in COVID-19 patients 5 months after hos- only the lungs but also the heart, kidneys, gut, liver (Batlle et al., 2020; pitalization and Mazza et al. (2021) found that half of their COVID- Long et al., 2020; Terpos et al., 2020), and the brain (Harapan & Yoo, 19 patient sample demonstrated executive function deficits and 30% 2021; Stein et al., 2021; Wei et al., 2020). Even when relatively little of them showed impairments in information processing, verbal fluency, was known about COVID-19 symptomatology, reports of neurological and working memory at a 3-month follow-up. In contrast to these find- complications associated with SARS-CoV-2 were published (Moriguchi ings, Mattioli et al. (2021) found no evidence of any cognitive impair- et al., 2020; Ye et al., 2020); subsequently, the impact of this coron- ment in patients with COVID-19 compared to a group of control par- avirus on the brain has been a topic of great interest (Leonardi et al., ticipants 4 months after SARS-CoV-2 infection. 2020). It is also important to define the nature of deficits in terms of Our understanding of COVID-19’s effect on the central nervous sys- single versus multiple-domain impact. In making this distinction, the tem (CNS) is still limited. However, researchers have proposed indi- existence of deficits within or across domains can begin to indicate rect pathways that may cause brain damage through inflammatory how widespread the impacts on underlying cognitive mechanisms are. changes, coagulopathy, and vascular endothelial dysfunction (Boldrini As research from neuroimaging studies in COVID-19 survivors has et al., 2021; Marshall, 2020; Peiris et al., 2021; Solomon, 2021). Addi- thus far shown a heterogeneous picture of brain damage, the presence tionally, brain imaging studies have uncovered altered cerebral glucose of multiple-domain deficits would further confirm the diverse effects metabolism in the subacute stage of COVID-19, predominantly at fron- of COVID-19 on the brain. Within the current literature, one line of toparietal level (Hosp et al., 2021). In other cortical areas such as the evidence is indicating that medial temporal structures and hippocam- superior temporal, precentral, and lateral occipital cortices (Parsons pus (Ladopoulos et al., 2021) are affected; given this, memory-related et al., 2021), as well as medial temporal structures and hippocampus deficits would then be expected, mainly for the consolidation of new (Ladopoulos et al., 2021), lesions due to ischemia, acute white matter information. Indeed, findings from studies that investigated neuropsy- abnormalities, encephalopathic changes, or intracranial hemorrhages chological impairments in COVID-19 reveal long-term memory deficits associated with COVID-19 (Gulko et al., 2020; Ladopoulos et al., 2021; (Almeria et al., 2020; Ferrucci et al., 2021). Other studies have found Mahammedi et al., 2021) have been found. changes in metabolism at frontoparietal level (Hosp et al., 2021), which Although the frequency and severity of neurological symptoms would suggest potential impairments in the attentional networks. associated with COVID-19 may vary to some degree according to the Linking this to neuropsychological findings, deficits of attention and severity of neuroinflammation and other medical conditions (Nordvig executive functions are indeed reported in many studies (Almeria et al., et al., 2021; Yassin et al., 2021), recent findings show that COVID-19 2020; Ortelli et al., 2021; Zhou et al., 2020). With these two emerging survivors with a wide range of disease courses, ranging from asymp- links between brain and behavior, it is crucial to know the extent to tomatic (Amalakanti et al., 2021) to those with severe symptoms which patients have both memory and executive function deficits in (Negrini et al., 2021; Whiteside et al., 2021), may present with both order to determine whether they could be explained by the same short- and long-term cognitive deficits. In a recent review, Alnefeesi processes. et al. (2021) assessed seven studies and concluded that COVID-19 pre- In the present study, we focus on investigating a sample of outpa- dominantly affects long-term memory and executive functions. tients who reported subjective cognitive complaints after SARS-CoV-2 To date, epidemiologic studies with large samples of patients have infection. Using tests spanning across