Association of Cerebral Microbleeds in Brain Magnetic Resonance Imaging with Apolipoprotein E4 in COVID-19 survivors. A prospective observational study

Association of Cerebral Microbleeds in Brain Magnetic Resonance Imaging with Apolipoprotein E4 in COVID-19 survivors. 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A prospective observational study Christoffer Wiklund, Juha Martola, Henriikka Ollila, Linda Kuusela, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6716518/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract COVID-19 has been associated with neurological sequelae ranging from mild cognitive impairment to ischemic and hemorrhagic stroke. Brain radiological abnormalities observed with COVID-19 include white matter hyperintensities and cerebral microbleeds (CMBs). Apolipoprotein ε4 (APOE4) is associated with an increased risk of CMBs and neurodegenerative disorders. We investigated whether possession of the APOE4 allele was associated with an increase in the number of CMBs in COVID-19 patients. In this substudy of the RECOVID study, 51 ICU-treated, 29 ward-treated and 35 home-treated COVID-19 patients and 52 non-COVID-19 controls underwent brain MRI six months after acute COVID-19 and their APOE genotype was identified. CMBs existed in 31 (33%) subjects after COVID-19 and 12 (23%) subjects in the control group. The number of CMBs increased with disease severity, with 8 (16%) of the ICU-group and 3 (10%) in the WARD-group having ≥ 5 CMBs compared with none in the HOME- and control groups. The subjects with CMBs were older and had a higher prevalence of hypertension and diabetes. In multivariable analysis, an increased number of CMBs was associated only with hypertension. No interaction between APOE4 and COVID-19 associated with an increased number of CMBs was found. Health sciences/Diseases/Infectious diseases/Viral infection Health sciences/Risk factors Health sciences/Neurology/Neurological disorders/Cerebrovascular disorders Health sciences/Neurology/Neurological disorders/Dementia Figures Figure 1 Figure 2 Introduction Cerebral microbleeds (CMBs) are small deposits of hemosiderin in brain parenchyma that can be visualized by Magnetic Resonance Imaging (MRI). The hemosiderin deposits form as a product of red blood cells that have leaked from arteries. CMBs have been associated with, among others, increased age, diabetes mellitus, hypertension, smoking, male sex and Apolipoproteins E2 and E4. 1 The Apolipoprotein E4 (APOE4) is a strong risk factor for cardiovascular disease, Cerebral Amyloid Angiopathy (CAA) and related hemorrhagic stroke, ischemic stroke and late onset Alzheimer’s disease (AD). It also leads to a higher probability of CMBs, possibly through a greater burden of amyloid in cerebral blood vessels. 2 APOE4 carriers specifically have a higher risk for lobar CMBs in the general population. 3 While strictly lobar CMBs may not be linked to an increase in mortality 4 , they are associated with neurodegenerative disorders, especially AD and CAA 5 , 6 . In contrast, deep and infratentorial CMBs that are linked to hypertensive and atherosclerotic arteriopathy, but not to APOE genotype, are associated with all-cause, cardiovascular, stroke and non-cardiovascular related mortality, with the risk increasing gradually with a larger number of CMBs. 4 APOE4 has also been associated with an increased risk for severe COVID-19. 7 , 8 Patients with COVID-19 have been shown to have an increased prevalence of CMBs and other brain abnormalities in MRI - and autopsy studies. 8 – 10 The clinical significance of CMBs in association with COVID-19 is not yet understood. The purpose of this study was to investigate if there is an interaction between COVID-19 and the APOE4 allele that would lead to a higher prevalence of MRI-detected CMBs in a post-acute cohort of COVID-19 survivors. We hypothesized that CMBs are more numerous in APOE4 carriers who had contracted COVID-19. Materials and methods Participants This is a post-hoc substudy of the RECOVID study, a multidisciplinary study investigating long-term findings in a cohort of adult patients with a laboratory confirmed SARS-CoV-2 infection between March 1 and December 31, 2020. Three different groups of COVID-19 survivors were identified and recruited for this study within three months from hospital discharge or home isolation. Detailed description of study subject recruitment, and inclusion and exclusion criteria have been published previously. 11 Briefly, the first group (ICU) consisted of patients who had suffered from critical COVID-19 requiring intensive care unit (ICU) treatment with ventilatory support (high flow nasal cannula, non-invasive ventilation or intubation) in Helsinki University Hospital ICUs and were identified through the quality database of intensive care. The second group (WARD) consisted of patients with moderate COVID-19 requiring admittance to a hospital ward without need for ICU during the acute phase of infection. They were recruited from a post COVID-19 follow-up clinic organized by the pulmonology clinic or during treatment in the pulmonology ward. A third group of non-hospitalized patients (HOME) was recruited through announcements in local newspapers and social media. A fourth group of participants who had no history of SARS-CoV-2 infection (CONTROL) was recruited to serve as a control group. All COVID-19 survivors had infections verified by real time polymerase chain reaction (RT-PCR) or antibody test. Criteria for exclusion were age <18 years, pregnancy, major neurologic disease prior to COVID-19 (e.g. progressive memory disorder, Parkinson’s disease), severely impaired hearing or vision, developmental disability, contraindications to MRI, such as severe claustrophobia, cardiac pacemaker or ferromagnetic fixation material or other MRI-incompatible foreign body. Additionally, we only recruited patients with Finnish as their primary language as neuropsychological assessment was a major part of the RECOVID main study. The study protocol was approved by the Ethics Board of Helsinki University Hospital (HUS-1949-2020). All participants provided written informed consent for participating in the study and separate written informed consent for APOE analysis. The study was conducted according to the principles of the declaration of Helsinki. Magnetic resonance imaging The subjects underwent MRI of the brain six months after the acute SARS-CoV-2 infection, and the imaging sequences were planned and analyzed by an experienced neuroradiologist blinded to the clinical details or severity group of the subjects. The number and the topography of the microbleeds was analyzed using the Microbleed Anatomical Rating Scale (MARS). 