key: cord-0968016-8t2tic9n authors: Crivelli, Lucia; Palmer, Katie; Calandri, Ismael; Guekht, Alla; Beghi, Ettore; Carroll, William; Frontera, Jennifer; García‐Azorín, David; Westenberg, Erica; Winkler, Andrea Sylvia; Mangialasche, Francesca; Allegri, Ricardo F.; Kivipelto, Miia title: Changes in cognitive functioning after COVID‐19: A systematic review and meta‐analysis date: 2022-03-17 journal: Alzheimers Dement DOI: 10.1002/alz.12644 sha: 51d9e2c0050f1e72d4e40470d54d2d1831d98dfb doc_id: 968016 cord_uid: 8t2tic9n INTRODUCTION: We conducted a systematic review and meta‐analysis of the cognitive effects of coronavirus disease 2019 (COVID‐19) in adults with no prior history of cognitive impairment. METHODS: Searches in Medline/Web of Science/Embase from January 1, 2020, to December 13, 2021, were performed following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. A meta‐analysis of the Montreal Cognitive Assessment (MoCA) total score comparing recovered COVID‐19 and healthy controls was performed. RESULTS: Oof 6202 articles, 27 studies with 2049 individuals were included (mean age = 56.05 years, evaluation time ranged from the acute phase to 7 months post‐infection). Impairment in executive functions, attention, and memory were found in post‐COVID‐19 patients. The meta‐analysis was performed with a subgroup of 290 individuals and showed a difference in MoCA score between post‐COVID‐19 patients versus controls (mean difference = −0.94, 95% confidence interval [CI] −1.59, −0.29; P = .0049). DISCUSSION: Patients recovered from COVID‐19 have lower general cognition compared to healthy controls up to 7 months post‐infection. With an increasing number of individuals recovering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there is an urgent need to study the medium-and long-term consequences of the disease. Growing evidence suggests that some patients exhibit symptoms such as fatigue, "brain fog," or cognitive complaints after the acute infection stage, commonly referred to as "Long COVID." 1 A 6month study using multidimensional data from the medical records of 73,435 coronavirus disease 2019 (COVID- 19) patients showed that, after the first 30 days of illness, individuals have an increased risk of death, higher health resource utilization, and an increased burden from neurocognitive disorders. 1 Indeed, evidence from previous epidemics shows that subsequent neurological and, particularly, cognitive complications can occur, such as in the severe influenza epidemic from 1918 to 1921 (also known as the Spanish flu). 2 More recently, cases of encephalitis, sensory impairment, coma, and severe neurological damage were reported during the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak in 2012 3 and vascular or inflammatory damage of the brain and central nervous system in people affected by the severe acute respiratory syndrome coronavirus (SARS-CoV) outbreak in 2003. 4 Cognitive dysfunction has a significant impact on functionality and quality of life. 5 Given the high incidence of COVID-19 and the associated economic, health, and social burden of the epidemic, studying its occurrence and underlying mechanisms is crucial. In the current systematic review, we assess whether there is an increased occurrence of cognitive deficits in adult patients with COVID-19 who previously had no cognitive impairment. The protocol of the present study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42021243026). This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. 6 The PICOS (Population, Intervention/issue of interest, Comparison, Outcome, and Study design) method was used. 7 The population included COVID-19 patients with no previous cognitive impair-ment. The intervention/exposure included being ill with COVID- A systematic search of the literature was performed on March 19, 2021 in three electronic databases: Medline, Web of Science, and Embase. The search terms used were devised by an expert group of neurologists, epidemiologists, and neuropsychologists, and included the following keywords: COVID-19, Coronavirus, COVID19, SARS-CoV-2, 2019-n-CoV, pandemic, cognition, Cognitive, Memory, Major cognitive disorder, mild cognitive impairment, mild neurocognitive disorder, MCI, cognitive decline, cognitive deficit, major neurocognitive disorder, cognitive impairment, memory impairment, MMSE, MoCA, neuropsychology, neuropsychological impact, executive function, attention deficit, language, visuospatial, dysexecutive syndrome, orientation, concentration, verbal fluency, and processing speed. Reference lists of publications were also screened to identify additional articles. Two reviewers independently screened the titles and abstracts according to the eligibility criteria. Disagreements were discussed with a third reviewer and subsequently resolved via consensus ( Figure 1 ). The following data categories were collected when available: study design, sample size, country, patient demographics, population setting, time of assessment related to COVID-19 infection, cognitive testing instruments, neuropsychological findings, and COVID-19 disease severity calculated using the World Health Organization (WHO) scale: WHO/2019-nCoV/clinical/2020.5. 