different cognitive domains, the used screening tests for global cognition or qualitative assessments of study sought to determine which cognitive abilities are most affected in mental status (García-Azorín et al., 2021; Raman et al., 2021; Taquet this population. Addressing remaining uncertainties outlined above, we et al., 2021). While the findings from these studies serve as useful evi- had two aims for this study: (1) to analyze the frequency of deficits for dence in revealing general cognitive impact associated with COVID- specific cognitive domains and (2) to discern the frequency of single- 19, results from screening tests cannot be used to address the ques- and multiple-domain impairments and to understand which combina- tion of specificity in cognitive deficits. Other studies with smaller sam- tions of deficits were a specific feature of post-COVID-19 cognitive ple sizes have begun to apply more comprehensive neuropsycholog- impairment. Additionally, we also investigated whether certain clinical ical evaluations, providing a more detailed picture of deficits in the factors were associated with cognitive impairment. 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GARCÍA-SÁNCHEZ ET AL . 3 of 11 2 METHODS First, we performed an analysis that aimed to describe the fre- quency of presence or absence of cognitive deficits according to the 2.1 Participants neuropsychological test scores as a function of the three categories, such as being a below average score/exceptionally low score, low aver- The study included 84 consecutive patients evaluated from July 5, age score, and average or above (Pc > 25). The distribution of test 2020 to May 26, 2021 at the Neuropsychology Unit of the Hospital de scores was analyzed by grouping them in cognitive domains. To define la Santa Creu i Sant Pau (HSCSP) in Barcelona (Spain) with subjective said cognitive domains, we ran a principal component analysis (PCA) cognitive complaints after SARS-CoV-2 infection. The inclusion criteria that included the entire test scores (see Table 1 and Figure 1) from the for this study were: (a) having had COVID-19 symptoms and confirmed neuropsychological assessment. positive for SARS-CoV-2 via polymerase chain reaction (PCR) and/or Second, we analyzed the frequency of cognitive deficits in patients serology (anti-SARS-CoV2 IgM or IgG); (b) referred for neuropsycho- by classifying neuropsychological tests according to the domains logical assessment after reporting subjective cognitive complaints; and defined by the PCA. A cognitive domain was classified as affected if (c) were 18+ years old. The exclusion criterion was documented med- matched one of these criteria: (a) at least 50% of the scores with a per- ical history of neurological or psychiatric conditions before the infec- centile below 8 for the tests having multiples scores; (b) at least 50% tion. After reviewing their medical records, 21 were excluded as proba- of the test scores with a percentile below 8 for the tests having single ble COVID (negative results when tested for SARS-CoV-2 or not tested scores; (c) at least 30% of the test scores with a percentile below 8 and at all). The final sample included 63 participants. 30% of the test scores with a percentile between 9 and 24. The aim of this analysis was to see whether the impact of SARS-CoV- 2 infection on cognition multi-domain or not. Additionally, we aimed 2.2 Neuropsychological assessment to explore the most frequent associations of cognitive deficits. Corre- lational analyses were performed between the mean T scores of the The neuropsychological study was carried out on patients who pre- more frequently affected cognitive domains. Mean T scores were cal- sented subjective complaints after having suffered COVID-19. The culated by averaging the T scores of the test within the same cognitive tests were administered by an expert neuropsychologist at HSCSP domain. over two sessions, with a maximum interval between these sessions of Finally, we performed further analyses to explore the effect of hos- 10 days. pitalization, disease duration, biomarkers, and affective scores on cog- A comprehensive neuropsychological assessment included multiple nition. tests for each of the following cognitive domains: general cognitive status, attention, short- and long-term memory, language, processing speed, visuoperceptual–visuoconstructive