12 White matter hyperintensities (WMHs) were categorized using the Fazekas scale ranging from 0 to 3 (0 = no changes, 1 = mild, 2 = moderate, and 3 = severe changes). 13 APOE genotyping A 5 mL sample of whole blood was drawn and stored frozen at -80° C until analysis. APOE genotype was derived from the single-nucleotide polymorphisms rs429358 and rs7412 that were genotyped using a microarray or imputed using a Finnish reference panel as described previously. 8 As the APOE 1/3 genotype is indistinguishable from the APOE 2/4 genotype, they were all considered as APOE 2/4, due to the E1 allele being exceedingly rare. We considered subjects with either one or two APOE4 alleles as APOE4 positive. Statistical analysis We describe continuous variables as medians and interquartile range (IQR) and categorical variables as numbers and percentages. Differences between groups are evaluated using Chi-square test, Fisher’s exact test for categorical variables and Kruskal-Wallis´ rank sum test for continuous variables. We first assessed the distribution of the data visually for the number of CMBs. To allow for robust modelling despite the strong zero-inflation in the data, we modelled the outcomes first as a binary response (zero vs non-zero). Then we included the non-zero counts in a negative binomial generalized linear model that fits the distribution of the data according to the visual assessment of the distribution, difference in variance and mean values, and assessment of residual values. We performed a univariate analysis to establish potential associations between the number of CMBs and variables, chosen based on previously reported factors associated with CMBs and available data. After this, the variables that reached a statistical significance of p≤0.05 were added to a multivariate model. Statistical analysis was performed with the statistical software R, with the negative binomial model as implemented in the MASS package. Results Altogether, 252 subjects were recruited for this study. After exclusion in accordance with Figure 1., 167 subjects remained in the final analyses. Characteristics of COVID-19 survivors and controls including the APOE4 carrier status are shown in Table 1. The median age of the subjects was 56 years (IQR = 17 years), 46% (N=76) were male. Of the subjects, 75 (45%) had comorbidities, with hypertension, asthma and diabetes being the most prevalent. The burden of comorbidities skewed toward the ICU group. Altogether, 37% (N=62) were carriers of the APOE4 allele, and nine of them were homozygous for the APOE4 allele. No differences in the prevalence of APOE4 carriership existed in those with no CMBs, one to four, or more than four CMBs (Table 1). The prevalence of any CMBs among COVID-19 survivors was 33%, and among controls 23% (p=0.2). While most CMBs were singular findings, 12% of COVID-19 patients who were hospitalized (ICU and WARD) with COVID-19 had multiple (≥5) CMBs, compared with none in HOME and control groups. The localization of the CMBs was predominantly lobar in both APOE4 carriers and carriers of other APOE alleles, with lobar CMBs accounting for 74% and 67% of the total number of CMBs, respectively. The data included two participants with extremely numerous CMBs, numbering 374 and 147. Of these two, one was a homozygous carrier of the APOE4 allele, while the other carried two APOE3 alleles. Both outliers belonged to the ICU group, both had hypertension and coronary artery disease, while one had diabetes. The results of univariable and multivariable analyses of the putative factors associated with the number of CMBs in the subjects with microbleeds are shown in Table 2. In univariable analysis, age [Incidence rate ratio, IRR=1.09 (1.04-1.14), p=1.7x10^ -4 ], a history of hypertension [IRR=10.0 (4.49-22.0), p=1.65x10 -8 ], APOE4 allele carriership [IRR=3.17 (1.30-8.32), p=0.014] and COVID-19 [IRR=11.7 (3.68-32.8), p=7.27x10 -6 ] were associated with an increased number of CMBs. When dividing the COVID-19 group by disease severity, only ICU-treated COVID-19 [IRR=19.8 (7.03-53.6), p=5.38x10 -9 ] was significantly associated with an increased number of CMBs. Sex or diagnoses of asthma and diabetes were not associated with an increased number of CMBs in the univariable model. Table 1 Subject characteristics according to groups of different number of cerebral microbleeds. Analysis was performed with Kruskal-Wallis´s rank sum test, Chi-square test or Fisher’s exact test as appropriate. One subject showed radiological demyelination and was later diagnosed with multiple sclerosis. CMB, cerebral microbleed; SD, standard deviation; APOE4, Apolipoprotein E4; ICU, Intensive Care Unit. Number of CMB = 0 Number of CMB =1-4 Number of CMB ≥5 p N=117 N=39 N=11 Age, years, median (SD) 53 (13) 60 (10) 63 (10) 2.2x10 -16 Sex (male), N (%) 50 (43) 20 (51) 6 (55) 0.53 Hypertension, N (%) 35 (30) 14 (36) 9 (82) 0.003 Asthma, N (%) 16 (14) 5 (13) 2 (18) 0.9 Diabetes, N (%) 11 (9.4) 4 (10) 5 (45) 0.009 Fazekas 0.11 0 22 (19) 2 (5.1) 0 1 88 (75) 34 (87) 9 (82) 2 5 (4.3) 2 (5.1) 2 (18) 3 1 (0.9) 1 (2.6) 0 Demyelination 1 (0.9) APOE4 carrier, N (%) 44 (38) 14 (36) 4 (36) 1 Severity 0.020 ICU, N (%) 30 (26) 13 (33) 8 (73) WARD, N (%) 20 (17) 6 (15) 3 (27) HOME, N (%) 27 (23) 8 (21) 0 CONTROL, N (%) 40 (34) 12 (31) 0 Topography of CMBs Lobar, % NA 71 64 Deep, % NA 15 22 Infratentorial, % NA 14 14 In multivariable analysis including significant (p<0.05) variables from the univariable analysis, only hypertension [adjusted incidence rate ratio, [aIRR=7.45 (2.77-19.5), p=3.04x10 -5 ] remained statistically significantly associated with the number of CMBs. No interaction effect was found between COVID-19 and APOE4 [aIRR=2.77 (0.33-21.2), p=0.33], as illustrated in Figure 2. Table 2: Results of statistical analysis of subjects with at least one cerebral microbleed using a negative binomial regression model. Adjusted Incidence Rate Ratio (aIRR) depicts results of a multivariate model of variables with p<0.05 in the univariate analysis. APOE4*Covid depicts the possible interaction between Apoe4-carriership and COVID-19 status on the number of CMBs. COVID-19 severity is only modelled in the univariate analysis. IRR, Incidence Rate Ratio; CMB, Cerebral Microbleed Subjects with CMB≥1 N=50 Number of microbleeds n (%) IRR (CI) p aIRR (CI) p Age (years) 1.09 (1.04-1.14) 1.7x10 ^ -4 1.03 (0.97-1.08) 0.24 Male sex 26 (52) 0.43 (0.17-1.08) 0.069 Asthma 7 (14) 0.36 (0.11-1.74) 0.13 Hypertension 23 (46) 10.0 (4.49-22.5) 1.65x10 -8 7.45 (2.77-19.5) 3.04x10 -5 Diabetes 9 (18) 1.91 (0.67-7.44) 0.28 APOE4-carriers 18 (36) 3.17 (1.30-8.32) 0.014 1.67 (0.27-11.7) 0.58 COVID-19 38 (76) 11.7 (3.68-32.8) 7.27x10 -6 2.77 (0.49-6.63) 0.32 APOE4*Covid 2.77 (0.33-21.2) 0.33 Covid severity ICU 21 (42) 19.8 (7.03-53.6) 5.38x10 -9 WARD 9 (18) 2.07 (0.61-7.44) 0.25 HOME 8 (16) 1.08 (0.29-4.29) 0.91 CONTROL 12 (24) Reference Discussion In this post hoc sub study of the observational RECOVID study, we assessed whether an interaction of APOE4 allele carrier status and COVID-19 was associated with the number of MRI-detected CMBs in a population of COVID-19 survivors and non-COVID-19 controls. We found no such interaction. In a previous study, we have shown that that APOE4 was associated with an increased prevalence of CMBs in a histopathological study of brain tissue of deceased COVID-19 patients. 