key: cord-0913529-cna7xi2q authors: Ferrucci, Roberta; Dini, Michelangelo; Rosci, Chiara; Capozza, Antonella; Groppo, Elisabetta; Reitano, Maria R.; Allocco, Elisa; Poletti, Barbara; Brugnera, Agostino; Bai, Francesca; Monti, Alessia; Ticozzi, Nicola; Silani, Vincenzo; Centanni, Stefano; D’Arminio Monforte, Antonella; Tagliabue, Luca; Priori, Alberto title: One‐year cognitive follow‐up of COVID‐19 hospitalized patients date: 2022-03-29 journal: Eur J Neurol DOI: 10.1111/ene.15324 sha: 4f349ab2278d1aed2ddafdf40a47ff146d5561c2 doc_id: 913529 cord_uid: cna7xi2q BACKGROUND AND PURPOSE: Cognitive dysfunction has been observed following recovery from COVID‐19. To the best of our knowledge, however, no study has assessed the progression of cognitive impairment after 1 year. The aim was to assess cognitive functioning at 1 year from hospital discharge, and eventual associations with specific clinical variables. METHODS: Seventy‐six patients (aged 22–74 years) who had been hospitalized for COVID‐19 were recruited. Patients received neuropsychological assessments at 5 (n = 76) and 12 months (n = 53) from hospital discharge. RESULTS: Over half (63.2%) of the patients had deficits in at least one test at 5 months. Compared to the assessment at 5 months, verbal memory, attention and processing speed improved significantly after 1 year (all p < 0.05), whereas visuospatial memory did not (all p > 0.500). The most affected domains after 1 year were processing speed (28.3%) and long‐term visuospatial (18.1%) and verbal (15.1%) memory. Lower PaO(2)/FiO(2) ratios in the acute phase were associated with worse verbal long‐term memory (p = 0.029) and visuospatial learning (p = 0.041) at 5 months. Worse visuospatial long‐term memory at 5 months was associated with hyposmia (p = 0.020) and dysgeusia (p = 0.037). CONCLUSION: Our study expands the results from previous studies showing that cognitive impairment can still be observed after 1 year. Patients with severe COVID‐19 should receive periodic cognitive follow‐up evaluations, as cognitive deficits in recovered patients could have social and occupational implications. Neurological complications are present in patients with coronavirus disease 2019 (COVID-19) [1] [2] [3] [4] . Amongst such complications, cognitive dysfunction following clinical recovery from acute respiratory symptoms has also been reported [5] [6] [7] [8] [9] [10] [11] [12] [13] . These studies, however, present a significant degree of heterogeneity in terms of sample size, sociodemographic and clinical characteristics of the patients, assessment methods and follow-up duration. As a result, many studies have found cognitive deficits in the months following hospitalization for COVID-19 to be frequent [5, 6, 10, 11] , whilst some others have observed significantly lower rates of cognitive impairment [8, 13] . This heterogeneity is also evident when one examines the qualitative profile of cognitive impairment in patients with COVID-19, with some studies reporting deficits of executive functions, attention and processing speed, as well as memory problems [5, 10, 12] , whilst others report verbal memory deficits to be the predominant feature [6, 11] and others report significant language impairment [11, 13] . Although somewhat contrasting, these studies show that persisting cognitive deficits can be frequently found in patients with It is also important to assess whether different clinical aspects of COVID-19 are associated with a greater risk of long-term cognitive impairment, as this could allow clinicians to predict which patients might be at an increased risk of developing such complications. As is known, COVID-19 is a disease which presents multiple pathological mechanisms that could lead to cognitive impairment [14] [15] [16] . In addition to prolonged respiratory distress, which can cause hypoxia-related brain injury [17, 18] , hyperinflammation also plays a significant role in determining the severity and mortality of COVID-19 [19, 20] . The activation of a systemic inflammation pathway could produce aberrant stress responses which could in turn damage the central nervous system (CNS) [21] , thus suggesting that the aetiology of COVID-19related cognitive dysfunction might be both inflammatory and not inflammatory [17] . For this reason, clinical indicators of respiratory function, hyperinflammation and coagulopathy, as well as potential indices of viral access to the CNS, should be assessed as potential predictors of cognitive impairment in COVID-19 patients. To date, no study has assessed the progression of cognitive impairment after 1 year from hospital discharge. Detailing the progression of cognitive impairment is key, as it represents an important indicator of functional recovery. Indeed, whilst most COVID-19 patients might show a good clinical recovery in the months following hospitalization, persisting cognitive symptoms can impact negatively on their quality of life. Our aim was to assess the prevalence of cognitive impairment in COVID-19 patients after 1 year from hospital discharge. Potential clinical predictors of cognitive impairment were also evaluated. Other clinical data were collected: (i) to assess hypoxia, the ratio of arterial oxygen partial pressure (PaO 2 ) to fractional inspired oxygen (FiO 2 ) (P/F ratio) was measured during hospitalization, as well as peripheral oxygen saturation (SpO 2 ) level upon hospital arrival; (ii) as inflammatory biomarkers, C-reactive protein blood levels upon hospital arrival and during hospitalization