functions, and executive 4 RESULTS functions. Specifically, the assessment included the following tests: MoCA, CPT-II, RAVLT, ROCFT, Digit Span Forward and Backward, BNT, 4.1 Patient sample characteristics Block Design, Coding, Symbol Search, TMT, Stroop, verbal fluency tasks, and the 15-Objects Test (see Supporting Information for a This final sample was composed of 22 males (35%) and 41 females complete list with full test names, descriptions, and normative data). (63%), with a mean age of 51.1 years (SD = 12.5; range: 22–78) and In addition to cognitive measures, patients were administered the mean level of education of 14.4 years (SD = 3.1). The time between the Hospital Anxiety and Depression Scale (HADS; Zigmond & Snaith, diagnosis of COVID-19 and the neuropsychological assessment was an 1983) as a brief measure for anxiety and depression levels in patients. average of 187 days (SD = 99). According to the World Health Orga- nization (2021), this duration is compatible with the definition of “post- COVID” with the presence of clinical symptoms after a probable or con- 3 ANALYSIS firmed SARS-CoV-2 infection 3 months after the onset of COVID-19 (World Health Organization, 2021). Individual raw scores from each test were transformed into T scores Thirty-three patients (52.4%) were hospitalized for an average 20 according to the normative data available. T scores were then trans- days (SD = 16.9) and 15 of them entered the intensive care unit (ICU) formed into percentiles (Pc) and classified according to the ranges (M = 13.6 days; SD = 10.0). Non-hospitalized patients were younger proposed by American Academy of Clinical Neuropsychology (Guil- (M = 46.7; SD = 11.8) than hospitalized patients (M = 55.9; SD = 11.9; mette et al., 2020). The classification is the following: exceptionally p < .001), but with the same mean year of education (non-hospitalized: high score: Pc > 98; above average score: Pc 91–97; high average M = 14.5, SD = 2.9; hospitalized: M = 14.2; SD = 3.3; p = .73) and with score: Pc 75–90; average score Pc: 25–74; low average score: Pc 9–24; no group difference for the days elapsed between diagnosis and test- below average score: Pc 2–8; exceptionally low score: Pc < 2. Then, we ing (non-hospitalized: M = 177.5, SD = 106.1; hospitalized: M = 198.6, classified individual test scores for each test according to these three SD = 92.3; p = .40). main categories: (a) below average score and exceptionally low score Fifteen patients were treated with hydroxychloroquine (400 mg/ (Pc < 8), low average score (Pc: 9–24), and average or above (Pc > 25). day) during a mean duration of 5 days and five of them were 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 11 GARCÍA-SÁNCHEZ ET AL . TA B L E 1 Distribution of test scores according to classification by Guilmette et al. (2020): Combined below average score and exceptionally low score (Pc < 8), low average score (Pc: 9–24), and average or above (Pc > 25) Distribution of test scores % Distribution of test scores Percentiles <8 9–24 >25 Total <8 9–24 >25 <24 Learning and long-term memory (L + LTM) RAVLT – Trial I 12 12 39 63 19.05 19.05 61.90 38.10 RAVLT – Trial V 13 10 40 63 20.63 15.87 63.49 36.51 RAVLT – Total 16 17 30 63 25.40 26.98 47.62 52.38 RAVLT – Delayed recall 17 8 38 63 26.98 12.70 60.32 39.68 RAVLT – Recognition 16 3 44 63 18.33 5.00 76.67 23.33 ROCFT – Delayed recall 13 18 32 63 20.63 28.57 50.79 49.21 Visuospatial and visuoconstructive abilities (VVA) 15-Objects test 5 – 58 63 7.94 – 92.06 7.94 ROCFT – Copy 6 15 42 63 9.52 23.81 66.67 33.33 ROCFT – Time 5 7 51 63 7.94 11.11 80.95 19.05 WAIS-IV – Block design 3 9 51 63 4.76 14.29 80.95 19.05 Short-term and working memory (ST/WM) Forward span 15 8 40 63 23.81 12.70 63.49 36.51 Backward span 6 7 50 63 9.52 11.11 79.37 20.63 Processing speed WAIS-IV – Coding test 4 8 51 63 6.35 12.70 80.95 19.05 WAIS-IV – Symbol search 4 6 53 63 6.35 9.52 84.13 15.87 Language Boston naming 5 4 54 63 7.94 6.35 85.71 14.29 Phonemic fluency 11 11 41 63 17.46 17.46 65.08 34.92 Semantic fluency 13 7 43 63 20.63 11.11 68.25 31.75 Attention CPT-II – Omissions % 21 10 32 63 33.33 15.87 50.79 49.21 CPT-II – Commissions % 16 14 33 63 25.40 22.22 52.38 47.62 CPT-II – Hit RT 25 11 27 63 39.68 17.46 42.86 57.14 CPT-II – Hit SE 33 16 14 63 52.38 25.40 22.22 77.78 CPT-II – Variability 25 19 19 63 39.68 30.16 30.16 69.84 