8 Our findings are in accordance with the previous results, but the power of the association in our study was weaker. The difference with this study may be partly explained by the differences in the methods used for detecting CMBs and the studied population. As the findings of the previous study were based on autopsy, important differences regarding subject characteristics and disease severity exist between the populations. The prevalence of CMBs in the general population varies between 5–24% in different studies, with age and APOE4 being associated with lobar CMBs, while age, hypertension and smoking are associated with deep or infratentorial CMBs. 14 CMBs have been implicated as a complication of severe COVID-19 in several observational studies. 9 , 10 , 15 , 16 In our sample, the prevalence of CMBs in the control group (23%) was in range with the previous studies of CMBs in the general population. COVID-19 was significantly associated with an increase in CMBs, but a closer analysis of the population revealed that significance only applied to severe COVID-19 treated in the ICU and may thus be related to factors other than COVID-19, for example severe hypoxemia. 11 Though often incidental findings, CMBs have been shown to be associated with increased risk for dementia in the general population. 17 Specifically lobar and cerebellar CMBs are considered preclinical markers of CAA 5 , and are also associated with AD. Deep CMBs are considered as a sign of small vessel arteriopathy, and they have been associated with an increased cardiovascular mortality. 4 The clinical significance of CMBs associated with severe COVID-19 is still unknown, as is the role of APOE4 that may have a role in modifying the acute, and long-term risks of COVID-19. Our findings may implicate that severe respiratory illness and treatment in the ICU are more relevant regarding CMBs than SARS-CoV-2 infection. This hypothesis is in line with two small studies where CMBs were observed in patients with respiratory failure requiring treatment in the ICU. 18 , 19 CMBs have also been found in conjunction with other conditions related to critical care, such as infective endocarditis, disseminated intravascular coagulation and extracorporeal membrane oxygenation. 20 This could have implications for a further study of cognitive decline in patients with post-intensive care syndrome. Our study has limitations. First, our patient groups were relatively small and heterogeneous, with older age and the disease burden skewing toward the ICU group. Second, we did not perform an a priori power calculation. Third, we did not have access to potentially important data related to CMBs, such as smoking status. Fourth, we had no baseline MRI results to compare the number of CMBs before and after SARS-CoV-2 infection. Fifth, this study was conducted during the first wave of COVID-19, thus our findings may not be extrapolated to later variants of SARS-CoV-2. Hence, it remains unknown whether the CMBs are linked to the SARS-CoV-2 infection. The clinical significance of CMBs after COVID-19 is still not fully understood, and whether they contribute to a risk of accelerated cognitive decline should be a target for further research to fully grasp the impact of the COVID-19 pandemic worldwide. Conclusions We hypothesized that possession of the APOE4 allele would be associated with an increase in the prevalence of CMBs in COVID-19 survivors. In this study we found no signs of an interaction between APOE4 and COVID-19 that would be associated with the number of CMBs, but in patients with detectable CMBs, hypertension and severe COVID-19 were associated with higher number of CMBs. Declarations Author Contribution J.M., J.H. and M.T. conceived and conducted the RECOVID study, of which this manuscript is a substudy. J.M. and L.K. planned and oversaw the analysis of the MRI studies. C.W. carried out the statistical analysis and prepared the manuscript. All authors critically revised the manuscript. All authors have approved the manuscript for submission for publication. Acknowledgement The authors thank biostatistician Hanna Granroth-Wilding for statistical support, and Samu Kurki, MD, PhD, for his valuable comments. Data Availability The datasets analyzed during the current study are available from the corresponding author upon reasonable request. Additional Information The authors declare no competing interests. References Vernooij, M. W. et al. Prevalence and Risk Factors of Cerebral Microbleeds The Rotterdam Scan Study .; (2008). https://www.neurology.org Belloy, M. E., Napolioni, V. & Greicius, M. D. 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APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study. Acta Neuropathol. Commun. 9 (1). 10.1186/s40478-021-01302-7 (2021). Egbert, A. R., Cankurtaran, S. & Karpiak, S. Brain abnormalities in COVID-19 acute/subacute phase: A rapid systematic review. Brain Behav. Immun. 89 , 543–554. 10.1016/j.bbi.2020.07.014 (2020). Gulko, E. et al. MRI brain findings in 126 patients with COVID-19: Initial observations from a descriptive literature review. Am. J. Neuroradiol. 41 (12), 2199–2203. 10.3174/ajnr.A6805 (2020). Ollila, H. et al. Brain magnetic resonance imaging findings six months after critical COVID-19: A prospective cohort study. J. Crit. Care . 80 10.1016/j.jcrc.2023.154502 (2024). Gregoire, S. M. et al. The Microbleed Anatomical Rating Scale (MARS) Reliability of a Tool to Map Brain Microbleeds .; www.neurology.org (2009). Fazekas1, F. Chawluk2 JB, Alavi1 A, Hurtig2 HI, Zimmerma& RA. MR Signal Abnormalities at 1.5 T in Alzheimer’s Dementia and Normal Aging . www.ajronline.org. Lu, D., Liu, J., MacKinnon, A. D., Tozer, D. J. & Markus, H. S. Prevalence and Risk Factors of Cerebral Microbleeds: Analysis From the UK Biobank. Neurology 97 (15), E1493–E1502. 