were noted; (iii) to assess hypercoagulability, D-dimer values were measured upon hospital arrival and during hospitalization; (iv) to assess systemic alterations and organ damage, serum levels of creatinine, alanine transaminase and aspartate transaminase were noted upon hospital arrival and during hospitalization. The primary aim was to assess cognitive function at 1 year from hospital discharge, compared to 5 months. A secondary aim was to evaluate associations with clinical factors (e.g., respiratory distress, inflammation, smell/taste alterations). Patients were screened using the Montreal Cognitive Assessment, a screening test for global cognitive functioning, in order to exclude those with global cognitive decline [22] . At the time of cognitive testing, patients were also evaluated with Beck's Depression Inventory-II (BDI-II) [24] in order to assess the presence of depressive symptoms. The BDI-II allows for a categorization of the severity of depressive symptoms, which can be defined as none or minimal (score ≤13), mild (score [14] [15] [16] [17] [18] [19] , moderate (score 20-28) or severe (score ≥29) [25] . All analyses were performed with SPSS 26.0 (IBM, 2019). All tests were two-sided, and a p value ≤0.05 was considered significant. Normality of distribution of the data was assessed by analysing skewness and kurtosis [26] . Descriptive analyses were conducted for demographic and clinical data [23] . Differences in performance to the eight subscales of the BRB-NT between T1 and T2 were assessed using a paired samples t test. As suggested by Armstrong [27] , multiple comparisons were not corrected for in order to minimize the risk of a type II error and because the eight neuropsychological scores represent different cognitive processes and functions. The potential predictors of cognitive performance were examined through a series of hierarchical multiple linear regression analyses. Our dependent variables were the raw scores to the eight tests of the BRB-NT. As independent variables, in block 1 four sociodemographic and clinical predictors were entered, namely age, sex, years of education and the time interval between hospital discharge and neuropsychological assessment. In block 2, the lowest P/F ratio observed in each patient during their hospital stay was entered. As effect sizes, the partial correlation coefficient r for each independent variable and the adjusted percentage of explained variance (R 2 ) for each block were reported. Associations between hyposmia, dysgeusia and BRB-NT subscale scores were assessed using analyses of covariance (ANCOVAs), with hyposmia or dysgeusia as independent variables (present vs. absent), BRB-NT test scores as dependent variables, and age, sex, education and discharge-assessment interval as covariates. As a measure of effect size, η p 2 values are reported. The study was approved by the Institutional Ethics Committee of the San Paolo Hospital of Milan (CogCov study: Reg. no. 2020/ST/105) and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent to participate in this study. Our study population (see Table 1 ) consisted predominantly of male patients (n = 56, 73.7%); mean age was 56.24 ± 12.08 (mean ± SD) and the majority of our participants (n = 54, 70.2%) had at least Table 2 . At T1, block 2 of the regression models reached significance only for SRT-LTS and SPART subscales. As for SRT-LTS, at block 1 sociodemographic and clinical variables contributed significantly to the regression model (see Table 3 Table 3 ). At T2, block 1 was significant for all cognitive tests with the exception of SPART-D (p = 0.620). The P/F ratio was added in block 2 but was not found to be a significant predictor of performance in any cognitive test at T2 (see Table S1 ). Table S2 ). Cognitive performance at T2 was not significantly different between patients who had ARDS and those who did not (see Table S3 ). Bivariate analyses were conducted to assess the relationships between other clinical variables and cognitive performance at T1. After controlling for age, sex, education and discharge-assessment interval, an inverse correlation was observed between serum alanine transaminase levels during hospitalization and long-term verbal memory performance (SRT-D, r = −0.294; p = 0.014). BDI-II scores did not correlate with cognitive performance. Detailed results are reported in Table S4 . The long-term cognitive profile of recovered patients with COVID-19 was assessed by neuropsychological assessments after 1 year from discharge. To the best of our knowledge, this is the first study to report cognitive data at 1 year from clinical recovery from COVID-19. More than half of our patients had deficits in at least one cognitive test after about 5 months from hospital discharge. Attention/ processing speed was the most frequently impaired domain, followed by long-term verbal and visuospatial memory. Whilst attention/processing speed remained the most frequently affected domains, the prevalence of long-term verbal memory deficits decreased significantly after 1 year, whereas no significant change was observed in visuospatial learning and delayed recall. Our study also expands the results from previous studies on cognitive functioning in the first months following clinical recovery and shows that, whilst attention/processing speed and long-term verbal memory deficits represent the dominant feature of cognitive impairment in the post-acute phase, they tend to improve as time progresses, whereas visuospatial memory deficits do not. Miskowiak