CPT-II – Detectability (d’) 15 24 24 63 23.81 38.10 38.10 61.90 CPT-II – Response Style (β) 10 15 38 63 15.87 23.81 60.32 39.68 CPT-II – Perseverations % 20 1 42 63 31.75 1.59 66.67 33.33 CPT-II – Hit RT block change 11 17 35 63 17.46 26.98 55.56 44.44 CPT-II – Hit SE block change 15 29 19 63 23.81 46.03 30.16 69.84 CPT-II – Hit RT ISI change 18 21 24 63 28.57 33.33 38.10 61.90 CPT-II – Hit SE ISI change 15 18 30 63 23.81 28.57 47.62 52.38 Executive functioning (EF) TMT-A 8 15 40 63 12.70 23.81 63.49 36.51 TMT-B 12 17 32 61 19.67 27.87 52.46 47.54 Stroop – Color 20 10 31 61 32.79 16.39 50.82 49.18 Stroop – Inhibition 14 9 38 61 22.95 14.75 62.30 37.70 Abbreviations: CPT-II, Conners’ continuous performance test II; RAVLT, Rey auditory verbal learning test; ROCFT, Rey–Osterrieth complex figure test; TMT-A, TMT-B, trail making test (part A and B); WAIS-IV, Wechsler adult intelligence scale – fourth edition. 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GARCÍA-SÁNCHEZ ET AL . 5 of 11 F I G U R E 1 Distribution of test scores according to classification by Guilmette et al. (2020): combined below average score and exceptionally low score (Pc < 8), low average score (Pc: 9–24), and average or above (Pc > 25) also treated with Tocilizumab (400 or 600 mg). Nine patients were 3. Language, including scores on the semantic (0.77) and phonological treated with corticosteroids for a mean duration of 6.3 days (various (0.43) fluency tests, as well as the Boston naming test (0.46). doses). 4. Attention, including sustained attention scores on the CPT-II (Omissions: 0.91; Commissions: 0.87; Variability: 0.83; Hit RT: 0.81; Detectability: 0.81; Perseveration: 0.77; Hit SE: 0.62; Hit RT ISI 4.2 Distribution of test scores Change: 0.46); 5. Executive Functioning (EF), including scores on the Stroop task Since we used several tests with many scores, we decided to reduce (Reading: 0.84; Color: 0.80; Inhibition: 0.79) and Trail Making Tests the number of variables by grouping them into cognitive domains. This (A: 0.65; B: 0.762). allowed us to better describe our results in terms of cognitive pro- cesses that are affected or spared in our sample. The scores from the forward and backward digit spans showed low To define the cognitive domains implicated in this study, we ran a loadings and were not clearly associated with any of the five main fac- PCA that included the percentiles from all tests used in the neuropsy- tors, so we grouped them under the category “Short-Term and Working chological assessment, excluding the MoCA due to its spanning of mul- Memory” (ST/WM). WAIS-IV Coding Test and WAIS-IV Symbol Search tiple cognitive domains as a screening tool. To correct for the common were not associated with the other main factors from the PCA, so we covariance of the variables, a rotation with the direct oblimin method grouped them under the category “Processing Speed..” was applied to the factor matrix. After rotation, the result of the PCA Finally, as some of the scores on the CPT-II remained outside suggested that the best factorial solution saturated into five main fac- the main factor “Attention” but were from the same test, they were tors, as it explained 80.3% of the variance. The factors from the PCA included in the same factor for the purpose of the analyses. The same were: reasoning was applied to the score on ROCFT – Delayed recall, which was included in the L + LTM factor. 1. Learning and Long-Term Memory (L + LTM), including all scores on As shown in Table 1, the amount of test scores that were suggestive the RAVLT (Delayed recall: 0.88; Trial V: 0.84; Recognition: 0.79; of cognitive deficits (below average score and exceptionally low score, Total: 0.78; Trial I: 0.47); Pc < 8) varied across domains. Specifically, the share of abnormal 2. Visuospatial and Visuoconstructive Abilities (VVA), including scores test scores ranged from 18.33% to 26.98% depending on the test on the Block Design Test (0.64), ROCFT – Copy (0.48) and 15- in the L + LTM factor, from 4.76% to 9.52% for VVA, was 9.52% for Objects Test (0.71). short-term memory and 23.81% for working memory within the 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 11 GARCÍA-SÁNCHEZ ET AL . FIGURE 2 Frequency of affected cognitive domains and distributions of deficits for single- and multi-domain cognitive impairment ST/WM factor, 6.35% for Processing