8 One of the reviewers performed the data extraction and the other reviewer assessed the accuracy of the extracted data. We performed a meta-analysis on articles (minimum n = 3) that included the same outcome (eg, the same neuropsychological test). After removing duplicates, a total of 6202 records were identified from the databases ( Figure 1 ); 6012 were excluded after screening the titles and abstracts. After reading the full text, 115 were excluded because they were not related to the aims (n = 64); had a pediatric popula- Five studies examined patients in the acute stage of COVID-19. [10] [11] [12] [13] A case report by Tolentino et al. 13 followed up a patient with moderate COVID-19 throughout the disease course and found that cognitive deficits increased until day 10, after which the cognitive functioning began to improve until a normal performance was achieved on day 16 . Another case-control study including young asymptomatic patients (mean age 36.2 ± 11.7) found differences between cases and healthy controls in fluency (P ≤.001), visual-perception (P = .032), and naming (P = .016). 11 The occurrence of cognitive impairment in the acute COVID-19 phase ranged from 61.5% in a cohort of mild to moderate patients in a general hospital 12 to 80% in a cohort of moderate to The case-control studies reported mainly consistent results; all found significantly lower scores in cognition in the post-COVID-19 patient group compared to controls. Although some studies found deficits in global scores of screening measures 23, 24 and sub-scores of attention, memory, and executive functions, others 25 Cohort studies showed a high occurrence of moderate cognitive impairment in post-COVID-19 patients, exceeding 50% in all studies that reported prevalence, 12, 15, 16, 27 ranging from 54% in a cohort of consecutive patients admitted to hospital with moderate COVID-19 15 to 65% in a cohort of moderate to severe patients. 27 A study 16 12, 15, [27] [28] [29] In a study by Hosp et al., 15 Conversely, a recent cohort study 30 There is an insufficient number of published papers to make conclusions about how the severity of COVID-19 or types of disease symptoms differentially affect cognition. A study that tested moderate to severe hospitalized patients with functional dependence 1 month after discharge found that patients who received treatment with mechanical ventilation had better cognitive performance than those who only received oxygen therapy. 10 The former group of subjects had significantly higher performance in visuospatial/executive functions, naming, short-and long-term memory, abstraction, and orientation but were also significantly younger than the latter group. Similarly, a cohort study by Manera et al. 32 found that patients presenting with adult respiratory distress syndrome (ARDS) who underwent intensive care suffered less from cerebral hypoxia and thus had less cognitive sequels than those treated with non-invasive ventilation. Woo et al. 33 .037). 28 Accordingly, two studies 34,35 compared ICU versus non-ICU post-COVID patients and found significantly more severe and broad impairment in ICU patients. A total of five studies reporting MoCA results, including COVID-19 patients versus a control group, 11, 24, 29, 31, 36 were included in the metaanalysis. There was evidence of an effect of COVID-19 infection on the total MoCA score (MD = −0.94, 95% CI −1.59, −0.29; P = .0049). In addition, although influential assessment reports no outliers, it is interesting to note that the study by Amalakanti 11 was large and may influence the overall findings (see Figure 2 ). This is the only study that included asymptomatic young patients (mean age 36.2 ± 11.7) and did not find cognitive differences in MoCA but found deficits in a more specific cognitive assessment. The heterogeneity was: I 2 = 48.3%, 95% The asymmetry in the figure (see Figure 4) indicates publication bias, F I G U R E 5 Meta-regression Model: MoCA by age the possibility that negative studies have not been submitted due to being of less interest to the journals to be published. However, it must be considered that Egger test may lack the statistical power to detect bias when the number of studies is small (ie, k < 10). In addition, a meta-regression analysis based on age was performed to study the effects of age on MoCA of post-COVID-19 patients (see Figure 5 ). We found an estimated change in MoCA total score of −0.064, 95% CI: −0.012, −0.116 for an increase of 1 year in age (z = −2.4148; P = .0157). Study designs and quality scoring using Newcastle-Ottawa Scale for non-randomized studies in meta-analyses and classification according to