The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic

Ludovica Brusaferri; Zeynab Alshelh; Daniel Martins; Minhae Kim; Akila Weerasekera; Hope Housman; Erin J Morrissey; Paulina C Knight; Kelly A Castro-Blanco; Daniel S Albrecht; Chieh-En Tseng; Nicole R Zürcher; Eva-Maria Ratai; Oluwaseun Akeju; Meena M Makary; Ciprian Catana; Nathaniel D Mercaldo; Nouchine Hadjikhani; Mattia Veronese; Federico Turkheimer; Bruce R Rosen; Jacob M Hooker; Marco L Loggia

doi:10.1016/j.bbi.2022.02.018

The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic

Ludovica Brusaferri, Zeynab Alshelh, Daniel Martins, Minhae Kim, Akila Weerasekera, Hope Housman, Erin J Morrissey, Paulina C Knight, Kelly A Castro-Blanco, Daniel S Albrecht, Chieh-En Tseng, Nicole R Zürcher, Eva-Maria Ratai, Oluwaseun Akeju, Meena M Makary, Ciprian Catana, Nathaniel D Mercaldo, Nouchine Hadjikhani, Mattia Veronese, Federico TurkheimerBruce R Rosen, Jacob M Hooker, Marco L Loggia

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

Abstract

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven ‘Pre-Pandemic’ and fifteen ‘Pandemic’ datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Original language	English
Pages (from-to)	89-97
Number of pages	9
Journal	Brain, Behavior, and Immunity
Volume	102
Early online date	15 Feb 2022
DOIs	https://doi.org/10.1016/j.bbi.2022.02.018
Publication status	Published - May 2022

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10.1016/j.bbi.2022.02.018

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Brusaferri, L., Alshelh, Z., Martins, D., Kim, M., Weerasekera, A., Housman, H., Morrissey, E. J., Knight, P. C., Castro-Blanco, K. A., Albrecht, D. S., Tseng, C.-E., Zürcher, N. R., Ratai, E.-M., Akeju, O., Makary, M. M., Catana, C., Mercaldo, N. D., Hadjikhani, N., Veronese, M., ... Loggia, M. L. (2022). The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic. Brain, Behavior, and Immunity, 102, 89-97. https://doi.org/10.1016/j.bbi.2022.02.018

@article{15ff604bf7814f599ea1c6c22bf02d95,

title = "The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic",

abstract = "While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven {\textquoteleft}Pre-Pandemic{\textquoteright} and fifteen {\textquoteleft}Pandemic{\textquoteright} datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.",

author = "Ludovica Brusaferri and Zeynab Alshelh and Daniel Martins and Minhae Kim and Akila Weerasekera and Hope Housman and Morrissey, {Erin J} and Knight, {Paulina C} and Castro-Blanco, {Kelly A} and Albrecht, {Daniel S} and Chieh-En Tseng and Z{\"u}rcher, {Nicole R} and Eva-Maria Ratai and Oluwaseun Akeju and Makary, {Meena M} and Ciprian Catana and Mercaldo, {Nathaniel D} and Nouchine Hadjikhani and Mattia Veronese and Federico Turkheimer and Rosen, {Bruce R} and Hooker, {Jacob M} and Loggia, {Marco L}",

note = "Funding Information: This work was funded by the NIH grants R01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01 and by The Landreth Family Foundation. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Funding Information: The authors would like to thank Dr. Shibani Mukerji and Dr. Julie Price for helpful discussion on data and quality control, and Angel Torrado-Carvajal, Atreyi Saha, Courtney Bergan and Yang Lin for help with data collection. We thank Dr. Pia Kivisakk and Bianca Trombetta for their work on serum biomarkers. We also thank Grae Arabasz, Regan Butterfield and Shirley Hsu and all the A.A. Martinos Radiochemistry team for producing and administering the radioligand. The authors acknowledge that a preprint of this manuscript is available on medRxiv (https://www.medrxiv.org/content/10.1101/2021.09.21.21263740v1). This work was funded by the NIH grants R01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01 and by The Landreth Family Foundation. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = may,

doi = "10.1016/j.bbi.2022.02.018",

language = "English",

volume = "102",

pages = "89--97",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "ACADEMIC PRESS INC",

}

Brusaferri, L, Alshelh, Z, Martins, D, Kim, M, Weerasekera, A, Housman, H, Morrissey, EJ, Knight, PC, Castro-Blanco, KA, Albrecht, DS, Tseng, C-E, Zürcher, NR, Ratai, E-M, Akeju, O, Makary, MM, Catana, C, Mercaldo, ND, Hadjikhani, N, Veronese, M , Turkheimer, F, Rosen, BR, Hooker, JM & Loggia, ML 2022, 'The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic', Brain, Behavior, and Immunity, vol. 102, pp. 89-97. https://doi.org/10.1016/j.bbi.2022.02.018

TY - JOUR

T1 - The Pandemic Brain

T2 - neuroinflammation in non-infected individuals during the COVID-19 pandemic

AU - Brusaferri, Ludovica

AU - Alshelh, Zeynab

AU - Martins, Daniel

AU - Kim, Minhae

AU - Weerasekera, Akila

AU - Housman, Hope

AU - Morrissey, Erin J

AU - Knight, Paulina C

AU - Castro-Blanco, Kelly A

AU - Albrecht, Daniel S

AU - Tseng, Chieh-En

AU - Zürcher, Nicole R

AU - Ratai, Eva-Maria

AU - Akeju, Oluwaseun

AU - Makary, Meena M

AU - Catana, Ciprian

AU - Mercaldo, Nathaniel D

AU - Hadjikhani, Nouchine

AU - Veronese, Mattia

AU - Turkheimer, Federico

AU - Rosen, Bruce R

AU - Hooker, Jacob M

AU - Loggia, Marco L

N1 - Funding Information: This work was funded by the NIH grants R01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01 and by The Landreth Family Foundation. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Funding Information: The authors would like to thank Dr. Shibani Mukerji and Dr. Julie Price for helpful discussion on data and quality control, and Angel Torrado-Carvajal, Atreyi Saha, Courtney Bergan and Yang Lin for help with data collection. We thank Dr. Pia Kivisakk and Bianca Trombetta for their work on serum biomarkers. We also thank Grae Arabasz, Regan Butterfield and Shirley Hsu and all the A.A. Martinos Radiochemistry team for producing and administering the radioligand. The authors acknowledge that a preprint of this manuscript is available on medRxiv (https://www.medrxiv.org/content/10.1101/2021.09.21.21263740v1). This work was funded by the NIH grants R01-NS094306-01A1, R01-NS095937-01A1, R01-DA047088-01 and by The Landreth Family Foundation. The funder had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022/5

Y1 - 2022/5

N2 - While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven ‘Pre-Pandemic’ and fifteen ‘Pandemic’ datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

AB - While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven ‘Pre-Pandemic’ and fifteen ‘Pandemic’ datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

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C2 - 35181440

SN - 0889-1591

VL - 102

SP - 89

EP - 97

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

The Pandemic Brain: neuroinflammation in non-infected individuals during the COVID-19 pandemic

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