Speed, ranged from 7.94% to 4.4.1 Hospitalization 20.63% for Language, from 15.87% to 52.38% for Attention, and from 12.70% to 32.79% for EF. If we include low average scores (Pc: 9–24), Hospitalized patients had lower MoCA scores (M = 15.8; SD = 3.8) an increase of cognitive domains affected can be observed, espe- than non-hospitalized ones (M = 17.8; SD = 2.5) (F (1, 61)) = 6.66; cially for L +LTM (23.33–52.38%), Attention (33.33–77.78%), and EF p < .05; age introduced as a covariate). To explore in more detail the (36.51–52.46%). cognitive deficits that may be associated with hospitalization, we per- formed group comparisons of the distributions for average score and exceptionally low score (Pc < 8), low average score (Pc: 9–24), and both 4.3 Proportions of patients with cognitive combined (Pc: 0–24). The only significant group difference was found deficits by domains when the percentiles were combined for the Coding test (χ2 (1) = 4.45, p = .03), suggesting that hospitalization is associated with decreased Multiple-domain impairment (60.3%) was more frequent than impair- performance in processing speed (see Figure 4). ment in only one domain (39.7%) (χ2 (1) = 5.36, p = .02). Attention deficits were the most frequent types of deficits in patients with single-domain impairment (19.0%), significantly exceeding deficits in 4.4.2 Disease duration EF (p = .01), ST/WM (p = .001), and Language (p < .001). Furthermore, attention was the cognitive domain that was most frequently impaired Correlations between individual disease durations and the compos- in conjunction with other domains in patients with multiple-domain ite scores for each cognitive domain were not significant (Attention: impairment, especially with L + LTM and EF (see Figure 2). r = 0.20, p = .25; L + LTM: r = −0.06, p = .72; EF: r = −0.07, p = .71; To see whether the performance in tests assessing attention, long- Language: r = −0.18, p = .32; Processing Speed: r < 0.01, p = .95; VVA: term memory, and executive functions were explained by overlap- r = −0.01, p = .91), suggesting that there is no effect of this variable on ping deficits, we performed correlational analyses using the composite the magnitude of cognitive impairment. scores derived from the T scores for the three domains. Only executive functions and attention were significantly correlated (r = .31, p = .01) (see Figure 3). 4.4.3 Biomarkers We correlated the composite scores of the cognitive domains with sev- 4.4 Hospitalization, disease duration, biomarkers, eral biomarkers that have been suggested to be altered in patients and affective scores with COVID-19 (Samprathi & Jayashree, 2020), including: C-reactive protein (CRP) levels, aspartate aminotransferase (AST), alanine amino- We performed further analyses to explore the effect of hospitalization, transferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), disease duration, and biomarkers on cognition. hemoglobin (Hg), platelets, leukocytes, lymphocytes, D-dimer, ferritin, 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GARCÍA-SÁNCHEZ ET AL . 7 of 11 FIGURE 3 Correlation between attention, long-term memory, and executive functions F I G U R E 4 Distribution of test scores between hospitalized and non-hospitalized patients according to classification by Guilmette et al. (2020): combined below average score and exceptionally low score (Pc < 8) versus low average score (Pc: 9–24). Asterisk indicates a significant difference in test performance between groups and interleukin-6 (IL-6). Significant correlations were found only for itive relationship between depression measures and this cognitive the composite scores of Language with ferritin (r = 0.32, p = .03) and domain. Attention with CK (r = −0.41, p = .007). 