AHRQ standards Two reviewers independently rated the quality of included studies using the Newcastle-Ottawa Scale (or NOS) 9 (see Table 2 ). The quality of case-control and cohort studies was assessed judging three categories: the selection of the study groups, the comparability of the groups; and the ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. In summary, when using the Agency for Health Research and Quality (AHRQ) threshold standards, 9 of the 20 studies were good, 15, 23, 25, 27, 29, 32, 33, 36, 31 1 was fair, 28 and 10 were poor. [10] [11] [12] 14, 16, 24, 30, 34, 35, 37 Our systematic review highlighted that the evidence assessing the con- Although few studies assess specific cognitive domains, generally the early results suggest that executive function, memory, and attention are the domains that more frequently show differences between COVID-19 patients and healthy controls up to 3 months after illness. 23, 27, 33 Deficits were also seen in some studies for working memory, learning, delayed control, inhibitory control, set-shifting, phonological verbal fluency, and processing speed. The pathological mechanisms that might underlie the potential cogni- In the case of post-COVID-19 cognitive impairment, this association is less clear. Two studies included in this review reported a relationship between cognitive impairment and poorer pulmonary function, 27, 28 suggesting that reduced oxygen delivery to the brain may play a role. However, not all studies report whether or not their subjects have had ARDS, and in those that do report it, the association between severity of ARDS (and therefore hypoxia) is not established, 27 or they present conflicting results, ie, patients with higher severity having better function. 10 The interaction between severity and age is something that should always be considered when interpreting the results, as COVID-19 severity is age dependent and age is a risk factor for cognitive impairment in the general population. Another aspect that may underlie the onset of cognitive impairment is vascular involvement. Only one of the studies reported D-dimer levels, 27 which were elevated in subjects with cognitive impairment. Five of the reviewed studies reported imaging 12, 15, 22, 31, 36 Furthermore, interventions to treat ARDS can lead to delirium. Other possible mechanisms are systematic inflammation infecting the central nervous system (CNS) or a storm of intracranial cytokines mediated by blood-brain barrier permeabilization. 42 These mechanisms could also contribute to cognitive impairment in patients in the acute phase of COVID-19. The strength of our study was that the systematic review process There is an urgent need for more studies on the topic of the cogni- preferably standardized to allow for cross-country comparisons. There was only one study from low-and middle-income countries (LMICs) 11 ; therefore, more extensive research into these regions is needed, especially due to the potential role of education on cognitive reserve. Low formal education has been found to have a deleterious impact on cognition. 46 This is why it would be interesting to include and promote post-COVID-19 cognitive studies in LMICs where education levels are low, and to study how cognitive reserve may interact with post-COVID-19 cognitive impairment. The results of the review have several implications from clinical, individual, and public health perspectives. It has been suggested that there may be a "Long-COVID" syndrome of which cognitive dysfunction might be a symptom. 47 Until now, although rapid guidelines for managing long-term symptoms of COVID-19 have been published, 48 there are no internationally established diagnostic criteria for longterm COVID syndrome. The research described in the current review may provide important insights into which cognitive deficits should be evaluated in any future diagnostic criteria, although more research is needed. Our systematic review highlighted a lack of studies investigating the effect of COVID-19 on cognitive functioning, particularly with regard to specific cognitive domains. Although the meta-analysis suggests that patients with COVID-19 have lower general cognition compared to healthy controls after they have recovered, evidence is still lacking, and no firm conclusions can be drawn. However, this preliminary evidence suggests that individuals may experience cognitive impairment after recovery from COVID-19, and future studies will need to further clarify how long these symptoms persist and whether they are associated with specific characteristics of the patient. 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Alzheimer's Dement The authors acknowledge the contribution of all the members of WHO's Neurology and COVID-19 Global Forum working group on Follow-up and Long-term Impact. ORCID Lucia Crivelli https://orcid.org/0000-0002-0083-9389Ismael Calandri https://orcid.org/0000-0002-6983-1430