10.1212/WNL.0000000000012673 (2021). Benson, J. C., Hunt, C. H., Klaas, J. P. & Kallmes, D. F. Intracranial microhemorrhages in the setting of COVID-19: what we know so far. Neuroradiol. J. 34 (5), 435–439. 10.1177/19714009211004144 (2021). Dixon, L. et al. Cerebral microhaemorrhage in COVID-19: A critical illness related phenomenon? Stroke Vasc Neurol. 5 (4), 315–322. 10.1136/svn-2020-000652 (2020). Akoudad, S. et al. Association of cerebral microbleeds with cognitive decline and dementia. JAMA Neurol. 73 (8), 934–943. 10.1001/jamaneurol.2016.1017 (2016). Fanou, E. M. et al. Critical Illness-Associated Cerebral Microbleeds. Stroke 48 (4), 1085–1087. 10.1161/STROKEAHA.116.016289 (2017). Shoskes, A. et al. MRI of Cerebrovascular Injury Associated With COVID-19 and Non-COVID-19 Acute Respiratory Distress Syndrome: A Matched Case-Control Study. Crit. Care Med. 50 (11), 1638–1643. 10.1097/CCM.0000000000005658 (2022). Renard, D. Cerebral microbleeds: a magnetic resonance imaging review of common and less common causes. Eur. J. Neurol. 25 (3), 441–450. 10.1111/ene.13544 (2018). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6716518","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":466346091,"identity":"b67945df-88db-4217-a8c9-fa8333a617be","order_by":0,"name":"Christoffer Wiklund","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIie3QMUvDQBjG8VcOzPKkWa9U6lc4KXQq9KscFG7KoBSKIAShkMnuFT+Fi/OVg3ZzDqSDRXAXlwgdvEuHKuTi2uH+w+UN3I+7hCgUOsU4kbaPJLp3b0Je2PXq3c3RvI1I6j7oA4FdBwM3w/gJHQnVZNiriW4WydNit/quRhzR4o3hWkGU85e7mzwjRJ5DththIBUHNoJBpBDb9ax8zA2BNRPBFRmSJhvbgaXiFqJIh2Wcaxq3kFUlDcflx5FMY3exFqLhCD93JK0Ji3PmJbywF4Ny32KHvVDoFmraw6uBjyRLxT6rkftj67Pdcj/pd4rJ8xdmWR+Jbja/+7MF/+8PhUKhkK8fyDRQzIoJWIEAAAAASUVORK5CYII=","orcid":"","institution":"Helsinki University Hospital and University of Helsinki","correspondingAuthor":true,"prefix":"","firstName":"Christoffer","middleName":"","lastName":"Wiklund","suffix":""},{"id":466346092,"identity":"5609cf6b-94a2-4075-a486-f03e0166117f","order_by":1,"name":"Juha Martola","email":"","orcid":"","institution":"Helsinki University Hospital and University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Juha","middleName":"","lastName":"Martola","suffix":""},{"id":466346093,"identity":"2d0b2019-38d9-40cf-b3e6-e8100335763b","order_by":2,"name":"Henriikka Ollila","email":"","orcid":"","institution":"Helsinki University Hospital and University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Henriikka","middleName":"","lastName":"Ollila","suffix":""},{"id":466346094,"identity":"12ed9643-99ea-40a0-a57f-1d52765d02b9","order_by":3,"name":"Linda Kuusela","email":"","orcid":"","institution":"Helsinki University Hospital and University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Linda","middleName":"","lastName":"Kuusela","suffix":""},{"id":466346095,"identity":"03ae2a13-3c08-4bf7-9bdc-9731323fad26","order_by":4,"name":"Marjaana Tiainen","email":"","orcid":"","institution":"Helsinki University Hospital and University of Helsinki","correspondingAuthor":false,"prefix":"","firstName":"Marjaana","middleName":"","lastName":"Tiainen","suffix":""},{"id":466346096,"identity":"c8e34026-4f06-4bff-a20f-d9c290e946fa","order_by":5,"name":"Johanna Hästbacka","email":"","orcid":"","institution":"Tampere University Hospital, Wellbeing Services County of Pirkanmaa and Tampere University","correspondingAuthor":false,"prefix":"","firstName":"Johanna","middleName":"","lastName":"Hästbacka","suffix":""}],"badges":[],"createdAt":"2025-05-21 12:23:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6716518/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6716518/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84214333,"identity":"a266a866-a191-44d0-bb4c-2a825c47ee4a","added_by":"auto","created_at":"2025-06-09 10:28:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":11945,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFlowchart depicting the recruitment process. MRI, magnetic resonance imaging; DAI, diffuse axonal injury; ICU, intensive care unit.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6716518/v1/f9eab373a2a492693518e776.png"},{"id":84212769,"identity":"dc1aa126-b148-4a80-95e9-5d78ff54d4de","added_by":"auto","created_at":"2025-06-09 10:20:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":21102,"visible":true,"origin":"","legend":"\u003cp\u003eInteraction plot depicting the number of microbleeds for APOE4 and COVID-19 as predicted by the negative binomial model (boxplot). Raw data is depicted as dots. There are 2 outliers in the COVID-group with a large number of CMBs that are not shown (number of CMBs: 374, APOE4 group, and 147, non-APOE4 group).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6716518/v1/a2d8cda42acbd854f4d2357b.png"},{"id":84215170,"identity":"f194144b-3859-4bd0-ae95-69dda8965578","added_by":"auto","created_at":"2025-06-09 10:36:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":585278,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6716518/v1/d6c8d863-c307-484d-b3dd-09629254efee.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association of Cerebral Microbleeds in Brain Magnetic Resonance Imaging with Apolipoprotein E4 in COVID-19 survivors. A prospective observational study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCerebral microbleeds (CMBs) are small deposits of hemosiderin in brain parenchyma that can be visualized by Magnetic Resonance Imaging (MRI). The hemosiderin deposits form as a product of red blood cells that have leaked from arteries. CMBs have been associated with, among others, increased age, diabetes mellitus, hypertension, smoking, male sex and Apolipoproteins E2 and E4. \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e The Apolipoprotein E4 (APOE4) is a strong risk factor for cardiovascular disease, Cerebral Amyloid Angiopathy (CAA) and related hemorrhagic stroke, ischemic stroke and late onset Alzheimer\u0026rsquo;s disease (AD). It also leads to a higher probability of CMBs, possibly through a greater burden of amyloid in cerebral blood vessels. \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e APOE4 carriers specifically have a higher risk for lobar CMBs in the general population. \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e While strictly lobar CMBs may not be linked to an increase in mortality \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, they are associated with neurodegenerative disorders, especially AD and CAA \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In contrast, deep and infratentorial CMBs that are linked to hypertensive and atherosclerotic arteriopathy, but not to APOE genotype, are associated with all-cause, cardiovascular, stroke and non-cardiovascular related mortality, with the risk increasing gradually with a larger number of CMBs. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAPOE4 has also been associated with an increased risk for severe COVID-19. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Patients with COVID-19 have been shown to have an increased prevalence of CMBs and other brain abnormalities in MRI - and autopsy studies. \u003csup\u003e\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e The clinical significance of CMBs in association with COVID-19 is not yet understood. The purpose of this study was to investigate if there is an interaction between COVID-19 and the APOE4 allele that would lead to a higher prevalence of MRI-detected CMBs in a post-acute cohort of COVID-19 survivors. We hypothesized that CMBs are more numerous in APOE4 carriers who had contracted COVID-19.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eThis is a \u003cem\u003epost-hoc\u003c/em\u003e substudy of the RECOVID study, a multidisciplinary study investigating long-term findings in a cohort of adult patients with a laboratory confirmed SARS-CoV-2 infection between March 1 and December 31, 2020. \u0026nbsp;Three different groups of COVID-19 survivors were identified and recruited for this study within three months from hospital discharge or home isolation. Detailed description of study subject recruitment, and inclusion and exclusion criteria have been published previously.\u0026nbsp;\u003csup\u003e11\u003c/sup\u003e Briefly, the first group (ICU) consisted of patients who had suffered from critical COVID-19 requiring intensive care unit (ICU) treatment with ventilatory support (high flow nasal cannula, non-invasive ventilation or intubation) in Helsinki University Hospital ICUs and were identified through the quality database of intensive care. The second group (WARD) consisted of patients with moderate COVID-19 requiring admittance to a hospital ward without need for ICU during the acute phase of infection. They were recruited from a post COVID-19 follow-up clinic organized by the pulmonology clinic or during treatment in the pulmonology ward. A third group of non-hospitalized patients (HOME) was recruited through announcements in local newspapers and social media. A fourth group of participants who had no history of SARS-CoV-2 infection (CONTROL) was recruited to serve as a control group. All COVID-19 survivors had infections verified by real time polymerase chain reaction (RT-PCR) or antibody test. Criteria for exclusion were age \u0026lt;18 years, pregnancy, major neurologic disease prior to COVID-19 (e.g. progressive memory disorder, Parkinson\u0026rsquo;s disease), severely impaired hearing or vision, developmental disability, contraindications to MRI, such as severe claustrophobia, cardiac pacemaker or ferromagnetic fixation material or other MRI-incompatible foreign body. Additionally, we only recruited patients with Finnish as their primary language as neuropsychological assessment was a major part of the RECOVID main study. The study protocol was approved by the Ethics Board of Helsinki University Hospital (HUS-1949-2020). All participants provided written informed consent for participating in the study and separate written informed consent for APOE analysis. The study was conducted according to the\u0026nbsp;\u003cbr\u003e\u0026nbsp;principles of the declaration of Helsinki.\u003c/p\u003e\n\u003ch3\u003eMagnetic resonance imaging\u003c/h3\u003e\n\u003cp\u003eThe subjects underwent MRI of the brain six months after the acute SARS-CoV-2 infection, and the imaging sequences were planned and analyzed by an experienced neuroradiologist blinded to the clinical details or severity group of the subjects. The number and the topography of the microbleeds was analyzed using the Microbleed Anatomical Rating Scale (MARS).\u003csup\u003e12\u003c/sup\u003e White matter hyperintensities (WMHs) were categorized using the Fazekas scale ranging from 0 to 3 (0 = no changes, 1 = mild, 2 = moderate, and 3 = severe changes).\u003csup\u003e\u003cspan lang=\"EN-US\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003ch3\u003eAPOE genotyping\u003c/h3\u003e\n\u003cp\u003eA 5 mL sample of whole blood was drawn and stored frozen at -80\u0026deg; C until analysis. APOE genotype was derived from the single-nucleotide polymorphisms rs429358 and rs7412 that were genotyped using a microarray or imputed using a Finnish reference panel as described previously.\u003csup\u003e8\u003c/sup\u003e As the APOE 1/3 genotype is indistinguishable from the APOE 2/4 genotype, they were all considered as APOE 2/4, due to the E1 allele being exceedingly rare. We considered subjects with either one or two APOE4 alleles as APOE4 positive.\u003c/p\u003e\n\u003ch3\u003eStatistical analysis\u003c/h3\u003e\n\u003cp\u003eWe describe continuous variables as medians and interquartile range (IQR)\u0026nbsp;and categorical variables as numbers and percentages. Differences between groups are evaluated using Chi-square test, Fisher\u0026rsquo;s exact test for categorical variables and Kruskal-Wallis\u0026acute; rank sum test for continuous variables. We first assessed the distribution of the data visually for the number of CMBs. To allow for robust modelling despite the strong zero-inflation in the data, we modelled the outcomes\u0026nbsp;first as a binary response (zero vs non-zero). Then we included the non-zero counts in a negative binomial generalized linear model that fits the distribution of the data according to\u0026nbsp;the\u0026nbsp;visual assessment of the distribution, difference in variance and mean values, and assessment of residual values.\u003c/p\u003e\n\u003cp\u003eWe performed a univariate analysis to establish potential associations between the number of CMBs and variables, chosen based on previously reported factors associated with CMBs and available data. After this, the variables that reached a statistical significance of p\u0026le;0.05 were added to a multivariate model. \u0026nbsp;Statistical analysis was performed with the statistical software R, with the negative binomial model as implemented in the MASS package.