et al. [10] reported similar rates of cognitive impairment at 4 months from hospital discharge, observing that verbal memory and executive function were the most affected domains. Méndez et al. [11] [30] . Notably, whilst hospitalized patients tended to present higher rates of long-term cognitive impairment (30%) compared to non-hospitalized patients (20%), this difference was not significant (p = 0.096) [29] . However, this metaanalysis did not further evaluate the prevalence of cognitive impairment TA B L E 2 Results of the cognitive assessments at 5 (T1) and 12 (T2) months from discharge across the different cognitive domains and did not differentiate between studies using a complete neuropsychological assessment and those that only used brief global cognition screening tests, probably due to the small number of published studies with formal neuropsychological testing. Future meta-analyses should aim to provide a more detailed cognitive profile of these patients, as our results suggest that not all cognitive domains and functions are affected equally. When the impact of clinical variables was assessed, it was found that worse P/F ratios were associated with worse long-term memory and visuospatial learning, whilst hyposmia and dysgeusia were associated with worse visuospatial long-term memory. Neither the P/F ratio nor hyposmia/dysgeusia were associated with cognitive dysfunction after 1 year, indicating that clinical illness variables affect the profile of cognitive impairment in the short and medium term but not in the long term. Overall, these results suggest that different-but not necessarily mutually exclusive-pathological processes may underlie cognitive dysfunction in recovered COVID-19 patients, and that time from clinical recovery also plays a significant role. Respiratory distress, which leads to hypoxaemia and hypoxia, can cause long-lasting cognitive impairment [17, 31] and brain abnormalities [32] . Prior to the current pandemic, studies on the cognitive sequelae of patients hospitalized for ARDS have highlighted substantial cognitive deficits at the time of discharge, with slow but evident improvement in the longer term [33, 34] . Recent studies found that hospitalization in the intensive care unit for severe COVID-19-related ARDS increases the risk of cognitive impairment [35, 36] . It is less clear, however, whether a distinct cognitive profile could be associated with ARDS. Indeed, some have found memory impairment to be predominant [18] , whilst others reported a greater impact on executive functioning [31] . memory performance. The specific association between memory deficits and respiratory distress could reflect a direct consequence of hypoxic damage, considering the known susceptibility of the hippocampus to hypoxia [37] . This hypothesis is supported by the fact that the P/F ratio selectively predicted the scores in two tests of memory which reflect in particular the integrity of memory encoding and storage processes, which are classically ascribed to the hippocampus and other medial temporal lobe areas [38, 39] . However, other factors such as cytokine-related hyperinflammation, coagulopathy, blood-brain barrier breakdown and production of antineuronal antibodies [16, 20, 40] might also play a significant role. Additionally, our data expand the findings of a study which reported an association between hyposmia and cognitive impairment at 6 months [9] . The authors did not conduct detailed neuropsychological assessments and therefore could not establish whether hyposmia was associated with an impairment of specific cognitive functions. The association between smell and taste alterations and memory deficits observed in our study might suggest a direct involvement of the olfactory tract and the entorhinal cortex, which is anatomically and functionally associated with the hippocampus [41] . Nevertheless, the direct relationship between hyposmia and cognitive dysfunction has not yet been fully understood. In the context of COVID-19, smell/ taste alterations have been hypothesized to reflect viral access of SARS-CoV-2 to the CNS via trans-synaptic olfactory pathways [42] . Although studies have demonstrated that SARS-CoV-2 can access both brainstem [43] and brain [16, 44] , the specific contribution of either viral neurotropism or inflammatory response to the aetiology of brain alterations observed in these patients is still debated. Our work has some key limitations, such as the lack of baseline data on cognitive function, that stem from the fact that adult participants were assessed who did not report cognitive problems prior to having COVID-19 and therefore had never required a cognitive assessment. A control group was also lacking, a limitation shared by most studies published on this topic to date [6, 9, 11, 13, 35] , reflecting the consequences of the ongoing pandemic, which limits the possibility of recruiting healthy participants for in-person hospital assessments. Finally, due to missing data at T2, results could not be generalized but, as appropriate analyses can eliminate or reduce bias, studies with larger sample sizes are needed in order to confirm our results. In conclusion, cognitive impairment can still be observed in al- All authors report no competing interests. writing-review and editing (equal). The data that support the findings of this study are available from the corresponding author, upon reasonable request. 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Eur J Neurol. 2022;00:1-9. doi:10.1111/ene.15324