5 DISCUSSION 4.4.4 Affective scores This study was conceived to further characterize the extent of cog- Correlations between anxiety and depression subscores from the nitive impairment in post-COVID-19 patients with subjective cogni- HADS and all domain factors were performed. There were no signif- tive complaints. A large US survey study found that difficulty concen- icant correlations between anxiety subscores and cognitive domains. trating and focusing was experienced by more than 50% of patients, Depression subscores only showed a significant correlation with Pro- being the fourth most reported long-term symptom after COVID-19 cessing Speed (r = 0.29, p = .02), suggesting a rather weak pos- (Lambert & Corps, 2020). While cognitive impairments appear to be 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 11 GARCÍA-SÁNCHEZ ET AL . most pronounced in people who were hospitalized, they have also with L + LTM and EF. Running correlations between Attention, L + been observed in non-hospitalized patients (Hampshire et al., 2021), LTM and EF, no significant relationship between L + LTM and Atten- mild cases of COVID-19 (Townsend et al., 2020), and in asymptomatic tion was found. However, there was a significant correlation between patients (Amalakanti et al., 2021). To investigate how far-reaching the EF and Attention, suggesting an interdependence between these two cognitive sequelae of COVID-19 are, the present study aimed to (1) domains. This could be explained by shared neural networks in fronto- provide information on the frequency of deficits in specific cognitive subcortical structures that, if damaged, would produce deficits in both domains and (2) discern the frequency of single- and multiple-domain domains. Alternatively, impairment in attention abilities could pro- impairment. voke a cascading impact on executive functions. Impairment in memory Our results show that all patients in the sample demonstrated cog- is likely due to hippocampal dysfunction and exists independently of nitive deficits in at least one domain. Because all patients were referred other types of impairment. To address this question, future studies on for evaluation due to subjective cognitive complaints, this overall result cognitive functioning post-COVID-19 will need to include neuroimag- is not surprising; it does, however, help to confirm these complaints ing and relate brain structural and functional integrity with cognitive with objective neuropsychological measures. performance. Considering this study’s first aim, the most common domain In addition to the associations between cognitive domains, we also affected overall was attention (61.9% of the sample). Additionally, examined whether other clinical factors might be linked to cognitive attentional deficits were the most frequent deficits in those patients performance. Comparing hospitalized and non-hospitalized patients in with single-domain impairment (19.0%), far exceeding isolated impair- our sample, we found significantly lower performance on the MoCA ment in EF, ST/WM, and Language. Of note, impairment in attentional and in Processing Speed for hospitalized patients. While the signifi- processes in post-Covid-19 patients and its potential to compromise cant group differences here are important, what might be more intrigu- other cognitive domains has been pointed out by different studies ing is that hospitalization did not have a significant effect on test per- (Almeria et al., 2020; Zhou et al., 2020). For the present study, attention formance in most domains. Given that much of the current litera- abilities were indexed by the CPT-II. Although many CPT-II subscores ture has focused specifically on COVID patients that were hospitalized revealed large percentages of low scores, most impaired performance (Alnefeesi et al., 2021), our study contributes to emerging evidence was shown on measures pertaining to overall variability of responses (Amalakanti et al., 2021; Lambert & Corps, 2020) that not only do (HIT SE, Variability, and HIT SE Block Change; see Figure 1), indicat- non-hospitalized patients suffer from post-COVID cognitive sequelae, ing problems in consistency of responses and inattentiveness. These but they also may experience similar levels of impairment in domains results provide evidence for pervasive difficulties in sustaining atten- such as attention, memory, and executive functioning as hospitalized tion throughout a task in this post-COVID population. patients. The second most affected domain overall was EF (43% of the sam- Finally, we found a strong correlation between ferritin levels during ple). However, EF impairment was not commonly isolated, as only 4.8% acute illness and the Language composite scores. This correlation of the sample demonstrated single-domain impairment in EF; in most could suggest a role for hyper inflammation in neuronal damage cases, EF was altered in combination with dysfunction in other cogni- underlying language impairment and especially in those