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAltogether, 252 subjects were recruited for this study. After exclusion in accordance with Figure 1., 167 subjects remained in the final analyses. Characteristics of COVID-19 survivors and controls including the APOE4 carrier status are shown in Table 1. The median age of the subjects was 56 years (IQR = 17 years), 46% (N=76) were male. Of the subjects, 75 (45%) had comorbidities, with hypertension, asthma and diabetes being the most prevalent. The burden of comorbidities skewed toward the ICU group. Altogether, 37% (N=62) were carriers of the APOE4 allele, and nine of them were homozygous for the APOE4 allele. No differences in the prevalence of APOE4 carriership existed in those with no CMBs, one to four, or more than four CMBs (Table 1).\u003c/p\u003e\n\u003cp\u003eThe prevalence of any CMBs among COVID-19 survivors was 33%, and among controls 23% (p=0.2). While most CMBs were singular findings, 12% of COVID-19 patients who were hospitalized (ICU and WARD) with COVID-19 had multiple (\u0026ge;5) CMBs, compared with none in HOME and control groups. The localization of the CMBs was predominantly lobar in both APOE4 carriers and carriers of other APOE alleles, with lobar CMBs accounting for 74% and 67% of the total number of CMBs, respectively. The data included two participants with extremely numerous CMBs, numbering 374 and 147. Of these two, one was a homozygous carrier of the APOE4 allele, while the other carried two APOE3 alleles. Both outliers belonged to the ICU group, both had hypertension and coronary artery disease, while one had diabetes.\u003c/p\u003e\n\u003cp\u003eThe results of univariable and multivariable analyses of the putative factors associated with the number of CMBs in the subjects with microbleeds are shown in Table 2. In univariable analysis, age [Incidence rate ratio, IRR=1.09 (1.04-1.14), p=1.7x10^\u003csup\u003e-4\u003c/sup\u003e], a history of hypertension [IRR=10.0 (4.49-22.0), p=1.65x10\u003csup\u003e-8\u003c/sup\u003e], APOE4 allele carriership [IRR=3.17 (1.30-8.32), p=0.014] and COVID-19 [IRR=11.7 (3.68-32.8), p=7.27x10\u003csup\u003e-6\u003c/sup\u003e] were associated with an increased number of CMBs. When dividing the COVID-19 group by disease severity, only ICU-treated COVID-19 [IRR=19.8 (7.03-53.6), p=5.38x10\u003csup\u003e-9\u003c/sup\u003e] was significantly associated with an increased number of CMBs. Sex or diagnoses of asthma and diabetes were not associated with an increased number of CMBs in the univariable model.\u003c/p\u003e\n\u003cp\u003eTable 1 Subject characteristics according to groups of different number of cerebral microbleeds. Analysis was performed with Kruskal-Wallis\u0026acute;s rank sum test, Chi-square test or Fisher\u0026rsquo;s exact test as appropriate. One subject showed radiological demyelination and was later diagnosed with multiple sclerosis. CMB, cerebral microbleed; SD, standard deviation; APOE4, Apolipoprotein E4; ICU, Intensive Care Unit.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNumber of CMB = 0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eNumber of CMB =1-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eNumber of CMB \u0026ge;5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eN=117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eN=39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eN=11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAge, years, \u0026nbsp; \u0026nbsp; \u0026nbsp;median (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e53 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e60 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e63 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e2.2x10\u003csup\u003e-16\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSex (male), N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e50 (43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e20 (51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHypertension, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e35 (30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e14 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e9 (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAsthma, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e16 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e5 (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDiabetes, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e11 (9.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e4 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5 (45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eFazekas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e22 (19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e88 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e34 (87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e9 (82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e5 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e2 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e2 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e1 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDemyelination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp class=\"Normal0\"\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp class=\"Normal0\"\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAPOE4 carrier, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e44 (38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e14 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e4 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eSeverity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eICU, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e30 (26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e13 (33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e8 (73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eWARD, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e20 (17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6 (15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e3 (27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eHOME, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e27 (23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e8 (21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eCONTROL, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e40 (34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12 (31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eTopography of CMBs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eLobar, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eDeep, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eInfratentorial, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn multivariable analysis including significant (p\u0026lt;0.05) variables from the univariable analysis, only hypertension [adjusted incidence rate ratio, [aIRR=7.45 (2.77-19.5), p=3.04x10\u003csup\u003e-5\u003c/sup\u003e] remained statistically significantly associated with the number of CMBs. No interaction effect was found between COVID-19 and APOE4 [aIRR=2.77 (0.33-21.2), p=0.33], as illustrated in Figure 2.