Severe COVID-19 induces molecular signatures of aging in the human brain

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   ScreenIT

   Nov 30, 2021

   SciScore for 10.1101/2021.11.24.21266779: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	Consent: Human brain tissues: Post-mortem brain tissue specimens from individuals with severe COVID-19 were collected through an excess tissue waived consent protocol approved by the Mass General Brigham Institutional Review Board. IRB: Human brain tissues: Post-mortem brain tissue specimens from individuals with severe COVID-19 were collected through an excess tissue waived consent protocol approved by the Mass General Brigham Institutional Review Board. IACUC: BIDMC) Institutional Biosafety Committee (IBC).
   Sex as a biological variable	not detected.
   Randomization	not detected.
   Blinding	not detected.
   Power Analysis	not detected.

   Table 2: Resources

   Software and Algorithms
   Sentences	Resources
   RNA-seq …

   SciScore for 10.1101/2021.11.24.21266779: (What is this?)

   Please note, not all rigor criteria are appropriate for all manuscripts.

   Table 1: Rigor

   Ethics	Consent: Human brain tissues: Post-mortem brain tissue specimens from individuals with severe COVID-19 were collected through an excess tissue waived consent protocol approved by the Mass General Brigham Institutional Review Board. IRB: Human brain tissues: Post-mortem brain tissue specimens from individuals with severe COVID-19 were collected through an excess tissue waived consent protocol approved by the Mass General Brigham Institutional Review Board. IACUC: BIDMC) Institutional Biosafety Committee (IBC).
   Sex as a biological variable	not detected.
   Randomization	not detected.
   Blinding	not detected.
   Power Analysis	not detected.

   Table 2: Resources

   Software and Algorithms
   Sentences	Resources
   RNA-seq analysis: For assessment of SARS-CoV-2 genome alignment: reads were aligned to the SARS-CoV-2 reference genome (NCBI reference sequence NC_045512.2) using bowtie2 v2.2.9 with options “-X 1000 --no-mixed”.	bowtie2 suggested: (Bowtie 2, RRID:SCR_016368)
   For assessment of differential gene expression: raw sequencing reads were aligned to a reference transcriptome generated from the Ensembl v104 human transcriptome with salmon v1.4.0 using options “--seqBias --useVBOpt --gcBias --posBias --numBootstraps 30 -- validateMappings”.	Ensembl suggested: (Ensembl, RRID:SCR_002344) salmon suggested: (Salmon, RRID:SCR_017036)
   Length-scaled transcripts per million were acquired using the tximport v1.18.0 function, and log2 fold changes and false discovery rates (FDR) were determined by DESeq2 v1.30.1 in R. t-stochastic neighboring embedding analysis was performed using Rtsne v0.15, with counts transformed by the varianceStabilizingTransformation (VST) function from DESeq2.	DESeq2 suggested: (DESeq, RRID:SCR_000154) Rtsne suggested: (Rtsne, RRID:SCR_016342)
   Heatmaps were generated using pheatmap v1.0.12 using VST-transformed counts, with further scaling across samples.	pheatmap suggested: (pheatmap, RRID:SCR_016418)
   Gene set enrichment analysis: Signed -log10 FDRs from DESeq2 analyses were used to rank genes for gene set enrichment analysis via fgsea v1.16.0, filtering out genes with an FDR < 0.5.	Gene set enrichment analysis suggested: (Gene Set Enrichment Analysis, RRID:SCR_003199)
   Public gene sets used for analyses: Gene Ontology Biological Processes (	Gene Ontology Biological suggested: None

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   Results from OddPub: Thank you for sharing your data.

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   Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:

   We recognize limitations in our study design: the variability in illness duration, the imperfect quality of several samples (as previously reported in similar studies [16]), the modest number of subjects (12 cases and 12 controls), the lack of young COVID-19 subjects, and the specificity of our findings due to COVID-19. Despite these constraints, we were sufficiently powered to identify substantial transcriptome-wide changes between COVID-19 cases and controls, including among younger patients in our patient cohort. Furthermore, in addition to being age-matched, our experimental sample size is larger than previously reported COVID-19 brain transcriptome studies [16, 17, 30], enabling the identification of aging-associated gene expression signatures in our samples. Although our study does not examine the specificity of COVID-19-induced transcriptomic changes in the brain, the implications of our findings may readily extend to related pathologies. For instance, prior clinical trials have shown that cognitive impairment is observed in 55% of survivors of severe acute respiratory syndrome (SARS) 12 months after discharge [31]. Such behavioral observations suggest that similar molecular effects in the brain may be observed not only in severe COVID-19 but also in other conditions characterized by increased peripheral and central inflammation, severe hypoxic insults, and microvascular brain pathologies [1, 32]. Aging is a major risk factor for the development of cognitive deficits a...

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   Results from TrialIdentifier: No clinical trial numbers were referenced.

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   Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

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   Results from JetFighter: We did not find any issues relating to colormaps.

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   Results from rtransparent:

   • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
   • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
   • No protocol registration statement was detected.

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   Results from scite Reference Check: We found no unreliable references.

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   Version published to 10.1101/2021.11.24.21266779v1 on medRxiv

   Nov 24, 2021