language tasks tive domains, possibly explained by its role in control and regulation of which are timed and involve cognitive flexibility along with optimal proper functioning in other cognitive functions and behaviors (Fuster, frontal functioning. Elevated levels of creatine kinase, associated with 2000). This finding is also in line with results from Miskowiak et al. decreased muscular function in the context of COVID-19 (Samprathi (2021), who found a positive correlation between executive function & Jayashree, 2021), were negatively correlated with performance on deficits and subjective cognitive complaints in a group of COVID-19 attention measures, indicating an important role for creatine in atten- patients assessed four months after hospitalization. tion processes. Furthermore, measures of mood alteration did not With the high frequency of low average performance in both atten- correlate with attention and EF deficits, indicating that dysfunction in tional and executive control tasks, it will be essential to continue to these domains are not associated with levels of depression and anxiety. assess this decreased performance with follow-up neuropsychological The only significant correlation found with affective measures was evaluations. At this point, we still do not know whether patients expe- between processing speed and depression; as scores in the domain of riencing post-COVID cognitive impairment are likely to revert to aver- processing speed also differed significantly for hospitalized patients, age test performance or not. If it is the case that these deficits are not future research should focus on this domain and its interplay with resolved over time, clinical and research professionals will need to for- attention and executive functions. Additionally, while our biomarker mulate specific interventions centered upon general cognitive stimula- data was obtained at the time of diagnosis, we suggest that future tion or restoring the efficiency of their attention functions. research should examine the relationship between biomarkers and Regarding our second aim, the results of this study indicate a larger cognitive deficits using clinical data collected at the time of the proportion of multi-domain than single-domain impairment, with the neuropsychological assessment. Results from this correlation could percentage of patients showing two and more cognitive affected provide a more accurate picture of how infection-related biomarkers domains at 60.3% and the percentage of patients with single-domain relate to individuals’ current cognitive deficits. impairment at 39.7%. Deficits in attention were present in most com- We acknowledge that our study has some limitations, namely the binations of multiple-domain impairment, especially in conjunction absence of a control group. The ideal condition would have been to 21579032, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.2508 by Readcube (Labtiva Inc.), Wiley Online Library on [27/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License GARCÍA-SÁNCHEZ ET AL . 9 of 11 compare the cognitive performance of our sample with a healthy PEER REVIEW group of individuals without COVID-19 or a group of COVID-19 The peer review history for this article is available at https://publons. survivors without subjective cognitive complaints. However, the use of com/publon/10.1002/brb3.2508. normative data allowed us to draw conclusions about the presence of cognitive deficits and lent support to the validity of our findings. ORCID It is important to keep in mind that, given the absence of a control Carmen García-Sánchez https://orcid.org/0000-0001-5672-9229 group without subjective cognitive complaints, our findings cannot be Marco Calabria https://orcid.org/0000-0003-4373-1316 generalized to any patient who was diagnosed with COVID-19. Nev- Nicholas Grunden https://orcid.org/0000-0002-7724-4316 ertheless, we believe that our results, though limited to patients with Pere Domingo https://orcid.org/0000-0003-1138-5770 cognitive complaints, are clinically relevant for neuropsychologists assessing cognition in COVID-19 survivors. REFERENCES Almeria, M., Cejudo, J. C., Sotoca, J., Deus, J., & Krupinski, J. (2020). Cogni- tive profile following COVID-19 infection: Clinical predictors leading to neuropsychological impairment. 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