\u003c/p\u003e\n\u003cp\u003eTable 2: Results of statistical analysis of subjects with at least one cerebral microbleed using a negative binomial regression model. \u0026nbsp;Adjusted Incidence Rate Ratio (aIRR) depicts results of a multivariate model of variables with p\u0026lt;0.05 in the univariate analysis. APOE4*Covid depicts the possible interaction between Apoe4-carriership and COVID-19 status on the number of CMBs. COVID-19 severity is only modelled in the univariate analysis. IRR, Incidence Rate Ratio; CMB, Cerebral Microbleed\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"570\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eSubjects with CMB\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003eN=50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003eNumber of microbleeds\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003eIRR (CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003eaIRR (CI)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1.09 (1.04-1.14)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1.7x10\u003cdel cite=\"mailto:Johanna%20Hästbacka%20(TAU)\" datetime=\"2025-03-15T17:30\"\u003e^\u003c/del\u003e\u003csup\u003e-4\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1.03 (0.97-1.08)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMale sex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e26 (52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e0.43 (0.17-1.08)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAsthma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e7 (14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e0.36 (0.11-1.74)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e23 (46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e10.0 (4.49-22.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1.65x10\u003csup\u003e-8\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e7.45 (2.77-19.5)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e3.04x10\u003csup\u003e-5\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eDiabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e9 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1.91 (0.67-7.44)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAPOE4-carriers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e18 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e3.17 (1.30-8.32)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e1.67 (0.27-11.7)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eCOVID-19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e38 (76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e11.7 (3.68-32.8)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e7.27x10\u003csup\u003e-6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2.77 (0.49-6.63)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eAPOE4*Covid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e2.77 (0.33-21.2)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eCovid severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eICU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e21 (42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e19.8 (7.03-53.6)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e5.38x10\u003csup\u003e-9\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eWARD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e9 (18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e2.07 (0.61-7.44)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eHOME\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e8 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003e1.08 (0.29-4.29)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 100px;\"\u003e\n \u003cp\u003eCONTROL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37px;\"\u003e\n \u003cp\u003e12 (24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 109px;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this \u003cem\u003epost hoc\u003c/em\u003e sub study of the observational RECOVID study, we assessed whether an interaction of APOE4 allele carrier status and COVID-19 was associated with the number of MRI-detected CMBs in a population of COVID-19 survivors and non-COVID-19 controls. We found no such interaction.\u003c/p\u003e \u003cp\u003eIn a previous study, we have shown that that APOE4 was associated with an increased prevalence of CMBs in a histopathological study of brain tissue of deceased COVID-19 patients.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Our findings are in accordance with the previous results, but the power of the association in our study was weaker. The difference with this study may be partly explained by the differences in the methods used for detecting CMBs and the studied population. As the findings of the previous study were based on autopsy, important differences regarding subject characteristics and disease severity exist between the populations.\u003c/p\u003e \u003cp\u003eThe prevalence of CMBs in the general population varies between 5\u0026ndash;24% in different studies, with age and APOE4 being associated with lobar CMBs, while age, hypertension and smoking are associated with deep or infratentorial CMBs.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e CMBs have been implicated as a complication of severe COVID-19 in several observational studies.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e In our sample, the prevalence of CMBs in the control group (23%) was in range with the previous studies of CMBs in the general population. COVID-19 was significantly associated with an increase in CMBs, but a closer analysis of the population revealed that significance only applied to severe COVID-19 treated in the ICU and may thus be related to factors other than COVID-19, for example severe hypoxemia.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThough often incidental findings, CMBs have been shown to be associated with increased risk for dementia in the general population.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Specifically lobar and cerebellar CMBs are considered preclinical markers of CAA\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, and are also associated with AD. Deep CMBs are considered as a sign of small vessel arteriopathy, and they have been associated with an increased cardiovascular mortality.