key: cord-0856254-ve55opbt authors: Tsvetanov, K. A.; Spindler, L. R. B.; Stamatakis, E. A.; Newcombe, V. F.; Lupson, V. C.; Chatfield, D. A.; Manktelow, A. E.; Outtrim, J. G.; Elmer, A.; Kingston, N.; Bradley, J. R.; Bullmore, E. T.; Rowe, J. B.; Menon, D. K.; the Cambridge NeuroCOVID Group,; the NIHR COVID-19 BioResource,; the Cambridge NIHR Clinical Research Facility,; collaboration, the CITIID-NIHR BioResource COVID-19 title: Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study date: 2022-02-02 journal: nan DOI: 10.1101/2022.02.01.22270235 sha: c2902308745e01d307850fd7e2931a7c85782ea1 doc_id: 856254 cord_uid: ve55opbt Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. Here we assess cerebrovascular health in 45 hospitalised patients using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode, as indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. Exploratory analysis suggests that the level of cerebrovascular dysfunction is associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing. The initial six volumes were discarded to allow for T1 equilibration. We quantified participant 128 motion using the root mean square volume-to-volume displacement as per Jenkinson et al (2002) . (Tsvetanov et al., 2020b) . RSFA maps were smoothed by a 12 mm FWHM Gaussian kernel. 139 To facilitate integrative multivariate analysis (see below), the RSFA maps were parcellated by 140 a prior cortical template into 360 bilaterally symmetric regions (Glasser et al., 2016). Regional The predictive specificity of COVID-19 severity on RSFA abnormality was tested using a 170 multivariate approach. We adopted a two-level procedure (Passamonti et al., 2019a; Tsvetanov et al., 171 2020a Tsvetanov et al., 171 , 2018 Tsvetanov et al., 171 , 2016 ). In the first-level analysis, the relationships between COVID-19 Severity and RSFA 172 data were identified using partial least squares (Krishnan et al., 2011) . Partial least squares described 173 the linear relationship between the two multivariate data sets, namely RSFA maps and COVID-19 174 Severity data by providing pairs of latent variables (RSFA-LV) and (COVID-19 Severity-LV) as linear 175 combinations of the original variables that were optimized to maximize their covariance. Data set 1 176 consisted of parcellated RSFA maps across all patients (45 patients x 360 nodes array, RSFA dataset). 177 Data set 2 included the COVID-19 WHO Progression scale and inpatient blood data (45 subjects x 9 178 measures array, COVID-19 Severity datasets). All variables were z-scored (mean of 0 and standard 179 deviation of 1) before entering to a permutation-based PLS analysis with 10.000 permutations to 180 determine the significance of the latent variables. 181 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint LV could be explained by other variables of interest and variables of no interest. To this end, we 183 performed a second-level analysis using robust multiple linear regression and commonality analysis 184 (Kraha et al., 2012; Nimon et al., 2008a) . Commonality analysis partitions the variance explained by all 185 predictors in MLR into variance unique to each predictor and variance shared between each 186 combination of predictors. Therefore, unique effects indicate the (orthogonal) variance explained by 187 one predictor over and above that explained by other predictors in the model, while common effects 188 indicate the variance shared between correlated predictors. Notably, the sum of variances, also 189 known as commonality coefficients, equals the total R2 for the regression model. We adapted a 190 commonality analysis algorithm (Nimon et al., 2008b) We further assessed the spatial overlap between COVID-19-related cerebrovascular burden 210 maps and a range of brain metabolic, neurotransmitter, protein expression and cell-type parameters, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint The spatial pattern of IC4 was consistent with the univariate approach (r=0.46, p<0.001, SI 287 Figure 5 ). In addition, the univariate approach revealed that the spatial pattern in RSFA associated 288 with age was highly consistent with the one reported on large-scale population-based cohorts, r=0.42, 289 p<0.001 (Tsvetanov et al., 2020b (Tsvetanov et al., , 2015 . This suggests that RSFA can detect reliably differences in 290 cerebrovascular health across various phenotypes in smaller samples. Though age is a risk factor of 291 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint regional distribution of RSFA abnormality showed little correlation with the expression of key proteins 366 implicated in SARS-CoV-2 cellular attachment, processing and viral defence (Figure 3) . Collectively, 367 these results demonstrate that the distribution of cerebrovascular impairment related to COVID-19 368 severity is aligned with the spatial distribution of receptors and processes involved in the coordination 369 of metabolic and vasoreactive responses. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint al., 2020b).These post-COVID-19 effects were observed over and above age. They are related to 420 severity of the acute illness and the host response in the acute stage. These effects also relate to the 421 post-COVID-19 cognitive function, common indices of mental health, and quality of life at an average 422 of six months after hospitalisation. 423 In exploratory analysis, we found overlap between the regional distribution of this is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint express abundantly the angiotensin-converting enzyme-2 (ACE2) receptor (He et al., 2020) . The 454 expression can be increased with by exposure to the viral S protein, and importantly, potentiated in 455 combination with hypoxia (Khaddaj-Mallat et al., 2021) , a mechanism which could account for the 456 modulation of RSFA abnormality by disease severity in our cohort. 457 Given this biological context the correlation of RSFA abnormalities with disease severity is 458 open to two potential interpretations. One possibility is that these changes in cerebrovascular 459 regulatory integrity are the consequence of direct viral invasion; while the other is that these 460 abnormalities are a consequence of the inflammatory host response, which is a consequence of, but 461 may not scale precisely with, viral infection. Spatial correlation of RSFA abnormality with the 462 expression of ACE2 and Neuropilin-1, or of genes involved in cellular responses to viral invasion would 463 have provided supportive evidence of a role for direct viral infection as a mechanism, but we were 464 unable to demonstrate such a correlation. This negative finding favours the explanation that host 465 inflammatory responses may be drivers in this context, and merit further investigation as mechanisms 466 of late cerebrovascular regulatory dysfunction. It is important to acknowledge that our correlations 467 with regional gene expression are based on expression patterns in normal brain, and that these 468 expression patterns may be substantially altered by the inflammatory milieu that prevails in the 469 context of COVID-19. Consequently, direct examination gene expression patterns in late COVID-19 470 survivors would provide additional insights. 471 472 Our study has several limitations. We are limited by the relatively small sample size, and by 473 the absence of longitudinal imaging data. We also do not draw any causal inferences from the 474 associations we observe. However, the demonstration of functional microvascular abnormalities 475 following COVID-19 is important to understand the potential mechanisms of persistent cognitive and 476 mental health problems. The association of microvascular abnormalities with late outcomes of 477 relevance to patients, and the fact that they represent an easily accessible biomarker, suggest both a 478 potential therapeutic target and/or a biomarker of treatment effect in interventional studies. It 479 remains to be shown whether the localisation of RSFA abnormalities to regions rich in 5HT-1b 480 receptors is a consequence of overactivity of these receptors (resulting in low cerebral blood flow), 481 underactivity or loss of these receptors (resulting in vasoparalysis and/or inflammation), or a 482 manifestation of flow-metabolism mismatching with inadequate substrate and oxygen delivery. This is 483 relevant as potential therapeutic agents that are available to modulate both 5HT-1b function is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint Evaluating resting-state BOLD variability in relation to biomarkers of preclinical Alzheimer's 852 . CC-BY-NC-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.02.01.22270235 doi: medRxiv preprint Association Between Administration of IL-6 Antagonists and Mortality Among Patients 665 Hospitalized for COVID-19: A Meta-analysis 717 misspecification in a common approach to resting-state fMRI preprocessing reintroduces noise 723 and obscures functional connectivity COVID-19 Neurologic Complication with CNS Mapping gene 730 transcription and neurocognition across human neocortex Mapping neurotransmitter systems to the structural and functional organization of 737 the human neocortex An anatomically comprehensive atlas of the adult human brain transcriptome 751 implications for microvascular inflammation and hypercoagulopathy in A systematic review on descending serotonergic 757 projections and modulation of spinal nociception in chronic neuropathic pain and after spinal 758 cord stimulation Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of Effects of COVID-19 on the Nervous System The coagulopathy, endotheliopathy, and vasculitis of COVID-770 19 Improved optimization for the robust and 773 accurate linear registration and motion correction of brain images In vivo measurement of intracellular pH in human 775 brain during different tensions of carbon dioxide in arterial blood. 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