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The clinical significance of CMBs associated with severe COVID-19 is still unknown, as is the role of APOE4 that may have a role in modifying the acute, and long-term risks of COVID-19.\u003c/p\u003e \u003cp\u003eOur findings may implicate that severe respiratory illness and treatment in the ICU are more relevant regarding CMBs than SARS-CoV-2 infection. This hypothesis is in line with two small studies where CMBs were observed in patients with respiratory failure requiring treatment in the ICU.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e CMBs have also been found in conjunction with other conditions related to critical care, such as infective endocarditis, disseminated intravascular coagulation and extracorporeal membrane oxygenation.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e This could have implications for a further study of cognitive decline in patients with post-intensive care syndrome.\u003c/p\u003e \u003cp\u003eOur study has limitations. First, our patient groups were relatively small and heterogeneous, with older age and the disease burden skewing toward the ICU group. Second, we did not perform an \u003cem\u003ea priori\u003c/em\u003e power calculation. Third, we did not have access to potentially important data related to CMBs, such as smoking status. Fourth, we had no baseline MRI results to compare the number of CMBs before and after SARS-CoV-2 infection. Fifth, this study was conducted during the first wave of COVID-19, thus our findings may not be extrapolated to later variants of SARS-CoV-2. Hence, it remains unknown whether the CMBs are linked to the SARS-CoV-2 infection.\u003c/p\u003e \u003cp\u003eThe clinical significance of CMBs after COVID-19 is still not fully understood, and whether they contribute to a risk of accelerated cognitive decline should be a target for further research to fully grasp the impact of the COVID-19 pandemic worldwide.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe hypothesized that possession of the APOE4 allele would be associated with an increase in the prevalence of CMBs in COVID-19 survivors. In this study we found no signs of an interaction between APOE4 and COVID-19 that would be associated with the number of CMBs, but in patients with detectable CMBs, hypertension and severe COVID-19 were associated with higher number of CMBs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.M., J.H. and M.T. conceived and conducted the RECOVID study, of which this manuscript is a substudy. J.M. and L.K. planned and oversaw the analysis of the MRI studies. C.W. carried out the statistical analysis and prepared the manuscript. All authors critically revised the manuscript. All authors have approved the manuscript for submission for publication.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank biostatistician Hanna Granroth-Wilding for statistical support, and Samu Kurki, MD, PhD, for his valuable comments.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch2\u003eAdditional Information\u003c/h2\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVernooij, M. 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Neurol.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e (3), 441\u0026ndash;450. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/ene.13544\u003c/span\u003e\u003cspan address=\"10.1111/ene.13544\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6716518/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6716518/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCOVID-19 has been associated with neurological sequelae ranging from mild cognitive impairment to ischemic and hemorrhagic stroke. Brain radiological abnormalities observed with COVID-19 include white matter hyperintensities and cerebral microbleeds (CMBs). Apolipoprotein ε4 (APOE4) is associated with an increased risk of CMBs and neurodegenerative disorders. We investigated whether possession of the APOE4 allele was associated with an increase in the number of CMBs in COVID-19 patients.\u003c/p\u003e \u003cp\u003eIn this substudy of the RECOVID study, 51 ICU-treated, 29 ward-treated and 35 home-treated COVID-19 patients and 52 non-COVID-19 controls underwent brain MRI six months after acute COVID-19 and their APOE genotype was identified.\u003c/p\u003e \u003cp\u003eCMBs existed in 31 (33%) subjects after COVID-19 and 12 (23%) subjects in the control group. The number of CMBs increased with disease severity, with 8 (16%) of the ICU-group and 3 (10%) in the WARD-group having\u0026thinsp;\u0026ge;\u0026thinsp;5 CMBs compared with none in the HOME- and control groups. The subjects with CMBs were older and had a higher prevalence of hypertension and diabetes. In multivariable analysis, an increased number of CMBs was associated only with hypertension. No interaction between APOE4 and COVID-19 associated with an increased number of CMBs was found.\u003c/p\u003e","manuscriptTitle":"Association of Cerebral Microbleeds in Brain Magnetic Resonance Imaging with Apolipoprotein E4 in COVID-19 survivors. A prospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-09 10:20:52","doi":"10.21203/rs.3.rs-6716518/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-09-28T16:20:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"126575906648991420177072307192522589477","date":"2025-09-22T17:22:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-03T11:06:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-03T11:04:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-03T10:01:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-02T13:15:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-05-21T12:20:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d32de173-8444-4dd1-b208-8b9004135849","owner":[],"postedDate":"June 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":49509249,"name":"Health sciences/Diseases/Infectious diseases/Viral infection"},{"id":49509250,"name":"Health sciences/Risk factors"},{"id":49509251,"name":"Health sciences/Neurology/Neurological disorders/Cerebrovascular disorders"},{"id":49509252,"name":"Health sciences/Neurology/Neurological disorders/Dementia"}],"tags":[],"updatedAt":"2025-06-09T10:20:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-09 10:20:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6716518","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6716518","identity":"rs-6716518","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}